JP2023530457A - Small molecule VE-PTP inhibitor - Google Patents

Abstract

The present disclosure relates to compounds capable of inhibiting vascular endothelial protein tyrosine phosphatase (VE-PTP). These compounds can also activate Tie2 receptor-mediated signaling. The present disclosure also provides pharmaceutically acceptable salts of such compounds, pharmaceutical compositions comprising such compounds and/or pharmaceutically acceptable salts thereof, as well as those mediated by angiopoietin/Tie2 signaling. The present invention relates to the use of such compounds, their pharmaceutically acceptable salts, and/or pharmaceutical compositions containing them in treating diseases and/or conditions mediated by VE-PTP signaling. [Selection diagram] Figure 2

Description

The present disclosure relates to compounds capable of inhibiting vascular endothelial protein tyrosine phosphatase (VE-PTP). These compounds can also activate Tie2 receptor-mediated signaling. The context-dependent function of Angiopoietin 2 is determined by the endothelial phosphatase VEPTP. The disclosure also provides pharmaceutically acceptable salts of such compounds, pharmaceutical compositions comprising such compounds and/or pharmaceutically acceptable salts thereof, and compounds such as those mediated by Angiopoietin/Tie2 signaling. The use of such compounds, pharmaceutically acceptable salts thereof, and/or pharmaceutical compositions comprising them in treating diseases and/or conditions mediated by VE-PTP signaling.

Vascular endothelial tyrosine phosphatase (VE-PTP) is the mouse orthologue of human receptor tyrosine-protein phosphatase beta (HPTP-β), although the two terms are often used interchangeably (Matozaki, T et al. (2010 Dec) Expression, localization, and biological function of the R3 subtype of receptor-type protein tyrosine phosphates in mammals, Cell Signal.22( 12): 1811-7). VE-PTP knockout mice have defective vascular remodeling (Dominguez, MG et al. (2007 Feb) Vascular endothelial tyrosine phosphatase (VE-PTP)-null mice undergo vasculogenesis but die embryo Literally because of defects in angiogenesis, Proc. Natl Acad Sci USA 104(9):3243-8, Winderlich, M et al.(2009 May) VE-PTP controls blood vessel development by balancing Tie-2 activity, J Cell Biol.18 ;185(4 ): 657-71). VE-PTP has an extracellular domain with multiple fibronectin type III repeats, a single transmembrane segment, and a single cytoplasmic catalytic domain (Chicote, JU et al. (2017 Mar) Phosphotyrosine phosphatase R3 receptors: Origin, evolution and structural diversification, PLoS ONE, 12(3), e0172887., Matozaki, T et al.(2010 Dec) Expression, localization, and biological function of the R 3 subtype of receptor-type protein tyrosine phosphates in mammals, Cell Signal. 22(12):1811-7). One of the substrates of VE-PTP is Tie2, an endothelial tyrosine kinase receptor that can regulate angiogenesis and lymphangiogenesis and support the integrity of endothelial junctions (Eklund, L et al. (2017 Jan) Angiopoietin-Tie signaling in the cardiovascular and lymphatic systems, Clin Sci.131(1):87-103, Frye, M et al.(2015 Dec) Interfering with VE- PTP stabilizes endothelial junctions in vivo via Tie -2 in the absence of VE-cadherin, J Exp Med.212(13):2267-87., Souma, T et al.(2018 Jan) Context-dependent functions of angiopoietin 2 are determined b Y the endothelial phosphatase VEPTP, Proc Natl Acad Sci U S A. pii: 1714446115). Antibodies to the extracellular domain of VE-PTP dissociate the phosphatase from Tie2, leading to Tie2 phosphorylation and activation signaling (Winderlich, M et al. (2009 May) VE-PTP controls blood vessel development by balancing Tie -2 activity, J Cell Biol. 185(4):657-71). Pharmacological inhibition of VE-PTP activity can also activate Tie2 and suppress ocular neovascularization and VEGF-mediated vascular leakage (Goel, S et al. (2013 Aug) Effects of vascular-endothelial protein Tyrosine phosphatase inhibition on breast cancer vascular and metastatic progression.J Natl Cancer Inst, 21;105(16):1188-201., Shen, J et al.(2014 Oct) Tar getting VE-PTP activates TIE2 and stabilizes the ocular vasculature, J Clin Invest.124(10):4564-76., Souma, T et al.(2018 Jan) Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. , Proc Natl Acad Sci USA pii: 1714446115 ). Indeed, stimulation of global Tie2 activity via inhibition of VE-PTP can promote endothelial barrier function (Frye, M et al. (2015 Dec) Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin, J Exp Med.212(13):2267-87., Gurnik, S et al.(2016 May) Angiopoietin-2-induced blood-brain barrier compromise an d increased stroke size are Rescued by VE-PTP-dependent restoration of Tie2 signaling, Acta Neuropathol.131(5):753-73., Milam, KE et al.(2015 Apr) The angiopoietin-Tie2 signaling axis. in the vascular leakage of systemic inflammation, tissue Barriers.3(1-2):e957508).

The angiopoietin-Tie2 signaling pathway is a key regulator of vascular development, vascular permeability, vascular remodeling, and postnatal angiogenesis, and changes in the expression of angiopoietin ligands, or activity of Tie2 receptors, are associated with cancer. , sepsis, diabetes, atherosclerosis, and ocular disease (Eklund, L et al. (2017 Jan) Angiopoietin-Tie signaling in the cardiovascular and lymphatic systems 131(1):87-103., Parikh, SM (2017 Jul) The Angiopoietin-Tie2 Signaling Axis in Systemic Inflammation, J Am Soc Nephrol.28(7):1973-1982. aharinen, pet (2017 Sep) Therapeutic targeting of the angiopoietin-TIE pathway, Nat Rev Drug Discov.16(9):635-661). In the vascular endothelium, Angiopoietin 2 (Angpt2 or Ang2) has been reported to function as a competitive antagonist of Angiopoietin 1/Tie2 signaling and inhibit Angiopoietin 1 (Angpt1 or Ang1)-mediated phosphorylation of Tie2 ( Thurston, G et al.(2012 Sep) The complex role of angiopoietin-2 in the angiopoietin-tie signaling pathway, Cold Spring Harb Perspect Med.2(9):a006550. Saharinen, P et al.(2017 Sep)Therapeutic Targeting of the angiopoietin-TIE pathway, Nat Rev Drug Discov. 16(9):635-661). Tie2 receptor activators include, for example, Angpt1 recombinant protein, vascular endothelial protein tyrosine phosphatase (VE-PTP) inhibitors, and Tie2-peptidomimetics (Saharinen, P et al. (2017 Sep) Therapeutic Targeting of the angiopoietin-TIE pathway, Nat Rev Drug Discov.16(9):635-661., Shen, J et al.(2014 Oct) Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature, J Clin Invest.124 (10): 4564-76, Souma, T et al.(2018 Jan) Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP, Proc Natl Acad. Sci USA pii: 1714446115). Angiopoietin-1 decreases endothelial cell permeability and increases vascular stability through the recruitment of pericytes and smooth muscle cells to growing vessels, whereas angiopoietin-2 regulates angiogenic sprouting and vascular (Eklund, L et al. (2017 Jan) Angiopoietin-Tie signaling in the cardiovascular and lymphatic systems, Clin Sci. 131(1):87-103., Koh, GY (2013 Jan.). ) Orchestral actions of angiopoietin -1 in vascular regeneration Trends Mol Med.19(1):31-9, Saharinen, P et al.(2017 Sep)Therapeutic targeting of the angiopoietin-TIE pathway, Nat Rev Drug D 16(9):635. -661). In addition, both Angpt1 and Angpt2 can promote lymphangiogenesis (Eklund, L et al. (2017 Jan) Angiopoietin-Tie signaling in the cardiovascular and lymphatic systems, Clin Sci. 131 (1 ): 87 -103., Souma, T et al.(2018 Jan) Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP, Proc Natl Acad Sci U S A. pii: 1714446115). Angpt2 deficiency in knockout mice resulted in widespread lymphatic dysfunction due to abnormal remodeling of the developing lymphatics, resulting in lymphedema (Dellinger, M et al. (2008 Jul) Defective remodeling and maturation of the Lymphatic vasculature in Angiopoietin-2 deficient mice, Dev Biol.319(2):309-20., Eklund, L et al.(2017 Jan) Angiopoietin-Tie signaling in the cardiov Ascular and lymphatic systems, Clin Sci.131(1) :87-103). Expression of Ang1 at the Ang2 locus rescued lymphatic abnormalities in Ang2-deficient mice, suggesting that Ang1 and Ang2 have overlapping functions in the lymphatic system (Gale, NW et al. (2002 Sep) Angiopoietin- 2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1, Dev Cell. 3(3):411-23).

Tie2 activation promotes the formation of Schlemm's canal, a specialized hybrid lymphatic vessel formed around the eye (Souma, T et al. (2016 Jul) Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable e xpressivity, J Clin Invest.126(7):2575-87., Thomson, BR et al.(2014 Oct) American lymphatic defect causes ocular hypertension and glaucoma in mice, J Clin Invest.124(10):43. 20-4., Thomson, BR et al. (2017 Nov) Angiopoietin-1 is required for Schlemm's canal development in mice and humans, J Clin Invest. pii:95545). Both Angpt1/Angpt2 double knockout mice and Tie2 knockout mice have defects in Schlemm's canal, leading to decreased aqueous humor outflow, increased intraocular pressure (IOP), and glaucoma (Souma, T et al. (2016 Jul. ) Angiopoietin receptor TEK mutations underlying primary congenital glaucoma with variable expressivity, J Clin Invest.126(7):2575-87., Thomson, BR et al. 2014 Oct) Alymphatic defect causes ocular hypertension and glaucoma in mice, J Clin Invest.124(10):4320-4., Thomson, BR et al.(2017 Nov) Angiopoietin-1 is required for Schlemm's canal development in mice and humans, J Clin Invest.pii:955. 45). However, knockout of VE-PTP rescued the Angpt1/Angpt2 double knockout phenotype as well as Tie2 haploinsufficiency, demonstrating the power of VE-PTP inhibition in activating Tie2 signaling (WO2017/190222). Introduction of a VE-PTP null allele into Angpt1/Angpt2 conditional knockout mice abrogates the phenotypic expression of high IOP and prevents pressure-related loss of retinal ganglion cells leading to glaucoma (WO2017/190222). Therefore, there is the use of pharmacological VE-PTP inhibitors, in particular some pharmacological VE-PTP inhibitors that may have improved physicochemical properties and are potent Tie2 activators. Such therapeutic agents may be useful in treating cancer, glaucoma, obstructive cardiovascular disease, vascular leak syndrome, and other vascular-related diseases (Parikh, SM (2017 Jul) The Angiopoietin-Tie2 Signaling Axis in Systemic Information, J Am Soc Nephrol.28(7):1973-1982., Saharinen, P et al.(2017 Sep)Therapeutic targeting of the angiopoietin-TIE pathway, Nat Rev. Drug Discov.16(9):635-661 .., Schmittnaegel, M et al. (2017 Dec) Reprogramming Tumor Blood Vessels for Enhancing Immunotherapy, Trends Cancer.3(12):809-812).

The present disclosure relates to compounds and pharmaceutically acceptable salts thereof capable of inhibiting vascular endothelial protein tyrosine phosphatase (VE-PTP). These compounds can activate the Tie-2 receptor. The disclosure also relates to pharmaceutical compositions comprising such compounds and/or pharmaceutically acceptable salts thereof. The disclosure also provides such compounds, pharmaceutically acceptable salts thereof, in treating diseases and/or conditions mediated by VE-PTP activity, including those associated with Ang/Tie2-mediated signaling. , and/or use of the pharmaceutical composition.

Many modifications and other embodiments of the disclosure described herein will come to mind to one skilled in the art to which these disclosures pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. deaf. Therefore, it is to be understood that the present disclosure is not limited to the particular embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

In some embodiments, the disclosure is directed to:

式中、
Ｒ_１が、

から選択され、
式中、
Ｒ_２が、置換又は非置換ヘテロアリール及び置換Ｃ_１－Ｃ_６直鎖アルキルから選択され、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、１つ以上のハロゲン原子で置換される。
Ｒ_３が、置換又は非置換ヘテロアリール、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキル、置換又は非置換Ｃ_１－Ｃ_６分岐鎖アルキル、及び置換又は非置換Ｃ_３－Ｃ_６環状アルキルから選択され、
ｎが、１、２、３、４、５、及び６から選択される整数であり、
Ｒ_４が、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキル、置換又は非置換Ｃ_１－Ｃ_６分岐鎖アルキル、及び置換又は非置換Ｃ_３－Ｃ_６環状アルキルから選択され、
Ｒ_５が、Ｈ、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキル、置換又は非置換Ｃ_１－Ｃ_６分岐鎖アルキル、及び置換又は非置換Ｃ_３－Ｃ_６環状アルキルから選択され、
Ｘ_１、Ｘ_２、及びＸ_３の各々が、独立して、ＣＨ及びＮから選択され、但し、Ｘ_１、Ｘ_２、及びＸ_３が、同時にＣＨではないことを条件とする、化合物。
２．Ｒ_１が、

である、実施形態１に記載の化合物。
３．Ｒ_１が、

である、実施形態１に記載の化合物。
４．Ｒ_２が、置換又は非置換ヘテロアリールである、実施形態２に記載の化合物。
５．Ｒ_２が、置換ヘテロアリールである、実施形態２に記載の化合物。
６．Ｒ_２が、非置換ヘテロアリールである、実施形態２に記載の化合物。
７．Ｒ_２が、２－チエニルである、実施形態２に記載の化合物。
８．Ｒ_２が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、１つ以上のハロゲン原子で置換されている、実施形態２に記載の化合物。
９．Ｒ_２が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、１つ以上のフッ素原子で置換されている、実施形態２に記載の化合物。
１０．Ｒ_２が、トリフルオロアルキル基である、実施形態２に記載の化合物。
１１．Ｒ_２が、トリフルオロエチルである、実施形態２に記載の化合物。
１２．Ｒ_３が、置換又は非置換ヘテロアリール、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキル、置換又は非置換Ｃ_１－Ｃ_６分岐鎖アルキル、及び置換又は非置換Ｃ_３－Ｃ_６環状アルキルから選択される、実施形態３に記載の化合物。
１３．Ｒ_３が、置換又は非置換ヘテロアリールである、実施形態３に記載の化合物。
１４．Ｒ_３が、置換ヘテロアリールである、実施形態３に記載の化合物。
１５．Ｒ_３が、非置換ヘテロアリールである、実施形態３に記載の化合物。
１６．Ｒ_３が、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキル、置換又は非置換Ｃ_１－Ｃ_６分岐鎖アルキル、及び置換又は非置換Ｃ_３－Ｃ_６環状アルキルから選択される、実施形態３に記載の化合物。
１７．Ｒ_３が、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキル、及び置換又は非置換Ｃ_３－Ｃ_６環状アルキルから選択される、実施形態３に記載の化合物。
１８．Ｒ_３が、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態３に記載の化合物。
１９．Ｒ_３が、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態３に記載の化合物。
２０．Ｒ_３が、非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態３に記載の化合物。
２１．Ｒ_３が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、１つ以上のハロゲン原子で置換されている、実施形態３に記載の化合物。
２２．Ｒ_３が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、１つ以上のフッ素原子で置換されている、実施形態３に記載の化合物。
２３．Ｒ_３が、トリフルオロアルキル基である、実施形態３に記載の化合物。
２４．Ｒ_３が、トリフルオロエチルである、実施形態３に記載の化合物。
２５．Ｒ_３が、トリフルオロプロピルである、実施形態３に記載の化合物。
２６．Ｒ_３が、置換又は非置換Ｃ_３－Ｃ_６環状アルキルである、実施形態３に記載の化合物。
２７．Ｒ_３が、非置換Ｃ_３－Ｃ_６環状アルキルである、実施形態３に記載の化合物。
２８．Ｒ_３が、シクロプロピルである、実施形態３に記載の化合物。
２９．Ｒ_３が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、Ｃ_５－Ｃ_２０ヘテロアリール基で置換されている、実施形態３に記載の化合物。
３０．Ｒ_３が、２－チエニル、トリフルオロエチル、トリフルオロプロピル、シクロプロピル、

から選択される、実施形態３に記載の化合物。
３１．Ｒ_３が、２－チエニルである、実施形態３に記載の化合物。
３２．Ｒ_３が、

である、実施形態３に記載の化合物。
３３．Ｒ_３が、

である、実施形態３に記載の化合物。
３４．Ｒ_４が、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態１に記載の化合物。
３５．Ｒ_４が、非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態１に記載の化合物。
３６．Ｒ_４が、メチルである、実施形態１に記載の化合物。
３７．Ｒ_５が、Ｈ及び置換又は非置換Ｃ_１－Ｃ_６直鎖アルキルから選択される、実施形態１に記載の化合物。
３８．Ｒ_５が、Ｈである、実施形態１に記載の化合物。
３９．Ｒ_５が、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態１に記載の化合物。
４０．Ｒ_５が、非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態１に記載の化合物。
４１．Ｒ_５が、メチルである、実施形態１に記載の化合物。
４２．Ｘ_１及びＸ_２が、ＣＨであり、Ｘ_３が、Ｎである、実施形態１に記載の化合物。
４３．Ｘ_１及びＸ_３が、ＣＨであり、Ｘ_２が、Ｎである、実施形態１に記載の化合物。
４４．Ｘ_２及びＸ_３が、ＣＨであり、Ｘ_１が、Ｎである、実施形態１に記載の化合物。
４５．Ｘ_１が、ＣＨであり、Ｘ_２及びＸ_３が、Ｎである、実施形態１に記載の化合物。
４６．Ｘ_２が、ＣＨであり、Ｘ_１及びＸ_３が、Ｎである、実施形態１に記載の化合物。
４７．ｎが、１、２、及び３から選択される整数である、実施形態１に記載の化合物。
４８．ｎが、１及び２から選択される整数である、実施形態１に記載の化合物。
４９．ｎが、１である、実施形態１に記載の化合物。
５０．式ＩＩの化合物であって、

式中、
Ｒ_６が、置換又は非置換ヘテロアリールであり、
ｍが、１、２、３、４、５、及び６から選択される整数であり、
Ｒ_７が、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキル、置換又は非置換Ｃ_１－Ｃ_６分岐鎖アルキル、及び置換又は非置換Ｃ_３－Ｃ_６環状アルキルから選択され、
Ｒ_８が、Ｈ、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキル、置換又は非置換Ｃ_１－Ｃ_６分岐鎖アルキル、及び置換又は非置換Ｃ_３－Ｃ_６環状アルキルから選択され、
Ｒ_９及びＲ_１０の各々が、独立して、Ｈ、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキル、置換又は非置換Ｃ_１－Ｃ_６分岐鎖アルキル、及び置換又は非置換Ｃ_３－Ｃ_６環状アルキルから選択される、化合物。
５１．Ｒ_６が、置換ヘテロアリールである、実施形態５０に記載の化合物。
５２．Ｒ_６が、非置換ヘテロアリールである、実施形態５０に記載の化合物。
５３．Ｒ_６が、２－チエニルである、実施形態５０に記載の化合物。
５４．Ｒ_７が、置換又は非置換Ｃ_１－Ｃ_６分岐鎖アルキルである、実施形態５０に記載の化合物。
５５．Ｒ_７が、置換又は非置換Ｃ_３－Ｃ_６環状アルキルである、実施形態５０に記載の化合物。
５６．Ｒ_７が、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態５０に記載の化合物。
５７．Ｒ_７が、置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態５０に記載の化合物。
５８．Ｒ_７が、非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態５０に記載の化合物。
５９．Ｒ_７が、メチルである、実施形態５０に記載の化合物。
６０．Ｒ_８が、Ｈ及び置換又は非置換Ｃ_１－Ｃ_６直鎖アルキルから選択される、実施形態５０に記載の化合物。
６１．Ｒ_８が、Ｈである、実施形態５０に記載の化合物。
６２．Ｒ_８が、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態５０に記載の化合物。
６３．Ｒ_８が、置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態５０に記載の化合物。
６４．Ｒ_８が、非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態５０に記載の化合物。
６５．Ｒ_８が、メチルである、実施形態５０に記載の化合物。
６６．Ｒ_９及びＲ_１０の各々が、独立して、Ｈ及び置換又は非置換Ｃ_１－Ｃ_６直鎖アルキルから選択される、実施形態５０に記載の化合物。
６７．Ｒ_９及びＲ_１０の各々が、Ｈである、実施形態５０に記載の化合物。
６８．Ｒ_９及びＲ_１０の各々が、独立して、置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態５０に記載の化合物。
６９．Ｒ_９及びＲ_１０の各々が、独立して、非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態５０に記載の化合物。
７０．Ｒ_９及びＲ_１０の各々が、メチルである、実施形態５０に記載の化合物。
７１．ｍが、１、２、３、及び４から選択される整数である、実施形態５０に記載の化合物。
７２．ｍが、２、３、及び４から選択される整数である、実施形態５０に記載の化合物。
７３．ｍが、３及び４から選択される整数である、実施形態５０に記載の化合物。
７４．ｍが、３である、実施形態５０に記載の化合物。
７５．ｍが、４である、実施形態５０に記載の化合物。
７６．式ＩＩＩの化合物であって、

式中、
Ｒ_１１が、置換又は非置換ヘテロアリール、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキル、置換又は非置換Ｃ_１－Ｃ_６分岐鎖アルキル、置換又は非置換Ｃ_３－Ｃ_６環状アルキル、及び置換又は非置換ヘテロシクリルから選択され、
ａが、０、１、２、３、４、５、及び６から選択される整数であり、
Ｙ_１－Ｙ_２が、存在しない、－ＣＨ_２－ＣＨ_２－、及び－ＣＨ＝ＣＨ－から選択される基であり、
ｂが、０、１、２、３、４、５、及び６から選択される整数であり、
Ｒ_１２が、置換又は非置換ヘテロアリール及び置換又は非置換アリールから選択される、化合物。
７７．Ｒ_１１が、置換又は非置換ヘテロアリールである、実施形態７６に記載の化合物。
７８．Ｒ_１１が、置換ヘテロアリールである、実施形態７６に記載の化合物。
７９．Ｒ_１１が、非置換ヘテロアリールである、実施形態７６に記載の化合物。
８０．Ｒ_１１が、置換又は非置換ヘテロシクリルである、実施形態７６に記載の化合物。
８１．Ｒ_１１が、置換ヘテロシクリルである、実施形態７６に記載の化合物。
８２．Ｒ_１１が、非置換ヘテロシクリルである、実施形態７６に記載の化合物。
８３．Ｒ_１１が、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキル、置換又は非置換Ｃ_１－Ｃ_６分岐鎖アルキル、及び置換又は非置換Ｃ_３－Ｃ_６環状アルキルから選択される、実施形態７６に記載の化合物。
８４．Ｒ_１１が、置換又は非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態７６に記載の化合物。
８５．Ｒ_１１が、置換又は非置換Ｃ_１－Ｃ_６分岐鎖アルキルである、実施形態７６に記載の化合物。
８６．Ｒ_１１が、置換又は非置換Ｃ_３－Ｃ_６環状アルキルである、実施形態７６に記載の化合物。
８７．Ｒ_１１が、置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態７６に記載の化合物。
８８．Ｒ_１１が、置換Ｃ_１－Ｃ_６分岐鎖アルキルである、実施形態７６に記載の化合物。
８９．Ｒ_１１が、置換Ｃ_３－Ｃ_６環状アルキルである、実施形態７６に記載の化合物。
９０．Ｒ_１１が、非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態７６に記載の化合物。
９１．Ｒ_１１が、非置換Ｃ_１－Ｃ_６分岐鎖アルキルである、実施形態７６に記載の化合物。
９２．Ｒ_１１が、非置換Ｃ_３－Ｃ_６環状アルキルである、実施形態７６に記載の化合物。
９３．Ｒ_１１が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、１つ以上のハロゲン原子で置換されている、実施形態７６に記載の化合物。
９４．Ｒ_１１が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、１つ以上のフッ素原子で置換されている、実施形態７６に記載の化合物。
９５．Ｒ_１１が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、ヘテロアリール基で置換されている、実施形態７６に記載の化合物。
９６．Ｒ_１１が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、Ｃ_３－Ｃ_６環状アルキル基で置換されている、実施形態７６に記載の化合物。
９７．Ｒ_１１が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、－（ＣＲ^ａＲ^ｂ）_ｚＮ（Ｒ^ｃ）（Ｒ^ｄ）で置換されており、Ｒ^ａ及びＲ^ｂの各々が、独立して、水素、及び置換又は非置換Ｃ_１－Ｃ_６直鎖、分岐鎖、又は環状アルキルから選択され、Ｒ^ｃ及びＲ^ｄの各々が、独立して、水素、置換又は非置換Ｃ_１－Ｃ_６直鎖、分岐鎖、又は環状アルキル及びアリールから選択されるか、又はＲ^ｃ及びＲ^ｄが一緒になって、３～７個の原子を含む環系を形成し、ｚが、０、１、２、３、及び４から選択される、実施形態７６に記載の化合物。
９８．Ｒ_１１が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、Ｎ（Ｒ^ｃ）（Ｒ^ｄ）で置換されており、Ｒ^ｃ及びＲ^ｄの各々が、独立して、置換又は非置換Ｃ_１－Ｃ_６直鎖、分岐鎖、又は環状アルキルであるか、又はＲ^ｃ及びＲ^ｄが一緒になって、３～７個の原子を含む環系を形成する、実施形態７６に記載の化合物。
９９．Ｒ_１１が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、Ｎ（Ｒ^ｃ）（Ｒ^ｄ）で置換されており、Ｒ^ｃ及びＲ^ｄの各々が、独立して、置換又は非置換Ｃ_１－Ｃ_６直鎖、分岐鎖、又は環状アルキルである、実施形態７６に記載の化合物。
１００．Ｒ_１１が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、Ｎ（Ｒ^ｃ）（Ｒ^ｄ）で置換されており、Ｒ^ｃ及びＲ^ｄの各々が、独立して、非置換Ｃ_１－Ｃ_６直鎖、分岐鎖、又は環状アルキルである、実施形態７６に記載の化合物。
１０１．Ｒ_１１が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、Ｎ（Ｒ^ｃ）（Ｒ^ｄ）で置換されており、Ｒ^ｃ及びＲ^ｄの各々が、独立して、非置換Ｃ_１－Ｃ_６直鎖アルキルである、実施形態７６に記載の化合物。
１０２．Ｒ_１１が、置換Ｃ_１－Ｃ_６直鎖アルキルであり、当該置換Ｃ_１－Ｃ_６直鎖アルキルが、－Ｎ（ＣＨ_３）_２で置換されている、実施形態７６に記載の化合物。
１０３．Ｒ_１１が、２－チエニル、トリフルオロエチル、トリフルオロプロピル、シクロプロピル、シクロプロピルメチル、シクロペンチルメチル、

から選択される、実施形態７６に記載の化合物。
１０４．Ｒ_１１が、２－チエニルである、実施形態７６に記載の化合物。
１０５．Ｒ_１１が、トリフルオロアルキル基である、実施形態７６に記載の化合物。
１０６．Ｒ_１１が、トリフルオロエチルである、実施形態７６に記載の化合物。
１０７．Ｒ_１１が、トリフルオロプロピルである、実施形態７６に記載の化合物。
１０８．Ｒ_１１が、シクロプロピルである、実施形態７６に記載の化合物。
１０９．Ｒ_１１が、シクロプロピルメチルである、実施形態７６に記載の化合物。
１１０．Ｒ_１１が、シクロペンチルメチルである、実施形態７６に記載の化合物。
１１１．Ｒ_１１が、

である、実施形態７６に記載の化合物。
１１２．Ｒ_１１が、

である、実施形態７６に記載の化合物。
１１３．Ｒ_１１が、

である、実施形態７６に記載の化合物。
１１４．Ｒ_１１が、

である、実施形態７６に記載の化合物。
１１５．Ｒ_１１が、

である、実施形態７６に記載の化合物。
１１６．Ｒ_１１が、

である、実施形態７６に記載の化合物。
１１７．Ｒ_１２が、置換又は非置換ヘテロアリールである、実施形態７６に記載の化合物。
１１８．Ｒ_１２が、置換ヘテロアリールである、実施形態７６に記載の化合物。
１１９．Ｒ_１２が、非置換ヘテロアリールである、実施形態７６に記載の化合物。
１２０．Ｒ_１２が、ピリジニルである、実施形態７６に記載の化合物。
１２１．Ｒ_１２が、置換又は非置換アリールである、実施形態７６に記載の化合物。
１２２．Ｒ_１２が、置換アリールである、実施形態７６に記載の化合物。
１２３．Ｒ_１２が、一置換アリールである、実施形態７６に記載の化合物。
１２４．Ｒ_１２が、一置換フェニルである、実施形態７６に記載の化合物。
１２５．Ｒ_１２が、非置換アリールである、実施形態７６に記載の化合物。
１２６．Ｒ_１２が、フェニルである、実施形態７６に記載の化合物。
１２７．Ｒ_１２が、１－ナフチル及び２－ナフチルから選択される、実施形態７６に記載の化合物。
１２８．Ｒ_１２が、１－ナフチルである、実施形態７６に記載の化合物。
１２９．Ｒ_１２が、２－ナフチルである、実施形態７６に記載の化合物。
１３０．Ｙ_１－Ｙ_２が、存在しない、実施形態７６に記載の化合物。
１３１．Ｙ_１－Ｙ_２が、－ＣＨ_２－ＣＨ_２－である、実施形態７６に記載の化合物。
１３２．Ｙ_１－Ｙ_２が、－ＣＨ＝ＣＨ－である、実施形態７６に記載の化合物。
１３３．ａが、０、１、２、及び３から選択される整数である、実施形態７６に記載の化合物。
１３４．ａが、０、１、及び２から選択される整数である、実施形態７６に記載の化合物。
１３５．ａが、０及び１から選択される整数である、実施形態７６に記載の化合物。
１３６．ａが、２である、実施形態７６に記載の化合物。
１３７．ａが、１である、実施形態７６に記載の化合物。
１３８．ａが、０である、実施形態７６に記載の化合物。
１３９．ｂが、０、１、２、及び３から選択される整数である、実施形態７６に記載の化合物。
１４０．ｂが、０、１、及び２から選択される整数である、実施形態７６に記載の化合物。
１４１．ｂが、０及び１から選択される整数である、実施形態７６に記載の化合物。
１４２．ｂが、２である、実施形態７６に記載の化合物。
１４３．ｂが、１である、実施形態７６に記載の化合物。
１４４．ｂが、０である、実施形態７６に記載の化合物。
１４５．Ｙ_１－Ｙ_２が、存在せず、ａが、１であり、ｂが、１である、実施形態７６に記載の化合物。
１４６．Ｙ_１－Ｙ_２が、存在せず、ａが、１であり、ｂが、０である、実施形態７６に記載の化合物。
１４７．Ｙ_１－Ｙ_２が、－ＣＨ＝ＣＨ－であり、ａが、０であり、ｂが、０である、実施形態７６に記載の化合物。
１４８．但し、Ｙ_１－Ｙ_２が、存在しない場合、ａ及びｂが、同時に０ではないことを条件とする、実施形態７６に記載の化合物。
１４９．以下から選択される化合物。

１５０．ＶＥ－ＰＴＰの阻害を必要とする哺乳動物対象におけるＶＥ－ＰＴＰを阻害するための方法であって、ＶＥ－ＰＴＰの阻害を必要とする対象に、有効量の実施形態１～１４９のいずれか１つに記載の化合物、又はその薬学的に許容される塩を投与することを含み、それによって、ＶＥ－ＰＴＰ活性が阻害される、方法。
１５１．対象が、がん、緑内障、閉塞性心血管疾患、血管漏出症候群、又は別の血管関連疾患のうちの１つ以上に罹患している、実施形態１５０に記載の方法。
１５２．ＶＥ－ＰＴＰ媒介性シグナル伝達の低減を必要とする哺乳動物対象におけるＶＥ－ＰＴＰ媒介性シグナル伝達を低減するための方法であって、ＶＥ－ＰＴＰ媒介性シグナル伝達の低減を必要とする哺乳動物対象に、有効量の実施形態１～１４９のいずれか１つに記載の化合物、又はその薬学的に許容される塩を投与することを含み、それによって、ＶＥＰＴＰ媒介性シグナル伝達が低減される、方法。
１５３．Ｔｉｅ２媒介性シグナル伝達の増加を必要とする哺乳動物対象におけるＴｉｅ２媒介性シグナル伝達を増加させるための方法であって、Ｔｉｅ２媒介性シグナル伝達の増加を必要とする哺乳動物対象に、有効量の実施形態１～１４９のいずれか１つに記載の化合物、又はその薬学的に許容される塩を投与することを含み、それによって、Ｔｉｅ２媒介性シグナル伝達が増加される、方法。
１５４．Ｔｉｅ２媒介性障害又はＶＥ－ＰＴＰ媒介性障害の治療を必要とする哺乳動物対象におけるＴｉｅ２媒介性障害又はＶＥ－ＰＴＰ媒介性障害を治療するための方法であって、Ｔｉｅ２媒介性障害又はＶＥ－ＰＴＰ媒介性障害の治療を必要とする哺乳動物対象に、治療有効量の実施形態１～１４９のいずれか１つに記載の化合物、又はその薬学的に許容される塩を投与することを含む、方法。
１５５．対象が、がん、緑内障、閉塞性心血管疾患、血管漏出症候群、又は別の血管関連疾患のうちの１つ以上に罹患している、実施形態１５４に記載の方法。
１５６．「有効量」が、１つ以上の生化学的及び／又は生物学的アッセイによってインビトロで決定される、実施形態１５０～１５５のいずれか１つに記載の方法。 1. a compound of formula I,

During the ceremony,
R ₁ is

is selected from
During the ceremony,
R ₂ is selected from substituted or unsubstituted heteroaryl and substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more halogen atoms.
R ₃ is from substituted or unsubstituted heteroaryl, substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl; selected,
n is an integer selected from 1, 2, 3, 4, 5, and 6;
R ₄ is selected from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl;
R ₅ is selected from H, substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl;
A compound wherein each of X ₁ , X ₂ and X ₃ is independently selected from CH and N, with the proviso that X ₁ , X ₂ and X ₃ are not simultaneously CH.
2. R ₁ is

The compound according to embodiment 1, which is
3. R ₁ is

The compound according to embodiment 1, which is
4. Compounds according to embodiment _{2, wherein R 2} is substituted or unsubstituted heteroaryl.
5. Compounds according to embodiment 2, wherein R ₂ is substituted heteroaryl.
6. Compounds according to embodiment ₂ , wherein R 2 is unsubstituted heteroaryl.
7. Compounds according to embodiment 2, wherein R ₂ is 2-thienyl.
8. Compounds according to embodiment ₂ , wherein R 2 is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more halogen atoms.
9. Compounds according to embodiment ₂ , wherein R 2 is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more fluorine atoms.
10. Compounds according to embodiment 2, wherein R ₂ is a trifluoroalkyl group.
11. Compounds according to embodiment 2, wherein R ₂ is trifluoroethyl.
12. R ₃ is from substituted or unsubstituted heteroaryl, substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl; A compound according to embodiment 3, selected.
13. Compounds according to embodiment ₃ , wherein R 3 is substituted or unsubstituted heteroaryl.
14. Compounds according to embodiment ₃ , wherein R 3 is substituted heteroaryl.
15. Compounds according to embodiment ₃ , wherein R 3 is unsubstituted heteroaryl.
16. Embodiment ₃ wherein R 3 is selected from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. The compound described in .
17. Compounds according to embodiment ₃ , wherein R 3 is selected from substituted or unsubstituted C ₁ -C ₆ linear alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl.
18. Compounds according to embodiment ₃ , wherein R 3 is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl.
19. Compounds according to embodiment ₃ , wherein R 3 is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl.
20. Compounds according to embodiment 3, wherein R ₃ is unsubstituted C ₁ -C ₆ straight chain alkyl.
21. Compounds according to embodiment ₃ , wherein R 3 is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more halogen atoms.
22. Compounds according to embodiment ₃ , wherein R 3 is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more fluorine atoms.
23. Compounds according to embodiment ₃ , wherein R 3 is a trifluoroalkyl group.
24. Compounds according to embodiment 3, wherein R ₃ is trifluoroethyl.
25. Compounds according to embodiment 3, wherein R ₃ is trifluoropropyl.
26. Compounds according to embodiment ₃ , wherein R 3 is substituted or unsubstituted C ₃ -C ₆ cyclic alkyl.
27. Compounds according to embodiment 3, wherein R ₃ is unsubstituted C ₃ -C ₆ cyclic alkyl.
28. Compounds according to embodiment ₃ , wherein R 3 is cyclopropyl.
29. Compounds according to embodiment ₃ , wherein R 3 is a substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with a C ₅ -C ₂₀ heteroaryl group.
30. R ₃ is 2-thienyl, trifluoroethyl, trifluoropropyl, cyclopropyl,

A compound according to embodiment 3, which is selected from
31. Compounds according to embodiment 3, wherein R ₃ is 2-thienyl.
32. _R3 is

The compound according to embodiment 3, which is
33. _R3 is

The compound according to embodiment 3, which is
34. Compounds according to embodiment 1, wherein R ₄ is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl.
35. Compounds according to embodiment 1, wherein R ₄ is unsubstituted C ₁ -C ₆ straight chain alkyl.
36. Compounds according to embodiment 1, wherein R ₄ is methyl.
37. Compounds according to embodiment 1, wherein R ₅ is selected from H and substituted or unsubstituted C ₁ -C ₆ straight chain alkyl.
38. Compounds according to embodiment 1, wherein R ₅ is H.
39. Compounds according to embodiment 1, wherein R ₅ is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl.
40. Compounds according to embodiment 1, wherein R ₅ is unsubstituted C ₁ -C ₆ straight chain alkyl.
41. Compounds according to embodiment 1, wherein R ₅ is methyl.
42. The compound of embodiment 1, wherein X ₁ and X ₂ are CH and X ₃ is N.
43. The compound of embodiment 1, wherein X ₁ and X ₃ are CH and X ₂ is N.
44. The compound of embodiment 1, wherein X ₂ and X ₃ are CH and X ₁ is N.
45. The compound of embodiment 1, wherein X ₁ is CH, and X ₂ and X ₃ are N.
46. The compound of embodiment 1, wherein _X2 is CH, and _X1 and _X3 are N.
47. The compound according to embodiment 1, wherein n is an integer selected from 1, 2, and 3.
48. The compound according to embodiment 1, wherein n is an integer selected from 1 and 2.
49. The compound according to embodiment 1, wherein n is 1.
50. A compound of formula II,

During the ceremony,
R ₆ is substituted or unsubstituted heteroaryl;
m is an integer selected from 1, 2, 3, 4, 5, and 6;
R ₇ is selected from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl;
R ₈ is selected from H, substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl;
Each of R ₉ and R ₁₀ is independently H, substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C A compound selected from _hexacyclic alkyls.
51. Compounds according to embodiment 50, wherein R ₆ is substituted heteroaryl.
52. Compounds according to embodiment 50, wherein R ₆ is unsubstituted heteroaryl.
53. Compounds according to embodiment 50, wherein R ₆ is 2-thienyl.
54. Compounds according to embodiment 50, wherein R ₇ is substituted or unsubstituted C ₁ -C ₆ branched alkyl.
55. Compounds according to embodiment 50, wherein R ₇ is substituted or unsubstituted C ₃ -C ₆ cyclic alkyl.
56. Compounds according to embodiment 50, wherein R ₇ is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl.
57. Compounds according to embodiment 50, wherein R ₇ is substituted C ₁ -C ₆ straight chain alkyl.
58. Compounds according to embodiment 50, wherein R ₇ is unsubstituted C ₁ -C ₆ straight chain alkyl.
59. 51. Compounds according to embodiment 50, wherein _R7 is methyl.
60. Compounds according to embodiment 50, wherein R ₈ is selected from H and substituted or unsubstituted C ₁ -C ₆ straight chain alkyl.
61. 51. Compounds according to embodiment 50, wherein R ₈ is H.
62. Compounds according to embodiment 50, wherein R ₈ is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl.
63. Compounds according to embodiment 50, wherein R ₈ is substituted C ₁ -C ₆ straight chain alkyl.
64. Compounds according to embodiment 50, wherein R ₈ is unsubstituted C ₁ -C ₆ straight chain alkyl.
65. A compound according to embodiment 50, wherein R ₈ is methyl.
66. Compounds according to embodiment 50, wherein each of R ₉ and R ₁₀ is independently selected from H and substituted or unsubstituted C ₁ -C ₆ straight chain alkyl.
67. Compounds according to embodiment 50, wherein each of R ₉ and R ₁₀ is H.
68. Compounds according to embodiment 50, wherein each of R ₉ and R ₁₀ is independently substituted C ₁ -C ₆ straight chain alkyl.
69. Compounds according to embodiment 50, wherein each of R ₉ and R ₁₀ is independently unsubstituted C ₁ -C ₆ straight chain alkyl.
70. Compounds according to embodiment 50, wherein each of R ₉ and R ₁₀ is methyl.
71. 51. The compound according to embodiment 50, wherein m is an integer selected from 1, 2, 3, and 4.
72. 51. The compound according to embodiment 50, wherein m is an integer selected from 2, 3, and 4.
73. 51. A compound according to embodiment 50, wherein m is an integer selected from 3 and 4.
74. 51. The compound according to embodiment 50, wherein m is 3.
75. 51. The compound according to embodiment 50, wherein m is 4.
76. A compound of formula III,

During the ceremony,
R ₁₁ is substituted or unsubstituted heteroaryl, substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, substituted or unsubstituted C ₃ -C ₆ cyclic alkyl, and is selected from substituted or unsubstituted heterocyclyl;
a is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
Y ₁ -Y ₂ is absent and is a group selected from -CH ₂ -CH ₂ - and -CH=CH-;
b is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
A compound wherein R ₁₂ is selected from substituted or unsubstituted heteroaryl and substituted or unsubstituted aryl.
77. Compounds according to embodiment 76, wherein R ₁₁ is substituted or unsubstituted heteroaryl.
78. Compounds according to embodiment 76, wherein R ₁₁ is substituted heteroaryl.
79. Compounds according to embodiment 76, wherein R ₁₁ is unsubstituted heteroaryl.
80. Compounds according to embodiment 76, wherein R ₁₁ is substituted or unsubstituted heterocyclyl.
81. Compounds according to embodiment 76, wherein R ₁₁ is substituted heterocyclyl.
82. Compounds according to embodiment 76, wherein R ₁₁ is unsubstituted heterocyclyl.
83. Embodiment 76 wherein R ₁₁ is selected from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. The compound described in .
84. Compounds according to embodiment 76, wherein R ₁₁ is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl.
85. Compounds according to embodiment 76, wherein R ₁₁ is substituted or unsubstituted C ₁ -C ₆ branched alkyl.
86. Compounds according to embodiment 76, wherein R ₁₁ is substituted or unsubstituted C ₃ -C ₆ cyclic alkyl.
87. Compounds according to embodiment 76, wherein R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl.
88. Compounds according to embodiment 76, wherein R ₁₁ is substituted C ₁ -C ₆ branched alkyl.
89. Compounds according to embodiment 76, wherein R ₁₁ is substituted C ₃ -C ₆ cyclic alkyl.
90. Compounds according to embodiment 76, wherein R ₁₁ is unsubstituted C ₁ -C ₆ straight chain alkyl.
91. Compounds according to embodiment 76, wherein R ₁₁ is unsubstituted C ₁ -C ₆ branched alkyl.
92. Compounds according to embodiment 76, wherein R ₁₁ is unsubstituted C ₃ -C ₆ cyclic alkyl.
93. Compounds according to embodiment 76, wherein R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more halogen atoms.
94. Compounds according to embodiment 76, wherein R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more fluorine atoms.
95. Compounds according to embodiment 76, wherein R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with a heteroaryl group.
96. Compounds according to embodiment 76, wherein R ₁₁ is a substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with a C ₃ -C ₆ cyclic alkyl group.
97. R ₁₁ is a substituted C ₁ -C ₆ straight chain alkyl, wherein the substituted C ₁ -C ₆ straight chain alkyl is substituted with —(CR ^a R ^b ) _z N(R ^c )(R ^d ); , R ^a and R ^b are each independently selected from hydrogen, and substituted or unsubstituted C ₁ -C ₆ linear, branched or cyclic alkyl, and each of R ^c and R ^d is independently is selected from hydrogen, substituted or unsubstituted C ₁ -C ₆ linear, branched or cyclic alkyl and aryl, or R ^c and R ^d together contain 3 to 7 atoms 77. Compounds according to embodiment 76, which form a ring system and z is selected from 0, 1, 2, 3, and 4.
98. R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with N(R ^c )(R ^d ), and each of R ^c and R ^d is independently a substituted or unsubstituted C ₁ -C ₆ straight, branched, or cyclic alkyl, or R ^c and R ^d together are a ring system containing 3 to 7 atoms 77. The compound according to embodiment 76, which forms
99. R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with N(R ^c )(R ^d ), and each of R ^c and R ^d 77. The compound according to embodiment 76, wherein is independently substituted or unsubstituted C ₁ -C ₆ straight chain, branched chain, or cyclic alkyl.
100. R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with N(R ^c )(R ^d ), and each of R ^c and R ^d 77. The compound according to embodiment 76, wherein is independently unsubstituted C ₁ -C ₆ straight, branched, or cyclic alkyl.
101. R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with N(R ^c )(R ^d ), and each of R ^c and R ^d Compounds according to embodiment 76, wherein is independently unsubstituted C ₁ -C ₆ straight chain alkyl.
102. Compounds according to embodiment 76, wherein R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with —N(CH ₃ ) ₂ .
103. R ₁₁ is 2-thienyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopentylmethyl,

A compound according to embodiment 76, which is selected from
104. Compounds according to embodiment 76, wherein R ₁₁ is 2-thienyl.
105. Compounds according to embodiment 76, wherein R ₁₁ is a trifluoroalkyl group.
106. Compounds according to embodiment 76, wherein R ₁₁ is trifluoroethyl.
107. Compounds according to embodiment 76, wherein R ₁₁ is trifluoropropyl.
108. Compounds according to embodiment 76, wherein R ₁₁ is cyclopropyl.
109. Compounds according to embodiment 76, wherein R ₁₁ is cyclopropylmethyl.
110. Compounds according to embodiment 76, wherein R ₁₁ is cyclopentylmethyl.
111. R ₁₁ is

The compound according to embodiment 76, which is
112. R ₁₁ is

The compound according to embodiment 76, which is
113. R ₁₁ is

The compound according to embodiment 76, which is
114. R ₁₁ is

The compound according to embodiment 76, which is
115. R ₁₁ is

The compound according to embodiment 76, which is
116. R ₁₁ is

The compound according to embodiment 76, which is
117. Compounds according to embodiment 76, wherein R ₁₂ is substituted or unsubstituted heteroaryl.
118. Compounds according to embodiment 76, wherein R ₁₂ is substituted heteroaryl.
119. Compounds according to embodiment 76, wherein R ₁₂ is unsubstituted heteroaryl.
120. Compounds according to embodiment 76, wherein R ₁₂ is pyridinyl.
121. Compounds according to embodiment 76, wherein R ₁₂ is substituted or unsubstituted aryl.
122. Compounds according to embodiment 76, wherein R ₁₂ is substituted aryl.
123. Compounds according to embodiment 76, wherein R ₁₂ is monosubstituted aryl.
124. Compounds according to embodiment 76, wherein R ₁₂ is monosubstituted phenyl.
125. Compounds according to embodiment 76, wherein R ₁₂ is unsubstituted aryl.
126. Compounds according to embodiment 76, wherein R ₁₂ is phenyl.
127. Compounds according to embodiment 76, wherein R ₁₂ is selected from 1-naphthyl and 2-naphthyl.
128. Compounds according to embodiment 76, wherein R ₁₂ is 1-naphthyl.
129. Compounds according to embodiment 76, wherein R ₁₂ is 2-naphthyl.
130. Compounds according to embodiment 76, wherein Y ₁ -Y ₂ are absent.
131. Compounds according to embodiment 76, wherein Y ₁ -Y ₂ is -CH ₂ -CH ₂ -.
132. Compounds according to embodiment 76, wherein Y ₁ -Y ₂ is -CH=CH-.
133. 77. The compound according to embodiment 76, wherein a is an integer selected from 0, 1, 2, and 3.
134. 77. The compound according to embodiment 76, wherein a is an integer selected from 0, 1, and 2.
135. 77. The compound according to embodiment 76, wherein a is an integer selected from 0 and 1.
136. 77. The compound according to embodiment 76, wherein a is 2.
137. 77. The compound according to embodiment 76, wherein a is 1.
138. 77. The compound according to embodiment 76, wherein a is 0.
139. 77. The compound according to embodiment 76, wherein b is an integer selected from 0, 1, 2, and 3.
140. 77. The compound according to embodiment 76, wherein b is an integer selected from 0, 1, and 2.
141. 77. The compound according to embodiment 76, wherein b is an integer selected from 0 and 1.
142. 77. The compound according to embodiment 76, wherein b is 2.
143. 77. The compound according to embodiment 76, wherein b is 1.
144. 77. The compound according to embodiment 76, wherein b is 0.
145. Compounds according to embodiment 76, wherein Y ₁ -Y ₂ are absent, a is 1 and b is 1.
146. Compounds according to embodiment 76, wherein Y ₁ -Y ₂ are absent, a is 1 and b is 0.
147. Compounds according to embodiment 76, wherein Y ₁ -Y ₂ are -CH=CH-, a is 0 and b is 0.
148. Compounds according to embodiment 76, with the proviso that if Y ₁ -Y ₂ are absent, a and b are not simultaneously 0.
149. A compound selected from:

150. A method for inhibiting VE-PTP in a mammalian subject in need of inhibition of VE-PTP, comprising administering to the subject in need of inhibition of VE-PTP an effective amount of any one of embodiments 1-149 A method comprising administering a compound as described in 1., or a pharmaceutically acceptable salt thereof, whereby VE-PTP activity is inhibited.
151. 151. The method of embodiment 150, wherein the subject is suffering from one or more of cancer, glaucoma, obstructive cardiovascular disease, vascular leak syndrome, or another vascular-related disease.
152. A method for reducing VE-PTP-mediated signaling in a mammalian subject in need of reducing VE-PTP-mediated signaling, comprising: administering an effective amount of a compound according to any one of embodiments 1-149, or a pharmaceutically acceptable salt thereof, whereby VEPTP-mediated signaling is reduced. .
153. A method for increasing Tie2-mediated signaling in a mammalian subject in need of increased Tie2-mediated signaling, comprising administering to the mammalian subject in need of increased Tie2-mediated signaling an effective amount of A method comprising administering a compound according to any one of Forms 1-149, or a pharmaceutically acceptable salt thereof, whereby Tie2-mediated signaling is increased.
154. A method for treating a Tie2-mediated disorder or a VE-PTP-mediated disorder in a mammalian subject in need thereof, comprising: A method comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1-149, or a pharmaceutically acceptable salt thereof, to a mammalian subject in need of treatment for a mediated disorder. .
155. 155. The method of embodiment 154, wherein the subject is suffering from one or more of cancer, glaucoma, obstructive cardiovascular disease, vascular leak syndrome, or another vascular-related disease.
156. 156. The method according to any one of embodiments 150-155, wherein the "effective amount" is determined in vitro by one or more biochemical and/or biological assays.

Figure 2 shows Western blot results of human umbilical vein endothelial cells (HUVEC) treated with the indicated concentrations of compounds of the disclosure that had _IC50s in the VE-PTP activity range of 0.1-5 nM. Figure 2 shows Western blot results of human umbilical vein endothelial cells (HUVEC) treated with the indicated concentrations of compounds of the disclosure that had _IC50s in the VE-PTP activity range of 0.1-5 nM. Figure 2 shows Western blot results of human umbilical vein endothelial cells (HUVEC) treated with the indicated concentrations of compounds of the disclosure that had _IC50s in the VE-PTP activity range of 0.1-5 nM. Figure 2 shows Western blot results of human umbilical vein endothelial cells (HUVEC) treated with the indicated concentrations of compounds of the disclosure that had _IC50s in the VE-PTP activity range of 0.1-5 nM. Figure 2 shows Western blot results of human umbilical vein endothelial cells (HUVEC) treated with the indicated concentrations of compounds of the disclosure that had _IC50s in the VE-PTP activity range of 0.1-5 nM. Results of dose-response titration experiments of compounds of the present disclosure with _IC50s in VE-PTP in the activity range of 0.1-5 nM over the range of 0.2-50 μM are shown, demonstrating a clear dose-response relationship. Angiopoietin 1 is the cognate ligand of the Tie2 receptor and is used to activate the Tie2 signaling pathway.

Reference will now be made to certain embodiments of the present disclosure. It should be understood that these references are not intended to limit the disclosure to those embodiments.

I. Definition:
Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art.

Unless otherwise noted, the techniques used or contemplated herein are standard methodologies well known to those skilled in the art. The practice of the present disclosure will employ conventional techniques of microbiology, tissue culture, molecular biology, chemistry, biochemistry, and recombinant DNA technology, within the skill of the art, unless otherwise indicated. The materials, methods, and examples are illustrative only and not limiting.

In some embodiments, numerical values expressing quantities of components, properties such as molecular weights, reaction conditions, results, and the like used to describe and claim certain embodiments of the present disclosure are sometimes referred to as " shall be understood as being modified by the term "about". Those skilled in the art will understand the meaning of the term "about" in the context of the values to which it limits. In some embodiments, the term "about" is used to indicate that a value includes the standard deviation of the mean for the device or method used to determine the value. In some embodiments, the numerical parameters set forth herein, which are incorporated in the claims in their entirety, are approximations that may vary depending on the desired properties sought to be obtained by a particular embodiment. is. In some embodiments, numeric parameters should be interpreted in light of reported significant digits and by applying normal rounding techniques. Notwithstanding that the numerical ranges and parameters setting out the broad scope of some embodiments of this disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the present disclosure can contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

As used herein, the term "administering" refers to administering a compound and/or a pharmaceutical composition comprising a compound to a desired site or tissue location, at least partially localizing the compound and/or composition. refers to placement in a mammalian tissue or subject by a method or route that results in

In this disclosure, terms such as "comprises," "comprising," "containing," and "having" may have the meaning ascribed under United States patent law. can mean "includes," "including," "consisting essentially of," or "consisting essentially of," etc. , has the meaning ascribed under United States patent law, and the term is open-ended and enumerated unless the basic or novel characteristics of the enumerated are altered by the presence of more than what is recited. Although more than one is allowed, prior art embodiments are excluded.

The "efficacy" of a compound or composition of the disclosure can be assessed by any method known to those of skill in the art, including those described in the Examples of the disclosure. Efficacy can be established in vitro (biochemically and/or biologically in cultured cells) and/or in vivo. In vitro efficacy can be used to infer or predict some degree of efficacy in vivo, in animals, or in human subjects. A reference or standard or comparison may be used. In the context of the present disclosure and claims, the term "effective" in inhibiting or activating an enzyme (VE-PTP and/or Tie2, respectively) and/or signaling mediated by an enzyme means downstream reduce the activity of an enzyme and/or the activation and propagation of a signaling pathway in terms of molecular activation or known biological effect by a detectable or measurable amount compared to baseline activity/ means to activate. This can be assessed in vitro or in vivo, and optionally extrapolated what the activity or benefit may be in vivo by one skilled in the art. In some embodiments, the reduction or activation is, for example, at least 5%, at least 10%, 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, Measured in terms of percentage reduction or activation compared to activity in the absence of exposure to a compound of the disclosure, including at least 90%, or about 100%. Activity can also be included within any other range interval, eg, from about 5-10%, from about 10-20%, and from about 1%-100%. An amount is "effective" in vivo if the compound provides some benefit to the subject to whom it is administered.

The terms "disease" or "disorder" are used interchangeably herein to prevent or interfere with the performance of a function, and/or cause discomfort, Refers to any change in the state of the body or some of its organs that causes symptoms such as impairment, pain, or even death. A disease or disorder can also relate to distemper, morbidity, disease, ailment, illness, illness, complaint, ill health, or morbidity.

A "VE-PTP-mediated disorder" or "Tie-2-mediated disorder" is any disease or adverse condition in which VE-PTP or Tie2 plays a role. Non-limiting examples of such disorders are provided elsewhere in this disclosure.

The phrase "pharmaceutically acceptable" is used herein to mean any undue toxicity, irritation, allergic reaction, or other Used to refer to compounds, materials, compositions and/or dosage forms suitable for use in contact with human and animal tissue without problems or complications. Drug approval agencies (eg, EMA, US-FDA) guide and approve pharmaceutically acceptable compounds, materials, compositions, and/or dosage forms. Examples of these are listed in Pharmacopeias.

The phrase "pharmaceutically acceptable excipient" as used herein includes solvents, dispersion media, diluents, dispersing agents, suspending aids, surfactants, isotonic agents, thickening agents or emulsifying agents, Used to refer to pharmaceutically acceptable materials selected from preservatives, polymers, peptides, proteins, cells, hyaluronidases, and mixtures thereof. In some embodiments, the solvent is an aqueous solvent.

As used herein, the terms "treatment," "treating," "efficacious," "therapeutically effective," and the like refer to Point. The effect can be prophylactic, in that it completely or partially prevents the disease or its symptoms, and/or therapeutic, in that it partially or completely cures the disease and/or the side effects caused by the disease. can be

By "subject" is meant a human or non-human mammal, such as, but not limited to, a bovine, equine, canine, ovine, or feline mammal.

Ranges provided herein are understood to be shorthand for all values within the range. For example, the range from 1 to 50 is 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49, or 50. The same rules apply to any other range described herein, even if the values within the range are not specifically invoked in this disclosure.

The terms "alkyl,""alkylunit," and "alkyl group," as used interchangeably herein, refer to saturated monovalent hydrocarbon radicals containing from 1 to 12 carbon atoms ( _C.sub.1 - _C.sub.12 ). point to Alkyl groups can be straight, branched, or cyclic. Alkyl groups can be unsubstituted or substituted as described elsewhere herein. In some embodiments, the alkyl group contains 1-8 carbon atoms (C ₁ -C ₈ ). In some embodiments, the alkyl group contains 1-6 carbon atoms (C ₁ -C ₆ ). In some embodiments, the alkyl group contains 1-4 carbon atoms (C ₁ -C ₄ ). In some embodiments, cyclic alkyl groups contain 3-6 carbon atoms (C ₃ -C ₆ ). Non-limiting examples of substituted and unsubstituted straight chain, branched chain, or cyclic alkyl groups include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl , tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl, chloromethyl, fluoromethyl, trifluoromethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, dimethylaminomethyl, 2-dimethylamino Ethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, trifluoroethyl and trifluoropropyl.

The terms "alkylene,""alkyleneunit," and "alkylene group," as used interchangeably herein, refer to saturated divalent hydrocarbon radicals containing from 1 to 12 carbon atoms ( _C.sub.1 - _C.sub.12 ). point to Alkylene groups can be straight, branched, or cyclic. Alkylene groups can be unsubstituted or substituted as described elsewhere herein. In some embodiments, the alkylene group contains 1-8 carbon atoms (C ₁ -C ₈ ). In some embodiments, the alkylene group contains 1-6 carbon atoms (C ₁ -C ₆ ). In some embodiments, the alkylene group contains 1-4 carbon atoms (C ₁ -C ₄ ). Non-limiting examples of alkylene groups include methylene and ethylene.

The terms “alkenyl,” “alkenyl unit,” and “alkenyl group,” as used interchangeably herein, refer to 2 to 2 having at least one site of unsaturation (ie, an sp ² carbon-carbon double bond). Refers to a monovalent hydrocarbon radical containing 8 carbon atoms (C ₂ -C ₈ ). Alkenyl groups can be straight chain, branched or cyclic. An alkenyl group can be unsubstituted or substituted as described elsewhere herein. In some embodiments, the alkenyl group contains 2-6 carbon atoms (C ₂ -C ₆ ). In some embodiments, the alkenyl group contains 2-4 carbon atoms (C ₂ -C ₄ ). Alkenyl groups can have an E or Z orientation. Non-limiting examples of alkenyl groups include ethenyl (also called vinyl), 1-propenyl, iso-propenyl, and 2-chloroethenyl.

The terms “alkenylene,” “alkenylene unit,” and “alkenylene group,” used interchangeably herein, refer to 2 to 2 having at least one site of unsaturation (eg, an sp ² carbon-carbon double bond). Refers to a divalent hydrocarbon radical containing 8 carbon atoms (C ₂ -C ₈ ). Alkenylene groups can be straight chain, branched or cyclic. An alkenylene group can be unsubstituted or substituted as described elsewhere herein. In some embodiments, the alkylene group contains 2-6 carbon atoms (C ₂ -C ₆ ). In some embodiments, the alkylene group contains 2-4 carbon atoms (C ₂ -C ₄ ). Alkylene groups can have an E or Z orientation. Non-limiting examples of alkenyl groups include ethenylene (also called vinylene).

The terms “alkynyl,” “alkynyl unit,” and “alkynyl group,” used interchangeably herein, refer to 2-8 groups having at least one site of unsaturation (ie, sp carbon-carbon triple bond). refers to a monovalent hydrocarbon radical containing carbon atoms (C ₂ -C ₈ ) of . Alkynyl groups can be straight or branched. An alkynyl group can be unsubstituted or substituted as described elsewhere herein. In some embodiments, the alkynyl group contains 2-6 carbon atoms (C ₂ -C ₆ ). In some embodiments, the alkynyl group contains 2-4 carbon atoms (C ₂ -C ₄ ). A non-limiting example of an alkynyl group includes ethynyl.

The terms “alkynylene,” “alkynylene unit,” and “alkynylene group,” as used interchangeably herein, refer to 2-8 groups having at least one site of unsaturation (ie, sp carbon-carbon triple bond). refers to a divalent hydrocarbon radical containing carbon atoms (C ₂ -C ₈ ) of Alkynylene groups can be straight or branched. An alkynylene group can be unsubstituted or substituted as described elsewhere herein. In some embodiments, the alkynylene group contains 2-6 carbon atoms (C ₂ -C ₆ ). In some embodiments, the alkynylene group contains 2-4 carbon atoms (C ₂ -C ₄ ). Non-limiting examples of alkynylene groups include ethynylene.

The terms “aryl,” “aryl unit,” and “aryl group,” used interchangeably herein, refer to 6 to 20 carbon atoms derived by removing a hydrogen atom from an aromatic ring. It refers to monovalent aromatic hydrocarbon radicals including (C ₆ -C ₂₀ ). An aryl group can be unsubstituted or substituted with one or more substituents as described elsewhere herein. Non-limiting examples of unsubstituted and substituted aryl groups include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl , 3-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxy phenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-aminophenyl, 3-methylaminophenyl, 3-(2-hydroxyethoxy)phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl fluoromethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 1-naphthyl, and 2-naphthyl.

The terms “arylene,” “arylene unit,” and “arylene group,” used interchangeably herein, refer to 6 to 20 hydrogen atoms derived by removing two hydrogen atoms from an aromatic ring. refers to a divalent aromatic hydrocarbon radical containing carbon atoms (C ₆ -C ₂₀ ) of . An arylene group can be unsubstituted or substituted with one or more substituents as described elsewhere herein. Non-limiting examples of arylene groups include phenylene.

The terms "heterocycle," "heterocyclyl," "heterocyclic unit," and "heterocyclic group," as used interchangeably herein, refer to saturated or partially unsaturated rings containing from 3 to 20 atoms. wherein at least one of the ring atoms is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur. A heterocyclic group can be unsubstituted or substituted with one or more substituents as described elsewhere herein. In some embodiments, the heterocyclic group contains 3-10 atoms. In some embodiments, the heterocyclic group contains 3-7 atoms. In some embodiments, a heterocyclic group is monocyclic. In some embodiments, a heterocyclic group is bicyclic. In some embodiments, heterocyclic groups contain fused rings. Non-limiting examples of unsubstituted and substituted heterocyclic groups include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, and 3-methoxypyrrolidinyl. dinyls.

The terms “heteroaryl,” “heteroaryl unit,” and “heteroaryl group,” used interchangeably herein, contain one or more 5-, 6-, or 7-membered rings, Refers to a monovalent aromatic radical containing one or more heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. A heteroaryl group can be unsubstituted or substituted with one or more substituents as described elsewhere herein. In some embodiments, the heteroaryl group contains 5-20 atoms. In some embodiments, the heteroaryl group contains 5-9 atoms. In some embodiments, the heteroaryl group contains 5 atoms. In some embodiments, the heteroaryl group contains 6 atoms. In some embodiments, the heteroaryl group contains 7 atoms. In some embodiments, heteroaryl groups are monocyclic. In some embodiments, heteroaryl groups are bicyclic. In some embodiments, the heteroaryl group contains fused rings. Non-limiting examples of heteroaryl groups include pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl -1,2,4-oxadiazolyl, 3-phenyl-1,2,4-oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazil, quinazolyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and 1H-pyrrolo[2,3-b]pyridinyl.

が含まれることを理解されることを意味する。 For the avoidance of doubt, non-limiting examples of heteroaryl groups include

is understood to include

As used herein, the term "substituted" refers to hydrocarbon radicals, alkyl groups, alkylene groups, alkenyl groups, alkenylene groups, alkynyl groups, alkynylene groups, aryl groups, heterocyclic groups, or heteroaryl groups. Refers to the replacement of one or more hydrogen atoms on one or more of a group with one or more substituents. In a substituted hydrocarbon radical, alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocyclic group, or heteroaryl group, any number of hydrogen atoms can be replaced by a substituent. . Non-limiting examples of substituents that replace a single hydrogen atom include halogen, hydroxyl, and amino. A non-limiting example of a substituent that replaces two hydrogen atoms includes carbonyl. A non-limiting example of a substituent that replaces three hydrogen atoms includes cyano.

A substitution that can be substituted for one or more hydrogen atoms of a hydrocarbon radical, an alkyl group, an alkylene group, an alkenyl group, an alkenylene group, an alkynyl group, an alkynylene group, an aryl group, a heterocyclic group, or a heteroaryl group. Non-limiting examples of groups include:
1. C ₁ -C ₆ straight, branched or cyclic alkyl groups (non-limiting examples thereof include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl sec-butyl, iso-butyl , tert-butyl, cyclobutyl, cyclopentyl, and cyclohexyl),
2. C ₂ -C ₈ straight chain, branched chain, or cyclic alkenyl groups, non-limiting examples of which include ethenyl (also called vinyl), 1-propenyl, and iso-propenyl;
3. C ₂ -C ₈ straight or branched chain alkynyl groups (non-limiting examples of which include ethynyl);
4. Substituted or unsubstituted aryl groups (non-limiting examples thereof include phenyl, 2-fluorophenyl, 3-methylphenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3-methylsulfonylphenyl, 4-trifluoromethylphenyl, 3-isopropylphenyl, 1-naphthyl, and 2-naphthyl),
5. substituted or unsubstituted heterocyclic groups, non-limiting examples of which include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, and 3-methoxy pyrrolidinyl),
6. substituted or unsubstituted heteroaryl groups (non-limiting examples thereof include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-1,2,4 -oxadiazolyl, 3-phenyl-1,2,4-oxadiazolyl, indolyl, benzothiazolyl, and 1H-pyrrolo[2,3-b]pyridinyl),
7. —(CR ^a R ^b ) _z OR ^c (non-limiting examples of which include —OH, —OCH ₃ , —OCH ₂ OH, and —OCH ₂ CH ₃ );
8. —(CR ^a R ^b ) _z N(R ^c )(R ^d ) (non-limiting examples thereof include —NH ₂ , —NHCH ₃ , —N(CH ₃ ) ₂ , —CH ₂ NH ₂ , — CH ₂ NHCH ₃ , and —CH ₂ N(CH ₃ ) ₂ ),
9. Halogen atoms (non-limiting examples of which include fluorine atoms (-F) and chlorine atoms (-Cl)).
10. -( ^{CRaRb )} _zCN ,
11. -( ^CRaRb ₎ ^zNO2 _,
12. —CH _x X _y (wherein X is a halogen atom and the sum of x+y is 3, non-limiting examples of which include —CH ₂ F, —CHF ₂ , and —CF ₃ ) ,
13. —(CR ^a R ^b ) _z C(O)R ^c (non-limiting examples of which include —COCH ₃ , —COCH ₂ CH ₃ , and —CH ₂ COCH ₃ );
14. —(CR ^a R ^b ) _z C(O)OR ^c (non-limiting examples thereof include —CO ₂ H, —CO ₂ CH ₃ , —CO ₂ CH ₂ CH ₃ , and —CH ₂ CO ₂ CH ₃ ),
15. —(CR ^a R ^b ) _z C(O)N(R ^c )(R ^d ) (non-limiting examples thereof include —CONH ₂ , —CONHCH ₃ , —CON(CH ₃ ) ₂ , —CH ₂ CONH ₂ , —CH ₂ CONHCH ₃ , and —CH ₂ CON(CH ₃ ) ₂ );
16. —(CR ^a R ^b ) _z SO ₂ R ^c (non-limiting examples thereof include —SO ₂ H, —SO ₂ CH ₃ , —CH ₂ SO ₂ H, —CH ₂ SO ₂ CH ₃ , —SO ₂ C ₆ H ₅ and —CH ₂ SO ₂ C ₆ H ₅ ), and 17. —(CR ^a R ^b ) _z SO ₃ R ^c (non-limiting examples thereof include —SO ₃ H, —SO ₃ CH ₃ , —CH ₂ SO ₃ H, —CH ₂ SO ₃ CH ₃ , —SO ₃ C ₆ H ₅ and —CH ₂ SO ₃ C ₆ H ₅ ),
wherein each of R ^a and R ^b is independently selected from hydrogen and substituted or unsubstituted C ₁ -C ₆ linear, branched, or cyclic alkyl; and each of R ^c and R ^d is independently selected from hydrogen, substituted or unsubstituted C ₁ -C ₆ linear, branched or cyclic alkyl and aryl, or R ^c and R ^d taken together, 3 to 7 atoms and z is selected from 0, 1, 2, 3, and 4.

The compounds of this disclosure may contain one or more chiral centers. Accordingly, the compounds of the disclosure may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds described herein including, as non-limiting examples, diastereomers, enantiomers, and mixtures thereof (including, as non-limiting examples, racemic mixtures) are intended to form part of this disclosure.

Various publications, articles, and patents are cited or described throughout the background and this specification, each of these references being incorporated herein by reference in its entirety. Any discussion of documents, acts, materials, devices, articles, etc. contained herein is for the purpose of providing context for the invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any invention disclosed or claimed.

式中、
Ｒ_１が、

から選択され、
式中、
Ｒ_２が、置換又は非置換アリール、置換又は非置換ヘテロアリール、置換又は非置換直鎖アルキル、置換又は非置換分岐鎖アルキル、置換又は非置換環状アルキル、置換又は非置換直鎖アルケニル、置換又は非置換分岐鎖アルケニル、置換又は非置換環状アルケニル、置換又は非置換直鎖アルキニル、及び置換又は非置換分岐鎖アルキニルから選択され、
Ｒ_３が、置換又は非置換アリール、置換又は非置換ヘテロアリール、置換又は非置換直鎖アルキル、置換又は非置換分岐鎖アルキル、置換又は非置換環状アルキル、置換又は非置換直鎖アルケニル、置換又は非置換分岐鎖アルケニル、置換又は非置換環状アルケニル、置換又は非置換直鎖アルキニル、及び置換又は非置換分岐鎖アルキニルから選択され、
ｎが、１、２、３、４、５、及び６から選択される整数であり、
Ｒ_４が、置換又は非置換直鎖アルキル、置換又は非置換分岐鎖アルキル、及び置換又は非置換環状アルキルから選択され、
Ｒ_５が、Ｈ、置換又は非置換直鎖アルキル、置換又は非置換分岐鎖アルキル、及び置換又は非置換環状アルキルから選択され、
Ｘ_１、Ｘ_２、及びＸ_３の各々が、独立して、ＣＨ及びＮから選択され、但し、Ｘ_１、Ｘ_２、及びＸ_３が、同時にＣＨではないことを条件とする、化合物である。 II. Compounds In some embodiments, the compound of the present disclosure is a compound of Formula I,

During the ceremony,
R ₁ is

is selected from
During the ceremony,
R ₂ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted straight-chain alkyl, substituted or unsubstituted branched-chain alkyl, substituted or unsubstituted cyclic alkyl, substituted or unsubstituted straight-chain alkenyl, substituted or unsubstituted selected from unsubstituted branched chain alkenyl, substituted or unsubstituted cyclic alkenyl, substituted or unsubstituted straight chain alkynyl, and substituted or unsubstituted branched chain alkynyl;
R ₃ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted cyclic alkyl, substituted or unsubstituted linear alkenyl, substituted or unsubstituted selected from unsubstituted branched chain alkenyl, substituted or unsubstituted cyclic alkenyl, substituted or unsubstituted straight chain alkynyl, and substituted or unsubstituted branched chain alkynyl;
n is an integer selected from 1, 2, 3, 4, 5, and 6;
_R4 is selected from substituted or unsubstituted straight chain alkyl, substituted or unsubstituted branched chain alkyl, and substituted or unsubstituted cyclic alkyl;
_R5 is selected from H, substituted or unsubstituted straight chain alkyl, substituted or unsubstituted branched chain alkyl, and substituted or unsubstituted cyclic alkyl;
each of X ₁ , X ₂ and X ₃ is independently selected from CH and N, with the proviso that X ₁ , X ₂ and X ₃ are not simultaneously CH .

である。 In some embodiments, R ₁ is

is.

である。 In some embodiments, R ₁ is

is.

In some embodiments, R ₂ is selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted straight chain alkyl, substituted or unsubstituted branched chain alkyl, and substituted or unsubstituted cyclic alkyl. In some embodiments, R ₂ is substituted or unsubstituted heteroaryl. In some embodiments, _R2 is substituted heteroaryl. In some embodiments, R ₂ is unsubstituted heteroaryl. In some embodiments, R ₂ is 2-thienyl. In some embodiments, R ₂ is 3-thienyl.

In some embodiments, R ₂ is not substituted or unsubstituted heteroaryl. In some embodiments, R ₂ is not substituted heteroaryl. In some embodiments, R ₂ is not unsubstituted heteroaryl. In some embodiments, R ₂ is not 2-thienyl. In some embodiments, R ₂ is not 3-thienyl.

In some embodiments, R ₂ is substituted or unsubstituted straight chain alkyl. In some embodiments, R ₂ is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₂ is unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₂ is substituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₂ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more halogen atoms. In some embodiments, R ₂ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more fluorine atoms. In some embodiments, _R2 is a trifluoroalkyl group. In some embodiments, R ₂ is trifluoroethyl.

In some embodiments, R ₂ is not substituted or unsubstituted straight chain alkyl. In some embodiments, R ₂ is not substituted or unsubstituted branched alkyl. In some embodiments, R ₂ is not substituted or unsubstituted cyclic alkyl. In some embodiments, R ₂ is not substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₂ is not unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₂ is not substituted C ₁ -C ₆ straight chain alkyl. In some embodiments, _R2 is not methyl. In some embodiments, _R2 is not ethyl. In some embodiments, _R2 is not isopropyl. In some embodiments, R ₂ is not cyclopropyl.

In some embodiments, _R3 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted straight chain alkyl, substituted or unsubstituted branched chain alkyl, and substituted or unsubstituted cyclic alkyl. be. In some embodiments, _R3 is substituted or unsubstituted heteroaryl. In some embodiments, _R3 is substituted heteroaryl. In some embodiments, _R3 is unsubstituted heteroaryl. In some embodiments, R ₃ is 2-thienyl. In some embodiments, R ₃ is 3-thienyl.

In some embodiments, R ₃ is not substituted or unsubstituted aryl. In some embodiments, _R3 is not substituted aryl. In some embodiments, _R3 is not unsubstituted aryl. In some embodiments, _R3 is not phenyl. In some embodiments, _R3 is not substituted or unsubstituted heteroaryl. In some embodiments, _R3 is not substituted heteroaryl. In some embodiments, _R3 is not unsubstituted heteroaryl. In some embodiments, R ₃ is not 2-thienyl. In some embodiments, R ₃ is not 3-thienyl.

In some embodiments, R ₃ is selected from substituted or unsubstituted straight chain alkyl, substituted or unsubstituted branched chain alkyl, and substituted or unsubstituted cyclic alkyl. In some embodiments, R ₃ is from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. selected. In some embodiments, R ₃ is selected from substituted C ₁ -C ₆ straight chain alkyl, substituted C ₁ -C ₆ branched chain alkyl, and substituted C ₃ -C ₆ cyclic alkyl. In some embodiments, R ₃ is selected from unsubstituted C ₁ -C ₆ straight chain alkyl, unsubstituted C ₁ -C ₆ branched chain alkyl, and unsubstituted C ₃ -C ₆ cyclic alkyl.

In some embodiments, R ₃ is not substituted or unsubstituted straight chain alkyl. In some embodiments, _R3 is not substituted or unsubstituted branched alkyl. In some embodiments, _R3 is not substituted or unsubstituted cyclic alkyl. In some embodiments, R ₃ is not substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₃ is not substituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₃ is not unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, _R3 is not methyl. In some embodiments, _R3 is not ethyl. In some embodiments, _R3 is not isopropyl. In some embodiments, _R3 is not cyclopropyl.

In some embodiments, R ₃ is unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₃ is substituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₃ is a substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with a C ₅ -C ₂₀ heteroaryl group. In some embodiments, R ₃ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more halogen atoms. In some embodiments, R ₃ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more fluorine atoms. In some embodiments, _R3 is a trifluoroalkyl group. In some embodiments, R ₃ is trifluoroethyl. In some embodiments, R ₃ is trifluoropropyl.

In some embodiments, R ₃ is substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. In some embodiments, R ₃ is unsubstituted C ₃ -C ₆ cyclic alkyl. In some embodiments, R ₃ is cyclopropyl.

から選択される。 In some embodiments, R ₃ is 2-thienyl, trifluoroethyl, trifluoropropyl, cyclopropyl,

is selected from

である。 In some embodiments, R ₃ is 2-thienyl. In some embodiments, R ₃ is

is.

である。 In some embodiments, R ₃ is

is.

In some embodiments, R ₄ is from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. selected. In some embodiments, R ₄ is selected from substituted C ₁ -C ₆ straight chain alkyl, substituted C ₁ -C ₆ branched chain alkyl, and substituted C ₃ -C ₆ cyclic alkyl. In some embodiments, R ₄ is selected from unsubstituted C ₁ -C ₆ straight chain alkyl, unsubstituted C ₁ -C ₆ branched chain alkyl, and unsubstituted C ₃ -C ₆ cyclic alkyl. In some embodiments, R ₄ is unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, _R4 is methyl.

In some embodiments, _R5 is H. In some embodiments, R ₅ is from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. selected. In some embodiments, R ₅ is substituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₅ is unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, _R5 is methyl.

In some embodiments, R ₅ is not substituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₅ is not unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, _R5 is not methyl. In some embodiments, _R5 is not H.

から選択されることを理解されることを意味する。 In some embodiments, X ₁ and X ₂ are CH and X ₃ is N. In some embodiments, X ₁ and X ₃ are CH and X ₂ is N. In some embodiments, X ₂ and X ₃ are CH and X ₁ is N. In some embodiments, X ₁ is CH and X ₂ and X ₃ are N. In some embodiments, X ₂ is CH and X ₁ and X ₃ are N. For the avoidance of doubt, in some embodiments

is understood to be selected from

In some embodiments, n is an integer selected from 1, 2, and 3. In some embodiments, n is an integer selected from 1 and 2. In some embodiments, n is 1.

式中、
Ｒ_６が、置換又は非置換ヘテロアリールであり、
ｍが、１、２、３、４、５、及び６から選択される整数であり、
Ｒ_７が、置換又は非置換直鎖アルキル、置換又は非置換分岐鎖アルキル、及び置換又は非置換環状アルキルから選択され、
Ｒ_８が、Ｈ、置換又は非置換直鎖アルキル、置換又は非置換分岐鎖アルキル、及び置換又は非置換環状アルキルから選択され、
Ｒ_９及びＲ_１０の各々が、独立して、Ｈ、置換又は非置換直鎖アルキル、置換又は非置換分岐鎖アルキル、及び置換又は非置換環状アルキルから選択される、化合物である。 In some embodiments, the compound of the disclosure is a compound of Formula II,

During the ceremony,
R ₆ is substituted or unsubstituted heteroaryl;
m is an integer selected from 1, 2, 3, 4, 5, and 6;
R ₇ is selected from substituted or unsubstituted straight chain alkyl, substituted or unsubstituted branched chain alkyl, and substituted or unsubstituted cyclic alkyl;
_R8 is selected from H, substituted or unsubstituted straight chain alkyl, substituted or unsubstituted branched chain alkyl, and substituted or unsubstituted cyclic alkyl;
Each of R ₉ and R ₁₀ is a compound independently selected from H, substituted or unsubstituted straight chain alkyl, substituted or unsubstituted branched chain alkyl, and substituted or unsubstituted cyclic alkyl.

In some embodiments, _R6 is substituted heteroaryl. In some embodiments, _R6 is unsubstituted heteroaryl. In some embodiments, R ₆ is 2-thienyl. In some embodiments, R ₆ is 3-thienyl.

In some embodiments, R ₇ is from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. selected. In some embodiments, R ₇ is substituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₇ is unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, _R7 is methyl.

In some embodiments, _R8 is H. In some embodiments, R ₈ is from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. selected. In some embodiments, R ₈ is substituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₈ is unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, _R8 is methyl.

In some embodiments, each of R ₉ and R ₁₀ is independently selected from H and substituted or unsubstituted straight chain alkyl. In some embodiments, each of R ₉ and R ₁₀ is independently selected from H and substituted or unsubstituted linear C ₁ -C ₆ alkyl. In some embodiments, _R9 is H. In some embodiments, R ₁₀ is H. In some embodiments, each of R ₉ and R ₁₀ is H. In some embodiments, each of R ₉ and R ₁₀ is independently substituted C ₁ -C ₆ straight chain alkyl. In some embodiments, each of R ₉ and R ₁₀ is independently unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, _R9 is methyl. In some embodiments, R ₁₀ is methyl. In some embodiments, each of R ₉ and R ₁₀ is methyl.

In some embodiments, m is an integer selected from 2, 3, 4, 5, and 6. In some embodiments, m is an integer selected from 2, 3, 4, and 5. In some embodiments, m is an integer selected from 2, 3, and 4. In some embodiments, m is an integer selected from 3 and 4. In some embodiments, m is three. In some embodiments, m is four.

式中、
Ｒ_１１が、置換又は非置換アリール、置換又は非置換ヘテロアリール、置換又は非置換ヘテロシクリル、置換又は非置換直鎖アルキル、置換又は非置換分岐鎖アルキル、置換又は非置換環状アルキル、置換又は非置換直鎖アルケニル、置換又は非置換分岐鎖アルケニル、置換又は非置換環状アルケニル、置換又は非置換直鎖アルキニル、及び置換又は非置換分岐鎖アルキニルから選択され、
ａが、０、１、２、３、４、５、及び６から選択される整数であり、
Ｙ_１－Ｙ_２が、存在しない、－ＣＨ_２－ＣＨ_２－、及び－ＣＨ＝ＣＨ－から選択される基であり、
ｂが、０、１、２、３、４、５、及び６から選択される整数であり、
Ｒ_１２が、置換又は非置換ヘテロアリール及び置換又は非置換アリールから選択される、化合物である。 In some embodiments, the compound of the disclosure is a compound of Formula III,

During the ceremony,
R ₁₁ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted cyclic alkyl, substituted or unsubstituted selected from straight chain alkenyl, substituted or unsubstituted branched chain alkenyl, substituted or unsubstituted cyclic alkenyl, substituted or unsubstituted straight chain alkynyl, and substituted or unsubstituted branched chain alkynyl;
a is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
Y ₁ -Y ₂ is absent and is a group selected from -CH ₂ -CH ₂ - and -CH=CH-;
b is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
R ₁₂ is a compound selected from substituted or unsubstituted heteroaryl and substituted or unsubstituted aryl.

In some embodiments, R ₁₁ is selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted straight chain alkyl, substituted or unsubstituted branched chain alkyl, and substituted or unsubstituted cyclic alkyl. be. In some embodiments, R ₁₁ is from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted branched C ₁ -C ₆ alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. selected.

In some embodiments, R ₁₁ is substituted or unsubstituted heteroaryl. In some embodiments, R ₁₁ is substituted heteroaryl. In some embodiments, R ₁₁ is unsubstituted heteroaryl. In some embodiments, R ₁₁ is 2-thienyl. In some embodiments, R ₁₁ is 3-thienyl.

In some embodiments, R ₁₁ is not substituted or unsubstituted heteroaryl. In some embodiments, R ₁₁ is not substituted heteroaryl. In some embodiments, R ₁₁ is not unsubstituted heteroaryl. In some embodiments, R ₁₁ is not 2-thienyl. In some embodiments, R ₁₁ is not 3-thienyl.

In some embodiments, R ₁₁ is not substituted aryl. In some embodiments, R ₁₁ is not unsubstituted aryl. In some embodiments, R ₁₁ is not phenyl.

In some embodiments, R ₁₁ is not substituted or unsubstituted straight chain alkyl. In some embodiments, R ₁₁ is not substituted or unsubstituted branched alkyl. In some embodiments, R ₁₁ is not substituted or unsubstituted cyclic alkyl. In some embodiments, R ₁₁ is not substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₁₁ is not substituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₁₁ is not unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₁₁ is not methyl. In some embodiments, R ₁₁ is not ethyl. In some embodiments, R ₁₁ is not isopropyl. In some embodiments, R ₁₁ is not cyclopropyl.

In some embodiments, R ₁₁ is substituted or unsubstituted straight chain alkyl. In some embodiments, R ₁₁ is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₁₁ is unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl.

In some embodiments, R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more halogen atoms. In some embodiments, R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with one or more fluorine atoms. In some embodiments, R ₁₁ is a trifluoroalkyl group. In some embodiments, R ₁₁ is trifluoroethyl. In some embodiments, R ₁₁ is trifluoropropyl.

In some embodiments, R ₁₁ is a substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with a C ₃ -C ₆ cyclic alkyl group. In some embodiments, R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with a cyclopropyl group. In some embodiments, R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with a cyclopentyl group. In some embodiments, R ₁₁ is cyclopropylmethyl. In some embodiments, R ₁₁ is cyclopentylmethyl.

In some embodiments, R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with a heteroaryl group. In some embodiments, R ₁₁ is a substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with an imidazolyl group.

In some embodiments, R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with —N(R ^c )(R ^d ) , R ^c and R ^d are each independently selected from hydrogen, substituted or unsubstituted linear, branched or cyclic alkyl, and aryl, or R ^c and R ^d taken together It forms a ring system containing 3 to 7 atoms. In some embodiments, R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with —N(R ^c )(R ^d ) , R ^c and R ^d are each independently selected from H and substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with —N(R ^c )(R ^d ) , R ^c and R ^d are each independently selected from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with —N(R ^c )(R ^d ) , R ^c and R ^d are each independently selected from unsubstituted C ₁ -C ₆ straight chain alkyl. In some embodiments, R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is amino group, dimethylamino group, diethylamino group, di-n-propyl It is substituted with an amino group or a di-n-butylamino group. In some embodiments, R ₁₁ is a dimethylaminomethyl group.

In some embodiments, R ₁₁ is substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. In some embodiments, R ₁₁ is unsubstituted C ₃ -C ₆ cyclic alkyl. In some embodiments, R ₁₁ is unsubstituted C ₃ -C ₆ cyclic alkyl. In some embodiments, R ₁₁ is cyclopropyl.

In some embodiments, R ₁₁ is substituted or unsubstituted heterocyclyl. In some embodiments, R ₁₁ is unsubstituted heterocyclyl. In some embodiments, R ₁₁ is substituted heterocyclyl. In some embodiments, R ₁₁ is selected from pyrrolidinyl, 3-hydroxypyrrolidinyl, and 3-methoxypyrrolidinyl.

から選択されることを理解されたい。 For the avoidance of doubt, in some embodiments, R ₁₁ is 2-thienyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopentylmethyl,

It should be understood that the selected from

In some embodiments, R ₁₂ is substituted or unsubstituted heteroaryl. In some embodiments, R ₁₂ is substituted heteroaryl. In some embodiments, R ₁₂ is unsubstituted heteroaryl. In some embodiments, R ₁₂ is pyridinyl. In some embodiments, R ₁₂ is substituted or unsubstituted aryl. In some embodiments, R ₁₂ is substituted aryl. In some embodiments, R ₁₂ is monosubstituted aryl. In some embodiments, R ₁₂ is monosubstituted phenyl. In some embodiments, R ₁₂ is unsubstituted aryl. In some embodiments, R ₁₂ is phenyl. In some embodiments, R ₁₂ is selected from 1-naphthyl and 2-naphthyl. In some embodiments, R ₁₂ is 1-naphthyl. In some embodiments, R ₁₂ is 2-naphthyl.

In some embodiments, Y ₁ -Y ₂ are absent. In some embodiments, Y ₁ -Y ₂ are -CH ₂ -CH ₂ -. In some embodiments, Y ₁ -Y ₂ is -CH=CH-.

In some embodiments, a is an integer selected from 0, 1, 2, and 3. In some embodiments, a is an integer selected from 0, 1, and 2. In some embodiments, a is an integer selected from 0 and 1. In some embodiments, a is two. In some embodiments, a is 1. In some embodiments, a is 0.

In some embodiments, b is an integer selected from 0, 1, 2, and 3. In some embodiments, b is an integer selected from 0, 1, and 2. In some embodiments, b is an integer selected from 0 and 1. In some embodiments, b is two. In some embodiments, b is 1. In some embodiments, b is 0.

を有する化合物であることを理解されたい。したがって、いくつかの実施形態では、本開示の化合物は、構造

を有する化合物であることも理解されたい。したがって、いくつかの実施形態では、本開示の化合物は、構造

を有する化合物であることも理解されたい。 In some embodiments, the compounds of the present disclosure are compounds of Formula III, wherein Y ₁ -Y ₂ are absent, a is 1 and b is 1. In some embodiments, the compounds of the present disclosure are compounds of Formula III, wherein Y ₁ -Y ₂ are absent, a is 1 and b is 0. In some embodiments, the compounds of the present disclosure are compounds of Formula III, wherein Y ₁ -Y ₂ are -CH=CH-, a is 0 and b is 0 . In some embodiments, the compounds of the present disclosure are compounds of Formula III, wherein Y ₁ -Y ₂ are -CH ₂ -CH ₂ -, a is 0, b is 0. In some embodiments, the compounds of the present disclosure are compounds of Formula III, wherein Y ₁ -Y ₂ are absent and a and b are not 0 at the same time. Thus, in some embodiments, compounds of the present disclosure have the structure

is understood to be a compound having Thus, in some embodiments, compounds of the present disclosure have the structure

It should also be understood to be a compound having Thus, in some embodiments, compounds of the present disclosure have the structure

It should also be understood to be a compound having

In some embodiments, compounds of the present disclosure are selected from compounds listed in Table I below:

III. Pharmaceutically Acceptable Salts In some embodiments, the compounds of this disclosure are in the form of pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable as defined herein and that possesses the desired pharmacological activity of the parent compound. Non-limiting examples of pharmaceutically acceptable salts include those derived from inorganic acids, including hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric , and phosphoric acid, including those derived from organic acids, non-limiting examples of which include acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, stearic acid, malic acid , maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and lactic acid.

Further non-limiting examples of pharmaceutically acceptable salts include those formed when an acidic proton in the parent compound is replaced by a metal ion, non-limiting examples of which are: Including alkali metal ions and alkaline earth metal ions, when acidic protons present in the parent compound are replaced by ammonium ions, primary ammonium ions, secondary ammonium ions, tertiary ammonium ions, or quaternary ammonium ions Including those that are formed. Non-limiting examples of alkali metals and alkaline earth metals include sodium, potassium, lithium, calcium, aluminum, magnesium, copper, zinc, iron, and manganese. Further non-limiting examples of pharmaceutically acceptable salts include those containing one or more counterions and zwitterions.

IV. Pharmaceutical Compositions The compounds of the disclosure can be used therapeutically as pharmaceutical compositions. The term "pharmaceutical composition" means that the active ingredients are in such a form as to permit the biological activity of the active ingredients to be effective, and do not contain any additional substances that are unacceptably toxic to subjects to whom the composition may be administered. Refers to preparations that do not contain ingredients. In some embodiments, such compositions can be sterile.

The components of the composition may be in solution, emulsion, or suspension (eg, incorporated into microparticles, nanoparticles, or liposomes). Colloidal dosage forms such as nanoparticles, nanomicelles, liposomes, and microemulsions can also be used. A suitable amount of a pharmaceutically acceptable salt is typically used in the formulation to render the formulation isotonic. Examples of pharmaceutically acceptable carriers include, but are not limited to, saline, Ringer's solution, and dextrose solution. The pH of the solution is preferably from about 5 to about 8, more preferably from about 7 to about 7.5. Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives and surface active agents. Additional carriers include sustained-release preparations such as semipermeable matrices of solid hydrophobic polymers containing the compound of this disclosure, which matrices are in the form of shaped particles, e.g. films, liposomes, or microparticles. is. It will be apparent to those skilled in the art that certain carriers may be more preferred depending, for example, on the route of administration and concentration of the composition administered. Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, antiinflammatory agents, and anesthetics.

Pharmaceutically acceptable carriers, excipients, vehicles, and diluents are well known to those skilled in the art, and non-limiting examples are found in Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins, Philadelphia, Pa.; (2013) and any other edition, which are incorporated herein by reference.

V. Methods of Treatment and Administration Compounds of the present disclosure, pharmaceutically acceptable salts of such compounds, and/or pharmaceutical compositions comprising such compounds and/or pharmaceutically acceptable salts thereof can be used as therapeutic agents. can be administered.

The compounds, pharmaceutically acceptable salts, and/or pharmaceutical compositions can be administered in unit dosage forms to mammalian subjects, including humans. Suitable unit forms for administration include, as non-limiting examples, forms administered orally and forms via parenteral/systemic routes, non-limiting examples of which include inhalation, subcutaneous administration, Intramuscular, intravenous, intradermal, intravitreal, and topical and topical ocular (ie, subconjunctival, intravitreal, retrobulbar, intracameral) modes of administration are included.

In some embodiments, pharmaceutical compositions for oral administration can be in the form of tablets, pills, powders, hard gelatin capsules, soft gelatin capsules, and/or granules. In some embodiments of such pharmaceutical compositions, compounds of the disclosure and/or pharmaceutically acceptable salts of compounds of the disclosure are admixed with one or more inert diluents ( or mixed), non-limiting examples of which include starch, cellulose, sucrose, lactose, and silica. In some embodiments, such pharmaceutical compositions may further comprise one or more substances other than diluents, such as (as non-limiting examples) lubricants, colorants, coating agents, or varnishes. good.

In some embodiments, pharmaceutical compositions for parenteral administration are aqueous solutions, non-aqueous solutions, suspensions, emulsions, drops (including, by way of non-limiting example, eye drops), or any of these. It can be in combination form. In some embodiments, such pharmaceutical compositions comprise water, pharmaceutically acceptable glycols, pharmaceutically acceptable oils, pharmaceutically acceptable organic esters, or other pharmaceutically acceptable may include one or more of the solvents used. Various vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are US Pat. No. 6,261,547, US Pat. No. 6,197,934, US Pat. Patent No. 5,776,445, U.S. Patent No. 5,698,219, U.S. Patent No. 5,521,222, U.S. Patent No. 5,403,841, U.S. Patent No. 5,077,033, United States No. 4,882,150 and US Pat. No. 4,738,851, all of which are hereby incorporated by reference in their entireties.

In some embodiments, the compounds of the present disclosure, pharmaceutically acceptable salts of such compounds, and/or pharmaceutical compositions comprising such compounds and/or pharmaceutically acceptable salts thereof are VE-PTP can be administered to a mammalian subject in need of inhibiting In some embodiments, the compounds of the present disclosure, pharmaceutically acceptable salts of such compounds, and/or pharmaceutical compositions comprising such compounds and/or pharmaceutically acceptable salts thereof are VE-PTP It can be administered to a mammalian subject in need of reducing or activating mediated signaling.

In some embodiments, a compound of the disclosure, a pharmaceutically acceptable salt of such compound, and/or a pharmaceutical composition comprising such compound and/or a pharmaceutically acceptable salt thereof is a Tie2-mediated It can be administered to a mammalian subject in need of increased signaling. In some embodiments, a compound of the disclosure, a pharmaceutically acceptable salt of such compound, and/or a pharmaceutical composition comprising such compound and/or a pharmaceutically acceptable salt thereof is a Tie2-mediated It can be administered to a mammalian subject in need of treating a disorder or a VEPTP-mediated disorder.

In some embodiments, the compounds of the present disclosure, pharmaceutically acceptable salts of such compounds, and/or pharmaceutical compositions comprising such compounds and/or pharmaceutically acceptable salts thereof are used to treat cancer, It may be administered as a therapeutic treatment for one or more of ocular disease, obstructive cardiovascular disease, vascular leak syndrome, and/or other vascular-related diseases.

In some embodiments, a compound of the disclosure, a pharmaceutically acceptable salt of the compound, and/or a pharmaceutical composition comprising the compound and/or a pharmaceutically acceptable salt thereof is used to treat ocular disease. It can be administered as a therapeutic treatment.

For these therapeutic treatments, the mode(s) of administration, dosage(s), and optimized pharmaceutical form(s) are, by way of non-limiting example, compounds and/or Potency of the pharmaceutically acceptable salt of the compound, age of the patient, weight of the patient, severity of the condition(s) of the patient, patient's tolerance of the treatment, and secondary effects observed with the treatment. etc., can be determined according to criteria commonly considered during the establishment of patient treatment. Determination of dosages effective to provide therapeutic benefit for a particular mode and frequency of administration is within the capabilities of those skilled in the art.

In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 5 μg to 2,000 μg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 5 μg to 1,000 μg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 5 μg to 500 μg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 5 μg to 250 μg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 5 μg to 100 μg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 5 μg to 50 μg.

In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 1 mg to about 5,000 mg. In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 1 mg to about 3,000 mg. In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 1 mg to about 2,000 mg. In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 1 mg to about 1,000 mg. In some embodiments, a compound of this disclosure or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount from about 1 mg to about 500 mg. In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 1 mg to about 250 mg. In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 1 mg to about 100 mg. In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 1 mg to about 50 mg.

In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 5 mg to 2,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 5 mg to 1,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 5 mg-500 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 5-250 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 5 mg to 100 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 5-50 mg.

In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 10 mg to 2,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 10 mg to 1,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 10 mg-500 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 10 mg-250 mg. In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 10 mg to 100 mg. In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 10 mg to 50 mg.

In some embodiments, a compound of this disclosure or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount from about 25 mg to 2,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 25 mg to 1,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 25mg-500mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 25mg-250mg. In some embodiments, a compound of this disclosure or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount of about 25 mg-100 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 25-50 mg.

In some embodiments, a compound of this disclosure or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an amount from about 50 mg to 2,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 50 mg to 1,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 50mg-500mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 50mg-250mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 50mg-100mg.

In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 100 mg to 2,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 100 mg to 1,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 100mg-500mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 100mg-250mg.

In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 250 mg to 2,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 250 mg to 1,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount of about 250mg-500mg.

In some embodiments, a compound of this disclosure, or pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 500 mg to 2,000 mg. In some embodiments, a compound of this disclosure, or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition in an amount from about 500 mg to 1,000 mg.

In some embodiments, the compound of the disclosure, or a pharmaceutically acceptable salt thereof, is about 1 μg, about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg, about 45 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg, about 200 μg, about 225 μg, about 250 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg, about 500 μg, about 550 μg, about 600 μg, about 650 μg, about 700 μg, about 750 μg, about 800 μg, about 850 μg, about 900 μg, about 1,000 μg, about 1,100 μg, about 1,200 μg , about 1,300 μg, about 1,400 μg, about 1,500 μg, about 1,600 μg, about 1,700 μg, about 1,800 μg, about 1,900 μg, about 2,000 μg, about 2,100 μg, about 2,200 μg , about 2,300 μg, about 2,400 μg, about 2,500 μg, about 2,600 μg, about 2,700 μg, about 2,800 μg, about 2,900 μg, about 3,000 μg, about 3,100 μg, about 3,200 μg , about 3,300 μg, about 3,400 μg, about 3,500 μg, about 3,600 μg, about 3,700 μg, about 3,800 μg, about 3,900 μg, about 4,000 μg, about 4,100 μg, about 4,200 μg in the pharmaceutical composition in an amount of about 4,300 μg, about 4,400 μg, about 4,500 μg, about 4,600 μg, about 4,700 μg, about 4,800 μg, about 4,900 μg, or about 5,000 μg exist.

In some embodiments, the compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 1,000 mg, about 1,100 mg, about 1,200 mg , about 1,300 mg, about 1,400 mg, about 1,500 mg, about 1,600 mg, about 1,700 mg, about 1,800 mg, about 1,900 mg, about 2,000 mg, about 2,100 mg, about 2,200 mg , about 2,300 mg, about 2,400 mg, about 2,500 mg, about 2,600 mg, about 2,700 mg, about 2,800 mg, about 2,900 mg, about 3,000 mg, about 3,100 mg, about 3,200 mg , about 3,300 mg, about 3,400 mg, about 3,500 mg, about 3,600 mg, about 3,700 mg, about 3,800 mg, about 3,900 mg, about 4,000 mg, about 4,100 mg, about 4,200 mg , about 4,300 mg, about 4,400 mg, about 4,500 mg, about 4,600 mg, about 4,700 mg, about 4,800 mg, about 4,900 mg, or about 5,000 mg in the pharmaceutical composition. exist.

In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 0.1 mg/mL to about 100 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 0.1 mg/mL to about 10 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 0.1 mg/mL to about 5 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 0.1 mg/mL to about 3 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 0.1 mg/mL to about 2 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 0.1 mg/mL to about 1 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 0.1 mg/mL to about 0.5 mg/mL.

In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 1 mg/mL to about 100 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 1 mg/mL to about 80 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 1 mg/mL to about 60 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 1 mg/mL to about 40 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 1 mg/mL to about 30 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 1 mg/mL to about 20 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount of about 1 mg/mL to about 10 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 1 mg/mL to about 5 mg/mL.

In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 5 mg/mL to about 100 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 5 mg/mL to about 80 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 5 mg/mL to about 60 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 5 mg/mL to about 40 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 5 mg/mL to about 30 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 5 mg/mL to about 20 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 5 mg/mL to about 10 mg/mL.

In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 10 mg/mL to about 100 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 10 mg/mL to about 80 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 10 mg/mL to about 60 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 10 mg/mL to about 40 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 10 mg/mL to about 30 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 10 mg/mL to about 20 mg/mL.

In some embodiments, pharmaceutical compositions comprise a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 20 mg/mL to about 100 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 20 mg/mL to about 80 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 20 mg/mL to about 60 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 20 mg/mL to about 40 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 20 mg/mL to about 30 mg/mL.

In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 30 mg/mL to about 100 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 30 mg/mL to about 80 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 30 mg/mL to about 60 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount of about 30 mg/mL to about 40 mg/mL.

In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 40 mg/mL to about 100 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 40 mg/mL to about 80 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 40 mg/mL to about 60 mg/mL.

In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 50 mg/mL to about 100 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 50 mg/mL to about 80 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 50 mg/mL to about 60 mg/mL.

In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 60 mg/mL to about 100 mg/mL. In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 60 mg/mL to about 80 mg/mL.

In some embodiments, pharmaceutical compositions comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 70 mg/mL to about 100 mg/mL. In some embodiments, the pharmaceutical composition comprises a compound of this disclosure, or a pharmaceutically acceptable salt thereof, in an amount from about 70 mg/mL to about 80 mg/mL.

In some embodiments, the pharmaceutical composition is about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.06 mg/mL, about 0 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.5 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 5 mg /mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 60 mg /mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, or about 100 mg/mL of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

Effective amounts and dosages can be estimated initially from in vitro assays. For example, an initial dosage for use in animals can be formulated to achieve a circulating blood or serum concentration of active compound that is greater than or equal to the _IC50 for that particular compound as determined in in vitro assays. Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound is well within the capabilities of skilled artisans. For guidance, the reader may refer to Fingl & Woodbury, "General Principles," In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Pergamagon Press, and references cited therein, which methods are hereby incorporated by reference in their entireties. Initial dosages can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent various diseases described in this disclosure are well known in the art.

In one embodiment, dosages range from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but the activity of the compound, its It may be higher or lower depending on bioavailability, mode of administration, and various factors discussed above. Dosage amount and interval can be adjusted individually to provide plasma levels of the compounds that are sufficient to maintain therapeutic or prophylactic effect. For example, compounds may be administered once weekly, several times weekly (e.g., every other day), once daily, or once daily, depending on, among other things, the mode of administration, the particular indication being treated, and the judgment of the prescribing physician. Multiple doses per day can be administered. In the case of local administration or selective uptake, eg local topical administration, the effective local concentration of active compound cannot be related to the plasma concentration. Those skilled in the art will be able to optimize effective topical doses without undue experimentation.

In some embodiments, the therapeutic treatment is an amount of 5 μg, 7.5 μg, 10 μg, 12.5 μg, 15 μg, 17.5 μg, 20 μg, 22.5 μg, 25 μg, 27.5 μg, or 30 μg of the present disclosure. or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic treatment comprises 5 μg, 7.5 μg, 10 μg, 12.5 μg, 15 μg, 17.5 μg, 20 μg, 22.5 μg of a compound of the disclosure or a pharmaceutically acceptable salt thereof. , 25 μg, 27.5 μg, or 30 μg once daily of a compound of the disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic treatment is an amount of 5 μg, 7.5 μg, 10 μg, 12.5 μg, 15 μg, 17.5 μg, 20 μg, 22.5 μg, 25 μg, 27.5 μg, or 30 μg of the present disclosure. or a pharmaceutically acceptable salt thereof twice daily.

In some embodiments, the therapeutic treatment is an amount of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, or 30 mg of the present disclosure. or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic treatment is an amount of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, or 30 mg of the present disclosure. or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the therapeutic treatment is an amount of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, or 30 mg of the present disclosure. or a pharmaceutically acceptable salt thereof twice daily.

Other features and advantages of the present disclosure appear in the continuation of the description of the examples and figures whose legends are presented below.

The following non-limiting examples and data describe various aspects and aspects of the compounds and/or methods of the invention, including the preparation of various VE-PTP inhibitor compounds available through the synthetic methods described herein. characterize. Compared to the prior art, in some embodiments, the compounds and/or methods of the invention provide surprising, unexpected, and contrary results and data. While the utility of the present invention is exemplified through the use of several compounds and moieties/groups that can be used therewith, one of skill in the art will recognize various compounds such that equivalent results are commensurate with the scope of the present invention. with other compounds, moieties and/or groups.

Example 1 In Vitro PTP Inhibition The potency and specificity of the compounds of the disclosure as inhibitors of three different phosphatases was determined by measuring _IC50 values. The following methods, drawn in the present tense, were used to obtain the results described in this section.

Assay principle:
Phosphatases hydrolyze the phosphorus substrate (DiFMUP) to release the fluorophore (DiFMU). Fluorophore-DiFMU can be detected using a FlexStation multimode microplate reader with excitation at 360 nm and emission at 460 nm. Fluorescence intensity represents reaction activity.

Equipment FlexStation M5 (molecular device)
Bravo (Agilent)

Reagents and Materials:

Preparation of reagents:

Final assay conditions:
1x reaction system: 25 mM HEPES pH 7.2, 50 mM NaCl, 5 mM DTT, and 100 μg/mL BSA

procedure:
Compound dilution:
- Add 30 μL compound to undiluted well column and 20 μL DMSO to other column except 100% inhibition well - Perform 3-fold serial dilution from 10 mM/0.1 mM for 10 points by Bravo

２．２倍の基質を調製する

３．２ｕＬの化合物／ＤＭＳＯを、低対照ウェルを除く４８ｕＬの緩衝液に移す
４．５ｕＬの化合物／ＤＭＳＯ溶液を、アッセイプレートに移す
５．５ｕＬの酵素溶液をアッセイプレートに加え、２３℃で１５分間プレインキュベートする
６．バナジン酸塩を調製する：
６．１ ５０ｕＬの予め活性化されたバナジン酸を、１４０ｕＬの３０％Ｈ_２Ｏ_２に加える
６．２ ２０ｕＬのバナジン酸塩及び４０ｕＬのＤＭＳＯを、９４０ｕＬの緩衝液に加える
６．３ ５ｕＬのバナジン酸塩溶液を、１００％阻害ウェルに加える
７．１０ｕｌの基質溶液を各ウェルに加え、１０００ｒｐｍを１０秒間遠心分離し、プレートを覆い、２３℃で１２０分間インキュベートする
８．３６０ｎｍでの励起及び４６０ｎｍでの発光を伴うＦｌｅｘＳｔａｔｉｏｎ上の信号を測定する 1. Prepare 4x Enzyme Solution

2. Prepare 2x Substrate

Transfer 3.2 uL compound/DMSO to 48 uL buffer except low control wells Transfer 4.5 uL compound/DMSO solution to assay plate Add 5.5 uL enzyme solution to assay plate and incubate at 23° C. for 15 6. Pre-incubate for 1 minute. Prepare vanadate:
6.1 Add 50 uL pre-activated vanadate to 140 uL 30% _{H2O2 6.2} Add 20 uL vanadate and 40 uL DMSO to 940 uL buffer 6.3 5 uL vanadine Add acid salt solution to 100% inhibition wells 7. Add 10 ul of substrate solution to each well, centrifuge at 1000 rpm for 10 seconds, cover plate and incubate at 23° C. for 120 minutes 8. Excitation at 360 nm and 460 nm Measure the signal on the FlexStation with luminescence at

Duplicate 3-fold serial dilutions were tested for each compound. Results are summarized in Tables 2-4.

Data analysis:
Signal transferred to inhibition (%): (AVG _{0% inhibition} -signal)/(AVG _{0% inhibition} -AVG _{100% inhibition} ) x 100%
Calculate IC50 by standard 4-parameter fit method (Model 205, XL-fit)

Example 2: Preparation of solubility study buffers pH 7.4 buffer: 0.2M potassium phosphate monobasic. Dissolve 27.22 g of monobasic potassium phosphate (KH ₂ PO ₄ ) in water and dilute to 1000 mL with water. Place 50 mL of monobasic potassium phosphate solution in a 200 mL volumetric flask, add 40 mL of sodium hydroxide solution, add water to the desired volume, and adjust the pH to 7.4.

Procedure Approximately 1.5 mg of a specific compound was weighed into two vials and volumes of 150 μL of various buffers or vehicles were added for a target concentration of 10 mg/mL. All formulations were stirred at room temperature for 24 hours. After 24 hours, pH was measured and appearance was observed. Supernatants were isolated by centrifugation at 14,000 rpm for 10 minutes. All supernatants diluted with 50% acetonitrile in water were measured by HPLC.

The solubility of compounds of the present disclosure in pH 7.4 buffer is reported in Table 5.

Example 3: Screening of compounds in HUVEC The ability of compounds of the present disclosure to activate Tie2 and its downstream signaling (phosphorylated AKT kinase) in human umbilical vein endothelial cells (HUVEC) is reported below. HUVEC cells were selected to endogenously express the Tie2/TEK receptor tyrosine kinase and its negative regulator VE-PTP (Souma, T et al. (2018 Jan) Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP, Proc Natl Acad Sci USA pii: 1714446115). In HUVECs, AKT is a validated downstream signaling effector of the Tie2 receptor tyrosine kinase, and its phosphorylation is a negative inhibitor of receptor activation or upon binding of angiopoietin ligands to the receptor. Inhibition of VE-PTP increases phosphorylation (Souma, T et al. (2018 Jan) Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP, Proc Natl Ac ad Sci USA pii: 1714446115 ).
List of abbreviations BSA - bovine serum albumin ECL - enhanced chemiluminescence EDTA - ethylenediaminetetraacetic acid GAPDH - glyceraldehyde 3-phosphate dehydrogenase HRP - horse horseradish peroxidase HUVEC - human umbilical vein endothelial cell pAKT - phosphorylated serine/threonine kinase 1
PVDF - Polyvinylidene fluoride RIPA - Radioimmunoprecipitation assay buffer SDS - Sodium dodecyl sulfate TBS - Tris buffered saline

1.0 Experimental Procedures 1.1 Primary Cell Culture Human umbilical vein/vascular endothelial cells (HUV-EC-C; ATCC; CRL-1730) were processed according to the instructions provided by the ATCC product sheet document. HUVEC cells were grown in an incubator at 37° C. in 5% CO ₂ with the EndoGro LS Complete Media Kit (Millipore, SCME 001) supplemented with penicillin-streptomycin cocktail (Corning, 30-002-CI). Cells were counted using a hemocytometer a few days before the experiment and recultured to reach 60-80% confluence on the day of the experiment.
1.2 Compound Preparation All compounds were diluted in 100% dimethylsulfoxide (DMSO) (Amresco, N182) to a final 5 mM stock concentration.
1.3 Compound Testing and Sample Preparation Selected compounds were added directly to each well of a 6-well plate to achieve a final concentration of either 5 or 15 μM in 2 mL of complete HUVEC cell culture growth medium. An equal volume of DMSO (Amresco, N182) was used as vehicle control. Recombinant human angiopoietin 1 protein (923-AN) was purchased from R & D Systems. Plates were swirled gently and incubated at 37°C for 10 minutes. After the indicated treatments, media was removed and each well was washed twice with ice-cold 1×PBS (Corning, 21-031-CV). Cells were lysed using 100 μL of ice-cold RIPA buffer per well. The resulting whole cell lysate was spun down at 13,300 rpm for 5 minutes at 4° C. to remove cell debris. Supernatants were mixed with 4× Laemmli sample buffer (Bio-Rad, #161-0747) to give a final 1× concentration. Samples were then boiled at 95°C for 5 minutes and either used directly in polyacrylamide gel electrophoresis or stored at -20°C.
1.4 SDS Polyacrylamide Gel Electrophoresis Protein samples were run to Precision Plus Protein Dual Color Standard (Bio-Rad, #165-8005) using Mini-PROTEAN® Tetra Vertical Electrophoresis Cells (Bio-Rad, #165-8005). #161-0374) on a 4-12% Mini-Protean TGX Stain-Free Precast gel (Bio-Rad, #456-8086). Gels were run at 100 volts for 10 minutes followed by 200 volts for 25 minutes in 1× Tris/glycine/SDS running buffer (Bio-Rad, #161-0732).
1.5 Transfer to Membrane Protein transfer to Immun-Blot® PVDF membrane (Bio-Rad, #162-01777) was performed using mini transblot electrophoresis transfer cells (Bio-Rad, #170-3930). or 25 volts for 30 minutes using a Trans-Blot® Turbo™ transfer system (Bio-Rad, #170-4150). performed by either method. The migration sandwich was assembled after equilibrating the gel and the required amount of filter paper (Bio-Rad, #170-4085) in migration buffer for at least 15 minutes as recommended by the Bio-Rad migration guidelines. The PVDF membrane was pre-wetted in pure methanol for 20 seconds before use.
1.6 Western Blotting After transfer, the PVDF membrane was washed once with 1×TBS-T and then blocked with 5% BSA in TBS-T for 1 hour at room temperature with gentle shaking. Blocked membranes were cut according to visible marker lanes and probed simultaneously but separately for different proteins of interest. The resulting PVDF membrane streaks were treated with either the primary phospho AKT (Ser473) (D9E) XP® rabbit mAb (Cell Signaling Technology, 4060) or the primary GAPDH (D16H11) XP® rabbit mAb (Cell Signaling Technology, 4060). 5174) overnight and gently shaken at 4°C. The next day, membrane streaks were washed three times for 5 minutes with 1×TBS-T and gently shaken at room temperature. A secondary anti-rabbit HRP-conjugated IgG (Cell Signaling Technology, 7074) antibody was applied for 1 hour at room temperature with gentle shaking. Membranes were then washed three times for 5 minutes in 1×TBS-T at room temperature with shaking. Additionally, to prevent residual phosphatase activity, a phosphatase inhibitor cocktail was added to the wash buffer at a dilution of 1:10,000 during all wash steps. In a final step, membranes were incubated with Clarity Western ECL substrate (Bio-Rad, #170-5060), chemiluminescent signals were detected and digitally imaged using a high resolution Amersham Imager 600 (GE Healthcare).
2.0 Buffer Compositions All buffers were prepared using stock solutions ordered directly from the manufacturer.
Radioimmunoprecipitation Assay Buffer (RIPA):
50 mM Tris-Cl (pH 8.0)
150 mM NaCl
1% IGEPAL CO-630
0.5% sodium deoxycholate 0.1% SDS
5 mM EDTA
Phosphatase inhibitor cocktail x 1
Protease inhibitor cocktail x 1
Gel electrophoresis buffer: 25 mM Tris, 192 mM glycine, and 0.1% SDS, pH ~8.6
Migration buffer: 25 mM Tris, 192 mM glycine, 20% (V/V) methanol Tris-buffered saline-Tween-20 (TBS-T): 50 mM Tris pH 7.4, 150 mM NaCl, and 0.5 mM Tris pH 7.4; 01% (v/v)) Tween-20
Blocking buffer: 5% BSA (w/v) in 1x TBS-T

Figures 1-6 show Western blot analysis performed according to the protocol described above. Compounds with IC ₅₀ for VE-PTP in the activity range of 0.1-5 nM were dissolved in DMSO and used to treat human umbilical vein endothelial cells (HUVEC).

HUVEC cells treated with the indicated concentrations of specific compounds for 10 min were used in whole cell lysate Western blot analysis to inhibit VE-PTP, activate the Tie2 signaling cascade, and induce serine/threonine-specific proteins. The efficacy of compounds leading to increased downstream phosphorylation of the kinase AKT/PKB was determined. The glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as a loading control. The results shown in Figures 1-5 represent two biological replicates for each compound. As shown in the Western blot images, certain compounds were much more effective at inducing AKT phosphorylation than others, despite being in the same _IC50 activity range for VE-PTP. be. As evidenced by Western blots, some compounds had the same or slightly higher levels of pAKT induction than the tested concentrations of DMSO, while others produced more pronounced responses.

FIG. 6 shows the results of dose-response titration experiments with compounds selected over the range 0.2-50 μM, demonstrating a clear dose-response relationship. Angiopoietin 1 (600 ng/mL) is the cognate ligand of the Tie2 receptor and is used to activate the Tie2 signaling pathway.

Example 4 Ocular Penetration Potent and soluble compounds 1, 2, 3 (Diastereomer 1), 3 (Diastereomer 2), 5, 16, and 17 administered topically to the rat eye as a single dose were , an ocular penetration test was performed to see if it was present in the aqueous humor 30 minutes after treatment.

All locally delivered compounds were detected in the aqueous humor after dosing. The compounds varied in performance, with compound 16 performing the best, achieving 25.08 ng/mL in the aqueous humor. This compound also exhibited the highest solubility of all compounds tested. Ultimately, its IC ₅₀ was determined to be 15-20 nM.

Protocol for Ocular Penetration and Bioanalysis Fifteen-week-old brown Norwegian rats obtained from Charles River were used for eye penetration experiments. Rats were fed ad libitum, housed in polycarbon cages, and direct contact bedding was changed as necessary to keep animals dry, clean, and to minimize odors. Environmental controls were set to maintain temperature, humidity, and a 12 hour light/dark cycle. All animals were checked for general health by animal facility staff and studies were conducted according to protocol and the Guide for the Care and Use of Laboratory Animals.

Compounds 1, 2, 3, 5, 16, and 17 were dissolved in 50 mM PBS pH 7.4 at maximum formulatable concentrations ranging from 5-15 mg/mL with a dose volume of 6 uL per eye. Delivered locally. Four rats per group were used, bilateral doses were administered into the central cornea using a calibrated micropipette, and a total of 8 eyes per group were collected after euthanasia. The rat was kept eyeing the treatment for several seconds before releasing the animal. After receiving a single dose per eye, the eye and aqueous humor were collected 30 minutes after dosing and immediately frozen.

After treatment, rats were euthanized by _CO2 inhalation, followed by thoracotomy according to accepted American Veterinary Medical Association guidelines. Eyes were washed with a balanced saline solution immediately after confirmation of death. Aqueous humor was collected from both eyes of each animal, flash-frozen in liquid nitrogen and stored in a −80° C. freezer. All tissues were then shipped on dry ice for bioanalysis. Mass spectrometric and chromatographic methods were established to separate, detect and quantify each compound used in the study. Aqueous humor samples were analyzed to detect and calculate the concentration of each analyte, then each analyte was averaged and expressed as ng/mL per compound group.

Example 5 Synthesis of Exemplary Compounds of the Disclosure Synthesis of Compound 1


A mixture of (S)-2-amino-3-(pyridin-4-yl)propanoic acid (4.50 g, 27.08 mmol, 1.00 eq) in MeOH (20.00 mL) was cooled to 0°C. Then sulfur dichloride (86.44 g, 54.16 mmol, 3.93 mL, 2.00 eq) was added dropwise, then the mixture was heated to 60° C. and stirred at 60° C. for 5 hours. The reaction was monitored upon completion by LCMS and the solution was concentrated in vacuo to yield (S)-methyl 2-amino-3-(pyridin-4-yl)propanoate (6.00 g, crude), white Obtained as a solid. LCMS: m/z = 181.1 (M+H ⁺ ).

A mixture of (S)-methyl 2-amino-3-(pyridin-4-yl)propanoate (6.00 g, 23.70 mmol, 1.00 eq, 2HCl) in DCM (20.0 mL) was brought to 0°C. Cool, then add diisopropylethylamine (12.25 g, 94.80 mmol, 16.55 mL, 4.00 eq) dropwise followed by methyl carbonochloridate (2.24 g, 23.70 mmol, 1.84 mL, 1.00 eq.) was added at 0° C. and the mixture was warmed to 10° C. and stirred at 10° C. for 1 hour. The reaction was monitored for completion by TLC, the mixture was poured into water (50 mL), extracted with DCM (3 x 50 mL), the organic phase was washed with brine (100 mL), dried over _{anhydrous Na2SO4} , Filtered and concentrated in vacuo to give crude material. The crude was purified by column chromatography (SiO ₂ , dichloromethane:methanol=10:1) to give (S)-methyl 2-((methoxycarbonyl)amino)-3-(pyridin-4-yl)propanoate ( 2.60 g, 46%), obtained as an off-white oil.

To a solution of (S)-methyl 2-((methoxycarbonyl)amino)-3-(pyridin-4-yl)propanoate (1.30 g, 5.46 mmol, 1.00 eq) in DMF (10.00 mL) , iodomethane (1.16 g, 8.19 mmol, 509.86 uL, 1.50 eq) was added, the mixture was cooled to 0° C., then sodium hydride (327.40 mg, 8.19 mmol, 60% pure, 1 .50 equivalents) was added at 0°C and the mixture was stirred at 0°C for 1 hour. The reaction was monitored for completion by TLC, the solution was poured into saturated _NH4Cl (50 mL), extracted with ethyl acetate (3 x 50 mL), the organic phase was washed with brine (100 mL) and anhydrous _Na2SO Dried at ₄ , filtered and concentrated in vacuo to give crude material. The crude was purified by column chromatography (SiO ₂ , dichloromethane:methanol=100:1 to 10:1) to give (S)-methyl 2-((methoxycarbonyl)(methyl)amino)-3-(pyridine -4-yl)propanoate (1.00 g, 33%) was obtained as a brown oil.

(S) _-Methyl 2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanoate (1.00 g, 3.96 mmol, 1.00 eq.) was cooled to 0° C., then lithium hydroxide hydrate (199.39 mg, 4.75 mmol, 1.20 eq.) was added at 0° C. and the mixture was brought to 20° C. C. and stirred at 20.degree. C. for 16 hours. The reaction was monitored for completion by TLC and the solution was lyophilized to give lithium (S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanoate (800.00 mg, crude), obtained as a yellow solid. LCMS: m/z = 239.0 (M+H ⁺ ).

Lithium (S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanoate (700.00 mg, 2.87 mmol, 1.00 equiv) in DMF (5.00 mL) and (S)-2-(4-nitrophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (591.03 mg, 1.43 mmol, 0.50 eq) 1H-benzo[d][1,2,3]triazol-1-ol (387.37 mg, 2.87 mmol, 1.00 equiv.) was added, then the mixture was cooled to 0° C. and diisopropylethylamine (741.02 mg, 5.73 mmol, 1.00 mL, 2.00 eq) was added dropwise followed by N ¹ -((ethylimino)methylene)-N ³ ,N ³ -dimethylpropane-1,3-diamine hydrochloride. (549.58 mg, 2.87 mmol, 1.00 eq) was added at 0° C. and the mixture was warmed to 15° C. and stirred at 15° C. for 5 hours. The reaction was monitored for completion by LCMS and TLC, the solution was poured into water (15 mL), extracted with ethyl acetate (3 x 10 mL), the organic phase was washed with brine (20 mL) and dried over anhydrous _{Na2SO4 .} Dried, filtered and concentrated in vacuo to give crude material. The crude was purified by column chromatography (SiO ₂ , dichloromethane:methanol=20:1) to give methyl ((S)-1-(((S)-2-(4-nitrophenyl)-1-( yielding 2-(thiophen-2-yl)thiazol-4-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)carbamate (600.00 mg, 38%) and obtained as a brown oil. LCMS: m/z = 552.2 (M+H ⁺ ).

Methylmethyl ((S)-1-(((S)-2-(4-nitrophenyl)-1-(2-(thiophen-2-yl) in EtOH (6.00 mL) and H ₂ O (2 mL) ) thiazol-4-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)carbamate (600.00 mg, 1.09 mmol, 1.00 equiv), NH ₄ Cl (290.90 mg, 5.44 mmol, 5.00 eq) was added, the mixture was heated to 80° C., Fe (303.73 mg, 5.44 mmol, 5.00 eq) was added at 80° C. and the mixture was was stirred at 80° C. for 3 hours. The reaction was monitored by TLC when complete, the solution was filtered, and the filtrate was concentrated in vacuo to give crude material. The crude is dissolved in water (10 mL), extracted with DCM (3 x 10 mL), the organic phase is washed with brine ( ₂₀ mL), dried over anhydrous _Na2SO4 , concentrated in vacuo and methyl ( (S)-1-(((S)-2-(4-aminophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)amino)-1-oxo-3- (Pyridin-4-yl)propan-2-yl)(methyl)carbamate (400.00 mg, crude) was obtained as a white solid. LCMS: m/z = 521.9 (M+H ⁺ ).

Methyl ((S)-1-(((S)-2-(4-aminophenyl)-1-(2-(thiophen-2-yl)) in pyridine (2.00 mL) and MeCN (2.00 mL) A solution of thiazol-4-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)(methyl)carbamate (400.00 mg, 766.80 umol, 1.00 equiv) was cooled to 0° C., then sulfur trioxide pyridine complex (366.13 mg, 2.30 mmol, 3.00 eq) was added batchwise at 0° C. and the mixture was stirred at 0° C. for 5 minutes. The reaction was monitored by LCMS when complete, 7% ammonium hydroxide (5 mL) was added to the solution, the solution was stirred at 0° C. for 20 min, then the mixture was dried by flushing with N ₂ to give a residue. rice field. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18 250*50mm*10um; mobile phase: [water ( _{10mM NH4HCO3} )-ACN]; B%: 20%-50%, 23 min), Ammonium (4-((S)-2-((S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanamide)-2-(2-(thiophene- Yield 2-yl)thiazol-4-yl)ethyl)phenyl)sulfamate (94.97 mg, 21%) as a white solid. LCMS: m/z = 602.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.33-8.49 (m, 3H) 7.68-7.72 (m , 1H) 7.60-7.64 (m, 1H) 7.17-7.29 (m, 4H) 7.1-7.17 (m, 1H) 7.02-7.10 (m, 1H) ) 6.93-6.99 (m, 1H) 6.83-6.92 (m, 4H) 5.05-5.20 (m, 1H) 4.78-5.04 (m, 1H) 3 .34-3.55 (m, 3H) 3.02-3.19 (m, 2H) 2.80-2.98 (m, 2H) 2.57 (s, 3H).

Synthesis of compound 2


A solution of diethyl 2-acetamidomalonate (14.00 g, 64.45 mmol, 1.00 eq) in DMF (50 mL) was cooled to 0° C. and then sodium hydride (150.00 mL) in DMF (150.00 mL). 7.73 g, 193.35 mmol, 60% purity, 3.00 eq) and 3-(bromomethyl)pyridine (16.30 g, 64.45 mmol, 1.00 eq) were added and the mixture was stirred at 0° C. for 2 hours. . The reaction was monitored for completion by TLC, the solution was poured into water (400 mL), extracted with ethyl acetate (3 x 400 mL), the combined organic phases were washed with _H2O (3 x 400 mL) and combined. The organic phase was washed with brine (1000 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give diethyl 2-acetamido-2-(pyridin-3-ylmethyl)malonate (11.86 g, crude), obtained as a yellow solid.

A solution of diethyl 2-acetamido-2-(pyridin-3-ylmethyl)malonate (11.86 g, 38.47 mmol, 1.00 eq) in EtOH (230.82 mL) was cooled to 0° C. and then treated with water. Sodium oxide (6M, 16.03 mL, 2.50 eq) was added, then the mixture was warmed to 15° C. and stirred at 15° C. for 1.5 hours. The reaction was monitored upon completion by TLC, _N2 was bubbled through the solution to remove solvent, the crude was dissolved in water (60 mL) and the solution was acidified with aqueous HCl (10 M, 9.62 mL). turned into The solution was concentrated in vacuo to yield 2-acetamido-2-(pyridin-3-ylmethyl)malonic acid (11.86 g, crude) as a brown solid.

A solution of 2-acetamido-2-(pyridin-3-ylmethyl)malonic acid (11.00 g, 38.10 mmol, 1.00 eq) in H ₂ O (120.00 mL) was heated to 110° C. and 110 C. for 15 hours. The reaction was monitored when complete by LCMS and the solution was concentrated in vacuo to yield 2-acetamido-3-(pyridin-3-yl)propanoic acid (9.00 g, crude) as a brown solid. . LCMS: m/z = 209.0 (M+H ⁺ ).

A solution of 2-acetamido-3-(pyridin-3-yl)propanoic acid (9.00 g, 36.78 mmol, 1.00 eq) in hydrogen chloride (5 M, 140.00 mL) was heated to 100° C. Stir at 100° C. for 4 hours. The reaction was monitored upon completion by LCMS and the solution was concentrated in vacuo to afford 2-amino-3-(pyridin-3-yl)propanoic acid (6.50 g, 87%) as a brown solid. . LCMS: m/z = 167.0 (M+H ⁺ ).

A solution of 2-amino-3-(pyridin-3-yl)propanoic acid (6.20 g, 37.31 mmol, 1.00 eq) in MeOH (100.00 mL) was cooled to 0° C. and then Sulfur chloride (13.32 g, 111.93 mmol, 8.12 mL, 3.00 eq) was added at 0° C., then the mixture was heated to 60° C. and stirred at 60° C. for 10 hours. The reaction was monitored when complete by LCMS and the solution was concentrated in vacuo to yield methyl 2-amino-3-(pyridin-3-yl)propanoate (6.00 g, crude) as a brown solid. . LCMS: m/z = 181.1 (M+H ⁺ ).

A solution of methyl 2-amino-3-(pyridin-3-yl)propanoate (6.00 g, 27.69 mmol, 1.00 eq) in DCM (150.00 mL) was cooled to 0° C. and then treated with N - Ethyl-N-isopropylpropan-2-amine (14.32 g, 110.77 mmol, 19.29 mL, 4.00 eq) was added followed by methyl carbonochloridate (2.62 g, 27.69 mmol, 2.00 eq). 14 mL, 1 eq.) was added dropwise and the mixture was warmed to 15° C. and stirred at 15° C. for 1 hour. The reaction was monitored for completion by LCMS and TLC, the solution was poured into water (100 mL), extracted with DCM (3 x 100 mL), the combined organic layers were washed with brine (10 mL) and _Na2SO . Dried at ₄ , filtered and concentrated in vacuo to give crude. The crude was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=1:1) to give methyl 2-((methoxycarbonyl)amino)-3-(pyridin-3-yl)propanoate (2. 90 g, 40%), obtained as a brown oil. LCMS: m/z = 239.0 (M+H ⁺ ).

Iodomethane (2 .59 g, 18.26 mmol, 1.14 mL, 1.50 eq.) was added and the mixture was then cooled to 0° C. followed by sodium hydride (730.36 mg, 18.26 mmol, 60% pure, 1.50 equivalent) was added at 0° C. and the mixture was warmed to 15° C. and stirred at 15° C. for 1 hour. The reaction was monitored for completion by LCMS, the solution was poured into saturated _NH4Cl (60 mL), extracted with ethyl acetate (3 x 60 mL), the combined organic layers were washed with brine (100 mL) and _Na2. Dry over SO ₄ , filter, and concentrate in vacuo to yield methyl 2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-3-yl)propanoate (1.68 g, 55%). and obtained as a brown oil. LCMS: m/z = 253.0 (M+H ⁺ ).

Methyl 2-(( _{methoxycarbonyl} )(methyl)amino)-3-(pyridin-3-yl)propanoate (1.68 g, 6.66 mmol, 1.00 eq.) was cooled to 0° C. and then LiOH. H ₂ O (335.33 mg, 7.99 mmol, 1.20 eq) was added at 0° C. and the mixture was warmed to 15° C. and stirred at 15° C. for 16 hours. The reaction was monitored for completion by LCMS and the solution was concentrated in vacuo to afford 2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-3-yl)propanoate (1.20 g, crude). Obtained as a brown solid. LCMS: m/z = 239.0 (M+H ⁺ ).

Lithium 2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-3-yl)propanoate (1.20 g, 4.91 mmol, 1 eq) and (S)-2 in DMF (10.0 mL) To a solution of -(4-nitrophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (1.01 g, 2.46 mmol, 0.5 eq) was added 1H- Benzo[d][1,2,3]triazol-1-ol (664.06 mg, 4.91 mmol, 1.00 equiv.) was added, the mixture was cooled to 0° C., and then N-ethyl-N-isopropionate was added. pan-2-amine (1.27 g, 9.83 mmol, 1.71 mL, 2.00 eq) and N ¹ -(ethylimino)methylene-N , ^{N 3} -dimethylpropane-1,3-diamine hydrochloride (942 .12 mg, 4.91 mmol, 1.00 eq.) was added at 0° C. and the mixture was warmed to 15° C. and stirred at 15° C. for 5 hours. The reaction was monitored for completion by LCMS and TLC, the solution was poured into water (50 mL), extracted with ethyl acetate (3 x 50 mL), the combined organic layers were washed with brine (80 mL) and _{Na2SO4 .} , filtered and concentrated in vacuo to give crude material. The crude was purified by column chromatography (SiO ₂ , dichloromethane:methanol=20:1) to give methyl (1-(((S)-2-(4-nitrophenyl)-1-(2-(thiophene -2-yl)thiazol-4-yl)ethyl)amino)-1-oxo-3-(pyridin-3-yl)propan-2-yl)carbamate (1.00 g, 37%), a brown oil. obtained as LCMS: m/z = 552.0 (M+H ⁺ ).

Methylmethyl (1-(((S)-2-(4-nitrophenyl)-1-(2-(thiophen-2-yl)thiazole) in EtOH (9.0 mL) and H ₂ O (3.0 mL) -4-yl)ethyl)amino)-1-oxo-3-(pyridin-3-yl)propan-2-yl)carbamate (1.00 g, 1.81 mmol, 1 eq) was added with NH ₄ Cl ( 484.83 mg, 9.06 mmol, 5 eq) was added, then the mixture was heated to 80° C., Fe (506.22 mg, 9.06 mmol, 5 eq) was added and the mixture was stirred at 80° C. for 3 hours. The reaction was monitored by LCMS and TLC when complete, the solution was filtered and the filtrate was concentrated in vacuo to give the crude. The crude was subjected to preparative TLC (dichloromethane:methanol=15:1) and preparative_HPLC (column: DuraShell 150*25mm*5um; mobile phase: [water (0.1% TFA)-ACN]; B%:1 %-40%, 8 min) to give 14_Diastereomer 1 (0.12 g, 13%) to yield 14_Diastereomer 2 (0.08 g, 8%) as a brown oil. rice field. LCMS: m/z = 522.1 (M+H ⁺ ).

Diastereoisomer 1:
A solution of 14_diastereomer 1 (0.30 g, 575.09 umol, 1.00 equiv.) in pyridine (2.0 mL) and CH ₃ CN (2.0 mL) was cooled to 0° C. followed by sulfur trioxide. Pyridine complex (274.60 mg, 1.73 mmol, 3.00 eq) was added at 0° C. and the mixture was stirred at 0° C. for 5 minutes. The reaction was monitored by LCMS when complete, 7% ammonium hydroxide (6 mL) was added dropwise, then the mixture was dried by blowing _N2 to give a residue. The residue was purified by preparative HPLC (Column: Phenomenex Gemini C18 250*50 10 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 12%-42%, 20 min) and ammonium (4-((2S)-2-(2-methoxycarbonyl)(methyl)amino)-3-(pyridin-3-yl)propanamide)-2-(2-(thiophen-2-yl)thiazole-4 -yl)ethyl)phenyl)sulfamate diastereomer 1 (165.20 mg, 45%) was obtained as a white solid. LCMS: m/z = 602.0 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.37-8.58 (m, 3H) 7.80-7.90 (m , 1H) 7.68-7.77 (m, 1H) 7.60-7.67 (m, 1H) 7.4-7.50 (m, 1H) 7.24-7.29 (m, 1H) ) 7.22 (s, 1H) 7.17 (dd, J = 4.89, 3.79Hz, 1H) 7.09 (s, 1H) 6.96 (s, 1H) 6.91 (s, 3H ) 5.07-5.25 (m, 1H) 4.75-5.03 (m, 1H) 3.50 (s, 2H) 3.34 (s, 1H) 3.14-3.22 (m , 1H) 3.05-3.13 (m, 1H) 2.86-2.99 (m, 2H) 2.57 (s, 3H).

Diastereoisomer 2:
A solution of 14_diastereomer 2 (240.00 mg, 460.08 umol, 1.00 eq) in pyridine (2.0 mL) and MeCN (2.0 mL) was cooled to 0° C. and then sulfur trioxide pyridine complex (219.68 mg, 1.38 mmol, 3.00 eq) was added at 0° C. and the mixture was stirred at 0° C. for 5 minutes. 7% ammonium hydroxide (4 mL) was added dropwise, then the mixture was dried by blowing _N2 to give a residue. The crude was purified by preparative HPLC (column: Phenomenex Gemini C18 250*50 10 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 12%-42%, 20 min), Ammonium (4-((2S)-2-(2-methoxycarbonyl)(methyl)amino)-3-(pyridin-3-yl)propanamide)-2-(2-(thiophen-2-yl)thiazole- 4-yl)ethyl)phenyl)sulfamate diastereomer 2 (101.50 mg, 34%) was obtained as a white solid. LCMS: m/z = 602.0 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 8.50 (s, 1H) 8.41 (s, 1H) 8.30-8 .38 (m, 1H) 7.80-8.00 (m, 1H) 7.57-7.61 (m, 1H) 7.53-7.57 (m, 2H) 7.16 (s, 1H) ) 7.13 (dd, J=5.01, 3.79Hz, 1H) 6.99-7.07 (m, 4H) 5.23-5.37 (m, 1H) 4.70-4.83 (m, 1H) 3.45-3.66 (m, 3H) 3.15-3.28 (m, 2H) 2.86-3.03 (m, 2H) 2.78 (s, 3H).

Synthesis of compound 3


A solution of diethyl 2-acetamidopropanedioate (16.08 g, 74.02 mmol, 1.04 eq) in DMF (4.0 mL) was cooled to 0° C. and then sodium hydride (160 mL) in DMF (160 mL). 8.54 g, 213.51 mmol, 60% purity, 3.00 eq.) and 2-(bromomethyl)pyridine (18.00 g, 71.17 mmol, 1.00 eq., HBr) were added and the mixture was stirred at 0° C. for 2 hours. Stirred. The reaction was monitored upon completion by TLC, the solution was poured into saturated NH ₄ Cl (500 mL), extracted with ethyl acetate (3×500 mL), the combined organic phases washed with brine (1000 mL), and anhydrous Na Dried over ₂ SO ₄ , filtered and concentrated in vacuo. The residue was washed with petroleum ether (150 mL), filtered, and the filter cake was dried in vacuo to yield diethyl 2-acetamido-2-(pyridin-2-ylmethyl)malonate (12.95 g, crude). , obtained as a yellow solid.

A solution of diethyl 2-acetamido-2-(pyridin-2-ylmethyl)malonate (12.95 g, 42.00 mmol, 1.00 eq) in EtOH (150 mL) was cooled to 0° C. and then sodium hydroxide. (6 M, 17.50 mL, 2.50 eq) was added and the mixture was warmed to 15° C. and stirred at 15° C. for 1.5 hours. The reaction was monitored by LCMS when completed and the solution was dried by blowing _N2 . The residue was dissolved in water (80 mL) and acidified with aqueous hydrogen chloride (10 M, 10.5 mL). The solution was concentrated in vacuo to yield 2-acetamido-2-(pyridin-2-ylmethyl)malonic acid (12.00 g, crude) as a brown solid.

A solution of 2-acetamido-2-(pyridin-2-ylmethyl)malonic acid (12.00 g, 41.57 mmol, 1.00 equiv. HCl) in H ₂ O (120 mL) was heated to 100° C. and 100 C. for 15 hours. The reaction was monitored when complete by LCMS and the solution was concentrated in vacuo to yield 2-acetamido-3-(pyridin-2-yl)propanoic acid (9.00 g, crude) as a brown solid. . LCMS: m/z = 209.0 (M+H ⁺ ).

A solution of 2-acetamido-3-(pyridin-2-yl)propanoic acid (9.00 g, 36.78 mmol, 1.00 equiv. HCl) in hydrogen chloride (5 M, 140.00 mL) was heated to 100°C. , and stirred at 100° C. for 4 hours. The reaction was monitored when completed by TLC and the solution was concentrated in vacuo to yield 2-amino-3-(pyridin-2-yl)propanoic acid (7.00 g, crude) as a brown solid. .

A solution of 2-amino-3-(pyridin-2-yl)propanoic acid (6.8 g, 33.56 mmol, 1.00 equiv. HCl) in MeOH (5.00 mL) was cooled to 0° C. and then , thionyl chloride (7.98 g, 67.11 mmol, 4.87 mL, 2.00 eq) was added, then the mixture was heated to 60° C. and stirred at 60° C. for 10 hours. The reaction was monitored for completion by LCMS and the solution was concentrated in vacuo to afford methyl 2-amino-3-(pyridin-2-yl)propanoate (7 g, crude) as a yellow solid. LCMS: m/z = 180.9 (M+H ⁺ ).

A solution of methyl 2-amino-3-(pyridin-2-yl)propanoate (7 g, 32.31 mmol, 1.00 equiv. HCl) in DCM (20 mL) was cooled to 0° C. and then diisopropylethylamine ( 16.70 g, 129.23 mmol, 22.57 mL, 4.00 eq.) and methyl carbonochloridate (3.05 g, 32.31 mmol, 2.50 mL, 1.00 eq.) were added dropwise at 0° C. and the mixture was warmed to 15° C. and stirred at 15° C. for 1 hour. The reaction was monitored upon completion by TLC, the solution was poured into water (50 mL), extracted with DCM (3 x 50 mL), the combined organic phases were washed with brine (100 mL) and dried over _{anhydrous Na2SO4} . , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO ₂ , dichloromethane:methanol=100:1 to 20:1) to give methyl 2-((methoxycarbonyl)amino)-3-(pyridin-2-yl)propanoate ( 3.5 g, 44%), obtained as a brown solid.

To a solution of methyl 2-((methoxycarbonyl)amino)-3-(pyridin-2-yl)propanoate (3.5 g, 14.69 mmol, 1.00 eq) in DMF (20 mL) was added iodomethane (3.13 g , 22.04 mmol, 1.37 mL, 1.50 eq) was added, then the mixture was cooled to 0° C. and sodium hydride (881.47 mg, 22.04 mmol, 60% purity, 1.50 eq) was added. The mixture was then warmed to 15°C and stirred at 15°C for 1 hour. The reaction was monitored upon completion by LCMS, the solution was poured into saturated NH ₄ Cl (50 mL), extracted with ethyl acetate (3×50 mL), the combined organic layers were washed with brine (100 mL) and dried over anhydrous Na. ₂ SO ₄ , filtered and concentrated in vacuo to give methyl 2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-2-yl)propanoate (2.5 g, crude). Obtained as a brown solid. LCMS: m/z = 253.2 (M+H ⁺ ).

Methyl 2-(( _{methoxycarbonyl} )(methyl)amino)-3-(pyridin-2-yl)propanoate (2.5 g, 9.91 mmol, 1.00 eq.) was cooled to 0° C., then lithium hydroxide hydrate (499.00 mg, 11.89 mmol, 1.20 eq.) was added at 0° C., then the mixture was brought to 15° C. Warmed and stirred at 15° C. for 16 hours. The reaction was monitored when complete by LCMS and the solution was concentrated in vacuo to give lithium 2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-2-yl)propanoate (1.8 g, crude). was obtained as a brown solid. LCMS: m/z = 239.2 (M+H ⁺ ).

Lithium 2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-2-yl)propanoate (1.8 g, 7.37 mmol, 1.00 eq) and (S)-2 in DMF (20 mL) To a solution of -(4-nitrophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (1.52 g, 3.69 mmol, 0.50 eq) was added 1H- Benzo[d][1,2,3]triazol-1-ol (996.08 mg, 7.37 mmol, 1.00 eq) was added and the mixture was then cooled to 0° C. and diisopropylethylamine (1.91 g, 14.74 mmol, 2.57 mL, 2.00 eq) and N ¹ -((ethylimino)methylene-N ³ ,N ³ -dimethylpropane-1,3-diamine hydrochloride (1.41 g, 7.37 mmol, 1.41 g, 7.37 mmol, 1.00 eq). 00 eq.) was added dropwise at 0° C., then the mixture was warmed to 15° C. and stirred for 5 h at 15° C. The reaction was monitored by LCMS and TLC when complete, the solution was poured into water (60 mL), Extract with ethyl acetate (3 x 40 mL), wash the organic phase with water (2 x 40 mL), wash the combined organic phase with brine ( ₁₀₀ mL), dry over anhydrous _Na2SO4 , filter and vacuum. The residue was purified by column chromatography (SiO ₂ , dichloromethane:methanol=100:1 to 20:1) to give methylmethyl (1-(((S)-2-(4-nitrophenyl )-1-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)amino)-1-oxo-3-(pyridin-2-yl)propan-2-yl)carbamate (1.40 g, Crude) was obtained as a brown oil, LCMS: m/z = 552.1 (M+H ⁺ ).

Methylmethyl (1-(((S)-2-(4-nitrophenyl)-1-(2-(thiophen-2-yl)thiazole) in EtOH (10.0 mL) and H ₂ O (3.0 mL) -4-yl)ethyl)amino)-1-oxo-3-(pyridin-2-yl)propan-2-yl)carbamate (1.40 g, 2.54 mmol, 1 eq) was added with NH ₄ Cl ( 135.75 mg, 2.54 mmol, 1 eq) was added, then the mixture was heated to 80° C., then Fe (141.74 mg, 2.54 mmol, 1 eq) was added and the mixture was stirred at 80° C. for 3 h. bottom. The reaction was monitored for completion by LCMS, the solution was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (10 mL), filtered and the filtrate was concentrated in vacuo. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate=0:1) and preparative HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.1% TFA)-ACN]; B%: 10%-30%, 10 min) to yield 10_diastereoisomer 1 (0.15 g, 18%) as a brown oil, LCMS: m/z=522.3 (M+H ⁺ ). and 10_diastereoisomer 2 (0.1 g, 18%) was obtained as a brown oil. LCMS: m/z = 522.3 (M+H+).

Diastereoisomer 1:
A solution of 10_diastereoisomer 1 (200.00 mg, 383.40 umol, 1.00 equiv.) in pyridine (2.0 mL) and MeCN (2.0 mL) was cooled to 0° C. followed by sulfur trioxide. Pyridine complex (183.06 mg, 1.15 mmol, 3.00 eq) was added batchwise and the mixture was stirred at 0° C. for 5 minutes. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (4 mL) was added slowly, then the mixture was dried by blowing _N2 . The residue was purified by preparative_HPLC (column: Phenomenex Gemini C18 250*50 10 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 15%-45%, 20 min) and ammonium (4-((2S)-2-(2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-2-yl)propanamide)-2-(2-(thiophen-2-yl)thiazole) -4-yl)ethyl)phenyl)sulfamate diastereoisomer 1 (0.074 g, 31%) was obtained as a white solid. LCMS: m/z = 602.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol- _d ) δ = 8.46 (brd, J = 4.85 Hz, 1H) 7.86 (brs, 1H) ) 7.57 (dd, J=11.14, 4.30 Hz, 2H) 7.24-7.48 (m, 2H) 6.98-7.17 (m, 6H) 5.32 (brdd, J = 9.37, 5.84Hz, 1H) 4.98-5.20 (m, 1H) 3.45-3.69 (m, 3H) 3.39 (brd, J = 13.89Hz, 1H) 3 .24 (brd, J=9.26Hz, 1H) 2.95-3.15 (m, 2H) 2.54-2.74 (m, 3H).

Diastereoisomer 2:
A solution of 10_diastereoisomer 2 (180.00 mg, 345.06 umol, 1.00 eq) in pyridine (2.00 mL) and CH ₃ CN (2.00 mL) was cooled to 0° C. Sulfur oxide pyridine complex (164.76 mg, 1.04 mmol, 3.00 eq) was added batchwise and the mixture was stirred at 0° C. for 5 minutes. The reaction was monitored by LCMS for completion and 7% ammonium hydroxide (4 mL) was added slowly, then the mixture was dried by blowing _N2 to give a residue. The residue was purified by preparative_HPLC (Column: Phenomenex Gemini C18 250*50 10 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 12%-42%, 20 min) and ammonium (4-((2S)-2-(2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-2-yl)propanamide)-2-(2-(thiophen-2-yl)thiazole) -4-yl)ethyl)phenyl)sulfamate (70.70 mg, 34%) was obtained as a white solid. LCMS: m/z = 602.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol- _d ) δ = 8.52 (d, J = 4.77 Hz, 1H) 7.93 (brs, 1H) ) 7.54-7.64 (m, 2H) 7.41 (brs, 2H) 7.15 (dd, J = 5.01, 3.79Hz, 2H) 6.97-7.11 (m, 4H) ) 5.32 (dd, J = 8.93, 6.11 Hz, 1H) 5.05 (brs, 1H) 3.45-3.68 (m, 3H) 3.37 (brs, 1H) 3.17 -3.29 (m, 1H) 2.93-3.16 (m, 2H) 2.80 (s, 3H).

Synthesis of compound 4


Carbonyldi-imidazole (20.64 g, 127.29 mmol, 1 eq) in DCM (50 mL) was treated with 3,3,3-trifluoropropanoic acid (16.3 g, 127.29 mmol, 11 .24 mL, 1 eq.) at 25° C., then the mixture was heated to 40° C. and refluxed at 40° C. for 0.5 h. The mixture was then cooled to 25° C., ammonia (2.17 g, 127.29 mmol, 2.13 mL, 1 eq) was added and stirred at 25° C. for an additional 0.5 hour. The reaction was monitored by LCMS for completion and the reaction mixture was poured into aqueous HCl (2N, 100 mL) and extracted with ethyl acetate (2 x 60 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to yield 3,3,3-trifluoropropanamide (10 g, crude). , was obtained as a white solid. LCMS: m/z = 128.0 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 7.63 (s, 1H) 7.27 (s, 1H) 3.19 (q , J=11.40 Hz, 2H).

A mixture of 3,3,3-trifluoropropanamide (5 g, 39.35 mmol, 1 eq), Lawesson's reagent (19.10 g, 47.22 mmol, 1.2 eq) and THF (50 mL) was degassed and ₂ three times, then the mixture was stirred at 25° C. for 13 h under N ₂ atmosphere. After the reaction was monitored by TLC for completion, the reaction mixture was diluted with saturated NaHCO ₃ (150 mL) and extracted with ethyl acetate (3×60 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20:1 to 5:1) to yield 3,3,3-trifluoropropanethioamide (2.7 g, 48%). , obtained as a yellow solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ=7.97 (brs, 1H) 7.27 (brs, 1H) 3.60 (q, J=10.36 Hz, 2H).

(S)-tert-butyl (4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-yl)carbamate (2 g, 5.16 mmol, 1 eq) and 3,3 in MeCN (10 mL) ,3-trifluoropropanethioamide (739.26 mg, 5.16 mmol, 1 eq) was heated to 80° C. and stirred at 80° C. for 10 hours. The reaction was monitored by LCMS when complete and the solution was concentrated in vacuo to give crude material. The crude is washed with petroleum ether:ethyl acetate (1:1, 5 mL) and the solid is filtered to give (S)-2-(4-nitrophenyl)-1-(2-(2,2,2 -trifluoroethyl)thiazol-4-yl)ethanamine hydrobromide (1.6 g, crude) obtained as a brown solid. LCMS: m/z = 332.0 (M+H ⁺ ).

(S)-2-(4-nitrophenyl)-1-(2-(2,2,2-trifluoroethyl)thiazol-4-yl)ethanamine hydrobromide (1.95 g, 4.73 mmol, 1 eq) and (S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanoic acid (1.88 g, 4.73 mmol, 1 eq). To was added triethylamine (2.87 g, 28.38 mmol, 3.95 mL, 6 eq), then the mixture was cooled to 0° C. and 2,4,6-tripropyl-1,3,5,2,4 ,6-trioxatriphosphinane 2,4,6-trioxide (6.02 g, 9.46 mmol, 5.63 mL, 50% purity, 2 eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 13 hours. The reaction was monitored for completion by LCMS and TLC, the reaction mixture was slowly poured into ice/water (150 mL), extracted with ethyl acetate (3 x 50 mL), the organic phase was washed with brine (150 mL) and dried dry. Dried over Na ₂ SO ₄ and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (petroleum ether/ethyl acetate=1:2) to give methylmethyl ((S)-1-(((S)-2-(4-nitrophenyl)-1-(2 -(2,2,2-trifluoroethyl)thiazol-4-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)carbamate (1.5 g, 57% ), obtained as a yellow oil. LCMS: m/z = 552.2 (M+H ⁺ ).

_Methylmethyl ((S)-1-(((S)-2-(4-nitrophenyl)-1-(2-(2,2,2-tri To a solution of fluoroethyl)thiazol-4-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)carbamate (1.4 g, 2.54 mmol, 1 eq) NH ₄ Cl (678.88 mg, 12.69 mmol, 5 eq) was added, then the mixture was heated to 90° C., then Fe (708.84 mg, 12.69 mmol, 5 eq) was added. The mixture was stirred at 90° C. for 2 hours. The reaction was monitored by LCMS for completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 1%-25%, 20 min). , methyl ((S)-1-(((S)-2-(4-aminophenyl)-1-(2-(2,2,2-trifluoroethyl)thiazol-4-yl)ethyl)amino) -1-oxo-3-(pyridin-4-yl)propan-2-yl)(methyl)carbamate (0.5 g, 38%) was obtained as a yellow solid. LCMS: m/z = 522.2 (M+H ⁺ ).

Methyl ((S)-1-(((S)-2-(4-aminophenyl)-1-(2-(2,2,2- trifluoroethyl)thiazol-4-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)(methyl)carbamate (0.3 g, 575.20 umol, 1 eq) was cooled to 0° C., then SO ₃ -pyridine (274.65 mg, 1.73 mmol, 3 eq) was added batchwise. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored by LCMS when complete, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by blowing _N2 to give a residue. The residue was analyzed by preparative HPLC (column: Phenomenex Gemini C18 250*50 10 u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 5%-30%, 20 min). to give ammonium (4-((S)-2-((S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanamide)-2-( Yield 2-(2,2,2-trifluoroethyl)thiazol-4-yl)ethyl)phenyl)sulfamate (75.57 mg, 21%) as a white solid. LCMS: m/z = 602.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 8.29 (d, J = 5.87 Hz, 2H) 7.21 (s, 2H) 6.97-7.13 (m, 5H) 5.23 (dd, J = 10.03, 5.50Hz, 1H) 4.80-4.91 (m, 1H) 3.86-4.01 ( m, 2H) 3.37-3.63 (m, 3H) 3.05-3.25 (m, 2H) 2.82-2.98 (m, 2H) 2.40-2.58 (m, 3H).

Synthesis of compound 5


Carbonyldiimidazole (23.08 g, 142.32 mmol, 1.01 eq.) was added, then warmed to 40° C., the mixture was stirred at 40° C. for 0.5 h, then cooled to 15° C., then NH ₃ (gas) was added to the solution. bubbled in and the mixture was stirred at 15° C. for 10 hours. The reaction was monitored upon completion by LCMS and the solution was washed with aqueous HCl (10%, 2×200.00 mL) and concentrated in vacuo to yield 4,4,4-trifluorobutanamide (10 g, crude). and obtained as a white solid. LCMS: m/z = 142.1 (M+H ⁺ ).

To a solution of 4,4,4-trifluorobutanamide (6 g, 42.53 mmol, 1 eq) in THF (100 mL) was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1, 3,2,4 Dithiadiphosphetane (20.64 g, 51.03 mmol, 1.2 eq) was added and the mixture was stirred at 15° C. for 10 hours. The reaction was monitored for completion by TLC, the mixture was diluted with NaHCO ₃ (aq, 2×100.0 mL), extracted with ethyl acetate (100.0 mL), dried over Na ₂ SO ₄ and the solution was filtered. , concentrated in vacuo. The residue was purified by column chromatography (dichloromethane:methanol=20:1) to yield 4,4,4-trifluorobutanethioamide (4 g, 60%) as a white solid.

(S)-tert-butyl (4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-yl)carbamate (2 g, 5.16 mmol, 1 eq) and 4,4 in MeCN (10 mL) A solution of ,4-trifluorobutanethioamide (811.71 mg, 5.16 mmol, 1 eq) was warmed to 80° C. and stirred at 80° C. for 10 hours. The reaction was monitored upon completion by LCMS, the solution was washed with petroleum ether:ethyl acetate=1:1 (8 mL), the filter cake was dried in vacuo and (S)-2-(4-nitrophenyl)- 1-(2-(3,3,3-Trifluoropropyl)thiazol-4-yl)ethanamine hydrobromide (1.50 g, crude) was obtained as a brown solid. LCMS: m/z = 346.0 (M+H ⁺ ).

(S)-2-(4-nitrophenyl)-1-(2-(3,3,3-trifluoropropyl)thiazol-4-yl)ethanamine hydrobromide (0.80 g, 1.88 mmol, 1 eq.) to a solution of lithium (S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanoate (705.03 mg, 1.88 mmol, 1 eq.) , triethylamine (1.14 g, 11.26 mmol, 1.57 mL, 6 eq) was added, then cooled to 0° C., followed by 2,4,6-tripropyl-1,3,5,2,4, 6-trioxatriphosphinane 2,4,6-trioxide (1.79 g, 2.82 mmol, 1.67 mL, 50% purity, 1.5 eq.) was added dropwise at 0° C. under N ₂ and the reaction was stirred at 20° C. for 16 hours. The reaction was monitored for completion by LCMS, the reaction mixture was washed with H ₂ O (15 mL), extracted with acetyl acetate (3×15 mL), the solution was filtered and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane:methanol=15:1) to give methylmethyl ((S)-1-(((S)-2-(4-nitrophenyl)-1-(2-( 3,3,3-trifluoropropyl)thiazol-4-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)carbamate (0.5 g, 47%) Obtained as a brown oil. LCMS: m/z = 566.1 (M+H ⁺ ).

_Methylmethyl ((S)-1-(((S)-2-(4-nitrophenyl)-1-(2-(3,3,3-tri fluoropropyl)thiazol-4-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)carbamate (0.5 g, 884.07 umol, 1 eq) and NH ₄ Cl A solution of (236.45 mg, 4.42 mmol, 5 eq) was heated to 90° C., then Fe (246.88 mg, 4.42 mmol, 5 eq) was added and the mixture was stirred at 90° C. for 1 hour. The reaction was monitored by LCMS for completion and the solution was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Agela Durashell C18 150*25 5u; mobile phase: [water (0.1% TFA)-ACN]; B%: 1%-30%, 10 min), methyl ((S)-1-(((S)-2-(4-aminophenyl)-1-(2-(3,3,3-trifluoropropyl)thiazol-4-yl)ethyl)amino)- Yield 1-oxo-3-(pyridin-4-yl)propan-2-yl)(methyl)carbamate (0.3 g, 61%) as a brown oil. LCMS: m/z = 536.2 (M+H ⁺ ).

Methyl ((S)-1-(((S)-2-(4-aminophenyl)-1-(2-(3,3,3-trifluoropropyl)) in pyridine (2 mL) and MeCN (2 mL) A solution of thiazol-4-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)(methyl)carbamate (0.27 g, 504.13 umol, 1.00 equiv) was cooled to 0°C and SO ₃ -pyridine (240.71 mg, 1.51 mmol, 3.00 eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (4 mL) was added dropwise, then the mixture was dried by blowing _N2 and the residue was analyzed by preparative HPLC (column: Phenomenex Gemini C18 250 *50 10 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 10%-40%, 20 min) to ammonium (4-((S)-2-( S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanamido)-2-(2-(3,3,3-trifluoropropyl)thiazol-4-yl )ethyl)phenyl)sulfamate (0.1 g, 31%) was obtained as a white solid. LCMS: m/z = 616.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 8.32 (d, J = 5.99 Hz, 2H) 7.28 (brs, 2H) 6.87-7.11 (m, 5H) 5.18 (dd, J=9.96, 5.44Hz, 1H) 4.83 (brs, 1H) 3.32-3.65 (m, 3H) 3.05-3.26 (m, 4H) 2.78-2.99 (m, 2H) 2.53-2.69 (m, 2H) 2.47 (brs, 3H).

Synthesis of compound 6


To a mixture of (S)-tert-butyl (4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-yl)carbamate (2 g, 5.16 mmol, 1 eq) in MeCN (60 mL) was Cyclopropanecarbothioamide (522.54 mg, 5.16 mmol, 1 eq) was added, then warmed to 90° C. and stirred at 90° C. for 16 hours. The reaction was monitored by LCMS for completion and the solvent was removed in vacuo. The residue is purified by column chromatography (SiO ₂ , small amount of triethylamine, DCM:MeOH=80:0 to 80:1) to give (S)-1-(2-cyclopropylthiazol-4-yl)-2 -(4-nitrophenyl)ethanamine hydrobromide (1.2 g, 63%) was obtained. LCMS: m/z = 289.9 (M+H ⁺ ).

(S)-1-(2-Cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrobromide (0.7 g, 1.51 mmol, 1 eq) and ( To a solution of S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanoic acid (615.49 mg, 1.51 mmol, 1 eq) was added triethylamine (918.26 mg, 9 .07 mmol, 1.26 mL, 6 eq.) was added, then cooled to 0° C., followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2, 4,6-trioxide (1.44 g, 2.27 mmol, 1.35 mL, 50% purity, 1.5 eq) was added dropwise at 0° C. under N ₂ and the reaction was stirred at 25° C. for 16 hours. . The reaction was monitored for completion by LCMS, the reaction mixture was washed with H ₂ O (15 mL), extracted with acetyl acetate (5 mL×3), dried with saturated brine, the solution was filtered and concentrated in vacuo. , purified by preparative HPLC (column: Phenomenex luna (2) C18 250*50 10 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 26%-56%, 20 min). , methyl ((S)-1-(((S)-1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl)amino)-1-oxo-3-(pyridine -4-yl)propan-2-yl)(methyl)carbamate was obtained as an off-white solid (0.48 g, 62%). LCMS: m/z = 510.1 (M+H ⁺ ).

Methyl ((S)-1-(((S)-1-(2-cyclopropylthiazol-4-yl)-2-(4-nitrophenyl)ethyl) in EtOH (10 mL) and H ₂ O (3 mL) ) amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)(methyl)carbamate (0.34 g, 667.22 umol, 1 eq) and NH ₄ Cl (178.45 mg, 3. 34 mmol, 116.64 uL, 5 eq) was heated to 90° C., then Fe (186.30 mg, 3.34 mmol, 5 eq) was added and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the solution was filtered, concentrated in vacuo and preparative HPLC (column: Phenomenex Gemini C18 250*50 10 u; mobile phase: [water (0.1% TFA)-ACN]). B %: 5%-30%, 20 min) to give methyl ((S)-1-(((S)-2-(4-aminophenyl)-1-(2-cyclopropylthiazole- Yield 4-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)(methyl)carbamate (0.34 g, 86%, TFA) obtained as a yellow oil. rice field. LCMS: m/z = 480.1 (M+H ⁺ ).

Methyl ((S)-1-(((S)-2-(4-aminophenyl)-1-(2-cyclopropylthiazol-4-yl)ethyl)amino in pyridine (3 mL) and MeCN (3 mL) )-1-oxo-3-(pyridin-4-yl)propan-2-yl)(methyl)carbamate (0.32 g, 539.07 umol, 1 eq, TFA) was cooled to 0° C. and SO ₃ -Pyridine (257.40mg, 1.62mmol, 3eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored upon completion by LCMS and HPLC, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Phenomenex Gemini C18 250*50 10 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; (2-cyclopropylthiazol-4-yl)-2-((S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanamido)ethyl)phenyl)sulfamate ( 0.09 g, 29%), obtained as a white solid. LCMS: m/z = 560.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.47 (d, J = 5.95 Hz, 2H) 8.22-8.37 (m, 1H) 7.28-7.36 (m, 2H) 7.22 (s, 1H) 7.05-7.13 (m, 1H) 6.96 (s, 2H) 6.80-6 .93 (m, 4H) 4.77-5.14 (m, 2H) 3.35-3.58 (m, 3H) 3.09-3.21 (m, 1H) 2.95-3.05 (m, 1H) 2.87 (td, J = 14.28, 10.03Hz, 2H) 2.57 (s, 3H) 2.38 (ddd, J = 12.95, 8.32, 4.96Hz , 1H) 1.05-1.17 (m, 2H) 0.85-0.98 (m, 2H).

Synthesis of compound 7


(2S)-2-Amino-3-(4-nitrophenyl)propanoic acid (32.00 g, 152.24 mmol, 1.00 equiv) and 4-methylmorpholine (15.40 g, 152.24 mmol, 16.74 mL, 1.00 eq) to a solution of iso-butyl-chloroformate (20.79 g, 152.24 mmol, 19.99 mL, 1.00 eq) was added dropwise at 0 °C, The mixture was then stirred at 0° C. for 2 h, then NH ₃ (2.59 g, 152.24 mmol, 1.00 eq) was bubbled through the reaction at 0° C. and the mixture was stirred at 0° C. for 0.5 h. bottom. The reaction was monitored for completion by LCMS and TLC and the solution was washed with aqueous HCl (5%, 500 mL), _H2O (2 x 400 mL), and aqueous _NaHCO3 (5%, 500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was washed with petroleum ether/ethyl acetate (3:1) and tert-butyl N-[(1S)-2-amino-1-[(4-nitrophenyl)methyl]-2-oxo-ethyl]carbamate (22.00 g, 47%) was obtained as a white solid. LCMS: m/z = 254.0 (M-55).

10.00 g of tert-butyl N-[(1S)-2-amino-1-[(4-nitrophenyl)methyl]-2-oxo-ethyl]carbamate in THF (100.00 mL), 32.33 mmol, 1 .00 eq) and 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4 dithiadiphosphetane (32.69 g, 80.82 mmol, 2.50 eq). The solution was stirred at 15° C. for 3 hours. The reaction was monitored for completion by TLC and the solution was washed with aqueous Na ₂ CO ₃ (500 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by recrystallization from petroleum ether (300 ml) to give tert-butyl N-[(1S)-2-amino-1-[(4-nitrophenyl)methyl]-2-thioxo-ethyl]carbamate. (8.00 g, 76%) was obtained as a white solid.

(S)-tert-butyl (1-amino-3-(4-nitrophenyl)-1-thioxopropan-2-yl)carbamate (2.00 g, 6.15 mmol, 1 .00 equiv) and 2-bromo-1-(thiophen-2-yl)ethanone (1.26 g, 6.15 mmol, 1.00 equiv) was stirred at 80° C. for 12 hours. The reaction was monitored by LCMS for completion and the mixture was stirred at 25° C. for 1 hour, then filtered and the filter cake was dried under vacuum to give (S)-2-(4-nitrophenyl)-1-( Yield 4-(thiophen-2-yl)thiazol-2-yl)ethanamine hydrobromide (1.70 g, 83%) as a yellow solid. LCMS: m/z = 332.0 (M+H ⁺ ).

(S)-2-(4-nitrophenyl)-1-(4-(thiophen-2-yl)thiazol-2-yl)ethanamine hydrobromide (0.6 g, 1.46 mmol, 1 eq, HBr) and (S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanoic acid (577.80 mg, 1.46 mmol, 1 eq) in a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (1.85 g, 2.91 mmol, 1.73 mL, 50% purity, 2 equivalents) and triethylamine (883.49 mg, 8.73 mmol, 1.22 mL, 6 equivalents) were added at 0° C., then the reaction was stirred at 25° C. under N ₂ for 13 h. The reaction was monitored upon completion by LCMS, the reaction mixture was slowly poured into ice/water (100 mL), extracted with ethyl acetate (3 x 30 mL), the organic phase washed with brine (100 mL) and Na ₂ SO. ₄ , filtered and concentrated in vacuo to give methylmethyl ((S)-1-(((S)-2-(4-nitrophenyl)-1-(4-(thiophen-2-yl) )thiazol-2-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)carbamate (0.8 g, crude) as a yellow solid. LCMS: m/z = 552.1 (M+H ⁺ ).

Methylmethyl ((S)-1-(((S)-2-(4-nitrophenyl)-1-(4-(thiophen-2-yl)thiazole) in EtOH (2 mL) and H ₂ O (2 mL) To a solution of (2-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)carbamate (0.25 g, 453.20 umol, 1 eq) was added Fe (126. 56 mg, 2.27 mmol, 5 eq) and _NH4Cl (121.21 mg, 2.27 mmol, 5 eq) were added at 90<0>C. The mixture was stirred at 90° C. under N ₂ for 2 hours. The reaction was monitored by LCMS for completion and the reaction mixture was filtered and concentrated under vacuum. The residue was purified by preparative TLC (SiO2, dichloromethane:methyl alcohol=10:1) to give methyl ((S)-1-(((S)-2-(4-aminophenyl)-1-(4 -(Thiophen-2-yl)thiazol-2-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)(methyl)carbamate (0.25 g, 74%) was obtained as a yellow solid. LCMS: m/z = 522.1 (M+H ⁺ ).

Methyl ((S)-1-(((S)-2-(4-aminophenyl)-1-(4-(thiophen-2-yl)thiazole-2-) in pyridine (1 mL) and MeCN (1 mL) yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)(methyl)carbamate (0.18 g, 345.06 umol, 1 eq) is cooled to 0° C. SO ₃ -pyridine (164.76 mg, 1.04 mmol, 3 eq) was then added and stirred under N ₂ atmosphere at 0° C. for 0.17 h. The reaction was monitored by LCMS when complete, 7% (2 mL) ammonium hydroxide was added dropwise to the reaction mixture, then the mixture was dried by blowing _N2 . The residue was purified by preparative HPLC (column: Phenomenex Gemini C18 250*50 10 u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 10%-40%, 20 min) to give ammonium (4 -((S)-2-((S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanamido)-2-(4-(thiophen-2-yl )thiazol-2-yl)ethyl)phenyl)sulfamate (45.55 mg, 22%) was obtained as a white solid. LCMS: m/z = 602.1 (M+H ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.77-8.95 (m, 1H) 8.47-8.67 (m, 2H) 7.84 (s, 1H) 7.41 -7.61 (m, 4H) 7.23 (s, 1H) 6.87-7.15 (m, 6H) 5.20-5.37 (m, 1H) 4.78-5.10 (m , 1H) 3.51 (brs, 3H) 3.23-3.30 (m, 2H) 2.88-3.13 (m, 2H) 2.52-2.56 (m, 3H).

Synthesis of compound 8


To a mixture of 4,4,4-trifluorobutan-2-one (3 g, 23.80 mmol, 1 eq) in ethyl acetate (15 mL) and CHCl ₃ (7 mL) was added CuBr ₂ (6.75 g, 30.22 mmol). , 1.42 mL, 1.27 eq.) was added, then the mixture was heated to 80° C. and stirred at 80° C. for 16 hours. The reaction was monitored upon completion by TLC and the solution was concentrated in vacuo to yield 1-bromo-4,4,4-trifluorobutan-2-one (4.88 g crude) as a white solid. Obtained.

(S)-tert-butyl (1-amino-3-(4-nitrophenyl)-1-thioxopropan-2-yl)carbamate (2 g, 6.15 mmol, 1 eq) in MeCN (80 mL) and 4 ,4,4-trifluorobutan-2-one (1.26 g, 6.15 mmol, 1 eq) was heated to 80° C. and stirred at 80° C. for 16 hours. The reaction was monitored for completion by TLC and the solution was concentrated in vacuo to give crude material. The crude is purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=2/1 to 0/1) to give (S)-2-(4-nitrophenyl)-1-(4-(2 ,2,2-trifluoroethyl)thiazol-2-yl)ethanamine hydrobromide (1.5 g, 41%) was obtained as a yellow solid.

(1S)-2-(4-nitrophenyl)-1-[4-(2,2,2-trifluoroethyl)thiazol-2-yl]ethanamine hydrobromide (0.62 g, 601.61 umol, 1 eq) and [(2S)-2-[methoxycarbonyl(methyl)amino]-3-(4-pyridyl)propanoyl]oxyl lithium (176.28 mg, 721.94 umol, 1.2 eq). To the solution was added triethylamine (365.26 mg, 3.61 mmol, 502.43 uL, 6 eq), then the mixture was cooled at 0° C. and 2,4,6-tripropyl-1,3,5,2, 4,6-trioxatriphosphinane 2,4,6-trioxide (574.26 mg, 902.42 umol, 536.70 uL, 50% purity, 1.5 eq) was added at 0°C and the mixture was warmed to 25°C, Stir at 25° C. for 16 hours. The reaction was monitored for completion by LCMS, the solution was poured into water (15 mL), extracted with ethyl acetate (3 x 10 mL), the organic phase was washed with brine (20 mL) and dried over _{anhydrous Na2SO4} . , filtered and concentrated in vacuo. The residue is purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=2/1 to 0:1) to give methylmethyl (1-(((S)-2-(4-nitrophenyl)-1 -(4-(2,2,2-trifluoroethyl)thiazol-2-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)carbamate (400 mg, crude product), obtained as a yellow solid. LCMS: m/z = 552.3 (M+H ⁺ ).

Methylmethyl (1-(((S)-2-(4-nitrophenyl)-1-(4-(2,2,2-trifluoroethyl) in EtOH (9.00 mL) and H ₂ O (3 mL) ) thiazol-2-yl)ethyl)amino)-1-oxo-3-(pyridin-4-yl)propan-2-yl)carbamate (400.00 mg, 725.25 umol, 1.00 eq) in a solution of NH ₄ Cl (193.97 mg, 3.63 mmol, 126.78 uL, 5 eq) was added, the mixture was heated to 90° C., Fe (202.52 mg, 3.63 mmol, 5 eq) was added at 90° C. and the mixture was was stirred at 90° C. for 2 hours. The reaction was monitored by LCMS when complete, the solution was filtered, and the filtrate was concentrated in vacuo to give crude material. The crude is dissolved in water (10 mL), extracted with DCM (3 x 10 mL), the organic phase is washed with brine ( ₂₀ mL), dried over anhydrous _Na2SO4 , concentrated in vacuo and methyl (1-(((S)-2-(4-aminophenyl)-1-(4-(2,2,2-trifluoroethyl)thiazol-2-yl)ethyl)amino)-1-oxo-3 -(Pyridin-4-yl)propan-2-yl)(methyl)carbamate (400.00 mg, crude) was obtained as a yellow solid. LCMS: m/z = 522.3 (M+H ⁺ ).

methyl (1-(((S)-2-(4-aminophenyl)-1-(4-(2,2,2-trifluoroethyl)thiazol-2-yl)ethyl)amino)-1-oxo- 3-(Pyridin-4-yl)propan-2-yl)(methyl)carbamate (400.00 mg, 766.94 umol, 1 eq) was purified by preparative TLC (SiO ₂ , DCM:MeOH=20:1, 1%). NH ₃ .H ₂ O) to yield 8_Diastereoisomer 1 (100 mg, 25%) and 8_Diastereoisomer 2 (75 mg, 18%) as yellow solids. LCMS: m/z = 522.3 (M+H ⁺ ).

Diastereoisomer 1:
A solution of 8_diastereoisomer 1 (80 mg, 153.39 umol, 1 eq) in pyridine (1.00 mL) and MeCN (1.00 mL) was cooled to 0° C. and then sulfur trioxide pyridine complex (73 .24 mg, 460.16 umol, 3 eq) was added in batches at 0°C and the mixture was stirred at 0°C for 5 minutes. The reaction was monitored by LCMS when complete, 7% ammonium hydroxide (5 mL) was added to the solution, the solution was stirred at 0° C. for 20 min, then the mixture was dried by flushing with N ₂ to give a residue. rice field. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 5%-30%, 11 min) to give ammonium (4- ((2S)-2-(2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanamide)-2-(4-(2,2,2-trifluoroethyl) Thiazol-2-yl)ethyl)phenyl)sulfamate diastereomer 1 (41 mg, 39%) was obtained as a white solid. LCMS: m/z = 602.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 8.51 (brd, J = 5.99 Hz, 2H) 7.53 (brs, 2H) 7.47 (s, 1H) 7.00-7.17 (m, 4H) 5.42 (brd, J=3.67Hz, 1H) 4.83-4.90 (m, 1H) 3.69 ( q, J = 10.84Hz, 2H) 3.49-3.64 (m, 3H) 3.36 (brdd, J = 13.88, 5.07Hz, 1H) 3.40-3.22 (m, 1H) 2.95-3.10 (m, 2H) 2.73 (s, 3H).

Diastereoisomer 2:
A solution of 8_diastereoisomer 2 (70 mg, 134.21 umol, 1 eq) in pyridine (1.00 mL) and MeCN (1.00 mL) was cooled to 0° C. and then sulfur trioxide pyridine complex (64 .08 mg, 402.64 umol, 3 eq) was added in batches at 0°C and the mixture was stirred at 0°C for 5 minutes. The reaction was monitored by LCMS when complete, 7% ammonium hydroxide (5 mL) was added to the solution, the solution was stirred at 0° C. for 20 min, then the mixture was dried by flushing with N ₂ to give a residue. rice field. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 100*30mm*5um; mobile phase: [water (0.04%NH3H2O)-ACN]; B%: 20%-40%, 12 min). ammonium (4-((2S)-2-(2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanamide)-2-(4-(2,2 ,2-trifluoroethyl)thiazol-2-yl)ethyl)phenyl)sulfamate diastereomer 2 (23 mg, 28%) was obtained as a white solid. LCMS: m/z = 602.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 8.51 (brd, J = 5.99 Hz, 2H) 7.53 (brs, 2H) 7.47 (s, 1H) 7.00-7.17 (m, 4H) 5.42 (brd, J=3.67Hz, 1H) 4.83-4.90 (m, 1H) 3.69 ( q, J = 10.84Hz, 2H) 3.49-3.64 (m, 3H) 3.36 (brdd, J = 13.88, 5.07Hz, 1H) 3.40-3.22 (m, 1H) 2.95-3.10 (m, 2H) 2.73 (s, 3H).

Synthesis of compound 9


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.5 g, 1.37 mmol, 1 eq.) and [(2S)-2-[methoxycarbonyl(methyl)amino]-3-(4-pyridyl)propanoyl]oxylithium (333.72 mg, 1.37 mmol, 1 eq.). , triethylamine (829.79 mg, 8.20 mmol, 1.14 mL, 6 eq) was added, then cooled to 0° C., followed by 2,4,6-tripropyl-1,3,5,2,4, 6-Trioxatriphosphinane 2,4,6-trioxide (1.74 g, 2.73 mmol, 1.63 mL, 50% purity, 2 eq) was added dropwise at 0° C. under N ₂ to bring the reaction to Stir at 25° C. for 16 hours. The reaction was monitored for completion by LCMS, the reaction mixture was washed with H ₂ O (30 mL), extracted with acetyl acetate (3×15 mL), dried with saturated brine (45 mL), the solution filtered and evaporated in vacuo. and the residue is purified by column chromatography (SiO2, ethyl acetate/methanol=5/1) to give methyl N-[(1S)-2-[[(1S)-1-[2-(1H- yielding imidazol-5-ylmethyl)thiazol-4-yl]-2-(4-nitrophenyl)ethyl]amino]-2-oxo-1-(4-pyridylmethyl)ethyl]-N-methyl-carbamate, Obtained as a yellow solid (0.3 g, 32%). LCMS: m/z = 550.3 (M+H ⁺ ).

Methyl N-[(1S)-2-[[(1S)-1-[2-(1H-imidazol-5-ylmethyl)thiazole-4 in EtOH (1.5 mL) and H ₂ O (0.5 mL) -yl]-2-(4-nitrophenyl)ethyl]amino]-2-oxo-1-(4-pyridylmethyl)ethyl]-N-methyl-carbamate (0.3 g, 545.85 umol, 1 eq) and A solution of NH ₄ Cl (145.99 mg, 2.73 mmol, 5 eq) was heated to 90° C., then Fe (152.43 mg, 2.73 mmol, 5 eq) was added and the mixture was stirred at 90° C. for 2 hours. Stirred. The reaction was monitored by LCMS for completion and the solution was filtered and concentrated in vacuo. The residue is purified by preparative TLC (SiO2, ethyl acetate:ethyl alcohol=2:1) to give methyl N-[(1S)-2-[[(1S)-2-(4-aminophenyl)-1 -[2-(1H-imidazol-5-ylmethyl)thiazol-4-yl]ethyl]amino]-2-oxo-1-(4-pyridylmethyl)ethyl]-N-methyl-carbamate (0.1 g, 32 %) and was obtained as a yellow oil. LCMS: m/z = 520.3 (M+H ⁺ ).

Methyl N-[(1S)-2-[[(1S)-2-(4-aminophenyl)-1-[2-(1H-imidazole-) in pyridine (1.5 mL) and MeCN (1.5 mL) 5-ylmethyl)thiazol-4-yl]ethyl]amino)-2-oxo-1-(4-pyridylmethyl)ethyl]-N-methyl-carbamate (0.2 g, 373.35 umol, 1 eq) in a solution of , cooled to 0°C and SO ₃ -pyridine (178.27 mg, 1.12 mmol, 3 eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (2.5 mL) was added dropwise, then the mixture was dried by blowing _N2 and the residue was analyzed by preparative HPLC (column: Agela Durashell C18 150*25 5u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-30%, 12 min) to give (4-((S)-2-( 2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-((S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl) Yield propamido)ethyl)phenyl)sulfamate (0.07 g, 30%) as a white solid. LCMS: m/z = 598.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 8.27 (brs, 2H) 7.66 (brs, 1H) 7.15 (brs, 2H) 7.04 (brd, J = 4.40Hz, 6H) 5.08-5.32 (m, 1H) 4.82-4.92 (m, 1H) 4.07-4.29 (m, 2H) 3.28-3.75 (m, 3H) 2.99-3.24 (m, 2H) 2.75-2.94 (m, 2H) 2.52 (brs, 3H).

Synthesis of compound 10


(1S)-1-[2-[(3-methylimidazol-4-yl)methyl]thiazol-4-yl]-2-(4-nitrophenyl)ethanamine in DMF (5 mL); hydrobromide (868. 88 mg, 2.05 mmol, 1 eq.) and [(2S)-2-[methoxycarbonyl(methyl)amino]-3-(4-pyridyl)propanoyl]oxylithium (0.5 g, 2.05 mmol, 1 eq.) To a solution of triethylamine (1.24 g, 12.29 mmol, 1.71 mL, 6 eq.) was added, cooled to 0° C. and then 2,4,6-tripropyl-1,3,5,2,4 ,6-trioxatriphosphinane 2,4,6-trioxide (260.62 g, 4.10 mmol, 243.57 mL, 0.5% purity, 2 eq) was added at 0°C. The mixture was stirred at 25° C. for 13 hours. The reaction was monitored for completion by LCMS and the reaction mixture was diluted with 20 mL of ice water and extracted with 30 mL of ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography (SiO2, ethyl acetate to ethyl acetate/methyl alcohol=5:1) and methyl N-methyl-N-[(1S)-2-[[(1S)-1-[2- [(3-methylimidazol-4-yl)methyl]thiazol-4-yl]-2-(4-nitrophenyl)ethyl]amino]-2-oxo-1-(4-pyridylmethyl)ethyl]carbamate (0 .3 g, 22%) was obtained as a yellow oil. LCMS: m/z = 564.1 (M+H ⁺ ).

Methyl N-methyl-N-[(1S)-2-[[(1S)-1-[2-[(3-methylimidazol-4-yl)methyl in EtOH (6 mL) and H ₂ O (2 mL) ]thiazol-4-yl]-2-(4-nitrophenyl)ethyl]amino]-2-oxo-1-(4-pyridylmethyl)ethyl]carbamate (0.33 g, 585.49 umol, 1 eq.) Then Fe (163.50 mg, 2.93 mmol, 5 eq) and _NH4Cl (156.59 mg, 2.93 mmol, 5 eq) were added at 90<0>C. The mixture was stirred at 90° C. for 2 hours. The reaction was monitored by LCMS for completion and the reaction mixture was filtered and concentrated in vacuo. The residue is purified by preparative TLC (SiO ₂ , dichloromethane:methyl alcohol=7:1) to give methyl N-[(1S)-2-[[(1S)-2-(4-aminophenyl)-1 -[2-[(3-methylimidazol-4-yl)methyl]thiazol-4-yl]ethyl]amino]-2-oxo-1-(4-pyridylmethyl)ethyl]-N-methyl-carbamate (0 .12 g 38%) was obtained as a yellow oil. LCMS: m/z = 534.3 (M+H ⁺ ).

Methyl N-[(1S)-2-[[(1S)-2-(4-aminophenyl)-1-[2-[(3-methylimidazole-4-) in pyridine (1 mL) and MeCN (1 mL) yl)methyl]thiazol-4-yl]ethyl]amino]-2-oxo-1-(4-pyridylmethyl)ethyl]-N-methyl-carbamate (0.1 g, 187.39 umol, 1 eq) in a solution of , SO3-pyridine (89.48 mg, 562.17 umol, 3 eq) was added. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, added 7% ammonium hydroxide (3 mL) and dried by blowing _N2 . The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 100*30mm*5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 10%-30%, 12 min), Ammonium (4-((S)-2-((S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanamide)-2-(2-((1 -methyl-1H-imidazol-5-yl)methyl)thiazol-4-yl)ethyl)phenyl)sulfamate (0.03810 g, 33%) was obtained as a white solid. LCMS: m/z = 614.2 (M+H ⁺ ). ¹ H NMR (400 MHz, D ₂ O) δ = 8.38 (s, 1H) 8.30 (d, J = 6.11 Hz, 2H) 7.21 (brs, 2H) 7.14 (s, 1H) 6.97-7.08 (m, 5H) 5.22 (dd, J = 8.99, 6.66Hz, 1H) 4.85-4.93 (m, 1H) 4.40 (s, 2H) 3.40-3.66 (m, 6H) 3.05-3.21 (m, 2H) 2.84-2.99 (m, 2H) 2.57 (brs, 3H).

Synthesis of compound 11


(S)-5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-5- in ethyl acetate (150.00 mL) and HCl/EtOAc (4M, 800.00 mL, 21.59 equiv.) A solution of oxopentanoic acid (50.00 g, 148.21 mmol, 1 eq) was stirred at 0° C. for 1 hour. The mixture was filtered and the filter cake was dried in vacuo to yield (S)-4-amino-5-(benzyloxy)-5-oxopentanoic acid (32.00 g crude) as a white solid. .

Diisopropylethylamine (19 .45 g, 150.52 mmol, 26.22 mL, 4 eq.) was added at 0° C., then methyl carbonochloridate (3.56 g, 37.63 mmol, 2.91 mL, 1 eq.) was added at 0° C. and the mixture was was stirred at 25° C. for 2 hours. The reaction was monitored by LCMS when complete, the solution was poured into water (2500 mL), adjusted to pH=2-3 with HCl (1 M), extracted with DCM (3×2500 mL), and the organic phase was brined. (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO ₂ , dichloromethane:methanol=15:1) to give (S)-5-(benzyloxy)-4-((methoxycarbonyl)amino)-5-oxopentanoic acid. (25.0 g, 63%) was obtained as a colorless oil. LCMS: m/z = 296.0 (M+H ⁺ ).

4-Methylmorpholine (3. 43 g, 33.87 mmol, 3.72 mL, 1 eq) was added at −15° C. followed by the dropwise addition of isobutyl chloroformate (4.63 g, 33.87 mmol, 4.45 mL, 1 eq) and the mixture was brought to −15° C. C. for 0.5 hours. NaBH ₄ (1.92 g, 50.80 mmol, 1.5 eq) was then added at 0° C. followed by H ₂ O (20 mL) at 0° C. and the mixture was stirred at 25° C. for 10 hours. The reaction was monitored for completion by TLC, the solution was poured into water (100 mL), then extracted with ethyl acetate (3 x 50 mL), the organic phase was washed with brine (50 mL) and dried _over anhydrous _Na2SO4 . Dried, filtered and concentrated to give a residue. The residue was purified by column (SiO ₂ , petroleum ether:ethyl acetate=1:1) to yield benzyl (2S)-5-hydroxy-2-(methoxycarbonylamino)pentanoate (5.91 g, 62%). and obtained as a colorless oil.

Imidazole (7.56 g, 111.09 mmol, 2 .5 eq) and tert-butylchlorodimethylsilane (8.04 g, 53.32 mmol, 6.53 mL, 1.2 eq) were added at 0°C. The mixture was warmed to 25° C. and stirred for 13 hours. The reaction was monitored upon completion by TLC, the solution was poured into H ₂ O (50 ml), then extracted with DCM (3×50 mL), washed with brine (50 mL), dried over Na ₂ SO ₄ , Then concentrated in vacuo. The residue is purified by column (SiO ₂ , petroleum ether:ethyl acetate=5:1) to give benzyl (2S)-5-[tert-butyl(dimethyl)silyl]oxy-2-(methoxycarbonylamino)pentanoate ( 17.24 g, 98%), obtained as a colorless oil.

Iodomethane (5. 38 g, 37.92 mmol, 2.36 mL, 1.5 eq.) was added at -20°C followed by sodium hydride (1.52 g, 37.92 mmol, 60% purity, 1.5 eq.) at -20°C. and the mixture was stirred at -20°C for 1 hour. The reaction was monitored for completion by TLC and the solution was poured into H ₂ O (50 mL), then extracted with ethyl acetate (3×50 mL), then concentrated in vacuo. The residue was purified by column (SiO ₂ , petroleum ether:ethyl acetate=5:1) to give benzyl(2S)-5-[tert-butyl(dimethyl)silyl]oxy-2-[methoxycarbonyl(methyl)amino ] pentanoate (7 g, 67%) was obtained as a colorless oil.

To a solution of benzyl (2S)-5-[tert-butyl(dimethyl)silyl]oxy-2-[methoxycarbonyl(methyl)amino]pentanoate (0.5 g, 1.22 mmol, 1 eq) in THF (10 mL) , aqueous HCl (1 M, 3.66 mL, 3 eq.) was added at 0° C. and the mixture was stirred at 0° C. for 0.5 h. The reaction was monitored by LCMS when completed and the solution was dried by blowing _N2 . The residue was purified by preparative TLC (petroleum ether:ethyl acetate=2:3) to give benzyl (2S)-5-hydroxy-2-[methoxycarbonyl(methyl)amino]pentanoate (0.26 g, 72%). was obtained as a colorless oil. LCMS: m/z = 296.1 (M+H ⁺ ).

Dess-Martin (1.11 g, 2.61 mmol, 807.18 uL, 1.1 eq) was added at 0° C. and the reaction was stirred at 25° C. under N ₂ for 2 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding 30 mL of NaS2O3 at 25° C. and extracted with 50 mL of DCM (3×25 mL). The combined organic layers were washed with saturated _NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=5:1 to 1:1) to give benzyl (2S)-2-[methoxycarbonyl(methyl)amino]-5-oxo-pentanoate. (0.6 g, 77%), obtained as a white solid, LCMS: m/z = 294.1 (M+H ⁺ ).

Benzyl (2S)-2-[methoxycarbonyl(methyl)amino]-5-oxo-pentanoate (0.55 g, 1.88 mmol, 1 eq) and N-methylmethanamine (764.53 mg, 9.38 mmol, 4.69 mL, 5 eq. HCl) was treated with NaBH ₃ CN (235.67 mg, 3.75 mmol, 2 eq.) at 0° C., then the reaction was warmed to 25° C. and 2 Stirred for an hour. The reaction was monitored for completion by LCMS, the reaction mixture was concentrated in vacuo and the residue was diluted with 20 mL water and extracted with 60 mL DCM (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography (SiO ₂ , ethyl acetate/methyl alcohol=50:1 to 10:1) to give benzyl (2S)-5-(dimethylamino)-2-[methoxycarbonyl(methyl)amino]pentanoate. (0.6 g, 84%), obtained as a colorless oil, LCMS: m/z = 323.1 (M+H ⁺ ).

Pd/C (1 .74 mmol, 10% purity, 1 eq) was added and the reaction was stirred under H ₂ (3.51 mg, 1.74 mmol, 1 eq) (15 psi) at 25° C. for 2 hours. The reaction was monitored upon completion by LCMS and the reaction mixture was filtered and concentrated in vacuo to give (2S)-5-(dimethylamino)-2-[methoxycarbonyl(methyl)amino]pentanoic acid (0.4 g crude product), obtained as an off-white solid, LCMS: m/z = 233.1 (M+H ⁺ ).

(1S)-2-(4-nitrophenyl)-1-[2-(2-thienyl)thiazol-4-yl]ethanamine in DMF (5 mL); hydrobromide (710.06 mg, 1.72 mmol, 1 eq. ), and 5-(dimethylamino)-2-[methoxycarbonyl(methyl)amino]pentanoic acid (0.4 g, 1.72 mmol, 1 eq) was added triethylamine (1.05 g, 10.33 mmol, 1.5 g, 10.33 mmol, 1 eq.). 44 mL, 6 eq.) was added, then the mixture was cooled to 0° C. and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (2.19 g, 3.44 mmol, 2.05 mL, 50% purity, 2 eq) was added at 0° C. and the mixture was warmed to 25° C. and stirred at 25° C. for 13 hours. The reaction was monitored by LCMS for completion and the reaction mixture was dried by blowing _N2 . The residue is purified by column chromatography (SiO ₂ , ethyl acetate:methyl alcohol:ammonium hydroxide=3:1:0.05) to give methyl N-[4-(dimethylamino)-1-[[(1S). )-2-(4-nitrophenyl)-1-[2-(2-thienyl)thiazol-4-yl]ethyl]carbamoyl]butyl]-N-methyl-carbamate (0.3 g, 28%). , obtained as a yellow oil. LCMS: m/z = 546.1 (M+H ⁺ ).

Methyl N-[4-(dimethylamino)-1-[[(1S)-2-(4-nitrophenyl)-1-[2-(2-thienyl) in EtOH (6 mL) and H ₂ O (2 mL) ) NH ₄ Cl (147.04 mg, 2.75 mmol, 5 eq) in a solution of thiazol-4-yl]ethyl]carbamoyl]butyl]-N-methyl-carbamate (0.3 g, 549.78 umol, 1 eq). was added and the mixture was heated to 90° C., Fe (153.53 mg, 2.75 mmol, 5 eq) was added at 90° C. and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS and the reaction mixture was filtered, concentrated under reduced pressure, and methyl N-[1-[[(1S)-2-(4-aminophenyl)-1-[2-(2) was obtained. -thienyl)thiazol-4-yl]ethyl]carbamoyl]-4-(dimethylamino)butyl]-N-methyl-carbamate (0.25 g, 88%) was obtained as a yellow oil.
LCMS: m/z = 516.1 (M+H ⁺ ).

Methyl N-[1-[[(1S)-2-(4-aminophenyl)-1-[2-(2-thienyl)thiazol-4-yl]ethyl]carbamoyl]-4-(dimethylamino)butyl] A mixture of -N-methyl-carbamates (0.25 g, 484.79 umol, 1 eq) was separated by SFC to give 18_diastereoisomer 1 (0.13 g, 46%) as a yellow oil, 18_dia Stereoisomer 2 (0.09 g, 32%) was obtained as a yellow oil. LCMS: m/z = 516.1 (M+H ⁺ ).

Diastereoisomer 1:
To a solution of 18_diastereoisomer 1 (0.12 g, 232.70 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then sulfur trioxide pyridine complex (111.11 mg , 698.09 umol, 3 eq.) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by blowing _N2 and the residue was analyzed by preparative HPLC (Column: Agela DuraShell 150mm_25mm_5um; Mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-50%, 10 min) to give ammonium (4-((2S)-2-(5-(dimethylamino)-2 -((methoxycarbonyl)(methyl)amino)pentanamido)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenyl)sulfamate diastereoisomer 1 (1.9 mg, 2%), obtained as a white solid. LCMS: m/z = 594.1 (MH ⁺ ). ¹ H-NMR: (400 MHz, D ₂ O) δ = 7.34-7.59 (m, 2H) 7.07-7.15 (m, 6H) 5.17-5.38 (m, 1H) 4.28-4.50 (m, 1H) 3.57 (brs, 3H) 3.14-3.34 (m, 1H) 2.82-3.06 (m, 3H) 2.76 (s, 6H) 2.68 (brs, 3H) 1.18-1.63 (m, 4H).

Diastereoisomer 2:
To a solution of 18_diastereoisomer 2 (0.08 g, 155.13 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then sulfur trioxide pyridine complex (74.07 mg , 465.40 umol, 3 eq.) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (Column: Agela DuraShell 150mm_25mm_5um; Mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 20%-50%, 10 min) to give ammonium (4-((2S)-2-(5-(dimethylamino )-2-((methoxycarbonyl)(methyl)amino)pentanamido)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenyl)sulfamate diastereoisomer 2 (1 .9 mg, 2%), obtained as a white solid. LCMS: m/z = 594.1 (MH ⁺ ). ¹ H-NMR: (400 MHz, D ₂ O) δ = 7.34-7.59 (m, 2H) 7.07-7.15 (m, 6H) 5.17-5.38 (m, 1H) 4.28-4.50 (m, 1H) 3.57 (brs, 3H) 3.14-3.34 (m, 1H) 2.82-3.06 (m, 3H) 2.76 (s, 6H) 2.68 (brs, 3H) 1.18-1.63 (m, 4H).

Synthesis of compound 12


To a solution of (S)-6-amino-2-(((benzyloxy)carbonyl)amino)hexanoic acid (10 g, 35.67 mmol, 1 eq) in MeOH (100 mL), then cooled to 0° C., two Sulfur chloride (14.77 g, 124.14 mmol, 9.01 mL, 3.48 eq) was added at 0° C. then warmed to 25° C. and stirred at 25° C. under N ₂ for 13 hours. The reaction was monitored for completion by LCMS and the reaction mixture was diluted with saturated NaHCO ₃ (100 mL) and extracted with dichloromethane (100 mL). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, concentrated in vacuo and treated with (S)-methyl 6-amino-2-(((benzyloxy)carbonyl)amino ) yielded hexanoate (9.8 g, crude) obtained as a yellow oil. LCMS: m/z = 295.2 (M+H ⁺ ).

To a solution of phthalic acid (9.93 g, 59.79 mmol, 1 eq) in MeCN (200 mL) under _N2 was added carbonyldiimidazole (20.94 g, 129.15 mmol, 2.16 eq) to give ( S)-Methyl 6-amino-2-(((benzyloxy)carbonyl)amino)hexanoate (22 g, 59.79 mmol, 1 eq) was added and the reaction was stirred at 25° C. for 13 hours. The reaction was monitored upon completion by TLC, the solution was concentrated in vacuo and purified by column chromatography (SiO2, petroleum ether/ethyl acetate=10:1 to 2:1) to give (S)-methyl 2- Yield (((benzyloxy)carbonyl)amino)-6-(1,3-dioxoisoindolin-2-yl)hexanoate (9 g, 28%) as a yellow oil.

(S)-Methyl 2-(((benzyloxy)carbonyl)amino)-6-(1,3-dioxoisoindolin-2-yl)hexanoate (9.00 g, 21.20 mmol, 1 eq.) was cooled to 0° C., sodium hydride (1.10 g, 27.57 mmol, 60% purity, 1.5 eq.) was added at 0° C. and the mixture was stirred at 0° C. for 0.5 h. was then warmed to 25° C., potassium iodide (24.08 g, 169.63 mmol, 10.56 mL, 8 eq) was added and the mixture was stirred at 25° C. for 1.5 hours. The reaction was monitored when completed by LCMS, the solution was poured into ice water (300 mL), extracted with ethyl acetate (3×200 mL), the solution was concentrated in vacuo and subjected to silica gel column chromatography (petroleum ether:ethyl acetate 10 :1 to 5:1)) to give methyl 2-(((benzyloxy)carbonyl)(methyl)amino)-6-(1,3-dioxoisoindolin-2-yl)hexanoate (4. 3 g, 26%), obtained as a colorless oil. LCMS: m/z = 439.0 (M+H ⁺ ).

Methyl 2-(((benzyloxy)carbonyl)(methyl)amino)-6-(1,3-dioxoisoindolin-2-yl)hexanoate (4.30 g, 9.81 mmol, 1 eq) under H ₂ was added Pd/C (6.00 g, 9.81 mmol, 10% purity, 1.00 eq) and the mixture was stirred under H ₂ at 15 psi at 20° C. for 10 h. Stirred. The reaction was monitored when complete by LCMS and the solution was concentrated in vacuo to give methyl 6-(1,3-dioxoisoindolin-2-yl)-2-(methylamino)hexanoate (2.7 g, crude). ), obtained as a colorless oil. LCMS: m/z = 305.0 (M+H ⁺ ).

A solution of methyl 6-(1,3-dioxoisoindolin-2-yl)-2-(methylamino)hexanoate (2.70 g, 8.87 mmol, 1 eq) in dichloromethane (40.0 mL) was added to 0 C., then diisopropylethylamine (3.44 g, 26.61 mmol, 4.64 mL, 3 eq.) and methyl carbonochloride (838.34 mg, 8.87 mmol, 687.17 uL, 1 eq.) at 0.degree. was added, then warmed to 15° C. and the mixture was stirred at 15° C. for 10 hours. The reaction was monitored upon completion by LCMS, the solution was poured into water (40 mL), extracted with dichloromethane (3×20 mL), the solution was concentrated in vacuo and subjected to silica gel column chromatography (petroleum ether:ethyl acetate=25). :1 to 3:1) to give (S)-methyl 6-(1,3-dioxoisoindolin-2-yl)-2-((methoxycarbonyl)(methyl)amino)hexanoate (2. 1 g, 52%), obtained as a colorless oil. LCMS: m/z = 363.0 (M+H ⁺ ).

(S)-Methyl 6-(1,3-dioxoisoindolin-2-yl)-2-((methoxycarbonyl)(methyl)amino)hexanoate (1.3 g, 3.59 mmol) in ethyl alcohol (20 mL) , 1 eq.) was added hydrazine hydrate (633.84 mg, 10.76 mmol, 615.37 uL, 85% purity, 3 eq.) then warmed to 80° C. and the mixture was stirred at 80° C. for 10 h. bottom. The reaction was monitored for completion by LCMS and the solution was concentrated in vacuo and purified by column chromatography (SiO ₂ , dichloromethane:methanol=2:1) to give methyl 6-amino-2-[methoxycarbonyl (methyl ) amino]hexanoate (0.56 g, 67%) was obtained as a colorless oil. LCMS: m/z = 233.2.0 (M+H ⁺ ).

Pd/C (0.1 g, 2.58 mmol, 50% purity, 1 eq) and formaldehyde (1.05 g, 12.97 mmol, 965.42 uL, 5.02 eq) were added. The mixture was stirred under H ₂ (2.58 mmol, 1 eq) at 50 psi at 25° C. for 13 hours. The reaction was monitored upon completion by LCMS and the solution was concentrated in vacuo to yield methyl 6-(dimethylamino)-2-((methoxycarbonyl)(methyl)amino)hexanoate (0.7 g, crude). , obtained as a colorless oil. LCMS: m/z = 260.9 (M+H ⁺ ).

To a solution of methyl 6-(dimethylamino)-2-((methoxycarbonyl)(methyl)amino)hexanoate (0.75 g, 1.73 mmol, 1 eq) in THF (9 mL) and H ₂ O (3 mL), Lithium hydroxide hydrate (49.68 mg, 2.07 mmol, 1.2 eq) was added slowly. The mixture was stirred at 25° C. for 0.5 hours. The mixture was dried by lyophilization to yield 6-(dimethylamino)-2-((methoxycarbonyl)(methyl)amino)hexanoic acid (0.55 g, crude) as a white solid. LCMS: m/z = 247.2 (M+H ⁺ ).

6-(dimethylamino)-2-((methoxycarbonyl)(methyl)amino)hexanoic acid (0.55 g, 2.23 mmol, 1 eq) and (1S)-2-(4-nitro) in DMF (10 mL) To a solution of phenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethanamine hydrochromide (920.73 mg, 2.23 mmol, 1 eq)) was added triethylamine (1.36 g, 13. 40 mmol, 1.86 mL, 6 eq) was added, then cooled to 0° C., followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4, 6-trioxide (2.84 g, 4.47 mmol, 2.66 mL, 50% purity, 2 eq) was added dropwise at 0° C. under N ₂ and the reaction was stirred at 25° C. for 13 hours. The reaction was monitored for completion by LCMS, the reaction mixture was diluted with ice water (50 mL), extracted with ethyl acetate 60 mL (2×30 mL), washed with brine (60 mL), dried over Na ₂ SO ₄ and filtered. was concentrated in vacuo and purified by column chromatography (SiO2, ethyl acetate/methanol = 10/1 to 2:1) to give methyl (6-(dimethylamino)-1-(((S)-2 -(4-nitrophenyl)-1-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)amino)-1-oxohexan-2-yl)(methyl)carbamate (800mg, 64%) was obtained as a yellow oil. LCMS: m/z = 560.3 (M+H ⁺ ).

Methyl (6-( _{dimethylamino} )-1-(((S)-2-(4-nitrophenyl)-1-(2-(thiophene-2- yl)thiazol-4-yl)ethyl)amino)-1-oxohexan-2-yl)(methyl)carbamate (0.1 g, 178.67 umol, 1 eq) and NH ₄ Cl (47.78 mg, 893. 33 umol, 31.23 uL, 5 eq) was heated to 90° C., then Fe (359.13 mg, 6.43 mmol, 10 eq) was added and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS and the solution was filtered, concentrated in vacuo, and methyl (1-(((S)-2-(4-aminophenyl)-1-(2-(thiophene-2- yl)thiazol-4-yl)ethyl)amino)-6-(dimethylamino)-1-oxohexan-2-yl)(methyl)carbamate (100 mg, crude) was obtained as a white solid. LCMS: m/z = 530.0 (M+H ⁺ ).

Methyl N-[1-[[(1S)-2-(4-aminophenyl)-1-[2-(2-thienyl)thiazol-4-yl]ethyl]carbamoyl]-5-(dimethylamino)pentyl] A mixture of -N-methyl-carbamates (0.4 g, 755.12 umol, 1 eq) was separated by SFC. The residue was separated by SFC (column: AD (250 mm*30 mm, 5 um); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B %: 48%-48%, 12 min). Compound diastereomer 1 (0.22 g, 42%) and diastereomer 2 (0.16 g, 34%) were obtained as yellow solids.

5_Diastereoisomer 1:
To a solution of diastereomer 1 (0.2 g, 377.56 umol, 1 eq) in pyridine (4 mL) and MeCN (1.3 mL) was cooled to 0° C. and SO ₃ . Pyridine (180.28mg, 1.13mmol, 3eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored when completed by LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by blowing _N2 and the residue was analyzed by preparative HPLC (column: Gemini 200*30 Mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 10%-60%, 12 min) to give (4-((2S)-2-(6-dimethylamino )-2-((methoxycarbonyl)(methyl)amino)hexanamido)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenyl)sulfamic acid 5_diastereomer 1 (52. 31 mg, 21%), obtained as a white solid. LCMS: m/z = 610.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.46 (brs, 1H) 7.92 (s, 1H) 7.72 (dd , J = 5.07, 0.88 Hz, 1H) 7.65 (dd, J = 3.75, 1.10 Hz, 1H) 7.32 (brs, 1H) 7.17 (dd, J = 4.96 , 3.64Hz, 1H) 7.00-7.07 (m, 2H) 6.93-7.00 (m, 2H) 5.14 (brt, J = 8.05Hz, 1H) 4.19-4 .50 (m, 1H) 3.57 (s, 3H) 3.14 (dd, J=13.89, 3.75Hz, 1H) 2.70-2.92 (m, 13H) 1.38-1 .56 (m, 3H) 1.30 (brd, J=10.58Hz, 1H) 0.96 (brs, 1H) 0.76 (brs, 1H)

5_Diastereoisomer 2:
To a solution of diastereomer 2 (148.87 mg, 281.03 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and SO ₃ . Pyridine (134.19 mg, 843.09 umol, 3 eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored when completed by LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by blowing _N2 and the residue was analyzed by preparative HPLC (column: Gemini 200*30 Mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 15%-45%, 12 min) to give (4-((2S)-2-(6-dimethylamino)-2 -((methoxycarbonyl)(methyl)amino)hexanamido)-2-(2-(thiophen-2-yl)thiazol-4-yl)ethyl)phenyl)sulfamic acid 5_diastereomer 2 (51.8 mg, 29 %), obtained as a white solid. LCMS: m/z = 610.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.98-9.35 (m, 1H) 8.12-8.26 (m , 1H) 7.68-7.76 (m, 2H) 7.65 (dd, J = 3.67, 1.10 Hz, 1H) 7.30 (s, 1H) 7.18 (dd, J = 5 .01, 3.79Hz, 1H) 6.85-6.98 (m, 4H) 5.11 (td, J = 8.74, 5.26Hz, 1H) 4.30-4.59 (m, 1H ) 3.54-3.75 (m, 3H) 3.06-3.16 (m, 1H) 2.85-3.03 (m, 3H) 2.72 (s, 6H) 2.62 (brs , 3H) 1.67-1.83 (m, 1H) 1.41-1.65 (m, 3H) 1.01-1.18 (m, 2H).

ＴＨＦ（１００ｍＬ）中の中間体２（１３．２８ｇ、４２．８０ｍｍｏｌ、１当量）及びＮＭＭ（４．７６ｇ、４７．０８ｍｍｏｌ、５．１７ｍＬ、１．１当量）の溶液に、中間体３（６．４３ｇ、４７．０８ｍｍｏｌ、６．１８ｍＬ、１．１当量）を、Ｎ_２下で、－１５℃で滴加した。温度を、－１５℃以下に０．５時間維持した。ＴＬＣによって、反応が完了したらモニタリングし、反応混合物を濾過し、濾液を、エーテル（３００ｍＬ）中のジアゾメタン（１２．７５ｇ、３０３．５１ｍｍｏｌ、７．０９当量）を加え、次いで、溶液を０℃で３時間撹拌した。ＴＬＣによって、反応が完了したらモニタリングし、反応混合物は、ＴＨＦ（１００ｍＬ）中の中間体４（１４．３１ｇ、粗物）を産出し、黄色液体として得た。 Synthesis of (S)-tert-butyl-(4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-yl)-carbamate

Intermediate 3 (6 .43 g, 47.08 mmol, 6.18 mL, 1.1 eq.) was added dropwise at −15° C. under N ₂ . The temperature was maintained below -15°C for 0.5 hours. The reaction was monitored for completion by TLC, the reaction mixture was filtered, the filtrate was added with diazomethane (12.75 g, 303.51 mmol, 7.09 eq) in ether (300 mL), then the solution was stirred at 0°C. Stirred for 3 hours. The reaction was monitored by TLC for completion and the reaction mixture yielded intermediate 4 (14.31 g, crude) in THF (100 mL) as a yellow liquid.

To a solution of intermediate 4 (14.3 g, 42.77 mmol, 1 eq) in THF (100 mL) was added aqueous HBr (17.42 mL, 128.32 mmol, 40% purity, 3 eq) under _N2 . Add dropwise at 0°C. The reaction mixture was then stirred at 0° C. for 1 hour. The reaction was monitored for completion by TLC and the reaction mixture was poured into aqueous Na ₂ CO ₃ (150 mL). The mixture was extracted with ethyl acetate (2×100 mL), then the combined organic phases were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with TBME (70 mL), filtered, then the filter cake was dried in vacuo and treated with (S)-tert-butyl-(4-bromo-1-(4-nitrophenyl)-3-oxobutane -2-yl)-carbamate (12 g, 72%) was obtained as a white solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.18 (d, J = 8.33 Hz, 2H) 7.37 (d, J = 8.33 Hz, 2H) 4.96-5.18 (m, 1H) 4.71-4.90 (m, 1H) 4.02 (s, 2H) 3.27-3.40 (m, 1H) 2.97-3.12 (m, 1H) 1 .40(s, 9H).

ＭｅＣＮ（２００ｍＬ）中の（Ｓ）－ｔｅｒｔ－ブチル－（４－ブロモ－１－（４－ニトロフェニル）－３－オキソブタン－２－イル）－カルバメート（２０ｇ、５１．６５ｍｍｏｌ、１当量）の溶液に、中間体５（７．４０ｇ、５１．６５ｍｍｏｌ、１当量）を加え、次いで、反応混合物を９０℃で１６時間撹拌した。ＴＬＣによって、反応が完了したらモニタリングし、反応混合物を濾過し、濾過ケーキを真空中で乾燥させ、（Ｓ）－２－（４－ニトロフェニル）－１－（２－チオフェン－２－イル）チアゾール－４－イル）エタンアミン臭化水素酸塩（１９．３ｇ、粗物）を産出し、白色固体として得た。^１Ｈ－ＮＭＲ：（４００ＭＨｚ，ＤＭＳＯ－ｄ_６）δ＝８．６４（ｓ，３Ｈ） ８．１３（ｄ，Ｊ＝８．７７Ｈｚ，２Ｈ） ７．７６（ｄ，Ｊ＝４．８２Ｈｚ，１Ｈ） ７．６９（ｄ，Ｊ＝３．０７Ｈｚ，１Ｈ） ７．６４（ｓ，１Ｈ） ７．４６（ｂｒｄ，Ｊ＝８．７７Ｈｚ，２Ｈ） ７．１８（ｔ，Ｊ＝４．３９Ｈｚ，１Ｈ） ４．７６－４．９６（ｍ，１Ｈ） ３．３５－３．５０（ｍ，２Ｈ）． Synthesis of (S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide

Solution of (S)-tert-butyl-(4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-yl)-carbamate (20 g, 51.65 mmol, 1 eq) in MeCN (200 mL) To was added intermediate 5 (7.40 g, 51.65 mmol, 1 eq) and then the reaction mixture was stirred at 90° C. for 16 h. The reaction was monitored for completion by TLC, the reaction mixture was filtered, the filter cake was dried in vacuo and (S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazole was obtained. -4-yl)ethanamine hydrobromide (19.3 g, crude) was obtained as a white solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.64 (s, 3H) 8.13 (d, J = 8.77 Hz, 2H) 7.76 (d, J = 4.82 Hz, 1H ) 7.69 (d, J = 3.07Hz, 1H) 7.64 (s, 1H) 7.46 (brd, J = 8.77Hz, 2H) 7.18 (t, J = 4.39Hz, 1H ) 4.76-4.96 (m, 1H) 3.35-3.50 (m, 2H).

Synthesis of (S)-tert-butyl-(1-amino-3-(4-nitrophenyl)-1-thioxopropan-2-yl)-carbamate


(S)-2-((tert-Butoxycarbonyl)amino)-3-(4-nitrophenyl)propanoic acid (50.00 g, 161.13 mmol, 1.00 eq) and NMM (16 .30 g, 161.13 mmol, 17.72 mL, 1.00 eq.) was added dropwise at 0° C. to a solution of isobutyl chloroformate (22.01 g, 161.13 mmol, 21.16 mL, 1.00 eq.) and the mixture was was stirred at 0° C. for 2 hours. NH ₃ (gas) was then bubbled through at 0° C. for 0.5 hours. The reaction was monitored for completion by TLC and LCMS, the reaction mixture was poured into water (700 mL), then the filter cake was dissolved in ethyl acetate (1000 mL) and washed with water (3 x 500 mL). The organic phase was then washed with HCl (5%, 2 x 500 mL), water (2 x 400 mL), and _NaHCO3 (3 x 500 mL), then the organic phase was dried over _{anhydrous Na2SO4} , Concentrate in vacuo. The residue was triturated with PE:EA=6:1 (100 mL), filtered and the filter cake was dried in vacuo and treated with (S)-tert-butyl-(1-amino-3-(4-nitrophenyl) -1-Oxopropan-2-yl)-carbamate (31.00 g, 62%) was yielded as a white solid. LCMS: m/z = 254.2 (M-55). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.16 (d, J = 8.60 Hz, 2H) 7.54 (d, J = 8.60 Hz, 2H) 7.40-7.46 (m, 1H) 7.07 (s, 1H) 6.93 (d, J = 8.82Hz, 1H) 4.09-4.22 (m, 1H) 3.03-3.15 (m, 1H) ) 2.80-2.92 (m, 1H) 1.27 (s, 9H).

(S)-tert-butyl-(1-amino-3-(4-nitrophenyl)-1-oxopropan-2-yl)-carbamate (25.3 g, 81.79 mmol, 1.5 mL) in THF (200 mL). 00 eq.) was added Lawesson's reagent (49.62 g, 122.69 mmol, 1.50 eq.) at 0° C. and the mixture was stirred at 15° C. for 10 h. The reaction was monitored upon completion by TLC, the reaction mixture was filtered, the filtrate was added to ice water (300 mL), the mixture was then extracted with ethyl acetate (3 x 300 mL) and the organic phase was washed with aqueous _NaHCO3 (5%, 3 x 200 mL). The combined organic phase was then washed with brine (300 mL), dried over anhydrous _Na2SO4 and concentrated in vacuo _. The residue was triturated with petroleum ether:ethyl acetate=80:1 (200 mL), filtered and the filter cake was dried in vacuo and treated with (S)-tert-butyl-(1-amino-3-(4-nitro Phenyl)-1-thioxopropan-2-yl)-carbamate (18 g, 67%) was obtained as an off-white solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 9.65 (s, 1H) 9.28 (s, 1H) 8.16 (d, J = 8.44Hz, 2H) 7.58 (d , J = 8.44Hz, 2H) 6.93-6.96 (m, 1H) 4.46-4.51 (m, 1H) 2.86-3.17 (m, 2H) 1.28 (s , 9H).

Synthesis of lithium (S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanoate


SOCl ₂ (42.96 g, 361.06 mmol, 26.19 mL, 2 eq.) was added dropwise at 0° C., then the reaction was heated to 60° C. and stirred at 60° C. for 13 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS and HPLC and the mixture was concentrated in vacuo to yield (S)-methyl-2-amino-3-(pyridin-4-yl)propanoate (30 g, 27%), Obtained as a white solid. LCMS: m/z = 181.1 (M+H ⁺ ).

To a solution of (S)-methyl-2-amino-3-(pyridin-4-yl)propanoate (30 g, 138.46 mmol, 1 eq, HCl) in DCM (250 mL) was added DIPEA (71.58 g, 553. 85 mmol, 96.47 mL, 4 eq.) was added dropwise at 0° C. and stirred for 10 minutes before methyl chloroformate (13.08 g, 138.46 mmol, 10.72 mL, 1 eq.) was added dropwise at 0° C. It was then stirred at 25° C. for 50 minutes under N ₂ . The reaction was monitored for completion by TLC and HPLC and the reaction mixture was concentrated in vacuo. The residue is purified by column chromatography (SiO ₂ , dichloromethane:methanol=1:0-30:1) to give (S)-methyl-2-((methoxycarbonyl)amino)-3-(pyridine-4- yl)propanoate (7 g, 21%) was obtained as a yellow oil. ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.45-8.56 (m, 2H) 7.02-7.11 (m, 2H) 5.38-5.47 (m, 1H) 4 .63-4.76 (m, 1H) 3.72 (s, 3H) 3.65 (s, 3H) 2.94-3.24 (m, 2H).

(S)-Methyl-2-((methoxycarbonyl)amino)-3-(pyridin-4-yl)propanoate (2 g, 8.39 mmol, 1 eq) and iodomethane (1.79 g, 12 NaH (503.70 mg, 12.59 mmol, 60% purity, 1.5 eq) was added slowly at −15° C., then under N ₂ . , -15° C. for 1 hour. The reaction was monitored for completion by LCMS and HPLC and the solution was quenched with saturated NH ₄ Cl (200 mL). The mixture is extracted with ethyl acetate (3×100 mL), then the combined organic phases are washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give (S)-methyl- Yield 2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanoate (1.8 g, 83%) as a yellow oil. LCMS: m/z = 253.2 (M+H ⁺ ).

(S)-methyl-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl)propanoate (1.8 g, 7.14 mmol) in THF (10 mL) and H ₂ O (20 mL) , 1 eq.) was slowly added LiOH (205.07 mg, 8.56 mmol, 1.2 eq.) at 0° C. and then stirred at 25° C. for 2 h under N ₂ . The reaction was monitored for completion by LCMS and HPLC, the reaction mixture was dried by flushing with N ₂ and lithium (S)-2-((methoxycarbonyl)(methyl)amino)-3-(pyridin-4-yl) was added. ) yielded propanoate (2 g, 97%), obtained as a green oil. LCMS: m/z = 239.1 (M+H ⁺ ).

Synthesis of (S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride


To a solution of 2-(1H-imidazol-5-yl)acetonitrile (5 g, 46.68 mmol, 1 eq) in DMF (30 mL) was added thioacetamide (7.01 g, 93.36 mmol, 2 eq) followed by , the mixture was stirred at 100° C. for 2 hours. The reaction was monitored by TLC for completion and HCl/EtOAc (4M, 300 mL) was added and stirred at 25° C. for 1 hour. The solvent was then evaporated in vacuo and the residue triturated with acetone to yield 2-(1H-imidazol-5-yl)ethanethioamide (16.2 g, 76%) as a pale yellow solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 14.45 (brs, 1H) 9.42-10.15 (m, 2H) 9.02 (s, 1H) 7.49 (s, 1H ) 3.97(s, 2H).

(S)-tert-butyl-(4-bromo-1-(4 -Nitrophenyl)-3-oxobutan-2-yl)-carbamate (16 g, 41.32 mmol, 8.33e ^-1 eq) was added and the reaction mixture was stirred at 90°C for 2 hours. The reaction was monitored for completion by LCMS and the reaction mixture was concentrated in vacuo and (S)-tert-butyl-(1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl). )-2-(4-nitrophenyl)ethyl)carbamate (20 g, crude) was obtained as a white solid. LCMS: m/z = 329.9 (M-100).

(S)-tert-butyl-(1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethyl in HCl/EtOAc (50 mL) ) carbamate (10 g, 23.28 mmol, 1 eq) was stirred at 25° C. for 2 h. The reaction was monitored for completion by LCMS and the reaction mixture was filtered, concentrated in vacuo and (S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)- 2-(4-Nitrophenyl)ethanamine hydrochloride (11 g, crude) was obtained as a yellow solid. LCMS: m/z = 351.9 (M+Na ⁺ ). ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 8.95 (d, J = 1.32 Hz, 1H) 8.09-8.16 (m, 2H) 7.57 (s, 1H) 7 .42 (s, 1H) 7.37 (d, J=8.82Hz, 2H) 4.76-4.86 (m, 1H) 4.52-4.66 (m, 2H) 3.45-3 .51(m, 2H).

Synthesis of compound 13


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrobromide (( 0.45 g, 1.23 mmol, 1 eq. HCl) and 3-phenylpropanoic acid (184.72 mg, 1.23 mmol, 172.64 uL, 1 eq.) was treated with Et ₃ N (746.82 mg, 7.38 mmol). , 1.03 mL, 6 eq) was added at 25° C., then the solution was cooled to 0° C. and T3P (1.17 g, 1.85 mmol, 1.10 mL, 50% purity, 1.5 eq) was added dropwise. and the mixture was stirred for 10 h at 25° C. After the reaction was monitored by LCMS and TLC when complete, the solution was poured into water (10 mL), extracted with ethyl acetate (3×10 mL), and then the combined organic The phase was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo.The residue was purified by silica gel column chromatography (SiO ₂ , dichloromethane:methanol=15:1) to give ( S)-N-(1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethyl)-3-phenylpropanamide (0.35 g , crude) and was obtained as a brown oil, LCMS: m/z = 462.0 (M+H ⁺ ).

(S)-N-(1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitro in EtOH (3 mL) and H ₂ O (1 mL) NH ₄ Cl (202.82 mg, 3.79 mmol, 132.56 uL, 5 eq) was added to a solution of phenyl)ethyl)-3-phenylpropanamide (0.35 g, 758.34 umol, 1 eq) at 20°C. Then Fe (211.77 mg, 3.79 mmol, 5 eq) was added at 90° C. and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS and HPLC, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 100*30mm*5um; mobile phase: [water (10mM _NH4HCO3 )-ACN]; B%: 15%-38%, _10min ). (S)-N-(1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-aminophenyl)ethyl)-3-phenylpropanamide (0.1 g, 26%) was obtained as a brown oil. LCMS: m/z = 432.3 (M+H ⁺ ).

(S)-N-(1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-amino in CH ₃ CN (2 mL) and pyridine (2 mL) To a solution of phenyl)ethyl)-3-phenylpropanamide (0.2 g, 463.44 umol, 1 eq) was added SO ₃ -pyridine (221.29 mg, 1.39 mmol, 3 eq) at 0 °C, and the reaction was stirred at 0° C. for 0.17 hours. The reaction was monitored upon completion by LCMS and HPLC and the solution was dried by flushing with _N2 . The residue was purified by preparative HPLC (column: Gemini 200*30 10μ; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 5%-35%, 12 min) to give compound 13 (0.09 g, 35%) was obtained as a white solid. LCMS: m/z = 512.1 (M+H ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.18-8.34 (m, 2H) 7.72 (brs, 1H) 7.21-7.29 (m, 2H) 7.13 -7.20 (m, 3H) 7.08 (s, 1H) 7.00 (s, 1H) 6.87-6.93 (m, 2H) 6.79-6.84 (m, 2H) 5 .02-5.16 (m, 1H) 4.30 (s, 2H) 2.95-3.00 (m, 1H) 2.74-2.83 (m, 3H) 2.36-2.45 (m, 2H).

Synthesis of compound 14


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (200 mg, 546.5 mL) in DMF (6 mL). 69 umol, 1 eq. HCl) and Intermediate 2B (82.64 mg, 546.69 umol, 1 eq.) was added _Et3N (331.92 mg, 3.28 mmol, 456.56 uL, 6 eq.) followed by , the solution was cooled to 0° C. and T3P (521.84 mg, 820.04 umol, 487.70 uL, 50% purity, 1.5 eq) was added dropwise, then the solution was warmed to 25° C. and stirred for 16 h. . The reaction was monitored upon completion by LCMS, the reaction mixture was poured into ice water (20 mL), the mixture was extracted with ethyl acetate (3 x 20 mL), then the combined organic phases were washed with brine (10 mL), dried and Dried over Na ₂ SO ₄ and concentrated in vacuo to yield Intermediate 8 (424 mg, crude) as a yellow oil. LCMS: m/z = 463.3 (M+H ⁺ ).

To a solution of intermediate 8 (0.3 g, _648.62 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was added _NH4Cl (173.48 mg, 3.24 mmol, 5 eq) at 25°C. was added, then the solution was heated to 90° C. and Fe (181.11 mg, 3.24 mmol, 5 eq) was added, then the solution was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 9 (450 mg, crude) as a yellow solid. LCMS: m/z = 433.0 (M+H ⁺ ).

To a solution of intermediate 9 (210 mg, 485.50 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was slowly added _SO3 -pyridine (231.82 mg, 1.46 mmol, 3 eq) at 0 °C. was added and then stirred at 0° C. for 10 minutes. The reaction was monitored for completion by LCMS and HPLC and NH ₃ . H ₂ O (7%, 1 mL) was added dropwise to the above mixture at 0° C. and stirred at 0° C. for 5 minutes, then the mixture was dried by flushing with N ₂ and the residue was analyzed by preparative HPLC ( column: Gemini 200*30 10μ; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; Obtained as a white solid. LCMS: m/z = 513.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 8.27 (d, J = 6.24 Hz, 2H) 8.12 (s, 1H) 7.16 (d, J = 6.11Hz, 2H) 7.08 (s, 1H) 6.90-6.99 (m, 4H) 6.87 (s, 1H) 5.03-5.13 ( m, 1H) 4.30 (s, 2H) 2.78-3.03 (m, 4H) 2.52-2.59 (m, 2H).

Synthesis of compound 15


Intermediate 1B (20 g, 212.51 mmol, 1 eq), Intermediate 1C (33.83 g, 318.76 mmol, 32.22 mL, 1.5 eq), and _ZnCl2 (11.59 g, 85.00 mmol, 0.5 eq). 4 equivalents) was stirred at 160° C. for 5 hours. The reaction was monitored for completion by TLC and the reaction mixture was concentrated in vacuo. The residue was purified by column (SiO ₂ , petroleum ether:ethyl acetate:ethyl alcohol=4:3:1) to yield Intermediate 2A (14 g, 36%) as a pale yellow solid. ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 9.37 (dd, J = 2.08, 1.10 Hz, 1H) 9.07-9.09 (m, 1H) 7.79-7 .87 (m, 1H) 7.64-7.76 (m, 3H) 7.34-7.43 (m, 3H) 7.19 (d, J = 16.51Hz, 1H).

Intermediate 2A (7 g, 38.41 mmol, 1 eq.) was dissolved in dioxane (140 mL) and H ₂ O (47 mL) was treated with OsO ₄ (0.1 M, 5.88 mL, 1.53e ⁻² eq.) and Added to _NaIO4 (16.68 g, 77.98 mmol, 2.03 eq) then stirred at 25[deg.]C for 6 hours. The reaction was monitored for completion by TLC, the reaction mixture was diluted with dioxane (20 mL), filtered, then concentrated in vacuo and the residue was purified by column (SiO ₂ , petroleum ether:ethyl acetate=1:1). Purification yielded Intermediate 1 (3 g, 72%) as a yellow solid. ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 9.22-9.25 (m, 1H) 9.15-9.18 (m, 1H) 7.73-7.83 (m, 1H ).

To a suspension of NaH (1.66 g, 41.63 mmol, 60% purity, 1.5 eq) in THF (20 mL) was added methyl intermediate 1A (5.83 g, 27.75 mmol, 1 eq) at 0 °C. was added dropwise. After the addition was complete, the mixture was packed for 30 minutes. Intermediate 1 (3 g, 27.75 mmol, 1 eq) in THF (10 mL) was then added. The reaction mixture was warmed to 25° C. for 2 hours. The reaction was monitored for completion by TLC, the reaction _mixture was neutralized with sat. ), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column (SiO ₂ , petroleum ether:ethyl acetate=3:2) to yield Intermediate 2 (1.5 g, 30%) as a yellow solid. LCMS: m/z = 165.1 (M+H ⁺ ).

To a solution of intermediate 2 (1.3 g, 7.30 mmol, 1 eq) in ethyl acetate (10 mL) was added Pd/C (700 mg, 7.30 mmol, 10% purity, 1.00 eq) under _N2 . added with The suspension was degassed under vacuum and purged with _H2 several times. The mixture was then stirred under H ₂ (15 psi) at 25° C. for 15 minutes. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 3 (0.693 g, 53%) as a colorless oil. LCMS: m/z = 167.1 (M+H ⁺ ).

Intermediate 3 (230.54 mg, 1.39 mmol, 1 eq) in THF (6 mL) and _H2O (12 mL) was treated with LiOH. H ₂ O (69.86 mg, 1.66 mmol, 1.2 eq) was added at 25° C., then the solution was stirred at 25° C. for 6 hours. The reaction was monitored by LCMS for completion and the reaction mixture was concentrated to yield Intermediate 2B (0.25 g, crude) as a colorless oil. LCMS: m/z = 153.1 (M+H ⁺ ).

To a solution of Intermediate 2C (480.89 mg, 1.31 mmol, 1 eq) and Intermediate 2B (200 mg, 1.31 mmol, 1 eq) in DMF (6 mL) was added _Et3N (798.08 mg, 7.89 mmol). , 1.10 mL, 6 eq.) was added, then the solution was cooled to 0 °C and then T3P (1.25 g, 1.97 mmol, 1.17 mL, 50% purity, 1.5 eq.) was added at 0 °C. was added dropwise and then the solution was stirred at 25° C. for 18 hours. The reaction was monitored by LCMS and TLC for completion and the reaction mixture was dried by flushing _N2 to give a residue. The residue was purified by preparative TLC (SiO ₂ , dichloromethane:methyl alcohol:ammonium hydroxide=20:2:1) to afford intermediate 10 (150 mg, 23%) as a yellow solid. LCMS: m/z = 464.0 (M+H ⁺ ).

To a solution of intermediate 10 (130 mg, _280.47 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was added _NH4Cl (75.01 mg, 1.40 mmol, 5 eq) at 25°C. The solution was then warmed to 90° C., then Fe (78.31 mg, 1.40 mmol, 5 eq) was added and the mixture was stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 11 (150 mg, crude) as a yellow solid. LCMS: m/z = 434.1 (M+H ⁺ ).

A solution of intermediate 11 (100 mg, 230.67 umol, 1 eq) in pyridine (0.5 mL) and MeCN (0.5 mL) was cooled to 0° C. and then SO ₃ -pyridine (110.14 mg, 692 .00 umol, 3 eq.) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (4 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Agela Durashell C18). 150*25 5 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 36%-66%, 10 min) to yield compound 15 (12 mg, 10%), Obtained as a white solid. LCMS: m/z = 514.1 (M+H ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.98-9.14 (m, 2H) 8.68 (s, 1H) 8.32 (d, J = 7.72Hz, 1H) 7 .58-7.91 (m, 1H) 7.37 (s, 1H) 7.07-7.20 (m, 3H) 6.73-7.00 (m, 5H) 5.08-5.10 (m, 1H) 4.36 (s, 2H) 2.91-3.00 (m, 2H) 2.78-2.82 (m, 4H).

Synthesis of compound 16


A mixture of Intermediate 1 (3 g, 7.75 mmol, 1 eq) and Intermediate 2 (915.75 mg, 5.92 mmol, 7.64e ⁻¹ eq, HCl) in MeCN ( ₂₀ mL) was degassed and three times, then the mixture was stirred at 90° C. for 13 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS and HPLC and the solution was concentrated in vacuo. The residue was analyzed by preparative HPLC (column: Phenomenex Gemini C18 250*50 10 u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 5%-48%, 20 min). yielded intermediate 3 (0.7 g, 23%) as a yellow oil. LCMS: m/z = 307.2 (M+H ⁺ ).

TEA (1.10 g, 10 .84 mmol, 1.51 mL, 6 eq) was added, then the solution was cooled to 0° C., then T3P (862.63 mg, 2.71 mmol, 806.19 uL, 1.5 eq) was added dropwise, followed by , the mixture was stirred at 25° C. for 13 hours. The reaction was monitored by LCMS when completed and the solution was dried by flushing with _N2 to yield intermediate 5 (0.794 g, 90%) as a pale yellow oil. LCMS: m/z = 440.3 (M+H ⁺ ).

To a solution of intermediate 5 (0.794 g, 1.81 mmol, 1 eq) in EtOH (4 mL) and _H2O (1 mL) was added NH4Cl ( _483.16 mg, 9.03 mmol, 5 eq) at 25°C. , then the solution was warmed to 90° C. and Fe (504.41 mg, 9.03 mmol, 5 eq) was added, then the solution was heated to 90° C. for 2 hours. The reaction was monitored for completion by LCMS and HPLC, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10Mm NH4HCO3)-ACN]; B%: 5%-35%, 10 min) to give intermediate 6 ( 600 mg, 81%), obtained as a colorless oil. LCMS: m/z = 410.2 (M+H ⁺ ).

To a solution of intermediate 6 (0.6 g, 1.47 mmol, 1 eq) in pyridine (5 mL) and MeCN (5 mL) was added SO ₃ -pyridine (699.54 mg, 4.40 mmol, 3 eq) at 0 °C. added. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Phenomenex Gemini C18). 250*50 10 u; mobile phase: [water (0.04% NH ₃ H ₂ O)—ACN]; B%: 0%-30%, 21 min) to give compound 16 (222.23 mg, 30 %), obtained as a white solid. LCMS: m/z = 490.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.44 (d, J = 5.99 Hz, 2H) 8.33 (d, J = 8.44Hz, 1H) 7.53-7.92 (m, 1H) 7.37 (s, 1H) 7.20 (d, J = 5.87Hz, 2H) 6.89 (d, J = 8 .44Hz, 2H) 6.80 (d, J = 8.44Hz, 2H) 5.10-5.22 (m, 1H) 4.48 (s, 2H) 2.95-3.07 (m, 1H) ) 2.78-2.90 (m, 3H) 2.70 (s, 6H) 2.44-2.49 (m, 2H).

Synthesis of compound 17


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (200 mg, 603.48 umol, 1 equiv) and Intermediate 2 (100.35 mg, 663.83 umol, 1.1 equiv) was added _Et3N (366.40 mg, 3.62 mmol, 503.98 uL, 6 equiv) followed by 0°C. was cooled to rt, then T3P (288.02 mg, 905.22 umol, 269.18 uL, 1.5 eq) was added dropwise at 0° C. under N ₂ and the reaction was stirred at 25° C. for 13 h. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding ice water (40 mL) at 25° C. and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated in vacuo and the residue was subjected to column chromatography on silica gel (SiO ₂ , petroleum ether:ethyl acetate=1). :1 to dichloromethane:methanol=50:1) yielded intermediate 3 (172 mg, 55%) as a yellow solid. LCMS: m/z = 465.2 (M+H ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.45 (d, J = 8.68 Hz, 1H) 8.28-8.38 (m, 2H) 8.09 (d, J = 8 .56Hz, 2H) 7.71 (d, J = 5.01Hz, 1H) 7.64-7.67 (m, 1H) 7.41-7.52 (m, 3H) 7.27 (s, 1H) ) 7.13-7.23 (m, 2H) 5.23-5.31 (m, 1H) 3.28-3.32 (m, 3H) 3.03-3.15 (m, 1H) 2 .69-2.80 (m, 2H) 2.42 (td, J=7.37, 3.61 Hz, 2H).

A solution of intermediate 3 (258 mg, 555.37 umol, 1 eq) and _NH4Cl (148.73 mg, 2.78 mmol, 5 eq) in EtOH (6 mL) was heated to 90°C and then Fe (155. 07 mg, 2.78 mmol, 5 eq.) was added and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 4 (400 mg, crude) as a yellow solid. LCMS: m/z = 435.1 (M+H ⁺ ).

A solution of intermediate 4 (255 mg, 586.78 umol, 1 eq.) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and SO ₃ . Pyridine (280.18mg, 1.76mmol, 3eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, the mixture was then dried by flushing with N ₂ and the residue was analyzed by preparative HPLC (column: YMC-Actus). Triart C18 100*30 mm*5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 10%-40%, 12 min) to give compound 17 (74.5 mg, 24% ), obtained as a white solid. LCMS: m/z = 512.9 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.35-8.45 (m, 2H) 8.31 (d, J = 8.56Hz, 1H) 7.71 (d, J = 5.01Hz, 1H) 7.57-7.66 (m, 2H) 7.31 (dd, J = 7.76, 4.95Hz, 1H) ) 7.21 (brs, 1H) 7.14-7.19 (m, 2H) 7.08 (brs, 1H) 6.96 (brs, 1H) 6.84-6.93 (m, 4H) 5 .02-5.18 (m, 1H) 3.03 (dd, J = 13.63, 5.69Hz, 1H) 2.72-2.87 (m, 3H) 2.40-2.47 (m , 2H).

Synthesis of compound 18


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (200 mg, 603.48 umol, 1 equiv) and Intermediate 2 (95.78 mg, 633.65 umol, 1.05 equiv) was added _Et3N (366.40 mg, 3.62 mmol, 503.98 uL, 6 equiv) followed by 0°C. was cooled to rt, then T3P (288.02 mg, 905.22 umol, 269.18 uL, 1.5 eq) was added dropwise at 0° C. under N ₂ and the reaction was stirred at 25° C. for 13 h. The reaction was monitored for completion by TLC and the reaction mixture was quenched by adding ice water (30 mL) at 25° C. and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated in vacuo and the residue was subjected to column chromatography on silica gel (SiO ₂ , petroleum ether:methanol=100: 1-50:1) yielded intermediate 3 (154 mg, 49%) as a white solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.49 (d, J = 8.56 Hz, 1H) 8.30-8.38 (m, 2H) 8.11 (d, J = 8 .68 Hz, 2H) 7.72 (dd, J = 5.01, 0.98 Hz, 1 H) 7.65 (dd, J = 3.67, 1.10 Hz, 1H) 7.48 (d, J = 8.80Hz, 2H) 7.31 (s, 1H) 7.17 (dd, J = 5.07, 3.73Hz, 1H) 7.11 (d, J = 5.87Hz, 2H) 5.27 (td, J = 8.86, 5.62Hz, 1H) 3.33-3.38 (m, 1H) 3.14 (dd, J = 13.63, 9.35Hz, 1H) 2.75 (t , J=7.46Hz, 2H) 2.38-2.46(m, 2H).

A solution of intermediate 3 (228 mg, 490.79 umol, 1 eq) and _NH4Cl (131.075 mg, 2.78 mmol, 5 eq) in EtOH (6 mL) was heated to 90°C and then Fe (137. 04 mg, 2.45 mmol, 5 eq.) was added and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 4 (240 mg, crude) as a yellow solid. LCMS: m/z = 435.2 (M+H ⁺ ).

A solution of intermediate 4 (240 mg, 552.26 umol, 1 eq.) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and SO ₃ . Pyridine (263.70mg, 1.66mmol, 3eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, the mixture was then dried by flushing with N ₂ and the residue was analyzed by preparative HPLC (column: YMC-Actus). Triart C18 100*30 mm*5 um; mobile phase: [water ( ₁₀ mM _NH4HCO3 )-ACN]; B%: 15%-35%, 12 min) to give compound 18 (42.3 mg, 14% ), obtained as a white solid. LCMS: m/z = 515.0 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.39 (brd, J = 5.95 Hz, 2H) 7.52-7.63 (m, 2H) 7.41 (d, J = 5.95Hz, 2H) 7.08-7.16 (m, 2H) 7.00 (d, J = 8.16Hz, 2H) 6.74 (d , J = 8.16Hz, 2H) 5.04 (dd, J = 9.15, 5.84Hz, 1H) 3.06 (brdd, J = 13.89, 5.73Hz, 1H) 2.82-2 .92 (m, 2H) 2.78 (brdd, J=13.78, 9.37 Hz, 1H) 2.42-2.44 (m, 2H).

Synthesis of compound 19


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (400 mg, 970.11 umol, 1 eq., HBr) and Intermediate 2 (159.16 mg, 1.07 mmol, 1.1 eq.) was added _Et3N (588.99 mg, 5.82 mmol, 810.17 uL, 6 eq.) followed by Cool to 0 °C, then T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 1.5 eq) was added dropwise at 0 °C under _N2 and the reaction was warmed to 25 °C. and stirred for 13 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding ice water (30 mL) at 25° C., then diluted with ice water (60 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography silica gel (SiO ₂ , petroleum ether:ethyl acetate=1:1 to dichloromethane:methanol=100:1) to yield intermediate 3 (383 mg, 85%) as a yellow solid. Obtained. LCMS: m/z = 463.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.89 (brd, J = 8.56 Hz, 1H) 8.60 (d, J = 5.87Hz, 2H) 8.13 (d, J = 8.56Hz, 2H) 7.63-7.74 (m, 2H) 7.44-7.57 (m, 5H) 7.36 (d , J = 15.89Hz, 1H) 7.17 (dd, J = 4.89, 3.91Hz, 1H) 6.89 (d, J = 15.89Hz, 1H) 5.37-5.50 (m , 1H) 3.42 (brdd, J = 13.57, 5.99Hz, 1H) 3.24-3.31 (m, 1H).

A solution of intermediate 3 (393 mg, 849.65 umol, 1 eq.) and _NH4Cl (227.375 mg, 4.25 mmol, 5 eq.) in EtOH (6 mL) was heated to 90°C and then treated with Fe (237 .24 mg, 4.25 mmol, 5 eq.) was added and the mixture was stirred at 90° C. for 2 h. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 4 (371 mg, crude) as a yellow solid. LCMS: m/z = 433.2 (M+H ⁺ ).

A solution of intermediate 4 (255 mg, 589.51 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and SO ₃ . Pyridine (281.49mg, 1.77mmol, 3eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, the mixture was then dried by flushing with N ₂ and the residue was analyzed by preparative HPLC (column: YMC-Actus). Triart C18 100*30 mm*5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 15%-35%, 12 min) to give compound 19 (17 mg, 5%). Obtained as a yellow solid. LCMS: m/z = 511.0 (MH ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 8.33 (d, J = 4.65 Hz, 2H) 7.39 (d, J=4.52Hz, 2H) 7.14-7.26(m, 3H) 7.01(m, 5H) 6.69-6.86(m, 2H) 5.32(m, J=6. 42Hz, 1H) 3.02-3.18 (m, 1H) 2.85-2.98 (m, 1H).

Synthesis of compound 20


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (200 mg, 603.48 umol, 1 Eqs) and Intermediate 2 (99.69 mg, 663.83 umol, 93.17 uL, 1.1 eq) was added _Et3N (366.40 mg, 3.62 mmol, 503.98 uL, 6 eq), It was then cooled to 0 °C, then T3P (288.02 mg, 905.22 umol, 269.18 uL, 1.5 eq) was added dropwise at 0 °C under _N2 and the reaction was stirred at 25 °C for 13 Stirred for an hour. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding ice water (30 mL) at 25° C. and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and the residue was subjected to column chromatography on silica gel ( _SiO2 , petroleum ether:ethyl acetate=5:1~). 1:1) yielded intermediate 3 (158 mg, 50%) as a yellow solid. LCMS: m/z = 464.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.42 (d, J = 8.68 Hz, 1H) 8.10 (d, J = 8.68Hz, 2H) 7.69-7.75 (m, 1H) 7.61-7.67 (m, 1H) 7.47 (d, J = 8.68Hz, 2H) 7.06-7 .26 (m, 7H) 5.13-5.36 (m, 1H) 3.37-3.40 (m, 1H) 3.13 (dd, J = 13.63, 9.35Hz, 1H) 2 .73 (t, J=7.52 Hz, 2H) 2.35-2.43 (m, 2H).

A solution of intermediate 3 (237 mg, 511.25 umol, 1 eq) and _NH4Cl (136.96 mg, 2.78 mmol, 5 eq) in EtOH ( ₈ mL) and H2O (3 mL) was heated to 90°C. and then Fe (142.75 mg, 2.56 mmol, 5 eq) was added and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 4 (312 mg, crude) as a yellow solid. LCMS: m/z = 434.1 (M+H ⁺ ).

A solution of intermediate 4 (312 mg, 719.58 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and SO ₃ . Pyridine (343.59mg, 2.16mmol, 3eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Agela Durashell C18). 150*25 5 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 22%-52%, 10 min) to yield compound 20 (62 mg, 16%), Obtained as a white solid. LCMS: m/z = 514.0 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.26 (d, J = 8.44 Hz, 1H) 7.70 (dd, J = 5.07, 1.04Hz, 1H) 7.63 (dd, J = 3.67, 0.98Hz, 2H) 6.97-7.36 (m, 11H) 6.85-6.91 (m , 4H) 5.06-5.11 (m, 1H) 3.02-3.07 (m, 1H) 2.81-2.86 (m, 1H) 2.75-2.78 (m, 2H) ) 2.38-2.42 (m, 2H).

Synthesis of compound 21


To a solution of Intermediate 1 (0.3 g, 727.76 umol, 1 eq) and Intermediate 2 (109.29 mg, 727.76 umol, 102.14 uL, 1 eq) in DMF (3 mL) was added _Et3N (441 .85 mg, 4.37 mmol, 607.77 uL, 6 eq.) was added, then cooled to 0° C., then T3P (926.24 mg, 1.46 mmol, 865.64 uL, 50% purity, 2 eq.) was added in N ₂ at 0° C. and the reaction was stirred at 25° C. for 3 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding ice water (30 mL) at 25° C., then diluted with ice water (20 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo to yield Intermediate 3 (360 mg, crude) as a brown solid. Obtained. LCMS: m/z = 464.2 (M+H ⁺ ). ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 8.06 (d, J = 8.68 Hz, 2H) 7.33 (d, J = 8.68 Hz, 2H) 7.18-7.23 (m, 2H) 7.10-7.16 (m, 3H) 7.03 (s, 1H) 5.34-5.41 (m, 1H) 3.95-4.08 (m, 2H) 3 .37 (dd, J = 13.57, 6.11Hz, 2H) 3.11 (dd, J = 13.69, 8.80Hz, 1H) 2.79-2.86 (m, 2H) 2.43 -2.52 (m, 2H).

A solution of intermediate 3 (0.35 g, 755.17 mol, 1 eq) in ethyl acetate (3.5 mL) was heated to 50° C., then SnCl ₂ . 2H ₂ O (852.01 mg, 3.78 mmol, 5 eq) was added and the mixture was stirred at 50° C. for 2 hours. The reaction was monitored for completion by LCMS, potassium sodium tartrate (15 mL) was added to the solution, filtered and concentrated in vacuo to yield Intermediate 4 (150 mg, crude) as a brown solid. LCMS: m/z = 434.2 (M+H ⁺ ), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.31 (d, J = 8.68 Hz, 1H) 7.05-7.32 (m , 8H) 6.97 (d, J = 8.19Hz, 2H) 6.73 (brd, J = 8.07Hz, 2H) 4.99-5.19 (m, 1H) 4.15-4.31 (m, 2H) 3.06 (dd, J=13.82, 5.75Hz, 1H) 2.78-2.87 (m, 1H) 2.71-2.75 (m, 2H) 2.34 -2.41 (m, 2H).

A solution of intermediate 4 (150 mg, 346.03 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and SO ₃ . Pyridine (165.23mg, 1.04mmol, 3eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O)-ACN]; B%: 1%-40%, 10 min) to give compound 21 (60.3 mg, yield 33%), obtained as a white solid. LCMS: m/z = 514.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) = 8.22 (d, J = 8.44 Hz, 1H) 7.61 (s, 1H) 7.20-7.28 (m, 2H) 7.13-7.19 (m, 4H) 7.06 (brs, 4H) 6.85-6.91 (m, 2H) 6.75-6. 81 (m, 2H) 4.98-5.16 (m, 1H) 4.10-4.29 (m, 2H) 3.00 (dd, J = 13.82, 5.99Hz, 1H) 72-2.84 (m, 3H) 2.36-2.43 (m, 2H).

Synthesis of compound 22


A mixture of Intermediate 1 (500 mg, 1.29 mmol, 1 eq) and Intermediate 2 (130.63 mg, 1.29 mmol, 1 eq) in MeCN (15 mL) was heated to 90° C., then the reaction was Stir at 90° C. for 13 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 3 (500 mg, crude) as a pale yellow solid. LCMS: m/z = 390.1 (M+H ⁺ ).

A mixture of Intermediate 3 (502 mg, 1.29 mmol, 1 eq) in HCl/EtOAc (4 M, 10 mL) was stirred at 25° C. for 1 hour. The reaction was monitored for completion by LCMS and the reaction mixture was concentrated in vacuo to yield Intermediate 4 (250 mg, crude) as a pale yellow solid. LCMS: m/z = 290.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol- _d ) δ = 8.14 (d, J = 8.56 Hz, 2H) 7.36 (d, J = 8.68 Hz, 2H) 7.17 (s, 1H) 3.54-3.67 (m, 1H) 3.43-3.44 (m, 2H) 2.37-2.47 (m, 1H) ) 1.17-1.22 (m, 2H) 1.08-1.13 (m, 2H).

To a solution of Intermediate 4 (250 mg, 767.31 umol, 1 eq, HCl) and Intermediate 5 (115.23 mg, 767.31 umol, 107.69 uL, 1 eq) in DMF (3 mL) was added _Et3N (465 .87 mg, 4.60 mmol, 640.80 uL, 6 eq) was added, then the mixture was cooled to 0° C. and T3P (976.57 mg, 1.53 mmol, 912.68 uL, 50% purity, 2 eq) was added to 0 °C, then the mixture was warmed to 25 °C and stirred at 25 °C for 13 hours. The reaction was monitored for completion by LCMS, the reaction mixture was diluted with H ₂ O (20 mL), extracted with ethyl acetate (2×10 mL), the combined organic layers were washed with brine (10 mL), anhydrous Na _{2 .} Dried over _SO4 , filtered and concentrated in vacuo to yield Intermediate 6 (200 mg, crude) as a pale yellow solid. LCMS: m/z = 422.2 (M+H ⁺ ).

To a solution of intermediate 6 (150 mg, 355.86 umol, 1 eq) in EtOAc (10 mL) was added _SnCl2 . 2H ₂ O (401.50 mg, 1.78 mmol, 5 eq) was added and the mixture was then heated to 50° C. and stirred for 2 hours. The reaction was monitored upon completion by LCMS, the reaction mixture was added with saturated Seniet's salt (20 mL) and then filtered, the filtrate was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine (5 mL). ), then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to yield Intermediate 7 (90 mg, crude) as a pale yellow solid. LCMS: m/z = 392.2 (M+H ⁺ ).

A mixture of intermediate 7 (0.09 g, 229.87 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (109.76 mg, 689.61 umol, 3 equivalents) was added. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored upon completion by TLC, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 to give a residue. The residue was purified by preparative HPLC (column: Agela Durashell C18 150*25 5 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 15%-45%, 10 min), Compound 22 (32.59 mg, 30%) was yielded and obtained as a white solid. LCMS: m/z = 470.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.14 (d, J = 8.56 Hz, 1H) 7.20-7 .27 (m, 3H) 7.12-7.19 (m, 3H) 7.08 (s, 1H) 6.96 (s, 1H) 6.86-6.91 (m, 2H) 6.76 -6.83 (m, 3H) 4.94-5.08 (m, 1H) 2.94-2.99 (m, 1H) 2.69-2.85 (m, 3H) 2.34-2 .43 (m, 3H) 1.05-1.17 (m, 2H) 0.87-1.00 (m, 2H).

Synthesis of compound 23

Preparation of Intermediate 2 CDI (1.78 g, 10.99 mmol, 1.1 eq) in DCM (10 mL) was added to a solution of Intermediate 7 (1 g, 9.99 mmol, 1 eq) in DCM (2 mL). Poured in at 0° C., then the mixture was stirred at 25° C. for 0.5 h, then NH ₃ (gas) was bubbled through the mixture at 0° C. for 1 h. The reaction was monitored upon completion by TLC, the reaction mixture was neutralized with aqueous HCl (10%, 20 mL), extracted with ethyl acetate (3 x 20 mL), then the combined organic phases were washed with brine (10 mL). , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to yield Intermediate 8 (0.35 g, crude) as a yellow solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 7.15 (s, 1H) 6.71 (s, 1H) 1.93 (d, J = 7.09Hz, 2H) 0.88- 1.01 (m, 1H) 0.37-0.50 (m, 2H) 0.00-0.19 (m, 2H). Intermediate 8 (0.34 g, 3.43 mmol, 1 eq) and Lawesson's reagent (1.39 g, 3.43 mmol, 1 eq) in THF (3.5 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 40° C. for 16 hours. The reaction was monitored for completion by LCMS, the reaction mixture was neutralized with saturated NaHCO ₃ (10 mL), extracted with ethyl acetate (2×10 mL), then the combined organic phases were washed with brine (10 mL), Dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to yield Intermediate 2 (0.16 g, crude) as a yellow solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 9.34 (s, 1H) 9.05 (s, 1H) 2.37 (d, J = 7.09Hz, 2H) 1.07-1 .14 (m, 1H) 0.36-0.52 (m, 2H) 0.15-0.19 (m, 2H).

A solution of Intermediate 1 (0.15 g, 387.37 umol, 1 eq) and Intermediate 2 (44.62 mg, 387.37 umol, 1 eq) in MeCN (5 mL) was stirred at 90°C for 13 hours. The reaction was monitored by LCMS for completion and the reaction mixture was concentrated in vacuo to yield Intermediate 3 (0.17 g, crude) as a yellow solid. LCMS: m/z = 304.0 (M+H ⁺ ).

To a solution of Intermediate 3 (0.16 g, 416.35 umol, 1 eq) and Intermediate 4 (62.53 mg, 416.35 umol, 58.44 uL, 1 eq) in DMF (3 mL) was added _Et3N (252 .78 mg, 2.50 mmol, 347.71 uL, 6 eq) was added, then the solution was cooled to 0° C. followed by T3P (529.90 mg, 832.70 umol, 495.23 uL, 50% purity, 2 eq). was added dropwise at 0°C, then the solution was stirred at 25°C for 3 hours. The reaction was monitored when complete by LCMS and the solution was dried by flushing with _N2 to yield Intermediate 5 (0.25 g, crude) as a yellow solid, LCMS: m/z=436. .1 (M+H ⁺ ).

Intermediate 5 (0.24 g, 551.04 umol, 1 eq) was dissolved in EtOAc (3 mL) and then _SnCl2 . 2H ₂ O (746.05 mg, 3.31 mmol, 6 eq) was added and stirred at 50° C. for 13 hours. The reaction was monitored upon completion by LCMS, saturated potassium sodium tartrate solution (20 mL) was poured into the reaction mixture, the mixture was then filtered, the aqueous phase was extracted with ethyl acetate (2 x 10 mL), and the combined organic phases were was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to yield Intermediate 6 (85 mg, crude) as a yellow solid. LCMS: m/z = 406.3 (M+H ⁺ ).

A solution of intermediate 6 (0.08 g, 197.26 umol, 1 eq) in pyridine (0.5 mL) and MeCN (0.5 mL) was cooled to 0° C. and then SO ₃ -pyridine (94.19 mg, 591.78 umol, 3 eq.) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). Purification by mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN] yielded compound 23 (20 mg, 21%) as a pale yellow solid. LCMS: m/z = 486.1 (M+H ⁺ ) ^.1 H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.18 (d, J = 8.68 Hz, 1H) 7.19-7. 27 (m, 3H) 7.12-7.18 (m, 3H) 7.08 (s, 1H) 6.91-6.98 (m, 2H) 6.85-6.90 (m, 2H) 6.78-6.84 (m, 2H) 4.99-5.11 (m, 1H) 2.95-3.04 (m, 1H) 2.87 (d, J = 6.97Hz, 2H) 2.72-2.81 (m, 3H) 2.35-2.42 (m, 2H) 1.03-1.17 (m, 1H) 0.51-0.63 (m, 2H) 26-0.33 (m, 2H).

Synthesis of compound 24


To a mixture of Intermediate 1 (2 g, 15.60 mmol, 1.96 mL, 1 eq) in DCM (20 mL) was added _SOCl2 (6.31 g, 53.02 mmol, 3.85 mL, 3.40 eq) at 0°C. was added at 25° C., then warmed to 25° C. and stirred at 25° C. for 2 hours under N ₂ atmosphere. The reaction mixture was concentrated in vacuo to yield Intermediate 2 (2.5 g, crude) as a yellow oil.

To a mixture of intermediate 2 (2.5 g, 17.05 mmol, 1.96 mL, 1 eq.) in DCM (20 mL) was added _NH3 (290.39 mg, 17.05 mmol, 1 eq.) at 0°C, followed by Warmed to 25° C. and stirred at 25° C. for 20 minutes under N ₂ atmosphere. The mixture was poured into water (50 mL), then the mixture was extracted with DCM (2 x 10 mL). The combined organic phases are washed with HCl solution (1N, 10 mL), saturated NaHCO ₃ solution (10 mL) and brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the intermediate Yield 3 (1 g, 46%) as a yellow solid. ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 7.21 (s, 1H) 6.66 (s, 1H) 2.07-2.20 (m, 1H) 1.95-2.03 (m, 2H) 1.66-1.75 (m, 2H) 1.40-1.64 (m, 4H) 1.03-1.30 (m, 2H).

To a mixture of intermediate 3 (1 g, 7.86 mmol, 1.96 mL, 1 eq.) in THF (10 mL) was added Lawesson's reagent (3.18 g, 7.86 mmol, 1 eq.) at 25° C. under N ₂ atmosphere. Stir at 25° C. for 16 hours. LCMS monitored when the reaction was complete. The mixture was poured into water (50 mL), then the mixture was extracted with dichloromethane (2 x 10 mL). The combined organic phases were washed with saturated NaHCO ₃ solution (10 mL) and brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give intermediate 4 (1.5 g, crude product), obtained as a yellow oil. LCMS: m/z = 144.1 (M+H ⁺ ).

(S)-tert-butyl-(4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-yl)-carbamate (2.97 g, 7.68 mmol, 1.00 in MeCN (50 mL) eq.) and Intermediate 4 (1.1 g, 7.68 mmol, 1 eq.) was heated to 90° C. and stirred at 90° C. for 16 h under N ₂ atmosphere. The reaction was monitored once complete by LCMS and the reaction mixture was concentrated in vacuo to yield Intermediate 6 (3.2 g, crude, HBr salt) as a dark brown oil. LCMS: m/z = 332.2 (M+H ⁺ ).

To a mixture of Intermediate 6 (400 mg, 970.06 umol, 1 eq, HBr) and Intermediate 7 (145.68 mg, 970.06 umol, 1 eq) in DMF (5 mL) was added _Et3N (588.96 mg, 5 .82 mmol, 810.13 uL, 6 eq) was added dropwise and cooled to 0°C, followed by T3P (925.97 mg, 1.46 mmol, 865.39 uL, 50% purity, 1.5 eq) at 0°C. The mixture was then warmed to 25° C. and stirred at 25° C. for 16 hours under N ₂ atmosphere. The reaction was monitored by LCMS for completion and the mixture was poured into ice water (25 mL) and stirred for 10 minutes. The mixture was then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=10:1 to 2:1) to yield Intermediate 8 (370 mg, 82%) as a yellow solid. LCMS: m/z = 464.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.04-8.06 (m, 1H) 7.18-7.37 (m, 6H) ) 7.10 (d, J = 8.68Hz, 2H) 6.63 (s, 1H) 6.49 (d, J = 8.19Hz, 1H) 5.26-5.39 (m, 1H) 3 .25-3.32 (m, 1H) 3.11-3.19 (m, 1H) 2.95-3.04 (m, 4H) 2.48-2.59 (m, 2H) 2.22 -2.33 (m, 1H) 1.76-1.88 (m, 2H) 1.67-1.75 (m, 2H) 1.58-1.66 (m, 2H) 1.25-1 .34(m, 2H).

A solution of intermediate 8 (370 mg, _798.12 umol, 1 eq) and _NH4Cl (213.46 mg, 3.99 mmol, 5 eq) in EtOH (12 mL) and H2O (4 mL) was heated to 90°C. and then Fe (222.85 mg, 3.99 mmol, 5 eq) was added at 90° C. under N ₂ and the mixture was then stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 9 (345 mg, crude) as a yellow solid. LCMS: m/z = 434.3 (M+H ⁺ ).

A solution of intermediate 3 (345 mg, 795.65 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (379.91 mg, 2.39 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5 u; mobile phase: [water (0.04% NH ₃ H ₂ O + ₁₀ Mm NH 4 HCO ₃ ) - ACN]; , 28%), obtained as a pale yellow solid. LCMS: m/z = 512.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.18 (d, J = 8.56 Hz, 1H) 7.21-7 .27 (m, 3H) 7.12-7.19 (m, 3H) 7.08 (s, 1H) 6.96 (s, 1H) 6.90 (s, 1H) 6.87 (d, J = 8.44Hz, 2H) 6.77 (d, J = 8.31Hz, 2H) 4.98-5.10 (m, 1H) 2.93-3.02 (m, 3H) 2.72-2 .81 (m, 3H) 2.36-2.42 (m, 2H) 2.19-2.27 (m, 1H) 1.70-1.80 (m, 2H) 1.48-1.65 (m, 4H) 1.20-1.30 (m, 2H).

Synthesis of compound 25

Preparation of Intermediate ₂ To a solution of Intermediate 2A (1 g, 14.06 mmol, 1.17 mL, 1 eq) in CH Cl (10 mL) was added isothiocyanato(trimethyl)silane (2.40 g, 18.28 mmol, 1.3 eq.) was added dropwise under _N2 . The reaction mixture was then stirred at 25° C. for 16 hours. MeOH (50 mL) was added and stirred at 25° C. for 1 hour. The mixture was then concentrated in vacuo to yield Intermediate 2 (0.65 g, crude) as a yellow solid. LCMS: m/z = 131.0 (M+H ⁺ ).

A mixture of Intermediate 1 (500.86 mg, 1.23 mmol, 1 eq) and Intermediate 2 (0.2 g, 1.23 mmol, 117.37 uL, 1 eq) in EtOH (10 mL) was heated to 85°C. , and stirred for 2 hours.

After the reaction was monitored by TLC and LCMS when complete, the mixture was cooled and concentrated in vacuo to yield Intermediate 3 (1.0 g, crude) as a yellow solid. LCMS: m/z = 419.1 (M+H ⁺ ).

A solution of intermediate 3 (1.0 g, 1.15 mmol, 1 eq) in HCl/EtOAc (4 mL) was stirred at 25° C. for 5 min. The reaction was monitored for completion by TLC and LCMS, the reaction mixture was filtered, concentrated in vacuo and the solid was washed with ethyl acetate (5 mL) to yield intermediate 4 (0.4 g, 81%), Obtained as a white solid. LCMS: m/z = 319.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.58 (s, 2H) 8.15 (d, J = 8.559 Hz, 2H ) 7.42-7.52 (m, 2H) 6.69 (s, 1H) 4.50-4.60 (m, 1H) 3.39-3.43 (m, 3H) 3.02-3 .13 (m, 3H) 1.99-2.02 (m, 2H) 1.80-1.84 (m, 2H).

To a solution of intermediate 4 (0.4 g, 1.03 mmol, 1 eq. HCl) and intermediate 5 (201.12 mg, 1.34 mmol, 1.3 eq.) in DMF (2 mL) was added Et ₃ N (625 .46 mg, 6.18 mmol, 860.33 uL, 6 eq) was added, the mixture was cooled to 0° C., then T3P (983.34 mg, 1.55 mmol, 919.01 uL, 50% purity, 1.5 eq). was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 2 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched with H ₂ O (20 mL), then filtered and the filtrate concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=1:1) to yield intermediate 6 (0.45 g, 58%) as a yellow solid. LCMS: m/z = 451.2 (M+H ⁺ ).

To a solution of intermediate 6 (462.37 mg, _513.11 umol, 1 eq) in EtOH (5 mL) and H2O (1 mL) was added _NH4Cl (164.68 mg, 3.08 mmol, 107.63 uL, 6 eq). ) was added, then the solution was heated to 90° C. and Fe (171.94 mg, 3.08 mmol, 6 eq) was added, then the reaction mixture was stirred at 90° C. for 2 h. The reaction was monitored for completion by TLC, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=0:1) to yield Intermediate 7 (0.17 g, 71%) as a yellow solid.

A solution of intermediate 7 (200 mg, 475.55 umol, 1 eq.) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (227.07 mg, 1.43 mmol, 3 eq. ) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Agela Durashell C18). 150*25 5 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 20%-50%, 10 min) to yield compound 25 (70.66 mg, 29%). and obtained as a white solid. LCMS: m/z = 499.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 7.19-7.26 (m, 2H) 7.09-7.17 (m, 3H) 6.85-6.95 (m, 4H) 6.18 (s, 1H) 4.80-4.90 (m, 1H) 3.30-3.40 (m, 4H) 2 .95 (dd, J = 13.82, 5.38Hz, 1H) 2.63-2.75 (m, 3H) 2.31-2.42 (m, 2H) 1.90-2.05 (m , 4H).

Synthesis of compound 26


(S)-tert-butyl-(4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-yl)-carbamate (2 g, 5.16 mmol, 1 eq) in EtOH (10 mL) and intermediate A mixture of Form 2 (471.79 mg, 6.20 mmol, 117.37 uL, 1.2 eq) was heated to 85° C. and stirred for 2 hours. After the reaction was monitored by TLC and LCMS when complete, the mixture was cooled and concentrated in vacuo to yield Intermediate 3 (1.8 g, 74%) as a white solid. LCMS: m/z = 365.0 (M+H ⁺ ).

A solution of intermediate 3 (1.7 g, 3.31 mmol, 1 eq) in HCl/EtOAc (4 mL) was stirred at 25° C. for 2 hours. The reaction was monitored for completion by TLC and LCMS, the reaction was filtered, the filter cake was washed with ethyl acetate (5 mL) and then dried in vacuo to give intermediate 4 (0.85 g, 85%, HCl salt) was obtained as a white solid. LCMS: m/z = 264.9 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.73-8.95 (m, 3H) 8.17 (d, J = 8 .56Hz, 2H) 7.49 (d, J = 8.56Hz, 2H) 6.84 (s, 1H) 4.53-4.69 (m, 1H) 3.28-3.50 (m, 2H) ).

To a solution of Intermediate 4A (439.39 mg, 2.93 mmol, 410.65 uL, 1.1 eq) and Intermediate 4 (0.8 g, 2.66 mmol, 1 eq, HCl) in DMF (10 mL) was added Et A mixture of ₃ N (565.22 mg, 5.59 mmol, 777.48 uL, 2.1 eq) and HATU (1.21 g, 3.19 mmol, 1.2 eq) was added dropwise at 0 °C under _N atmosphere. added. During that time the temperature was kept below 0°C. The reaction mixture was then warmed to 25° C. and stirred at 25° C. for 2 hours. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was quenched with H ₂ O (20 mL) and then filtered. The filter cake was dried in vacuum. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=1:1) to yield Intermediate 5 (0.89 g, 42%) as a yellow solid. LCMS: m/z = 397.2 (M+H ⁺ ).

To a mixture of intermediate 5 (0.3 g, 756.69 umol, 1 eq) and _CuCl2 (162.78 mg, 1.21 mmol, 1.6 eq) in MeCN (10 mL) was added tert-butyl nitrite (117. 05 mg, 1.14 mmol, 135.00 uL, 1.5 eq) was added dropwise at 0° C. under N ₂ . The mixture was stirred at 0° C. for 2 hours. The reaction was monitored for completion by TLC and LCMS and the reaction was quenched with _H2O (50 mL) and then extracted with ethyl acetate (2 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=3:1) to yield Intermediate 7 (0.11 g, 28%) as a yellow solid. LCMS: m/z = 416.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.06-8.08 (m, 2H) 7.19-7.26 (m, 3H ) 7.12-7.18 (m, 4H) 6.65 (s, 1H) 6.02 (brd, J=8.56Hz, 1H) 5.24-5.30 (m, 1H) 3.19 -3.25 (m, 1H) 3.01-3.13 (m, 1H) 2.91-2.96 (m, 2H) 2.44-2.53 (m, 2H).

KI (5 A solution of DBU (95.17 mg, 625.16 umol, 94.23 uL, 2 eq) was added dropwise under _N2 atmosphere. The reaction mixture was heated to 130° C. and stirred at 130° C. for 1 hour under microwave. The reaction was monitored by TLC and LCMS for completion and the reaction was quenched with water (20 mL) and then extracted with ethyl acetate (2 x 5 mL). The combined organic phases were washed with brine (3 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=0:1) to yield intermediate 9 (0.11 g, 72%) as a yellow solid. LCMS: m/z = 467.2 (M+H ⁺ ). ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.03-8.05 (m, 2H) 7.27-7.29 (m, 1H) 7.24-7.26 (m, 1H) 7 .17-7.23 (m, 3H) 7.11-7.17 (m, 2H) 6.26 (brd, J=7.95Hz, 1H) 5.86-5.90 (m, 1H) 4 .99-5.11 (m, 1H) 4.60-4.71 (m, 1H) 3.58-3.68 (m, 2H) 3.48-3.56 (m, 2H) 3.43 -3.46 (m, 1H) 3.18-3.22 (m, 1H) 3.05-3.10 (m, 1H) 2.94-3.01 (m, 2H) 2.48-2 .52 (m, 2H) 2.18-2.24 (m, 1H) 2.08-2.16 (m, 1H).

To a solution of intermediate 9 (0.11 g, 223.98 umol, 1 eq) in EtOH (5 mL) and _H2O (1 mL) was added _NH4Cl (71.89 mg, 1.34 mmol, 46.98 uL, 6 eq). ) was added and heated to 90° C., then Fe (75.06 mg, 1.34 mmol, 6 eq) was added. The reaction mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by TLC and the reaction was filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=0:1) to yield intermediate 10 (0.08 g, 79%) as a yellow oil.

A solution of intermediate 5 (80 mg, 183.25 umol, 1 eq) in pyridine (1 mL) and CH ₃ CN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (87.50 mg, 549.74 umol, 3 eq.) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1% to 30%, 10 min) to give compound 26 (25. 3 mg, 26%), obtained as a pale yellow solid. LCMS: m/z = 515.1 (MH ⁺ ). ¹ H-NMR: (400MHz, DMSO- _d6 ) δ = 7.05-7.28 (m, 6H) 6.97 (d, J = 8.19Hz, 1H) 6.83-6.92 (m , 1H) 6.66 (d, J=8.19Hz, 1H) 6.00-6.07 (m, 1H) 4.76-4.87 (m, 1H) 4.39 (brs, 1H) 3 .35-3.50 (m, 3H) 3.20-3.22 (m, 1H) 2.92-3.03 (m, 1H) 2.60-2.74 (m, 3H) 2.29 -2.37 (m, 2H) 2.00-2.09 (m, 1H) 1.87-1.91 (m, 1H).

Synthesis of compound 27

1.1 Preparation of Intermediate 2 To a solution of Intermediate 2A (0.2 g, 1.45 mmol, 1.17 mL, 1 equiv. HCl) in THF (4 mL) was added di(imidazol-1-yl)methanethione (336 .72 mg, 1.89 mmol, 1.3 eq) was added dropwise under _N2 . The reaction mixture was stirred at 25° C. for 16 hours. The reaction was monitored by LCMS for completion and MeOH (50 mL) was added and stirred at 25° C. for 1 hour. The mixture was then concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=0:1) to yield Intermediate 2 (70 mg, 15%) as a yellow solid. LCMS: m/z = 161.1 (M+H ⁺ ).

(S)-tert-butyl-(4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-yl)-carbamate (457.88 mg, 1.12 mmol, 1 eq) in EtOH (10 mL) and Intermediate 2 (0.2 g, 1.12 mmol, 117.37 uL, 1 eq) was heated to 85° C. and stirred for 2 hours. After the reaction was monitored by LCMS for completion, the mixture was cooled and concentrated in vacuo. The residue was triturated with ethyl acetate (5 mL) and dried in vacuo to yield Intermediate 3 (0.7 g, 83%) as a yellow solid. LCMS: m/z = 449.3 (M+H ⁺ )

A solution of intermediate 3 (0.8 g, 1.07 mmol, 1 eq) in HCl/EtOAc (4 mL) was stirred at 25° C. for 5 min. The reaction was monitored by LCMS for completion and the reaction was filtered and concentrated in vacuo. The residue was washed with ethyl acetate (5 mL) and dried in vacuo to yield Intermediate 3 (0.6 g, 73%, HCl salt) as a yellow solid. LCMS: m/z = 349.1 (M+H ⁺ )

To a solution of intermediate 4A (254.47 mg, 1.69 mmol, 237.82 uL, 1.2 eq) and intermediate 3 (0.6 g, 1.41 mmol, 1 eq, HCl) in DMF (6 mL) was ₃ N (857.34 mg, 8.47 mmol, 1.18 mL, 6 eq.) was added, then cooled to 0° C. and T3P (1.35 g, 2.12 mmol, 1.26 mL, 50% pure, 1.5 equivalent) was added dropwise at 0° C. under N ₂ . The reaction mixture was then warmed to 25° C. and stirred at 25° C. for 2 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched with H ₂ O (20 mL) then filtered and the filtrate dried in vacuo. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=1:1) to yield Intermediate 5 (0.6 g, crude) as a dark brown oil. LCMS: m/z = 481.3 (M+H ⁺ ).

To a solution of intermediate 5 (0.6 g, _873.95 umol, 1 eq) in EtOH (5 mL) and H2O (1 mL) was added _NH4Cl (280.48 mg, 5.24 mmol, 183.32 uL, 6 eq). ) and heated to 90° C., then Fe (292.86 mg, 5.24 mmol, 6 eq) was added and stirred at 90° C. for 2 h. The reaction was monitored for completion by TLC and the reaction was filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/ethyl acetate=0:1) to yield intermediate 6 (0.2 g, 48%) as a yellow solid. LCMS: m/z = 481.3 (M+H ⁺ ).

A solution of intermediate 6 (0.25 g, 554.82 umol, 1 eq) in pyridine (2 mL) and CH ₃ CN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (264.92 mg, 1 .66 mmol, 3 eq.) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5% to 35%, 10 min) to give compound 27 (183. 3 mg, 61%), obtained as a white solid. LCMS: m/z = 529.0 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 7.16-7.24 (m, 2H) 7.04-7.16 (m, 4H) 6.80-6.96 (m, 4H) ) 6.00 (d, J=5.14Hz, 1H) 4.76-4.87 (m, 1H) 4.07-4.08 (m, 1H) 3.27-3.50 (m, 4H ) 3.22 (s, 3H) 2.91-3.07 (m, 1H) 2.65-2.74 (m, 2H) 2.56-2.65 (m, 1H) 2.29-2 .40 (m, 2H) 2.03-2.09 (m2 H).

Synthesis of compound 28


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.1 g, 243.73 umol, 1 eq) and intermediate 2 (33.18 mg, 243.73 umol, 30.73 uL, 1 eq) was added TEA (147.98 mg, 1.46 mmol, 203.55 uL, 6 eq). The solution was then cooled to 0° C., then T3P (23.27 g, 365.60 umol, 21.74 mL, 50% purity, 1.5 eq) was added dropwise and stirred at 20° C. for 13 hours. The reaction was monitored upon completion by LCMS, the solution was poured into cold water (20 mL), extracted with ethyl acetate (3 x 10 mL), then the combined organic phases were washed with brine (2 x 10 mL) and dried over anhydrous Na. ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to yield Intermediate 3 (80 mg, 73%) as a white solid. LCMS: m/z = 448.2 (M+H ⁺ ).

To a solution of intermediate 3 (0.08 g, 178.77 umol, 1 eq) in EtOH (3 mL) and water (1 mL) was added _NH4Cl (47.81 mg, 893.84 umol, 31.25 uL, 5 eq). was added at 25° C., then the solution was heated to 90° C., then Fe (49.92 mg, 893.84 umol, 5 eq) was added and the solution was hearted at 90° C. for 2 hours. The reaction was monitored for completion by LCMS and HPLC, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (80 mg, crude) as a colorless oil. LCMS: m/z = 418.2 (M+H ⁺ ).

To a solution of intermediate 4 (0.07 g, 167.65 umol, 1 eq) in MeCN (1 mL) and pyridine (980.00 mg, 12.39 mmol, 1 mL, 73.90 eq) was added SO ₃ -pyridine (80. 05 mg, 502.96 umol, 3 eq) was added at 0°C and the mixture was stirred at 0°C for 10 minutes. The reaction was monitored upon completion by LCMS and HPLC and the solution was dried by flushing with _N2 . The crude was purified by preparative HPLC (column: Agela Durashell C18 150*25 5u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-35%, 10 min). yielded compound 28 (19.8 mg, 23%) as a white solid. LCMS: m/z = 498.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.74 (s, 1H) 8.48 (d, J = 8.33 Hz, 1H ) 7.66-7.91 (m, 1H) 7.22-7.29 (m, 3H) 7.12-7.17 (m, 5H) 7.07-7.09 (m, 1H) 6 .95-6.96 (m, 1H) 6.86-6.92 (m, 2H) 6.77-6.83 (m, 2H) 5.04-5.20 (m, 1H) 4.38 (s, 2H) 3.38-3.45 (m, 2H) 2.88-2.89 (m, 1H) 2.52-2.70 (m, 1H).

Synthesis of compound 29

Preparation of Intermediate 2 Intermediate 5 (1.01 g, 6.11 mmol, 935.19 uL, 1 eq) in THF (9 mL) and _H2O (6 mL) was treated with LiOH. H ₂ O (513.15 mg, 12.23 mmol, 2 eq) was added at 0° C., then the solution was warmed to 25° C. and stirred for 3 hours. The reaction was monitored when completed by TLC and the solution was concentrated in vacuo to yield Intermediate 2 (0.8 g, 91%) as a white solid. ¹ H-NMR: (400 MHz, D ₂ O) δ = 8.37 (d, J = 1.75 Hz, 2H) 7.27 (s, 2H) 3.52 (d, J = 3.0 Hz, 2H) .

(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.1 g, 243.73 umol, 1 eq) and Intermediate 2 (34.87 mg, 243.73 umol, 245.80 uL, 1 eq) was treated with _Et3N (147.98 mg, 1.46 mmol, 203.55 uL, 6 eq). was added, then the solution was cooled to 0 °C, T3P (23.27 g, 365.60 umol, 21.74 mL, 50% purity, 1.5 eq) was added dropwise, the mixture was warmed to 25 °C, and and stirred for 13 hours. The reaction was monitored upon completion by LCMS, the solution was poured into cold water (20 mL) and extracted with ethyl acetate (3 x 10 mL), then the combined organic phases were washed with brine (2 x 10 mL) and anhydrous _Na2. Dried over _SO4 , filtered and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane:methyl alcohol=10:1) to yield Intermediate 3 (20 mg, 18%) as a white solid. LCMS: m/z = 449.2 (M+H ⁺ ).

Intermediate 3 (0.03 g, 66.89 umol, 1 eq.) in EtOH (3 mL) and HO (1 mL) was added with _NH4Cl (17.89 mg, 334.45 umol, 5 eq.) at 25°C, followed by , the solution was heated to 90° C., Fe (3.74 mg, 66.89 umol, 1 eq) was added at this temperature, then the solution was stirred at 90° C. for 2 h. The reaction was monitored for completion by LCMS and HPLC, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (40 mg, crude) as a colorless oil. LCMS: m/z = 419.2 (M+H ⁺ ).

To a solution of intermediate 4 (40 mg, 95.58 umol, 1 eq) in MeCN (1 mL) and pyridine (1 mL) was added SO _-pyridine (15.21 mg, 95.58 umol, 1 eq) at 0 °C, The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored upon completion by LCMS and HPLC and the solution was dried by flushing with _N2 . The residue was purified by preparative HPLC (column: Agela Durashell C18 150*30 5u; mobile phase: [water (0.04% NH3H2O)-ACN]; B%: 1%-15%, 10 min), Compound 29 (9.04 mg, 18%) was yielded as a white solid. LCMS: m/z = 497.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 8.35 (d, J = 5.26 Hz, 2H) 7.94 (s, 1H) 7.15 (s, 1H) 7.04-7.10 (m, 3H) 6.93-7.02 (m, 4H) 5.19-5.23 (m, 1H) 4.30 ( s, 2H) 3.19 (dd, J = 13.88, 6.05Hz, 1H) 2.94 (dd, J = 13.82, 9.54Hz, 1H) 2.67 (s, 2H).

Synthesis of compound 31


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (100 mg, 273.0 mg) in DMF (2 mL). 35 umol, 1.2 eq) and Intermediate 2 (42.05 mg, 227.79 umol, 1 eq) was added _Et3N (1.37 mmol, 190.23 uL, 6 eq) and the mixture was brought to 0°C. Cooled and then T3P (341.68 umol, 203.21 uL, 50% purity, 1.5 eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 18 hours. The reaction was monitored for completion by LCMS and the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phase was then washed with brine (2 x 10 mL), dried over anhydrous _Na2SO4 and concentrated in vacuo _. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to yield Intermediate 3 (70 mg, 62%) as a yellow oil. LCMS: m/z = 496.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.02 (d, J = 8.681 Hz, 2H) 7.66 (brs, 1H) 7 .11-7.21 (m, 5H) 7.02-7.06 (m, 1H) 6.96 (s, 1H) 6.68 (s, 1H) 5.28-5.33 (m, 1H) ) 3.50 (s, 2H) 3.24-3.33 (m, 1H) 3.14-3.23 (m, 1H) 2.87-2.94 (m, 2H) 2.46-2 .52(m, 2H).

To a solution of intermediate 3 (70 mg, _141.13 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was added _NH4Cl (37.75 mg, 705.67 umol, 5 eq) at 25°C. The solution was then heated to 90° C. and Fe (39.41 mg, 705.67 umol, 5 eq) was added to the mixture and stirred at 90° C. for 2 hours. The reaction was monitored by TLC and LCMS for completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (90 mg, crude) as a yellow solid. LCMS: m/z = 466.2 (M+H ⁺ ).

To a solution of intermediate 4 (90 mg, 193.13 umol, 1 eq) in MeCN (1 mL) and pyridine (1 mL) was added SO _-pyridine (92.22 mg, 579.40 umol, 3 eq) at 0 °C, Stirred for 0.17 hours. The reaction was monitored for completion by TLC and LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge). 150*25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 5%-30%, 11 min) to give compound 31 (14 mg, 13% ), obtained as a white solid. LCMS: m/z = 546.0 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 14.07 (brs, 1H) 8.85 (s, 1H) 8.23 (d , J = 8.437 Hz, 1H) 7.54-7.98 (m, 1H) 7.19-7.31 (m, 3H) 7.08-7.17 (m, 3H) 6.89 (d , J = 8.436 Hz, 2H) 6.77 (d, J = 8.436 Hz, 2H) 5.08-5.17 (m, 1H) 4.38 (s, 2H) 2.93 (dd, J = 13.510, 6.908 Hz, 1H) 2.76-2.87 (m, 3H) 2.40-2.46 (m, 2H).

Synthesis of compound 32


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (100 mg, 273.0 mg) in DMF (2 mL). 35 umol, 1.2 eq) and Intermediate 2 (41.05 mg, 227.79 umol, 1 eq) was added _Et3N (1.37 mmol, 190.23 uL, 6 eq) and the mixture was brought to 0°C. Cooled and then T3P (341.68 umol, 203.21 uL, 50% purity, 1.5 eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 18 hours. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phase was then washed with brine (2 x 10 mL), dried over anhydrous _Na2SO4 and concentrated in vacuo _. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to yield Intermediate 3 (70 mg, 63%) as a yellow oil. LCMS: m/z = 492.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 8.05 (d, J = 8.803 Hz, 2H) 7.73 (s, 1H ) 7.31 (d, J=8.681Hz, 2H) 7.03-7.13 (m, 2H) 6.88 (s, 1H) 6.66-6.73 (m, 3H) 5.32 -5.36 (m, 1H) 4.30 (s, 2H)

A solution of intermediate 3 (68 mg, _138.33 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was added to _NH4Cl (37.00 mg, 691.67 umol, 5 eq) followed by The solution was heated to 90° C. and Fe (38.63 mg, 691.67 umol, 5 eq) was added to the mixture and stirred at 90° C. for 2 hours. The reaction was monitored by TLC and LCMS for completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (100 mg, crude) as a yellow solid. LCMS: m/z = 462.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol- _d ) δ = 8.43 (s, 1H) 7.29 (s, 1H) 7.13 (s , 1H) 6.88-6.95 (m, 2H) 6.71 (m, 6H) 4.41 (s, 2H) 3.69-3.77 (m, 3H) 3.57-3.64 (m, 1H) 3.13 (m, 1H) 2.71-2.92 (m, 3H) 2.46 (m, 2H).

SO ₃ -pyridine (103.45 mg, 649.94 umol, 3 eq) was added to a solution of intermediate 4 (100 mg, 216.65 umol, 1 eq) in pyridine (0.5 mL) and MeCN (0.5 mL). °C and stirred for 0.17 hours. The reaction was monitored upon completion by TLC and LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Agela Durashell C18 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 5%-40%, 10 min) to yield compound 32 (21.4 mg, 18%), Obtained as a white solid. LCMS: m/z = 542.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.62 (s, 1H) 8.21 (d, J = 8.436 Hz, 1H ) 7.70 (brs, 1H) 7.00-7.28 (m, 4H) 6.86-6.92 (m, 2H) 6.70-6.82 (m, 5H) 5.06-5 .16 (m, 1H) 4.35 (s, 2H) 3.71 (s, 3H) 2.92-2.97 (m, 1H) 2.79-2.84 (m, 1H) 2.72 -2.7 (m, 2H) 2.37-2.43 (m, 2H).

Synthesis of compound 33


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (100 mg, 273.0 mg) in DMF (2 mL). 35 umol, 1.2 eq) and Intermediate 2 (37.40 mg, 227.79 umol, 1 eq) was added _Et3N (1.37 mmol, 190.23 uL, 6 eq) and the mixture was brought to 0°C. Cooled, then T3P (341.68 umol, 203.21 uL, 50% purity, 1.5 equiv) was added dropwise and the solution was stirred at 25°C for 13 hours. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phase was then washed with brine (2 x 10 mL), dried over anhydrous _Na2SO4 and concentrated in vacuo _. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to yield Intermediate 3 (80 mg, 74%) as a yellow oil. LCMS: m/z = 476.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol- _d ) δ = 8.05 (d, J = 8.681 Hz, 2H) 7.75 (s, 1H ) 7.32 (d, J=8.559Hz, 2H) 7.03-7.10 (m, 2H) 6.92-6.97 (m, 2H) 6.89 (d, J=7.458Hz) , 1H) 6.83 (s, 1H) 5.31-5.35 (m, 1H) 4.31 (s, 2H) 3.33-3.39 (m, 1H) 3.04-3.10 (m, 1H) 2.74-2.81 (m, 2H) 2.41-2.49 (m, 2H) 2.24 (s, 3H).

To a solution of intermediate 3 (80 mg, _168.22 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was added _NH4Cl (44.99 mg, 841.11 umol, 5 eq) at 25°C. The solution was then heated to 90° C. and Fe (46.97 mg, 841.11 umol, 5 eq) was added to the mixture and stirred at 90° C. for 2 hours. The reaction was monitored by TLC and LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (100 mg, crude) as a yellow solid. LCMS: m/z = 446.3 (M+H ⁺ ).

SO ₃ -pyridine (107.16 mg, 673.28 umol, 3 eq) was added to a solution of intermediate 4 (100 mg, 224.43 umol, 1 eq) in pyridine (0.5 mL) and MeCN (0.5 mL). °C and stirred for 0.17 hours. The reaction was monitored upon completion by TLC and LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was purified by preparative HPLC (column: Purified by Agela Durashell C18 150*25 5u; mobile phase: [water (10 mM NH4HCO3)-ACN]; B %: 8% to 43%, 10 min) to yield compound 33 (22.64 mg, 19%). and obtained as a white solid. LCMS: m/z = 526.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.82 (s, 1H) 8.20 (d, J = 8.559 Hz, 1H ) 7.40-7.96 (m, 1H) 7.09-7.17 (m, 2H) 7.06 (s, 1H) 6.93-7.01 (m, 3H) 6.89 (d , J = 8.436Hz, 2H) 6.77 (d, J = 8.437Hz, 2H) 5.08-5.16 (m, 1H) 4.38 (s, 2H) 2.90-2.98 (m, 1H) 2.79-2.86 (m, 1H) 2.74 (t, J = 7.642Hz, 2H) 2.40 (t, J = 7.703Hz, 2H) 2.25 (s , 3H).

Synthesis of compound 34


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (100 mg, 273.0 mg) in DMF (2 mL). 35 umol, 1.2 eq) and Intermediate 2 (37.85 mg, 227.79 umol, 1 eq) was added _Et3N (1.37 mmol, 190.23 uL, 6 eq) and the mixture was brought to 0°C. Cooled and then T3P (341.68 umol, 203.21 uL, 50% purity, 1.5 eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 18 hours. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phase was then washed with brine (2 x 10 mL), dried over anhydrous _Na2SO4 and concentrated in vacuo _. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to yield Intermediate 3 (55 mg, 51%) as a yellow oil. LCMS: m/z = 478.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 8.06 (d, J = 8.681 Hz, 2H) 7.76 (s, 1H ) 7.32 (d, J=8.681Hz, 2H) 7.07 (s, 1H) 6.96-7.03 (m, 1H) 6.87 (s, 1H) 6.54-6.62 (m, 3H) 5.32-5.37 (m, 1H) 4.32 (s, 2H) 3.36-3.37 (m, 1H) 3.05-3.11 (m, 1H) 2 .74 (t, J=7.275 Hz, 2H) 2.40-2.48 (m2 H).

A solution of intermediate 3 (55 mg, 115.17 umol, 1 eq) in EtOH (6 mL) and _H2O (2 mL) was added to _NH4Cl (30.80 mg, 575.87 umol, 20.13 uL, 5 eq). The solution was then heated to 90° C. and Fe (32.16 mg, 575.87 umol, 5 eq) was added to the mixture and stirred at 90° C. for 2 hours. The reaction was monitored by TLC and LCMS for completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (70 mg, crude) as a yellow solid. LCMS: m/z = 448.2 (M+H ⁺ ).

To a solution of intermediate 4 (70 mg, 156.41 umol, 1 eq) in MeCN (1 mL) and pyridine (1 mL) was added SO _-pyridine (74.68 mg, 469.22 umol, 3 eq) at 0 °C, Stirred for 0.17 hours. The reaction was monitored upon completion by TLC and LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Agela Durashell C18 150*25 5u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 4%-34%, 10 min) to yield compound 34 (14 mg, 17%). , was obtained as a white solid. LCMS: m/z = 526.0 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 9.21 (brs, 1H) 8.67 (s, 1H) 8.21 (d, J = 8.436Hz, 1H) 7.74 (brs, 1H) 7.14 (s, 1H) 7.00-7.07 (m, 2H) 6.86-6.92 (m, 2H) ) 6.76-6.83 (m, 2H) 6.53-6.61 (m, 3H) 5.06-5.13 (m, 1H) 4.36 (s, 2H) 2.96 (dd , J = 13.694, 6.847Hz, 1H) 2.82 (dd, J = 13.694, 7.580Hz, 1H) 2.67 (t, J = 7.703Hz, 2H) 2.30-2 .40(m, 2H).

Synthesis of compound 35


To a solution of Intermediate 1 (0.1 g, 246.01 mol, 1 eq) and Intermediate 2 (41.37 mg, 246.01 mol, 1 eq) in DMF (3 mL) was added Et ₃ N (149.36 mg, 1 .48 mmol, 205.45 uL, 6 eq) was added, then the mixture was cooled to 0° C. and T3P (313.10 mg, 492.02 mol, 292.62 uL, 50% purity, 2 eq) was added dropwise, followed by , the reaction was warmed to 25° C. and stirred for 13 h under N ₂ atmosphere. The reaction was monitored for completion by TLC and LCMS and the solution was diluted with ice water (15 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to yield Intermediate 3 (35 mg, 30%) as a yellow solid. LCMS: m/z = 480.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol- _d ) δ = 8.07 (d, J = 8.68 Hz, 2H) 7.66 (s, 1H ) 7.34 (d, J=8.68Hz, 2H) 7.08-7.15 (m, 2H) 7.01 (s, 1H) 6.86-6.93 (m, 3H) 5.28 -5.38 (m, 1H) 4.29 (s, 2H) 3.33-3.40 (m, 1H) 3.06-3.15 (m, 1H) 2.79-2.82 (m , 2H) 2.41-2.48 (m, 2H).

A solution of intermediate 3 (0.04 g, _83.42 umol, 1 eq) and _NH4Cl (22.31 mg, 417.08 umol, 5 eq) in EtOH (1.5 mL) and H2O (0.5 mL) was heated to 90° C., then Fe (23.29 mg, 417.08 umol, 5 eq) was added and the reaction was stirred at 90° C. for 2 hours. The reaction was monitored by TLC and LCMS for completion, the mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (0.03 g, crude) as a yellow solid. LCMS: m/z = 450.3 (M+H ⁺ ).

A solution of intermediate 4 (0.065 g, 144.59 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (69.04 mg, 433.77 umol, 3 eq.) was added at 0°C. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Agela Durashell C18 150). Purified by *25 5u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 7% to 37%, 10 min) to yield compound 35 (7.8 mg, 10%). , was obtained as a white solid. LCMS: m/z = 530.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.83 (s, 1H) 8.24 (d, J = 8.56 Hz, 1H ) 7.74 (brs, 1H) 7.14-7.22 (m, 3H) 7.01-7.11 (m, 3H) 6.86-6.92 (m, 2H) 6.77-6 .79 (m, 2H) 5.08-5.14 (m, 1H) 4.38 (s, 2H) 2.91-2.97 (m, 1H) 2.80-2.86 (m, 1H) ) 2.73-2.77 (m, 2H) 2.37-2.41 (m, 2H).

Synthesis of compound 36


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.1 g, 273.35 umol, 1 eq) and Intermediate 2 (50.46 mg, 273.35 umol, 1 eq) was added _Et3N (165.96 mg, 1.64 mmol, 228.28 uL, 6 eq) followed by After cooling the mixture to 0° C., T3P (34.79 g, 546.69 umol, 32.51 mL, 50% purity, 2 eq) was added dropwise and the reaction was warmed to 25° C. and stirred for 13 h. The reaction was monitored for completion by LCMS and the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo to give a residue. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to yield Intermediate 3 (35 mg, 26%) as a yellow solid. LCMS: m/z = 496.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 8.08 (d, J = 8.80 Hz, 2H) 7.67 (s, 1H ) 7.34 (d, J=8.68Hz, 2H) 7.15-7.20 (m, 2H) 7.07-7.13 (m, 2H) 7.02 (s, 1H) 6.87 (s, 1H) 5.30-5.33 (m, 1H) 4.29 (s, 2H) 3.33-3.39 (m, 1H) 3.05-3.15 (m, 1H) 2 .77-2.85 (m, 2H) 2.42-2.49 (m, 2H).

To a solution of intermediate 3 (0.065 g, _131.05 umol, 1 eq) in EtOH (3 mL) and H2O (1 mL) was added _NH4Cl (35.05 mg, 655.27 umol, 5 eq), The mixture was heated to 90° C. and Fe (36.60 mg, 655.27 umol, 5 eq) was added. The mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (60 mg, 88%) as a yellow solid. LCMS: m/z = 466.2 (M+H ⁺ ).

A mixture of intermediate 4 (0.07 g, 150.22 umol, 1 eq) in Py (1 mL) and MeCN (1 mL) was cooled to 0° C. and SO ₃ -pyridine (71.72 mg, 450.65 umol, 3 equivalent) was added. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored by LCMS when complete, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 to give a residue. The residue was purified by preparative HPLC (column: Agela Durashell C18 150*25 5 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 14%-44%, 10 min), Compound 36 (19.8 mg, 24%) was yielded as a white solid. LCMS: m/z = 546.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.69 (s, 1H) 8.21 (d, J = 8.56 Hz, 1H ) 7.71 (brs, 1H) 7.15-7.33 (m, 4H) 7.02-7.14 (m, 2H) 6.74-6.93 (m, 4H) 5.07-5 .13 (m, 1H) 4.36 (s, 2H) 2.90-3.00 (m, 1H) 2.71-2.86 (m, 3H) 2.37-2.41 (m, 2H ).

Synthesis of compound 37


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.1 g, 273.35 umol, 1 eq) and Intermediate 2 (49.26 mg, 273.35 umol, 1 eq) was added _Et3N (165.96 mg, 1.64 mmol, 228.28 uL, 6 eq) followed by The mixture was cooled to 0° C. and T3P (347.89 mg, 546.69 umol, 325.13 uL, 50% purity, 2 eq) was added dropwise, then warmed to 25° C. and stirred at 25° C. for 13 hours. The reaction was monitored for completion by LCMS and the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (30 mL) _, dried over _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to yield Intermediate 3 (40 mg, 30%) as a yellow solid. LCMS: m/z = 492.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 8.05-8.11 (m, 2H) 7.78 (s, 1H), 7.36 (d, J = 8.68Hz, 2H) 7.08 (s, 1H) 7.04 (d, J = 8.56Hz, 2H) 6.84-687 (m, 1H) 6.73- 6.79 (m, 2H) 5.30-5.40 (m, 1H) 4.33 (s, 2H) 3.75 (s, 3H) 3.35-3.40 (m, 1H) 07-3.12 (m, 1H) 2.76-2.80 (m, 2H) 2.43-2.47 (m, 2H).

To a solution of intermediate 3 (0.075 g, _152.58 umol, 1 eq) in EtOH (3 mL) and H2O (1 mL) was added _NH4Cl (40.81 mg, 762.88 umol, 5 eq), The mixture was heated to 90° C., then Fe (42.61 mg, 762.88 umol, 5 eq) was added. The mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (65 mg, crude) as a yellow solid. LCMS: m/z = 462.3 (M+H ⁺ ).

A mixture of intermediate 4 (0.065 g, 140.82 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (67.24 mg, 422.46 umol). , 3 equivalents) was added slowly. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored upon completion by TLC, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 to give a residue. The residue was purified by preparative HPLC (column: Agela Durashell C18 150*25 5 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-35%, 10 min), Compound 37 (11.7 mg, 15%) was yielded as a white solid. LCMS: m/z = 542.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.87 (s, 1H) 8.17 (s1 H) 6.99-7. 24 (m, 4H) 6.85-6.95 (m, 2H) 6.74-6.84 (m, 4H) 5.00-5.20 (m, 1H) 4.39 (s, 2H) 3.71 (s, 3H) 2.87-2.97 (m, 1H) 2.77-2.86 (m, 1H) 2.67-2.76 (m, 2H) 2.34-2. 43(m, 2H).

Synthesis of compound 38


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.1 g, 246.01 umol, 1 eq) and Intermediate 2 (40.40 mg, 246.01 umol, 1 eq) was added _Et3N (149.36 mg, 1.48 mmol, 205.45 uL, 6 eq) and the mixture was cooled to 0° C., then T3P (313.10 mg, 492.02 umol, 292.62 uL, 50% purity, 2 eq) was added dropwise at 0° C., the reaction was warmed to 25° C., and under N ₂ atmosphere at 25° C. for 13 hours. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo to give a residue. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to yield Intermediate 3 (40 mg, 34%) as a yellow solid. LCMS: m/z = 476.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 8.02-8.07 (m, 2H) 7.65 (d, J = 0 .98Hz, 1H) 7.27-7.37(m, 2H) 7.07-7.12(m, 1H) 7.02-7.06(m, 1H) 7.02-7.10(m , 3H) 6.78 (s, 1H) 5.30-5.33 (m, 1H) 4.28 (s, 2H) 3.35 (dd, J = 13.75, 5.93Hz, 1H) 3 .08 (dd, J=13.69, 8.80 Hz, 1H) 2.75-2.82 (m, 2H) 2.42-2.48 (m, 2H) 2.26 (s, 3H).

To a solution of intermediate 3 (0.04 g, 84.11 umol, 1 eq) in EtOH (1.5 mL) and _H2O (0.5 mL) was added _NH4Cl (22.50 mg, 420.56 umol, 5 eq). ) was added and the mixture was heated to 90° C., then Fe (23.49 mg, 420.56 umol, 5 eq) was added at 90° C. and the reaction was stirred at 90° C. for 2 h. The reaction was monitored for completion by TLC and LCMS, the mixture was filtered and concentrated in vacuo to yield Intermediate 4 (40 mg, crude) as a yellow solid. LCMS: m/z = 446.0 (M+H ⁺ ).

A mixture of intermediate 4 (0.065 g, 145.88 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (69.65 mg, 437.63 umol, 3 eq.) was added in batches. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored by TLC when complete, 7% ammonium hydroxide (1 mL) was added slowly and the mixture was dried by flushing with _N2 to give a residue. The residue was purified by preparative HPLC (column: Agela Durashell C18 150*25 5 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-35%, 10 min), Compound 38 (28.4 mg, 37%) was yielded as a white solid. LCMS: m/z = 526.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.87 (s, 1H) 8.19 (d, J = 8.44 Hz, 1H ) 7.16 (s, 1H) 7.02-7.09 (m, 5H) 6.89 (d, J = 8.44Hz, 2H) 6.77 (d, J = 8.44Hz, 2H) 5 .01-5.18 (m, 1H) 4.39 (s, 2H) 2.94 (dd, J = 13.63, 7.15Hz, 1H) 2.82 (dd, J = 13.51, 7 .40 Hz, 1H) 2.71-2.74 (m, 2H) 2.36-2.40 (m, 2H) 2.25 (s, 3H).

Synthesis of compound 40


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (400 mg, 874.5 mL) in DMF (2 mL). 71 umol, 1 eq) and Intermediate 2 (147.09 mg, 874.71 umol, 1 eq) was added _Et3N (5.25 mmol, 730.49 uL, 6 eq) and the mixture was cooled to 0°C. Then T3P (1.31 mmol, 780.32 uL, 50% purity, 1.5 eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 18 hours. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (30 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic phases were then washed with brine (2 x 10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _yielding Intermediate 3 (540 mg, crude), a yellow oil. obtained as LCMS: m/z = 480.3 (M+H ⁺ ).

To a solution of Intermediate 3 (540 mg, 1.13 mmol, 1 eq) in EtOH (6 mL) and _H2O (2 mL) was added _NH4Cl (301.19 mg, 5.63 mmol, 5 eq) at 25°C. The solution was then heated to 90° C. and Fe (314.44 mg, 5.63 mmol, 5 eq) was added to the mixture and stirred at 90° C. for 2 hours. The reaction was monitored upon completion by TLC and LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (510 mg, crude) as a yellow oil. LCMS: m/z = 450.3 (M+H ⁺ ).

SO ₃ -pyridine (531.07 mg, 3.34 mmol, 3 eq) was added to a solution of intermediate 4 (500 mg, 1.11 mmol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) at 0° C. Stirred for 0.17 hours. The reaction was monitored upon completion by TLC, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with N ₂ and the residue was analyzed by preparative HPLC (column: YMC-Actus Triart). C18 100*30 mm*5 um; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-35%, 10 min) to give compound 40 (62.1 mg, 10%) was obtained as a white solid. LCMS: m/z = 528.1 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.25 (d, J = 8.559 Hz, 1H) 8.05 (s , 1H) 7.66 (brs, 1H) 7.14-7.29 (m, 3H) 6.99-7.10 (m, 6H) 6.85-6.90 (m, 2H) 6.77 -6.82 (m, 2H) 5.01-5.11 (m, 1H) 4.25 (s, 2H) 2.96 (dd, J = 13.694, 6.236Hz, 1H) 2.73 -2.82 (m, 3H) 2.35-2.41 (m2 H).

Synthesis of compound 41


Et ₃ N (150.92 mg, 1.49 mmol, 207.59 uL, 6 eq) was treated with (S)-1-(2-((1H-imidazol-5-yl)methyl)thiazole- in DMF (2 mL). To a solution of 4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.1 g, 248.57 umol, 1 eq) and Intermediate 2 (45.89 mg, 248.57 umol, 1 eq) was added 0 C., then T3P (237.27 mg, 372.86 umol, 221.75 uL, 50% purity, 1.5 eq) was added at 0.degree. C. and the mixture was warmed to 25.degree. C. and stirred for 16 h. The reaction was monitored for completion by TLC and the reaction mixture was poured into ice water (20 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phase was then washed with brine (2 x 10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo . The residue was purified by preparative TLC (dichloromethane:methyl alcohol=10:1) to yield Intermediate 3 (60 mg, 49%) as a white solid. LCMS: m/z = 496.0 (M+H ⁺ ).

A solution of Intermediate 3 (0.06 g, 120.97 umol, 1 eq) in EtOH (1.5 mL) and _H2O (0.5 mL) was heated to 90°C, then _NH4Cl (32. 35 mg, 604.86 umol, 21.15 uL, 5 eq), Fe (33.78 mg, 604.86 umol, 5 eq) were added to the mixture and stirred for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (70 mg, crude) as a yellow solid. LCMS: m/z = 466.2 (M+H ⁺ ).

SO ₃ -pyridine (71.73 mg, 450.65 umol, 3 eq) was added to a solution of intermediate 4 (70 mg, 150.22 umol, 1 eq) in pyridine (0.5 mL) and MeCN (0.5 mL). °C and stirred for 0.17 hours. The reaction was monitored by TLC and LCMS and once complete, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-38%, 12 min) to yield compound 41 (11.5 mg, 14%) as a white solid. LCMS: m/z = 546.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.84 (s, 1H) 8.28 (d, J = 8.436 Hz, 1H ) 7.72 (brs, 1H) 7.37-7.43 (m, 1H) 7.19-7.26 (m, 3H) 7.10-7.18 (m, 3H) 7.07 (s , 1H) 6.95 (s, 1H) 6.89 (d, J = 8.436Hz, 2H) 6.78 (d, J = 8.436Hz, 2H) 5.13 (q, J = 7.254Hz , 1H) 4.38 (s, 2H) 2.81-2.97 (m4 H) 2.41-2.46 (m, 2H).

Synthesis of compound 42


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (200 mg, 546.5 mL) in DMF (2 mL). 69 umol, 1.2 eq) and Intermediate 2 (82.09 mg, 455.58 umol, 1 eq) was added _Et3N (2.73 mmol, 380.47 uL, 6 eq) and the mixture was brought to 0°C. Cooled and then T3P (683.36 umol, 406.42 uL, 50% purity, 1.5 eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 18 hours. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was then washed with brine (2 x 20 mL), dried over anhydrous _Na2SO4 and concentrated in vacuo _. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to yield Intermediate 3 (90 mg, 40%) as a yellow oil. LCMS: m/z = 492.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d4) δ = 8.07 (d, J = 8.314 Hz, 2H) 7.68 (s, 1H) 7.34 (d, J = 8.436Hz, 2H) 7.14 (t, J = 8.070Hz, 1H) 6.96-7.06 (m, 2H) 6.85-6.93 (m, 2H) 6.71-6.79 (m, 1H) 5.29-5.37 (m, 1H) 4.29 (s, 2H) 3.80 (s, 3H) 3.08 (dd, J = 13.572, 8.803 Hz, 1H) 2.68-2.96 (m, 3H) 2.38-2.48 (m, 2H).

To a solution of intermediate 3 (90 mg, _183.09 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was added _NH4Cl (48.97 mg, 915.45 umol, 5 eq) at 25°C. The solution was then heated to 90° C. and Fe (51.12 mg, 915.45 umol, 5 eq) was added to the mixture and stirred at 90° C. for 2 hours. The reaction was monitored by TLC and LCMS for completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (150 mg, crude) as a yellow solid. LCMS: m/z = 462.3 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 8.02 (brs, 1H) 7.09-7.20 (m, 2H) 7 .0 (d, J = 5.733Hz, 1H) 6.74-6.92 (m, 5H) 6.63 (d, J = 7.277Hz, 2H) 5.14-5.24 (m, 1H ) 4.35 (s, 2H) 3.81 (s, 3H) 3.07 (brdd, J = 12.789, 5.513Hz, 1H) 2.78-2.92 (m, H) 2.42 -2.45 (m2 H).

SO ₃ -pyridine (155.17 mg, 974.92 umol, 3 eq) was added to a solution of intermediate 4 (150 mg, 324.97 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) at 0 °C, Stirred for 0.17 hours. The reaction was monitored by TLC and LCMS and once complete, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Agela Durashell C18 150*25 5u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-35%, 10 min) to give compound 42 (34.8 mg, 19%). Obtained as a white solid. LCMS: m/z = 540.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.75 (s, 1H) 8.20 (d, J = 8.314 Hz , 1H) 7.74 (s, 1H) 7.10-7.21 (m, 3H) 7.07 (d, J = 7.214Hz, 1H) 6.86-6.96 (m, 3H) 6 .74-6.85 (m, 3H) 5.08-5.04 (m, 1H) 4.37 (s, 2H) 3.77 (s, 3H) 2.91-2.96 (m, 1H) ) 2.80-2.85 (m, 1H) 2.71-2.75 (m, 2H) 2.33-2.37 (m, 2H).

Synthesis of compound 43


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.1 g, 248.57 umol, 1 eq. HCl), to a solution of Intermediate 2 (40.82 mg, 248.57 umol, 1 eq.) was added _Et3N (150.92 mg, 1.49 mmol, 207.59 uL, 6 eq.). , the mixture was cooled to 0° C., then T3P (237.27 mg, 372.86 umol, 221.75 uL, 50% purity, 1.5 eq) was added dropwise. The reaction was then warmed to 25° C. and stirred at 25° C. for 3 hours. TLC monitored when the reaction was complete. The solution was poured into ice water (20 mL), extracted with ethyl acetate (3 x 10 mL), washed with brine ( ₁₀ mL), dried over anhydrous _Na2SO4 , filtered, then the organic phase was concentrated in vacuo. yielded intermediate 3 (0.15 g, crude) as a yellow oil.

To a solution of intermediate 3 (0.07 g, 147.19 umol, 1 eq) in EtOH (1.5 mL) and _H2O (0.5 mL) was added _NH4Cl (39.37 mg, 735.97 umol, 5 eq). ) was added and the mixture was heated to 90° C., then Fe (41.10 mg, 735.97 umol, 5 eq) was added. The reaction was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (80 mg, crude) as a yellow oil. LCMS: m/z = 446.3 (M+H ⁺ ).

A mixture of intermediate 4 (99.56 mg, 223.44 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (106.69 mg, 670.31 umol, 3 eq.) was added in batches. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored when complete by TLC, 7% ammonium hydroxide (1 mL) was added dropwise and the mixture was dried by flushing with _N2 to give a residue. The residue was purified by preparative HPLC (column: Agela Durashell C18 150*25 5 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 4%-34%, 10 min), Compound 43 (13.5 mg, 11%) was yielded and obtained as a white solid. LCMS: m/z = 526.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.79 (s, 1H) 8.25 (d, J = 8.44 Hz, 1H ) 7.73 (s, 1H) 7.17 (s, 1H) 7.04-7.14 (m, 5H) 6.85-6.92 (m, 2H) 6.73-6.82 (m , 2H) 5.09-5.14 (m, 1H) 4.38 (s, 2H) 2.90-2.98 (m, 1H) 2.79-2.87 (m, 1H) 2.70 -2.77 (m, 2H) 2.34-2.40 (m, 2H) 2.25 (s, 3H).

Synthesis of compound 44


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (300 mg, 820. 04 umol, 1 eq) and Intermediate 2 (158.02 mg, 902.04 umol, 1.1 eq) was added _Et3N (497.88 mg, 4.92 mmol, 684.84 uL, 6 eq) followed by , cooled to 0 °C, then T3P (782.76 mg, 1.23 mmol, 731.55 uL, 50% purity, 1.5 eq) was added dropwise under _N2 at 0 °C and the reaction was brought to 25 °C. and stirred for 3 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding ice water (30 mL) at 25° C. and then extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated in vacuo and the residue was subjected to column chromatography on silica gel (SiO ₂ , petroleum ether:ethyl acetate=5). :1 to 1:1) yielded Intermediate 3A (193 mg, crude) as a yellow solid. LCMS: m/z = 644.2 (M+H ⁺ ).

A solution of Intermediate 3A (511 mg, 793.83 umol, 1 eq) in _NH3 /MeOH (7 M, 2.00 mL, 17.64 eq) was stirred at 60°C for 2 h. The reaction was monitored by LCMS when complete and the solution was dried by flushing with _N2 to yield Intermediate 3 (400 mg, crude) as a yellow solid. LCMS: m/z = 487.2 (M+H ⁺ ).

A solution of intermediate 3 (350 mg, _719.36 umol, 1 eq) and _NH4Cl (192.6 mg, 3.60 mmol, 5 eq) in EtOH (8 mL) and H2O (2 mL) was heated to 90°C. Then Fe (200.86 mg, 3.60 mmol, 5 eq) was added and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored when completed by LCMS, the solution was filtered, concentrated in vacuo and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% _{NH3H 2} O+10 mM NH ₄ HCO ₃ )-ACN]; B%: 5% to 45%, 10 min) yielded intermediate 4 (85 mg, 25%) as a yellow solid. LCMS: m/z = 457.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.22 (d, J = 8.80 Hz, 1H) 7.68 (d, J = 8.19Hz, 2H) 7.60 (d, J = 0.86Hz, 1H) 7.30 (d, J = 8.19Hz, 2H) 6.93-7.03 (m, 2H) 6.79 (d, J = 8.31 Hz, 2H) 6.43 (d, J = 8.31 Hz, 2H) 4.96-5.04 (m, 1H) 4.82 (brs, 2H) 4.19 (s , 2H) 2.96 (brdd, J = 13.82, 5.38Hz, 1H) 2.79-2.85 (m, 2H) 2.71 (brdd, J = 13.75, 9.23Hz, 1H) ) 2.39 (brt, J=7.46 Hz, 2H).

A solution of intermediate 4 (85.00 mg, 186.17 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and SO ₃ . Pyridine (88.90 mg, 558.52 umol, 3 eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*). Mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1%-25%, 10 min) to give compound 44 (38 mg, 37 %), obtained as a white solid. LCMS: m/z = 535.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.56 (s, 1H) 7.63 (d, J = 8.19 Hz , 2H) 7.29 (d, J = 8.19Hz, 2H) 7.19 (s, 1H) 6.95 (s, 1H) 6.79-6.88 (m, 4H) 5.04 (t , J = 7.27Hz, 1H) 4.33 (s, 2H) 2.94 (dd, J = 13.76, 6.42Hz, 1H) 2.81 (brt, J = 7.40Hz, 2H) 2 .73 (dd, J=13.75, 8.25 Hz, 1 H) 2.41 (t, J=7.40 Hz, 2 H).

Synthesis of compound 45


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (300 mg, 820. 04 umol, 1 eq. HCl) and Intermediate 2 (143.66 mg, 820.04 umol, 1 eq.) was added _Et3N (497.88 mg, 4.92 mmol, 684.84 uL, 6 eq.). C., then T3P (521.84 mg, 820.04 umol, 487.70 uL, 50% purity, 1 eq) was added at 0.degree. C., then the mixture was warmed to 25.degree. C. and stirred for 14 h. The reaction was monitored by TLC and LCMS and once complete, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (3 x 10 mL), the combined organic layers were washed with brine (20 mL) and anhydrous _Na2. Dried over _SO4 , filtered and concentrated in vacuo to yield Intermediate 3A (450 mg, crude) as a yellow oil. LCMS: m/z = 644.3 (M+H ⁺ ).

A mixture of Intermediate 3A (450 mg, 699.07 umol, 1 eq) in NH3/MeOH (7 M, 3 mL) was degassed and purged with N2 three times, then the mixture was heated to 60 °C under _N2 atmosphere. and stirred for 1 hour. The reaction was monitored by LCMS for completion and the reaction mixture was concentrated in vacuo to yield Intermediate 3 (370 mg, crude) as a yellow oil. LCMS: m/z = 487.2 (M+H ⁺ ).

A mixture of intermediate 3 (370 mg, _760.46 umol, 1 eq) and _NH4Cl (245.54 mg, 4.56 mmol, 6 eq) in EtOH (15 mL) and H2O (5 mL) was heated to 90°C. Then Fe (254.81 mg, 4.56 mmol, 6 eq) was added and stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS and HPLC and the reaction mixture was concentrated in vacuo. The residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-45%, 10 min) yielded intermediate 4 (90 mg, 25%) as a yellow oil. LCMS: m/z = 457.1 (M+H ⁺ ).

SO ₃ -pyridine (94.13 mg, 591.38 umol, 3 eq) was added to a solution of intermediate 4 (90 mg, 197.13 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) at 0 °C, Stirred for 0.17 hours. The reaction was monitored for completion by TLC and LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge). 150*25 5 u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; .7 mg, 36%), obtained as a white solid. LCMS: m/z = 535.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.71 (s, 1H) 8.26 (d, J = 8.44 Hz , 1H) 7.55-7.67 (m, 3H) 7.39-7.54 (m, 2H) 7.21 (brs, 1H) 7.14 (s, 1H) 7.08 (s, 1H) ) 6.93-6.99 (m, 1H) 6.84-6.92 (m, 2H) 6.74-6.79 (m, 2H) 5.05-5.15 (m, 1H) 4 .37 (s, 2H) 2.92-2.97 (m, 1H) 2.76-2.88 (m, 3H) 2.43-2.47 (m, 2H).

Synthesis of compound 46


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (300 mg, 820. 04 umol, 1 eq) and Intermediate 2 (158.02 mg, 902.04 umol, 1.1 eq) was added _Et3N (497.88 mg, 4.92 mmol, 684.84 uL, 6 eq) followed by Cooled to 0 °C, then T3P (782.76 mg, 1.23 mmol, 731.55 uL, 50% purity, 1.5 eq) was added dropwise at 0 °C under _N2 and the reaction was warmed to 25 °C. and stirred for 3 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding ice water (30 mL) at 25° C. and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 3A (230 mg, crude) as a yellow solid. . LCMS: m/z = 644.2 (M+H ⁺ ).

A solution of Intermediate 3A (406 mg, 630.72 umol, 1 eq) in _NH3 /MeOH (7 M, 2.00 mL, 22.20 eq) was stirred at 60°C for 1 hour. The reaction was monitored by LCMS when complete and the solution was dried by flushing with _N2 to yield Intermediate 3 (365 mg, crude) as a yellow solid. LCMS: m/z = 487.2 (M+H ⁺ ).

A solution of intermediate 3 (365 mg, _750.19 umol, 1 eq) and _NH4Cl (200.62 mg, 3.75 mmol, 5 eq) in EtOH (8 mL) and H2O (2 mL) was heated to 90°C. and then Fe (209.47 mg, 3.75 mmol, 5 eq) was added and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the solution was filtered, concentrated in vacuo and followed by preparative _HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% _NH3H2O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5% to 45%, 10 min) yielded intermediate 4 (95 mg, 27%) as a yellow solid. LCMS: m/z = 455.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.27 (d, J = 8.68 Hz, 1H) 7.75 (dd , J = 7.70, 0.98Hz, 1H) 7.60 (s, 1H) 7.54 (td, J = 7.64, 1.22Hz, 1H) 7.34-7.40 (m, 1H ) 7.28 (d, J = 7.83Hz, 1H) 6.93-7.05 (m, 2H) 6.78 (d, J = 8.31Hz, 2H) 6.42 (d, J = 8 .31Hz, 2H) 4.95-5.05 (m, 1H) 4.80 (s, 2H) 4.17 (brs, 2H) 2.90-2.99 (m, 3H) 2.72 (dd , J=13.69, 9.05 Hz, 1H) 2.43-2.48 (m, 2H).

A solution of intermediate 4 (95 mg, 208.08 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and SO ₃ . Pyridine (99.35mg, 624.23umol, 3eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1% to 25%, 10 min) to give compound 46 (43. 6 mg, 39%), obtained as a white solid. LCMS: m/z = 535.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ +D ₂ O) δ = 8.56 (s, 1H) 7.63 (d, J = 8.19Hz, 2H) 7.29 (d, J = 8.19Hz, 2H) 7.19 (s, 1H) 6.95 (s, 1H) 6.79-6.88 (m, 4H) 04 (t, J = 7.27Hz, 1H) 4.33 (s, 2H) 2.94 (dd, J = 13.76, 6.42Hz, 1H) 2.81 (t, J = 7.40Hz, 2H) 2.73 (dd, J=13.75, 8.25Hz, 1H) 2.41 (t, J=7.40Hz, 2H).

Synthesis of compound 47


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (300 mg, 820. 04 umol, 1 eq) and Intermediate 2 (178.91 mg, 820.04 umol, 1 eq)) was added _Et3N (497.88 mg, 4.92 mmol, 684.84 uL, 6 eq) followed by Cooled to 0 °C, then T3P (782.76 mg, 1.23 mmol, 731.55 uL, 50% purity, 1.5 eq) was added dropwise at 0 °C under _N2 and the reaction was warmed to 25 °C. and stirred for 3 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding ice water (30 mL) at 25° C. and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 3A (200 mg, crude) as a yellow solid. rice field. LCMS: m/z = 730.1 (M+H ⁺ ).

A solution of Intermediate 3A (411 mg, 563.25 umol, 1 eq) in _NH3 /MeOH (7 M, 2.00 mL, 24.86 eq) was stirred at 60°C for 1 hour. The reaction was monitored by LCMS when complete and the solution was dried by flushing with _N2 to yield Intermediate 3 (352 mg, crude) as a yellow solid. LCMS: m/z = 530.1 (M+H ⁺ ).

A solution of intermediate 3 (352 mg, _664.74 umol, 1 eq) and _NH4Cl (177.62 mg, 3.75 mmol, 5 eq) in EtOH (8 mL) and H2O (2 mL) was heated to 90°C. and then Fe (185.61 mg, 3.32 mmol, 5 eq) was added and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the solution was filtered, concentrated in vacuo and followed by preparative _HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% _NH3H2O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 25%-45%, 10 min) yielded intermediate 4 (94 mg, 25%) as a yellow solid. LCMS: m/z = 500.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 11.92 (brs, 1H) 8.24 (d, J = 8.82 Hz, 1H ) 7.52-7.63 (m, 3H) 7.33 (d, J = 8.16Hz, 2H) 7.02 (s, 1H) 6.87 (s, 1H) 6.79 (d, J = 8.16Hz, 2H) 6.42 (d, J = 8.38Hz, 2H) 4.91-5.11 (m, 1H) 4.16 (s, 2H) 2.89-3.02 (m , 1H) 2.78-2.86 (m, 2H) 2.68-2.74 (m, 1H) 2.36-2.42 (m, 2H).

A solution of intermediate 4 (91 mg, 182.16 umol, 1 eq.) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and SO ₃ . Pyridine (86.98mg, 546.49umol, 3eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (1.5 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-35%, 10 min) to give compound 47 ( 36.04 mg, 33%), obtained as a white solid. LCMS: m/z = 578.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.73 (s, 1H) 8.26 (d, J = 8.44 Hz , 1H) 7.72 (brs, 1H) 7.60 (d, J = 8.19Hz, 2H) 7.39 (d, J = 7.95Hz, 2H) 7.20 (s, 1H) 7.13 (s, 1H) 7.08 (s, 1H) 6.86-6.91 (m, 2H) 6.79 (d, J = 8.44Hz, 2H) 5.11 (q, J = 7.70Hz , 1H) 4.36 (s, 2H) 2.94 (dd, J = 13.63, 6.91Hz, 1H) 2.76-2.87 (m, 3H) 2.38-2.46 (m , 2H).

Synthesis of compound 48


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (300 mg, 820. 04 umol, 1 eq. HCl), Intermediate 2 (178.91 mg, 820.04 umol, 1 eq.), and _Et3N (497.88 mg, 4.92 mmol, 684.84 uL, 6 eq.) at 0°C. was cooled to , then T3P (782.76 mg, 1.23 mmol, 731.55 uL, 50% purity, 1.5 eq) was added at 0° C., then the mixture was warmed to 25° C. and stirred for 14 hours. The reaction was monitored for completion by TLC and LCMS, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (3 x 10 mL), the combined organic layers were washed with brine 20 mL, anhydrous _{Na2SO4 .} , filtered and concentrated in vacuo to give Intermediate 3A (420 mg, crude). LCMS: m/z = 730.3 (M+H ⁺ ).

A mixture of Intermediate 3A (420 mg, 575.59 umol, 1 eq) in _NH3 /MeOH (7 M, 3 mL) was degassed and purged with _N2 three times, then the mixture was treated under _N2 atmosphere with Stir at 60° C. for 1 hour. The reaction was monitored by LCMS for completion and the reaction mixture was concentrated in vacuo to yield Intermediate 3 (390 mg, crude) as a yellow oil. LCMS: m/z = 530.2 (M+H ⁺ ).

A mixture of intermediate 3 (390 mg, _736.50 umol, 1 eq) and _NH4Cl (237.80 mg, 4.42 mmol, 6 eq) in EtOH (15 mL) and H2O (5 mL) was heated to 90°C. Then Fe (246.78 mg, 4.42 mmol, 6 eq) was added and stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS and HPLC and the reaction mixture was concentrated in vacuo. The residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 10%-50%, 10 min) yielded intermediate 4 (80 mg, 21%) as a yellow oil. LCMS: m/z = 500.2 (M+H ⁺ ).

SO ₃ -pyridine (76.47 mg, 480.43 umol, 3 eq) was added to a solution of intermediate 4 (80 mg, 160.14 umol, 1 eq) in pyridine (0.5 mL) and MeCN (0.5 mL). C. and stirred for 0.17 hours. The reaction was monitored for completion by TLC and LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was purified by preparative HPLC (column : Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-35%, 10 min) to give compound Yield 48 (50.1 mg, 52%) as a white solid. LCMS: m/z = 578.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.80 (s, 1H) 8.26 (d, J = 8.44 Hz , 1H) 7.75 (s, 1H) 7.43-7.59 (m, 4H) 7.21 (s, 1H) 7.15 (s, 1H) 7.09 (s, 1H) 7.06 (s, 1H) 6.95 (s, 1H) 6.88 (d, J = 8.31Hz, 2H) 6.77 (d, J = 8.31Hz, 2H) 5.03-5.19 (m , 1H) 4.20-4.45 (s, 2H) 2.75-2.99 (m, 4H) 2.42-2.48 (m, 2H).

Synthesis of compound 49


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.3 g, 731.19 umol, 1 eq) and Intermediate 2 (159.53 mg, 731.19 umol, 1 eq) was added _Et3N (443.94 mg, 4.39 mmol, 610.64 uL, 6 eq) followed by , the solution was cooled to 0° C., then T3P (930.61 mg, 1.46 mmol, 869.73 uL, 50% purity, 2 eq) was added dropwise at 0° C., then the solution was stirred at 25° C. for 3 h. bottom. The reaction was monitored upon completion by LCMS, the solution was poured into ice water, extracted with ethyl acetate (3 x 10 mL), the combined organic phases were washed with brine (10 mL) and dried over _{anhydrous Na2SO4} . , filtered and concentrated in vacuo to yield Intermediate 3 (412 mg, crude) as a yellow solid. LCMS: m/z = 730.0 (M+H ⁺ ).

Intermediate 3 (400 mg, 548.18 umol, 1 eq) in _NH3 /MeOH (7 M, 2 mL, 25.54 eq) was stirred at 50°C for 1 hour. The reaction was monitored for completion by LCMS and the solution was concentrated in vacuo to yield Intermediate 4 (320 mg, crude) as a yellow solid. LCMS: m/z = 530.2 (M+H ⁺ ).

To a solution of intermediate 4 (300 mg, 566.54 umol, 1 eq) in EtOH (7 mL) and _H2O (5 mL) was added _NH4Cl (155.26 mg, 2.83 mmol, 5 eq) at 25°C. The solution was then warmed to 90° C., Fe (158.19 mg, 2.83 mmol, 5 eq) was then added, and the mixture was then stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: UniSil 120*30*10um; mobile phase: [water (0.05% HCl)-ACN]; B%: 1%-35%, 11 min) to give an intermediate Yield 5 (100 mg, 34%) obtained as a yellow solid. LCMS: m/z = 500.2 (M+H ⁺ ).

A solution of intermediate 5 (100 mg, 200.15 umol, 1 eq) in pyridine (2 mL) and CH ₃ CN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (95.58 mg, 0.6 mmol). , 3 equivalents) was added at 0°C and the reaction mixture was stirred at 0°C for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*). Mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-35%, 10 min) to give compound 49 (55 mg, 15 %), obtained as a white solid. LCMS: m/z = 578.0 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.66 (s, 1H) 8.35 (d, J = 8.33 Hz, 1H) 7.76 (brs, 1H) 7.65 (d , J=7.89Hz, 1H) 7.50-7.58(m, 1H) 7.33-7.42(m, 2H) 7.21(s, 1H) 7.13-7.20(m , 2H) 7.09 (s, 1H) 6.97 (s, 1H) 6.86-6.92 (m, 2H) 6.80 (d, J = 8.33Hz, 2H) 5.10-5 .15 (m, 1H) 4.36 (s, 2H) 2.92-2.98 (m, 3H) 2.80-2.87 (m, 1H) 2.41-2.45 (m, 2H ).

Synthesis of compound 50


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.3 g, 731.19 umol, 1 eq) and Intermediate 2 (140.57 mg, 731.19 umol, 1 eq) was added _Et3N (443.94 mg, 4.39 mmol, 610.64 uL, 6 eq) followed by , the solution was cooled to 0° C., then T3P (930.61 mg, 1.46 mmol, 869.73 uL, 50% purity, 2 eq) was added dropwise at 0° C., then the solution was stirred at 25° C. for 3 h. bottom. The reaction was monitored when complete by LCMS and the solution was dried by flushing with _N2 to yield Intermediate 3 (456 mg, crude) as a yellow solid, LCMS: m/z=678.3. (M+H ⁺ ).

Intermediate 3 (450 mg, 663.86 umol, 1 eq) in _NH3 /MeOH (7 M, 2 mL, 21.09 eq) was stirred at 50°C for 1 hour. The reaction was monitored for completion by LCMS and the solution was concentrated in vacuo to yield Intermediate 4 (341 mg, crude) as a yellow solid. LCMS: m/z = 504.2 (M+H ⁺ ).

To a solution of intermediate 4 (0.33 g, _655.26 umol, 1 eq) in EtOH (7 mL) and H2O (5 mL) was added _NH4Cl (179.58 mg, 3.28 mmol, 5 eq) at 25°C. then the solution was warmed to 90° C., then Fe (182.97 mg, 3.28 mmol, 5 eq) was added, then the mixture was stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 20%-50%, 10 min) yielded intermediate 5 (80 mg, 26%) as a pale yellow solid. LCMS: m/z = 474.4 (M+H ⁺ ).

A solution of intermediate 5 (80 mg, 168.91 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (80.65 mg, 506.72 umol, 3 equivalent) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5% to 35%, 10 min) to give compound 50 (45. 6 mg, 49%), obtained as a white solid. LCMS: m/z = 552.4 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.84 (s, 1H) 8.21 (d, J = 8.68 Hz, 1H) 7.21 (s, 1H) 7.15 (s , 1H) 7.06-7.13 (m, 5H) 7.02 (s, 1H) 6.95 (s, 1H) 6.88 (d, J = 8.31Hz, 2H) 6.77 (d , J = 8.31Hz, 2H) 5.06-5.18 (m, 1H) 4.38 (s, 2H) 2.93 (dd, J = 13.69, 7.21Hz, 1H) 2.79 -2.86 (m, 2H) 2.73 (t, J = 7.58Hz, 2H) 2.39 (t, J = 7.70Hz, 2H) 1.17 (d, J = 6.85Hz, 6H) ).

Synthesis of compound 51


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (400 mg, 874.5 mL) in DMF (3 mL). 71 umol, 1 eq.) and Intermediate 2 (199.66 mg, 874.71 umol, 1 eq.) was added _Et3N (531.07 mg, 5.25 mmol, 730.49 uL, 6 eq.) dropwise. C., then T3P (1.11 g, 1.75 mmol, 1.04 mL, 50% purity, 2 eq) was added at 0.degree. C., then the mixture was warmed to _25.degree . C. for 3 hours. LCMS monitored when the reaction was complete. The mixture was poured into ice water (25 mL), then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 3 (376 mg, crude) as a yellow oil. LCMS: m/z = 540.1 (M+H ⁺ ).

A solution of intermediate 3 (345 mg, _639.33 umol, 1 eq) and _NH4Cl (169.6 mg, 3.20 mmol, 5 eq) in EtOH (3 mL) and H2O (1 mL) was heated to 90°C. and then Fe (178.52 mg, 3.20 mmol, 5 eq) was added at 90° C. under N ₂ and the mixture was then stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 4 (433 mg, crude) as a yellow solid. LCMS: m/z = 510.0 (M+H ⁺ ).

A solution of intermediate 4 (383 mg, 751.51 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (358.83 mg, 2.25 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1% to 25%, 10 min) to give compound 51 (71. 4 mg, 15%), obtained as a white solid. LCMS: m/z = 590.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ = 8.70 (s, 1H) 8.28 (d, J = 8.6 Hz, 1H) 7.79 (d, J = 7.9Hz, 2H) 7.65-7.76 (m, 1H) 7.42 (d, J = 7.9Hz, 2H) 7.20 (s, 1H) 7.13 (d, J = 13.1Hz, 2H) 7.08 (s, 1H) 6.95 (s, 1H) 6.84-6.92 (m, 2H) 6.75-6.83 ( m, 2H) 5.11 (m, 1H) 4.36 (s, 2H) 3.17 (s, 3H) 2.77-3.00 (m, 4H) 2.43-2.47 (m, 2H).

Synthesis of compound 52


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (400 mg, 874.5 mL) in DMF (4 mL). 71 umol, 1 eq) and Intermediate 2 (175.14 mg, 874.71 umol, 1 eq) was added _Et3N (531.07 mg, 5.25 mmol, 730.49 uL, 6 eq) and then the solution was was cooled to 0° C., then T3P (1.11 g, 1.75 mmol, 1.04 mL, 50% purity, 2 eq) was added dropwise at 0° C., then the solution was stirred at 25° C. for 3 hours. The reaction was monitored by LCMS when complete and the solution was dried by flushing with _N2 to yield Intermediate 3 (776 mg, crude) as a yellow solid. LCMS: m/z = 694.2 (M+H ⁺ ).

_NH3 . Intermediate 3 (770 mg, 1.11 mmol, 1 eq) in MeOH (2 mL, 1.00 eq) was stirred at 50° C. for 1 hour. The reaction was monitored by LCMS when complete and the solution was dried by flushing with _N2 to yield Intermediate 4 (996 mg, crude) as a yellow solid. LCMS: m/z = 512.3 (M+H ⁺ ).

To a solution of intermediate 5 (900 mg, 1.76 mmol, 1 eq) in EtOH (20 mL) and _H2O (5 mL) was added _NH4Cl (482.11, 8.80 mmol, 5 eq) at 25°C. The solution was then warmed to 90° C., then Fe (491.21 mg, 8.80 mmol, 5 eq) was added, and the mixture was then stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 5 (310 mg, 35%) as a yellow solid. LCMS: m/z = 482.3 (M+H ⁺ ).

A solution of intermediate 5 (300 mg, 622.91 umol, 1 eq) in pyridine (2 mL) and CH ₃ CN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (297.43 mg, 1.87 mmol). , 3 equivalents) was added at 0°C and the reaction mixture was stirred at 0°C for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; 11%), obtained as a white solid. LCMS: m/z = 560.1 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.35-8.44 (m, 1H) 7.97-8.04 (m, 1H) 7.81-7.91 (m, 1H) ) 7.69-7.77 (m, 1H) 7.42-7.59 (m, 2H) 7.29-7.39 (m, 1H) 7.21-7.27 (m, 1H) 7 .10-7.17 (m, 1H) 6.93-7.01 (m, 1H) 6.76-6.89 (m, 4H) 5.01-5.10 (m, 1H) 4.30 (s, 2H) 3.14-3.24 (m, 2H) 2.88-3.00 (m, 1H) 2.70-2.79 (m, 1H), 2.53-2.54 ( m, 2H).

Synthesis of compound 53


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (400 mg, 874.5 mL) in DMF (5 mL). 71 umol, 1 eq) and Intermediate 2 (175.14 mg, 874.71 umol, 1 eq)) was added _Et3N (531.07 mg, 5.25 mmol, 730.49 uL, 6 eq) followed by Cooled to 0 °C, then T3P (834.94 mg, 1.31 mmol, 780.32 uL, 50% purity, 1.5 eq) was added dropwise at 0 °C under _N2 and the reaction was warmed to 25 °C. and stirred for 1 hour. The reaction was monitored by LCMS when completed and the reaction mixture was dried by flushing with _N2 to yield Intermediate 3A (220 mg, crude) as a yellow solid. LCMS: m/=694.2 (M+H ⁺ ).

A solution of Intermediate 3A (447 mg, 644.27 umol, 1 eq) in _NH3 /MeOH (7 M, 2.00 mL, 21.73 eq) was stirred at 60°C for 1 hour. The reaction was monitored by LCMS when complete and the solution was dried by flushing with _N2 to yield Intermediate 3 (329 mg, crude) as a yellow solid. LCMS: m/z = 512.1 (M+H ⁺ ).

A solution of intermediate 3 (329 mg, 643.09 umol, 1 eq) and _NH4Cl (237.0 mg, 4.43 mmol, 10 eq) in EtOH ( ₈ mL) and H2O (2 mL) was heated to 90°C. and then Fe (359.13 mg, 6.43 mmol, 10 eq) was added and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the solution was filtered, concentrated in vacuo and preparative HPLC (column: Phenomenex luna(2) C18 250*50 10 u; mobile phase: [water (10 mM _{NH4HCO3 )} -ACN]; B%: 40%-50%, 20 min) yielded intermediate 4 (153 mg, 47%) as a blue solid. LCMS: m/z = 480.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.24 (d, J = 8.38 Hz, 1H) 7.83-7 .89 (m, 1H) 7.73-7.82 (m, 2H) 7.61 (d, J=12.79Hz, 2H) 7.41-7.49 (m, 2H) 7.32 (dd , J = 8.38, 1.54 Hz, 1H) 6.97 (brs, 1H) 6.87 (s, 1H) 6.79 (d, J = 8.16Hz, 2H) 6.41 (d, J = 8.38Hz, 2H) 4.97-5.04 (m, 1H) 4.83 (brs, 1H) 4.17 (s, 2H) 2.88-2.99 (m, 3H) 2.68 -2.75 (m, 1H) 2.42-2.47 (m, 2H).

A solution of intermediate 4 (153 mg, 317.68 umol, 1 eq.) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and SO ₃ . Pyridine (151.69 mg, 953.05 umol, 3 eq) was added at 0°C. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (1.5 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge). 150*25 5 u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; .0 mg, 33%), obtained as a white solid. LCMS: m/z = 560.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.14 (s, 1H) 7.83 (d, J = 7.46 Hz , 1H) 7.77 (t, J = 7.95Hz, 2H) 7.62 (s, 1H) 7.39-7.47 (m, 2H) 7.32 (d, J = 8.56Hz, 1H) ) 7.04 (s, 1H) 6.85-6.92 (m, 2H) 6.80-6.82 (m, 3H) 5.04 (t, J = 7.27Hz, 1H) 4.23 (s, 2H) 2.93-3.00 (m, 1H) 2.88-2.93 (m, 2H) 2.73 (dd, J = 13.82, 8.56Hz, 1H) 2.39 -2.48 (m, 2H).

Synthesis of compound 54


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (300 mg, 820. 04 umol, 1 eq) and Intermediate 2 (198.67 mg, 820.04 umol, 1 eq) was added _Et3N (497.88 mg, 4.92 mmol, 684.84 uL, 6 eq) dropwise. C., then T3P (521.84 mg, 1.64 mmol, 487.70 uL, ₂ eq) was added at 0.degree. C., then the mixture was warmed to 25.degree. Stirred. LCMS monitored when the reaction was complete. The mixture was poured into ice water (25 mL) and stirred for 10 minutes. The mixture was then extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 3 (320 mg, crude) as a yellow oil. LCMS: m/z = 778.3 (M+H ⁺ ).

A solution of Intermediate 3 (320 mg, 411.84 umol, 1 eq) in _NH3 /MeOH (10 mL) was heated to 60 C and stirred at 60 C for 2 hours under _N2 atmosphere. LCMS monitored when the reaction was complete. The mixture was concentrated in vacuo to yield Intermediate 4 (200 mg, crude) as a yellow oil. LCMS: m/z = 554.2 (M+H ⁺ ).

To a solution of intermediate 4 (200 mg, 361.66 umol, 1 eq) in EtOAc (5 mL) was added _SnCl2 . 2H ₂ O (407.58 mg, 1.81 mmol, 5 eq) was added, heated to 50° C. and stirred at 90° C. under N ₂ for 2 hours. The reaction was monitored by LCMS for completion and the solution was added to saturated Seniet's salt (20 mL) then filtered, the filtrate was extracted with ethyl acetate (2 x 10 mL) and the combined organic layers were washed with brine (5 mL). , filtered and concentrated in vacuo to give Intermediate 5 (80 mg, crude) as a pale yellow solid. LCMS: m/z = 546.2 (M+Na ⁺ ).

A solution of intermediate 5 (80 mg, 152.77 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (72.95 mg, 458.32 umol, 3 eq). ) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5% to 35%, 10 min) to give compound 54 (7. 0 mg, 7%), obtained as a white solid. LCMS: m/z=602.0 (M−H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ=8.82 (s, 1H) 8.25 (d, J=8. 4Hz, 1H) 7.76 (brs, 1H) 7.26-7.44 (m, 2H) 7.14-7.25 (m, 3H) 7.06-7.14 (m, 2H) 96 (m, J = 8.6, 2H) 6.84-6.93 (m, 4H) 6.79 (m, 2H) 5.08-5.16 (m, 1H) 4.38 (s, 2H) 2.90-2.97 (m 1H) 2.70-2.87 (m, 3H) 2.37-2.43 (m, 2H).

Synthesis of compound 55


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (400 mg, 874.5 mL) in DMF (4 mL). 71 umol, 1 eq) and Intermediate 2 (169.03 mg, 874.71 umol, 1 eq) was added _Et3N (531.07 mg, 5.25 mmol, 730.49 uL, 6 eq) and then the solution was was cooled to 0° C., then T3P (1.11 g, 1.75 mmol, 1.04 mL, 50% purity, 2 eq) was added dropwise at 0° C., then the solution was stirred at 25° C. for 3 hours. The reaction was monitored by LCMS when complete and the solution was dried by flushing with _N2 to yield Intermediate 3 (715 mg, crude) as a yellow solid. LCMS: m/z = 505.2 (M+H ⁺ ).

To a solution of intermediate 3 (700 mg, 1.39 mmol, 1 eq) in EtOH (16 mL) and _H2O (5 mL) was added _NH4Cl (380.17 mg, 6.94 mmol, 5 eq) at 25°C. The solution was then warmed to 90° C., Fe (387.35 mg, 6.94 mmol, 5 eq) was then added, and the mixture was then stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (628 mg, crude) as a dark brown solid. LCMS: m/z = 475.1

A solution of intermediate 4 (628 mg, 1.32 mmol, 1 eq) in pyridine (3 mL) and MeCN (3 mL) was cooled to 0° C. and then SO ₃ -pyridine (631.80 mg, 3.97 mmol, 3 eq). ) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*). Mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5% to 35%, 10 min) to give compound 55 (10 mg, 1 %), obtained as a pale yellow solid. LCMS: m/z = 553.1 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.69-8.86 (m, 1H) 8.10-8.27 (m, 1H) 7.11-7.18 (m, 1H) ) 6.97-6.99 (m, 3H) 6.85-6.91 (m, 2H) 6.78 (d, J = 8.44Hz, 2H) 6.63 (d, J = 8.68Hz , 2H) 5.02-5.17 (m, 1H) 4.37 (s, 2H) 2.90-3.00 (m, 1H) 2.76-2.84 (m, 7H) 2.64 -2.66 (m, 2H) 2.32-2.33 (m2 H).

Synthesis of compound 56


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (400 mg, 970.11 umol, 1 eq., HBr), to a solution of Intermediate 2 (186.94 mg, 1.07 mmol, 1.1 eq.) was added _Et3N (588.99 mg, 5.82 mmol, 810.17 uL, 6 eq.) and the reaction mixture was was cooled to 0° C., then T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 1.5 eq) was added, which was then warmed to 25° C. under N ₂ atmosphere. and stirred for 13 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding ice water (60 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo to give a residue. The residue was purified by column chromatography silica gel (SiO ₂ , petroleum ether:ethyl acetate=10:1 to 1:1) to yield Intermediate 3 (440 mg, 88%) as a yellow solid. LCMS: m/z = 489.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.47 (d, J = 8.68 Hz, 1H) 8.07-8.15 (m, 2H) 7.72 (dd, J=5.07, 1.04 Hz, 1H) 7.59-7.69 (m, 3H) 7.45-7.50 (m, 2H) 24-7.34 (m, 3H) 7.17 (dd, J = 5.01, 3.79Hz, 1H) 5.21-5.30 (m, 1H) 3.32-3.37 (m, 1H) 3.09-3.17 (m, 1H) 2.80-2.84 (m, 2H) 2.36-2.45 (m, 2H).

To a solution of intermediate 3 (440 mg, _900.57 umol, 1 eq) in EtOH (7 mL) and H2O (2 mL) was added _NH4Cl (246.80 mg, 4.50 mmol, 5 eq) followed by The mixture was heated to 90° C., Fe (251.46 mg, 4.50 mmol, 5 eq) was added and the mixture was stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (453 mg, crude) as a yellow solid. LCMS: m/z = 459.2 (M+H ⁺ ).

A mixture of intermediate 3 (453 mg, 987.79 umol, 1 eq.) in MeCN (3 mL) and pyridine (3 mL) was cooled to 0° C. and then SO ₃ -pyridine (471.66 mg, 2.96 mmol, 3 equivalent) was added and the reaction was stirred at 0° C. for 10 minutes. The reaction was monitored by TLC when complete, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with _N2 to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O)-ACN]; B%: 10%-40%, 10 min). yielded compound 56 (163 mg, 31%) as a white solid. LCMS: m/z = 537.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.32 (d, J = 8.44 Hz, 1H) 7.63-7 .73 (m, 4H) 7.33 (d, J=7.82Hz, 2H) 7.15-7.23 (m, 3H) 7.08 (s, 1H) 6.96 (s, 1H) 6 .85-6.93 (m, 4H) 5.04-5.12 (m, 1H) 3.01-3.06 (m, 1H) 2.79-2.88 (m, 3H) 2.40 -2.45 (m, 2H).

Synthesis of compound 57


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (400 mg, 970.11 umol, 1 equiv., HBr), to a mixture of Intermediate 2 (178.45 mg, 1.02 mmol, 1.05 equiv.) was added _Et3N (588.99 mg, 5.82 mmol, 810.17 uL, 6 equiv.) at 25°C. The solution was then cooled to 0° C. and T3P (1.23 g, 1.94 mmol, 1.15 mL, 50% purity, 2 eq) was added dropwise, which was then warmed to 25° C. and stirred for 15 h. bottom. The reaction was monitored for completion by TLC, H ₂ O (50 mL) was added to the reaction mixture, extracted with ethyl acetate (3 x 30 mL), then the combined organic phases were washed with brine (50 mL) and dried over anhydrous Na. ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , dichloromethane:methyl alcohol=100:1 to 50:1) to yield Intermediate 3 (420 mg, 74%) as a yellow oil. LCMS: m/z = 489.2 (M+H ⁺ ).

A mixture of intermediate 3 (420 mg, _859.63 umol, 1 eq) and _NH4Cl (284.06, 5.16 mmol, 6 eq) in EtOH (10 mL) and H2O (2 mL) was heated to 90°C. Then Fe (288.04 mg, 5.16 mmol, 6 eq) was added and then stirred at 90° C. for 2 h under N ₂ atmosphere. The reaction was monitored when completed by TLC and the solution was concentrated in vacuo to yield Intermediate 4 (450 mg, crude) as a yellow oil. ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.46 (d, J = 8.68 Hz, 1H) 8.09 (d, J = 8.68 Hz, 2H) 7.72 (dd, J = 5.07, 0.92Hz, 1H) 7.65 (dd, J = 3.67, 0.98Hz, 1H) 7.53-7.61 (m, 2H) 7.44-7.47 (m , 3H) 7.36-7.42 (m, 1H) 7.27 (s, 1H) 7.17 (dd, J = 5.01, 3.79Hz, 1H) 5.17-5.33 (m , 1H) 3.29-3.31 (m, 1H) 3.08-3.14 (m, 1H) 2.74-2.85 (m, 2H) 2.38-2.46 (m, 2H) ).

SO ₃ -pyridine (499.77 mg, 3.14 mmol, 3 eq) was added to a solution of intermediate 4 (480 mg, 1.05 mmol, 1 eq), pyridine (5 mL), and MeCN (5 mL) at 0° C. Then it was stirred at 0° C. for 10 minutes. The reaction was monitored upon completion by LCMS and HPLC and the solution was dried by flushing with _N2 . The residue was first analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O)-ACN]; B%: 10%-40%, 10 min). and then it was subjected to preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 10%-40%, 10 min) yielded compound 57 (24.5 mg, 4%). LCMS: m/z = 537.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.30 (d, J = 8.56 Hz, 1H) 7.69-7 .73 (m, 1H) 7.62-7.64 (m, 2H) 7.60 (d, J=7.34Hz, 1H) 7.38-7.50 (m, 2H) 7.20-7 .23 (m, 1H) 7.15-7.18 (m, 1H) 7.12 (s, 1H) 7.08 (s, 1H) 6.96 (s, 1H) 6.83-6.91 (m, 4H) 4.99-5.15 (m, 1H) 2.98-3.07 (m, 1H) 2.60-2.83 (m, 3H) 2.38-2.47 (m , 2H).

Synthesis of compound 58


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (400 mg, 970.11 umol, 1 eq., HBr), to a solution of Intermediate 2 (186.94 mg, 1.07 mmol, 1.1 eq.) was added _Et3N (588.99 mg, 5.82 mmol, 810.17 uL, 6 eq.) and the mixture was Cool to 0° C. and add T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 1.5 eq), then warm it to 25° C. under N ₂ atmosphere for 13 h. Stirred. The reaction was monitored by LCMS for completion and the reaction mixture was quenched with ice water (40 mL) and then extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography silica gel (SiO ₂ , petroleum ether:ethyl acetate=10:1 to 5:1) to yield Intermediate 3 (362 mg, 76%) as a yellow solid. LCMS: m/z = 489.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.51 (d, J = 8.56 Hz, 1H) 8.09 (d, J = 8.68Hz, 2H) 7.68-7.77 (m, 2H) 7.65 (dd, J = 3.67, 1.10Hz, 1H) 7.44-7.53 (m, 3H) 7 .29-7.35 (m, 3H) 7.17 (dd, J = 5.01, 3.79Hz, 1H) 5.22-5.30 (m, 1H) 3.33-3.37 (m , 1H) 3.09-3.15 (m, 1H) 2.91-2.95 (m, 2H) 2.44-2.49 (m, 2H).

To a solution of intermediate 3 (362 mg, _740.92 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was added _NH4Cl (204.53 mg, 3.70 mmol, 5 eq) followed by The mixture was heated to 90° C. and Fe (206.88 mg, 3.70 mmol, 5 eq) was added, then the mixture was stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (562 mg, crude) as a yellow solid. LCMS: m/z = 459.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.44 (d, J = 8.56 Hz, 1H) 7.68-7.77 (m, 2H) 7.62 (d, J=3.06Hz, 1H) 7.49-7.60 (m, 2H) 7.27-7.34 (m, 2H) 7.13-7.20 (m, 2H) 6.80 (d, J = 7.95Hz, 2H) 6.42 (d, J = 7.95Hz, 2H) 4.97-5.10 (m, 1H) 2.91-3 .12 (m, 4H) 2.69-2.90 (m, 2H).

A mixture of intermediate 4 (562 mg, 1.23 mmol, 1 eq) in MeCN (3 mL) and pyridine (3 mL) was cooled to 0° C. and then SO ₃ -pyridine (585.15 mg, 3.68 mmol, 3 equivalent) was added dropwise and it was then stirred for 10 minutes. The reaction was monitored by TLC when complete, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with _N2 to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O)-ACN]; B%: 5%-40%, 10 min). yielded compound 58 (140 mg, 21%) as a white solid. LCMS: m/z = 537.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.37 (d, J = 8.38 Hz, 1H) 7.68-7 .76 (m, 2H) 7.63 (dd, J=3.53, 0.88Hz, 1H) 7.52-7.58 (m, 1H) 7.28-7.37 (m, 2H) 7 .21 (s, 1H) 7.14-7.18 (m, 2H) 7.08 (s, 1H) 6.95 (s, 1H) 6.79-6.93 (m, 4H) 5.01 -5.11 (m, 1H) 2.95-3.05 (m, 3H) 2.80-2.86 (m, 1H) 2.51-2.53 (m, 2H).

Synthesis of compound 59


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (400 mg, 970.11 umol, 1 .1 eq) and Intermediate 1 (192.41 mg, 881.92 umol, 1 eq) was added dropwise _Et3N (535.45 mg, 5.29 mmol, 736.52 uL, 6 eq) at 0°C. and then T3P (420.91 mg, 1.32 mmol, 393.38 uL, 1.5 eq) was added at 0 °C, then the mixture was warmed to 25 °C and 16 at 25 °C under _N2 atmosphere. Stirred for an hour. LCMS monitored when the reaction was complete. The mixture was poured into ice water (25 mL) and stirred for 10 minutes. The mixture was then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=10:1 to 1:1) to yield Intermediate 2 (430 mg, 87%) as a yellow solid. LCMS: m/z = 532.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.06 (d, J = 8.82 Hz, 2H) 7.49-7.54 (m , 3H) 7.44 (dd, J = 5.07, 1.10Hz, 1H) 7.31 (d, J = 7.94Hz, 2H) 7.17 (d, J = 8.82Hz, 2H) 7 .11 (dd, J = 4.96, 3.64Hz, 1H) 6.64 (s, 1H) 6.27 (d, J = 8.38Hz, 1H) 5.27-5.35 (m, 1H ) 3.28-3.35 (m, 1H) 3.15-3.23 (m, 1H) 3.04 (t, J = 7.50Hz, 2H) 2.55 (td, J = 7.55 , 2.09Hz, 2H).

A solution of Intermediate 2 (430 mg, 808.93 umol, 1 eq) and _NH4Cl ( _216.35 mg, 4.04 mmol, 5 eq) in EtOH (12 mL) and H2O (4 mL) was heated to 90°C. and then Fe (225.87 mg, 4.04 mmol, 5 eq) was added at 90° C. under N ₂ and the mixture was then stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 3 (405 mg, crude) as a yellow solid. LCMS: m/z = 502.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 7.46-7.52 (m, 3H) 7.40 (d, J = 4.85 Hz , 1H) 7.23-7.33 (m, 2H) 7.09 (d, J = 3.31Hz, 1H) 6.77 (d, J = 7.94Hz, 2H) 6.58 (s, 1H ) 6.46-6.56 (m, 2H) 6.27 (d, J=7.50Hz, 1H) 5.20-5.28 (m, 1H) 3.07-3.15 (m, 1H) ) 3.01 (t, J=7.39 Hz, 2H) 2.89-2.96 (m, 1H) 2.46-2.55 (m, 2H).

A solution of intermediate 3 (405 mg, 807.44 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (385.54 mg, 2.42 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 h. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-35%, 10 min) to yield compound 59 (222 mg, 45%), white Obtained as a solid. LCMS: m/z = 580.0 (M-H ⁺ ), ¹ H-NMR: 400 MHz, DMSO-d ₆ ) δ = 8.32 (d, J = 8.31 Hz, 1H) 7.71 (d, J = 5.01Hz, 1H) 7.63 (d, J = 3.30Hz, 1H) 7.57 (d, J = 8.07Hz, 2H) 7.37 (d, J = 7.82Hz, 2H) 7.21 (s, 1H) 7.15-7.18 (m, 1H) 7.12 (s, 1H) 7.08 (s, 1H) 6.95 (s, 1H) 6.85-6. 92 (m, 4H) 5.04-5.13 (m, 1H) 3.01-3.07 (m, 1H) 2.79-2.89 (m, 3H) 2.43 (t, J = 7.46Hz, 2H).

Synthesis of compound 60


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (350 mg, 848.85 umol, 1 eq., HBr) and intermediate 2 (194.45 mg, 891.29 umol, 1.05 eq.) was added _Et3N (515.37 mg, 5.09 mmol, 708.90 uL, 6 eq.) at 25°C. Then the solution was cooled to 0° C. and T3P (1.08 g, 1.70 mmol, 1.01 mL, 50% purity, 2 eq.) was added dropwise at 0° C., then it was warmed to 25° C., 15 Stirred for an hour. The reaction was monitored for completion by TLC, H ₂ O (50 mL) was added, the reaction mixture was extracted with ethyl acetate (3×30 mL), then the combined organic phases were washed with brine (50 mL), dried and dried. Dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , dichloromethane:methyl alcohol=50:1) to yield Intermediate 3 (410 mg, 81%) as a yellow oil. LCMS: m/z = 532.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.46 (d, J = 8.68 Hz, 1H) 8.08 (d, J = 8.68Hz, 2H) 7.72 (dd, J = 5.01, 0.98Hz, 1H) 7.65 (dd, J = 3.73, 1.04Hz, 1H) 7.38-7.53 (m, 6H) 7.26 (s, 1H) 7.17 (dd, J=5.01, 3.67Hz, 1H) 5.22-5.28 (m, 1H) 3.26-3.32 (m, 1H) 3.08-3.14 (m, 1H) 2.78-2.87 (m, 2H) 2.40-2.48 (m, 2H).

A mixture of intermediate 3 (410 mg, _771.30 umol, 1 eq) and _NH4Cl (270.32 mg, 4.63 mmol, 6 eq) in EtOH (10 mL) and H2O (2 mL) was heated to 90°C. and then Fe (258.44 mg, 4.63 mmol, 6 eq) was added and the mixture was then stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored by LCMS for completion and the solution was concentrated in vacuo to yield Intermediate 4 (450 mg, crude) as a yellow oil. LCMS: m/z = 502.0 (M+H ⁺ ).

To a solution of intermediate 4 (450 mg, 897.15 umol, 1 eq), pyridine (5 mL), and MeCN (5 mL) was added SO _-pyridine (428.38 mg, 2.69 mmol, 3 eq) at 0 °C, Then it was stirred at 0° C. for 10 minutes. The reaction was monitored upon completion by LCMS and HPLC and the solution was dried by flushing with _N2 . The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O)-ACN]; B%: 20%-50%, 10 min ) to yield compound 60 (92.1 mg, 17%) as a white solid. LCMS: m/z = 580.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.31 (d, J = 8.56 Hz, 1H) 7.68-7 .74 (m, 1H) 7.61-7.66 (m, 1H) 7.55 (s, 1H) 7.43-7.51 (m, 3H) 7.09-7.21 (m, 4H ) 6.97 (brs, 1H) 6.81-6.92 (m, 4H) 5.05-5.14 (m, 1H) 2.98-3.10 (m, 1H) 2.78-2 .93 (m, 3H) 2.40-2.47 (m, 2H).

Synthesis of compound 61


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (400 mg, 970.11 umol, 1 .1 eq) and Intermediate 1 (192.41 mg, 881.92 umol, 1 eq) was added dropwise _Et3N (535.45 mg, 5.29 mmol, 736.52 uL, 6 eq) at 0°C. and then T3P (420.91 mg, 1.32 mmol, 393.38 uL, 1.5 eq) was added at 0 °C, then the mixture was warmed to 25 °C and 16 at 25 °C under _N2 atmosphere. Stirred for an hour. LCMS monitored when the reaction was complete. The mixture was poured into ice water (25 mL), then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=10:1 to 1:1) to yield Intermediate 2 (430 mg, 87%) as a yellow solid. LCMS: m/z = 532.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.07 (d, J = 8.82 Hz, 2H) 7.60 (d, J = 7 .94Hz, 1H) 7.51 (dd, J = 3.64, 0.99Hz, 1H) 7.39 (brd, J = 7.28Hz, 2H) 7.31-7.35 (m, 1H) 7 .24-7.28 (m, 1H) 7.20 (d, J = 8.60Hz, 2H) 7.11 (dd, J = 5.07, 3.75Hz, 1H) 6.68 (s, 1H ) 6.25 (d, J = 8.16Hz, 1H) 5.30-5.38 (m, 1H) 3.30-3.36 (m, 1H) 3.11-3.24 (m, 3H ) 2.52 (t, J=7.83 Hz, 2H).

A solution of Intermediate 2 (430 mg, 808.93 umol, 1 eq) and _NH4Cl ( _216.35 mg, 4.04 mmol, 5 eq) in EtOH (12 mL) and H2O (4 mL) was heated to 90°C. and then Fe (225.87 mg, 4.04 mmol, 5 eq) was added at 90° C. under N ₂ and the mixture was then stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 3 (405 mg, crude) as a yellow solid. LCMS: m/z = 502.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 7.62 (d, J = 7.94 Hz, 1H) 7.52 (d, J = 2 .87 Hz, 1 H) 7.38-7.46 (m, 2 H) 7.32 - 7.37 (m, 1 H) 7.29 (s, 1 H) 7.11 (brt, J=4. 19Hz, 1H) 6.81 (d, J=7.94Hz, 2H) 6.65 (s, 1H) 6.56 (brd, J=8.16Hz, 2H) 6.27 (d, J=7. 94Hz, 1H) 5.24-5.32 (m, 1H) 3.09-3.21 (m, 3H) 2.95 (m, 1H) 2.51 (t, J = 7.61Hz, 2H) .

A solution of intermediate 3 (405 mg, 807.44 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (385.54 mg, 2.42 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-35%, 10 min) to yield compound 61 (252 mg, 52%), white Obtained as a solid. LCMS: m/z = 580.0 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.37 (d, J = 8.4 Hz, 1H) 7.71 (d , J = 4.6Hz, 1H) 7.64 (brd, J = 4.52Hz, 2H) 7.56-7.49 (m, 1H) 7.40-7.33 (m, 2H) 7.25 (s, 1H) 7.21 (s, 1H) 7.18-7.15 (m, 1H) 7.08 (s, 1H) 6.95 (s, 1H) 6.92-6.85 (m , 4H) 5.15-5.06 (m, 1H) 3.05 (brdd, J = 13.57, 5.99Hz, 1H) 2.97-2.83 (m, 3H) 2.44 (t , J=7.7 Hz, 2H).

Synthesis of compound 62

Preparation of Intermediate 2 HCOOH (5.00 g, 104.08 mmol, 3 eq) was added dropwise to DMF (12.5 mL) with stirring and cooling with ice water. _Et3N (4.56 g, 45.10 mmol, 6.28 mL, 1.3 eq) was added in the same manner followed by intermediate 6 (5 g, 34.69 mmol, 1 eq). Intermediate 5 (5.14 g, 34.69 mmol, 5.26 mL, 1 eq) was then added and the mixture was heated to 80° C. and stirred for 14 hours. The reaction was monitored upon completion by LCMS and the solution was cooled and poured into ice water (30 mL) with vigorous stirring. Concentrated HCl was added until pH=1-2. The precipitate was filtered, washed with water and dried in vacuo to yield Intermediate 2 (6.6 g, crude) as a yellow solid. LCMS: m/z = 191.2 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 7.11-7.21 (m, 4H) 2.84-3.03 (m, 3H) 2.63-2.75 (m, 2H ) 1.25 (d, J = 6.85 Hz, 6H).

(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (0.3 g, 727.58 umol, 1 eq), intermediate Form 2 (139.88 mg, 727.58 umol, 1 eq) was added in DMF (3 mL) followed by _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq) at 0°C. Then T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 2 eq) was added and the solution was then stirred at 25° C. for 3 hours. The reaction was monitored for completion by LCMS, the solution was added to ice water (8 mL), then extracted with ethyl acetate (3 x 10 mL), then the combined organic phases were washed with brine (10 mL), anhydrous _Na2. Dried over _SO4 and concentrated in vacuo to yield Intermediate 3 (400 mg, crude) as a yellow solid. LCMS: m/z = 506.0 (M+H ⁺ ).

To a solution of intermediate 3 (400 mg, 791.06 umol, 1 eq) in EtOH (8.5 mL) and _H2O (3 mL) was added _NH4Cl (216.78 mg, 3.96 mmol, 5 eq) at 25°C. then the solution was warmed to 90° C., then Fe (220.88 mg, 3.96 mmol, 5 eq) was added, then the mixture was stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (360 mg, crude) as a yellow solid. LCMS: m/z = 476.3 (M+H ⁺ ).

A solution of intermediate 4 (350 mg, 735.81 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (351.34 mg, 2.21 mmol, 3 equivalent) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, the mixture was then dried by flushing with N ₂ and the residue was analyzed by preparative HPLC (column: YMC-Actus). Triart C18 100*30 mm*5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 30%-50%, 12 min) to give compound 62 (91.2 mg, 21% ), obtained as a pale yellow solid. LCMS: m/z = 554.0 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ +D ₂ O) δ = 8.29-8.39 (m, 1H) 7.55-7.65 (m, 2H) 7.13 (t, J = 4.22Hz, 1H) 6.96-7.06 (m, 4H) 6.82-6.94 (m, 5H) 4.95-5.13 (m, 1H) 2.95-3.09 ( m, 1H) 2.62-2.84 (m, 4H) 2.26-2.42 (m, 2H) 1.08 (brd, J=6.85Hz, 6H).

Synthesis of compound 63


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (0.4 g, 970.11 umol) in DMF (5 mL) , 1 eq.) and Intermediate 1 (265.73 mg, 1.16 mmol, 1.2 eq.) was added _Et3N (588.99 mg, 5.82 mmol, 810.17 uL, 6 eq.) and the mixture was Cooled to 0° C., then T3P (1.23 g, 1.94 mmol, 1.15 mL, 50% purity, 2 eq) was added dropwise. The mixture was then warmed to 25° C. and stirred for 5 hours. The reaction was monitored for completion by TLC and the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 x 15 mL). _The combined organic layers were washed with brine (40 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=2:1 to 0:1) to yield Intermediate 2 (0.4 g, 76%) as a yellow solid. ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.04-8.11 (m, 2H) 7.78-7.86 (m, 2H) 7.52 (dd, J = 3.67, 0 .98Hz, 1H) 7.38-7.44 (m, 3H) 7.17-7.23 (m, 2H) 7.11 (dd, J = 5.07, 3.73Hz, 1H) 6.67 (s, H) 6.38 (d, J=8.19Hz, 1H) 5.22-5.39 (m, 1H) 3.28-3.37 (m, 1H) 3.17-3.22 (m, 1H) 3.04-3.08 (m, 2H) 3.00 (s, 3H) 2.54-2.59 (m, 2H).

To a solution of Intermediate 2 (0.4 g, 738.47 umol, 1 eq) in EtOH (6 mL) and _H2O (2 mL) was added _NH4Cl (197.50 mg, 3.69 mmol, 5 eq), The mixture was heated to 90° C., then Fe (206.22 mg, 3.69 mmol, 5 eq) was added. The mixture was then stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 3 (0.35 g, crude) as a yellow solid. LCMS: m/z = 512.0 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 8.00-8.20 (m, 2H) 7.60-7.85 (m , 4H) 7.41 (s, 1H) 7.02-7.26 (m, 3H) 6.80-7.00 (m, 2H) 5.51 (s, 1H) 4.11-4.44 (m, 4H) 3.65 (s, 3H) 2.70-2.95 (m, 2H).

A mixture of intermediate 3 (0.35 g, 684.02 umol, 1 eq) in pyridine (2.5 mL) and MeCN (2.5 mL) was cooled to 0° C. and then SO ₃ -pyridine (326.61 mg , 2.05 mmol, 3 eq.) was added. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored when complete by TLC, 7% ammonium hydroxide (4 mL) was added dropwise, then the mixture was dried by flushing with _N2 . The residue was purified by preparative HPLC (Column: YMC-Exphere C18 10 um 300*50 mm 12 nm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 15%-45%, 20 min). yielded compound 63 (304.2 mg, 74%) as a white solid. LCMS: m/z = 590.0 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.35 (d, J = 8.77 Hz, 1H) 7.78 (d , J = 8.33Hz, 2H) 7.71 (dd, J = 5.04, 1.10Hz, 1H) 7.68 (s, 1H) 7.64 (dd, J = 3.73, 1.10Hz , 1H) 7.42 (d, J=8.33Hz, 2H) 7.13-7.20 (m, 2H) 7.08 (s, 4H) 6.83-6.93 (m, 4H) 5 .03-5.15 (m, 1H) 3.15 (s, 3H) 3.05 (dd, J = 13.81, 5.92Hz, 1H) 2.79-2.91 (m, 3H) 2 .40-2.47 (m, 2H).

Synthesis of compound 64


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (0.4 g, 970.11 umol) in DMF (5 mL) , 1 eq.) and Intermediate 1 (194.25 mg, 970.11 umol, 1 eq.) was added _Et3N (588.99 mg, 5.82 mmol, 810.17 uL, 6 eq.) and the solution was brought to 0°C. was cooled to , then T3P (1.23 g, 1.94 mmol, 1.15 mL, 50% purity, 2 eq) was added dropwise at 0°C. The mixture was warmed to 25° C. and stirred for 13 hours. The reaction was monitored for completion by TLC and the reaction mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (3 x 25 mL). _The combined organic layers were washed with brine (50 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=5:1 to 0:1) to yield Intermediate 2 (0.5 g, 90%) as a yellow solid. ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 7.90-8.04 (m, 3H) 7.80 (d, J = 7.89 Hz, 1H) 7.60-7.69 (m, 1H ) 7.36-7.55 (m, 4H) 7.24-7.35 (m, 2H) 7.00-7.11 (m, 3H) 6.60 (s, 1H) 6.30 (d , J = 8.33Hz, 1H) 5.22-5.38 (m, 1H) 3.31-3.51 (m, 2H) 3.15-3.28 (m, 1H) 3.00-3 .15 (m, 1H) 2.62-2.66 (m, 2H).

Intermediate 2 (0.5 g, 876.12 umol, 1 eq) and _SnCl2 . A mixture of 2H ₂ O (988.48 mg, 4.38 mmol, 5 eq) was heated to 50° C. and the reaction was stirred at 50° C. for 2 hours. The reaction was monitored for completion by LCMS and the reaction mixture was diluted with saturated Seniet's salt (50 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _yielding Intermediate 3 (0.35 g, 83%) as a yellow solid. Obtained. LCMS: m/z = 484.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 7.97 (d, J = 8.31 Hz, 1H) 7.75 (d, J = 7 .70Hz, 1H) 7.53-7.66 (m, 1H) 7.36-7.49 (m, 3H) 7.23-7.34 (m, 3H) 6.96-7.07 (m , 1H) 6.64 (d, J = 8.31Hz, 2H) 6.47 (s, 1H) 6.42 (d, J = 8.31Hz, 2H) 6.04 (d, J = 8.31Hz , 1H) 5.07-5.23 (m, 1H) 3.27-3.41 (m, 2H) 3.01 (dd, J = 13.33, 5.62Hz, 1H) 2.78 (dd , J=13.33, 8.56 Hz, 1H) 2.56 (t, J=7.70 Hz, 2H).

A mixture of intermediate 3 (0.33 g, 682.32 umol, 1 eq) in pyridine (3 mL) and MeCN (3 mL) was cooled to 0° C. and then SO ₃ -pyridine (325.79 mg, 2.05 mmol). , 3 eq.) was added in batches and the reaction was stirred at 0° C. for 0.17 h. The reaction was monitored by TLC and LCMS for completion, 7% ammonium hydroxide (5 mL) was added dropwise and the mixture was dried by flushing with _N2 to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O)-ACN]; B%: 15%-45%, 10 min). yielded compound 64 (16.3 mg, 4%) as a white solid. LCMS: m/z = 562.1 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.35 (d, J = 8.44 Hz, 1H) 8.07 (d , J = 8.44Hz, 1H) 7.90 (d, J = 7.95Hz, 1H) 7.69-7.78 (m, 2H) 7.61-7.67 (m, 2H) 7.47 -7.60 (m, 2H) 7.34-7.41 (m, 1H) 7.26-7.32 (m, 1H) 7.14-7.18 (m, 2H) 7.09 (brs) , 3H) 6.84-6.94 (m, 4H) 5.05-5.19 (m, 1H) 3.20-3.26 (m, 2H) 3.05 (dd, J = 13.63 , 5.81 Hz, 1 H) 2.85 (dd, J=13.63, 8.38 Hz, 1 H) 2.53-2.57 (m, 2 H).

Synthesis of compound 65


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (350 mg, 848.85 umol, 1 equiv.) and Intermediate 1 (186.96 mg, 933.73 umol, 1.1 equiv.) was added _Et3N (515.37 mg, 5.09 mmol, 708.90 uL, 6 equiv.) dropwise at 0°C. and then T3P (540.17 mg, 1.70 mmol, 504.84 uL, 2 eq) was added at 0 °C, then the mixture was warmed to 25 °C and stirred at 25 °C for 13 h under _N2 atmosphere. bottom. LCMS monitored when the reaction was complete. The mixture was poured into ice water (20 mL), then the mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 2 (200 mg, crude) as a pale yellow oil. . LCMS: m/z = 514.2 (M+H ⁺ ).

To a solution of intermediate 2 (200 mg, 389.39 umol, 1 eq) in EtOAc (10 mL) was added _SnCl2 . 2H ₂ O (439.32 mg, 1.95 mmol, 5 eq) was added, heated to 50° C. and stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored upon completion by LCMS, the solution was added to saturated Seniet's salt (40 mL) then filtered, the filtrate was extracted with ethyl acetate (2 x 10 mL), washed with brine (5 mL) and filtered. , concentrated in vacuo to afford Intermediate 5 (100 mg, crude) as a pale yellow solid. LCMS: m/z = 482.3 (MH ⁺ ).

A solution of intermediate 3 (100 mg, 207.04 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (177.71 mg, 1.12 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% _NH3H2O )-ACN]; B%: 5%-40%, 10 _min ) to give compound 65 (44.1 mg, 20% ), obtained as a white solid. LCMS: m/z = 562.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.33 (d, J = 8.77 Hz, 1H) 7.76-7 .85 (m, 3H) 7.67-7.72 (m, 2H) 7.65 (s, 1H) 7.62 (dd, J = 3.51, 1.32Hz, 1H) 7.39-7 .48 (m, 2H) 7.34 (dd, J = 8.55, 1.53Hz, 1H) 7.16 (dd, J = 5.04, 3.73Hz, 1H) 7.07 (s, 4H ) 7.02 (s, 1H) 6.85-6.92 (m, 4H) 5.04-5.13 (m, 1H) 3.04 (dd, J = 13.81, 5.92Hz, 1H ) 2.90-2.98 (m, 2H) 2.82 (dd, J = 13.59, 8.77Hz, 1H) 2.52-2.56 (m, 2H).

Synthesis of compound 66


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300 mg, 727.58 umol, 1 eq.) in DMF (3 mL) ) and Intermediate 1 (176.27 mg, 727.58 umol, 1 eq) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq) dropwise and cooled to 0°C. Then T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 2 eq) was added at 0 °C, then the mixture was warmed to 25 °C and stirred at 25 °C for 3 h under _N2 atmosphere. Stirred. The reaction was monitored for completion by LCMS, the mixture was poured into ice water (20 mL), then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 2 (300 mg, crude) as a pale yellow oil. . LCMS: m/z = 556.2 (M+H ⁺ ).

To a solution of intermediate 2 (300 mg, 539.89 umol, 1 eq) in EtOAc (10 mL) was added _SnCl2 . 2H ₂ O (609.13 mg, 2.70 mmol, 5 eq) was added, heated to 50° C. and stirred at 50° C. under N ₂ for 1 hour. The reaction was monitored for completion by LCMS, the solution was added to saturated Seniet's salt (40 mL), then filtered, the filtrate was extracted with ethyl acetate (3 x 10 mL), washed with brine (1 x 5 mL), Filtration and concentration in vacuo yielded Intermediate 3 (260 mg, crude) as a pale yellow solid. LCMS: m/z = 526.1 (M+H ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.28 (d, J = 8.56 Hz, 1H) 7.70 (dd, J = 5.01, 0.98 Hz, 1H) 7.62 (dd, J = 3.67, 0.98Hz, 1H) 7.30-7.43 (m, 2H) 7.07-7.20 (m, 5H) 6.90-6.98 (m, 2H) ) 6.85-6.89 (m, 2H) 6.81-6.83 (m, 2H) 6.43 (d, J=8.31Hz, 2H) 5.01-5.10 (m, 1H) ) 2.98-3.03 (m, 1H) 2.74-2.83 (m, 3H) 2.35-2.42 (m, 2H).

A solution of intermediate 3 (260 mg, 494.59 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (236.16 mg, 1.48 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 15% to 55%, 10 min) to give compound 66 (44. 1 mg, 20%), obtained as a white solid. LCMS: m/z = 604.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.29 (d, J = 8.56 Hz, 1H) 7.69-7 .70 (m, 1H) 7.65 (s, 1H) 7.61-7.62 (m, 1H) 7.32-7.39 (m, 2H) 7.04-7.20 (m, 8H ) 6.82-6.98 (m, 8H) 5.04-5.13 (m, 1H) 3.04 (dd, J = 13.75, 5.93Hz, 1H) 2.71-2.89 (m, 3H) 2.35-2.43 (m, 2H).

Synthesis of compound 67


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (400 mg, 970.11 umol, 1 .1 eq.) and Intermediate 1 (170.42 mg, 881.92 umol, 1 eq.) was added _Et3N (535.45 mg, 5.29 mmol, 736.52 uL, 6 eq.) dropwise at 0°C. and then T3P (420.91 mg, 1.32 mmol, 393.38 uL, 1.5 eq) was added at 0 °C, then the mixture was warmed to 25 °C and 16 at 25 °C under _N2 atmosphere. Stirred for an hour. LCMS monitored when the reaction was complete. The mixture was poured into ice water (25 mL), then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=10:1 to 1:1) to yield Intermediate 2 (350 mg, 78%) as a yellow solid. LCMS: m/z = 507.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.01-8.08 (m, 2H) 7.49-7.52 (m, 1H ) 7.41-7.45 (m, 1H) 7.09-7.16 (m, 3H) 7.06 (d, J=8.60Hz, 2H) 6.60-6.67 (m, 3H ) 6.16 (d, J=8.60Hz, 1H) 5.30-5.39 (m, 1H) 3.27-3.34 (m, 1H) 3.16-3.23 (m, 1H) ) 2.83-2.93 (m, 8H) 2.50 (t, J=7.50Hz, 2H).

A solution of Intermediate 2 (350 mg, 690.83 umol, 1 eq) and _NH4Cl ( _184.76 mg, 3.45 mmol, 5 eq) in EtOH (12 mL) and H2O (4 mL) was heated to 90°C. and then Fe (192.90 mg, 3.45 mmol, 5 eq) was added at 90° C. under N ₂ and the mixture was then stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 3 (329 mg, crude) as a yellow solid. LCMS: m/z = 477.2 (M+H ⁺ ).

A solution of intermediate 3 (329 mg, 690.23 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (329.58 mg, 2.07 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% _NH3H2O )-ACN]; B%: 15%-45%, 10 _min ) to give compound 67 (182 mg, 45%). Obtained as a white solid. LCMS: m/z = 555.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 8.27 (brd, J = 8.80 Hz, 1H) 7.57 (dd , J = 3.67, 1.10Hz, 1H) 7.52-7.56 (m, 1H) 7.12 (dd, J = 5.01, 3.79Hz, 1H) 7.00-7.09 (m, 6H) 6.94 (brd, J = 3.18Hz, 2H) 6.86 (brs, 1H) 5.18-5.33 (m, 1H) 3.17 (dd, J = 14.00 , 5.32Hz, 1H) 2.98 (s, 6H) 2.89-2.95 (m, 2H) 2.73-2.88 (m, 2H) 2.48 (t, J = 6.91Hz , 2H).

Synthesis of compound 68


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (300 mg, 820. 04 umol, 1 eq) and Intermediate 1 (123.96 mg, 820.04 umol, 1 eq) was added _Et3N (4.92 mmol, 684.84 uL, 6 eq) and the mixture was cooled to 0°C. and then T3P (1.23 mmol, 731.55 uL, 50% purity, 1.5 eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 6 hours. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were then washed with brine (2×20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo yielding Intermediate 2 (350 mg, crude) as a yellow oil. . LCMS: m/z = 463.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.25-8.57 (m, 2H) 8.03-8.05 (m, 1H) ) 7.57-7.68 (m, 1H) 7.46-7.54 (m, 1H) 7.09-7.21 (m, 3H) 6.91-6.99 (m, 1H) 6 .65-6.70 (m, 1H) 6.54-6.58 (m, 1H) 5.21-5.34 (m, 1H) 4.30 (s, 2H) 3.19-3.31 (m, 2H) 3.05-3.19 (m, 2H) 2.42-2.60 (m, 2H).

To a solution of Intermediate 2 (350 mg, 756.72 umol, 1 eq) in EtOH (6 mL) and _H2O (2 mL) was added _NH4Cl (202.39 mg, 3.78 mmol, 5 eq) at 25°C. The solution was then heated to 90° C. and Fe (211.29 mg, 3.78 mmol, 5 eq) was added to the mixture and stirred at 90° C. for 2 hours. The reaction was monitored for completion by TLC and LCMS, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1%-35%, 10 min) yielded intermediate 3 (100 mg, 29%) as a yellow oil. LCMS: m/z = 433.3 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.39 (d, J = 3.791 Hz, 1H) 8.28 (s, 1H) 7 .62 (s, 1H) 7.51 (d, J = 7.703Hz, 1H) 7.19 (dd, J = 7.641, 4.952Hz, 1H) 6.90 (s, 1H) 6.74 (d, J = 8.192Hz, 2H) 6.68 (s, 1H) 6.52 (d, J = 8.314Hz, 2H) 6.29 (d, J = 7.947Hz, 1H) 5.15 -5.22 (m, 1H) 4.30 (s, 2H) 2.89-3.07 (m, 4H) 2.50-2.59 (m, 1H) 2.38-2.46 (m , 1H).

To a solution of intermediate 3 (100 mg, 231.19 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was added SO _-pyridine (110.39 mg, 693.58 umol, 3 eq) at 0 °C, Stirred for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*). Mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1%-20%, 10 min) to give compound 68 (42.3 mg , 36%), obtained as a white solid. LCMS: m/z = 511.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.61 (s, 1H) 8.35-8.46 (m, 2H ) 8.26 (d, J = 8.559Hz, 1H) 7.76 (brs, 1H) 7.56 (d, J = 7.825Hz, 1H) 7.26-7.29 (m, 1H) 7 .21 (brs, 1H) 7.15 (s, 1H) 7.08 (s, 1H) 6.96 (brs, 1H) 6.89 (d, J = 8.437Hz, 2H) 6.75-6 .84 (m, 2H) 5.06-5.13 (m, 1H) 4.35 (s, 2H) 2.94 (dd, J = 13.633, 6.663Hz, 1H) 2.74-2 .83(m, 3H) 2.43(t, J=7.519Hz, 2H).

Synthesis of compound 69


To a solution of Intermediate 1 (300 mg, 565.62 umol, 1 eq) and Intermediate 2 (85.50 mg, 565.62 umol, 1 eq) in DMF (4 mL) was added _Et3N (3.39 mmol, 472.36 uL). , 6 eq) was added and the mixture was cooled to 0° C., then T3P (848.43 umol, 504.58 uL, 50% purity, 1.5 eq) was added dropwise. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was then washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=5:1 to dichloromethane:methanol=10:1) to yield intermediate 3 (150 mg, 50%) as a yellow oil. LCMS: m/z = 477.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.37-8.51 (m, 2H) 8.05 (d, J = 8.770 Hz , 2H) 7.43-7.54 (m, 2H) 7.18 (dd, J = 7.454, 4.823Hz, 1H) 7.12 (d, J = 8.770Hz, 2H) 6.99 (s, 1H) 6.70 (s, 1H) 6.29 (brd, J=8.331Hz, 1H) 5.31-5.36 (m, 1H) 4.28 (s, 2H) 3.55 (s, 3H) 3.22-3.30 (m, 1H) 3.09-3.14 (m, 1H) 2.90-3.01 (m, 2H) 2.47-2.57 (m , 2H).

A solution of intermediate 3 (150 mg, _314.76 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was added _NH4Cl (84.19 mg, 1.57 mmol, 5 eq) followed by The solution was heated to 90° C. and Fe (87.89 mg, 1.57 mmol, 5 eq) was added to the mixture and stirred at 90° C. for 2 hours. The reaction was monitored by TLC and LCMS for completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (200 mg, crude) as a yellow solid. LCMS: m/z = 447.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 8.22-8.59 (m, 3H) 7.62 (brd, J = 7 .497Hz, 1H) 7.20-7.37 (m, 2H) 7.01 (s, 1H) 6.85 (d, J = 7.938Hz, 2H) 6.62 (d, J = 8.379Hz , 2H) 5.15-5.21 (m, 1H) 4.48 (s, 2H) 3.76 (s, 3H) 3.05 (dd, J = 13.892, 6.395Hz, 1H) 2 .77-2.94 (m, 3H) 2.46-2.56 (m, 2H).

SO ₃ -pyridine (213.85 mg, 1.34 mmol, 3 eq) was added to a solution of intermediate 4 (200 mg, 447.86 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) at 0 °C. , and stirred for 0.17 hours. The reaction was monitored upon completion by TLC and LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge). 150*25 5 u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; .1 mg, 31%), obtained as a white solid. LCMS: m/z = 525.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.70 (s, 1H) 8.34-8.44 (m, 2H ) 8.29 (d, J = 8.437Hz, 1H) 7.76 (brs, 1H) 7.56 (brd, J = 7.825Hz, 1H) 7.27 (dd, J = 7.641, 4 .829Hz, 1H) 7.21 (brs, 1H) 7.16 (s, 1H) 7.10 (brd, J = 12.349Hz, 1H) 7.00 (s, 1H) 6.96 (brs, 1H) ) 6.87 (d, J = 8.314Hz, 2H) 6.75 (d, J = 8.436Hz, 2H) 5.09-5.17 (m, 1H) 4.44 (s, 2H) 3 .64 (s, 3H) 2.74-2.93 (m, 4H) 2.42-2.47 (m, 2H).

Synthesis of compound 70


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (0.3 g, 727.58 umol) in DMF (5 mL) , 1 eq.) and Intermediate 2 (110.70 mg, 727.58 umol, 1 eq.) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq.) and the mixture was brought to 0°C. was cooled to , then T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 2 eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 13 hours. The reaction was monitored for completion by LCMS and the reaction mixture was diluted with ice water (40 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _yielding Intermediate 3 (0.3 g, crude) as a yellow oil. Obtained. LCMS: m/z = 466.0 (M+H ⁺ ).

To a solution of intermediate 3 (0.3 g, _644.40 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was added _NH4Cl (172.35 mg, 3.22 mmol, 5 eq), The mixture was then heated to 90° C. and then Fe (179.95 mg, 3.22 mmol, 5 eq) was added. The mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (0.3 g, crude) as a yellow solid. LCMS: m/z = 436.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 9.02 (s, 1H) 8.51-8.62 (m, 2H) 8.01 (s, 1H) 7.49 (d, J = 3.51Hz, 1H) 7.40 (d, J = 4.82Hz, 1H) 7.02-7.14 (m, 1H) 6.77 (d , J = 7.89 Hz, 2H) 6.66 (s, 1H) 6.46-6.58 (m, 3H) 5.14-5.31 (m, 1H) 3.64-3.80 (m , 1H) 3.02-3.20 (m, 1H) 2.46-2.56 (m, 2H) 1.20-1.31 (m, 2H).

A mixture of intermediate 4 (0.3 g, 688.76 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (328.87 mg, 2.07 mmol). , 3 equivalents) was added. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored when complete by TLC, 7% ammonium hydroxide (3 mL) was added dropwise and the mixture was dried by flushing with _N2 to give a residue. The residue was analyzed by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 10 u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 5%-35%, 11 min) yielded compound 70 (96.4 mg, 27%) as a white solid. LCMS: m/z = 513.9 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.97 (s, 1H) 8.62 (s, 2H) 8.32 (d, J = 8.44Hz, 1H) 7.71 (d, J = 5.01Hz, 1H) 7.63 (d, J = 2.81Hz, 1H) 7.21 (s, 1H) 7.14 -7.18 (m, 2H) 7.08 (s, 1H) 6.96 (s, 1H) 6.81-6.91 (m, 4H) 5.04-5.12 (m, 1H) 2 .96-3.07 (m, 1H) 2.74-2.87 (m, 3H) 2.44-2.48 (m, 2H).

Synthesis of compound 71


Intermediate 1 (2 g, 7.57 mmol, 1 eq), Intermediate 2 methylprop-2-enoate (977.85 mg, 11.36 mmol, 1.02 mL, 1.5 eq), phenyl urea in anhydrous DMF (20 mL) ₍ 206.20 mg, 1.51 mmol, 0.2 eq) and _K2CO3 (2.09 g, 15.14 mmol, 2 eq) to a solution of diacetoxypalladium (170.01 mg, 757.24 umol, 0.1 equivalent) was added, then degassed and purged with N ₂ three times and stirred at 130° C. for 3 hours. The reaction was monitored for completion by TLC and LCMS, 50 mL of water was added to the reaction mixture, extracted with ethyl acetate (2 x 10 mL), the combined organic layers were washed with 5 mL of brine, filtered and concentrated in vacuo. yielded Intermediate 3 (1.73 g, crude) as a dark brown solid. LCMS: m/z = 269.9 (M+H ⁺ ). ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.39 (d, J = 2.81 Hz, 1H) 8.37 (d, J = 1.59 Hz, 1H) 7.66 (d, J = 16 .14Hz, 1H) 7.34-7.47 (m, 6H) 6.48 (d, J = 16.14Hz, 1H) 5.15 (s, 2H) 3.83 (s, 3H)

To a solution of methyl intermediate 3 (1.5 g, 1 eq) in EtOH (5 mL) was added Pd/C (200 mg, 10% purity), then degassed and washed with H ₂ (15 Psi) three times. After purging, the reaction mixture was stirred at 25° C. for 2 hours. The reaction was monitored by LCMS when complete, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (2 g, crude) as a dark brown oil. LCMS: m/z = 182.1 (M+H ⁺ ).

To a solution of intermediate 4 (500 mg, 2.76 mmol, 1 eq) in THF (1 mL) and H ₂ O (1 mL) was added LiOH. H ₂ O (231.60 mg, 5.52 mmol, 2 eq) was added and the reaction was then stirred at 25° C. for 2 hours. The reaction was monitored by LCMS for completion and the reaction mixture was concentrated in vacuo to yield Intermediate 5 (400 mg, crude) as a pale yellow oil. LCMS: m/z = 166.0 (M+H ⁺ ).

(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300 mg, 727.58 umol, 1 eq), Intermediate 5 (243.25 mg, 1.46 mmol, 2 eq), and _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq) was cooled to 0°C and then , T3P (463.01 mg, 1.46 mmol, 432.72 uL, 50% purity, 1 eq.) was added at 0° C., then the mixture was stirred at 0° C. for 1 hour. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (30 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with 5 mL of brine, dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _yielding Intermediate 7 (300 mg, crude) as a yellow oil. LCMS: m/z = 481.1 (M+H ⁺ ).

To a solution of intermediate 7 (300 mg, 624.27 umol, 1 eq) in EtOH (5 mL) was saturated NH ₄ Cl (1.53 g, 1 mL), then the mixture was heated to 90° C. and then Fe (348. 63 mg, 6.24 mmol, 10 eq.) was added and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 8 (200 mg, crude) as a pale yellow solid. LCMS: m/z = 451.0 (M+H ⁺ ).

Intermediate 8 (200 mg, 443.88 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was added at 0°C (141.30 mg, 887.75 umol, 2 eq) and stirred for 10 min. The reaction was monitored for completion by TLC and LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5 u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; 13%), obtained as a white solid. LCMS: m/z = 529.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 9.94 (brs, 1H) 8.28 (d, J = 8.56 Hz , 1H) 7.98 (brd, J = 1.96Hz, 1H) 7.88 (s, 1H) 7.71 (dd, J = 5.01, 1.10Hz, 1H) 7.64 (dd, J = 3.67, 1.10Hz, 1H) 7.21 (brs, 1H) 7.17 (dd, J = 5.01, 3.67Hz, 1H) 7.14 (s, 1H) 7.08 (brs , 1H) 7.06 (brs, 1H) 6.95 (brs, 1H) 6.88 (q, J = 8.56Hz, 4H) 5.09 (brd, J = 5.87Hz, 1H) 3.05 (dd, J = 13.82, 5.75Hz, 1H) 2.82 (dd, J = 13.88, 8.62Hz, 1H) 2.72 (t, J = 7.52Hz, 2H) 2.38 -2.44 (m, 2H).

Synthesis of compound 72


HCOOH (1.04 g, 21.19 mmol, 98% purity, 3 eq.) was added dropwise to DMF (3 mL) with stirring and cooling with ice water (0° C.), followed by Et ₃ N (929.30 mg, 9.3 mol). 18 mmol, 1.28 mL, 1.3 eq) was added in the same manner followed by intermediate 2 (1.02 g, 7.06 mmol, 1 eq). After dissolution, Intermediate 1 (1 g, 7.06 mmol, 1 eq) was added and the mixture was heated to 80° C. for 14 hours. After the reaction was monitored by LCMS for completion, the solution was cooled and poured into ice-cold (30 mL) water with vigorous stirring. Concentrated HCl was added until pH=1-2. The precipitate was filtered, washed with water and air dried to yield Intermediate 3 (600 mg, 31%) as a white solid. LCMS: m/z = 270.2 (M+H ⁺ ).

HCl (2M, 1.5 mL, 2.70 eq) was added to a stirred solution of intermediate 3 (0.3 g, 1.11 mmol, 1 eq) in THF (15 mL) and the resulting solution was heated to 70°C. Heat and stir for 7 hours. The reaction was monitored for completion by LCMS and concentrated in vacuo to yield Intermediate 3A (255.43 mg, crude) as a colorless oil. LCMS: m/z = 227.9 (MH ⁺ ).

Intermediate 3A (255.43 mg, 1.11 mmol, 1 eq) in DMSO (5 mL) was heated to 140° C. and stirred for 3 hours. The reaction was monitored once complete by LCMS and the solution was concentrated in vacuo to yield Intermediate 4 (206.47 mg, crude) as a pale yellow solid. LCMS: m/z = 186.1 (M+H ⁺ ).

(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (458.69 mg, 1.11 mmol, 1 eq) and intermediate Form 4 (206.48 mg, 1.11 mmol, 1 eq) was added in DCM (10 mL) followed by _Et3N (675.42 mg, 6.67 mmol, 929.05 uL, 6 eq) at 0°C. Then T3P (1.06 g, 1.67 mmol, 992.42 uL, 50% purity, 1.5 eq) was added and the solution was then stirred at 25° C. for 2 hours. The reaction was monitored for completion by LCMS and the solution was concentrated in vacuo.

The residue was purified by preparative TLC (petroleum ether:ethyl acetate=5:1) to yield Intermediate 6 (180 mg, 32%) as a white solid. LCMS: m/z = 499.1 (M+H ⁺ ).

To a solution of intermediate 6 (180 mg, _360.72 umol, 1 eq) in EtOH (4 mL) and H2O (2 mL) was added _NH4Cl (96.48 mg, 1.80 mmol, 5 eq) followed by The solution was heated to 90° C. and Fe (100.72 mg, 1.80 mmol, 5 eq) was added, then the solution was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS and HPLC and the solution was concentrated in vacuo to yield Intermediate 7 (169.18 mg, crude) as a pale yellow solid. LCMS: m/z = 469.2 (M+H ⁺ ).

SO _3- pyridine (172.23 mg, 1.08 mmol, 3 eq) was added to a solution of intermediate 7 (169.18 mg, 360.71 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) at 0 °C. A slow addition was made and the reaction was stirred at 0° C. for 0.17 hours. The reaction was monitored upon completion by LCMS and HPLC and the solution was dried by flushing with _N2 . The residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1%-40%, 10 min) yielded compound 72 (101.9 mg, 51%) as a white solid. LCMS: m/z = 547.4 (M-H ⁺ ), ¹ H NMR: (400 MHz, DMSO-d ₆ +D ₂ O) δ = 8.24-8.25 (m, 1H) 8.25 (d , J = 2.19Hz, 1H) 8.19-8.22 (m, 1H) 7.56-7.59 (m, 2H) 7.10-7.14 (m, 1H) 6.94 (s , 1H) 6.83-6.88 (m, 5H) 4.98-5.06 (m, 1H) 2.93-3.01 (m, 1H) 2.72-2.78 (m, 3H) ) 2.39-2.44 (m, 2H).

Synthesis of compound 73


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (0.3 g, 727.58 umol) in DMF (5 mL) , 1 eq.) and Intermediate 2 (101.96 mg, 727.58 umol, 1 eq.) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq.) and the mixture was brought to 0°C. was cooled to , then T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 2 eq) was added dropwise. The mixture was warmed to 25° C. and stirred for 13 hours. The reaction was monitored for completion by LCMS and the reaction mixture was diluted with ice water (40 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _yielding Intermediate 3 (0.3 g, crude) as a yellow oil. Obtained. LCMS: m/z = 454.0 (M+H ⁺ ).

To a solution of intermediate 3 (0.3 g, _661.47 umol, 1 eq) in EtOH (3 mL) and H2O (1 mL) was added _NH4Cl (176.91 mg, 3.31 mmol, 5 eq), The reaction was heated to 90° C., then Fe (184.71 mg, 3.31 mmol, 5 eq) was added. The mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (0.3 g, crude) as a yellow solid. LCMS: m/z = 424.2 (M+H ⁺ ).

A mixture of intermediate 4 (0.3 g, 708.29 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (338.20 mg, 2.12 mmol). , 3 equivalents) was added. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored when complete by TLC, 7% ammonium hydroxide (4 mL) was added dropwise and the mixture was dried by flushing with _N2 to give a residue. The residue was analyzed by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 10 u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 15%-40%, 11 min) yielded compound 73 (105.9 mg, 28%) as a white solid. LCMS: m/z = 502.0 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.49 (d, J = 8.93 Hz, 1H) 8.40 (s , 1H), 7.90 (brs, 1H) 7.72 (d, J = 5.01Hz, 1H) 7.65 (d, J = 2.81Hz, 1H) 7.49 (s, 1H) 40 (s, 1H) 7.35 (s, 1H) 7.17 (dd, J=5.01, 3.79Hz, 1H) 6.89-6.97 (m, 4H) 5.10-5. 21 (m, 1H) 4.27-4.40 (m, 1H) 4.15-4.26 (m, 1H) 3.07 (dd, J = 13.88, 4.22Hz, 1H) 75 (dd, J=13.82, 10.88 Hz, 1H) 2.64-2.70 (m, 2H).

Synthesis of compound 74

Ｈ_２Ｏ（２０ｍＬ）中の中間体５（１ｇ、７．２４ｍｍｏｌ、１当量）の溶液に、Ｐｄ／Ｃ（２００ｍｇ、１０％純度、１．００当量）を加えた。懸濁液を脱気し、Ｈ_２で数回パージした。次いで、混合物を、Ｈ_２（３０ｐｓｉ）下で、２５℃で２時間撹拌した。ＬＣＭＳによって、反応が完了したらモニタリングし、反応混合物を濾過し、濾液を真空中で濃縮し、中間体２（９６４．８ｍｇ、粗物）を産出し、白色固体として得た。ＬＣＭＳ：ｍ／ｚ＝１３９．２（Ｍ－Ｈ^＋）．^１Ｈ－ＮＭＲ：（４００ＭＨｚ，ＤＭＳＯ－ｄ_６）δ＝７．５０（ｓ，１Ｈ） ６．７３（ｓ，１Ｈ） ２．６６－２．７４（ｍ，２Ｈ） ２．４４－２．５０（ｍ，２Ｈ）． Preparation of Intermediate 2

To a solution of intermediate 5 (1 g, 7.24 mmol, 1 eq) in _H2O (20 mL) was added Pd/C (200 mg, 10% purity, 1.00 eq). The suspension was degassed and purged with _H2 several times. The mixture was then stirred under H ₂ (30 psi) at 25° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 2 (964.8 mg, crude) as a white solid. LCMS: m/z = 139.2 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 7.50 (s, 1H) 6.73 (s, 1H) 2.66-2.74 (m, 2H) 2.44-2.50 (m, 2H).

(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide ((400 mg, 970.11 umol, 1 eq.)) and Intermediate 2 (163.14 mg, 1.16 mmol, 1.2 eq.) was added _Et3N (588.99 mg, 5.82 mmol, 810.17 uL, 6 eq.) followed by The solution was cooled to 0° C., then T3P (617.34 mg, 970.11 umol, 576.95 uL, 50% purity, 1 eq) was added dropwise at 0° C., then the solution was stirred at 25° C. for 3 hours. . The reaction was monitored for completion by LCMS, the solution was poured into water (3 mL) and extracted with dichloromethane (2 x 10 mL), then the combined organic phases were washed with brine (10 mL) and _{anhydrous Na2SO4} . and concentrated in vacuo to yield Intermediate 3 (703.7 mg, crude) as a yellow oil. LCMS: m/z = 454.0 (M+H ⁺ ).

To a solution of intermediate 3 (700 mg, 1.54 mmol, 1 eq) in EtOH (16 mL) and _H2O (5 mL) was added _NH4Cl (422.58 mg, 7.72 mmol, 5 eq) at 25°C. The solution was then warmed to 90° C., Fe (430.96 mg, 7.72 mmol, 5 eq) was then added, and the mixture was then stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (996 mg, crude) as a yellow solid. LCMS: m/z = 424.2 (M+H ⁺ ).

A solution of intermediate 4 (990 mg, 2.34 mmol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (1.12 g, 7.01 mmol, 3 equivalent) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, the mixture was then dried by flushing with N ₂ and the residue was analyzed by preparative HPLC (column: YMC-Actus). Purified by Triart C18 100*30 mm*5 um; mobile phase: [water (0.04% _NH3H2O + ₁₀ mM _NH4HCO3 )-ACN]; B%: 13%-33 _% , 12 min) to give compound Yield 74 (90.3 mg, 7%) as a white solid. LCMS: m/z = 502.0 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.77 (d, J = 1.22 Hz, 1H) 8.43 (d, J = 8.80 Hz, 1H) 7.99 (d, 1H ) 7.70-7.74 (m, 1H) 7.63-7.67 (m, 1H) 7.37 (s, 1H) 7.17 (dd, J = 5.01, 3.79Hz, 1H ) 6.98-7.04 (m, 4H) 6.35 (s, 1H) 5.06-5.30 (m, 1H) 3.09-3.16 (m, 1H) 2.74-2 .86 (m, 2H) 2.60-2.70 (m, 1H) 2.41-2.47 (m, 2H).

Synthesis of compound 75

Preparation of Intermediate 5 A solution of Intermediate 1 (5 g, 36.20 mmol, 1 eq) in HCl/MeOH (4 M, 50 mL) was heated to 90° C. and stirred at 90° C. for 2 hours. LCMS monitored when the reaction was complete. The reaction mixture was concentrated in vacuo yielding Intermediate 2 (2 g, crude) as a yellow oil. LCMS: m/z = 153.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 9.27 (s, 1H) 8.07 (s, 1H) 7.57 (d , J=16.26 Hz, 1H) 6.93 (d, J=16.26 Hz, 1H) 3.72 (s, 3H).

A solution of intermediate 2 (2 g, 10.60 mmol, 1 eq. HCl) in DMF (15 mL) was cooled to 0° C. followed by NaH (933 mg, 23.33 mmol, 60% purity, 2.2 eq.). was added and stirred at 0° C. for 10 min, then MeI (1.66 g, 11.66 mmol, 726.14 uL, 1.1 eq) was added at 0° C., then the mixture was warmed to 25° C. under N ₂ atmosphere. Stir at 25° C. for 1 hour. The reaction was monitored by LCMS for completion and the mixture was quenched with saturated NH ₄ Cl solution (20 mL) and then extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 3 (1.5 g, crude) obtained as a dark brown solid. rice field. LCMS: m/z = 167.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d ₆ ) δ = 7.67-7.86 (m, 1H) 7.40-7.63 (m , 2H) 6.32-6.52 (m, 1H) 3.72-3.82 (m, 6H). To a solution of intermediate 3 (1.4 g, 8.42 mmol, 1 eq) in EtOH (15 mL) was added Pd/C (1 g, 8.42 mmol, 10% purity, 1 eq), then the mixture was Stirred at 25° C. for 2 h under H ₂ atmosphere (30 Psi). The reaction was monitored by LCMS for completion and the mixture was filtered and concentrated in vacuo to yield Intermediate 4 (495 mg, crude) as a white solid. LCMS: m/z = 169.1 (M+H ⁺ ). ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 7.26 (m, 1H) 6.50-6.67 (m, 1H) 3.43-3.59 (m, 6H) 2.70-2 .79 (m, 2H) 2.51-2.59 (m, 2H). To a solution of intermediate 4 (495 mg, 2.94 mmol, 1 eq.) in MeOH (5 mL) and _H2O (5 mL) was added LiOH (140.96 mg, 5.89 mmol, 2 eq.), then the mixture was Stir at 25° C. for 1 hour. The reaction was monitored by LCMS for completion and the mixture was concentrated in vacuo to yield Intermediate 5 (480 mg, crude) as a dark brown solid. LCMS: m/z = 153.2 (MH ⁺ ).

(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (200 mg, 485.06 umol, 1 equiv.) and intermediate 5 (232.97 mg, 1.46 mmol, 3 equiv.) was added _Et3N (294.50 mg, 2.91 mmol, 405.08 uL, 6 equiv.) dropwise and cooled to 0°C. and then T3P (617.34 mg, 970.11 umol, 576.95 uL, 50% purity, 2 eq.) was added at 0 °C, then the mixture was warmed to 25 °C and stirred at 25 °C for 2 cycles under _N2 atmosphere. Stirred for an hour. LCMS monitored when the reaction was complete. The mixture was poured into ice water (20 mL) and stirred for 10 minutes. The mixture was then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 7 (62 mg, 27%) as a yellow solid. LCMS: m/z = 468.2 (M+H ⁺ ).

A solution of intermediate 7 (62 mg, _132.60 umol, 1 eq) and _NH4Cl (35.14 mg, 663.01 umol, 5 eq) in EtOH (12 mL) and H2O (4 mL) was heated to 90°C. and then Fe (37.03 mg, 663.01 umol, 5 eq) was added at 90° C. under N ₂ and the mixture was then stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 8 (229 mg, crude) as a yellow solid. LCMS: m/z = 438.2 (M+H ⁺ ).

A solution of intermediate 8 (229 mg, 523.33 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (249.88 mg, 1.57 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1% to 30%, 10 min) to give compound 75 (5. 9 mg, 2%), obtained as a white solid. LCMS: m/z = 516.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.71 (s, 1H) 8.37 (d, J = 8.68 Hz , 1H) 7.79 (brs, 1H) 7.72 (dd, J = 5.01, 0.98Hz, 1H) 7.65 (dd, J = 3.67, 0.98Hz, 1H) 7.33 (s, 1H) 7.21 (s, 1H) 7.16-7.18 (m, 1H) 7.09 (s, 1H) 7.05 (s, 1H) 6.96 (s, 1H) 6 .88-6.94 (m, 4H) 5.07-5.13 (m, 1H) 3.73 (s, 3H) 3.06 (dd, J=13.88, 4.71Hz, 1H) 2 .60-2.85 (m, 3H) 2.38-2.45 (m, 2H).

Synthesis of compound 76


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300.00 mg, 727.58 umol) in DMF (5 mL) , 1 eq.) and Intermediate 1 (122.35 mg, 727.58 umol, 1 eq.) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq.) dropwise at 0°C. and then T3P (694.51 mg, 1.09 mmol, 649.07 uL, 50% purity, 1.5 eq) was added at 0° C., then the mixture was warmed to 25° C., under N ₂ atmosphere, Stir at 25° C. for 16 hours. The reaction was monitored for completion by LCMS, the mixture was poured into ice water (25 mL), then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=10:1 to 1:1) to yield Intermediate 2 (320 mg, 91%) as a yellow solid. LCMS: m/z = 482.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.06 (d, J = 8.60 Hz, 2H) 7.51 (dd, J = 3 .53, 1.10Hz, 1H) 7.44 (dd, J = 5.07, 0.88Hz, 1H) 7.07-7.26 (m, 4H) 6.96 (d, J = 7.72Hz , 1H) 6.79-6.93 (m, 2H) 6.66 (s, 1H) 6.23 (d, J=8.16Hz, 1H) 5.29-5.36 (m, 1H) 3 .27-3.34 (m, 1H) 3.14-3.22 (m, 1H) 2.91-3.03 (m, 2H) 2.52 (t, J=7.50Hz, 2H).

A solution of Intermediate 2 (320 mg, 664.50 umol, 1 eq) and _NH4Cl ( _177.73 mg, 3.32 mmol, 5 eq) in EtOH (12 mL) and H2O (4 mL) was heated to 90°C. and then Fe (185.55 mg, 3.32 mmol, 5 eq) was added at 90° C. under N ₂ and the mixture was then stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 3 (300 mg, crude) as a yellow solid. LCMS: m/z = 452.2 (M+H ⁺ ).

A solution of intermediate 3 (300 mg, 664.34 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (317.21 mg, 1.99 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (0.8 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O 10 mM NH ₄ HCO ₃ )-ACN]; B%: 10%-40%, 10 min) to give compound 76 (169.1 mg, 45%) was obtained as a white solid. LCMS: m/z = 530.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.29 (d, J = 8.44 Hz, 1H) 7.69-7 .73 (m, 1H) 7.62-7.65 (m, 1H) 7.23-7.29 (m, 1H) 7.21 (s, 1H) 7.15-7.18 (m, 1H) ) 7.13 (s, 1H) 7.08 (s, 1H) 6.94-7.03 (m, 4H) 6.84-6.92 (m, 4H) 5.04-5.14 (m , 1H) 3.04 (dd, J=13.82, 5.87Hz, 1H) 2.74-2.88 (m, 3H) 2.38-2.44 (m, 2H).

Synthesis of compound 77


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300.00 mg, 727.58 umol) in DMF (5 mL) , 1 eq.) and Intermediate 1 (134.33 mg, 727.58 umol, 1 eq.) was added dropwise _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq.) at 0°C. and then T3P (694.51 mg, 1.09 mmol, 649.07 uL, 50% purity, 1.5 eq) was added at 0° C., then the mixture was warmed to 25° C., under N ₂ atmosphere, Stir at 25° C. for 16 hours. The reaction was monitored for completion by LCMS, the mixture was poured into ice water (25 mL), then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=10:1 to 1:1) to yield Intermediate 2 (360 mg, 99%) as a yellow solid. LCMS: m/z = 498.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.05 (d, J = 8.60 Hz, 2H) 8.01 (s, 1H) 7 .44-7.54 (m, 1H) 7.40-7.46 (m, 1H) 7.02-7.21 (m, 6H) 6.66 (s, 1H) 6.34 (d, J = 8.38 Hz, 1H) 5.27-5.37 (m, 1H) 3.25-3.34 (m, 1H) 3.14-3.23 (m, 1H) 2.91-3.01 (m, 2H) 2.51 (t, J=7.50 Hz, 2H).

A solution of Intermediate 2 (360 mg, _722.87 umol, 1 eq) and NH4Cl ( _193.34 mg, 3.61 mmol, 5 eq) in EtOH (12 mL) and H2O (4 mL) was heated to 90°C. and then Fe (201.84 mg, 3.61 mmol, 5 eq) was added at 90° C. under N ₂ and the mixture was then stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 3 (338 mg, crude) as a yellow solid. LCMS: m/z = 468.2 (M+H ⁺ ).

A solution of intermediate 3 (338 mg, 722.17 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (344.83 mg, 2.17 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored upon completion by LCMS, 7% ammonium hydroxide (0.8 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; .1 mg, 38%), obtained as a white solid. LCMS: m/z = 546.0 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.28 (d, J = 8.56 Hz, 1H) 7.71 (dd , J = 5.07, 0.92Hz, 1H) 7.63 (dd, J = 3.67, 0.98Hz, 1H) 7.23-7.28 (m, 2H) 7.14-7.22 (m, 3H) 7.07-7.13 (m, 3H) 6.97 (s, 1H) 6.83-6.92 (m, 4H) 5.01-5.14 (m, 1H) 3 .04 (dd, J=13.75, 5.93 Hz, 1H) 2.72-2.88 (m, 3H) 2.41 (td, J=7.55, 2.38 Hz, 2H).

Synthesis of compound 78


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (0.3 g, 727.58 umol) in DMF (5 mL) , 1 eq, HBr) and Intermediate 1 (145.09 mg, 873.10 umol, 1.2 eq) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq), The mixture was cooled to 0° C., then T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 2 eq) was added dropwise. The reaction mixture was warmed to 25° C. and stirred for 13 hours. The reaction was monitored for completion by LCMS and TLC and the reaction mixture was diluted with ice water (40 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo yielding _Intermediate 2 (0.4 g, crude) as a yellow oil. Obtained. LCMS: m/z = 480.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 7.98-8.02 (m, 3H) 7.49 (d, J = 2.93 Hz , 1H) 7.41 (d, J = 4.52Hz, 1H) 7.01-7.16 (m, 4H) 6.60-6.78 (m, 4H) 6.48 (d, J = 8 .44Hz, 1H) 5.27-5.45 (m, 1H) 3.14-3.30 (m, 2H) 2.81-2.88 (m, 2H) 2.43-2.53 (m , 2H).

To a solution of Intermediate 2 (400 mg, 834.08 umol, 1 eq) in EtOH (6 mL) and _H2O (2 mL) was added _NH4Cl (223.08 mg, 4.17 mmol, 5 eq) followed by The mixture was heated to 90° C., Fe (232.90 mg, 4.17 mmol, 5 eq) was added and the reaction was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated to yield Intermediate 3 (600 mg, crude) as a yellow solid. LCMS: m/z = 450.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol- _d ) δ = 7.51-7.60 (m, 2H) 7.12 (dd, J = 5 .07, 3.75 Hz, 1H) 7.00-7.07 (m, 1H) 6.93-6.98 (m, 2H) 6.82 (s, 1H) 6.67-6.74 (m , 2H) 6.56-6.66 (m, 3H) 5.19-5.22 (m, 1H) 3.57-3.65 (m, 1H) 3.12-3.21 (m, 1H) ) 2.70-2.81 (m, 2H) 2.39-2.53 (m, 2H).

A mixture of intermediate 3 (0.35 g, 778.49 umol, 1 eq.) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (371.71 mg, 2.34 mmol, 3 eq.) was added in batches. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by TLC, 7% ammonium hydroxide (4 mL) was added dropwise and the mixture was dried by flushing with _N2 . The residue was analyzed by preparative HPLC (column: Phenomenex luna (2) C18 250*50 10 u; mobile phase: [water (0.04% NH ₃ H ₂ O)-ACN]; B%: 12%-42%, 20 min) yielded compound 78 (78.1 mg, 19%) as a white solid. LCMS: m/z = 528.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 9.21 (s, 1H) 8.25 (d, J = 8.56 Hz , 1H) 7.70 (d, J = 4.89Hz, 1H) 7.63 (d, J = 3.55Hz, 1H) 7.21 (s, 1H) 7.14-7.18 (m, 1H ) 7.08 (s, 2H) 6.99-7.05 (m, 1H) 6.95 (s, 1H) 6.84-6.92 (m, 4H) 6.50-6.62 (m , 3H) 5.01-5.12 (m, 1H) 3.06 (dd, J = 13.75, 5.69Hz, 1H) 2.83 (dd, J = 13.69, 8.56Hz, 1H) ) 2.61-2.72 (m, 2H) 2.30-2.41 (m, 2H).

Synthesis of compound 79


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (0.3 g, 727.58 umol) in DMF (5 mL) , 1 eq, HBr) and Intermediate 1 (157.33 mg, 873.10 umol, 1.2 eq) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq), The mixture was cooled to 0° C., then T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 2 eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 13 hours. The reaction was monitored for completion by LCMS and the reaction mixture was diluted with ice water (40 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo yielding _Intermediate 2 (0.4 g, crude) as a yellow oil. Obtained. LCMS: m/z = 494.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.02-8.06 (m, 2H) 7.50 (dd, J = 3.67 , 0.86Hz, 1H) 7.42 (dd, J = 5.01, 0.86Hz, 1H) 7.08-7.19 (m, 4H) 6.69-6.78 (m, 3H) 6 .64 (s, 1H) 6.31 (d, J=8.44Hz, 1H) 5.26-5.40 (m, 1H) 3.75 (s, 3H) 3.25-3.34 (m , 1H) 3.14-3.24 (m, 1H) 2.89-2.94 (m, 2H) 2.52 (t, J = 7.52Hz, 2H).

To a solution of Intermediate 2 (400 mg, 810.38 umol, 1 eq) in EtOH (6 mL) and _H2O (2 mL) was added _NH4Cl (216.74 mg, 4.05 mmol, 5 eq) followed by The mixture was heated to 90° C. and Fe (226.30 mg, 4.05 mmol, 5 eq) was added to the mixture and stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 3 (500 mg, crude) as a yellow solid. LCMS: m/z = 464.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, methanol-d ₄ ) δ = 7.47-7.64 (m, 2H) 7.09-7.17 (m , 2H) 6.93 (brd, J=7.95Hz, 2H) 6.80 (s, 1H) 6.63-6.76 (m, 5H) 5.15-5.27 (m, 1H) 3 .71 (s, 3H) 3.09-3.19 (m, 1H) 2.87-2.94 (m, 1H) 2.74-2.83 (m, 2H) 2.40-2.54 (m, 2H).

A mixture of intermediate 3 (0.35 g, 754.94 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (360.47 mg, 2.26 mmol). , 3 equivalents) was added. The mixture was stirred at 0° C. for 0.17 hours. The reaction was monitored upon completion by HPLC and LCMS, 7% ammonium hydroxide (4 mL) was added dropwise and the mixture was dried by flushing with _N2 to give a residue. The residue was analyzed by preparative HPLC (column: Phenomenex Gemini C18 250*50 10 u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 15%-45%, 20 min). yielded compound 79 (227.6 mg, 55%) as a white solid. LCMS: m/z = 542.1 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.27 (d, J = 8.44 Hz, 1H) 7.71 (d , J = 5.01Hz, 1H) 7.63 (d, J = 2.93Hz, 1H) 7.22 (brs, 1H) 7.12-7.18 (m, 2H) 7.06-7.11 (m, 2H) 6.96 (brs, 1H) 6.82-6.92 (m, 4H) 6.67-6.77 (m, 3H) 5.04-5.13 (m, 1H) 3 .70 (s, 3H) 3.05 (dd, J=13.82, 5.87Hz, 1H) 2.84 (dd, J=13.75, 8.50Hz, 1H) 2.69-2.78 (m, 2H) 2.35-2.44 (m, 2H).

Synthesis of compound 80


A mixture of Intermediate 1 (5 g, 25.62 mmol, 1 eq) and HCl/MeOH (50 mL) was heated to 60° C. and the mixture was stirred at 60° C. for 1 hour. The reaction was monitored for completion by LCMS and the reaction mixture was concentrated in vacuo to yield Intermediate 2 (5.3 g, crude) as a white solid. LCMS: m/z = 210.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.10 (s, 1H) 8.05 (dd, J = 8.13, 1 .65Hz, 1H) 7.71 (d, J = 7.58Hz, 1H) 7.53-7.61 (m, 1H) 3.57 (s, 3H) 2.94-3.03 (m, 2H) ) 2.66-2.75 (m, 2H).

To a solution of Intermediate 2 (4.3 g, 20.55 mmol, 1 eq) in EtOH (40 mL) and _H2O (15 mL) was added _NH4Cl (5.43 g, 102.77 mmol, 5 eq), The reaction was heated to 90° C., then Fe (5.74 g, 102.77 mmol, 5 eq) was added and the mixture was stirred at 90° C. under N ₂ atmosphere for 2 hours. The reaction was monitored by LCMS for completion and the reaction mixture was filtered and concentrated in vacuo to yield Intermediate 3 (3.7 g, crude) as a yellow solid. LCMS: m/z = 180.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 6.91 (t, J = 7.52 Hz, 1H) 6.28-6.44 (m, 3H) 4.94 (s, 2H) 3.58 (s, 3H) 2.63-2.74 (m, 2H) 2.52-2.59 (m, 2H).

To a solution of intermediate 3 (2.5 g, 13.95 mmol, 1 eq) in THF (15 mL) was added (Boc) _2O (3.96 g, 18.13 mmol, 4.17 mL, 1.3 eq) and Et ₃ N (1.84 g, 18.13 mmol, 2.52 mL, 1.3 eq) was added and the mixture was stirred at 25° C. for 15 hours under N ₂ atmosphere. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding water (60 mL) at 25° C. and then extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, the filtrate was concentrated in vacuo and the residue was subjected to column chromatography (SiO ₂ , petroleum ether:ethyl acetate=10). :1 to 5:1) yielded intermediate 4 (2.9 g, 68%) as a yellow solid. LCMS: m/z = 302.1 (M+Na ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 9.26 (brs, 1H) 7.33 (s, 1H) 7.24 (d , J = 8.19Hz, 1H) 7.10-7.17 (m, 1H) 6.81 (d, J = 7.46Hz, 1H) 3.58 (s, 3H) 2.73-2.83 (m, 2H) 2.55-2.61 (m, 2H) 1.47 (s, 9H).

A solution of intermediate 4 (2.9 g, 10.38 mmol, 1 eq) in DMF (20 mL) was cooled to 0° C. and then NaH (622.86 mg, 15.57 mmol, 60% pure, 1.5 eq.) was added and the mixture was stirred at 0° C. for 1 h, then MeI (11.79 g, 83.06 mmol, 5.17 mL, 8 eq.) was added and the reaction was allowed to warm to 25° C. under N ₂ atmosphere. and stirred for 3 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding saturated NH ₄ Cl (40 mL) at 25° C. and then extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (70 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in _vacuo to yield Intermediate 5 (3 g, crude) as a pale yellow solid. rice field. LCMS: m/z = 316.1 (M+Na ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 7.12-7.24 (m, 1H) 7.01-7.08 (m , 2H) 6.94-6.98 (m, 1H) 3.63 (s, 3H) 3.20 (s, 3H) 2.87-2.91 (m, 2H) 2.54-2.64 (m, 2H) 1.41 (s, 9H).

To a solution of Intermediate 5 (3 g, 10.23 mmol, 1 eq) in MeOH (15 mL) and _H2O (15 mL) was added LiOH (489.81 mg, 20.45 mmol, 2 eq) at 25 <0>C. The mixture was stirred at 25° C. for 3 hours. The reaction was monitored by LCMS for completion and the reaction mixture was concentrated in vacuo to yield Intermediate 6 (3 g, crude) as a yellow solid. LCMS: m/z = 278.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 7.13-7.22 (m, 1H) 7.07 (s, 1H ) 6.95-7.05 (m, 2H) 3.15 (s, 3H) 2.69-2.83 (m, 2H) 2.10-2.28 (m, 2H) 1.38 (s , 9H).

Intermediate 6 (400 mg, 970.11 umol, 1 eq., (S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl) in DCM (8 mL) To a solution of ethanamine hydrobromide (415.11 mg, 1.46 mmol, 1.5 eq) was added _Et3N (588.99 mg, 5.82 mmol, 810.17 uL, 6 eq) and the reaction was Cool to 0° C., then add T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 1.5 eq) dropwise, then warm it to 25° C. under N ₂ atmosphere. and stirred for 2 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding ice water (40 mL) at 25° C. and then extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo yielding _Intermediate 7 (577 mg, crude) as a yellow oil. . LCMS: m/z = 593.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.46 (d, J = 8.56 Hz, 1H) 8.11 (d, J = 8.19Hz, 2H) 7.72 (d, J = 5.01Hz, 1H) 7.65 (d, J = 3.55Hz, 1H) 7.47 (d, J = 8.19Hz, 2H) 7 .26 (s, 1H), 7.13-7.21 (m, 2H) 7.02-7.09 (m, 2H) 6.92 (d, J = 7.46Hz, 1H) 5.21- 5.34 (m, 1H) 3.34-3.39 (m, 1H) 3.09-3.17 (m, 4H) 2.68-2.75 (m, 2H) 2.34-2. 43 (m, 2H) 1.37 (s, 9H).

To a solution of Intermediate 7 (500 mg, _843.56 umol, 1 eq) in EtOH (15 mL) and H2O (5 mL) was added _NH4Cl (222.92 mg, 4.22 mmol, 5 eq) and the reaction was was heated to 90° C., then Fe (235.54 mg, 4.22 mmol, 5 eq) was added, the mixture was degassed, purged with N ₂ three times, and stirred at 90° C. for 2 h under N ₂ atmosphere. Stirred. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 8 (450 mg, crude) as a yellow solid. LCMS: m/z = 563.3 (M+H ⁺ ).

A solution of intermediate 8 (50 mg, 88.85 umol, 1 eq) in MeCN (0.5 mL) and pyridine (0.5 mL) was cooled to 0° C. and then SO ₃ -pyridine (28.28 mg, 177 .70 umol, 2 eq.) was added and the mixture was then stirred at 0° C. for 0.17 h. The reaction was monitored by LCMS for completion and the compound of Intermediate 10 (57 mg, crude) in MeCN and pyridine was obtained as a yellow liquid and used directly in the next step. LCMS: m/z = 641.1 (MH ⁺ ).

A solution of intermediate 10 (57 mg, 88.81 umol, 1 eq) in DCM (2 mL) was cooled to 0° C., then TFA (0.5 mL) was added and the mixture was stirred at 0° C. for 0.5 h. . The reaction was monitored by TLC when complete and the mixture was dried by flushing with _N2 to yield Intermediate 11 (48 mg, crude) as a yellow solid.

Intermediate 11 (48 mg, 88.45 umol, 1 eq) and _NH3 . The mixture in H ₂ O (1 mL) was cooled to 0° C. and the mixture was stirred at 0° C. for 0.1 hour. The reaction was monitored by LCMS when complete and the mixture was dried by flushing _N2 to give a residue. The residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 15%-45%, 10 min) yielded compound 80 (3.4 mg, 7%) as a white solid. LCMS: m/z = 541.0 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.27 (d, J = 8.31 Hz, 1H) 7.71 (d , J = 4.89Hz, 1H) 7.63 (d, J = 3.30Hz, 1H) 7.21 (s, 1H) 7.14-7.18 (m, 1H) 7.10 (d, J = 10.51Hz, 2H) 7.03 (t, J = 7.70Hz, 1H) 6.96 (s, 1H) 6.85-6.93 (m, 4H) 6.42-6.59 (m , 3H) 5.00-5.14 (m, 1H) 3.06 (dd, J = 13.76, 5.44Hz, 1H) 2.83 (dd, J = 13.69, 8.93Hz, 1H) ) 2.63-2.71 (m, 5H) 2.27-2.43 (m, 2H).

Synthesis of compound 81


HCOOH (1.56 g, 32.57 mmol, 3 eq) was added dropwise to DMF (5 mL) with stirring and cooling with ice water. Et ₃ N (1.43 g, 14.11 mmol, 1.96 mL, 1.3 eq) was similarly added followed by Intermediate 2 (1.56 g, 10.86 mmol, 1 eq). After dissolution, Intermediate 1 (2 g, 10.86 mmol, 1 eq) was added and the mixture was heated to 80° C. and stirred for 14 hours. The reaction was monitored upon completion by LCMS and the solution was cooled and poured into ice water (20 mL) with vigorous stirring. Concentrated HCl was added until pH=1-2 and the solution was concentrated in vacuo to yield Intermediate 3 (2.4 g, crude) as a red solid. LCMS: m/z = 227.0 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 7.82 (brs, 1H) 7.74 (d, J = 6.58 Hz, 1H) 7.59-7.66 (m, 1H) 7 .49-7.58 (m, 1H) 3.36 (s, 2H) 3.11-3.16 (m, 3H) 2.48-2.52 (m, 2H).

(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300 mg, 727.58 umol) in DCM (1.2 mL) , 1 eq.) and intermediate 2 (199.30 mg, 873.10 umol, 1.2 eq.) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq.) followed by The solution was cooled to 0° C., then T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 2 eq) was added dropwise at 0° C., then the solution was stirred at 25° C. for 3 hours. . The reaction was monitored for completion by LCMS, the solution was poured into water (5 mL) and extracted with dichloromethane (3 x 10 mL), then the combined organic phases were washed with brine (10 mL) and _{anhydrous Na2SO4} . and concentrated in vacuo to yield Intermediate 4 (452 mg, crude) as a yellow oil. LCMS: m/z = 542.2 (M+H ⁺ ).

To a solution of intermediate 4 (500 mg, _923.09 umol, 1 eq) in EtOH (10 mL) and H2O (3 mL) was added _NH4Cl (240.23 mg, 4.62 mmol, 5 eq) at 25°C. The solution was then warmed to 90° C., Fe (257.75 mg, 4.62 mmol, 5 eq) was then added, and the mixture was then stirred at 90° C. for 2 hours under N ₂ atmosphere. LCMS yielded complete reaction 5 (638 mg, crude) as a yellow solid. LCMS: m/z = 510.1 (MH ⁺ ).

A solution of intermediate 5 (638 mg, 1.25 mmol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (595.37 mg, 3.74 mmol, 3 equivalent) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5 u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; 17%), obtained as a white solid. LCMS: m/z = 590.0 (MH ⁺ ). ¹ H-NMR: (400 MHz, D ₂ O) δ = 7.56-7.60 (m, 1H) 7.46-7.52 (m, 1H) 7.39-7.44 (m, 1H) 7.34-7.38 (m, 1H) 7.22-7.33 (m, 2H) 6.90-7.04 (m, 5H) 6.67 (s, 1H) 5.00-5. 10 (m, 1H) 3.00 (s, 3H) 2.89-2.97 (m, 1H) 2.86-2.89 (m, 3H) 2.46 (s, 2H).

Compound 82

Preparation of Intermediate 4 To intermediate 8 (5 g, 40.01 mmol, 2.84 mL, 1 eq) in DCM (50 mL), intermediate 9 (6.63 g, 43.99 mmol, 5.39 mL, 1.10 eq) ) followed by Et ₃ N (80.02 mmol, 11.14 mL, 2.00 eq) and finally DMAP (39.07 mg, 319.76 umol, 7.99e-3 eq), then the solution was warmed to 20 °C. and stirred for 18 hours. The reaction was monitored for completion by LCMS and the reaction mixture was poured into 1N HCl (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were then washed with brine (2×50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo yielding Intermediate 4 (6 g, crude) as a yellow liquid. . LCMS: m/z = 239.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 3.88 (t, J = 5.685 Hz, 2H) 3.52 (t, J = 5.685Hz, 2H) 0.88(s, 9H) 0.06(s, 6H).

(S)-2- ₍ 4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (2 g, 4.85 mmol, 1 eq) and intermediate 2 (806.03 mg, 4. 85 mmol, 1 eq.) at 0° C. and the mixture was warmed to 25° C. and stirred for 1 hour. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (50 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic phase was then washed with brine (2 x 20 mL), dried over anhydrous _Na2SO4 and concentrated in vacuo _. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=5:1 to 3:1) to yield Intermediate 3 (1.8 g, 77%) as a white solid. LCMS: m/z = 480.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 9.21 (s, 1H) 8.42 (d, J = 8.559 Hz, 1H ) 8.10 (d, J = 8.681Hz, 2H) 7.72 (dd, J = 5.074, 1.039Hz, 1H) 7.65 (dd, J = 3.668, 0.978Hz, 1H) ) 7.46 (d, J = 8.681Hz, 2H) 7.21 (s, 1H) 7.17 (dd, J = 5.013, 3.668Hz, 1H) 6.96-7.03 (m , 1H) 6.48-6.59 (m, 3H) 5.22-5.28 (m, 1H) 3.33-3.40 (m, 1H) 3.13 (dd, J = 13.694 , 9.292 Hz, 1H) 2.64 (t, J=7.642 Hz, 2H) 2.30-2.39 (m, 2H).

Intermediate 3 (200 mg, 417.04 umol, 1 eq), Intermediate 4 (149.65 mg, 625.56 umol, 1.5 eq), _K2CO3 ( _230.55 mg, 1.67 mmol) in DMF (3 mL). , 4 eq.) was degassed and purged with N ₂ three times, then the mixture was stirred at 100° C. under N ₂ atmosphere for 18 h. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were then washed with brine (2 x 20 mL), dried over anhydrous _Na2SO4 and concentrated in vacuo _yielding Intermediate 5 (320 mg, crude) as a yellow oil. . LCMS: m/z = 638.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.43 (d, J = 8.681 Hz, 1H) 8.10 (d, J = 8.803Hz, 2H) 7.72 (dd, J = 5.013, 1.101Hz, 1H) 7.64 (dd, J = 3.729, 1.161Hz, 1H) 7.46 (d, J = 8.803Hz, 2H) 7.23 (s, 1H) 7.17 (dd, J = 5.074, 3.729Hz, 1H) 7.10 (t, J = 7.947Hz, 1H) 6.64 -6.77 (m, 3H) 5.21-5.31 (m, 1H) 3.92-4.02 (m, 2H) 3.80-3.91 (m, 2H) 3.34-3 .35 (m, 1H) 3.06-3.19 (m, 1H) 2.65-2.72 (m, 2H) 2.35-2.44 (m, 2H) 0.86 (s, 9H) ) 0.04-0.08 (m, 6H).

To a solution of intermediate 5 (300 mg, _470.31 umol, 1 eq.) in EtOH (6 mL) and H2O (2 mL) was heated to 90°C followed by _NH4Cl (125.79 mg, 2.35 mmol, 5 eq), Fe (131.32 mg, 2.35 mmol, 5 eq) was added to the mixture and stirred for 2 hours. The reaction was monitored by TLC and LCMS for completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 6 (400 mg, crude) as a yellow solid. LCMS: m/z = 608.2 (M+H ⁺ ).

To a solution of intermediate 6 (400 mg, 658.00 umol, 1 eq) in THF (8 mL) was slowly added aqueous HCl (2M, 239.27 uL, 7.27e ^-1 eq) at 20°C and stirred for 1 h. bottom. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into saturated NaHCO ₃ (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phases were then washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo yielding Intermediate 7 (220 mg, crude) as a yellow oil. . LCMS: m/z = 494.1 (M+H ⁺ ).

To a solution of intermediate 7 (220 mg, 445.67 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was added SO _-pyridine (106.40 mg, 668.50 umol, 1.5 eq) at 0 °C. added and stirred for 0.17 hours. The reaction was monitored for completion by TLC, 7% ammonium hydroxide (5 mL) was added dropwise, then the mixture was dried by flushing with N ₂ and the residue was analyzed by preparative HPLC (water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 30%-50%, 10 min) to yield compound 82 (12.0 mg, 5.5%) as a white solid. LCMS: m/z = 572.0 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.27 (d, J = 8.436 Hz, 1H) 7.71 (dd , J = 5.074, 1.039Hz, 1H) 7.58-7.68 (m, 2H) 7.02-7.19 (m, 7H) 6.81-6.94 (m, 4H) 6 .67-6.78 (m, 3H) 5.02-5.14 (m, 1H) 4.83 (t, J=5.563Hz, 1H) 3.86-4.01 (m, 2H) 3 .68 (q, J = 5.380Hz, 2H) 3.05 (dd, J = 13.694, 5.869Hz, 1H) 2.83 (dd, J = 13.816, 8.559Hz, 1H) 2 .69-2.78 (m, 2H) 2.34-2.43 (m, 2H).

Synthesis of compound 83


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (250 mg, 606.32 umol, 1 equivalents), to a solution of Intermediate 2 (126.19 mg, 666.95 umol, 1.1 eq) was added _Et3N (368.12 mg, 3.64 mmol, 506.36 uL, 6 eq) and the mixture was stirred at 0°C. and then added T3P (578.76 mg, 909.48 umol, 540.90 uL, 50% purity, 1.5 eq), which was then warmed to 25 °C under _N2 atmosphere for 2 h. Stirred. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding ice water (40 mL) and then extracted with dichloromethane (3 x 40 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to yield _Intermediate 3 (300 mg, crude) as a yellow solid. . LCMS: m/z = 503.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 10.73 (brs, 1H) 8.43 (d, J = 8.56 Hz, 1H ) 8.08 (d, J = 8.31Hz, 2H) 7.72 (d, J = 5.01Hz, 1H) 7.65 (d, J = 3.55Hz, 1H) 7.41-7.53 (m, 3H) 7.32 (d, J = 8.07Hz, 1H) 7.22 (s, 1H) 7.17 (t, J = 4.34Hz, 1H) 7.02-7.08 (m , 2H) 6.93-6.99 (m, 1H) 5.24-5.33 (m, 1H) 3.34-3.39 (m, 1H) 3.08-3.18 (m, 1H) ) 2.81-2.85 (m, 2H) 2.42-2.47 (m, 2H).

To a solution of Intermediate 3 (360 mg, _716.27 umol, 1 eq) in EtOH (5 mL) and H2O (2 mL) was added _NH4Cl (196.35 mg, 3.58 mmol, 5 eq) at 25°C. The solution was then heated to 90° C. and Fe (200.00 mg, 3.58 mmol, 5 eq) was added, then the mixture was stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (363 mg, crude) as a yellow solid. LCMS: m/z = 473.2 (M+H ⁺ ).

A solution of intermediate 4 (363 mg, 768.05 umol, 1 eq) in MeCN (2 mL) and pyridine (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (366.74 mg, 2.30 mmol, 3 equivalent) was added and the mixture was stirred at 0° C. for 10 minutes. The reaction was monitored for completion by TLC, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 15% to 45%, 10 min) to give compound 83 (107. 2 mg, 25%), obtained as a pale yellow solid. LCMS: m/z = 551.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 10.66 (brs, 1H) 8.32 (d, J = 8.56 Hz , 1H) 7.79 (brs, 1H) 7.71 (dd, J = 5.07, 1.04Hz, 1H) 7.64 (dd, J = 3.67, 0.98Hz, 1H) 7.47 (d, J = 7.70Hz, 1H) 7.29 (d, J = 8.07Hz, 1H) 7.14-7.22 (m, 3H) 7.07-7.13 (m, 1H) 7 .00-7.07 (m, 2H) 6.95-6.99 (m, 5H) 6.90-6.94 (m, 1H) 6.67 (d, J=1.96Hz, 1H) 5 .09-5.18 (m, 1H) 3.10 (dd, J = 13.82, 5.01Hz, 1H) 2.77-2.94 (m, 3H) 2.42-2.48 (m , 2H).

Synthesis of compound 84


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (0.3 g, 7.75 mmol) in DCM (10 mL) , 1 eq.) and Intermediate 2 (113.65 mg, 727.58 umol, 1 eq.) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq.) and cooled to 0°C. and then T3P (463.01 mg, 727.58 umol, 432.72 uL, 50% purity, 1 eq) was added dropwise at 0°C under _N2 and the reaction was stirred at 25°C for 3 hours. The reaction was monitored when complete by LCMS and the solution was dried by flushing with _N2 to yield Intermediate 3 (0.3 g, crude) as a yellow oil. LCMS: m/z = 470.0 (M+H ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.50 (d, J = 8.56 Hz, 1H) 8.07-8.16 (m, 2H) 7.71-7.75 (m , 1H) 7.65 (dd, J = 3.67, 1.10Hz, 1H) 7.49 (d, J = 8.68Hz, 2H) 7.31 (s, 1H) 7.22 (dd, J = 5.14, 1.22Hz, 1H) 7.17 (dd, J = 5.01, 3.67Hz, 1H) 6.83 (dd, J = 5.14, 3.42Hz, 1H) 6.72 (dd, J = 3.42, 0.98 Hz, 1H) 5.20-5.34 (m, 1H) 3.34-3.38 (m, 1H) 3.14 (dd, J = 13.63 , 9.35 Hz, 1 H) 2.94 (t, J=7.27 Hz, 2 H) 2.37-2.46 (m, 2 H).

Intermediate 3 (0.3 g, _638.84 umol, 1 eq) and _NH4Cl (170.86 mg, 3.19 mmol, 111.68 uL, 5 eq) in EtOH (5 mL) and H2O (2 mL) was Heated to 90° C., then Fe (178.38 mg, 3.19 mmol, 5 eq) was added and the mixture was stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 4 (400 mg, crude) as a green solid. LCMS: m/z = 440.2 (M+H ⁺ ).

Intermediate 4 (400 mg, 909.88 umol, 1 eq.) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ . Pyridine (349.78mg, 1.36mmol, 1.5eq) was added at 0°C. The mixture was then stirred at 0° C. for 10 minutes. The reaction was monitored for completion by LCMS, HPLC and TLC, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with _N2 . The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-25%, 11 min) to give compound Yield 84 (0.11 g, 22%) as a white solid. LCMS: m/z = 518.0 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.36 (d, J = 8.44 Hz, 1H) 7.71 (d , J = 5.01Hz, 1H) 7.60-7.68 (m, 2H) 7.26 (d, J = 5.01Hz, 1H) 7.13-7.21 (m, 2H) 7.07 (s, 4H) 6.83-6.93 (m, 5H) 6.77 (d, J = 2.81Hz, 1H) 5.02-5.16 (m, 1H) 3.06 (dd, J = 13.69, 5.75Hz, 1H) 2.97 (t, J = 7.34Hz, 2H) 2.85 (dd, J = 13.75, 8.62Hz, 1H) 2.40-2.46 (m, 2H).

Synthesis of compound 85


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300.00 mg, 727.58 umol) in DCM (5 mL) , 1 eq.) and Intermediate 1 (159.39 mg, 727.58 umol, 1 eq.) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq.) dropwise at 0°C. and then T3P (694.51 mg, 1.09 mmol, 649.07 uL, 50% purity, 1.5 eq) was added at 0° C., then the mixture was warmed to 25° C., under N ₂ atmosphere, Stir at 25° C. for 16 hours. LCMS monitored when the reaction was complete. The mixture was poured into ice water (25 mL), then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 2 (380 mg, crude) as a yellow solid. LCMS: m/z = 532.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 8.06 (d, J = 8.60 Hz, 2H) 7.47-7.53 (m , 1H) 7.39-7.44 (m, 1H) 7.15-7.26 (m, 4H) 7.07-7.12 (m, 1H) 6.99-7.05 (m, 1H) ) 6.69 (s, 1H) 6.33 (d, J=8.16Hz, 1H) 5.28-5.37 (m, 1H) 3.34-3.40 (m, 1H) 3.22 -3.26 (m, 2H) 3.02-3.12 (m, 1H) 2.44-2.51 (m, 2H).

A solution of Intermediate 2 (380 mg, _713.67 umol, 1 eq) and _NH4Cl (190.88 mg, 3.57 mmol, 5 eq) in EtOH (12 mL) and H2O (4 mL) was heated to 90°C. and then Fe (199.27 mg, 3.57 mmol, 5 eq) was added at 90° C. under N ₂ and the mixture was then stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 3 (300 mg, crude) as a yellow solid. LCMS: m/z = 502.1 (M+H ⁺ ).

A solution of intermediate 3 (300 mg, 597.04 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (285.08 mg, 1.79 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 10%-50%, 10 min) to give compound 85 (188. 2 mg, 51%), obtained as a white solid. LCMS: m/z = 580.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.33-8.41 (m, 1H) 7.71 (d, J = 4.89Hz, 1H) 7.60-7.66 (m, 1H) 7.39-7.47 (m, 2H) 7.23-7.31 (m, 2H) 7.21 (s, 1H) ) 7.15-7.18 (m, 1H) 7.08 (s, 1H) 6.96 (s, 1H) 6.83-6.92 (m, 3H) 6.48 (d, J = 8 .31Hz, 1H) 5.02-5.15(m, 1H) 2.97-3.10(m, 3H) 2.78-2.94(m, 1H) 2.26-2.38(m , 2H).

Synthesis of compound 86


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300 mg, 727.58 umol, in DCM (5 mL) 1 eq), to a solution of Intermediate 2 (148.99 mg, 800.34 umol, 1.1 eq) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq) and the mixture was Cool to 0° C., then add T3P (694.51 mg, 1.09 mmol, 649.07 uL, 50% purity, 1.5 eq) dropwise and warm the reaction to 25° C. under N ₂ atmosphere. Stirred for 2 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding ice water (30 mL) and then extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to yield _Intermediate 3 (350 mg, crude) as a yellow solid. . LCMS: m/z = 500.0 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.45 (d, J = 8.68 Hz, 1H) 8.10 (d, J = 8.68Hz, 2H) 7.68-7.75 (m, 1H) 7.59-7.67 (m, 1H) 7.47 (d, J = 8.68Hz, 2H) 7.30 (s , 1H) 7.11-7.25 (m, 3H) 6.88-6.97 (m, 1H) 5.20-5.31 (m, 1H) 3.32-3.36 (m, 1H) ) 3.07-3.17 (m, 1H) 2.73 (t, J=7.34Hz, 2H) 2.34-2.45 (m, 2H).

A solution of intermediate 3 (350 mg, _700.63 umol, 1 eq) in EtOH (5 mL) and H2O (2 mL) was added _NH4Cl (185.14 mg, 3.50 mmol, 5 eq) followed by The solution was heated to 90° C., Fe (195.63 mg, 3.50 mmol, 5 eq) was added and the reaction was stirred at 90° C. under N ₂ atmosphere for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (350 mg, crude) as a yellow solid. LCMS: m/z = 470.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.36 (d, J = 8.60 Hz, 1H) 7.67-7.75 (m, 1H) 7.60-7.65 (m, 1H) 7.13-7.24 (m, 3H) 6.86-7.00 (m, 2H) 6.80 (d, J = 8 .38Hz, 2H) 6.42 (d, J = 8.16Hz, 2H) 4.97-5.09 (m, 1H) 2.88-3.05 (m, 3H) 2.71-2.82 (m, 1H) 2.36-2.42 (m, 2H).

A solution of intermediate 4 (350 mg, 745.36 umol, 1 eq.) in MeCN (2 mL) and pyridine (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (355.90 mg, 2.24 mmol, 3 eq. ) was added. The reaction was stirred at 0° C. for 10 minutes. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 10% to 40%, 10 min) to give compound 86 (77. 2 mg, 19%), obtained as a white solid. LCMS: m/z = 547.9 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.30 (d, J = 8.31 Hz, 1H) 7.71 (d , J = 4.89Hz, 1H) 7.64 (d, J = 3.42Hz, 1H) 7.22-7.29 (m, 2H) 7.21 (brs, 1H) 7.14-7.19 (m, 1H) 7.08 (brs, 1H), 6.83-6.98 (m, 6H) 5.00-5.15 (m, 1H) 3.03 (dd, J = 13.63, 5.81Hz, 1H) 2.83 (dd, J = 13.57, 8.68Hz, 1H) 2.72-2.77 (m, 2H) 235-2.44 (m, 2H).

Synthesis of compound 87


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300 mg, 727.58 umol, 1 eq.) and Intermediate 2 (150.79 mg, 727.58 umol, 1 eq.) was added _Et3N (4.37 mmol, 607.63 uL, 6 eq.), the mixture was cooled to 0°C and then T3P (1.09mmol, 649.07uL, 50% purity, 1.5eq) was added dropwise. The mixture was then warmed to 25° C. and stirred for 1 hour. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (30 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic phases were then washed with brine (2 x 20 mL), dried over anhydrous _Na2SO4 and concentrated in vacuo _yielding Intermediate 3 (320 mg, crude) as a yellow oil. . LCMS: m/z = 521.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.64 (d, J = 8.558 Hz, 1H) 8.07 (d, J = 8.681Hz, 2H) 7.92-7.98 (m, 1H) 7.87 (d, J = 7.703Hz, 1H) 7.71 (dd, J = 5.074, 1.039Hz, 1H) ) 7.64 (dd, J = 3.668, 1.100Hz, 1H) 7.42-7.52 (m, 3H) 7.33-7.40 (m, 2H) 7.17 (dd, J = 5.013, 3.790Hz, 1H) 5.24-5.30 (m, 1H) 3.38 (dd, J = 13.694, 9.414Hz, 1H) 3.26 (t, J = 7 .153Hz, 2H) 3.16 (dd, J = 13.694, 9.414Hz, 1H) 2.63-2.78 (m, 2H).

A solution of intermediate 3 (320 mg, _614.62 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was added _NH4Cl (164.39 mg, 3.07 mmol, 5 eq) followed by The solution was heated to 90° C. and Fe (171.62 mg, 3.07 mmol, 5 eq) was added to the mixture and stirred at 90° C. for 2 hours. The reaction was monitored by TLC and LCMS for completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (370 mg, crude) as a yellow oil. LCMS: m/z = 491.2 (M+H ⁺ ).

To a solution of intermediate 4 (370 mg, 754.08 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was added SO _-pyridine (180.03 mg, 1.13 mmol, 1.5 eq) at 0 °C. added and stirred for 0.17 hours. The reaction was monitored for completion by TLC, 7% ammonium hydroxide (5 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*). Mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5% to 35%, 10 min) to give compound 87 (93.3 mg , 22%), obtained as a white solid. LCMS: m/z = 568.9 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.47 (d, J = 8.436 Hz, 1H) 7.97-8 .04 (m, 1H) 7.90 (d, J = 7.703Hz, 1H) 7.70 (dd, J = 5.074, 1.039Hz, 1H) 7.67 (s, 1H) 7.63 (dd, J = 3.668, 1.100Hz, 1H) 7.46-7.48 (m, 1H) 7.34-7.40 (m, 1H) 7.26 (s, 1H) 7.07 -7.17 (m, 1H) 7.07 (s, 4H) 6.84-6.96 (m, 4H) 5.01-5.15 (m, 1H) 3.26-3.31 (m , 2H) 3.08 (dd, J = 13.755, 5.808Hz, 1H) 2.87 (dd, J = 13.755, 8.620Hz, 1H) 2.65-2.80 (m, 2H) ).

Synthesis of compound 88


To a solution of Intermediate 1 (0.3 g, 727.58 umol, 1 eq) and Intermediate 2 (158.76 mg, 727.58 umol, 1 eq) in DCM (5 mL) was added _Et3N (441.74 mg, 4 .37mmol, 607.63uL, 6eq) was added, the mixture was cooled to 0°C, then T3P (463.00mg, 1.46mmol, 432.71uL, 2eq) was added dropwise at 0°C. The reaction mixture was warmed to 25° C. and stirred at 25° C. for 2 hours. The reaction was monitored by LCMS for completion and the reaction mixture was diluted with ice water (20 mL) and extracted with DCM (3 x 10 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to give Intermediate 3 (0.5 g, crude) as a yellow oil. LCMS: m/z = 532.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 7.97-8.09 (m, 4H) 7.40-7.53 (m, 5H ) 7.20 (d, J = 8.56Hz, 2H) 7.11 (t, J = 4.34Hz, 1H) 6.66-6.76 (m, 2H) 5.32-5.39 (m , 1H) 3.33-3.41 (m, 1H) 3.27-3.31 (m, 2H) 3.02-3.09 (m, 1H) 2.80-2.89 (m, 2H) ).

To a solution of intermediate 3 (0.5 g, _752.44 umol, 1 eq) in EtOH (9 mL) and H2O (3 mL) was added _NH4Cl (201.24 mg, 3.76 mmol, 5 eq), The solution was heated to 90° C., then Fe (210.12 mg, 3.76 mmol, 5 eq) was added. The mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (0.5 g, crude) as a yellow solid. LCMS: m/z = 502.1 (M+H ⁺ ).

A mixture of intermediate 4 (0.06 g, 119.61 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (57.11 mg, 358.84 umol). , 3 equivalents) was added. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise and the mixture was dried by flushing with _N2 to give a residue. The residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 10%-50%, 10 min) yielded compound 88 (18.4 mg, 26%) as a white solid. LCMS: m/z = 580.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ +D ₂ O) δ = 7.86-7.91 (m, 2H) 7.59 ( dd, J = 5.07, 0.92Hz, 1H) 7.44-7.56 (m, 4H) 7.18 (s, 1H) 7.12 (dd, J = 4.95, 3.85Hz, 1H) 6.84-6.95 (m, 4H) 4.99-5.10 (m, 1H) 3.01-3.23 (m, 3H) 2.80-2.90 (m, 1H) 2.60-2.79 (m, 2H).

Synthesis of compound 89


To a stirred solution of Intermediate 1 (0.1 g, 713.57 umol, 1 eq) in anhydrous DMF (2 mL) was added DIPEA (368.90 mg, 2.85 mmol, 497.17 uL, 4 eq) followed by ( S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (294.22 mg, 713.57 umol, 1 eq) was added and PyBOP (427.04 mg, 820.61 umol, 1.15 eq) was added. The reaction was stirred at 20° C. for 1 hour and at 50° C. for an additional 12 hours under N ₂ atmosphere. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding water (40 mL) at 25° C. and then extracted with ethyl acetate (3×15 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to yield _Intermediate 2 (0.4 g, crude) as a yellow solid. rice field. LCMS: m/z = 454.0 (M+H ⁺ ).

To a solution of Intermediate 2 (0.38 g, 837.86 umol, 1 eq) in EtOH (6 mL) and _H2O (2 mL) was added _NH4Cl (224.09 mg, 4.19 mmol, 5 eq), The mixture was then heated to 90° C. and then Fe (233.97 mg, 4.19 mmol, 5 eq) was added. The mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.05% HCl)-ACN]; B%: 1%-30%, 10 min) to give intermediate Yield 3 (0.12 g, 34%) obtained as a yellow solid. LCMS: m/z = 424.0 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 14.19 (brs, 1H) 10.38 (brs, 2H) 8.73 (d , J = 8.56Hz, 1H) 7.72 (dd, J = 5.01, 1.10Hz, 1H) 7.65 (dd, J = 3.67, 1.10Hz, 1H) 7.51 (s , 2H) 7.41 (s, 1H) 7.25-7.37 (m, 4H) 7.17 (dd, J = 5.01, 3.67Hz, 1H) 5.00-5.30 (m , 1H) 3.22 (dd, J = 13.69, 5.50Hz, 1H) 2.96-3.09 (m, 3H) 2.65-2.80 (m, 2H).

A mixture of intermediate 3 (0.12 g, 283.32 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (67.64 mg, 424.98 umol). , 1.5 equivalents) was added. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored when complete by TLC, 7% ammonium hydroxide (2 mL) was added dropwise and the mixture was dried by flushing with _N2 to give a residue. The residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5%-35%, 10 min) yielded compound 89 (50.1 mg, 33%) as a white solid. LCMS: m/z = 502.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 7.20-7.28 (m, 2H) 6.96-7.02 ( m, 2H) 6.88-6.95 (m, 4H) 6.80-6.87 (m, 2H) 5.05-5.20 (m, 1H) 2.90-3.05 (m, 1H) 2.77-2.87 (m, 2H) 2.65-2.77 (m, 1H) 2.40-2.57 (m, 2H).

Synthesis of compound 90


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300 mg, 727.58 umol, 1 eq.) and Intermediate 2 (138.39 mg, 727.58 umol, 1 eq.) was added _Et3N (4.37 mmol, 607.63 uL, 6 eq.), the mixture was cooled to 0°C and then T3P (1.09mmol, 649.07uL, 50% purity, 1.5eq) was added dropwise. The mixture was then warmed to 25° C. and stirred for 1 hour. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (30 mL) and extracted with DCM (3 x 20 mL). The combined organic phases were then washed with brine (2×20 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo yielding Intermediate 3 (360 mg, crude) as a yellow oil. . LCMS: m/z = 504.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, CDCl ₃ ) δ = 10.01 (s, 1H) 8.25 (dd, J = 4.707, 1.284 Hz , 1H) 7.98 (d, J = 8.559Hz, 2H) 7.92 (dd, J = 7.825, 1.100Hz, 1H) 7.45 (dd, J = 3.668, 0.978Hz 5 .31-5.38 (m, 1H) 3.24 (dd, J = 13.205, 5.869Hz, 1H) 3.06-3.17 (m, 3H) 2.60 (t, J = 7 .214Hz, 2H).

A solution of intermediate 3 (360.00 mg, _714.86 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was treated with _NH4Cl (191.19 mg, 3.57 mmol, 5 eq) at 25°C. C, then the solution was heated to 90° C. and Fe (199.61 mg, 3.57 mmol, 5 eq) was added to the mixture and stirred at 90° C. for 2 hours. The reaction was monitored by TLC and LCMS for completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (410 mg, crude) as a yellow solid. LCMS: m/z = 474.1 (M+H ⁺ ).

SO ₃ -pyridine (413.36 mg, 2.60 mmol, 3 eq) was added to a solution of intermediate 4 (410 mg, 865.69 umol, 1 eq) in MeCN (1 mL) and pyridine (1 mL) at 0 °C. , and stirred for 0.17 hours. The reaction was monitored for completion by TLC, 7% ammonium hydroxide (5 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 10% to 40%, 10 min) to give compound 90 (139. 6 mg, 29%), obtained as a white solid. LCMS: m/z = 552.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 7.80-7.98 (m, 2H) 7.50-7.62 ( m, 2H) 7.11-7.20 (m, 1H) 7.05 (s, 1H) 6.91-7.00 (m, 3H) 6.86 (d, J = 8.379Hz, 2H) 6.47 (s, 1H) 4.91-5.05 (m, 1H) 2.94-3.01 (m, 2H) 2.74-2.92 (m, 2H) 2.48-2. 60 (m2 H).

Synthesis of compound 91


(S)-2-(4-nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300.00 mg, 727.58 umol) in DCM (5 mL) , 1 eq.) and Intermediate 1 (120.19 mg, 727.58 umol, 1 eq.) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq.) dropwise at 0°C. and then T3P (694.51 mg, 1.09 mmol, 649.07 uL, 50% purity, 1.5 eq) was added at 0° C., then the mixture was warmed to 25° C., under N ₂ atmosphere, Stir at 25° C. for 16 hours. LCMS monitored when the reaction was complete. The mixture was poured into ice water (25 mL), then the mixture was extracted with DCM (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 2 (348 mg, crude) as a yellow solid. LCMS: m/z = 479.2 (M+H ⁺ ), ¹ H-NMR (400 MHz, CDCl ₃ ) δ = 8.26-8.34 (m, 1H) 8.06 (d, J = 8.60 Hz, 2H) 7.48-7.53 (m, 1H) 7.42-7.46 (m, 1H) 7.36-7.41 (m, 1H) 7.18 (d, J=8.60Hz, 2H) 7.08-7.13 (m, 1H) 6.96-7.02 (m, 1H) 6.67 (s, 1H) 6.36 (d, J=8.16Hz, 1H) 29-5.36 (m, 1H) 3.28-3.36 (m, 1H) 3.15-3.23 (m, 1H) 2.94-3.01 (m, 2H) 2.55 ( s, 3H) 2.47-2.53 (m, 2H).

A solution of _Intermediate 2 (348 mg, 727.14 umol, 1 eq) and _NH4Cl (194.48 mg, 3.64 mmol, 127.11 uL, 5 eq) in EtOH (12 mL) and H2O (4 mL) was Heated to 90° C., then Fe (203.04 mg, 3.64 mmol, 5 eq) was added at 90° C. under N ₂ , then the mixture was stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 3 (326 mg, crude) as a yellow solid. LCMS: m/z = 449.2 (M+H ⁺ ), ¹ H-NMR: δ = 8.18 (dd, J = 4.96, 1.43 Hz, 1H) 7.58 (dd, J = 3.75 , 1.10Hz, 1H) 7.56 (d, J = 5.07Hz, 1H) 7.48-7.53 (m, 1H) 7.10-7.17 (m, 2H) 7.01 (s , 1H) 6.93 (d, J = 8.16Hz, 2H) 6.65 (d, J = 8.38Hz, 2H) 5.20 (dd, J = 8.71, 6.50Hz, 1H) 3 .13 (dd, J=13.78, 6.28 Hz, 1H) 2.83-2.95 (m, 3H) 2.43-2.58 (m, 5H).

A solution of intermediate 3 (326 mg, 726.70 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (346.99 mg, 2.18 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5 u; mobile phase: [water (0.04% NH ₃ H ₂ O 10 mM NH ₄ HCO ₃ )-ACN]; .1 mg, 13%), obtained as a white solid. LCMS: m/z = 527.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.33 (d, J = 8.56 Hz, 1H) 8.23-8 .28 (m, 1H) 7.57-7.82 (m, 3H) 7.46 (d, J = 7.46Hz, 1H) 7.12-7.26 (m, 4H) 7.10 (s , 1H) 6.96 (s, 1H) 6.85-6.92 (m, 4H) 5.03-5.13 (m, 1H) 2.99-3.07 (m, 1H) 2.73 -2.86 (m, 3H) 2.44 (s, 3H) 2.37-2.43 (m, 2H).

Synthesis of compound 92


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300 mg, 820.04 umol, 1 equivalents) and Intermediate 2 (120.19 mg, 727.58 umol, 1 eq) was added _Et3N (497.88 mg, 4.92 mmol, 684.84 uL, 6 eq), then the solution was cooled to 0°C. was cooled to , then T3P (521.84 mg, 820.04 umol, 487.70 uL, 50% purity, 1 eq) was added dropwise at 0°C, then the solution was stirred at 25°C for 3 hours. The reaction was monitored for completion by LCMS, the solution was poured into water (5 mL), extracted with DCM (2 x 10 mL), then the combined organic phases were washed with brine (10 mL) and anhydrous _{Na2SO4 .} and concentrated in vacuo to yield Intermediate 3 (492.2 mg, crude) as a yellow oil. LCMS: m/z = 479.0 (M+H ⁺ ).

To a solution of intermediate 3 (490 mg, 1.02 mmol, 1 eq) in EtOH (8 mL) and _H2O (3 mL) was added _NH4Cl (274.58 mg, 5.12 mmol, 5 eq) at 25°C. The solution was then warmed to 90° C., Fe (285.88 mg, 5.12 mmol, 5 eq) was then added, and the mixture was then stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS and HPLC, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (317 mg, crude) as a yellow solid (soli). LCMS: m/z = 449.2 (M+H ⁺ ).

A solution of intermediate 4 (310 mg, 691.03 umol, 1 eq) in pyridine (1 mL) and CH ₃ CN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (329.96 mg, 2.07 mmol). , 3 equivalents) was added at 0°C and the reaction mixture was stirred at 0°C for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*). Mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1% to 30%, 10 min) to give compound 92 (70.6 mg , 19%), obtained as a white solid. LCMS: m/z = 527.0 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ +D ₂ O) δ=8.42 (d, J=8.44 Hz, 1H) 8.27-8.30 (m, 1H) 7.60-7. 65 (m, 2H) 7.30 (s, 1H) 7.08-7.23 (m, 3H) 6.87-6.92 (m, 4H) 5.01-5.07 (m, 1H) 2.99-3.04 (m, 1H) 2.72-2.89 (m, 3H) 2.45-2.50 (m, 5H).

Synthesis of compound 93


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (400 mg, 1.09 mmol, 1 eq.) in DCM (10 mL) ) and Intermediate 1 (169.77 mg, 1.09 mmol, 1 eq) was added _Et3N (330.08 mg, 3.26 mmol, 454.03 uL, 3 eq) dropwise and cooled to 0°C. Then T3P (1.04 g, 1.63 mmol, 970.00 uL, 50% purity, 1.5 eq) was added at 0 °C, then the mixture was warmed to 25 °C and stirred at 25 °C under _N2 atmosphere. Stirred for 2 hours. TLC monitored when the reaction was complete. The mixture was poured into ice water (15 mL), then the mixture was extracted with dichloromethane (2 x 15 mL). The combined organic phase was washed with brine (15 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to give Intermediate 2 (371 mg, crude) as a white solid.

To a solution of intermediate 2 (341 mg, 726.25 umol, 1 eq) in EtOAc (5 mL) was added _SnCl2 . 2H ₂ O (1.31 g, 5.81 mmol, 8 eq) was added, heated to 50° C. and stirred at 50° C. for 2 hours. The reaction was monitored for completion by LCMS, the solution was added to saturated Seniet's salt (50 mL), then filtered, the filter was extracted with ethyl acetate (2×30 mL), dried over anhydrous Na ₂ SO ₄ and filtered. , concentrated in vacuo to give Intermediate 3 (300 mg, crude) as a white solid. LCMS: m/z = 440.2 (M+H ⁺ ).

A solution of intermediate 3 (300 mg, 682.51 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (325.89 mg, 2.05 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 h. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5% to 30%, 10 min) to give compound 93 (104. 3 mg, 28%), obtained as a white solid. LCMS: m/z = 517.9 (M-H ⁺ ), ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ = 8.47 (d, J = 8.436 Hz, 1H) 7.71 (dd, J=5.135, 0.978Hz, 1H) 7.68(s, 1H) 7.64(dd, J=3.668, 1.100Hz, 1H) 7.29(s, 1H) 7.17( dd, J = 5.013, 3.790Hz, 1H) 7.08 (s, 4H) 6.85-6.92 (m, 4H) 5.01-5.11 (m, 1H) 2.99- 3.10 (m, 3H) 2.86 (dd, J=13.755, 8.375Hz, 1H) 2.58-2.69 (m, 2H) 2.27 (s, 3H).

Synthesis of Compound 94


Pd(OAc) ₂ (1 .14 g, 5.08 mmol, 0.25 eq), _PPh3 (2.66 g, 10.15 mmol, 0.5 eq) and _Et3N (6.16 g, 60.90 mmol, 8.48 mL, 3 eq). added. The mixture was then heated to 140° C. and stirred at 140° C. for 16 hours under N ₂ atmosphere. LCMS monitored when the reaction was complete. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=20:1 to 5:1) to yield Intermediate 3 (1.3 g, 31%) as a yellow solid. LCMS: m/z = 203.3 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 11.89 (s, 1H) 8.55 (d, J = 1.96 Hz, 1H ) 8.37 (d, J = 1.83Hz, 1H) 7.80 (d, J = 16.02Hz, 1H) 7.48-7.57 (m, 1H) 6.68 (d, J = 16 .02Hz, 1H) 6.45-6.53 (m, 1H) 3.73 (s, 3H).

Intermediate 3 (1.2 g, 5.93 mmol, 1 eq) was added to a mixture of Pd/C ((1 g, 8.42 mmol, 10% purity, 1.42 eq) in MeOH (10 mL) at 25°C. The suspension was degassed and purged several times with H _2. The mixture was then stirred under H ₂ (15 psi) for 1 h at 25° C. The reaction was monitored by LCMS when complete and the solution was was filtered and concentrated in vacuo to give Intermediate 4 (805 mg, crude) as a white solid, LCMS: m/z = 205.3 (M+H ⁺ ).

To a solution of intermediate 4 (980 mg, 4.80 mmol, 1 eq) in THF (20 mL) and _H2O (5 mL) was added LiOH (459.68 mg, 19.19 mmol, 4 eq) under _N2 atmosphere. addition followed by stirring at 25° C. for 16 hours. The reaction was monitored by LCMS when complete, the solution was filtered and concentrated in vacuo to give Intermediate 5 (1.9 g, crude) as a white solid. LCMS: m/z = 191.3 (M+H ⁺ ).

(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300 mg, 727.58 umol, 1 eq.) and Intermediate 5 (570.80 mg, 2.91 mmol, 4 eq.) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq.) dropwise and cooled to 0°C. and then T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 2 eq.) was added at 0 °C, then the mixture was warmed to 25 °C and stirred for 3 at 25 °C under _N2 atmosphere. Stirred for an hour. LCMS monitored when the reaction was complete. The mixture was poured into ice water (25 mL), then the mixture was extracted with DCM (3 x 25 mL). The combined organic phase was washed with brine (25 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 7 (360 mg, crude) as a yellow solid. LCMS: m/z = 504.2 (M+H ⁺ ).

A solution of Intermediate 2 (360 mg, 714.86 umol, 1 eq) and _NH4Cl ( _191.19 mg, 3.57 mmol, 5 eq) in EtOH (12 mL) and H2O (4 mL) was heated to 90°C. and then Fe (199.61 mg, 3.57 mmol, 5 eq) was added at 90° C. under N ₂ atmosphere, then the mixture was stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 8 (330 mg, crude) as a yellow solid. LCMS: m/z = 474.3 (M+H ⁺ ).

A solution of intermediate 8 (330 mg, 696.77 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (332.70 mg, 2.09 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*). Mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5% to 35%, 10 min) to give compound 94 (52.3 mg, 12%), obtained as a white solid. LCMS: m/z = 552.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 11.61 (s, 1H) 8.28 (d, J = 8.56 Hz , 1H) 7.99-8.08 (m, 1H) 7.80 (s, 1H) 7.67-7.73 (m, 1H) 7.58-7.65 (m, 1H) 7.39 -7.47 (m, 1H) 7.21 (s, 1H) 7.13-7.19 (m, 1H) 7.09 (s, 1H) 7.00 (s, 1H) 6.96 (s , 1H) 6.82-6.93 (m, 4H) 6.31-6.43 (m, 1H) 5.02-5.13 (m, 1H) 2.99-3.07 (m, 1H) ) 2.75-2.90 (m, 3H) 2.41-2.47 (m, 2H).

Synthesis of compound 95


(S)-1-(2-((1H-imidazol-5-yl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrobromide (500 mg, 1 .09 mmol, 1 eq), to a solution of Intermediate 2 (206.88 mg, 1.09 mmol, 1 eq) was added _Et3N (663.84 mg, 6.56 mmol, 913.12 uL, 6 eq) and the mixture was Cool to 0° C., then add T3P (1.04 g, 1.64 mmol, 975.40 uL, 50% purity, 1.5 eq) dropwise, then warm it to 25° C. and cool under N ₂ atmosphere. was stirred for 2 h.The reaction was monitored by LCMS when complete and the reaction mixture was concentrated in vacuo to yield Intermediate 3A (267 mg, crude) as a yellow solid.LCMS: m/z= 672.2 (M+H ⁺ ).

A mixture of Intermediate 3A (497 mg, 739.84 umol, 1 eq) and _NH3 /MeOH (7 M, 5 mL) was heated to 60°C and stirred at 60°C for 1 hour. The reaction was monitored for completion by LCMS and the reaction mixture was concentrated in vacuo to give Intermediate 3 (419 mg, crude) as a yellow solid. LCMS: m/z = 501.0 (M+H ⁺ ).

To a solution of Intermediate 3 (460 mg, 918.95 umol, 1 eq) in EtOH (8 mL) and _H2O (3 mL) was added _NH4Cl (485.23 mg, 9.19 mmol, 10 eq) at 25°C. The solution was then heated to 90° C., Fe (513.19 mg, 9.19 mmol, 10 eq) was added and the reaction was stirred at 90° C. under N ₂ atmosphere for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.05% HCl)-ACN]; B%: 1%-30%, 10 min) to give intermediate Yield 4 (301 mg, 67%) as a yellow solid. LCMS: m/z = 471.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 10.81 (s, 1H) 9.11 (s, 1H) 8.49 (d , J = 8.8Hz, 1H) 7.59 (s, 1H) 7.50 (d, J = 7.9Hz, 1H) 7.33 (d, J = 8.2Hz, 1H) 7.25-7 .30 (m, 4H) 7.15-7.19 (m, 1H) 7.05 (t, J=7.5Hz, 1H) 6.91-7.01 (m, 2H) 5.13-5 .23 (m, 1H) 4.49 (s, 2H) 3.17-3.23 (m, 1H) 2.89-2.98 (m, 1H) 2.79-2.84 (m, 2H ) 2.40-2.47 (m, 2H).

A solution of intermediate 4 (301 mg, 639.63 umol, 1 eq.) in MeCN (2 mL) and pyridine (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (305.41 mg, 1.92 mmol, 3 eq. ) was added. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5% to 35%, 10 min) to give compound 95 (38. 1 mg, 11%), obtained as a white solid. LCMS: m/z = 549.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 13.90 (brs, 1H) 10.70 (s, 1H) 8.64 (s, 1H) 8.29 (d, J = 8.60Hz, 1H) 7.86 (brs, 1H) 7.48 (d, J = 7.72Hz, 1H) 7.29 (d, J = 7 .94Hz, 1H) 7.22 (s, 1H) 7.14 (s, 1H) 7.08 (s, 1H) 7.03 (t, J = 7.50Hz, 1H) 6.91-6.97 (m, 3H) 6.86-6.91 (m, 2H) 6.71 (s, 1H) 5.08-5.21 (m, 1H) 4.37 (s, 2H) 3.01 (dd , J=13.67, 5.73 Hz, 1H) 2.74-2.95 (m, 3H) 2.41-2.48 (m, 2H).

Synthesis of compound 96


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.5 g, 1.37 mmol, 1 eq.) and Intermediate 2 (213.49 mg, 1.37 mmol, 1 eq.) was added _Et3N (8.20 mmol, 1.14 mL, 6 eq.) and the mixture was brought to 0°C. Cooled, then T3P (1.37 mmol, 812.84 uL, 50% purity, 1 eq) was added dropwise and the solution was then stirred at 25° C. for 2 hours. The reaction was monitored by LCMS when complete, then the mixture was dried by flushing with _N2 to yield Intermediate 3 (500 mg, crude) as a yellow oil. LCMS: m/z = 468.2 (M+H ⁺ ).

To a solution of intermediate 3 (0.5 g, 1.07 mmol, 1 eq.) in EtOH (5 mL) and _H2O (2 mL) was added _NH4Cl (286.00 mg, 5.35 mmol, 5 eq.) The solution was then heated to 90° C. and Fe (298.62 mg, 5.35 mmol, 5 eq) was added to the mixture and stirred for 2 hours. The reaction was monitored by LCMS for completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (0.8 g, crude) as a brown solid. LCMS: m/z = 438.2 (M+H ⁺ ).

To a solution of intermediate 4 (0.4 g, 914.12 umol, 1 eq) in MeCN (2 mL) and pyridine (2 mL) was added SO _-pyridine (351.40 mg, 1.37 mmol, 1.5 eq). °C and stirred for 0.17 hours. The reaction was monitored for completion by TLC, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Agela Durashell C18). 150*25 5 u; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B %: 5%-40%, 10 min) to yield compound 96 (61.4 mg, 14%). and obtained as a white solid. LCMS: m/z = 516.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.62 (s, 1H) 8.31 (d, J = 8.436 Hz , 1H) 7.74 (brs, 1H) 7.28 (dd, J = 5.135, 1.100Hz, 1H) 7.21 (brs, 1H) 7.11-7.17 (m, 2H) 7 .08 (brs, 1H) 6.95 (brs, 1H) 6.86-6.92 (m, 3H) 6.74-6.84 (m, 3H) 5.12 (q, J=7.499Hz , 1H) 4.35 (s, 2H) 3.58-3.59 (m, 1H) 2.94-2.99 (m, 3H) 2.43-2.47 (m, 2H).

Synthesis of Compound 97


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (300 mg, 820. 04 umol, 1 eq) and Intermediate 2 (179.64 mg, 820.04 umol, 1 eq) was added _Et3N (497.88 mg, 4.92 mmol, 684.84 uL, 6 eq), then the solution was was cooled to 0° C., then T3P (521.84 mg, 820.04 umol, 487.70 uL, 50% purity, 1 eq) was added dropwise at 0° C., then the solution was stirred at 25° C. for 3 hours. The reaction was monitored for completion by LCMS, the solution was poured into water (3 mL) and extracted with dichloromethane (2 x 10 mL), then the combined organic phases were washed with brine (10 mL) and _{anhydrous Na2SO4} . and concentrated in vacuo to yield Intermediate 3 (612 mg, crude) as a yellow oil. LCMS: m/z = 530.1 (M+H ⁺ ).

To a solution of intermediate 3 (600 mg, 1.13 mmol, 1 eq) in EtOH (10 mL) and _H2O (3 mL) was added _NH4Cl (295.85 mg, 5.66 mmol, 5 eq) at 25°C. The solution was then warmed to 90° C., then Fe (315.85 mg, 5.66 mmol, 5 eq) was added and the mixture was then stirred at 90° C. for 2 hours under N2 atmosphere. The reaction was monitored for completion by LCMS and HPLC, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: UniSil 120*30*10um; mobile phase: [water (0.05% HCl)-ACN]; B %: 1%-40%, 10 min) to give intermediate Yield 4 (167.7 mg, 25%) obtained as a yellow solid. LCMS: m/z = 500.1 (M+H ⁺ ).

A solution of intermediate 4 (160 mg, 319.72 umol, 1 eq.) in pyridine (1 mL) and CH ₃ CN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (50.89 mg, 319.72 umol, 1 eq.) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored upon completion by LCMS and HPLC, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: UniSil 120*30*10 um; mobile phase: [water (0.05% HCl)-ACN]; B%: 1%-40%, 11 min) to give compound 97 (35.3 mg, 18%). Obtained as a white solid. LCMS: m/z = 578.2 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 13.19-14.46 (m, 1H) 8.69 (s, 1H) 8.35 (d, J = 8.56Hz, 1H) 7 .74 (brs, 1H) 7.42-7.46 (m, 2H) 7.22-7.31 (m, 2H) 7.17-7.22 (m, 1H) 7.13 (s, 1H ) 7.04-7.10 (m, 1H) 6.92-6.98 (m, 1H) 6.85-6.92 (m, 2H) 6.76-6.83 (m, 2H) 5 .10-5.18 (m, 1H) 4.37 (s, 2H) 3.00-3.09 (m, 2H) 2.93-3.00 (m, 1H) 2.83-2.92 (m, 1H) 2.30-2.36 (m, 2H).

Synthesis of compound 98


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (300 mg, 820. 04 umol, 1 eq) and Intermediate 2 (152.65 mg, 820.04 umol, 1 eq) was added _Et3N (497.88 mg, 4.92 mmol, 684.84 uL, 6 eq), then the solution was was cooled to 0° C., then T3P (521.84 mg, 820.04 umol, 487.70 uL, 50% purity, 1 eq) was added dropwise at 0° C., then the solution was stirred at 25° C. for 3 hours. The reaction was monitored for completion by LCMS, the solution was poured into water (10 mL), extracted with DCM (2 x 10 mL), then the combined organic phases were washed with brine (10 mL) and anhydrous _{Na2SO4 .} and concentrated in vacuo to yield Intermediate 3 (406 mg, crude) as a yellow oil. LCMS: m/z = 498.3 (M+H ⁺ ).

To a solution of intermediate 3 (406 mg, 816.05 umol, 1 eq) in EtOH (8 mL) and _H2O (3 mL) was added _NH4Cl (214.86 mg, 4.08 mmol, 5 eq) at 25°C. The solution was then warmed to 90° C., Fe (227.86 mg, 4.08 mmol, 5 eq) was then added, and the mixture was then stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (822.0 mg, crude) as a yellow solid. LCMS: m/z = 468.0 (M+H ^<+ >).

A solution of intermediate 4 (822 mg, 1.76 mmol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (839.50 mg, 5.27 mmol, 3 equivalent) was added at 0° C. and the reaction mixture was stirred at 0° C. for 0.17 h. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (2 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1%-20%, 10 min) to give compound 98 (32. 9 mg, 3%), obtained as a white solid. LCMS: m/z = 546.1 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.65 (s, 1H) 8.25 (d, J = 8.56 Hz, 1H) 7.73 (brs, 1H) 7.21-7 .34 (m, 2H) 7.17-7.20 (m, 1H) 7.08-7.15 (m, 2H) 7.07 (brs, 1H) 6.93-7.03 (m, 2H) ) 6.84-6.91 (m, 2H) 6.78 (d, J=8.56Hz, 2H) 5.02-5.19 (m, 1H) 4.35 (s, 2H) 2.91 -2.96 (m, 1H) 2.70-2.86 (m, 3H) 2.36-2.41 (m, 2H).

Synthesis of Compound 99


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (500 mg, 1.5 mL) in DCM (5 mL). 37 mmol, 1 eq) and Intermediate 2 (283.25 mg, 1.37 mmol, 1 eq) was added _Et3N (8.20 mmol, 1.14 mL, 6 eq) and the mixture was cooled to 0°C. Then T3P (1.30 g, 2.05 mmol, 1.22 mL, 50% purity, 1.5 eq) was added dropwise. The mixture was then warmed to 25° C. and stirred for 2 hours. The reaction was monitored for completion by LCMS and the reaction mixture was poured into water (75 mL) and extracted with DCM (3 x 25 mL). The combined organic phases were then washed with brine (3×30 mL), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo yielding Intermediate 3 (705 mg, crude) as a pale yellow oil. rice field. LCMS: m/z = 519.2 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.58 (d, J = 8.681 Hz, 1H) 8.02-8.09 (m, 3H) 7.98 (d, J=7.825Hz, 1H) 7.83-7.92 (m, 2H) 7.43-7.49 (m, 4H) 7.35-7.42 (m, 2H) 5.17-5.28 (m, 1H) 4.14-4.31 (m, 2H) 3.64-3.69 (m, 1H) 3.50-3.55 (m , 1H) 3.20-3.29 (m, 3H) 3.06-3.12 (m, 1H).

To a solution of intermediate 3 (705 mg, 1.36 mmol, 1 eq) in EtOH (12 mL) and _H2O (4 mL) was added _NH4Cl (363.58 mg, 6.80 mmol, 237.64 uL, 5 eq). The solution was then heated to 90° C. and Fe (379.58 mg, 6.80 mmol, 5 eq) was added to the mixture and stirred for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.05% HCl)-ACN]; B%: 1%-30%, 10 min) to give intermediate Yield 4 (260 mg, 39%) obtained as a pale yellow oil. LCMS: m/z = 489.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 10.48 (brs, 1H) 9.10 (s, 1H) 8.69 (d , J = 8.600Hz, 1H) 8.04 (d, J = 7.717Hz, 1H) 7.90 (d, J = 7.938Hz, 1H) 7.56 (s, 1H) 7.45-7 .51 (m, 1H) 7.37-7.42 (m, 1H) 7.31 (s, 1H) 7.28 (s, 4H) 5.12-5.21 (m, 1H) 4.47 (s, 2H) 3.17-3.28 (m, 3H) 2.95-3.00 (m, 1H) 2.60-2.79 (m, 2H).

To a solution of intermediate 4 (260 mg, 532.10 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was added SO _-pyridine (127.04 mg, 798.16 umol, 1.5 eq) at 0 °C. added and stirred for 0.17 hours. The reaction was monitored for completion by TLC, 7% ammonium hydroxide (5 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1% to 30%, 10 min) to give compound 99 (126. 4 mg, 41%), obtained as a white solid. LCMS: m/z = 567.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.57 (s, 1H) 8.43 (d, J = 8.436 Hz , 1H) 7.99-8.07 (m, 1H) 7.90 (d, J = 7.703Hz, 1H) 7.74-7.75 (m, 1H) 7.45-7.49 (m , 1H) 7.35-7.42 (m, 1H) 7.21 (s, 1H) 7.12 (s, 1H) 7.09 (brs, 1H) 6.96 (brs, 1H) 6.87 -6.92 (m, 2H) 6.78-6.85 (m, 2H) 5.11 (q, J = 7.580Hz, 1H) 4.33 (s, 2H) 3.29 (t, J = 7.519Hz, 2H) 2.99 (dd, J = 13.633, 6.541Hz, 1H) 2.84 (dd, J = 13.694, 7.703Hz, 1H) 2.65-2.79 (m2 H).

Synthesis of compound 100


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.5 g, 1.09 mmol, 1 eq.) and Intermediate 2 (238.59 mg, 1.09 mmol, 1 eq.) was added _Et3N (663.84 mg, 6.56 mmol, 913.12 uL, 6 eq.) and the mixture was was cooled to 0° C., then T3P (1.39 g, 2.19 mmol, 1.30 mL, 50% purity, 2 eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 2 hours. The reaction was monitored for completion by LCMS and the reaction mixture was diluted with ice water (40 mL) and extracted with DCM (3 x 15 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 3 (0.6 g, crude) obtained as a yellow oil. rice field. LCMS: m/z = 530.1 (M+H ⁺ ).

Intermediate 3 (0.6 g, 1.13 mmol, 1 eq) and _SnCl2 . A solution of _2H2O (1.28 g, 5.66 mmol, 5 eq) was heated to 50 <0>C. The mixture was stirred at 50° C. for 2 hours. After the reaction was monitored by LCMS and TLC for completion, the reaction mixture was diluted with saturated seignet salt (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (80 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by preparative TLC (dichloromethane:ethyl acetate=10:1) to yield Intermediate 4 (0.08 g, 13%) as a yellow solid. LCMS: m/z = 500.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.44 (d, J = 8.77 Hz, 1H) 7.92-8.01 (m, 2H) 7.51-7.64 (m, 4H) 7.10 (s, 1H) 6.98 (s, 1H) 6.80 (d, J = 8.33Hz, 2H) 6.42 (d, J = 8.33Hz, 2H) 4.92-5.06 (m, 1H) 4.18 (s, 2H) 3.09-3.15 (m, 2H) 2.99 (dd, J = 13.59, 5.70 Hz, 1H) 2.63-2.81 (m3 H).

A mixture of intermediate 4 (0.08 g, 160.13 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (38.23 mg, 240.20 umol). , 1.5 equivalents) was added. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored by LCMS for completion, 7% ammonium hydroxide (2 mL) was added dropwise and the mixture was dried by flushing with _N2 to give a residue. The residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1%-30%, 10 min) yielded compound 100 (17.6 mg, 19%) as a white solid. LCMS: m/z = 578.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.45 (d, J = 8.44 Hz, 1H) 7.93-8 .02 (m, 2H) 7.62-7.77 (m, 2H) 7.50-7.60 (m, 3H) 7.09-7.15 (m, 1H) 6.88-6.95 (m, 3H) 6.81-6.87 (m, 2H) 4.97-5.12 (m, 1H) 4.10-4.30 (m, 2H) 3.11-3.17 (m , 2H) 2.99-3.06 (m, 1H) 2.79-2.86 (m, 1H) 2.67-2.77 (m, 2H).

Synthesis of compound 101


To a stirred solution of Intermediate 1 (0.1 g, 713.57 umol, 1 eq) in anhydrous DMF (5 mL) was added PyBOP (427.04 mg, 820.61 umol, 1.15 eq) followed by (S). -1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrobromide (326.31 mg, 713.57 umol, 1 eq. ) was added and DIPEA (368.89 mg, 2.85 mmol, 497.16 uL, 4 eq) was added. The reaction was stirred at 20° C. for 3 hours and under N ₂ atmosphere at 50° C. for an additional 10 hours. The reaction was monitored by LCMS for completion and the reaction mixture was quenched by adding water (40 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo yielding _Intermediate 2 (0.4 g, crude) as a yellow oil. Obtained. LCMS: m/z = 452.2 (M+H ⁺ ).

To a solution of Intermediate 2 (0.4 g, 885.93 umol, 1 eq) in EtOH (6 mL) and _H2O (2 mL) was added _NH4Cl (236.94 mg, 4.43 mmol, 5 eq), The mixture was then heated to 90° C. and then Fe (247.40 mg, 4.43 mmol, 5 eq) was added. The mixture was stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo yielding Intermediate 3 (0.4 g, crude) as a green oil. LCMS: m/z = 422.1 (M+H ⁺ ).

A mixture of intermediate 3 (0.4 g, 948.95 umol, 1 eq.) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (226.55 mg, 1.42 mmol, 1.5 eq.) was added in batches. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (5 mL) was added dropwise and the mixture was dried by flushing with _N2 to give a residue. The residue was purified by preparative HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.05% HCl)-ACN]; B %: 1%-15%, 10 min) and preparative Re-purification by HPLC (column: Waters _Xbridge 150*25 5u; mobile phase: [water (0.04% _NH3H2O + _10mM NH4HCO3)-ACN]; B%: 1%-25 _% , 10 min) yielded compound 101 (13.6 mg, 3%) as a white solid. LCMS: m/z = 500.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 7.87 (s, 1H) 7.16 (s, 2H) 7.07- 7.10 (m, 1H) 7.06 (s, 1H) 7.00-7.04 (m, 4H) 5.12-5.22 (m, 1H) 4.30 (s, 2H) 3. 14 (dd, J=13.88, 6.17Hz, 1H) 3.01-3.08 (m, 2H) 2.93 (dd, J=13.82, 9.05Hz, 1H) 2.62- 2.70(m, 2H).

Synthesis of compound 102


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (400 mg, then in DCM (6 mL) 1.09 mmol, 1 eq.) and Intermediate 2 (207.96 mg, 1.09 mmol, 1 eq.) was added _Et3N (6.56 mmol, 913.12 uL, 6 eq.) and the mixture was brought to 0°C. Cooled and then T3P (1.64 mmol, 487.70 uL, 1.5 eq) was added dropwise. The mixture was then warmed to 25° C. and stirred for 1 hour. The reaction was monitored for completion by LCMS and the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were then washed with brine (2 x 20 mL), dried over anhydrous _Na2SO4 and concentrated in vacuo _yielding Intermediate 3 (350 mg, crude) as a yellow oil. . LCMS: m/z = 502.1 (M+H ⁺ ).

To a solution of intermediate 3 (350 mg, _697.82 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was added _NH4Cl (186.64 mg, 3.49 mmol, 5 eq) followed by The solution was heated to 90° C. and Fe (194.85 mg, 3.49 mmol, 5 eq) was added to the mixture and stirred for 2 hours. The reaction was monitored by TLC and LCMS for completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (310 mg, crude) as a yellow oil. LCMS: m/z = 472.3 (M+H ⁺ ).

To a solution of intermediate 4 (310 mg, 657.37 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was added SO _-pyridine (313.89 mg, 1.97 mmol, 3 eq) at 0 °C, Stirred for 0.17 hours. The reaction was monitored for completion by TLC and LCMS, 7% ammonium hydroxide (3 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 5% to 35%, 10 min) to give compound 102 ( 28.8 mg, 41%), obtained as a white solid. LCMS: m/z = 550.0 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 11.25 (s, 1H) 8.46 (s, 1H) 8.26 (d, J = 8.559Hz, 1H) 8.15 (dd, J = 4.646, 1.589Hz, 1H) 7.91 (dd, J = 7.825, 1.467Hz, 1H) 7.78 (s, 1H) 7.21 (s, 1H) 7.14 (s, 1H) 7.09 (s, 1H) 6.95-7.02 (m, 2H) 6.89-6.94 (m , 2H) 6.81-6.88 (m, 2H) 5.08-5.16 (m, 1H) 4.33 (s, 2H) 2.95-3.00 (m, 1H) 2.75 -2.90 (m, 3H) 2.44-2.48 (m, 2H).

Synthesis of compound 103


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (500 mg, 1.5 mL) in DCM (5 mL). _Et3N (829.80 mg, 8.20 mmol, 1.14 mL, 6 eq) was added dropwise to a mixture of Intermediate 2 (225.77 mg, 1.37 mmol, 1 eq) and Intermediate 2 (225.77 mg, 1.37 mmol, 1 eq). C., then T3P (1.30 g, 2.05 mmol, 1.22 mL, 50% purity, 1.5 eq) was added at 0.degree. C., then the mixture was warmed to _25.degree . at 25° C. for 3 hours. LCMS monitored when the reaction was complete. The mixture was poured into ice water (75 mL), then the mixture was extracted with DCM (3 x 25 mL). The combined organic phases were washed with brine (3 x 30 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to yield _Intermediate 3 (500 mg, crude) as a yellow oil. rice field. LCMS: m/z = 624.4 (M+H ⁺ ).

A solution of intermediate 3 (500 mg, 1.05 mmol, 2.62 eq) in _NH3 /MeOH (7 M, 2.31 mL, 40.30 eq) was heated to 60°C under _N2 atmosphere. and stirred for 1 hour. LCMS monitored when the reaction was complete. The mixture was concentrated in vacuo to yield Intermediate 4 (690 mg, crude) as a yellow oil. LCMS: m/z = 477.3 (M+H ⁺ ).

To a solution of intermediate 4 (690 mg, 1.45 mmol, 1 eq.) in EtOH (12 mL) and _H2O (3 mL) was added _NH4Cl (387.25 mg, 7.24 mmol, 253.11 uL, 5 eq.). Add at 25° C., then heat the solution to 90° C. and add Fe (404.29 mg, 7.24 mmol, 5 eq), then stir the mixture at 90° C. for 2 h. The reaction was monitored for completion by LCMS, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 20%-50%, 10 min) yielded intermediate 5 (180 mg, 28%) as a yellow oil. LCMS: m/z = 447.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ): δ = 11.92 (brs, 1H) 8.15-8.34 (m, 2H) 7.53-7.66 (m, 1H) 7.33 (d, J = 7.580Hz, 1H) 6.99-7.09 (m, 2H) 6.96 (s, 1H) 6.79 ( d, J = 8.070Hz, 2H) 6.42 (d, J = 7.948Hz, 2H) 4.93-5.07 (m, 1H) 4.82 (s, 2H) 2.95 (dd, J = 13.633, 5.196Hz, 1H) 2.72-2.76 (m, 1H) 2.51-2.53 (m, 2H) 2.43 (s, 3H) 2.30-2. 35(m, 2H).

A solution of intermediate 5 (180 mg, 403.08 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (192.46 mg, 1.21 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1% to 25%, 10 min) to give compound 103 (44. 2 mg, 20%), obtained as a white solid. LCMS: m/z = 525.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O): δ = 8.22 (dd, J = 5.318, 1.528 Hz, 1H) .99 (d, J = 0.978Hz, 1H) 7.57 (dd, J = 7.825, 1.345Hz, 1H) 7.24 (dd, J = 7.703, 5.380Hz, 1H) 7 .07 (s, 1H) 6.90-7.02 (m, 5H) 5.09 (dd, J = 8.436, 6.724Hz, 1H) 4.29 (s, 2H) 3.01 (dd , J=13.938, 6.480 Hz, 1H) 2.83-2.91 (m, 3H) 2.49-2.57 (m, 2H) 2.43 (s, 3H).

Synthesis of compound 104


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (300 mg, 820. 04 umol, 1 eq) and Intermediate 2 (135.46 mg, 820.04 umol, 1 eq) was added _Et3N (497.88 mg, 4.92 mmol, 684.84 uL, 6 eq), then the solution was was cooled to 0° C., then T3P (521.84 mg, 820.04 umol, 487.70 uL, 50% purity, 1 eq) was added dropwise at 0° C., then the solution was stirred at 25° C. for 3 hours. The reaction was monitored for completion by LCMS, the solution was poured into water (3 mL) and extracted with dichloromethane (2 x 10 mL), then the combined organic phases were washed with brine (10 mL) and _{anhydrous Na2SO4} . and concentrated in vacuo to yield Intermediate 3 (325.3 mg, crude) as a yellow oil. LCMS: m/z = 477.3 (M+H ⁺ ).

To a solution of Intermediate 3 (320 mg, _671.49 umol, 1 eq) in EtOH (6 mL) and H2O (2 mL) was added _NH4Cl (175.20 mg, 3.36 mmol, 5 eq) at 25°C. The solution was then warmed to 90° C., Fe (187.50 mg, 3.36 mmol, 5 eq) was then added, and the mixture was then stirred at 90° C. for 2 hours under N ₂ atmosphere. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (612.7 mg, crude) as a yellow solid. LCMS: m/z = 447.1 (M+H ⁺ ).

A solution of intermediate 4 (610 mg, 1.37 mmol, 1 eq) in pyridine (2 mL) and CH ₃ CN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (652.24 mg, 4.10 mmol). , 3 equivalents) was added at 0°C and the reaction mixture was stirred at 0°C for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*). Mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1%-20%, 10 min) to give compound 104 (38.7 mg , 5%), obtained as a white solid. LCMS: m/z = 525.1 (MH ⁺ ). ¹ H-NMR: (400 MHz, DMSO-d ₆ +D ₂ O) δ=8.16-8.41 (m, 2H) 7.13 (d, J=8.56 Hz, 2H) 7.02-7. 04 (m, 2H) 6.85-6.91 (m, 2H) 6.77-6.84 (m, 2H) 4.97-5.12 (m, 1H) 4.30 (s, 2H) 2.90-3.01 (m, 1H) 2.71-2.82 (m, 3H) 2.38-2.44 (m, 5H).

Synthesis of compound 105


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrochloride (0.5 g, 1.37 mmol, 1 eq.) and Intermediate 2 (213.91 mg, 1.37 mmol, 1 eq.) was added _Et3N (831.78 mg, 8.22 mmol, 1.14 mL, 6 eq.) and the mixture was was cooled to 0° C., then T3P (1.74 g, 2.74 mmol, 1.63 mL, 50% purity, 2 eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 2 hours. The reaction was monitored for completion by LCMS and TLC and the reaction mixture was quenched by adding ice water (40 mL) and then extracted with DCM (3 x 15 mL). The combined organic phases were washed with brine (40 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by column chromatography (SiO ₂ , dichloromethane:methanol=1:0 to 10:1) to yield Intermediate 3 (0.25 g, 39%) as a yellow oil. LCMS: m/z 468.0 (M+H ⁺ ).

Intermediate 3 (0.23 g, 491.98 umol, 1 eq) and _SnCl2 . 2H ₂ O (555.07 mg, 2.46 mmol, 5 eq) was heated to 50° C. and stirred at 50° C. for 2 hours. The reaction was monitored for completion by LCMS and the reaction mixture was diluted with saturated salt (100 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 4 (0.08 g, crude) as a yellow solid. rice field. LCMS: m/z = 438.1 (M+H ⁺ ).

A mixture of intermediate 4 (0.08 g, 182.85 umol, 1 eq) in MeCN (1 mL) and pyridine (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (43.65 mg, 274.28 umol). , 1.5 equivalents) was added. The mixture was stirred at 0° C. for 10 minutes. The reaction was monitored by LCMS for completion, 7% ammonium hydroxide (2 mL) was added dropwise and the mixture was dried by flushing with _N2 to give a residue. The residue was analyzed by preparative HPLC (column: YMC-Actus Triart C18 100*30mm*5um; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1%~ 15%, 10 min) to yield compound 105 (40.2 mg, 41%) as a white solid. LCMS: m/z = 516.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 7.73 (s, 1H) 7.08 (s, 1H) 7.01- 7.06 (m, 4H) 7.01 (s, 1H) 5.15-5.21 (m, 1H) 4.27 (s, 2H) 3.06-3.18 (m, 3H) 97-3.06 (m, 1H) 2.70-2.79 (m, 2H) 2.29 (s, 3H).

Synthesis of compound 106


(S)-1-(2-((1H-imidazol-5-yl)methyl)thiazol-4-yl)-2-(4-nitrophenyl)ethanamine hydrobromide (400 mg, 1.09 mmol, 1 eq.) and Intermediate 2 (1.07 g, 5.47 mmol, 5 eq.) was added _Et3N (663.84 mg, 6.56 mmol, 913.12 uL, 6 eq.). C., then T3P (1.04 g, 1.64 mmol, 975.40 uL, 50% purity, 1.5 equiv) was added at 0.degree. C., then the mixture was warmed to _25.degree . at 25° C. for 16 hours. LCMS monitored when the reaction was complete. The mixture was poured into ice water (75 mL), then the mixture was extracted with DCM (3 x 25 mL). The combined organic phases were washed with brine (3 x 30 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to yield _Intermediate 3 (900 mg, crude) as a yellow oil. rice field. LCMS: m/z = 502.3 (M+H ⁺ ).

To a solution of intermediate 3 (900 mg, 1.79 mmol, 1 eq) in ETOH (12 mL) and _H2O (3 mL) was added _NH4Cl (479.93 mg, 8.97 mmol, 313.68 uL, 5 eq). Add, then heat the solution to 90° C. and add Fe (501.04 mg, 8.97 mmol, 5 eq). The mixture was then stirred at 90° C. for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10Mm NH ₄ HCO ₃ )-ACN]; B%: 5%-35%, 10 min) yielded intermediate 4 (30 mg, 4%) as a pale yellow solid. LCMS: m/z = 472.1 (M+H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 11.92 (s, 1H) 11.47 (s, 1H) 8.18 (d , J = 8.558Hz, 1H) 8.03 (d, J = 2.078Hz, 1H) 7.68 (d, J = 1.834Hz, 1H) 7.59 (s, 1H) 7.40 (d , J = 3.179Hz, 1H) 7.01 (s, 1H) 6.75-6.82 (m, 3H) 6.40 (d, J = 8.314Hz, 2H) 6.33 (d, J = 3.423Hz, 1H) 4.93-5.03 (m, 1H) 4.15 (s, 2H) 2.95 (dd, J = 13.755, 5.441Hz, 1H) 2.82 (t , J=7.519 Hz, 2H) 2.68-2.73 (m, 1H) 2.38-2.50 (m, 2H).

A solution of intermediate 4 (30 mg, 63.62 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (30.38 mg, 190.85 umol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 hours. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 1% to 25%, 10 min) to give compound 106 (6. 9 mg, 19%), obtained as a white solid. LCMS: m/z = 550.0 (M-H ⁺ ), ¹ H-NMR: (400 MHz, D ₂ O) δ = 8.29 (s, 1H) 7.91 (d, J = 1.834 Hz, 1H) 7.76 (d, J = 1.712Hz, 1H) 7.40 (d, J = 3.546Hz, 1H) 7.03 (s, 1H) 6.87 (d, J = 8.436Hz, 2H) 6.73 (d, J = 8.436Hz, 2H) 6.48 (s, 1H) 6.43 (d, J = 3.546Hz, 1H) 5.03 (t, J = 7.214Hz, 1H) 4.12-4.27 (m, 2H) 2.86-3.05 (m, 2H) 2.76-2.86 (m, 2H) 2.52-2.63 (m, 2H) .

Synthesis of compound 107


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300 mg, 727.58 umol, 1 eq.) in DMF (3 mL) ) and Intermediate 1 (122.35 mg, 727.58 umol, 1 eq) was added _Et3N (441.74 mg, 4.37 mmol, 607.63 uL, 6 eq) dropwise and cooled to 0°C. Then T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 2 eq) was added at 0 °C, then the mixture was warmed to 25 °C and stirred at 25 °C for 3 h under _N2 atmosphere. Stirred. The reaction was monitored for completion by LCMS, the mixture was poured into ice water (25 mL), then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to yield _Intermediate 2 (260 mg, crude) as a yellow solid. LCMS: m/z = 482.2 (M+H ⁺ ).

A solution of Intermediate 2 (260 mg, 539.91 umol, 1 eq) and _NH4Cl ( _143.1 mg, 2.70 mmol, 5 eq) in EtOH (12 mL) and H2O (4 mL) was heated to 90°C. and then Fe (150.77 mg, 2.70 mmol, 5 eq) was added at 90° C. under N ₂ and the mixture was then stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 3 (294 mg, crude) as a yellow solid. LCMS: m/z = 452.2 (M+H ⁺ ).

A solution of intermediate 3 (294 mg, 651.05 umol, 1 eq) in pyridine (2 mL) and MeCN (2 mL) was cooled to 0° C. and then SO ₃ -pyridine (310.86 mg, 1.95 mmol, 3 equivalent) was added in portions and stirred at 0° C. for 0.17 h. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v) - ACN]; B%: 15%-45%, 10 min) to give compound 107 (89.5 mg, %), obtained as a white solid. LCMS: m/z = 530.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.33 (d, J = 8.44 Hz, 1H) 7.71 (d , J = 4.89Hz, 1H) 7.61-7.66 (m, 2H) 7.03-7.23 (m, 9H) 6.82-6.91 (m, 4H) 5.05-5 .10 (m, 1H) 3.01-3.06 (m, 1H) 2.76-2.89 (m, 3H) 2.38-2.43 (m, 2H).

Synthesis of compound 108


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300 mg, 727.58 umol, 1 eq.) and Intermediate 2 (134.33 mg, 727.58 umol, 1 eq.) was added _Et3N (4.37 mmol, 607.62 uL, 6 eq.), the mixture was cooled to 0°C and then T3P (1.46mmol, 865.43uL, 50% purity, 2eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 3 hours. The reaction was monitored for completion by LCMS and the reaction mixture was poured into water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were then washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo yielding Intermediate 3 (360 mg, crude) as a yellow oil. LCMS: m/z = 498.1 (M+H ⁺ ).

To a solution of intermediate 3 (360 mg, _722.87 umol, 1 eq) in EtOH (3 mL) and H2O (1 mL) was added _NH4Cl (201.86 mg, 3.61 mmol, 5 eq) followed by The solution was heated to 90° C. and Fe (194.63 mg, 3.61 mmol, 5 eq) was added to the mixture and stirred for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (419 mg, crude) as a yellow solid. LCMS: m/z = 468.1 (M+H ⁺ ).

SO ₃ -pyridine (427.46 mg, 2.69 mmol, 3 eq) was added to a solution of intermediate 4 (419 mg, 895.24 umol, 1 eq) in MeCN (1 mL) and pyridine (1 mL) at 0 °C, Stirred for 0.17 hours. The reaction was monitored upon completion by HPLC and LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 15%-45%, 10 min) to give compound 108 (79.7 mg , 16%), obtained as a white solid. LCMS: m/z = 546.0 (MH ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.35 (d, J = 8.437 Hz, 1H) 7.71 (d , J = 5.013Hz, 1H) 7.64 (d, J = 3.546Hz, 1H) 7.34-7.41 (m, 1H) 7.14-7.25 (m, 6H) 7.08 (brs, 1H) 6.95 (brs, 1H) 6.83-6.92 (m, 4H) 5.02-5.14 (m, 1H) 3.04 (dd, J = 13.633, 5 .808Hz, 1H) 2.81-2.91 (m, 3H) 2.42 (t, J = 7.458Hz, 2H).

Synthesis of compound 109


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300 mg, 727.58 umol, 1 equiv.) and Intermediate 1 (131.11 mg, 727.58 umol, 1 equiv.) was added _Et3N (441.74 mg, 4.37 mmol, 607.62 uL, 6 equiv.) dropwise and cooled to 0°C. and then T3P (926.01 mg, 1.46 mmol, 865.43 uL, 50% purity, 2 eq) was added at 0 °C, then the mixture was warmed to 25 °C and stirred for 3 at 25 °C under _N2 atmosphere. Stirred for an hour. LCMS monitored when the reaction was complete. The mixture was poured into ice water (25 mL) and stirred for 10 minutes. The mixture was then extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to yield Intermediate 2 (218 mg, crude) as a yellow oil. LCMS: m/z = 494.2 (M+H ⁺ ).

A solution of Intermediate 2 (218 mg, _441.66 umol, 1 eq) and _NH4Cl (117.13 mg, 2.21 mmol, 5 eq) in EtOH (12 mL) and H2O (4 mL) was heated to 90°C. and then Fe (123.33 mg, 2.21 mmol, 5 eq) was added at 90° C. under N ₂ and the mixture was then stirred at 90° C. for 2 hours. The reaction was monitored when complete by LCMS, the solution was filtered and concentrated in vacuo to yield Intermediate 3 (353 mg, crude) as a yellow solid. LCMS: m/z = 464.2 (M+H ⁺ ).

A solution of intermediate 3 (353 mg, 761.41 umol, 1 eq) in pyridine (1 mL) and MeCN (1 mL) was cooled to 0° C. and then SO ₃ -pyridine (363.56 mg, 2.28 mmol, 3 equivalent) was added and stirred at 0° C. for 0.17 h. The reaction was monitored for completion by LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing with _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150). *25 5 u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 10% to 50%, 10 min) to give compound 109 (80. 2 mg, 19%), obtained as a white solid. LCMS: m/z = 542.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.24 (d, J = 8.44 Hz, 1H) 7.71 (dd , J = 5.07, 1.04Hz, 1H) 7.63 (dd, J = 3.67, 1.10Hz, 1H) 7.21 (s, 1H) 7.12-7.19 (m, 3H ) 7.04-7.09 (m, 2H) 6.77-6.97 (m, 7H) 5.04-5.12 (m, 1H) 3.77 (s, 3H) 3.04 (dd , J = 13.75, 5.93Hz, 1H) 2.85 (dd, J = 13.82, 8.44Hz, 1H) 2.68-2.76 (m, 2H) 2.29-2.41 (m, 2H).

Synthesis of compound 110


(S)-2-(4-Nitrophenyl)-1-(2-thiophen-2-yl)thiazol-4-yl)ethanamine hydrobromide (300 mg, 727.58 umol, 1 eq.) and Intermediate 2 (119.47 mg, 727.58 umol, 1 eq.) was added _Et3N (4.37 mmol, 607.62 uL, 6 eq.), the mixture was cooled to 0°C and then T3P (1.09mmol, 649.07uL, 50% purity, 1.5eq) was added dropwise. The mixture was warmed to 25° C. and stirred at 25° C. for 3 hours. The reaction was monitored for completion by TLC and LCMS and the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phase was then washed with brine (2 x 10 mL), dried over anhydrous _Na2SO4 and concentrated in vacuo _. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to yield Intermediate 3 (70 mg, 63%) as a yellow oil. LCMS: m/z = 478.2 (M+H ⁺ ).

To a solution of intermediate 3 (245 mg, _512.98 umol, 1 eq) in EtOH (3 mL) and H2O (1 mL) was added _NH4Cl (143.25 mg, 2.56 mmol, 5 eq) followed by The solution was heated to 90° C. and Fe (138.04 mg, 2.56 mmol, 5 eq) was added to the mixture and stirred for 2 hours. The reaction was monitored for completion by LCMS, the reaction mixture was filtered and the filtrate was concentrated in vacuo to yield Intermediate 4 (269 mg, crude) as a yellow solid. LCMS: m/z = 448.2 (M+H ⁺ ).

To a solution of intermediate 4 (269 mg, 600.96 umol, 1 eq) in MeCN (1 mL) and pyridine (1 mL) was added SO _-pyridine (286.95 mg, 1.80 mmol, 3 eq) at 0 °C, Stirred for 0.17 hours. The reaction was monitored upon completion by HPLC and LCMS, 7% ammonium hydroxide (1 mL) was added dropwise, then the mixture was dried by flushing _N2 and the residue was analyzed by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN]; B%: 10%-50%, 10 min) to give compound 110 ( 94.6 mg, 28%), obtained as a white solid. LCMS: m/z = 526.1 (M-H ⁺ ), ¹ H-NMR: (400 MHz, DMSO-d ₆ ) δ = 8.30 (d, J = 8.558 Hz, 1H) 7.71 (dd , J = 5.074, 1.039 Hz, 1H) 7.63 (dd, J = 3.668, 1.101 Hz, 1H) 7.21 (brs, 1H) 7.15-7.17 (m, 1H ) 7.04-7.13 (m, 6H) 6.96 (brs, 1H) 6.82-6.92 (m, 4H) 5.01-5.14 (m, 1H) 3.05 (brdd , J = 13.694, 5.869Hz, 1H) 2.84 (dd, J = 13.694, 8.559Hz, 1H) 2.69-2.78 (m, 2H) 2.33-2.40 (m, 2H).

Claims (156)

A compound of formula I,

During the ceremony,
R ₁ is

is selected from
During the ceremony,
R ₂ is selected from substituted or unsubstituted heteroaryl and substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl substituted with one or more halogen atoms;
R ₃ is from substituted or unsubstituted heteroaryl, substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl; selected,
n is an integer selected from 1, 2, 3, 4, 5, and 6;
R ₄ is selected from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl;
R ₅ is selected from H, substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl;
A compound wherein each of X ₁ , X ₂ and X ₃ is independently selected from CH and N, with the proviso that X ₁ , X ₂ and X ₃ are not simultaneously CH. R ₁ is

A compound according to any one of the preceding claims, which is R ₁ is

A compound according to any one of the preceding claims, which is A compound according to any one of the preceding claims, wherein _R2 is substituted or unsubstituted heteroaryl. A compound according to any one of the preceding claims, wherein _R2 is substituted heteroaryl. A compound according to any one of the preceding claims, wherein _R2 is unsubstituted heteroaryl. A compound according to any one of the preceding claims, wherein R ₂ is 2-thienyl. 4. Any one of the preceding claims, wherein R ₂ is a substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with one or more halogen atoms. compound. 2. Any one of the preceding claims, wherein R ₂ is a substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with one or more fluorine atoms. compound. A compound according to any one of the preceding claims, wherein _R2 is a trifluoroalkyl group. A compound according to any one of the preceding claims, wherein _R2 is trifluoroethyl. R ₃ is from substituted or unsubstituted heteroaryl, substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl; A compound according to any one of the preceding claims selected. A compound according to any one of the preceding claims, wherein _R3 is substituted or unsubstituted heteroaryl. A compound according to any one of the preceding claims, wherein _R3 is substituted heteroaryl. A compound according to any one of the preceding claims, wherein _R3 is unsubstituted heteroaryl. The preceding claim, wherein R ₃ is selected from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. A compound according to any one of A compound according to any one of the preceding claims, wherein R ₃ is selected from substituted or unsubstituted C ₁ -C ₆ linear alkyl and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. A compound according to any one of the preceding claims, wherein R ₃ is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. A compound according to any one of the preceding claims, wherein R ₃ is substituted C ₁ -C ₆ straight chain alkyl. A compound according to any one of the preceding claims, wherein R ₃ is unsubstituted C ₁ -C ₆ straight chain alkyl. 4. Any one of the preceding claims, wherein R ₃ is a substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with one or more halogen atoms. compound. 3. Any one of the preceding claims, wherein R ₃ is a substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with one or more fluorine atoms. compound. A compound according to any one of the preceding claims, wherein _R3 is a trifluoroalkyl group. A compound according to any one of the preceding claims, wherein _R3 is trifluoroethyl. A compound according to any one of the preceding claims, wherein _R3 is trifluoropropyl. A compound according to any one of the preceding claims, wherein R ₃ is a substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. A compound according to any one of the preceding claims, wherein R ₃ is unsubstituted C ₃ -C ₆ cyclic alkyl. A compound according to any one of the preceding claims, wherein _R3 is cyclopropyl. Any one of the preceding claims, wherein R ₃ is a substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with a C ₅ -C ₂₀ heteroaryl group. The compound described in . R ₃ is 2-thienyl, trifluoroethyl, trifluoropropyl, cyclopropyl,

A compound according to any one of the preceding claims, selected from A compound according to any one of the preceding claims, wherein R ₃ is 2-thienyl. _R3 is

A compound according to any one of the preceding claims, which is _R3 is

A compound according to any one of the preceding claims, which is A compound according to any one of the preceding claims, wherein R ₄ is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. A compound according to any one of the preceding claims, wherein R ₄ is unsubstituted C ₁ -C ₆ straight chain alkyl. A compound according to any one of the preceding claims, wherein _R4 is methyl. A compound according to any one of the preceding claims, wherein R ₅ is selected from H and substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. A compound according to any one of the preceding claims, wherein _R5 is H. A compound according to any one of the preceding claims, wherein R ₅ is substituted C ₁ -C ₆ straight chain alkyl. A compound according to any one of the preceding claims, wherein R ₅ is unsubstituted C ₁ -C ₆ straight chain alkyl. A compound according to any one of the preceding claims, wherein _R5 is methyl. A compound according to any one of the preceding claims, wherein _X1 and _X2 are CH and _X3 is N. A compound according to any one of the preceding claims, wherein _X1 and _X3 are CH and _X2 is N. A compound according to any one of the preceding claims, wherein _X2 and _X3 are CH and _X1 is N. A compound according to any one of the preceding claims, wherein _X1 is CH and _X2 and _X3 are N. A compound according to any one of the preceding claims, wherein _X2 is CH and _X1 and _X3 are N. A compound according to any one of the preceding claims, wherein n is an integer selected from 1, 2 and 3. A compound according to any one of the preceding claims, wherein n is an integer selected from 1 and 2. A compound according to any one of the preceding claims, wherein n is 1. A compound of formula II,

During the ceremony,
R ₆ is substituted or unsubstituted heteroaryl;
m is an integer selected from 1, 2, 3, 4, 5, and 6;
R ₇ is selected from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl;
R ₈ is selected from H, substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl;
Each of R ₉ and R ₁₀ is independently H, substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C A compound selected from _hexacyclic alkyls. 51. The compound of claim 50, wherein _R6 is substituted heteroaryl. The compound of any one of claims 50 to immediately preceding the preceding claim, wherein R ₆ is unsubstituted heteroaryl. A compound according to any one of claims 50 to immediately preceding the preceding claim, wherein R ₆ is 2-thienyl. The compound of claim 50 through any one of the preceding claims, wherein R ₇ is a substituted or unsubstituted C ₁ -C ₆ branched chain alkyl. The compound of any one of claims 50 to immediately preceding the preceding claim, wherein R ₇ is a substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. The compound of claim 50 through any one of the preceding claims, wherein R ₇ is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. The compound of any one of claims 50 to immediately preceding the preceding claim, wherein R ₇ is substituted C ₁ -C ₆ straight chain alkyl. The compound of any one of claims 50 to immediately preceding the preceding claim, wherein R ₇ is unsubstituted C ₁ -C ₆ straight chain alkyl. The compound of any one of claims 50 to immediately preceding the preceding claim, wherein R ₇ is methyl. A compound according to any one of claims 50 to the immediately preceding claim, wherein R ₈ is selected from H and substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. A compound according to any one of claims 50 to immediately preceding the preceding claim, wherein R ₈ is H. The compound of claim 50 through any one of the preceding claims, wherein R ₈ is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. The compound of any one of claims 50 to immediately preceding the preceding claim, wherein R ₈ is substituted C ₁ -C ₆ straight chain alkyl. The compound of any one of claims 50 to immediately preceding the preceding claim, wherein R ₈ is unsubstituted C ₁ -C ₆ straight chain alkyl. The compound of any one of claims 50 to immediately preceding the preceding claim, wherein R ₈ is methyl. The compound of claim 50 through any one of the preceding claims, wherein each of R ₉ and R ₁₀ is independently selected from H and substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. . A compound according to any one of claims 50 to the immediately preceding claim, wherein each of R ₉ and R ₁₀ is H. The compound of claim 50 through any one of the preceding claims, wherein each of R ₉ and R ₁₀ is independently substituted C ₁ -C ₆ straight chain alkyl. The compound of claim 50 through any one of the preceding claims, wherein each of R ₉ and R ₁₀ is independently unsubstituted C ₁ -C ₆ straight chain alkyl. The compound of any one of claims 50 to immediately preceding the preceding claim, wherein each of R ₉ and R ₁₀ is methyl. A compound according to any one of claims 50 to the immediately preceding claim, wherein m is an integer selected from 1, 2, 3, and 4. A compound according to claim 50 or any one of the preceding claims, wherein m is an integer selected from 2, 3 and 4. A compound according to claim 50 or any one of the preceding claims, wherein m is an integer selected from 3 and 4. A compound according to claim 50 or any one of the preceding claims, wherein m is 3. A compound according to claim 50 or any one of the preceding claims, wherein m is 4. A compound of formula III,

During the ceremony,
R ₁₁ is substituted or unsubstituted heteroaryl, substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, substituted or unsubstituted C ₃ -C ₆ cyclic alkyl, and is selected from substituted or unsubstituted heterocyclyl;
a is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
Y ₁ -Y ₂ is absent and is a group selected from -CH ₂ -CH ₂ - and -CH=CH-;
b is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
A compound wherein R ₁₂ is selected from substituted or unsubstituted heteroaryl and substituted or unsubstituted aryl. 77. The compound of claim 76, wherein _R11 is substituted or unsubstituted heteroaryl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is substituted heteroaryl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is unsubstituted heteroaryl. The compound of claim 76 through any one of the preceding claims, wherein R ₁₁ is substituted or unsubstituted heterocyclyl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is substituted heterocyclyl. The compound of claim 76 through any one of the preceding claims, wherein R ₁₁ is unsubstituted heterocyclyl. 76. R ₁₁ is selected from substituted or unsubstituted C ₁ -C ₆ straight chain alkyl, substituted or unsubstituted C ₁ -C ₆ branched chain alkyl, and substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. - A compound according to any one of the preceding claims immediately preceding. The compound of claim 76 through any one of the preceding claims, wherein R ₁₁ is substituted or unsubstituted C ₁ -C ₆ straight chain alkyl. The compound of claim 76 through any one of the preceding claims, wherein R ₁₁ is substituted or unsubstituted C ₁ -C ₆ branched alkyl. The compound of claim 76 through any one of the preceding claims, wherein R ₁₁ is a substituted or unsubstituted C ₃ -C ₆ cyclic alkyl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is substituted C ₁ -C ₆ branched chain alkyl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is substituted C ₃ -C ₆ cyclic alkyl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is unsubstituted C ₁ -C ₆ straight chain alkyl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is unsubstituted C ₁ -C ₆ branched chain alkyl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is unsubstituted C ₃ -C ₆ cyclic alkyl. of claim 76 to the immediately preceding claim, wherein R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with one or more halogen atoms; A compound according to any one of clauses. of claim 76 to the immediately preceding claim, wherein R ₁₁ is substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with one or more fluorine atoms; A compound according to any one of clauses. Any one of claims 76 to the immediately preceding claim, wherein R ₁₁ is a substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl substituted with a heteroaryl group. The compound according to the item. Claim 76 to the preceding claim immediately preceding claim, wherein R ₁₁ is a substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with a C ₃ -C ₆ cyclic alkyl group A compound according to any one of the clauses. R ₁₁ is a substituted C ₁ -C ₆ straight chain alkyl, wherein said substituted C ₁ -C ₆ straight chain alkyl is substituted with —(CR ^a R ^b ) _z N(R ^c )(R ^d ); , R ^a and R ^b are each independently selected from hydrogen, and substituted or unsubstituted C ₁ -C ₆ linear, branched or cyclic alkyl, and each of R ^c and R ^d is independently is selected from hydrogen, substituted or unsubstituted C ₁ -C ₆ linear, branched or cyclic alkyl and aryl, or R ^c and R ^d together contain 3 to 7 atoms A compound according to claim 76 to any one of the preceding claims, which forms a ring system and z is selected from 0, 1, 2, 3, and 4. R ₁₁ is a substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with N(R ^c )(R ^d ), each of R ^c and R ^d is independently a substituted or unsubstituted C ₁ -C ₆ straight, branched, or cyclic alkyl, or R ^c and R ^d together are a ring system containing 3 to 7 atoms The compound of claim 76 to any one of the immediately preceding claims which forms a R ₁₁ is a substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with N(R ^c )(R ^d ), each of R ^c and R ^d is independently a substituted or unsubstituted C ₁ -C ₆ straight chain, branched chain, or cyclic alkyl. R ₁₁ is a substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with N(R ^c )(R ^d ), each of R ^c and R ^d is independently unsubstituted C ₁ -C ₆ straight chain, branched chain, or cyclic alkyl. R ₁₁ is a substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with N(R ^c )(R ^d ), each of R ^c and R ^d is independently unsubstituted C ₁ -C ₆ straight chain alkyl. Claim 76 to the preceding claim wherein R ₁₁ is a substituted C ₁ -C ₆ straight chain alkyl, said substituted C ₁ -C ₆ straight chain alkyl being substituted with —N(CH ₃ ) ₂ A compound according to any one of R ₁₁ is 2-thienyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopentylmethyl,

The compound of claim 76 through any one of the preceding claims immediately preceding, which is selected from The compound of claim 76 through any one of the preceding claims, wherein R ₁₁ is 2-thienyl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is a trifluoroalkyl group. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is trifluoroethyl. The compound of claim 76 through any one of the preceding claims, wherein R ₁₁ is trifluoropropyl. The compound of claim 76 through any one of the preceding claims, wherein R ₁₁ is cyclopropyl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is cyclopropylmethyl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₁ is cyclopentylmethyl. R ₁₁ is

The compound of claim 76 through any one of the immediately preceding claims which is R ₁₁ is

The compound of claim 76 through any one of the immediately preceding claims which is R ₁₁ is

The compound of claim 76 through any one of the immediately preceding claims which is R ₁₁ is

The compound of claim 76 through any one of the preceding claims immediately preceding claim . R ₁₁ is

The compound of claim 76 through any one of the immediately preceding claims which is R ₁₁ is

The compound of claim 76 through any one of the immediately preceding claims which is The compound of claim 76 through any one of the preceding claims, wherein R ₁₂ is substituted or unsubstituted heteroaryl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₂ is substituted heteroaryl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₂ is unsubstituted heteroaryl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₂ is pyridinyl. The compound of claim 76 through any one of the preceding claims, wherein R ₁₂ is substituted or unsubstituted aryl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₂ is substituted aryl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₂ is monosubstituted aryl. A compound according to any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₂ is monosubstituted phenyl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₂ is unsubstituted aryl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein R ₁₂ is phenyl. A compound according to any one of claim 76 to the immediately preceding claim, wherein R ₁₂ is selected from 1-naphthyl and 2-naphthyl. The compound of claim 76 through any one of the preceding claims, wherein R ₁₂ is 1-naphthyl. The compound of claim 76 through any one of the preceding claims, wherein R ₁₂ is 2-naphthyl. The compound of any one of claims 76 to immediately preceding the preceding claim, wherein Y ₁ -Y ₂ are absent. The compound of claim 76 through any one of the preceding claims, wherein Y ₁ -Y ₂ is -CH ₂ -CH ₂ -. The compound of claim 76 through any one of the preceding claims, wherein Y ₁ -Y ₂ is -CH=CH-. The compound of claim 76 through any one of the preceding claims, wherein a is an integer selected from 0, 1, 2, and 3. The compound of claim 76 through any one of the preceding claims, wherein a is an integer selected from 0, 1, and 2. The compound of claim 76 to any one of the preceding claims, wherein a is an integer selected from 0 and 1. The compound of claim 76 through any one of the preceding claims, wherein a is 2. A compound according to claim 76 or any one of the preceding claims, wherein a is 1. The compound of claim 76 through any one of the preceding claims, wherein a is 0. A compound according to any one of claims 76 to the immediately preceding claim, wherein b is an integer selected from 0, 1, 2, and 3. The compound of claim 76 through any one of the preceding claims, wherein b is an integer selected from 0, 1, and 2. A compound according to any one of claims 76 to the immediately preceding claim, wherein b is an integer selected from 0 and 1. The compound of claim 76 through any one of the preceding claims, wherein b is 2. The compound of claim 76 through any one of the preceding claims, wherein b is 1. The compound of claim 76 through any one of the preceding claims, wherein b is 0. The compound of claim 76 to any one of the preceding claims, wherein Y ₁ -Y ₂ are absent, a is 1 and b is 1. The compound of claim 76 to any one of the preceding claims, wherein Y ₁ -Y ₂ are absent, a is 1 and b is 0. The compound of claim 76 to any one of the preceding claims, wherein Y ₁ -Y ₂ are -CH=CH-, a is 0 and b is 0. A compound according to any one of claims 76 to the immediately preceding claim, provided that when Y ₁ -Y ₂ are absent, a and b are not 0 simultaneously. A compound selected from:

149. A method for inhibiting VE-PTP in a mammalian subject in need of inhibition of VE-PTP, wherein said subject in need of inhibition of VE-PTP is administered an effective amount of any of claims 1-149 A method comprising administering a compound according to claim 1, or a pharmaceutically acceptable salt thereof, whereby VE-PTP activity is inhibited. 151. The method of claim 150, wherein the subject is suffering from one or more of cancer, glaucoma, obstructive cardiovascular disease, vascular leak syndrome, or another vascular-related disease. A method for reducing VE-PTP-mediated signaling in a mammalian subject in need of reducing VE-PTP-mediated signaling, said mammal in need of reducing VE-PTP-mediated signaling administering to the subject an effective amount of a compound of any one of claims 1-149, or a pharmaceutically acceptable salt thereof, whereby VEPTP-mediated signaling is reduced; Method. A method for increasing Tie2-mediated signaling in a mammalian subject in need of increased Tie2-mediated signaling, comprising administering to said mammalian subject in need of increased Tie2-mediated signaling an effective amount of 150. A method comprising administering a compound of any one of claims 1-149, or a pharmaceutically acceptable salt thereof, whereby Tie2-mediated signaling is increased. A method for treating a Tie2-mediated disorder in a mammalian subject in need of treatment of a Tie2-mediated disorder, comprising administering to said mammalian subject in need of treatment of a Tie2-mediated disorder a therapeutically effective amount of: A method comprising administering a compound according to any one of 1-149, or a pharmaceutically acceptable salt thereof. 155. The method of claim 154, wherein the subject is suffering from one or more of cancer, glaucoma, obstructive cardiovascular disease, vascular leak syndrome, or another vascular-related disease. 156. The method of any one of claims 150-155, wherein said "effective amount" is determined in vitro by one or more biochemical and/or biological assays.