KETO amide compounds as calpain inhibitors

Abstract

Provided are novel compounds of Formula I and Formula II, processes for their production, their use as pharmaceuticals, and pharmaceutical compositions comprising them. These compounds are useful in treating calpain-mediated disorders, such as, pain, autoimmune and inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, or a disorder associated with transplantation.

Description

Attorney Docket No. NTG-08-PCTKETO AMIDE COMPOUNDS AS CALPAIN INHIBITORS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 726,193 filed November 27, 2024, which is hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0002] Provided are novel compounds of Formula I and Formula II as described below, processes for their production, their use as pharmaceuticals, and pharmaceutical compositions comprising them. These compounds are useful in treating cal pain -mediated disorders, such as, pain, autoimmune and inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, or a disorder associated with transplantation.BACKGROUND

[0003] Calpain is a cytosolic calcium-dependent cysteine protease. It is found in all mammalian tissue and cell types. The calpain family of proteases consists of two recognized proteins. The first member of the calpain family is calpain I or L-calpain which is the high sensitivity form and is activated by a low calcium concentration (2-75 uM). Calpain I is concentrated in synapses and neuronal cell bodies. The second member of the calpain family is calpain II or m-calpain. It has a ribbon like structure and is the lower sensitivity form. It is activated by higher concentrations of calcium (200-800 uM). Calpain II is the dominant form. Calpastatin is a known endogenous inhibitor of calpain I and calpain II. It has four internally repeated domains, each of which independently binds a calpain molecule in its active, Ca2+-bound conformation with high affinity. Calpains play an important role in various physiological processes. These processes include, inter alia, the cleavage of regulatory proteins such as protein kinase C (PKC) and degradation of cytoskeletal or microtubule-associated proteins (MAP) such as tau. Research has demonstrated that calpain inhibitors have improved recovery from the memory performance deficits and neuromotor disturbances. Calpain inhibitors inhibit the release of the 13-AP4 protein. Therefore, it has been suggested that they have a potential use as therapeutic agents in Alzheimer’s disease. Calpain inhibitors have also had a protective effect on hypoxia-damaged kidneys and have had favorable effects following cardiac damage produced by ischemias of the heart (e.g., myocardial infarction) or reperfusion. It has also been found that calpain inhibitors have cytotoxic effects on tumor cells. Elevated calpain levels are also implicated in the pathophysiology of cerebralAttorney Docket No. NTG-08-PCTischemia, platelet activation, NF-KB activation, muscular dystrophy, cataract progression, and rheumatoid arthritis. Calpains reside in the cytosol of cells and are activated by Ca2+at a physiological pH. Its proteolytic activity appears to be selective against certain target proteins, such as components of the cytoskeleton and calmodulin-dependent enzymes. Excessive excitation by a neurotransmitter glutamate can lead to death of nerve cells (neurons) and neurodegeneration. It is believed that toxic effects of glutamate may be due to overactivation of its target glutamate receptors. This in turn produces an influx of calcium ion (Ca2+) into the neurons. The rise of cellular Ca2+level triggers the activation of calpain I. Calpain I then goes on to degrade cytoskeletal protein such as spectrin, which is believed to disrupt normal cellular functions, and eventually leads to cell death.

[0004] The exogenous regulation of calpain activity is therefore of interest for the development of therapeutics in a wide array of pathological states.

[0005] For instance, both calpain- 1 and calpain-2 are ubiquitously expressed in the central nervous system (CNS), where in the presence of normal Ca2+levels, calpains are activated, and are vital for synaptic regulation. However, dysregulation of Ca2+homeostasis results in the overactivation of calpains, which may cause or contribute to chronic neuropathic pain, chronic sickle cell disease (SCD) pain, inflammatory pain, diabetic neuropathy, and cancer-induced bone pain, chemotherapy-induced peripheral neuropathy, and acute post-operative pain.

[0006] Chronic pain affects more than 20% of US adults (~70 million people). Despite their addictive potential, and inability to improve function, opioids have become the mainstay of chronic pain management, resulting in an opioid epidemic that is ravaging communities throughout the United States. Thus, there is an urgent unmet medical need to develop novel, nonopioid therapies for chronic pain management.BRIEF SUMMARY

[0007] Provided are novel keto amides (e.g., chromanyl keto amides), in free or pharmaceutically acceptable salt form, processes for their production, their use as pharmaceuticals, for instance as calpain inhibitors, and pharmaceutical compositions comprising them.

[0008] Provided is a compound of Formula I:Attorney Docket No. NTG-08-PCTR2bFormula Iwherein:A is C3-7-cycloalkyl substituted with -Ci-4-alkyl, aryl (e.g., phenyl), -O-CFh-aryl (e.g., -O-CH2-phenyl), or -C(O)O-Ci-4-alkyl or A is the fragment:wherein:B is a 4- to 8-membered non-aromatic ring, e.g., a 4- to 7-membered non-aromatic ring, which is fused to the benzene ring and which optionally contains one heteroatom selected from O, S, and N (e.g., O),the wavy line shows the point of attachment of the fragment to Formula I,the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, Ca-e-heterocyclyl, -CN, -C(0)NH2, and 5-to 6-membered heteroaryl optionally substituted with Ci-4-alkyl, andx is 0 or 1;Ri is C3-7-cycloalkyl, aryl (e.g., phenyl), or 5- to 6-membered heteroaryl each of which is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, C1.4-alkoxy, Ci-4-haloalkyl, -CN, and halogen; andR.2aand R.2b are independently selected from H, C3-7-cycloalkyl, Ci-4-alkyl, C3-7-cyloalkyl-Ci-4-alkyl, and benzyl optionally substituted with Ci-4-alkyl;in free or pharmaceutically acceptable salt form.

[0009] Further provided is a compound of Formula I, which is a compound of Formula II:Attorney Docket No. NTG-08-PCTFormula II,wherein:Ri is C3-7-cycloalkyl, aryl (e.g., phenyl), or 5- to 6-membered heteroaryl each of which is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, C1.4-alkoxy, Ci-4-haloalkyl, -CN, and halogen;R2aand R2bare independently selected from H, C3-7-cycloalkyl, Ci-4-alkyl, C3-7-cyloalkyl-Ci-4-alkyl, and benzyl optionally substituted with Ci-4-alkyl; andR3 and R4 are independently bonded to either ring of the chromanyl fragment and are independently selected from H, Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, C3-6-heterocyclyl, -CN, -C(0)NH2, and 5- to 6-membered heteroaryl optionally substituted with C1.4-alkyl;in free or pharmaceutically acceptable salt form.

[0010] Further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.DETAILED DESCRIPTION

[0011] The following description of the embodiment(s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.

[0012] All references cited herein are hereby incorporated by reference in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.

[0013] In a first embodiment, provided is a compound of Formula I:Attorney Docket No. NTG-08-PCTR2bFormula Iwherein:A is C3-7-cycloalkyl substituted with -Ci-4-alkyl, aryl (e.g., phenyl), -O-CFh-aryl (e.g., -O-CH2-phenyl), or -C(O)O-Ci-4-alkyl or A is the fragment:wherein:B is a 4- to 8-membered non-aromatic ring, e.g., a 4- to 7-membered non-aromatic ring, which is fused to the benzene ring and which optionally contains one heteroatom selected from O, S, and N (e.g., O),the wavy line shows the point of attachment of the fragment to Formula I,the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, Ca-e-heterocyclyl, -CN, -C(0)NH2, and 5-to 6-membered heteroaryl optionally substituted with Ci-4-alkyl, andx is 0 or 1;Ri is C3-7-cycloalkyl, aryl (e.g., phenyl), or 5- to 6-membered heteroaryl each of which is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, C1.4-alkoxy, Ci-4-haloalkyl, -CN, and halogen; andR.2aand R.2b are independently selected from H, C3-7-cycloalkyl, Ci-4-alkyl, C3-7-cyloalkyl-Ci-4-alkyl, and benzyl optionally substituted with Ci-4-alkyl;in free or pharmaceutically acceptable salt form.

[0014] In further embodiments, provided is a compound of Formula I, in free or pharmaceutically acceptable salt form, as follows:Attorney Docket No. NTG-08-PCTFormula I, wherein R.2a is H.Formula I or 1.1, wherein A is C3-7-cycloalkyl mono-substituted with -Ci-4-alkyl, aryl (e.g., phenyl), -O-CH2-aryl (e.g., -O-CFF-phenyl), or -C(O)O-Ci-4-alkyl. Formula 1.2, wherein A is the fragment:wherein the wavy line shows the point of attachment of the fragment to Formula I.Formula I or 1.1, wherein A is the fragment:wherein:B is a 4- to 8-membered non-aromatic ring, e.g., a 4- to 7-membered nonaromatic ring, which is fused to the benzene ring and which optionally contains one heteroatom selected from O, S, and N (e.g., O),the wavy line shows the point of attachment of the fragment to Formula I, the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl (e.g., Ci-3-alkyl), Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, C3-6-heterocyclyl, -CN, -C(0)NH2, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl, and x is 0 or 1. For instance, wherein B is a 4- to 7-membered non-aromatic ring, e.g., a 4- to 6-membered non-aromatic ring, which is fused to the benzene ring and which optionally contains one heteroatom selected from O, S, and N (e.g., O), wherein the wavy line shows the point of attachment of the fragment to Formula I and the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl (e.g., C1-3-alkyl), Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, C3-6-heterocyclyl, -CN, -C(0)NH2, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl,Attorney Docket No. NTG-08-PCTand x is 0 or 1. For instance, wherein the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl (e.g., Ci-3-alkyl), Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl.Formula I, 1.1, or 1.4, wherein x is 0, so A is the fragment:wherein B is a 4- to 8-membered non-aromatic ring, e.g., 4- to 7-membered nonaromatic ring, e.g., 4- to 6-membered non-aromatic ring, which is fused to the benzene ring and which optionally contains one heteroatom selected from O, S, and N (e.g., O), the wavy line shows the point of attachment of the fragment to Formula I, and the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl (e.g., Ci-3-alkyl), Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, C3-6-heterocyclyl, -CN, -C(O)NH2, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl. For instance, wherein B is a 4- to 6-membered non-aromatic ring which is fused to the benzene ring and which optionally contains one heteroatom selected from O, S, and N (e.g., O), the wavy line shows the point of attachment of the fragment to Formula I, the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl (e.g., Ci-3-alkyl), Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, C3-6-heterocyclyl, -CN, -C(0)NH2, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl. For instance, wherein the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl (e.g., Ci-3-alkyl), Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl.Formula 1.4 or 1.5, wherein B is a 6-membered non-aromatic ring which is fused to the benzene ring and which contains one N and which is optionally substituted with one or more substituents (e.g., two substituents) independently selected from Ci-4-alkyl (e.g., -CH3) and oxo.Attorney Docket No. NTG-08-PCTFormula 1.6, wherein A is the fragment:wherein the wavy line shows the point of attachment of the fragment to Formula I.Formula 1.4 or 1.5, wherein B is a 5- or 6-membered non-aromatic ring which is fused to the benzene ring and which contains one O.Formula 1.8, wherein A is the fragment:wherein the wavy line shows the point of attachment of the fragment to Formula I and the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl (e.g., Ci-3-alkyl), Ci-4-alkoxy, Ci-4-haloalkyl, halogen, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl.Formula 1.9, wherein A is the fragment:wherein the wavy line shows the point of attachment of the fragment to Formula I and the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl (e.g., Ci-3-alkyl), Ci-4-alkoxy, Ci-4-haloalkyl, halogen, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl.Attorney Docket No. NTG-08-PCTFormula 1.10, wherein the fragment is optionally substituted with one or two substituents independently selected from Ci-4-alkyl (e.g., Ci-3-alkyl, e.g., -CH3), halogen (e.g., F or Cl), and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl (e.g., pyrazolyl, e.g., e.g., pyrazolyl mono-substituted with C1-4-alkyl (e.g., -CH3)). For instance, Formula 1.10, wherein the fragment is substituted with one or two substituents independently selected from Ci-4-alkyl (e.g., Ci-3-alkyl, e.g., -CH3), halogen (e.g., F or Cl), and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl (e.g., pyrazolyl, e.g., e g., pyrazolyl mono-substituted with Ci-4-alkyl (e.g., -CH3)). For instance, Formula 1.10, wherein the fragment is optionally substituted with one or two substituents independently selected from Ci-4-alkyl (e.g., Ci-3-alkyl, e.g., -CH3) and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl (e.g., pyrazolyl, e.g., e.g., pyrazolyl mono- substituted with Ci-4-alkyl (e.g., -CH3)).Formula 1.10 or 1.11, wherein the fragment is substituted with one substituent selected from halogen.Formula 1.12, wherein the fragment is substituted with F or Cl.Formula 1.10 or 1.11, wherein the fragment is substituted with one 5- to 6-membered heteroaryl (e.g., pyrazolyl) optionally mono-substituted with Ci-4-alkyl (e g., -CH3).Formula 1.14, wherein the fragment is substituted with one pyrazolyl monosubstituted with -CH3.Formula 1.10 or 1.11, wherein the fragment is substituted with one or two substituents selected from Ci-4-alkyl (e.g., -CH3or isopropyl). For instance, F ormula 1.10 or 1.11, wherein the fragment i s sub stituted with one or two -CH3. For instance, Formula 1.10 or 1.11, wherein the fragment is substituted with two -CH3. Or, for instance Formula 1.10 or 1.11, wherein the fragment is substituted with one -CH3or one isopropyl.Any of Formula I, 1.1, or 1.4-1.16, wherein the fragmentAttorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCTwherein the wavy line shows the point of attachment of the fragment to Formula I. For instance, wherein the fragmentAttorney Docket No. NTG-08-PCTwherein the wavy line shows the point of attachment of the fragment to Formula I.Formula 1.4 or 1.5, wherein A is the fragment:wherein the wavy line shows the point of attachment of the fragment to Formula I and the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl (e.g., -CH3) and -CN.Formula 1.18, wherein the fragment is mono-substituted with -CH3. Or, for instance, Formula 1.18, wherein the fragment is mono-substituted with -CN. Formula 1.18 or 1.19, wherein the fragmentAttorney Docket No. NTG-08-PCTAny of Formula I or 1.1-1.20, wherein Ri is phenyl optionally substituted with one substituent selected from halogen (e.g., F or Cl), alkoxy (e.g., methoxy), and -CN. For instance, any of Formula I or 1.1-1.20, wherein Ri is phenyl optionally substituted with F, Cl, methoxy, or -CN.Formula 1.21, wherein Ri is phenyl. Or, Formula 1.21, wherein Ri is:wherein the wavy line shows the point of attachment of the fragment to Formula I.Any of Formula I or 1.1-1.20, wherein Ri is pyridyl. For instance, any of Formula I or 1.1-1.20, wherein Ri is:wherein the wavy line shows the point of attachment of the fragment to Formula I.Attorney Docket No. NTG-08-PCTAny of Formula I or 1.1-1.23, wherein R.2b is H.Any of Formula I or 1.1-1.23, wherein R.2b is Ci-4-alkyl (e.g., -CH3).Any of Formula I or 1.1-1.23, wherein R2b is C3-7-cycloalkyl (e.g., cyclopropyl or cyclobutyl). For instance, any of Formula I or 1.1-1.23, wherein R.2b is cyclopropyl.Any of Formula I or 1.1-1.26, wherein the stereochemistry at the position with the asterisk in Formula I below is (S):R*2bFormula I.Any of Formula I or 1.1-1.27, wherein the compound is selected from those set forth in Table 1 below, in free or pharmaceutically acceptable form:Attorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCT1.29 Any of Formula I or 1.1-1.28, wherein the compound is selected from those set forth in Table 2 below, in free or pharmaceutically acceptable salt form:Table 2.Structure StructureAttorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCT1.30 Any of Formula I or 1.1-1.29, wherein the compound is selected from those set forth in Table 3 below, in free or pharmaceutically acceptable salt form:Table 3.Attorney Docket No. NTG-08-PCT1.31 Any of Formula I or 1.1-1.30, wherein the compound is selected from those set forth in Table 4 below, in free or pharmaceutically acceptable salt form:Table 4.Attorney Docket No. NTG-08-PCT1.32 Any of Formula I or 1.1-1.31, wherein the compound is selected from those set forth in Table A below, in free or pharmaceutically acceptable salt form:Table A.Attorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCT1.33 Any of Formula I or 1.1-1.32, wherein the compound is selected from those set forth in Table B below, in free or pharmaceutically acceptable salt form:Table B.Structure StructureAttorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCTAny of Formula I or 1.1-1.33, wherein the compound is in free form.Any of Formula I or 1.1-1.33, wherein the compound is in pharmaceutically acceptable salt form.Any of Formula I or 1.1-1.35, wherein the compound is in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier. For instance, any of Formula I or 1.1-1.35, wherein a therapeutically effective amount of the compound is in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier.Attorney Docket No. NTG-08-PCT

[0015] Further provided is a compound of Formula I, which is a compound of Formula II:^2bFormula II,wherein:Ri is C3-7-cycloalkyl, aryl (e.g., phenyl), or 5- to 6-membered heteroaryl each of which is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, -CN, and halogen;R2aand R2bare independently selected from H, C3-7-cycloalkyl, Ci-4-alkyl, C3-7-cyloalkyl-Ci-4-alkyl, and benzyl optionally substituted with Ci-4-alkyl; andR3 and R4 are independently bonded to either ring of the chromanyl fragment and are independently selected from H, Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, C3-6-heterocyclyl, -CN, -C(O)NH2, and 5- to 6-membered heteroaryl optionally substituted with C1.4-alkyl;in free or pharmaceutically acceptable salt form.

[0016] In further embodiments, provided is a compound of Formula II, in free or pharmaceutically acceptable salt form, as follows:2.1 Formula II, wherein R2a is H.2.2 Formula II or 2.1, wherein R3 and R4 are independently selected from H, C1-4- alkyl (e.g., Ci-3-alkyl), Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, and 5- to 6- membered heteroaryl optionally substituted with Ci-4-alkyl. Or, Formula II or 2.1, wherein R3 and R4 are independently selected from H, Ci-4-alkyl (e.g., Ci-3-alkyl, e.g., -CH3), halogen (e.g., F or Cl), and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl (e g., pyrazolyl, e.g., e.g., pyrazolyl mono-substituted with Ci-4-alkyl (e.g., -CH3)). For instance, Formula II or 2.1, wherein R3 and R4 are independently selected from H, Ci-4-alkyl (e.g., Ci-3-alkyl, e.g., -CH3), and 5-Attorney Docket No. NTG-08-PCTto 6-membered heteroaryl optionally substituted with Ci-4-alkyl (e.g., pyrazolyl, e.g., e.g., pyrazolyl mono-substituted with Ci-4-alkyl (e.g., -CH3)).Formula II, 2.1, or 2.2, wherein R3 is H.Any of Formula II or 2.1-2.3, wherein R4 is halogen.Formula 2.4, wherein R4 is F or Cl.Any of Formula 11 or 2.1-2.3, wherein R4 is a 5- to 6-membered heteroaryl (e.g., pyrazolyl) optionally mono- substituted with Ci-4-alkyl (e.g., -CH3).Formula 2.6, wherein R4 is a pyrazolyl mono-substituted with -CH3.Formula II, 2.1, or 2.2, wherein R3 and R4 are independently selected from H and Ci-4-alkyl (e.g., Ci-3-alkyl). For instance, Formula II or 2.1, wherein R3 is H and R4 is -CH3. Or, for instance, Formula II, 2.1, or 2.2, wherein R3 and R4 are -CH3. Or, for instance, Formula II, 2.1, or 2.2, wherein R3 is H and R4 is isopropyl. Any of Formula II or 2.1-2.8, wherein the fragmentAttorney Docket No. NTG-08-PCTwherein the wavy line shows the point of attachment of the fragment to Formula II. For instance, any of Formula II or 2.1-2.8, wherein the fragmentAttorney Docket No. NTG-08-PCTwherein the wavy line shows the point of attachment of the fragment to Formula II. Attorney Docket No. NTG-08-PCTAny of Formula II or 2.1-2.9, wherein Ri is phenyl optionally substituted with one substituent selected from halogen (e.g., F or Cl), alkoxy (e.g., methoxy), and -CN. For instance, any of Formula II or 2.1-2.9, wherein Ri is phenyl optionally substituted with F, Cl, methoxy, or -CN.Formula 2.10, wherein Ri is phenyl. Or, Formula 2.10, wherein Ri is:wherein the wavy line shows the point of attachment of the fragment to Formula II.Any of Formula II or 2.1-2.9, wherein Ri is pyridyl. For instance, any of Formula II or 2.1-2.9, wherein Ri is:wherein the wavy line shows the point of attachment of the fragment to Formula II.Any of Formula II or 2.1-2.12, wherein R2b is H.Any of Formula II or 2.1-2.12, wherein R2b is Ci-4-alkyl (e.g., -CH3).Any of Formula II or 2.1-2.12, wherein R2b is C3-7-cycloalkyl (e.g., cyclopropyl or cyclobutyl). For instance, any of Formula II or 2.1-2.12, wherein R2b is cyclopropyl.Any of Formula II or 2.1-2.15, wherein the stereochemistry at the position with the asterisk in Formula II below is (S):Attorney Docket No. NTG-08-PCT2aFormula 11.2.17 Any of Formula II or 2.1-2.16, wherein the compound is selected from those set forth in Table 5 below, in free or pharmaceutically acceptable salt form:Table 5.Attorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCT2.18 Any of Formula II or 2.1-2.17, wherein the compound is selected from those set forth in Table 6 below, in free or pharmaceutically acceptable salt form:Table 6.Attorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCT2.19 Any of Formula II or 2.1-2.18, wherein the compound is selected from those set forth in Table 7 below, in free or pharmaceutically acceptable salt form:Table 7.2.20 Any of Formula II or 2.1-2.19, wherein the compound is selected from those set forth in Table 8 below, in free or pharmaceutically acceptable salt form Table 8.Structure StructureAttorney Docket No. NTG-08-PCT2.21 Any of Formula II or 2.1-2.20, wherein the compound is selected from those set forth in Table C below, in free or pharmaceutically acceptable salt form:Table C.Structure StructureAttorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCT2.22 Any of Formula II or 2.1-2.21, wherein the compound is selected from those set forth in Table D below, in free or pharmaceutically acceptable salt form:Table D.Attorney Docket No. NTG-08-PCTAttorney Docket No. NTG-08-PCT2.23 Any of Formula II or 2.1-2.22, wherein Formula II is:in free or pharmaceutically acceptable salt form.2.24 Any of Formula II or 2.1-2.23, wherein the compound is in free form.2.25 Any of Formula II or 2.1-2.23, wherein the compound is in pharmaceutically acceptable salt form.2.26 Any of Formula II or 2.1-2.25, wherein the compound is in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier. For instance, any of Formula II or 2.1-2.25, wherein a therapeutically effective amount of the compound is in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier.

[0017] If not otherwise specified or clear from context, the following terms herein have the following meanings:Definitions and Conventions Used

[0018] Terms that are not specifically defined here have the meanings that would be apparent to a person skilled in the art, in the light of the overall disclosure and the context as a whole.

[0019] As used herein, the following definitions apply, unless stated otherwise:

[0020] The use of the prefix Cx-y, wherein x and y each represent a natural number, indicates that the chain or ring structure or combination of chain and ring structure as a whole, specified and mentioned in direct association, may consist of a maximum of y and a minimum of x number of carbon atoms.

[0021] In general, for groups comprising two or more subgroups, unless otherwise indicated the last named subgroup is the radical attachment point, for example, the substituent “aryl-Ci-3-alkyl” means an aryl group which is bound to a Ci-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached. However, if a bond is depicted just prior to the first named subgroup, then that first named subgroup is the radical attachment point,Attorney Docket No. NTG-08-PCTfor example, the substituent “-S(O)nCi.6-alkyl” means a Ci-6-alkyl-group which is bound to an S(O)ngroup, the latter of which is bound to the core or to the group to which the substituent is attached.

[0022] As used herein, alkyl denotes monovalent, saturated hydrocarbon chains, which may be present in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono- or polysubstitution in each case, on all the hydrogen-carrying carbon atoms. For example, the term “Ci-5-alkyl” includes for example H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-,H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-. Further examples of alkyl are methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1 -propyl ( / / -propyl; / z-Pr; -CFECEECFE), 2-propyl (z-Pr; z.w-propyl; -CH(CH3)2), 1 -butyl (zz-butyl; zz-Bu; -CH2CH2CH2CH3), 2-methyl- 1-propyl (z o-butyl; z-Bu; -CH2CH(CH3)2), 2-butyl (scc-butyl; ec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (Zcz7-butyl; Z-Bu; -C(CH3)3), 1 -pentyl (zz-pentyl; -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3 -pentyl (-CH(CH2CH3)2), 3 -methyl- 1 -butyl (iso-pentyl; -CH2CH2CH(CH3)2), 2-methyl -2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2,2-dimethyl-l -propyl (zzeo-pentyl; -CH2C(CH3)3), 2-methyl- 1 -butyl (-CH2CH(CH3)CH2CH3), 1 -hexyl (zz-hexyl; -CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3 -hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3 -methyl-3 -pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3 -pentyl(-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), 2,3-dimethyl-l-butyl (-CH2CH(CH3)CH(CH3)CH3), 2,2-dimethyl-l -butyl (-CH2C(CH3)2CH2CH3), 3, 3 -dimethyl- 1 -butyl (-CH2CH2C(CH3)3), 2-methyl- 1 -pentyl(-CH2CH(CH3)CH2CH2CH3), 3-methyl-l-pentyl (-CH2CH2CH(CH3)CH2CH3), 1-heptyl(zz-heptyl), 2-methyl- 1 -hexyl, 3 -methyl- 1 -hexyl, 2,2-dimethyl-l -pentyl, 2,3-dimethyl-l -pentyl, 2,4-dimethyl-l -pentyl, 3,3-dimethyl-l-pentyl, 2,2,3-trimethyl-l -butyl, 3 -ethyl- 1 -pentyl, 1-octyl (zz-octyl), 1 -nonyl (zz-nonyl), 1 -decyl (zz-decyl), etc.Attorney Docket No. NTG-08-PCT

[0023] By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. without any further definition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein all isomeric forms are included.

[0024] The above definition for alkyl also applies if alkyl is a part of another (combined) group such as for example Cx-y-alkylamino or Cx-y-alkoxy.

[0025] Unlike alkyl, alkenyl, when used alone or in combination herein, consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond and a carbon atom can only be part of one C-C double bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl is formed. Alkenyl may optionally be present in the cis or trans or E ox Z orientation with regard to the double bond(s).

[0026] Unlike alkyl, alkynyl, when used alone or in combination herein, consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl is formed.

[0027] Haloalkyl (haloalkenyl, haloalkynyl), when used alone or in combination herein, is derived from the previously defined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If a haloalkyl (haloalkenyl, haloalkynyl) is to be further substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Examples of haloalkyl (haloalkenyl, haloalkynyl) are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, -CF=CF2, -CC1=CH2, -CBr=CH2, -C=C-CF3, -CHFCH2CH3, -CHFCH2CF3, etc.

[0028] The term “aryl,” when used alone or in combination herein, refers to an aromatic hydrocarbon ring containing from six to fourteen carbon ring atoms (e g., a Ce-i4 aryl, preferably Ce-io aryl). The term Ce-14 aryl includes monocyclic rings, fused rings and bicyclic rings where at least one of the rings is aromatic. Non-limiting examples of Ce-i4 aryls include phenyl, indanyl,Attorney Docket No. NTG-08-PCTindenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, benzocycloheptanyl, and benzocycloheptenyl.

[0029] As used herein, the term “heteroaryl,” when used alone or in combination herein, refers to a heteroaromatic ring system that contains 2-10 carbon atoms and 1-4 heteroatom ring atoms selected from N, NH, O, and S and includes aromatic 5 to 6-membered monocyclic heteroaryls and aromatic 7 to 11 -membered heteroaryl bicyclic or fused rings where at least one of the rings is aromatic. Non-limiting examples of 5 to 6-membered monocyclic heteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl. Nonlimiting examples of 7 to 11 -membered heteroaryl bicyclic or fused rings include purinyl, benzimidazolyl, quinolinyl, dihydro-2H-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzopyranyl, benzodi oxolyl, benzoxazolyl, benzothiazolyl, pyrrolo[2,3-b]pyridinyl, and imidazo[4,5-b]pyridinyl.

[0030] Sulfur and nitrogen may optionally be present in all the possible oxidation stages (sulphur: sulphoxide -SO-, sulphone -SO2-; nitrogen: N-oxide).

[0031] The compounds of the invention are only those which are contemplated to be chemically stable as will be appreciated by those skilled in the art. For example, a compound which would have a “dangling valency,” or a carbanion are not compounds contemplated by the inventive methods disclosed herein.

[0032] “Alkoxy” as used herein refers to an alkyl-O- group wherein the alkyl group is as defined before. The term “Cx-y-alkoxy” (x and y each being an integer) as used herein refers to an alkoxy group as defined before containing x to y carbon atoms. For example, a Ci-6-alkoxy group means a group of the formula Ci-6-alkyl-O- in which the term “Ci-6-alkyl” has the previously given significance. Examples of alkoxy groups are methoxy and ethoxy.

[0033] “Halogen” as used herein refers to F, Cl, Br, or I.

[0034] The term “cycloalkyl,” when used alone or in combination herein, refers to a nonaromatic 3 to 12-membered (but preferably, 3 to 6-membered) monocyclic carbocyclic radical or a nonaromatic 6 to 10-membered fused bicyclic, bridged bicyclic, propellane, or spirocyclic carbocyclic radical. The C3-12 cycloalkyl may be either saturated or partially unsaturated, and the carbocycle may be attached by any atom of the cycle which results in the creation of a stableAttorney Docket No. NTG-08-PCTstructure. Non-limiting examples of 3 to 10-membered monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, and cyclohexanone. Non-limiting examples of 6 to 10-membered fused bicyclic carbocyclic radicals include bicyclo[l.l.l]pentane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, and bicyclo[4.4.0]decanyl (decahydronaphthalenyl). Non-limiting examples of 6 to 10-membered bridged bicyclic carbocyclic radicals include bicyclo[2.2.2]heptanyl, bicyclo[2.2.2]octanyl, and bicyclo[3.2.1]octanyl. Non-limiting examples of 6 to 10-membered propellane carbocyclic radicals include but are not limited to [1.1.1,]propellane,[3.3.3]propellane, and [3.3.1]propellane. Non-limiting examples of 6 to 10-membered spirocyclic carbocyclic radicals include but are not limited to spiro[3,3]heptanyl, spiro[3,4]octanyl, and spiro[4,4]heptanyl.

[0035] The term “heterocyclyl,” when used alone or in combination herein, refers to a heterocyclic ring system that contains 2-10 carbon atoms and one to four heteroatom ring atoms chosen from NH, O, and S and includes stable nonaromatic 4-8 membered monocyclic heterocyclic radical or a stable nonaromatic 6 to 11 -membered fused bicyclic, bridged bicyclic, or spirocyclic heterocyclic radical. The heterocycle may be either completely saturated or partially unsaturated. In one embodiment, the heterocycle is a C3-6 heterocycle, i.e., containing 3 to 6 ring carbon atoms. Non-limiting examples of nonaromatic monocyclic heterocyclic radicals include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl, and azepinyl. Non-limiting examples of nonaromatic 6 to 11-membered fused bicyclic radicals include octahydroindolyl, octahydrobenzofuranyl, and octahydrobenzothiophenyl. Non-limiting examples of nonaromatic 6 to 11 -membered bridged bicyclic radicals include 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.2.1]octanyl. Non-limiting examples of nonaromatic 6 to 11 -membered spirocyclic heterocyclic radicals include 7-aza-spiro[3,3]heptanyl, 7-spiro[3,4]octanyl, and 7-aza-spiro[3,4]octanyl.

[0036] “Hydroxy” as used herein refers to -OH.

[0037] “Carboxy” as used herein refers to -COOH.

[0038] Compounds disclosed herein, e.g., any of Formula I or Formula II, may exist in free or salt form, e.g., as acid addition salts. In this patent application, unless otherwise indicated, language such as “compounds disclosed herein, e.g., any of Formula I or Formula II,” is to beAttorney Docket No. NTG-08-PCTunderstood as embracing the compounds in any form, for example free or acid addition salt form, or where the compounds contain acidic substituents, in base addition salt form. Any reference to compound(s) of Formula I or Formula II is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient. Compounds disclosed herein are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts that are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free forms of compounds disclosed herein or their pharmaceutically acceptable salts, so therefore are also included. In this patent application, unless otherwise indicated, language such as “any of Formula I” or “any of Formula II,” includes 1.1 et seq. and 2.1 et seq. as described above.

[0039] “Pharmaceutically acceptable salt” as used herein refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and / or base addition salts depending on the presence of basic and / or acidic groups in the subject compound.

[0040] Some compounds disclosed herein may contain one or more asymmetric centers. This patent application provides the use of any of the optically pure stereoisomers as well as any combination of stereoisomers. Accordingly, compounds disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or salt (e.g., pharmaceutically acceptable salt) form, include their enantiomers, diastereoisomers, stereoisomers, and racemates. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.

[0041] Compounds disclosed herein may also contain one or more double bonds.Representations of double bonds in this invention are meant to include both the E and the Z isomer of the double bond.

[0042] Compounds disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or salt (e.g., pharmaceutically acceptable salt) form, also encompass their stable and unstable isotopes. Stable isotopes are nonradioactive isotopes that contain one additional neutron compared to the abundant nuclides of the same species (i.e., element). For example, the hydrogen atom at a certain position on a compound disclosed herein, e g., any of Formula I et seq. or Formula II et seq., in free or salt (e.g., pharmaceutically acceptable salt) form, may be replaced with deuterium (a stable isotope which is non-radioactive). Examples of known stable isotopes include, but are not limited to, deuterium,13C,15N,18O. Alternatively, unstable isotopes,Attorney Docket No. NTG-08-PCTwhich are radioactive isotopes that contain additional neutrons compared to the abundant nuclides of the same species (i.e., element), e.g.,123I,131I,125I,11C,18F, may replace the corresponding abundant species of I, C, and F. Another example of a useful isotope of the compound of the invention is the11C isotope. These radio isotopes are useful for radio-imaging and / or pharmacokinetic studies of compounds disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or salt (e.g., pharmaceutically acceptable salt) form.

[0043] In this patent application, a bond drawn with a wavy line shows the point of attachment of the radical drawn.

[0044] Further provided is a pharmaceutical composition comprising a compound disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form. For instance, provided is a pharmaceutical composition comprising a compound as disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, in admixture with a pharmaceutically acceptable carrier.

[0045] Further provided is a method for inhibiting calpain 1 (CAPN1), calpain 2 (CAPN2), and / or calpain 9 (CAPN9) in a patient (e.g., a human) in need thereof or in a biological sample (e.g., cell or tissue), wherein the method comprises contacting the patient or biological sample with an effective amount of a compound (including a pharmaceutical composition comprising an effective amount of a compound) disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form. For instance, provided is a method for inhibiting CAPN1, CAPN2, and / or CAPN9, wherein the method comprises contacting a cell (e.g., a neuron, a microglia, an invading microphage, or a cell of the skeletal muscle) with an effective amount of a compound (including a pharmaceutical composition comprising an effective amount of a compound) disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form.

[0046] Further provided is a method for inhibiting myofibroblast differentiation (e.g., Epithelial / Endothelial-to-Mesenchymal Transition (EpMT / EnMT), for instance, a TGF-beta mediate myofibroblast differentiation) in vitro or in vivo comprising contacting a cell with an effective amount of a compound (including a pharmaceutical composition comprising an effective amount of a compound) disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form.Attorney Docket No. NTG-08-PCT

[0047] Further provided is a method for inhibiting fibroblast to myofibroblast transition (FMT) in vitro or in vivo comprising contacting a cell with an effective amount of a compound (including a pharmaceutical composition comprising an effective amount of a compound) disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form.

[0048] Further provided are methods of using the compounds and pharmaceutical compositions disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, for treatment or prophylaxis of diseases and disorders as set forth herein. For instance, for treatment or prophylaxis of calpain-mediated disorders in a patient (e.g., a human) in need thereof. For instance, disorders mediated by one or more of calpain 1 (CAPN1), calpain 2 (CAPN2), and / or calpain 9 (CAPN9). For instance, for treatment or prophylaxis of a disorder or condition associated with elevated calpain activity in a patient (e.g., a human) in need thereof. For instance, disorders with elevated levels of calpain 1 (CAPN1), calpain 2 (CAPN2), and / or calpain 9 (CAPN9). For instance, for treatment of calpain-mediated disorders in a patient (e.g., a human) in need thereof, such as, pain, autoimmune and inflammatory disorders (includes any disease having an inflammatory or autoimmune component), proliferative disorders, endocrine disorders, neurological disorders, or a disorder associated with transplantation.

[0049] Further provided are methods of using the compounds and pharmaceutical compositions disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, for treatment or prophylaxis of diseases and disorders associated with elevated interleukin-I, TNF, and / or A0 level.

[0050] Further provided is a method of prophylaxis or treatment of any one or more of the following conditions in a patient (e.g., a human) in need thereof:(i) a calpain-mediated disorder;(ii) a CAPN1, CAPN2, and / or CAPN9-mediated disorder;(iii) pain, an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, cancer, and / or a disorder associated with transplantation;(iv) disorders relating to fibrosis, myofibroblast differentiation, and / or inflammation (e.g., acute and / or chronic inflammation);Attorney Docket No. NTG-08-PCT(v) liver fibrosis (e.g., alcoholic, viral, autoimmune, metabolic, or hereditary chronic disease), renal fibrosis (e.g., resulting from chronic inflammation, infections, or type II diabetes), lung fibrosis (e.g., idiopathic or resulting from environmental insults including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, or bacterial infection including tuberculosis), hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis (e.g., resulting from, for example, alcohol abuse and chronic inflammatory disease of the pancreas), fibrosis of the spleen (e.g., from sickle cell anemia or other blood disorders), cardiac fibrosis (e.g., resulting from infection, inflammation, or hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and / or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, postvasectomy pain syndrome, rheumatism, and / or rheumatoid arthritis;(vi) a disease or disorder, affected at least in part by the enzymatic activity of CAPN1, CAPN2, and / or CAPN9, or mediated at least in part by the enzymatic activity of CAPN1, CAPN2, and / or CAPN9, wherein the condition includes or produces a symptom which includes: liver fibrosis, renal fibrosis, lung fibrosis, hypersensitivity pneumonitis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, chronic allograft vasculopathy and / or chronic rejection in transplanted organs, ischemic-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, postvasectomy pain syndrome, and / or rheumatoid arthritis;(vii) a fibrotic disease;(viii) liver fibrosis;(ix) cardiac fibrosis;(x) fibrosis in rheumatoid arthritis;(xi) stiff skin syndrome,(xii) sclerotic and / or post-inflammatory disease or condition;Attorney Docket No. NTG-08-PCT(xiii) primary sclerosing cholangitis, primary biliary cholangitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and / or liver chirrhosis (e.g., caused by alcoholic liver disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, celiac disease, chronic viral hepatitis, hemochromatosis, idiopathic portal fibrosis, and / or Wilson’s disease);(xiv) cancer;(xv) cancer of epithelial origin, breast cancer, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, brain, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, skin cancer, prostate cancer, and / or renal cell carcinoma;(xvi) neurodegenerative disorders, for instance, neurodegenerative disorders occurring as a result of a deficit of oxygen and / or blood to the brain, of an ischemia (stroke), or of a trauma such as brain trauma;(xvii) Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, and / or damage to the nervous system associated with multiple sclerosis, for instance, damage to the optic nerve (optic neuritis) and the nerves which control the movement of the eye;(xviii) epilepsy;(xix) pain (e.g., acute and / or chronic pain), neuropathic pain, chronic neuropathic pain;(xx) a painful condition;(xxi) a disease or condition associated with damage to the heart following cardiac ischemia (e.g., myocardial infarction), damage to the lungs following lung ischemia, damage to the liver following liver ischemia, damage to the kidneys following renal ischemia, and / or damage to the central nervous system following ischemia (e.g., a stroke);(xxii) chronic kidney disease, skeletal muscle damage, muscular dystrophy, diabetes, damage resulting from proliferation of smooth muscle cells, coronary vasospasms, cerebral vasospasms, macular degeneration, cataracts of the eyes, restenosis of blood vessels following angioplasty, glomerulonephritis, and / or chronic kidney disease (e.g., diabetic nephropathy);Attorney Docket No. NTG-08-PCT(xxiii) cardiovascular remodeling in angiotensin Il-induced hypertension and / or impaired synaptic transmission in slow-channel congenital myasthenic syndrome;(xxiv) tumors and metastasis thereof;(xxv) impairments associated with an HIV disorder, for instance, nerve damage (HIV-induced neurotoxicity);(xxvi) a protozoan infection, e.g., malaria or toxoplasmosis;(xxvii) sickle cell crisis / pain;(xxviii) chemotherapy induced peripheral neuropathy pain;(xxix) post-operative pain;(xxx) spinal cord injury pain;(xxxi) osteoarthritis pain;(xxxii) rheumatoid arthritis pain; and / or(xxxiii) diabetic peripheral neuropathy pain,wherein the method comprises administering an effective amount of a compound disclosed herein (including a pharmaceutical composition comprising an effective amount of a compound disclosed herein), e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, to the patient.

[0051] Further provided is a method for neuroprotective effect in a patient (e.g., a human) in need thereof (e.g., following stroke or brain trauma), wherein the method comprises administering an effective amount of a compound disclosed herein (including a pharmaceutical composition comprising an effective amount of a compound disclosed herein), e g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, to the patient.

[0052] Further provided is use of the compounds disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, in metabolic and reaction kinetic studies, detection and imaging techniques, and radioactive treatments.

[0053] Further provided is:(i) a compound disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, for use in any method or in the treatment or prophylaxis of any disease or condition set forth herein;Attorney Docket No. NTG-08-PCT(ii) the use of a compound disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, for treatment or prophylaxis of any disease or condition set forth herein;(iii) the use of a compound disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, in the manufacture of a medicament for treatment or prophylaxis of any disease or condition set forth herein;(iv) a pharmaceutical composition comprising a compound disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier; and(v) a pharmaceutical composition comprising a compound disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, in combination or association with a pharmaceutically acceptable diluent or carrier for use in the treatment or prophylaxis of any disease or condition set forth herein.

[0054] In some embodiments, compounds disclosed herein, any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, may be used in the foregoing methods of treatment or prophylaxis as a sole therapeutic agent, but may also be used in combination or for co-admini strati on with other active agents. For co-administration, the compound disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, may be administered sequentially (e.g., contemporaneously or as part of the same treatment regimen) or simultaneously with the second active agent. Where two active agents are administered, the effective amount of each agent may be below the amount needed for activity as monotherapy. Accordingly, a subthreshold amount (i.e., an amount below the level necessary for efficacy as monotherapy) may be considered therapeutically effective and may also be referred alternatively as a therapeutically effective amount. Indeed, an advantage of administering different agents with different mechanisms of action and different side effect profiles may be to reduce the dosage and side effects of either or both agents, as well as to enhance or potentiate their activity as monotherapy.Attorney Docket No. NTG-08-PCT

[0055] For methods of treatment, “effective amount” as used herein is intended to encompass a therapeutically effective amount to treat a specific disease or disorder.

[0056] “Patient” as used herein includes human and non-human (i.e., animal).

[0057] “Comprising” as used herein is intended to be open-ended and does not exclude additional, unrecited elements or method steps.

[0058] Dosages employed in practicing the methods disclosed herein will of course vary depending, e.g., on the patient, on the particular disease or condition to be treated, the particular compound used, the mode of administration, and the therapy desired. Compounds disclosed herein, e g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, but are preferably administered orally.

[0059] Compounds disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or salt (e.g., pharmaceutically acceptable salt) form, may be made using the methods as described and exemplified herein and by methods similar thereto and by methods known in the chemical art. Such methods include, but are not limited to, those described below. If not commercially available, starting materials for these processes may be made by procedures, which are selected from the chemical art using techniques which are similar or analogous to the synthesis of known compounds.

[0060] Accordingly, also provided are methods of making the compounds and pharmaceutical compositions disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or salt (e.g., pharmaceutically acceptable salt) form. For instance, provided is a method (Method 1) for a making a compound disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or salt form (e.g., pharmaceutically acceptable salt form). Salts that are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free forms of compounds disclosed herein or their pharmaceutically acceptable salts, so therefore are also included.

[0061] Pharmaceutical compositions comprising a compound disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form, may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions, and the like.General Administration and Pharmaceutical CompositionsAttorney Docket No. NTG-08-PCT

[0062] When used as pharmaceuticals, the compounds of the invention (e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form) are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and generally comprise at least one compound of the invention and at least one pharmaceutically acceptable carrier. The compounds of the invention may also be administered alone or in combination with adjuvants that enhance stability of the compounds of the invention, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increased antagonist activity, provide adjunct therapy, and the like. The compounds according to the invention may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances. In general, the compounds of this invention are administered in a therapeutically or pharmaceutically effective amount but may be administered in lower amounts for diagnostic or other purposes.

[0063] Administration of the compounds of the invention (e.g., any of Formula I et seq. or Formula II et seq., in free or pharmaceutically acceptable salt form), in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted modes of administration of pharmaceutical compositions. Thus, administration can be, for example, orally, buccally (e.g., sublingually), nasally, parenterally, topically, transdermally, vaginally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The pharmaceutical compositions will generally include a conventional pharmaceutical carrier or excipient and a compound of the invention as the / an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles, or combinations thereof. Such pharmaceutically acceptable excipients, carriers, or additives as well as methods of making pharmaceutical compositions for various modes or administration are well-known to those of skill in the art. The state of the art is evidenced, e.g., by Remington: The Science and Practice of Pharmacy, 20th Edition, A. Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook of Pharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995; Handbook of Pharmaceutical Excipients, A. H. Kibbe (ed.),Attorney Docket No. NTG-08-PCTAmerican Pharmaceutical Ass’n, 2000; H. C. Ansel and N. G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger, 1990; each of which is incorporated herein by reference in their entireties to better describe the state of the art. As one of skill in the art would expect, the forms of the compounds of the invention utilized in a particular pharmaceutical formulation will be selected (e.g., salts) that possess suitable physical characteristics (e.g., water solubility) that are required for the formulation to be efficacious.General Synthetic Methods

[0064] Compounds of Formula I et seq. and Formula II et seq., in free or pharmaceutically acceptable salt form, may be prepared by the methods of synthesis, synthetic examples, methods known to those of ordinary skill in the art, and methods reported in the chemical literature. In the methods of synthesis and examples described hereinafter, the substituents A, R, Ri, R2a, R2b, R3, and R4 shall have the meanings defined hereinbefore in the detailed description of the compounds of Formula I and Formula II. These methods that are described here are intended as an illustration and for the enablement of the instant invention without restricting the scope of its subject matter, the claimed compounds, and the examples. Where the preparation of starting compounds is not described, they are commercially obtainable, may be prepared analogously to compounds or methods described herein, or are described in the chemical literature. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art.

[0065] Intermediates may be prepared by one skilled in the art using methods described in the chemical literature.

[0066] Compounds of Formula I and Formula II may be prepared from intermediate X.Intermediate X may be synthesized according to Scheme 1.Attorney Docket No. NTG-08-PCTScheme 1

[0067] As illustrated in Scheme 1, an amine protected X-l (e.g., Boc-Phe-OH) is reacted with N, O-dimethylhydroxylamine hydrogen chloride in a suitable solvent such as DMF in the presence of a suitable base and HATU to provide the corresponding carbamate intermediate X-2.

[0068] Reacting the carbamate intermediate X-2 in a suitable solvent such as THF at a suitable temperature with a reducing agent such as LAH provides the corresponding intermediate X-3.

[0069] Reacting intermediate X-3 with 2-hydroxy-2-methylpropanenitrile in a suitable solvent such as dichloromethane in the presence of a suitable base provides the corresponding cyano compound X-4.

[0070] Hydrolysis / oxidation of the intermediate cyano compound X-4 in a suitable solvent such as DMSO in the presence of a base and hydrogen peroxide provides the corresponding 4-amino-3-hydroxy-4-oxo carbamate intermediate X-5.

[0071] Deprotection of the above Boc intermediate X-5 with hydrochloric acid in a suitable solvent such as 1,4-dioxane provides the corresponding hydrochloride salt of 3-amino-2-hydroxy-4-phenylbutanamide intermediate X.

[0072] Alternatively, intermediate X may be synthesized according to Scheme 2.Scheme 2Attorney Docket No. NTG-08-PCT

[0073] As illustrated in Scheme 2, cyano compound X-4 is hydrolyzed in a methanolic solution of HC1 to afford methyl 3-amino-2-hydroxy-4-phenylbutanoate intermediate X-6.

[0074] Amine X-6 is substituted with a suitable protecting group such as / c' / 7-buty I oxy carbonyl (Boc) to arrive at intermediate X-7, which is hydrolyzed to carboxylic acid X-8.

[0075] Amide coupling of intermediate X-8 with a suitable primary or secondary amine provides X-9 which undergoes deprotection of the Boc protecting group with hydrochloric acid in a suitable solvent such as 1,4-dioxane to provide the corresponding hydrochloride salt of 3-amino-2-hydroxy-4-phenylbutanamide intermediate X.

[0076] Compounds of Formula I et seq. and Formula II et seq. may be prepared from intermediate X according to Scheme 3.Scheme 3O Intermediate XHATU, baseFormula I

[0077] As illustrated in Scheme 3, amide coupling of a suitable carboxylic acid with intermediate X, in a suitable solvent such as DMF in the presence of a suitable base and HATU and subsequent work up provides a compound of Formula I et seq.

[0078] Compounds of Formula II et seq. may also be prepared according to Scheme 4.Attorney Docket No. NTG-08-PCT

[0079] As illustrated in Scheme 4, reacting a suitable substituted chroman-4-one Y-l with TMSCN in a suitable solvent such as dichloromethane in the presence of zinc iodide, provides the corresponding trimethylsilyl intermediate Y-2.

[0080] Deprotection and oxidation of the trimethyl silyl intermediate Y-2 in acetic acid in the presence of HC1 and SnCh provides the corresponding racemic chromane-4- carboxylic acid Y- 3. Chiral resolution of the racemic carboxylic acid Y-3, provides the corresponding stereoisomers Y and Y*.

[0081] Amide coupling of the optically pure carboxylic acid Y or Y' with intermediate X in a suitable solvent such as DMF in the presence of a suitable base and HATU and subsequent work up provides a compound of Formula II et seq.Synthetic Examples

[0082] Non-limiting examples demonstrating the preparation of compounds of Formula I et seq. and Formula II et seq. are provided below. Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Intermediates and products may be purified by, for example, chromatography on silica gel and / or reverse phase HPLC (RHPLC). Discrete enantiomers may be obtained by resolution of racemic products using chiral HPLC.Attorney Docket No. NTG-08-PCTEXAMPLES

[0083] The synthetic methods for various compounds disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or salt (e.g., pharmaceutically acceptable salt) form, are illustrated below. The intermediates of compounds disclosed herein, e.g., any of Formula I et seq. or Formula II et seq., in free or salt (e.g., pharmaceutically acceptable salt) form, as well as other compounds disclosed herein and their salts (e.g., pharmaceutically acceptable salts), may be made using the methods as similarly described below and / or by methods similar to those generally described in the detailed description and by methods known in the chemical art.Abbreviations:ACN AcetonitrileAc Acetic acidc ConcentrationCDI 1,1’ -Carbonyldiimidazole(BOC)2O Di-tert-butyl dicarbonateDCE Di chloroethaneDCM DichloromethaneDEA DiethylamineDIBAL Diisobutylaluminum hydrideDIPEA Di isopropyl ethyl amineDMF Dimethyl formamideDMP Dess Martin periodinaneDMSO DimethylsulfoxideEDC l-Ethyl-3-(3-dimethylaminopropyl)carbodiimideeq equivalentsEt2O Diethyl etherEtOAc Ethyl acetateEtOH Ethanolh Hour(s)l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3- HATUoxide hexafluorophosphateAttorney Docket No. NTG-08-PCTHC1 Hydrochloric AcidHPLC High-pressure liquid chromatographyHOBt 1 -Hydroxybenzotri azoleIPA Isopropyl alcoholK2CO3 Potassium carbonateKO / Bu Potassium terz-ButoxideLAH Lithium aluminum hydrideM MolarityMeOH MethanolMel Methyl iodidemin Minute(s)mL MilliliterMPLC Medium-pressure liquid chromatographyMS Mass spectrometrym / z Mass to Charge RatioN NormalityNa2CO3Sodium carbonateNa2S2O8Sodium persulfateNa2S2O3Sodium thiosulphateNa2SO4Sodium sulphateNaHCO3Sodium bicarbonateNMR Nuclear magnetic resonance spectrometrypet ether Petroleum etherRf Retention factorrt Room (ambient) temperatureRT Retention timesat saturatedSFC Supercritical fluid chromatographySnCl2.2H2O Tin(II) chloride dihydrateSOCl2Thionyl chlorideTEA Tri ethyl amineAttorney Docket No. NTG-08-PCTTFA Trifluoroacetic acidTHF TetrahydrofuranTLC Thin layer chromatographyTMS TrimethylsilylTMSCN Trimethylsilyl cyanideSynthesis of Intermediate 3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-phenylbutanoic acid (Int 1)Step 1: Synthesis of tert-butyl (l-(methoxy(methyl)amino)-l-oxo-3-phenylpropan-2-yl)carbamateNH. HCIHOOC NHBoc I HATU, DIPEA DMF, RT, 16 h

[0084] To a stirred solution of ( / e / 7-butoxycarbonyl)pheny I alanine (25.0 g, 94.3 mmol, 1 eq) in DMF (150 mL) is added DIPEA (49.2 ml, 282.7 mmol, 3 eq) dropwise at rt. After 10 min, HATU (43.0 g, 113.1 mmol, 1.2 eq), and N, O-dimethylhydroxylamine hydrochloride (11.0 g, 113.1 mmol, 1.2 eq) are added to the reaction mixture. The resulting reaction mixture is stirred for 16 h at rt. The progress of the reaction is monitored by TLC (mobile phase: 5% MeOH in DCM, Rf: 0.43, visualization: UV active). After consumption of the starting material is confirmed by TLC, ice-cold water (500 mL) is added to the reaction mixture and stirred for 20 mins. The precipitated solid is filtered and washed with ice-cold water (2 x 300 mL) to yield the crude product (28.0 g) as an off-white solid. The solid is triturated with n-pentane (2 x 250 mL) to afford the desired product (28 g, 96%) as a white solid. LCMS (ESI): 309.21 [M+H]+.XH NMR (400 MHz, CDCl3) 8 ppm: 7.28-7.27 (m, 2H), 7.23-7.16 (m, 3H), 5.71-5.60 (m, 1H), 4.89-5.03 (m, 1H), 3.65 (s, 3H), 3.07-3.02 (dd, Ji=6 Hz, J2=13.6 Hz, 1H), 2.92-2.81 (m, 1H), 1.38 (s, 9 H).Step 2: Synthesis of terf-butyl (l-oxo-3-phenylpropan-2-yl)carbamateAttorney Docket No. NTG-08-PCToLiAlH4(2M in THF)THF, -5 °C, 1.5 h

[0085] To a stirred solution of zc / 7-butyl (l-(methoxy(methyl)amino)-l-oxo-3-phenylpropan-2-yl)carbamate (10.0 g, 32.4 mmol, 1 eq) in THF (200 mL) is added LiAlHt, 2M solution in THF (19.5 mL, 38.9 mmol, 1.2 eq) dropwise at -5 °C. The reaction mixture is stirred at -5 °C for 1. 5 h. The progress of the reaction is monitored by TLC (mobile phase: 20% EtOAc in petroleum ether, Rf: 0.44, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is quenched with a saturated NH4CI solution (60 mL) and filtered on a celite pad. The pad is rinsed with EtOAc (3 x 100 mL). The filtrate is extracted with EtOAc (2 x 150 mL). The combined organic layers are dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford desired aldehyde product (8.0 g, 99%) as a pale yellow gum. 'H NMR(400 MHz, CDCh) 8 ppm: 9.63 (s, 1H), 7.31-7.16 (m, 6H), 4.43-4.41 (m, 1H), 3.11 (d, J=6.4Hz, 2H), 1.43 (s, 9H).Step 3: Synthesis of tert-butyl (l-cyano-l-hydroxy-3-phenylpropan-2-yl)carbamateAcetonecyanohydrinTEA DCM, RT, 4 h

[0086] To a stirred solution of tert-butyl (l-oxo-3-phenylpropan-2-yl)carbamate (9 g, 36.1 mmol, 1 eq) in DCM (90 mL) is added TEA (6 mL, 43.3 mmol, 1.2 eq) and 2-hydroxy-2-methylpropanenitrile (9.9 mL, 108.3 mmol, 3 eq) at 0 °C. The resulting reaction mixture is stirred at rt for 3 h. The progress of the reaction is monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.39, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is quenched with water (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers are washed with brine (2 x 100 mL), dried over anhydrous Na2SC>4, and concentrated under reduced pressure to obtain crude product (9 g) as a pale yellow gum. The crude compound is purified via combi-flash normalphase column chromatography using an 80 g silica (100-200 mesh size) cartridge). TheAttorney Docket No. NTG-08-PCTcompound is eluted with a gradient of 0-30% EtOAc in hexane. The pure fractions are concentrated under reduced pressure to afford the desired product (6.8 g, 68%) as a white solid. LCMS (ESI): 277.31 [M+H]+. ’HNMR (400 MHz, CDCl3) 8 ppm: 7.36-7.20 (m, 5H), 5.03-5.01 (m, 1H), 5.38 (bs, 1H), 4.55-4.46 (m, 1H), 3.11-2.89 (m, 2H), 1.41 (s, 9H).Step 4: Synthesis of methyl 3-amino-2-hydroxy-4-phenylbutanoic acid hydrochloride OHConc. HCI, Anisole Dioxane, Reflux, 16 h

[0087] To a stirred solution of zc / 7-butyl (l-cyano-l-hydroxy-3-phenylpropan-2-yl)carbamate (28.0 g, 101.4 mmol, 1 eq) in 112 mL of MeOH is added 112 mL of 4 M HC1 in 1,4-dioxane. The mixture is heated in a sealed tube at 60 °C for 16 h. The solvent is evaporated and the resulting yellow solid is triturated with Et2O (2 x 250 mL) and dried. The solid is stirred in 150 mL of water for 15 min. The aqueous solution is basified with solid sodium bicarbonate and extracted with (2 x 200 mL) of EtOAc. The aqueous phase is saturated with NaCl and extracted with (3 x 350 mL) of EtOAc. The combined organic extracts are dried over Na2SO4 and evaporated to dryness to afford 18.22 g of the desired product. LCMS (ESI) z: 210.2 [M+H]L Step 5: Synthesis of 3-(( rt-butoxycarbonyl)amino)-2-hydroxy-4-phenylbutanoic acidOH °HO. Jk / NH2HCI 1- BOC2O, NaHCO3HO^ / L / NHBoc Y J Dioxane, H2O, RT,16 h [J ] O 2. LiOH, H2O, THF0

[0088] To a solution of methyl 3-amino-2-hydroxy-4-phenylbutanoate (0.7 g, 3.3 mmol, 1 eq) in 5 mL DCM at 0 °C is added TEA (0.7 mL, 5.0 mmol, 1.5 eq) and (Boc^O (0.73 mL, 3.3 mmol, 1 eq). The resulting mixture is stirred at rt for 16 h. Upon completion of the reaction, as monitored by TLC, the reaction mixture is diluted with 100 mL of DCM and washed with 100 mL of brine (150 mL x 2). The organic phase is dried over Na2SC>4 and evaporated to dryness to afford the crude product, which is purified by combi-flash column chromatography (silica gel column, elution which 10% EtOAc in hexane) to deliver 0.6 g methyl 3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-phenylbutanoate (Mass (ESI) m / z 210.35[M-Boc]+). ThisAttorney Docket No. NTG-08-PCTmaterial (0.6 g, 1.9 mmol, 1 eq) is dissolved in 3 mL of THF and a solution of lithium hydroxide monohydrate (0.2 g, 5.8 mmol, 3 eq) in 1 mL water is added. The resulting mixture is stirred at rt for 4 h as the progress of the reaction is monitored by TLC. The reaction mixture is diluted with water (20 mL) and acidified with aqueous 0.05 N HC1 (2 mL). The desired product is extracted with EtOAc (3 x 100 mL), the combined organic extracts are washed with brine (30 mL), dried over Na2SC>4, and evaporated to dryness to afford the desired product as an off-white solid, which is used without further purification.Alternative Synthesis of Intermediate 3-(( rt-butoxycarbonyl)amino)-2-hydroxy-4-phenylbutanoic acidStep 1: Synthesis of tert-butyl (4-cyano-3-oxo-l-phenyl-4-(tetrahydro-lH-thiophen-l-ylidene)butan-2-yl)carbamate

[0089] To a stirred solution of (tert-butoxycarbonyl)phenylalanine (5 g, 18.8 mmol, 1 eq) in DMF (40 mL) is added DIPEA (9.8 mL, 56.5 mmol, 3 eq) and HATU (8.6 g, 22.6 mmol, 1.2 eq) at 0 °C. After 10 min, a solution of 1 -(cyanomethyl) tetrahydro-lH-thiophen-l-ium (3.6 g, 28.3 mmol, 1.5 eq) is added portionwise to the reaction mixture at the same temperature. The resulting reaction mixture is stirred at rt for 16 h. The progress of the reaction is monitored by TLC (mobile phase: 5% MeOH / DCM, Rf: 0.41, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is quenched with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers are washed with brine solution (2 x 100 mL), saturated sodium bicarbonate solution, dried over Na2SO4. and filtered. The filtrate is concentrated under reduced pressure to afford the crude product (9 g) as a yellowish gum. The obtained crude product is triturated with Et2O (3 x 80 mL) and dried under reduced pressure to afford the desired product (6.5 g, 92%) as a brown solid. LCMS (ESI): 375.16 [M+H]+.Step 2: Synthesis of 3-((tert-butoxycarbonyl)amino)-2-oxo-4-phenylbutanoic acidAttorney Docket No. NTG-08-PCT

[0090] To a stirred solution of tert-butyl (4-cyano-3-oxo-l-phenyl-4-(tetrahydro-lH-thiophen-l-ylidene) butan-2-yl)carbamate (1.7 g, 4.5 mmol, 1 eq) in THF (14 mL) and water (6 mL) is added OXONE® monopersulfate (4.2 g, 13.6 mmol, 3 eq) at 0 °C and stirred at rt for 3 h. The reaction progress is monitored by TLC (mobile phase: 10% MeOH in DCM, Rf value: 0.11, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers are washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford crude product (1.4 g) as a brown gum. The crude product is triturated in petroleum ether (50 mL) to afford the desired product (1.2 g, 90%) as pale yellow gum. LCMS (ESI) m / z: 292.1 [M+H]+.Step 3: Synthesis of 3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-phenylbutanoic acid

[0091] To a stirred solution of 3-((terLbutoxycarbonyl)amino)-2-oxo-4-phenylbutanoic acid (1.2 g, 4.1 mmol, 1 eq) in dry THF (20 mL) is added NaCNBH3(257.1 mg, 4.1 mmol, 1 eq) portionwise at 0 °C. The resulting reaction mixture is stirred at the same temperature for 1 h. The progress of the reaction is monitored by LCMS. After consumption of the starting material is confirmed by TLC, the reaction mixture is diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers are washed with saturated brine solution (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford crude product (900 mg) as a brown solid. The crude compound is triturated with / / -pentane (50 mL) to afford the desired product (700 mg, 57.94%) as an off-white solid. LCMS (ESI) m / z 240.1 [M+56]+.Attorney Docket No. NTG-08-PCTAlternative Synthesis of Intermediate 3-((tert-butoxycarbonyl)amino)-2-hydroxy-4-phenylbutanoic acidStep 1: Synthesis of tert-butyl (4-amino-3-hydroxy-4-oxo-l-phenylbutan-2-yl)carbamate

[0092] To a solution of tert-butyl ( l-cyano- l-hydroxy-3-phenylpropan-2-yl)carbamate (23 g, 83.3 mmol, 1 eq) in DMSO (250 mL) at 0 °C is added potassium carbonate (23.0 g, 166.6 mmol, 35 eq), followed by the drop-wise addition of hydrogen peroxide (100 mL, 2915.0 mmol, 35 eq). The resulting mixture is stirred for 2 h at 0 °C as progress of the reaction is monitored by TLC. Reaction mixture is quenched with water (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic extracts are washed with brine, dried over sodium sulphate, and evaporated to dryness to afford the desired product, which is triturated with hexane, filtered, and dried under reduced pressure to afford a white solid (16 g). Mass (ESI) m / z: 195.2 [M-Boc]+.Step 2: Synthesis of 3-amino-2-hydroxy-4-phenylbutanamideOH OH

[0093] To / ert-butyl (4-amino-3,4-dioxo-l-phenylbutan-2-yl)carbamate (16 g, 54.4 mmol, 1 eq) is added 4 M HC1 in 1,4-dioxane (136 mL, 543.9 mmol, 10 eq) and the resulting solution is stirred at rt for 1 h as progress of the reaction is monitored by TLC. The resulting solid is triturated with diethyl ether, filtered, washed with ether, and dried under reduced pressure to afford the desired product as a hydrochloride salt (12 g). Mass (ESI) m z: 195.2 [M]+.Synthesis of Intermediate (2 / ?,35)-3-amino-2-hydroxy-4-phenylbutanamide hydrochloride (Int 2)Step 1: Synthesis of benzyl (A)-(l-oxo-3-phenylpropan-2-yl)carbamateAttorney Docket No. NTG-08-PCTOH1) GDI, DCM 0°C, 60 min 2) DIBAL-H (1M in Toluene)-78°C, 60 min

[0094] A stirred solution of benzyl (S)-(l-oxo-3-phenylpropan-2-yl)carbamate (50 g, 176.5 mmol, 1 eq) in DCM (1.2 L) is cooled to 0 °C and treated with CDI (97%, 31.5 g, 194.1 mmol, 1.1 eq). The mixture is stirred at 0 °C stirred for 1 h. The reaction mixture is then cooled to -78 °C and treated with DIBAL (1.0 M) in toluene (370.6 mL, 370.6 mmol, 2.1 eq) dropwise at -78 °C and the resulting reaction mixture is stirred for 60 min. The progress of the reaction is monitored by TLC. EtOAc (1.2 L) is added dropwise at -78 °C and stirred for 15 min. The mixture is allowed to warm to rt, after which 25% tartaric acid solution (800 mL) is added. The layers are separated and the aqueous fraction is extracted with EtOAc (500 mL). The combined organic fractions are washed with 1 M HC1 (800 mL) and 0.8 M NaHCO3 solution(800 mL), dried over anhydrous Na2SO4, and filtered. The filtrate is concentrated under reduced pressure. The crude product is triturated with pentane (2 x 300 mL) to afford the desired product (37.5 g, 68%) as a white solid.1H NMR(400 MHz, CDCl3) δ ppm: 9.64 (s, 1H), 7.37-7.22 (m, 8H), 7.14-7.12 (m, 2H), 5.29-5.27 (m, 1H), 5.11-5.07 (m, 3H), 3.15-3.13 (m, 2H).Step 2: Synthesis of benzyl ((25,3?)-4-amino-3-hydroxy-4-oxo-l-phenylbutan-2-yl)carbamate

[0095] To a stirred solution of benzyl (S)-(l-oxo-3-phenylpropan-2-yl)carbamate (40 g, 141.2 mmol, 1 eq) in DCM (460 mL) is added a solution of trimethylsilanecarbonitrile (28.3 mL, 225.9 mmol, 1.6 eq) in DCM (40 mL) at -70 °C. The mixture is stirred for 4 h, warmed to rt, and stirred for 48 h. The reaction mixture is diluted with water (500 mL) and extracted with DCM (2 x 500 mL). The combined organic fractions are dried over anhydrous Na2SC>4 and filtered. The filtrate is concentrated under reduced pressure to obtain the crude compound (50 g)Attorney Docket No. NTG-08-PCTas a yellow liquid. The crude compound is dissolved in THF (400 mL) and treated with 1 N HC1 (60 mL) at 10 °C. The resulting reaction mixture is stirred for 30 min at 10 °C. The reaction mixture is diluted with saturated NaCl solution (200 mL) and extracted with Et? O (2 x 300 mL). The combined organic fractions are dried over anhydrous Na? SO4 and filtered. The filtrate is concentrated under reduced pressure to get the crude compound (26 g) as a white solid. LCMS (ESI) m / z: 311.24 [M+H]+.Step 3: Synthesis of (2?,3‘^)-3-amino-2-hydroxy-4-phenylbutanamide hydrochloride OH 9HH2N?NHCbzuH2N • NH2HCI 10%Pd / C, H2MeOH, 2N HCI RT, 4 h

[0096] To a stirred mixture of benzyl ((25',37?)-4-amino-3-hydroxy-4-oxo-l-phenylbutan-2-yl) carbamate (10 g, 30.5 mmol, 1 eq) in MeOH (300 mL), 10% Pd / C (5 g), and 2 N HCI (20 mL) is stirred at rt for 4 h under a hydrogen balloon. The progress of the reaction is monitored by TLC (mobile phase: 10% MeOH in DCM). The reaction mixture is filtered through a celite pad, and the filter pad is washed with MeOH (50 mL). The filtrate is concentrated under reduced pressure to provide the crude product. The crude product is co-distilled with toluene (2 x 20 mL) and triturated with pentane (2 x 50 mL) to afford the desired product (4.6 g, 65%) as a white solid. LCMS (ESI) m / z: 195.1 [M+H]+. SOR: -3.7 (c = 0.7 in water). 'H NMR (400 MHz, CD3OD) 5 ppm: 7.39-7.21 (m, 5H), 4.03 (d, 1H), 3.83-3.79 (m, 1H), 3.10-3.04 (m, 1H), 2.99-2.94 (m, 1H).Synthesis of Intermediate 3-amino-A-cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride (Int 3)Step 1: Synthesis of tert-butyl (4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)carbamateAttorney Docket No. NTG-08-PCT

[0097] To a stirred solution of 3-((ter / -butoxycarbonyl)amino)-2-hydroxy-4-phenylbutanoic acid (0.8 g, 2.7 mmol, 1 eq) in DMF (6.4 mL) is added triethylamine (1.1 mL, 8.1 mmol, 3 eq) dropwise at rt. After 10 min, EDC-HC1 (0.5 g, 3.3 mmol, 1.2 eq), HOBt (0.4 g, 3.3 mmol, 1.2 eq), and cyclopropanamine (0.2 g, 2.7 mmol, 1 eq) are added and the resulting reaction mixture is stirred at rt for 16 h. After consumption of the starting material is confirmed by TLC (mobile phase: 5% MeOH / DCM, Rf: 0.37, visualization: UV active), the reaction mixture is diluted with ice-cold water (40 mL) and stirred for ten min. The precipitate is filtered and washed with ice-cold water (3 x 30 mL). The residue is dried under reduced pressure to obtain the crude product (0.25 g) as an off-white solid. The obtained crude is purified by flash chromatography, using 100-200 mesh size silica, eluted with 5% MeOH in DCM to afford the desired product (0.2 g, 25%) as a white solid. LCMS (ESI) m / z: 335.39 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 ppm: 7.70 (d, J=4Hz, 2H), 7.25-7.21 (m, 2H), 7.15-7.13 (m, 3H), 6.53 (d, J=5.2Hz, 1H), 5.69 (bs, 1H), 3.99-3.95 (m, 1H), 3.89 (bs, 1H), 2.67-2.54 (m, 3H), 1.27 (s, 9H), 0.61-0.56 (m, 2H), 0.50-0.48 (m, 2H).Step 2: Synthesis of 3-amino-JV-cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride

[0098] To a stirred solution of tert-butyl (4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)carbamate (0.3 g, 0.7 mmol, 1 eq) in DCM (7.5 mL) is added hydrochloric acid (4 M in 1,4-dioxane) (0.1 g, 3.0 mmol, 4 eq) dropwise at 0 °C. The resulting solution is stirred at rt for 2 h. After consumption of the starting material is confirmed by TLC (mobile phase: 10% MeOH / DCM, Rf: 0.20, visualization: UV active), the reaction mixture is concentrated under reduced pressure to obtain the crude product (0.3 g). The obtained crude is triturated with n-pentane (2 x 50 mL) and dried under reduced pressure to afford the desired product (0.2 g, 99%) as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 8 ppm: 8.03-8.02 (d, J=4.4Hz, 2H), 7.34-7.30 (m, 2H), 7.27-7.21 (m, 3H), 6.37 (d, 5.6 Hz, 1H), 4.17-4.14 (m, 1H), 3.65 (bs, 1H), 2.77-2.75 (d, >7.2Hz, 2H), 2.58-2.55 (m, 2H), 0.57 (t, Ji=5.6 Hz, J2=7.2Hz, 2H), 0.45 (d, J=4Hz, 2H).Attorney Docket No. NTG-08-PCTAlternative synthesis of Intermediate 3-amino-N-cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride (Int 3)Step 1: Synthesis of 3-((terf-butoxycarbonyl) amino)-l-(cyclopropylamino)-l-oxo-4-phenylbutan-2-yl acetateO

[0099] To a stirred solution of tert-butyl (l-oxo-3-phenylpropan-2-yl)carbamate (0.4 g, 1.5 mmol, 1 eq) in EtOAc (14 mL) is added isocyanocyclopropane (0.1 mL, 2.2 mmol, 1.5 eq) and AcOH (1.4 mL) at 0 °C. The reaction mixture is stirred at rt for 16 h. The progress of the reaction is monitored by TLC (mobile phase: 30 % EtOAc in petroleum ether, UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is diluted with EtOAc (100 mL). The organic layer is washed with ice-cold water (2 x 50 mL) and brine solution (2 x 50 mL), dried over Na2SO4, and concentrated under reduced pressure to afford the desired product (0.5 g, 88%) as an off-white solid. LCMS (ESI) m / z: 377.2 [M+H]+.Step 2: Synthesis of tert-butyl (4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)carbamateO

[0100] To a stirred solution 3-((te77-butoxycarbonyl)amino)-l-(cyclopropylamino)-l-oxo-4-phenylbutan-2-yl acetate (0.5 g, 1.4 mmol, 1 eq) in MeOH (25 mL) and water (5.4 mL) at rt is added K2CO3 (0.9 g, 6.8 mmol, 1.5 eq) and the resulting reaction mixture is stirred at rt for 16 h. The progress of the reaction is monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.38, UV active). After consumption of the starting material is confirmed byAttorney Docket No. NTG-08-PCTTLC, the reaction mixture is concentrated under reduced pressure, acidified with 1 N HC1 (pH 2), and extracted with EtOAc (3 x 30 mL). The combined organic layers are washed with brine solution (2 x 30 mL), dried over Na2SO4, and concentrated under reduced pressure to afford the desired product (0.4 g, 98%) as an off-white solid. LCMS (ESI) m / z 335.2 [M+H]+.Step 3: Synthesis of 3-amino-N-cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride4M HCI Dioxane, RT, 4 h

[0100] To a stirred solution of tert-butyl (4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)carbamate (0.4 g, 1.2 mmol, 1 eq) in 1,4-dioxane (5 mL) is added 4 M HC1 in 1,4-dioxane (3.1 mL, 6.1 mmol, 5 eq) at 0 °C. The resulting reaction mixture is stirred at 0 °C for 2 h. The progress of the reaction is monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.10, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is concentrated under reduced pressure to afford the crude product (0.3 g). The obtained crude product is triturated with Et2O (2 x 30 mL) to afford the desired product (0.2 g, 66 %) as an off-white solid. LCMS (ESI) m / z: 235.2 [M+H]+.

[0101] Intermediates 4-8 in Table 9 are prepared similarly to Intermediates 1-3 above.Table 9.MassIntermediate Structure (ESI)1H NMR (ppm)m / zInt 4 (400 MHz, CDCl3) δ 7.39-HCIH2N< SLA. N. 7.29 (m, 5 H), 4.03 (d, 1H), Y (R / AT209.09 3.82 (d, 1H), 3.08-3.02 (m,0[M+H]+1H), 2.98-2.93 (m, 1H), 2.77(s, 3H)Attorney Docket No. NTG-08-PCT Int 5 (400 MHz, DMSO-de) 88.19H?H_, N>A^. NH2-HCI (d, 1=8.0 Hz, 1H), 8.04 (bs,3H), 7.32-7.19 (m, 5H), 6.43 249.34 (d, J=5.6 Hz, 1H), 4.19-4.08 ° So[M+H]+(m, 2H), 3.65-3.64 (m, 1H),2.78-2.67 (m, 2H), 2.10-1.92 (m, 4H), 1.62-1.53 (m, 2H)Int 6H?H229.10Not Recorded [M+H]+ / N 0uInt 7 (400 MHz, CD3OD) 87.39- H?H7.28 (m, 5 H), 4.35-4.33 (m, 2H), 4.09 (s, 1H), 3.94-3.84 278.2 / 0(m, 2H), 3.66 (s, 3H), 3.13- [M+H]+2.87 (m, 2H), 2.53-2.47 (m, 2H), 2.18-1.99 (m, 2H)Int 8 OH—,14. / L.NH2-hci289.20Not Recorded [M+H]+—Synthesis of intermediate 3-amino-4-cyclopropyl-2-hydroxybutanamide hydrochloride (Int 9)Step 1: Synthesis of tert-butyl (3-cyclopropyl-l-(methoxy(methyl)amino)-l-oxopropan-2-yl)carbamateAttorney Docket No. NTG-08-PCTA YX / \ NH. HCIf I1 Q HATU, DIPEABocHN Y - ' DMF, RT, 16 h

[0102] To a stirred solution of 2-(( / ert-butoxycarbonyl)amino)-3 -cyclopropylpropanoic acid (1.5 g, 6.5 mmol, 1 eq) and N, O-dimethylhydroxylamine hydrochloride (0.8 g, 7.9 mmol, 1.2 eq) in DMF (30 mL) is added DIPEA (3.6 mL, 19.6 mmol, 3 eq) at rt. After 15 min, HATU (3.2 g, 8.5 mmol, 1.3 eq) is added to the above reaction mixture at rt. The resulting reaction mixture is stirred at rt for 16 h. The progress of the reaction is monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.45, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product (2.1 g). The crude is purified by combi-flash normal-phase column chromatography using a 120 g silica gel column with 3-30% EtOAc in petroleum ether as the gradient. The collected fractions are concentrated under reduced pressure to afford the purified product (1.7 g, yield: 95%) as a colorless liquid. LCMS (ESI) m / z:273.33 [M+H]+. 'H NMR (400 MHz, CDCl3) 8 ppm: 5.26-5.24 (m, 1H), 4.77 (s, 1H), 3.78 (s, 3H), 3.30 (s, 3H), 1.68-1.62 (m, 1H), 1.51-1.48 (m, 1H), 1.47-1.40 (m, 9 H), 0.79-0.73 (m, 1H), 0.49-0.48 (m, 2H), 0.02-0.01 (m, 2H).Step 2: Synthesis of tert-butyl (1-cyclopropyl-3-oxopropan-2-yl)carbamateQLiAlH4(2M in THF)BocHNN THF, -5 °C, 2 hBDOCHnNiN" Cl

[0103] To a stirred solution of tert-butyl (3-cyclopropyl-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (2.0 g, 7.3 mmol, 1 eq) in THF (40 mL) is added LiAlH4 (2.0 M solution in THF, 4.4 mL, 8.8 mmol, 1.2 eq) dropwise at -5 °C. The resulting reaction mixture is stirred at -5 °C for 2 h. The progress of the reaction is monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.44, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is quenched with saturated NH4CI solutionAttorney Docket No. NTG-08-PCT(50 mL) and filtered on a celite pad. The pad is rinsed with EtOAc (100 mL). The layers are separated, and the aqueous layer is extracted with EtOAc (2 x 50 mL). The combined organic layers are dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product (1.5 g, 95 %) as a colorless liquid.1H NMR (400 MHz, CDCl3) δ ppm: 9.67 (s, 1H), 5.23 (m, 1H), 4.33-4.32 (m, 1H), 1.76-1.63 (m, 2H), 1.45 (s, 9 H), 0.75-0.71 (m, 1H), 0.54-0.47 (m, 2H), 0.13-0.12 (m, 2H).Step 3: Synthesis of tert-butyl (l-cyano-3-cyclopropyl-l-hydroxypropan-2-yl)carbamateActonecyanohydrine TEA DCM, RT, 4 h BocHNCN

[0104] To a stirred solution of tert-butyl (l-cyclopropyl-3-oxopropan-2-yl)carbamate (1.5 g, 7.0 mmol, 1 eq) in DCM (15 mL) is added TEA (1.2 mL, 8.4 mmol, 1.2 eq) and 2-hydroxy-2-methylpropanenitrile (1.9 mL, 21.1 mmol, 3 eq) subsequently at 0 °C. The resulting reaction mixture is stirred at rt for 4 h. The progress of the reaction is monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.39, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is diluted with water (50 mL) and extracted with DCM (3 x 70 mL). The combined organic layers are dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product as a pale yellow gum. The obtained crude is purified by flash chromatography by using 100-200 mesh size silica, eluted with 30% EtOAc in Hexane to afford the desired product (1.1 g, 65%) as a pale yellow liquid. LCMS (ESI) m / z 241.18 [M+H]+.Step 4: Synthesis of tert-butyl (4-amino-l-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)carbamateHgCl2, Acetaldoxime BocHN EtOH, H2OCN 0°C-RT, 16 h

[0105] To a stirred solution of tert-butyl (l-cyano-3 -cyclopropyl- 1-hy droxypropan-2-yl)carbamate (1.1 g, 4.6 mmol, 1 eq) in a 10:1 mixture of EtOH (11 mL) and waterAttorney Docket No. NTG-08-PCT(1 mL) is added SnCl2·2H2O (2.5 g, 9.2 mmol, 2 eq) and acetaldoxime (3.3 mL, 45.8 mmol, 10 eq) at 0 °C stirred for 10 min. The resultant reaction mixture is stirred at rt for 16 h. The reaction progress is monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.27, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is quenched with ice-cold water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure to afford the desired crude product (1.5 g). The crude product is purified by column chromatography using 100-200 silica gel and eluting with 5 % MeOH in DCM to afford the desired product (1.1 g, yield: 88%) as an off-white solid. LCMS (ESI) m / z: 259.15 [M+H]+. 'HNMR (400 MHz, CDCl3) 8 ppm: 7.22-7.13 (m, 2H), 5.97-5.95 (m, 1H), 5.46-5.43 (m, 1H), 3.91-3.86 (m, 2H), 1.42 (s, 9H), 1.39-1.30 (m, 2H), 0.65-0.65 (m, 1H), 0.38-0.33 (m, 2H), 0.07-0.01 (m, 2H).Step 5: Synthesis of 3-amino-4-cyclopropyl-2-hydroxybutanamide hydrochloride (Int 9)4M HCI in Dioxane BocHN DCM, 0 °C-RT, 3 h

[0106] To a stirred solution of tert-butyl (4-amino-l-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)carbamate (1.1 g, 4.1 mmol, 1 eq) in DCM (10 mL) at 0 °C is added 4 M HCI in dioxane (2.1 mL). The resulting reaction mixture is stirred at rt for 4 h. The progress of the reaction is monitored by TLC (mobile phase: 30% EtOAc in petroleum ether, Rf: 0.1, visualization: KMnO4 active). After consumption of the starting material is confirmed by TLC, the mixture is concentrated under reduced pressure and dried to afford the crude compound (1.0 g) as a brown solid. The crude is washed with Et2O (2 x 10 mL) and dried to afford the desired product (735 mg, 93%) as an off-white solid. LCMS (ESI) m / z: 159.05 [M+H]+.Synthesis of Intermediate 3-amino-l-(cyclopropyl amino)-l-hydroxy-4-(pyridin-3-yl)butan-2-one (Int 10)Step 1: Synthesis of tert-butyl (l-(methoxy(methyl)amino)-l-oxo-3-(pyridin-3-yl) propan-2-yl)carbamateAttorney Docket No. NTG-08-PCT

[0107] To a stirred solution of 2-((ter / -butoxycarbonyl) amino)-3-(pyridin-3-yl)propanoic acid (5.0 g, 18.8 mmol, 1 eq) in DMF (50 mL) is added DIPEA (9.8 mL, 56.3 mmol, 3 eq) followed by HATU (8.6 g, 22.5 mmol, 1.2 eq) and N, O-dimethylhydroxylamine hydrochloride (2.2 g, 22.5 mmol, 1.2 eq) at 0 °C. The resulting reaction mixture is stirred for 16 h at rt. The progress of the reaction is monitored by TLC (TLC mobile phase: 50% EtOAc in petroleum ether, Rf: 0.30, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is quenched with water (100 mL) and extracted with EtOAc (70 mL x 3). The combined organic extracts are washed with brine (2 x 50 mL) and dried over Na2SO4. The solvent is removed under reduced pressure to afford the desired product (3.93 g, LCMS: 98.2%) as a white solid. This material is used directly in the next step. LCMS (ESI) m / z 310.32 [M+H]+. 'H-NMR (400 MHz, CDCl3) 8 ppm: 8.47 (t, 1H), 8.41 (bs, 1H), 7.50 (d, 1H), 7.23-7.19 (m, 1H), 5.25 (d, 1H), 4.93 (d, 1H), 3.71 (s, 3H), 3.18 (s, 3H), 2.91-2.89 (m, 1H), 2.88-2.86 (m, 1H), 1.38 (s, 9 H).Step 2: Synthesis of tert-butyl (l-oxo-3-(pyridin-3-yl) propan-2-yl)carbamate

[0108] To a stirred solution of tert-butyl (1 -(m ethoxy (methyl)amino)-l-oxo-3-(pyri din-3 -yl)propan-2-yl)carbamate (5.0 g, 16.2 mmol, 1 eq) in THF (60 mL) is added LAH (2 M in THF, 9.7 mL, 19.4 mmol, 1.2 eq) at -5 °C. The reaction mixture is stirred for 2 h at -5 °C. The progress of the reaction is monitored by TLC (TLC mobile phase: 80% EtOAc in petroleum ether, Rf: 0.38, visualization: UV active). After consumption of the starting material is confirmed by TLC, EtOAc (50 mL) is carefully added portion wise, and the reaction mixture is stirred vigorously at rt for 30 min. The reaction is quenched with saturated NH4CI solution (100 mL)Attorney Docket No. NTG-08-PCTand filtered through celite. The filtrate is extracted with EtOAc (3 x 60 mL), and the combined organic layers are dried over Na2SC>4 and concentrated under reduced pressure to afford the desired product (3.8 g, LCMS: 70%) as a pale yellow gum. The crude compound is taken to the next step without purification LCMS (ESI) m / z: 249.2 [M+H]Step 3: Synthesis of 3-((tert-butoxycarbonyl)amino)-l-(cyclopropylamino)-2-oxo-4-(pyridin-3-yl)butan-2-yl acetate

[0109] To a stirred solution of tert-butyl (l-oxo-3-(pyridin-3-yl) propan-2-yl)carbamate (2 g, 8.0 mmol) in EtOAc (70 mL) is added isocyanocyclopropane (0.7 mL, 12.0 mmol) and acetic acid (0.7 mL, 1.0 mmol) at 0 °C. The reaction mixture is stirred at rt for 16 h. The progress of the reaction is monitored by TLC (mobile phase: 70% EtOAc in petroleum ether, Rf: 0.16, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is concentrated under reduced pressure and diluted with EtOAc (120 mL). The organic layer is washed with cold water (2 x 40 mL) and brine solution (2 x 35 mL), dried over Na2SO4 and concentrated under reduced pressure to afford the crude desired product (2.4 g, 80%) as a light-yellow gum. LCMS (ESI) m / z: 378.37 [M+H]Step 4: Synthesis of tert-butyl (4-(cyclopropyl amino)-4-hydroxy-3-oxo-l-(pyridin-3-yl) butan-2-yl)carbamate

[0110] To a stirred solution of 3 -((tert-butoxycarbonyl)amino)-l -(cyclopropyl amino)- l-oxo-4-(pyridin-3-yl)butan-2-yl acetate (2.2 g, 5.8 mmol) in MeOH (52 mL) is added K2CO3 (1.2 g, 8.7 mmol) and water (22 mL) at 0° C and the reaction mixture is stirred for at rt for 16 h. Progress of the reaction is monitored by TLC (mobile phase: 50% EtOAc in petroleum ether, visualization:Attorney Docket No. NTG-08-PCTUV active, Rf: 0.14). After consumption of the starting material is confirmed by TLC, the reaction mixture is concentrated under reduced pressure and acidified by 1 N HC1 up to pH 2; the precipitated solid is filtered to afford the crude product (2.2 g) as an off-white solid. The crude compound is triturated in Et2O and pentane and then dried under vacuum to afford the desired product (1.1 g, LCMS: 95%) as an off-white solid. LCMS (ESI) m / z 336.2 [M+H]+. 'H-NMR (400 MHz, DMSO) 5 ppm: 8.35 (t, J=4.4Hz, 2H), 7.78 (t, J=5.8Hz, 1H), 7.57 (dd, J=25.8, 8.2Hz, 1H), 7.30-7.25 (m, 1H), 6.62-6.25 (m, 1H), 5.75-5.50 (m, 1H), 3.90-3.32 (m, 2H), 2.67-2.60 (m, 2H), 2.59-2.49 (m, 1H), 1.26-1.17 (m, 8H), 1.14-1.12 (m, 2H), 0.60-0.49 (m, 2H), 0.45-0.42 (m, 2H).Step 5: Synthesis of 3-amino-l-(cyclopropyl amino)-l-hydroxy-4-(pyridin-3-yl) butan-2-one hydrochloride salt (Int 10)[OHl] To a stirred solution of tert-butyl (4-(cyclopropylamino)-4-hydroxy-3-oxo-l-(pyridin-3-yl) butan-2-yl)carbamate (0.9 g, 2.6 mmol) in DCM (9 mL) is added 4 M HC1 in dioxane (3.3 mL, 13.4 mmol) at 0 °C for 5 min. The resulting solution is stirred at rt for 2 h as the progress of the reaction is monitored by TLC (mobile phase: 10% MeOH in DCM, Rf value: 0.05, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is concentrated under reduced pressure to give crude (1 g) as an off-white solid. The crude is triturated in DCM and Et2O and dried under reduced pressure to afford the desired product (730 mg, 100%) as an off-white solid. LCMS (ESI) m / r. 236.2 [M+H]+.

[0112] Intermediates 11-14 in Table 10 are prepared similarly to Intermediates 9 and 10 above.Table 10.MassIntermediate Structure (ESI)1HNMR (ppm)m / zAttorney Docket No. NTG-08-PCTInt 11 (400Hz, CD3OD) 8 8.86-8.81 (m,?HHHCIH2. NXA^N 1H), 8.63-8.56 (m, 1H), 8.13-8.08236.2(m, 1H), 8.05-8.00 (m, 1H), 4.38- [M+H]4.37 (m, 1H), 4.18-4.16 (m, 1H), a ° +3.66-3.51 (m, 2H), 2.73-2.41 (m, 1H), 0.76-0.66 (m, 4H)Int 12?HHHCIH2229.10[M+H] Not Recorded+Int 13229.10[M+H] Not Recorded HCIHg N^V01"1+cr NH2Int 14?HHH2199.13N.[M+H]Not Recorded+Synthesis of Intermediate 6-chlorochromane-4-carboxylic acid (Int 15)Step 1: Synthesis of 6-chIoro-4-((trimethylsilyl)oxy)chromane-4-carbonitrile

[0113] To a stirred solution of 6-chlorochroman-4-one (14.0 g, 76.7 mmol, 1 eq) in DCM (200 mL) is added zinc iodide (1.2 g, 3.8 mmol, 0.05 eq) and TMSCN (19.8 g, 199.3 mmol, 2.6 eq) at rt. The resulting reaction mixture is stirred for 16 h at rt. The reaction mixture is then dilutedAttorney Docket No. NTG-08-PCTwith water (400 mL) and extracted ethyl acetate (3 x 400 mL). The combined organic layers are washed with saturated aqueous NaHCCh solution (2 x 300 mL) and brine (350 mL), dried over Na2SO4, and evaporated. The product is then triturated with pentane (200 mL), filtered, and dried to afford the desired product as an off-white solid (18.0 g).Step 1: Synthesis of 6-chlorochromane-4-carboxylic acidCl ClSnCI2-2H2O Ol| I OTMS - ‘ - * |l J IIAcOH: HCI (1:1) UN IRacemate

[0114] To a stirred solution of 6-chloro-4-((trimethylsilyl)oxy)chromane-4-carbonitrile (10.0 g, 35.6 mmol, 1 eq) in acetic acid (80 mL) is added concentrated HCI (80 mL) and SnCl2·2H2O (48.2 g, 213.5 mmol, 6 eq) at rt. The resulting reaction mixture is stirred for 36 h at 120 °C. The reaction mixture is diluted with water (500 mL), extracted ethyl acetate (3 x 400 mL), and the combined organic extracts are washed with brine (400 mL), dried over Na2SO4, and evaporated under reduced pressure to obtain crude product. The crude product is purified by MPLC (CombiFlash, orochem 80 g column, elusion gradient 2-4% MeOH in DCM) to obtain the desired product as an off-white solid (4.0 g). LCMS (ESI) m / z 211.0 [M+H]+.Separation of 6-chlorochromane-4-carboxylic acid stereoisomers

[0115] Next, 2.3 g of the racemate undergoes chiral resolution via preparative HPLC (Chiralpak IA column (250 x 20 x 5 pm); mobile phase A 0.1% TFA in hexane; mobile phase B IPA: DCM (90:10); Isocratic A: B (95:5); Flow rate 15 mL / min). The pure fractions are concentrated under reduced pressure to deliver 0.7 g of enantiomer-1 (peak-1, RT 4.3 min) and 1 g of enantiomer 2 (peak-2, RT 4.6 min).Synthesis of Intermediate 6-(3-methyl-lH-pyrazol-l-yl)chromane-4-carboxylic acid (Int 16)Attorney Docket No. NTG-08-PCTStep 1: Synthesis of intermediate 4-(3-methyl-lH-pyrazol-l-yl)phenolHN-NBrOH K2CO3, CuiOH

[0116] To a stirred solution of 4-bromophenol (10.0 g, 58.2 mmol, 1 eq) in toluene (200 mL) is added 3-methylpyrazole (4.8 g, 58.2 mmol, 1 eq), K2CO3 (16.1 g, 116.3 mmol, 2 eq), N, N-dimethylcyclohexane-l,2-diamine (0.8 g, 5.8 mmol, 0.1 eq), and Cui (1.1 g, 5.8 mmol, 0.1 eq) at rt. The resulting reaction mixture is heated to 100 °C for 12 h as progress of the reaction is monitored by TLC. After consumption of the starting material is confirmed by TLC, the reaction is cooled to rt, diluted with water (200 mL), and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts are washed with brine (200 mL), dried over sodium sulphate, and evaporated to dryness under reduced pressure. The resulting crude product is purified by MPLC (CombiFlash, orochem 80 g column, elusion gradient 0-30% EtOAc in hexane) to obtain the desired product (6.0 g). MS (ESI) m / z. 175.3 [M+H]+.Step 2: Synthesis of intermediate 2-(4-(3-methyl-lH-pyrazol-l-yl)phenoxy)acetic acid

[0117] To a stirred solution of 4-(3-methyl-lH-pyrazol-l-yl)phenol (6.0 g, 34.4 mmol, 1 eq) in acetonitrile (100 mL) is added K2CO3 (11.9 g, 86.1 mmol, 2.5 eq) and ethyl 2-chloroacetate (5.1 g, 41.3 mmol, 1.2 eq). The resulting mixture is heated to 60 °C for 4 h as progress of the reaction is monitored by TLC. After consumption of the starting material is confirmed by TLC, the solvent is evaporated under reduced pressure. The crude product is dissolved in THF (30 mL) and MeOH:water (1:1, 30 mL) is added, followed by LiOH (0.7 g, 29.97 mmol, 1.3 eq). The mixture is stirred at rt for 2 h as progress of the reaction is monitored by TLC. After consumption of the starting material is confirmed by TLC, the organic solvents are evaporated under reduced pressure and the resulting aqueous solution is acidified with IM HC1. The productAttorney Docket No. NTG-08-PCTis then extracted with 10% MeOH in DCM (50 mL x 2). The combined organic extracts are dried over Na2SC>4 and evaporated to obtain the desired product (4 g).Step 3: Synthesis of intermediate 6-(3-methyl-lH-pyrazol-l-yl)chromane-4-carboxylic acid

[0118] To a stirred solution of 2-(4-(3-methyl-lH-pyrazol-l-yl)phenoxy)acetic acid (3.0 g, 12.9 mmol, 1 eq) in a mixture of H2O (50 mL), DCE (50 mL), and ACN (50 mL) is added ethyl acrylate (2.8 mL, 25.8 mmol, 2 eq), sodium persulfate (3.1 g, 12.9 mmol, 1 eq), silver nitrate (439 mg, 2.6 mmol, 0.2 eq), and iron(III) citrate nonahydrate (522 mg, 1.3 mmol, 0.1 eq) at rt. The reaction mixture is then stirred at reflux for 8 h as completion of the reaction is monitored by TLC. The reaction mixture is diluted with water (100 mL), extracted ethyl acetate (2 x 100 mL), and the combined organic extracts are washed with brine (100 mL), dried over Na2SC>4, and evaporated. The crude material is purified by MPLC (CombiFlash, Florochem 24 g column, elution gradient 10-15% EtOAc in hexane) to obtained ethyl 6-(3-methyl-lH-pyrazol-l-yl)chromane-4-carboxylate (0.25 g). LCMS (ESI) m / z. 286.9 [M+H]+. This material (0.25 g, 0.9 mmol, 1 eq) is dissolved in THF (10 mL) and MeOH:water (1:1, 10 mL) is added followed by LiOH (27 mg, 1.14 mmol, 1.3 eq). The reaction mixture is then stirred for 2 h at rt as completion of the reaction is monitored by TLC. The organic solvents are evaporated under reduced pressure and the resulting aqueous solution is acidified with 1 M HC1. The mixture is extracted with 10% MeOH in DCM (50 mL x 2). The combined organic extracts are dried over Na2SO4 and evaporated to obtain 0.2 g of the desired product.Synthesis of Intermediate 2-methylchromane-4-carboxylic acid (Int 17)Step 1: Synthesis of 2-methylchroman-4-oneO CH3CHOPyrrolidineEtOH, 75 °C, 16 hAttorney Docket No. NTG-08-PCT

[0119] A mixture of 1 -(2-hydroxyphenyl) ethan-l-one (25 g, 183.6 mmol), acetaldehyde (15.5 mL, 275.4 mmol) in EtOH (250 mL), and pyrrolidine (2.3 mL, 27.5 mmol) is heated at 75 °C for 16 h. Progress of the reaction is monitored by TLC (5% EtOAc in petroleum ether, Rf: 0.29, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is allowed to cool to rt, diluted with water (120 mL), and extracted with EtOAc (3 x 120 mL). The combined organic layers are washed with saturated NaCl (2 x 60 mL), dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure to afford the crude product (28.5 g) as a pale yellow gum. The crude residue is pre-adsorbed onto silica gel (230-400 mesh) and purified by normal-phase flash column chromatography with a 0-20% EtOAc in petroleum ether gradient. The collected pure fractions (determined by TLC) are concentrated under reduced pressure to afford the desired product (6.5 g) as a pale yellow liquid. LCMS (ESI) m / z: 163.25 [M+H]+. 'H NMR (400 MHz, CDCl3) 5 ppm: 7.89-7.87 (m, 1H), 7.49-7.45 (m, 1H), 7.02-6.95 (m, 2H), 4.62-4.57 (m, 1H), 2.69 (t, 2H), 1.53 (t, 3H).Step 2: Synthesis of 2-methyl-4-((trimethylsilyl)oxy)chromane-4-carbonitrile? TMSO ON TMSCN, Znl2L / LDCM, 0 °C-RT, 16 h 1 JL JL

[0120] To a stirred solution of 2-m ethyl chroman-4-one (1.4 g, 8.6 mmol, 1 eq) in DCM (20 mL) at 0 °C under a nitrogen atmosphere is added ZnI2(0.1 g, 0.4 mmol, 0.05 eq) portion wise. After 60 min, TMSCN (4.3 mL, 34.5 mmol, 4 eq) is added dropwise. The resulting reaction mixture is stirred at rt for 16 h. Progress of the reaction is monitored by TLC (20% EtOAc in petroleum ether, visualization: UV active, Rf: 0.41). Upon completion of the reaction, the mixture is allowed to cool to rt, quenched with water (20 mL), and extracted with DCM (2 x 30 mL). The combined organic layers are dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford the crude product (2.2 g, 97%) as a brown gum. LCMS (ESI) m / z: 262.10 [M+H]+. 'H NMR (400 MHz, CDCl3) 8 ppm: 7.52-7.50 (m, 1H), 7.25-7.21 (m, 1H), 7.00-6.96 (m, 1H), 6.82-6.80 (dd,lH), 4.51-4.46 (m, 1H), 2.49-2.45 (dd, 1H), 2.14-2.04 (dd, 1H), 1.47 (t, 3H), 0.34 (s, 9 H).Step 3: Synthesis of 2-methylchromane-4-carboxylic acidAttorney Docket No. NTG-08-PCTCOOHSnCI2AcOH, HCI120 °C, 40 h

[0121] A mixture of 2-methyl-4-((trimethylsilyl)oxy)chromane-4-carbonitrile (2.2 g, 8.4 mmol, 1 eq) and SnCh (5.7 g, 25.2 mmol, 3 eq) in a blend of AcOH (8.8 mL) and 37% HCI (8.8 mL) is heated at 120 °C for 40 h. Progress of the reaction is monitored by TLC (10% EtOAc in petroleum ether, Rf: 0.1, visualization: UV active). The reaction mixture is evaporated under reduced pressure to remove AcOH and dissolved in DCM (50 mL), washed with saturated NaCl solution (50 mL), washed with saturated brine solution (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford (2.2 g) of crude material. This material is purified by Combi-flash normal-phase column chromatography using a 25 g silica gel column with 3-30% EtOAc in pet ether as the gradient. The collected fractions are concentrated under reduced pressure to afford the desired product (0.71 g, yield: 43.89 %), a mixture of isomers, as an off-white solid. LCMS (ESI): m / z: 193.08 [M+H]+.Synthesis of Intermediate 2-methylchromane-4-carboxylic acid (Int 18)Step 1: Synthesis of methyl chromane-4-carboxylateCOOH COOMeSOCI2, MeOHReflux, 12 h

[0122] To a stirred solution of chromane-4-carboxylic acid (3 g, 16.8 mmol, 1 eq) in MeOH (60 mL) is added SOCI2 (3.7 mL, 50.5 mmol, 3 eq) and heated to reflux temperature for 12 h. The progress of the reaction is monitored by TLC (20% EtOAc / petroleum ether, Rf: 0.61, visualization: UV active). The reaction mixture is concentrated under reduced pressure, diluted with water (50 mL), and extracted with EtOAc (2 x 50 mL). The organic layer is dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product (3.8 g). This residue is purified by Combi-flash normal-phase column chromatography using a silica gel (100-200 mesh) column with 3-20% EtOAc in petroleum ether as the gradient. The collected pure fractions are concentrated under reduced pressure to afford the desired product (3.1 g, 94%) as a pale yellow liquid. LCMS (ESI) m / z: 193.15 [M+H]+. 'H NMR (400Attorney Docket No. NTG-08-PCTMHz, CDCl3) δ ppm: 7.26-7.23 (m, 1H), 7.18-7.14 (m, 1H), 6.90-6.83 (m, 2H), 4.31-4.22 (m, 2H), 3.79 (t, J = 5.0 Hz, 1H), 3.74 (s, 3H), 2.36-2.30 (m, 1H), 2.16-2.10 (m, 1H).Step 2: Synthesis of methyl 4-methylchromane-4-carboxylateCOOMeMe| COOMeKOtBu YY lQJ THF, 0°C-RT, 3 h

[0123] To a stirred, cooled (0 °C) solution of methyl chromane-4-carboxylate (2 g, 10.4 mmol, 1 eq) in THF (40 mL) is added KOtBu (2.3 g, 20.8 mmol, 2 eq). After 10 min, Mel (0.7 mL, 11.4 mmol, 1.1 eq) is added and stirred at rt for 3 h. The progress of the reaction is monitored by TLC (mobile phase 20% EtOAc in hexane. Rf: 0.54, Visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is quenched with saturated NH4CI solution and extracted with (3 x 20 mL) of EtOAc. The combined organic layers are washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to afford the crude product (1.2 g) as a yellow liquid. The crude material is purified by Combi-flash normal-phase column chromatography using a silica gel (100-200 mesh) column with 0-30% EtOAc in petroleum ether as the gradient. The collected fractions are concentrated under reduced pressure to afford the desired product (900 mg, 42%) as a pale yellow liquid. LCMS 77.4%, MS (ESI) m / z 207.22 [M+H]+. 'HNMR (400 MHz, CDCl3) δ ppm: 7.32 (dd, J=8.0, 1.6 Hz, 1H), 7.16-7.12 (m, 1H), 6.92-6.88 (m, 1H), 6.82 (dd, J = 8.4, 1.2 Hz, 1H), 4.24-4.20 (m, 2H), 3.69 (s, 3H), 2.54-2.48 (m, 1H), 1.91-1.84 (m, 1H), 1.61 (s, 3H).Step 3: Synthesis of 4-methylchromane-4-carboxylic acidCOOMe COOHLiOH. H2OrAAMeOH, THF, H2O^ XTvRT, 16 h

[0124] To a stirred solution of methyl 4-methylchromane-4-carboxylate (900 mg, 4.4 mmol, 1 eq) in a mixture of THF (6.0 mL), water (6 mL), and MeOH (6 mL) is added LiOH·H2O (915.6 mg, 21.8 mmol, 5 eq) at 0 °C. The resulting reaction mixture is stirred for 16 h at rt. The progress of the reaction is monitored by TLC (mobile phase 20% EtOAc in hexane. Rf: 0.1, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixtureAttorney Docket No. NTG-08-PCTis neutralized with 1 N HC1 (10 mL) and extracted with (2 x 50 mL) of EtOAc. The combined organic layers are washed with brine solution, dried over Na2SC>4, and concentrated under reduced pressure to afford the desired product (650 mg, 77%) as a yellow liquid. LCMS (ESI) m / z:'z. 190.91 [M+H]'. 'H NMR (400 MHz, CDCk) 5 ppm: 7.37 (dd, J=7.6, 1.6 Hz, 1H), 7.18-7.14 (m, 1H), 6.93-6.89 (m, 1H), 6.83 (dd, J=8.4, 1.2 Hz, 1H), 4.29-4.18 (m, 2H), 2.53-2.47 (m, 1H), 1.94-1.87 (m, 1H), 1.63 (s, 3H).

[0125] Intermediates 19-25 in Table 11 are prepared similarly to Intermediates 15-18 above. Table 11.MassIntermediate Structure (ESI)JH NMR (ppm)m / zInt 19 O^OH (400 MHz, DMSO-de) 6 ppm: 12.76 (s, 1H),194.4 7.04-6.96 (m, 2H), 6.81-6.77 (m, 1H), 4.21-4.09 [M+H]+(m, 1H), 4.09-4.06 (m, 1H), 3.77 (t, J=5.2 Hz, I 1 J1H), 2.50-2.14 (m, 1H), 2.06-1.98 (m, 1H) Int 20 O^OH (400 MHz, DMSO-d6) 5 ppm: 12.74 (s, 1H),7.23 (d, J=8.4 Hz, 1H), 6.92 (dd, J=8.2, 2.2 Hz, 210.95MLI 1H), 6.86 (d, J=2.0 Hz, 1H), 4.24-4.24 (m, 1H),[M+H]+4.13-4.08 (m, 1H), 3.75 (t, J=5.2 Hz, 1H), 2.19- 2.15 (m, 1H), 2.05-2.01 (m, 1H)Int 21 CK / OH (400 MHz, CDCl3) 8 ppm: 7.23-7.21 (m, 1H),195.01 6.74-6.72 (m, 1H), 6.57-6.55 (m, 1H), 4.25-4.23 [M+H]+(m, 2H), 3.77 (t, >4.4 MHz, 2H), 2.34-2.32 (m,1H), 2.15-2.13 (m, 1H)Int 22 O^OH (400 MHz, CDCl3) δ ppm: 7.26 (d, J=2.8 Hz,1H), 7.16 (t, >3.6 Hz, 1H), 6.87 (t, >3.8 Hz, 207.11H), 6.81 (d, >1.2 Hz, 1H), 3.92-3.88 (m, 1H), [M+H]+2.29-2.23 (m, 1H), 2.13-2.05 (m, 1H), 1.42 (s, 3H), 1.29 (s, 3H)Attorney Docket No. NTG-08-PCTInt 23 O^OH (400 MHz, DMSO-de) 8 ppm: 7.30 (d, J=7.6 Hz, 1H), 7.19 (d, J=8.0, 1 Hz), 6.87 (dd, J=8.0, 211.1C JO 7.6 Hz, 1H), 4.33 (m, 1H), 4.18 (m, 1H), 3.83[M+H]+(m, 1H), 2.22 (m, 1H), 2.07 (m, 1H)ClInt 24 (400 MHz, DMSO-de) 8 ppm: 12.74 (s, 1H),°MHci7.16 (t, J=8.2 Hz, 1H), 7.00 (dd, J=8.0, 1.2 Hz, 210.98MM 1H), 6.81 (dd, J=8.4, 0.8 Hz, 1H), 4.29-4.25 (m,[M+H]+1H), 3.98-3.92 (m, 1H), 3.83-3.81 (m, 1H), 2.20-2.15 (m, 2H)Int 25 O^OH (400 MHz, DMSO-de) 8 ppm: 10.79 (bs, 1H),7.28-7.26 (m, 1H), 7.19-7.15 (m, 1H), 6.91-6.86 C JQ 177.03(m, 1H), 6.85-6.83 (m, 1H), 4.29-4.24 (m, 2H), [M+H]+3.82-3.80 (m, 1H), 2.36-2.30 (m, 1H), 2.19-2.10 (m, 1H)Resolution of chromane-4-carboxylic acid stereoisomers (Int 25(1?) and Int 25(5))COOH

[0126] (7?)-l-phenylethan-l-amine (6.8 g, 56.1 mmol, 1 eq) is added to a solution of chromane-4-carboxylic acid (Int 25, 10 g, 56.1 mmol, 1 eq) in EtOH (40 mL). The reaction mixture is heated at 80-85 °C and stirred for 1 h at the same temperature. The reaction mixture is cooled to 25-30 °C and stirred for 4 h. 5 mL of solvent is removed by distillation under reduced pressure and the resulting solid is collected by filtration and dried under reduced pressure (4 g). EtOH (30 mL) is added to the above compound at 25-30 °C and stirred at 80-85 °C for 2 h. The reaction mixture is cooled to 25-30 °C and stirred for 2 h. 1 mL of solvent is removed under reduced pressure and the precipitated solid is collected by filtration, washed with EtOH, and dried to afford the target compound (3 g) as the (A)-phenethylamine salt. The salt is dissolved in EtOAc (200 mL) and washed with a 1% citric acid (100 mL) solution. The combined organic fractionsAttorney Docket No. NTG-08-PCTare dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (5)-chromane-4-carboxylic acid as a colorless gum liquid (1.9 g, 19%). MS (ESI): 179.38 [M+H]+; Chiral SFC (CHIRALPAK AD-H (250 mm x 4.6 x 0.5 pM), 15% (0.5% DEA in MeOH), 85% CO2, RT: 3.54 min 95.7%. 'H NMR (400 MHz, DMSO-d6) 8 ppm: 10.79 (bs, 1H), 7.28-7.26 (m, 1H), 7.19-7.15 (m, 1H), 6.91-6.86 (m, 1H), 6.85-6.83 (m, 1H), 4.29-4.24 (m, 2H), 3.82-3.80 (m, 1H), 2.36-2.30 (m, 1H), 2.19-2.10 (m, 1H).COOH1% Citric acid workup

[0127] (A)-chromane-4-carboxylic acid is resolved similarly to that described for the ( )-chromane-4-carboxylic acid using (S)-l -phenyl ethan-1 -amine. MS (ESI): 177.03 [M+H]', 'H NMR (400 MHz, DMSO-^ 8 ppm: 7.28 (d, J=8.0 Hz, 1H), 7.15 (t, 0.8 Hz, 1H), 6.91-6.83 (m, 2H), 4.30-4.23 (m, 2H), 3.83-3.81 (m, 1H), 2.37 - 2.31 (m, 1H), 2.20 - 2.14 (m, 1H).Confirmation of absolute stereochemistryCOOH BH3. THF THF, 0°C-RT, 16 hBH3. THFTHF, 0°C-RT, 16 h

[0128] To a stirred solution of (S)-chromane-4-carboxylic acid (0.2 g, 1.1 mmol, 1 eq) in THF (2 m ) at 0 °C under nitrogen atmosphere is added borane’THF complex solution (1 M in THF, 3.3 mb, 3.4 mmol, 3 eq) at 0 °C and the reaction mixture is stirred for 16 h at rt. The progress of the reaction is monitored by TLC (30% EtOAc in petroleum ether, Rf: 0.45, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is cooled to 0 °C and quenched with MeOH (5 mL). The MeOH is removed under reduced pressure and the residue is dissolved in ice water (15 mL). The mixture is extracted with EtOAc (2 x 15 mL) and the combined organic layers are washed with saturated brine solution, dried overAttorney Docket No. NTG-08-PCTanhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford the crude product (0.25 g). The crude product is purified by combi-flash chromatography using a silica gel (100-200 mesh) column with 20-50% EtOAc / petroleum ether as the gradient to afford (S)-chroman-4-ylmethanol (0.13 g, 70 %) as a colorless liquid. LCMS (ESI): 165.20 [M+H]+. 'H NMR (400 MHz, CDCl3) 8 ppm: 7.25-7.10 (m, 2H), 6.89-6.81 (m, 2H), 4.20-4.18 (m, 2H), 3.91-3.87 (m, 1H), 3.82-3.75 (m, 1H), 3.02-2.96 (m, 1H), 2.10-2.05 (m, 2H). SOR: -11.55° (c=1.2, CHCh) and matched with reference SOR data = -10.1° (c=0.8, CHCI3).Synthesis of Intermediate l-(2,3-dihydro-lH-inden-5-yl)-5-oxopyrrolidine-3-carboxylic acid (Int 26)

[0129] To 2,3-dihydro-lH-inden-5-amine (0.5 g, 3.8 mmol, 1 eq) is added 2-methylenesuccinic acid (0.5 g, 3.8 mmol, 1 eq) at rt. The reaction mixture is stirred at 130 °C in a sealed tube for 16 h as the progress of the reaction is monitored by TLC. After 16 h, 10% NaOH solution (20 mL) is added to the reaction mixture and the aqueous solution is then washed with EtOAc (2X30 mL). The aqueous phase is acidified with 1 N HC1 to pH ~4 and the desired product precipitates out as a solid, which is filtered and dried under vacuum to afford 0.7 g of the desired product. LCMS (ESI)mzz: 243.9 [M+H]+.chromane-4-carboxylic acid stereoisomers

[0130] Commercially available (±)-ethyl chromane-4-carboxylate undergoes chiral resolution via preparative HPLC (Chiralpak IC column (250 x 20 x 5 pm); mobile phase A 0.1% DEA inAttorney Docket No. NTG-08-PCThexane; mobile phase B IPA: DCM (90:10); Isocratic A: B (95:5); Flow rate 15 mL / min). The pure fractions ae concentrated under reduced pressure to deliver 0.16 g of enantiomer- 1 (peak-1, RT 4.868 min) and 0.17 g of enantiomer 2 (peak-2, RT 6.131 min).

[0131] To the stirred solution of optically pure ethyl chromane-4-carboxylate (peak-1, RT 4.868 min), (0.16 g, 0.8 mmol, 1 eq) in THF: MeOH: water (2:2:1, 10 mL) is added LiOH. FBO (0.1 g, 2.3 mmol, 3 eq) at 25-30 °C. The reaction mixture is stirred at rt for 1 h as progress of the reaction is monitored by TLC. Solvents are evaporated under reduced pressure and the reaction mixture is then diluted with water (50 mL) and extracted with EtOAc (25 mL). The aqueous phase is acidified to pH 3 with IN HCL and then extracted with EtOAc (2 x 50 mL). The combined organic extracts are washed with brine and dried over anhydrous Na2SO4 to obtain stereoisomer- 1 of chromane-4-carboxylic acid (0.12 g). Mass (ESI) m / z'. 177.1 [M]’

[0132] Stereoisomer-2 of chromane-4-carboxylic acid is prepared from optically pure ethyl chromane-4-carboxylate (peak-2, RT 6.131 min), (0.17 g, 0.8 mmol, 1 eq) following a similar procedure (0.12 g). Mass (ESI) m / z \T1.1 [M]’Example 1: N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)-6-chlorochromane-4-carboxamide Step 1: Synthesis of N-(4-amino-3-hydroxy-4-oxo-l-phenylbutan-2-yl)-6-chlorochromane-4-carboxamide

[0133] To a stirred solution optically pure 6-chlorochromane-4-carboxylic acid (peak-1) (1.9 g, 8.96 mmol, 1 eq) in DMF (40 mL) at rt is added DIPEA (9.4 mL, 53.8 mmol, 6 eq) and HATU (5.1 g, 13.4 mmol, 1.5 eq) and the mixture is stirred for 30 min. To this mixture is added 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride (2.5 g, 10.8 mmol, 1.2 eq) and the reaction mixture is stirred at rt for 16 h as progress of the reaction is monitored by TLC. After consumption of the starting material is confirmed by TLC, chilled water (300 mL) is added and the reaction is stirred for 20 mins. The precipitate is filtered and dried under reduced pressure to obtain desired product (1.9 g) as a mixture of diastereomers. LCMS (ESI) m / . 389.1 [M+H]+.Attorney Docket No. NTG-08-PCTStep 2: Synthesis of \-(4-aniino-3.4-dioxo-l-phenylbiitan-2-yl)-6-chlorochroinane-4-carboxamide

[0134] To a stirred solution of N-(4-amino-3 -hydroxy -4-oxo-l -phenylbutan-2 -yl)-6-chlorochromane-4-carboxamide (1.3 g, 3.3 mmol, 1 eq) in DCM cooled to 0 °C is added DMP (3.6 g, 8.4 mmol, 2.5 eq). The resulting mixture is stirred for 3 hours at rt as progress of the reaction is monitored by TLC. After consumption of the starting material is confirmed by TLC, the reaction mixture is diluted with DCM (300 mL) and washed with aqueous Na2S20s (sodium thiosulphate solution) (150 mL), saturated aqueous NaHCCL (200 mL), and brine (200 mL). The organic phase is dried over Na2SC>4 and evaporated under reduced pressure. The resulting crude product is washed with Et2O and dried under vacuum to deliver an off-white solid (0.65 g) of the desired product as a mixture of diastereomers.JH NMR (DMSO-de, 400 MHz) 8 ppm: 8.72-8.66 (m, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.32-7.22 (m, 6H, (excess of protons due to diastereomers)), 7.15-7.09 (m, 2H), 6.82-6.73 (m, 2H), 5.26-5.19 (m, 1H), 4.27-4.03 (m, 3H), 3.74-3.69 (m, 1H), 3.21-3.16 (m, 1H), 2.81-2.74 (m, 1H), 1.96-1.83 (m, 2H). LC-MS (ESI) w / z: 387.1 [M+H]+. Example 2: N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)chromane-3-carboxamideStep 1: Synthesis of N-(4-amino-3-hydroxy-4-oxo-l-phenylbutan-2-yl)chromane-3-carboxamideOH

[0135] To a stirred solution of chromane-3 -carboxylic acid (231.7 mg, 1.3 mmol, 1 eq) in DMF (10 mL) is added DIPEA (0.7 mL, 3.9 mmol, 3 eq), followed by EDC-HC1 (299.2 mg, 1.6Attorney Docket No. NTG-08-PCTmmol, 1.2 eq), HOBt (210.9 mg, 1.6 mmol, 1.2 eq), and 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride (300 mg, 1.3 mmol, 1 eq) at 0 °C. The resulting reaction mixture is stirred at rt for 16 h. The reaction progress is monitored by TLC (mobile phase 10% MeOH in DCM, Rf value 0.47, Visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is diluted with ice-cold water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers are washed with saturated NaCl solution (50 mL) and NaHCCL solution (20 mL). The organic layer is separated, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford the crude product (400 mg) as a yellow gum. The crude residue is pre-adsorbed onto silica gel (100-200 mesh) and purified by normal-phase flash column chromatography (80% EtOAc in petroleum ether). The pure fractions containing the desired product (determined by TLC) are combined and concentrated under reduced pressure to afford the desired product (250 mg, 54%) as an off-white solid. LCMS (ESI) m / z: 355.1 [M+H]+.Step 2: Synthesis of N-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)chromane-3-carboxamide

[0136] To a stirred solution of N-(4-amino-3-hydroxy-4-oxo-l-phenylbutan-2-yl)chromane-3-carboxamide (200 mg, 0.6 mmol, 1 eq) in DCM (10 mL) is added DMP (97%, 718.1 mg, 1.7 mmol, 3 eq) portion wise at 0 °C. The resulting reaction mixture is stirred at the same temperature for 2 h. The progress of the reaction is monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.56, visualization: UV active). After consumption of the starting material is confirmed by TLC, the reaction mixture is quenched with a saturated solution of Na2S20a (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers are washed with a saturated solution of NaHCOs (3 x 100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product (180 mg). The crude residue is pre-adsorbed onto silica gel (100-200 mesh) and purified on normal-phase flash column chromatography (80% EtOAc in DCM). The pure fractions containing the desired product (determined by TLC) areAttorney Docket No. NTG-08-PCTcombined and concentrated under reduced pressure to afford crude material (90 mg, LCMS: 84%) as an off-white solid. The crude material is triturated by EtzO (10 mL) to afford the desired product (44.5 mg, 22%) as an off-white solid. LCMS (ESI) m / z'. 353.13 [M+H]+.JH NMR (400 MHz, DMSO-de) 8 ppm: 88.59-8.57 (m, 1H), 8.06 (s, 1H), 7.82 (s, 1H), 7.33-7.22 (m, 5H), 7.10-7.04 (m, 2H), 6.84-6.81 (m, 1H), 6.76-6.72 (m, 1H), 5.26-5.20 (m, 1H), 4.26-4.07 (m, 1H), 3.81-3.66 (m, 1H), 3.18-3.14 (m, 1H), 2.87-2.67 (m, 4H).Examples 3-9

[0137] Table 12 shows representative examples of compounds of Formula I prepared from intermediate 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride or (27?,3 )-3-amino-2-hydroxy-4-phenylbutanamide hydrochloride and the appropriate substituted chromane-4-carboxylic acid according to the described procedures used for Examples 1 and 2 and procedures described herein. CMITable 12. _ zEx. < n° Mass1H NMR (ppm)Structure\ / N-o=No. (ESI) z (400 MHz, DMSO-de)3 ZI 88.66 (d, J=8.0 Hz, 1H), 8.11 (bs, 1H),^ o=7.86 (bs, 1H), 7.34-7.21 (m, 5H), 7.07- / \ge7.01 (m, 1H), 6.74-6.59 (m, 3H), 5.25- 353.35\ / ° 5.20 (m, 1H), 4.27-4.22 (m, 1H), 4.06- [M+H]+4.03 (m, 1H), 3.72-3.67 (m, 1H), 3.23 - 3.16 (m, 1H), 2.81 -2.73 (m, 1H), 2.00- 1.85 (m, 2H)4 88.66 (d, J=8.0 Hz, 1H), 8.11 (bs, 1H), o 7.85 (bs, 1H), 7.34-7.19 (m, 5H), 7.08- (A^l O ( O 7.01 (m, 1H), 6.73-6.58 (m, 3H,), 5.25- 352.95LX A 1 A 5.20 (m, 1H), 4.27-4.22 (m, 1H), 4.06- Ywf N ITNH2 [M+H]+o / dH0 4.00 (m, 1H), 3.70-3.67 (m, 1H), 3.23- 3.16 (m, 1H), 2.81-2.65 (m, 1H), 1.95- 1.86 (m, 2H)Attorney Docket No. NTG-08-PCT88.60 (d, J=7.2 MHz, 1H), 8.07 (s, o 1H), 7.83 (bs, 1H), 7.32-7.21 (m, 5 H), 0 Z O 7.10-7.03 (m, 2H), 6.82-6.78 (m, 1H), Ol X A AN'W'rf 'NHj 353.27 6.72 (d, J=8.4 MHz, 1H), 5.26-5.20 (m,H0 [M+H]+1H), 4.18-4.14 (m, 1H), 4.03-3.98 (m,1H), 3.70 (t, J=12.0 MHz, 1H), 3.20- 3.15 (m, 1H), 2.82-2.76 (m, 1H), 1.88- 1.85 (m, 2H)88.62 (d, J=7.6 MHz, 1H), 8.07 (s, 1 1H), 7.83 (s, 1H), 7.34-7.27 (m, 5 H), ° T Ar AH27.14-7.07 (m, 1H), 6.87-6.80 (m, 1H), N^Xg^NH XX353.2 6.78-6.75 (m, 2H), 5.24-5.20 (m, 1H),0[M+H]+4.27-4.21 (m, 1H), 4.06-4.01 (m, 1H), O 3.69 (t, J=12.0 MHz, 1H), 3.31-3.25 (m, 1H), 2.71-2.63 (m, 1H), 1.96-1.95 (m, 2H)88.60 (d, J=7.6 MHz, 1H), 8.07 (s, O^J^j 1 1H), 7.83 (bs, 1H), 7.32-7.29 (m, 2H), ° i Ar A^N^JA^NH 7.27-7.21 (m, 3H), 7.11-7.03 (m, 2H),XA353.27 6.82-6.80 (m, 1H), 6.73-6.68 (m, 1H), [M+H]+5.26-5.20 (m, 1H), 4.19-4.14 (m, 1H), X 4.03-3.97 (m, 1H), 3.70 (t, 1H), 3.22- 3.15 (m, 1H), 2.82-2.76 (m, 1H), 1.88- 1.83 (m, 2H)Attorney Docket No. NTG-08-PCT8 88.60 (d, J=7.2 MHz, 1H), 8.07 (s,O\ 1H), 7.83 (bs, 1H), 7.32-7.21 (m, 5 H),01 |] 7.10-7.03 (m, 2H), 6.82-6.78 (m, 1H),Not 6.72 (d, J=8.4 MHz, 1H), 5.26-5.20 (m, Recorded 1H), 4.18-4.14 (m, 1H), 4.03-3.98 (m, ° b 1H), 3.70 (t, J=12.0 MHz, 1H), 3.20- 3.15 (m, 1H), 2.82-2.76 (m, 1H), 1.88- 1.85 (m, 2H)9 88.59-8.57 (m, 1H), 8.06 (s, 1H), 7.82- 7.76 (m, 1H), 7.33-7.14 (m, 5H), 7.10- 0353.13 7.00 (m, 2H), 6.84-6.79 (m, 1H), 6.76- 1 II 1 H 1 [M+H]+6.70 (m, 1H), 5.26-5.20 (m, 1H), 4.26- cr NH24.07 (m, 1H), 3.82-3.65 (m, 1H), 3.18- 3.15 (m, 1H), 2.87-2.50 (m, 4H)Examples 10-22

[0138] Table 13 shows representative examples of compounds of Formula I prepared from intermediate 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride and the appropriate substituted chromane-4-carboxylic acid according to the described procedures used for Examples 1 and 2 and procedures described herein.Table 13.MassEx.1H NMR (ppm)Structure (ESI)No. (400 MHz, DMSO-d6)m / z10 88.67-8.62 (m, 1H), 8.07 (bs, 1H),7.82 (d, 1H), 7.35-7.23 (m, 5 H), H2N^ A.•,bNH XACI387.1 6.88-6.67 (m, 3H), 5.25-5.19 (m,[M+H]+1H), 4.28-4.04 (m, 2H), 3.70-3.660b (m, 1H) 3.23-3.15 (m, 1H), 2.81-2.73(m, 1H), 1.97 (d, 2H)Attorney Docket No. NTG-08-PCT58.65-8.59 (m, 1H), 8.05 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.44-7.22 (m, 5H), 7.14-7.09 (m, 1H), 6.92-6.86 387.1 (m, 1H), 6.76-6.72 (m, 1H), 5.20-0[M+H]+5.15 (m, 1H), 4.19-3.81 (m, 2H), X J 3.80-3.75 (m, 1H), 3.32-3.15 (m,1H), 2.83-2.72 (m, 1H), 2.10-1.91 (m, 2H)58.62-8.6 (m, 1H), 8.06 (s, 1H), 7.81 (d, J=9.6 MHz, 1H), 7.34-7.24 (m, 5 H2N_A °o,rNHSA H), 7.08-6.46 (m, 3H), 5.22-5.21 (m,371.1 1H), 4.16-4.15 (m, 1H), 4.06-4.04 [M+H]+(m, 1H), 3.76-3.75 (m, 1H), 3.17-0So 3.15 (m, 1H), 2.79-2.77 (m, 1H),1.94-1.92 (m, 1H), 1.84-1.82 (m, 1H)58.01 (d, J=6.8Hz, 1H), 7.99-7.98 A^f°° (m, 1H), 7.4-7.00 (m, 8H), 6.85-6.70 0.^ (m, 2H), 5.19-5.09 (m, 1H), 4.09- HN JL^NH; 367.224.05 (m, 1H), 3.88 (t, J=9.0 Hz, 1H), [M+H]+3.14-3.09 (m, 1H), 2.89-2.83 (m, cr01H), 2.33-2.23 (m, 1H), 1.72-1.65 (m, 1H), 1.40 (d, J=3.6 Hz, 3H) 58.73-7.84 (m, 2H), 7.38-6.99 (m, » <o 7H), 6.65-6.10 (m, 3H), 5.35-4.39381.33 (m, 1H), 3.68-3.65 (m, 1H), 3.17- [M+H]+ 3.08 (m, 1H), 2.78-2.67 (m, 1H), Y jj 0^NH21.87-1.78 (m, 2H), 1.34 (d, J=15.2 Hz, 3H), 1.13 (d, J=14.8 Hz, 3H)Attorney Docket No. NTG-08-PCT58.78-8.73 (m, 1H), 8.12 (d, J=7.6 „ X* Hz, 1H), 7.86 (d, J=5.2Hz, 1H), 7.39- 7.24 (m, 5H), 6.80-6.55 (m, 4H), 381.15.36-5.33 (m, 1H), 3.76-3.72 (m, [M+H]+H< A H21H), 3.33-3.17 (m, 1H), 2.83-2.71 (m, 1H), 1.87-1.77 (m, 2H), 1.35 (s, 3H), 1.15 (s, 3H)58.60 (d, J=7.6 Hz, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.33-7.29 (m, 2H), 7.25-7.21 (m, 3H), 7.04 (t, J=7.6 Hz, <j i\ri2 1H), 6.66 (t, J=4.4 Hz, 1H), 6.59 (dd,371.1 J=10.6, 2.6 Hz, 1H), 5.25-5.20 (m, [M+H]+1H), 4.19-4.14 (m, 1H), 4.06-4.02 (m, 1H), 3.66 (t, J=6.0 Hz, 1H), 3.16 (d, J=3.2 Hz, 1H), 2.77 (d, J=10.0 Hz, 1H), 1.83 (t, J=4.8 Hz, 2H)F5 8.64-6.34 (m, 11H), 5.25-5.20 (m, V 1H), 4.19-4.14 (m, 1H), 4.06-4.02 Y Cki<0fj'W 371.12 (m, 1H), 3.66 (t, J=6.0 Hz, 1H), 3.16[M+H]+(d, J=3.2 Hz, 1H), 2.77 (d, J=10.0 yHCT NH2Hz, 1H), 1.83 (t, J=4.8Hz, 2H)88.23 (d, J=9.6 Hz,lH), 7.71 (bs, 1H), 7.51 (bs, 1H), 7.29-7.17 (m, 5H), 6.89-6.83 (m, 2H), 6.74-6.71 <yB& 371.20 (m, 1H), 5.27-5.19 (m, 1H), 4.18- [M+H]+4.12 (m, 1H), 4.03-3.982 (m, 1H),3.72 (t, J=6.0 Hz, 1H), 3.23-3.17 (m, 1H), 2.88-2.82 (m, 1H), 2.00-1.87 (m, 2H)Attorney Docket No. NTG-08-PCT58.69-8.53 (m, 1H), 8.09-8.04 (m, o4o—# 1H), 7.84-7.79 (m, 1H), 7.35-7.21 \ / g o >3 (m, 5 H), 7.09-6.66 (m, 4H), 5.22- 367.13o / \ 5.42 (m, 1H), 4.05-3.67 (m, 1H),HNH2[M+H]Y J OX+° — \ 3.65-3.16 (m, 1H), 2.82-2.79 (m, / \ IZ - O w 1H), 2.54-2.50 (m, 1H), 1.93-1.75;<• (m, 2H), 1.32-1.20 (m, 4H)4 O A Z / / A I ' ' o KJ - 58.65 (d, J=6.8Hz, 1H), 8.10 (s, 1H),7.81 (s, 1H), 7.34-7.09 (m, 7H), 6.82 (s, 1H), 6.73 (d, J= 7.6 Hz, 1H), 387.125.25-5.20 (m, 1H), 4.29-4.03 (m, [M+H]+2H), 3.71 (t, J=5.8Hz, 1H), 3.17 (d, J=3.6 Hz, 1H), 2.75 (t, J=7.0 Hz, 1H), 1.87 (q, J=12.3 Hz, 2H)88.65 (d, J=8.0 Hz, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.39 (d, J=8.4Hz, 2H), 7.30 (d, J=8.4Hz, 2H), 7.03 (t, J=4.2Hz, 1H), 6.71-6.64 (m, 2H), 387.16.55 (d, J=13.6 Hz, 1H), 5.24-5.18 [M+H]+(m, 1H), 4.28-4.22 (m, 1H), 4.07- 4.02 (m, 1H), 3.66 (t, J=5.8 Hz, 1H), 3.18- 3.12 (m, 1H), 2.74 (t, J=6.8Hz, 1H), 1.95 (d, J=1.6 Hz, 2H)Q 88.32-8.48 (m, 1H), 8.03-8.06 (m,1H), 7.91 (d, J=2.1 Hz, 1H), 7.82 (bs, \ / H / C / 1H), 7.58 (bs, 1H), 7.38-7.43 (m, H. H 433.70 2H), 7.14-7.21 (m, 6H), 6.76-6.79 / - U J |\k 3 'J [M+H]+(m, 1H), 6.24 (s, 1H), 5.17-5.24 (m, Q~—( y1H), 4.03-4.28 (m, 4H), 3.74-3.78 ^H21(m, 1H), 2.82-2.87 (m, 1H), 2.64- 2.71 (m, 1H), 2.24 (d, J = 1.2 Hz,Attorney Docket No. NTG-08-PCT4H), 1.90-1.99 ppm (m, 2H), excess of protons due to diastereomersExamples 23-30

[0139] Table 14 shows representative examples of compounds of Formula I prepared from the appropriate intermediate from Table 9 and the appropriately substituted chromane-4-carboxylic acid from Table 11 according to the procedures described in Examples 1 and 2 and procedures described herein.Table 14.MassEx.rH NMR (ppm)Structure (ESI)No. (400 MHz, DMSO-de)m / z23 88.79-8.69 (m, 2H), 7.37-7.22 (m, 5 H),XI 7.09-6.99 (m, 1H), 6.79-6.39 (m, 3H),H5.33-5.24 (m, 1H), 3.81-3.71 (m, 1H),395.23.28-3.16 (m, 1H), 2.89-2.71 (m, 1H), [M+H]+2.69-2.66 (m, 3H), 1.90-1.70 (m, 2H),01.35-1.31 (m, 3H), 1.14 (s, 3H)24 88.96-8.94 (m, 1H), 8.76-8.69 (m, 1H),7.33-7.21 (m, 5H), 7.15-7.08 (m, 1H), 6.83-6.78 (m, 2H), 5.21-5.08 (m, 1H), NH^k^NH 439.174.28-4.2, 2 (m, 2H), 4.10-4.07 (m, 1H), [M+H]+3.72-3.70 (m, 1H), 3.20-3.16 (m, 1H),0Sy12.81-2.75(m, 1H), 2.11-2.03(m, 4H), 1.93-1.91(m, 2H), 1.65-1.60 (m, 2H)Attorney Docket No. NTG-08-PCT 58.79 (d, J=5.2 Hz, 1H), 8.44 (d, J=7.2 Hz, 1H), 7.33-7.21 (m, 5 H), 7.11-7.03 u(m, 2H), 6.80-6.69 (m, 2H), 5.28-5.24 407.2 (m, 1H), 4.09-3.99 (m, 2H), 3.32-3.13 HZN. ASLNH [M+H]+(m, 1H), 3.08-3.06 (m, 1H), 2.78-2.67 (m, 2H), 2.58-2.57 (m, 1H), 2.33-2.24 (m, 1H), 1.66-1.65 (m, 2H), 0.68-0.59 (m, 4H)p08.78-8.69 (m, 2H), 7.34-7.09 (m, 5H),6.74 (t, J=8.2 Hz, 3H), 5.24-5.13 (m, 1H), 4.25-4.02 (m, 2H), 3.72 (s, 1H), 427.13.19 (d, J=14.4 Hz, 1H), 2.82-2.76 (m, [M+H]+V7\ / °U_2H), 1.94-1.86 (m, 2H), 0.67-0.58 (m, f / \ / T S 4H)\ / XO ~r^o 58.80-8.70 (m, 2H), 7.32-7.15 (m, 5H), \ °> O 6.97-6.46 (m, 3H), 5.10-5.30 (m,lH), H IZ411.2 4.24-4.21 (m, 1H), 4.20-4.02 (m, 1H), [M+H]+3.71-3.68 (m, 1H), 3.22-3.13 (m, 1H), -W?2.81-2.75 (m, 2H), 1.95-1.85 (m, 2H), 0.66-0.57 (m, 4H)88.78-8.72 (m, 2H), 7.30-7.25 (m, 5H), 6.92-6.89 (m, 1H), 6.75-6.71 (m, 1H), 6.53 (d, J=7.6 Hz, 1H), 4.25-4.03 (m, 411.32H), 3.20 (d, J=13.6 Hz, 1H), 2.82-2.76 [M+H]+(m, 2H), 1.94 (d, J=4.4 Hz, 2H), 0.67- 0.57 (m, 4H)Attorney Docket No. NTG-08-PCT29 58.80-8.70 (m, 2H), 7.33-7.22 (m, 5H),6.97-6.71 (m, 3H), 5.24-5.19 (m, 1H), ZI( O= 4.23-4.15 (m, 2H), 4.06-3.99 (m, 1H),411.2\°= 3.22-3.17 (m, 1H), 2.80-2.76 (m, 2H),[M+H]+&1.94-1.85 (m, 2H), 0.66-0.57 (m, 2H) / \ \ I _\30 ft O -n— 8 8.82-8.74 (m, 2H), 7.36-7.22 (m, 5 H),7.06-6.99 (m, 1H), 6.78-6.67 (m, 1H), 6.57-6.41 (m, 1H), 5.30-5.27 (m, 1H), 421.33.80-3.70 (m, 1H), 3.27-3.18 (m, 1H), [M+H]+2.89-2.73 (m, 2H), 1.87-1.74 (m, 2H), iz 1.32 (s, 3H), 1.15 (s, 3H), 0.69-0.64 (m, ^O= 2H), 0.62-0.57 (m, 2H).\ \ \ / 1° '\ / 7 / O —ZExamples 31-35 y z z O—_ \ / #\ x

[0140] Table 15 sho \w °s representative examples of compounds of Formula I prepared )O=from the appropriately N-substituted 3-amino-2-hydroxy-4-alkyl-butanamide or N-substituted 3- / / o—Z Tamino-2-hydroxy-4-heterocyclic-butanamide hydrochloride and the appropriately substituted Vchromane-4-carboxylic acid according to the procedures described in Examples 1 and 2 and procedures described herein.Table 15.Mass1H NMR (ppm)Ex. No. Structure(ESI) m / z (400 MHz, DMSO-de)31 88.71-8.69 (m, 2H), 8.50-8.47(m, 1H), 7.78-7.75 (m, 1H), 7.35-7.25 (m, 2H), 7.09-7.02 422.2(m, 1H), 6.77-6.61 (m, 3H), [M+H]+5.50 (s, 1H), 3.77-3.73 (m,1H), 3.19-3.08 (m, 2H), 3.08(s, 1H), 1.91-1.79 (m, 2H),Attorney Docket No. NTG-08-PCT1.35 (s, 3H), 1.14 (s, 3H),0.68-0.59 (m, 4H)88.52-8.45 (m, 2H), 8.38 (bs, 2H), 7.76-7.60 (m, 1H), 7.38- ' o — 7.33 (m, 1H), 7.07-6.97 (m,° / 1H), 6.75-6.64 (m, 2H), 5.26O=\ ZI 422.2 (t, 1H), 3.76 (m, 1H), 3.27- [M+H]+3.23 (m, 1H), 2.96-2.90 (m,1H), 2.76-2.75 (m, 1H), 1.89- 1.79 (m, 2H), 1.34 (d, 3H),1.16 (d, 3H), 0.96 (t, 2H), 0.66 (t, 2H)88.60 (d, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.19 (d, 1H),7.12-7.08 (m, 1H), 6.80 (t,1H), 6.74 (t, 1H), 5.06-5.06(m, 1H), 4.32-4.29 (m, 1H), 317.204.12-4.09 (m, 1H), 3.82-3.79 [M+H]+(m, 1H), 2.04-1.99 (m, 2H),1.67-1.56 (m, 2H), 0.86-0.82(m, 1H), 0.46-0.39 (m, 2H), 0.15-0.13 (m, 1H), 0.07-0.04(m, 1H)88.79-8.69 (m, 2H), 7.20-7.01 (m, 2H), 6.82-6.69 (m, 2H),5.14-5.08 (m,lH), 3.91-3.87 385.2 (m, 1H), 2.81-2.70 (m, 1H), [M+H]+2.0-1.85 (m, 2H), 1.78-1.65(m, 1H), 1.65-1.48(m, 1H),1.37 (s, 3H), 1.18 (s, 3H),0.95-0.80 (m, 1H), 0.72-Attorney Docket No. NTG-08-PCT0.53(m, 4H), 0.45-0.43(m,2H), 0.15-0.07 (m, 2H)88.82-8.75 (m, 2H), 7.36-7.31 (m, 2H), 7.20-7.07 (m, 2H), 6.78-6.59 (m, 4H), 5.25-5.23(m, 1H), 3.32-3.16 (m, 1H), 439.22.84-2.74 (m, 1H), 2.51-2.50 [M+H]+(m, 1H), 1.87-1.75 (m, 1H),1.24 (s, 3H), 1.15 (s, 3H),1.15-1.05 (m, 1H), 0.68-0.55(m, 4H)Examples 36-41

[0141] Table 16 shows representative examples of compounds of Formula I prepared from the appropriately N-substituted-3-amino-2-hydroxy-4-phenylbutanamide and the appropriately substituted carboxylic acid according to the procedures described in Examples 1 and 2 and procedures described herein.Table 16.MassEx. ’HNMR Cppm)Structure (ESI)No. (400 MHz, DMSO-d6)m / z368 8.61-8.55 (m, 1H), 8.11-8.05 (m, o 1H), 7.85-7.64 (m, 1H), 7.35-7.20 (m, V / NW 380.19H), 5.22-5.17 (m, 1H), 3.87-3.84 (m, [M+H]+1H), 3.22-3.11 (m, 5H), 2.89-2.75 (m,0<^NH21H), 2.73-2.67 (m, 1H)Attorney Docket No. NTG-08-PCT8 8.42-8.32 (m, 1H), 8.07 (d, 1H), 7.83 (d, 1H), 7.35-7.11 (m, 6 H), 6.98-6.79 0339.1 (m, 3H), 5.26-5.23 (m, 1H), 5.15-5.07 [M+H]+(m, 1H), 3.43-3.37 (m, 1H), 3.18-3.14 < \r_v / o izHCT XNH2(m, 1H), 3.09-2.99 (m, 1H), 2.89-2.50(m, 1H))J o= \ 88.60-8.54 (m, 1H), 8.05 (bs, 1H), zo I 7.81 (bs, 1H), 7.24-7.03 (m, 8H), 7.11- NJo ( o 7.07 (m, 2H), 5.27-5.19 (m, 1H), 3.14- L I A V 337.0N Y NH2 3.10 (m,V H 0 [M+H]+1H), 3.00-2.93 (m, 1H), 2.15-2.13 (m, 1H), 1.97-1.87 (m, 1H), 1.28-1.06 (m, 2H)8 8.95-8.54 (m, 1H), 8.03 (bs, 1H), 7.79 (bs, 1H), 7.32-7.15 (m, 8H), 7.11- 337.2 7.07 (m, 2H), 5.27-5.19 (m, 1H), 3.13- [M+H]+3.10 (m, 1H), 2.77-2.71 (m, 1H), 2.14-v H0 2.11 (m, 1H), 1.97-1.94 (m, 1H), 1.26- 1.17 (m, 2H)8 8.04 (d, J=8.0 Hz, 1H), 7.6 (bs, 2H), 6 9-7.2 (m, 9H), 5.23 (m, 1H), 4.2 (m, 323.01H), 3.25-3.28 (m, 2H), 3.15-3.20 [M+H]+(m,l H), 2.83-2.9 (m, 1H)8 8.42 (d, J=7.6 Hz, 1H), 8.05 (bs, o 1H), 7.80 (bs, 1H), 7.32-7.08 (m, 9H), O [ 0 337.0 5.23-5.18 (m, 1H), 3.23-3.12 (m, 2H), N N H2[M+H]+3.03-2.94 (m, 4H), 2.87-2.73 (m, 1H) / yJHAAttorney Docket No. NTG-08-PCTResolution of (l?)-A-((. R)-4-amino-3,4-dioxo-l-phenylbutan-2-yl)chromane-4-carboxamide and (7?)-Az-((5)-4-amino-3,4-dioxo-l-phenylbutan-2-yl)chromane-4-carboxamidePeak 1 Peak 2

[0142] Crude (47?)-A-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)chromane-4-carboxamide (example 2, 0.5 g) is pre-adsorbed onto silica gel and purified via combi-flash (12 g, Flashpure-Buchi) and eluted with 1-40% EtOAc in DCM with a flow rate of 30 mL / minute. The pure fractions (determined by TLC) are combined and concentrated under reduced pressure to afford (47?)-A-(4-amino-3,4-dioxo-l-phenylbutan-2-yl)chromane-4-carboxamide (0.230 g) as an off-white solid. This compound is further purified to pure diastereomers by Chiral SFC (Column: Chiracel (250 x 30 x 5p), %CC>2: 65%, Co-solvent: 35% ACNTPA (1:1)). The two pure fractions are collected, concentrated under reduced pressure, and lyophilized to dryness.Example 5:

[0143] Peak 1: (7?)-A-((7?)-4-amino-3,4-dioxo-l-phenylbutan-2-yl)chromane-4-carboxamide (11.97 mg). Chiral HPLC purity 98.4%, 'H NMR (400 MHz, DMSO-d6) 5 ppm: 8.60 (d, J=7.2 MHz, 1H), 8.07 (s, 1H), 7.83 (bs, 1H), 7.32-7.21 (m, 5 H), 7.10-7.03 (m, 2H), 6.82-6.78 (m, 1H), 6.72 (d, J=8.4 MHz, 1H), 5.26-5.20 (m, 1H), 4.18-4.14 (m, 1H), 4.03-3.98 (m, 1H), 3.70 (t, J=12.0 MHz, 1H), 3.20-3.15 (m, 1H), 2.82-2.76 (m, 1H), 1.88-1.85 (m, 2H).Example 8:

[0144] Peak 2: (7?)-A-((5)-4-amino-3,4-dioxo-l-phenylbutan-2-yl)chromane-4-carboxamide (27.93 mg). Chiral HPLC purity 99.6%, ‘HNMR (400 MHz, DMSO-d6) 8 ppm: 8.62 (d, J=8.0 MHz, 1H), 8.07 (bs, 1H), 7.83 (bs, 1H), 7.34-7.21 (m, 5 H), 7.07-7.01 (m, 1H), 6.69 (d, J=8.4 MHz, 1H), 6.63-6.60 (m, 2H), 5.25-5.20 (m, 1H), 4.27-4.21 (m, 1H), 4.07-4.01 (m, 1H), 3.70-3.67 (m, 1H), 3.23-3.18 (m, 1H), 2.80-2.74 (m, 1H), 1.96-1.93 (m, 2H).

[0145] The stereochemistry of Peak 1 is confirmed by performing this exact synthesis using (25,3 / ?)-3-amino-2-hydroxy-4-phenylbutanamide hydrochloride as the starting material toAttorney Docket No. NTG-08-PCTmake (7?)-A-((7?)-4-amino-3,4-dioxo-l -phenylbutan-2-yl)chromane-4-carboxamide and comparing the desired product with that of the resolved materials.Resolution of (5)-7V-((5)-4-amino-3,4-dioxo-l-phenylbutan-2-yl)-2,2-dimethylchromane-4-carboxamide and (R)-7V-((S)-4-amino-3,4-dioxo-l-phenylbutan-2-yl)-2,2-dimethylchromane-4-carboxamide

[0146] Column / Dimensions: Lux Amylose-3 (250 x 30 x 5p), %CC>2: 70%, 30% 100% ACN: IPA (98:2). The collected two pure peak fractions are distilled off under reduced pressure at 30 °C and lyophilized to afford the desired products.Example 42:

[0147] Peak 1: (A)-A-(( )-4-amino-3,4-dioxo-l-phenylbutan-2-yl)-2,2-dimethylchromane-4-carboxamide (80.6 mg, 24.9%, as an off-white solid). LCMS (ESI): m / z: 381.2 [M+H]+. Chiral HPLC: RT- 2.50 min (purity 97.4%), 'HNMR (400 MHz, DMSO-d6) 5 ppm: 8.76 (d, J=7.2Hz, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.38-7.21 (m, 5H), 7.09 (d, J=7.6 Hz, 2H), 6.78 (t, J=3.6 Hz, 1H), 6.76-6.40 (m, 1H), 5.30-5.27 (m, 1H), 3.81-3.68 (m, 1H), 3.17 (t, J=6.8Hz, 1H), 2.83-2.80 (m, 1H), 1.80-1.74 (m, 2H), 1.32 (s, 3H), 1.15 (s, 3H).Example 43:

[0148] Peak 2: (A)-A-((5)-4-amino-3,4-dioxo-l-phenylbutan-2-yl)-2,2-dimethylchromane-4-carboxamide (56.1 mg, 22%, as an off-white solid). LCMS (ESI): m / z 381.15 [M+H]+. Chiral HPLC: RT- 3.41 min (purity 99.6%), ’HNMR (400 MHz, DMSO-d6) 8 ppm: 8.73 (d, J=7.2Hz, 1H), 8.09 (s, 1H), 7.85 (bs, 1H), 7.38-7.26 (m, 5 H), 7.02 - 6.96 (m, 1H), 6.65 - 6.62 (m, 1H), 6.59-6.54 (m, 1H), 6.40-6.24 (m, 1H), 5.38 - 5.32 (m, 1H), 3.76 - 3.68 (m, 1H), 3.27 - 3.23 (m, 1H), 2.78 - 2.69 (m, 1H), 1.87 - 1.76 (m, 2H), 1.31 (s, 3H), 1.15 (s, 3H).Examples 44-51

[0149] Table 17 shows representative examples of compounds of Formula I prepared from intermediate 3-amino-2-hydroxy-4-phenylbutanamide hydrochloride and the appropriate substituted chromane-4-carboxylic acid according to procedures described herein.Attorney Docket No. NTG-08-PCT Table 17.Ex. No. Structure Mass (ESI) m / z 44H3N^ _ p 0^353.00 [M]+11O -Pi| |JL “2L 22 XT T45 387.20 [M]+p—\4 / \ H 4 #Cl (f ) — '\ — nH2N46 371.20 [M]+Attorney Docket No. NTG-08-PCT371. 20 [M]+W VN W0 — <\~-~QH2Nn _ _ / C f~\ H O371.20 [M]+H2N387.15 [M]+Cl / " A0^= / X — nH2hTa o— x? \_y / ^NVJ^ VN W 387.15 [M]+V ^_ — / vnH2NAttorney Docket No. NTG-08-PCTExample 52Synthesis of N-(4-(cyclopropylamino)-l-(3-methoxyphenyl)-3,4-dioxobutan-2-yl)-2,2-dimethylchromane-4-carboxamideHN

[0150] To a stirred solution of N-(4-(cyclopropylamino)-3 -hydroxy- 1 -(3 -methoxyphenyl)-4-oxobutan-2-yl)-2,2-dimethylchromane-4-carboxamide (100 mg, 0.2 mmol, 1 eq) in DCM (5 mL) is added Dess-Martin Periodinane (281.2 mg, 0.7 mmol, 3 eq) at 0 °C. The resulting reaction mixture is stirred at rt for 3 h. The progress of the reaction is monitored by TLC.(mobile phase: 100% EtOAc, Rf: 0.45, UV active). After completion of reaction, the reaction mixture is quenched with sodium thiosulphate (10 mL) and sodium bicarbonate (10 mL) and stirred for 15 min and extracted with DCM (2 x 30 mL). The combined organic layer is washed with sodium thiosulphate (30 mL x 2), sodium bicarbonate brine solution (30 mL x 2), and brine (30 mL), dried over anhydrous sodium sulphate, filtered, and the filtrate is concentrated under reduced pressure to afford crude product (110 mg) as a pale yellow solid. The crude product is purified by trituration with diethyl ether (2 x 3 mL) and pentane (2 x 3 mL) and dried under vacuum to afford the product (44.2 mg) as an off-white solid. MS (ESI): m / z: 451.42 [M+H]+.rH NMR (400 MHz, DMSO-d6) 8 ppm: 8.82-8.73 (m, 2H), 7.29-7.21 (m, 1H), 7.09-6.74 (m, 5H),Attorney Docket No. NTG-08-PCT6.69-6.46 (m, 2H), 5.32-5.23 (m, 1H), 3.83-3.73 (m, 4H), 3.24-3.15 (m, 1H), 2.82-2.75 (m, 2H), 1.91-1.72 (m, 2H), 1.36-1.32 (m, 3H), 1.15 (s, 3H), 0.71-0.66 (m, 2H), 0.64-0.60 (m, 2H).Example 53Synthesis of N-((S)-l-(3-methoxyphenyl)-4-(methylamino)-3,4-dioxobutan-2-yl)-2,2-dimethylchromane-4-carboxamide

[0151] To a stirred solution of N-((2S)-3-hydroxy-l-(3-methoxyphenyl)-4-(methylamino)-4-oxobutan-2-yl)-2,2-dimethylchromane-4-carboxamide (50 mg, 0.1 mmol, 1 eq) in DCM (4 mL) at 0 °C is treated with Dess-Martin Periodinane (149.2 mg, 0.4 mmol, 3 eq) and the resulting reaction mixture is stirred for 3 h at rt. The progress of the reaction is monitored by TLC (mobile phase: 70% EtOAc in DCM, Rf: 0.45, UV active). After completion of reaction, the reaction mixture is quenched with 10 mL of sodium thiosulphate and 10 mL of sodium bicarbonate, stirred for 15 min, and extracted with DCM (2 x 20 mL). The combined organic extracts are washed with saturated sodium thiosulphate (20 mL x 2), saturated sodium bicarbonate (20 mL x 2), and brine (20 mL). The organic layer is dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product (56 mg) as an off-white solid which is triturated with Et2O (20 mL) and dried under high vacuo to afford the crude product (51.3 mg) as an off-white solid which is purified by flash column chromatography on silica gel and eluted with 0-70% EtOAc in DCM gradient. The pure fractions containing product are combined and concentrated under reduced pressure to afford the product (16.1 mg) as an off-white solid. MS (ESI): m / z: 425.42 [M+H]+. 'HNMR (400 MHz, CDCl3) 8 ppm: 8.79-8.68 (m, 2H), 7.29-7.21 (m, 1H), 7.08-6.75 (m, 5H), 6.70-6.63 (m, 1H), 6.59-6.44 (m, 1H), 5.31-5.23 (m, 1H), 3.78-3.72 (m, 4H), 3.25-3.15 (m, 1H), 2.79-2.68 (m, 4H), 1.88-1.75 (m, 2H), 1.36-1.32 (m, 3H), 1.15 (s, 3H).Example 54 (with Example 56 below)Attorney Docket No. NTG-08-PCTExample 55Synthesis of N-(4-(cyclopropylamino)-l-(2-fluorophenyl)-3,4-dioxobutan-2-yl)-2,2-dimethylchromane-4-carboxamide

[0152] To a stirred solution of N-(4-(cyclopropylamino)-l-(2-fluorophenyl)-3-hydroxy-4-oxobutan-2-yl)-2,2-dimethylchromane-4-carboxamide (70 mg, 0.2 mmol, 1 eq) in 5 mL of DCM at 0 °C is added Dess-Martin Periodinane (202.2 mg, 0.5 mmol, 3 eq) and the resulting solution is stirred for 3 h at rt. The progress of the reaction is monitored by TLC (mobile phase: 70% EtOAc in pet ether, Rf: 0.45, UV active). After completion of reaction, the reaction mixture is quenched with 20 mL of saturated aqueous sodium thiosulphate and 20 mL of saturated aqueous sodium bicarbonate and stirred for 15 minutes, and then extracted with DCM (2 x 20 mL). The combined organic layer is washed with saturated aqueous sodium thiosulphate (20 mL x 2) and saturated aqueous sodium bicarbonated (20 mL x 2) and brine solution (20 mL). The organic layer is dried over sodium sulphate and concentrated under reduced pressure to afford the crude product (56 mg) as an off-white solid which is triturated with Et2O and dried under high vacuo to afford the product (21.4 mg) as an off-white solid. MS (ESI): m / z: 439.37 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 ppm: 8.81-8.74 (m, 2H), 7.39-7.29 (m, 2H), 7.21-7.14 (m, 2H), 7.09-Attorney Docket No. NTG-08-PCT6.63 (m, 4H), 5.30-5.27 (m, 1H), 3.81-3.70 (m, 1H), 3.26-3.20 (m, 2H), 2.98-2.89 (m, 1H), 1.86- 1.76 (m, 2H), 1.33 (d, 9.60 Hz, 3H), 1.14 (s, 3H), 0.67-0.64 (m, 2H), 0.59-0.55 (m, 2H). Example 56

[0153] Examples 54 and 56 are purified by chiral preparative supercritical fluid chromatography (SFC).

[0154] Isolated 32.6 mg as an off-white solid. MS (ESI): m / z: 422.40 [M+H]+. Chiral SFC: 97.1%, RT: 2.05 minutes. 'H NMR (400 MHz, DMSO-d6) 8 ppm: 8.73-8.69 (m, 2H), 8.49 (d, J = 4.00 Hz, 1H), 7.79-7.75 (m, 1H), 7.34 (d, J= 7.60 Hz, 1H), 7.31-7.27 (m, 1H), 7.06-7.02 (m, 1H), 6.67-6.59 (m, 3H), 5.52-5.49 (m, 1H), 3.77-3.73 (m, 1H), 3.38 (d, J = 4.80 Hz, 1H), 3.12-3.08 (m, 1H), 2.78-2.75 (m, 1H), 1.92-1.80 (m, 2H), 1.35 (s, 3H), 1.14 (s, 3H), 0.68-0.58 (m, 4H).Example 54

[0155] Isolated 31.4 mg as an off-white solid. MS (ESI): m / z: 422.40 [M+H]+. Chiral SFC: 97.8%, RT: 3.79 minutes. 'H NMR (400 MHz, DMSO-d6) 8 ppm: 8.73-8.69 (m, 2H), 8.49 (d, J = 4.00 Hz, 1H), 7.79-7.75 (m, 1H), 7.34 (d, J= 7.60 Hz, 1H), 7.30-7.27 (m, 1H), 7.07-7.02 (m, 1H), 6.67-6.59 (m, 3H), 5.52-5.49 (m, 1H), 3.77-3.73 (m, 1H), 3.38 (d, J = 4.80 Hz, 1H), 3.12-Attorney Docket No. NTG-08-PCT3.08 (m, 1H), 2.78-2.75 (m, 1H), 1.92-1.80 (m, 2H), 1.35 (s, 3H), 1.14 (s, 3H), 0.68-0.58 (m, 4H).Example 57Synthesis of (4S)-N-(4-(cyclopropylamino)-3,4-dioxo-l-(pyridin-2-yl) butan-2-yl)-2,2-dimethylchromane-4-carboxamide

[0156] To a stirred solution of (4S)-N-(4-(cyclopropylamino)-3-hydroxy-4-oxo-l-(pyridin-2-yl) butan-2-yl)-2,2-dimethylchromane-4-carboxamide (0.03 g, 0.07 mmol, 1 eq) in DCM (2 mL) is added Dess-Martin periodinane (90.1 mg, 0.2 mmol, 3 eq) portion wise at 0 °C under nitrogen atmosphere. The resultant reaction mixture is stirred for 6 h at room temperature. The progress of the reaction is monitored by TLC (50% EtOAc in pet ether, Rf: 0.65, UV active). After completion, the reaction mixture is quenched with saturated aqueous sodium thiosulphate (1 x 20 mL) and saturated aqueous sodium bicarbonate solution (1 x 20 mL) and extracted with DCM (2 x 20 mL). The combined organic layer is washed with saturated sodium thiosulphate (3 x 20 mL), sodium bicarbonate solution (3 x 20 mL), followed by brine solution (1 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the crude product (0.03 g) as an off-white solid. The crude product is triturated with Et2O (1 x 5 mL) and n-pentane (2 x 10 mL) and dried under high vacuo to afford the product (4.1 mg) as an off-white solid. MS (ESI): m / z: 422.40[M+H]+. 'H-NMR (400 MHz, DMSO-d6) 58.73-8.69 (m, 2H), 8.50 (d, J= 4.00 Hz, 1H), 7.79-7.75 (m, 1H), 7.35-7.27 (m, 2H), 7.09-7.02 (m, 1H), 6.77-6.59 (m, 3H), 5.53-5.48 (m, 1H), 3.79-3.73 (m, 1H), 3.41-3.38 (m, 1H), 3.19-3.09 (m, 1H), 2.79-2.72 (m, 1H), 1.89-1.79 (m, 2H), 1.35 (s, 3H), 1.14 (s, 3H), 0.68-0.58 (m, 4H).Example 58Attorney Docket No. NTG-08-PCTSynthesis of N-((S)-4-(cyclopropylamino)-3,4-dioxo-l-phenylbutan-2-yl)-2-methyl-l-oxo-l,2,3,4-tetrahydroisoquinoline-4-carboxamide

[0157] To a stirred solution of N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)-2-methyl-l-oxo-l,2,3,4-tetrahydroisoquinoline-4-carboxamide (21 mg, 0.05 mmol, 1 eq) in (3 mL) of DCM at 0 °C is added Dess-Martin Periodinane (63.4 mg, 0.1 mmol, 3 eq) and the resulting solution is stirred for 3 hours at rt. The progress of the reaction is monitored by TLC (mobile phase: 100% ethyl acetate, Rf: 0.30, UV active). After completion of reaction, the reaction mixture is quenched with (5 mL) of sodium thiosulphate and (5 mL) of sodium bicarbonate, stirred for 15 minutes, and extracted with (2 x 20 mL) of DCM. The combined organic extracts are washed with sodium thiosulphate and (20 mL x 2) and sodium bicarbonate brine solution (20 mL x 2) and brine (50 mL). The organic layer is dried over sodium sulphate and concentrated under reduced pressure to afford the crude product (17 mg) as an off-white solid. The crude product is pre-adsorbed onto silica gel and purified on normal phase flash column chromatography on silica gel eluted with 100% EtOAc gradient. The pure fractions containing product are combined and concentrated under reduced pressure to afford the product (7.5 mg) as an off-white solid. MS (ESI): m / z: 418.28 [M+H]+.JH NMR (400 MHz, DMSO-d6) 8 ppm: 8.80 (d, J = 4.80 Hz, 1H), 8.69-8.60 (m, 1H), 7.87-7.83 (m, 1H), 7.47-6.83 (m, 8H), 5.29-5.24 (m, 1H), 3.99-3.93 (m, 1H), 3.64-3.52 (m, 2H), 3.22-3.18 (m, 1H), 2.98-2.89 (m, 3H), 2.82-2.76 (m, 2H), 0.70-0.64 (m, 2H), 0.60-0.59 (m, 2H).Example 59Synthesis of (4R)-N-(4-(cyclopropylamino)-3,4-dioxo-l-(pyridin-2-yl)butan-2-yl)-2,2-dimethylchromane-4-carboxamideAttorney Docket No. NTG-08-PCT

[0158] To a stirred solution of (4R)-N-(4-(cyclopropylamine)-3-hydroxy-4-oxo-l-(pyridin-2-yl) butan-2-yl)-2,2-dimethylchromane-4-carboxamide (55 mg, 0.1 mmol, 1 eq) in DCM (3 mL) atO °C is added Dess-Martin Periodinane (165.2 mg, 0.4 mmol, 3 eq) and the resulting solution is stirred for 3 h at rt. The progress of the reaction is monitored by TLC (mobile phase: 100% EtOAc, Rf: 0.45, UV active). After completion of reaction, the reaction mixture is quenched with 10 mL of saturated aqueous sodium thiosulphate and 10 mL of saturated aqueous sodium bicarbonate, stirred for 15 min, and extracted with DCM (2 x 30 mL). The combined organic layer is washed with saturated aqueous sodium thiosulphate (20 mL) and saturated aqueous sodium bicarbonate (30 mL x 2) and brine (20 mL). The combined organic layer is dried over sodium sulphate and concentrated under reduced pressure to afford the crude product (55 mg) as an off-white solid. The crude product is purified by column chromatography and eluted with 0-100% EtOAc in pet ether gradient. The pure fractions are concentrated under reduced pressure to afford the product (5 mg) as an off-white solid. MS (ESI): m / z: 422.40 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 ppm: 8.73-8.69 (m, 2H), 8.50-8.46 (m, 1H), 7.79-7.73 (m, 1H), 7.35-7.23 (m, 2H), 7.09-6.61 (m, 4H), 5.52-5.49 (m, 1H), 3.81-3.71 (m, 1H), 3.39-3.36 (m, 1H), 3.21-3.08 (m, 1H), 2.79-2.75 (m, 1H), 1.88-1.77 (m, 2H), 1.35 (s, 3H), 1.14 (s, 3H), 0.68-0.65 (m, 2H), 0.60-0.58 (m, 2H).Example 60Synthesis of (S)-N-(4-(cyclopropylamino)-3,4-dioxo-l-phenylbutan-2-yl)-2,2-dimethyl-2,3-dihydro-4H-benzo[b][l,4]oxazine-4-carboxamideAttorney Docket No. NTG-08-PCT

[0159] To a stirred solution ofN-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)-2,2-dimethyl-2,3-dihydro-4H-benzo[b][l,4]oxazine-4-carboxamide (50 mg, 0.1 mmol, 1 eq) in (15 mL) of DCM at 0 °C is added Dess-Martin Periodinane (150.2 mg, 0.4 mmol, 3 eq) and the resulting solution is stirred for 3 h at rt. The progress of the reaction is monitored by TLC (mobile phase: 100 % EtOAc, Rf: 0.27, UV active). After completion of reaction, the reaction mixture is quenched with 20 mL of sodium thiosulphate and 20 mL of sodium bicarbonate, stirred for 15 min, and extracted with DCM (2 x 30 mL). The combined organic layer is washed with saturated aqueous sodium thiosulphate (10 mL) and saturated aqueous sodium bicarbonate (30 mL x 2) and then with brine solution (30 mL). The resultant organic layer is dried over sodium sulphate and concentrated under reduced pressure to afford the crude product (45 mg) as a white solid. The crude product is triturated with n-pentane (20 mL) and dried under high vacuo to afford the product (21.9 mg) as a white solid. MS (ESI): m / z: 422.40 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 ppm: 8.79 (d, J = 4.80 Hz, 1H), 7.35-7.21 (m, 6H), 7.13 (dd, J= 1.20, 8.00 Hz, 1H), 6.95-6.91 (m, 1H), 6.79-6.74 (m, 2H), 5.14-5.11 (m, 1H), 3.62-3.59 (m, 1H), 3.28-3.24 (m, 1H), 3.21-3.16 (m, 1H), 2.87-2.78 (m, 2H), 1.32 (s, 3H), 1.08 (s, 3H), 0.70-0.59 (m, 4H).Example 61Synthesis of N-((S)-4-amino-3,4-dioxo-l-phenylbutan-2-yl) spiro[chromane-2,l'-cyclopropane]-4-carboxamideAttorney Docket No. NTG-08-PCTSynthesis of N-((2S,3R)-4-amino-3-hydroxy-4-oxo-l-phenylbutan-2-yl)spiro[chromane-2,l'-cyclopropane]-4-carboxamide

[0160] To a stirred solution of spiro[chromane-2,l'-cyclopropane]-4-carboxylic acid (100 mg, 0.5 mmol, 1 eq) in DMF (4 mL) are added DIPEA (0.4 mL, 2.4 mmol, 5 eq) followed by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (187.7 mg, 1 mmol, 2 eq), HOBt (132.3 mg, 1 mmol, 2 eq) and (2R,3S)-3-amino-2-hydroxy-4-phenylbutanamide hydrochloride (113 mg, 0.5 mmol, 1 eq) at 0 °C. The resulting reaction mixture is stirred at rt for 16 h. The reaction progress is monitored by TLC (mobile phase: 70% EtOAc in pet ether, Rf: 0.22, Visualization: UV active). After completion, the reaction mixture is quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer is washed with cold water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product (156 mg) as a brown sticky liquid. The crude product is purified by combi flash chromatography and eluted with (70% EtOAc in pet ether). The combined pure fractions are concentrated under reduced pressure to afford the product (60 mg) as a brown solid. MS (ESI): m / z: 381.32 [M+H]+.Synthesis of N-((S)-4-amino-3,4-dioxo-l-phenylbutan-2-yl)spiro[chromane-2,l'-cyclopropane]-4-carboxamide

[0161] To a solution of N-((2S,3R)-4-amino-3-hydroxy-4-oxo-l-phenylbutan-2-yl)spiro[chromane-2,1'-cyclopropane]-4-carboxamide (60 mg, 0.2 mmol, 1 eq) in (3 mL) of DCM at 0 °C is added Dess-Martin Periodinane (201 mg, 0.5 mmol, 3 eq) and the resulting solution is stirred for 3 h at rt. The progress of the reaction is monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.45, UV active). After completion of reaction, the reaction mixture is quenched with 10 mL of saturated aqueous sodium thiosulphate and 10 mL of saturated aqueous sodium bicarbonate, stirred for 15 minutes, and extracted with DCM (2 x 20 mL). TheAttorney Docket No. NTG-08-PCTcombined organic layer is washed with saturated aqueous sodium thiosulphate (10 mb x 2) and saturated aqueous sodium bicarbonate (10 mL x 2) and brine (10 mL). The resultant organic layer is dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product (26 mg) as an off white solid. The crude compound is triturated with Et₂O and pentane (20 mL, 1:1) and dried under high vacuo to afford the product (9.8 mg) as an off-white solid. MS (ESI): m / z: 377.24 [M-H]’. 'H NMR (400 MHz, DMSO-d6) 5 ppm: 8.57-8.54 (m, 1H), 8.08-8.07 (m, 1H), 7.83-7.82 (m, 1H), 7.36-7.21 (m, 6H), 7.10-6.98 (m, 2H), 6.68-6.60 (m, 1H), 5.36-5.26 (m, 1H), 3.90-3.84 (m, 1H), 3.22-3.16 (m, 1H), 2.82-2.75 (m, 1H), 2.22-2.17 (m, 1H), 1.69-1.64 (m, 1H), 0.95-0.86 (m, 1H), 0.78-0.41 (m, 3H).Example 62Synthesis of N-((S)-4-(cyclopropylamino)-3,4-dioxo-l-(pyridin-2-yl)butan-2-yl)-2,2-dimethylchromane-4-carboxamide

[0162] To a stirred solution of N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-(pyridin-2-yl)butan-2-yl)-2,2-dimethylchromane-4-carboxamide (120 mg, 0.3 mmol, 1 eq) in (5 mL) of DCM at 0 °C is added Dess-Martin Periodinane (361 mg, 0.9 mmol, 3 eq) and the resulting solution is stirred for 3 h at rt. The progress of the reaction is monitored by TLC (mobile phase: 100% EtOAc, Rf: 0.45, UV active). After completion of reaction, the reaction mixture is quenched with 20 mL of saturated aqueous sodium thiosulphate and 20 mL of saturated aqueous sodium bicarbonate, stirred for 15 min, and extracted with DCM (2 x 30 mL). The combined organic extracts are washed with saturated aqueous sodium thiosulphate (20 mL x 2)and saturated aqueous sodium bicarbonate (20 mL x 2) and brine (30 mL). The combined organic layer is dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product which is triturated with Et2O / Pentane (56 mg) as an off-white solid. The compound is further purified by using silica gel and eluted with 0-100% EtOAc in pet etherAttorney Docket No. NTG-08-PCTgradient to afford the product (12.3 mg) as an off-white solid. MS (ESI): m / z: 422.1 [M+H]+. NMR(400 MHz, DMSO-d6) 8 ppm: 8.73-8.69 (m, 2H), 8.51-8.46 (m, 1H), 7.79-7.72 (m, 1H), 7.35-7.24 (m, 2H), 7.09-6.65 (m, 4H), 5.52-5.48 (m, 1H), 3.81-3.72 (m, 1H), 3.40-3.36 (m, 1H), 3.20-3.09 (m, 1H), 2.79-2.72 (m, 1H), 1.92-1.78 (m, 2H), 1.35-1.33 (m, 3H), 1.14 (s, 3H), 0.68-0.65 (m, 2H), 0.60-0.58 (m, 2H).Example 63

[0163] To a stirred solution of N-((2S)-l-(4-cyanophenyl)-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-yl)-2,2-dimethylchromane-4-carboxamide (150 mg, 0.3 mmol, 1 eq) in (5 mL) of DCM at 0 °C is added Dess-Martin Periodinane (426.5 mg, 1 mmol, 3 eq) and the resulting solution is stirred for 3 h at rt. The progress of the reaction is monitored by TLC (mobile phase: 50 % EtOAc in pet ether, Rf: 0.30, UV active). After completion of reaction, the reaction mixture is quenched with 10 mL of saturated aqueous sodium thiosulphate and 10 mL of saturated aqueous sodium bicarbonate, stirred for 15 min, and extracted with DCM (2 x 40 mL). The combined organic extracts are washed with saturated aqueous sodium thiosulphate (40 mL x 2) and saturated aqueous sodium bicarbonate (40 mL x 2) and brine (30 mL). The organic layer is dried over sodium sulphate and concentrated under reduced pressure to afford the crude product (147 mg) as an off white solid. The crude product is triturated with diethyl ether and pentane (10 ml each) to afford the product (147 mg) as an off-white solid. MS (ESI): m / z: 446.22 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 8 ppm: 8.86-8.79 (m, 2H), 7.86-7.79 (m, 2H), 7.53-7.47 (m, 2H), 7.10-6.75 (m, 2H), 6.70-6.62 (m, 1H), 6.61-6.38 (m, 1H), 5.30-5.25 (m, 1H), 3.78-3.68 (m, 1H), 3.30 (s, 1H), 2.94-2.84 (m, 1H), 2.80-2.76 (m, 1H), 1.85-1.73 (m, 2H), 1.38-1.33 (m, 3H), 1.14 (s, 3H), 0.69-0.57 (m, 4H).Example 64Attorney Docket No. NTG-08-PCTSynthesis of N-((S)-4-(cyclopropylamino)-3,4-dioxo-l-phenylbutan-2-yl)spiro [chromane-2,l'-cyclopropane]-4-carboxamide

[0164] To a stirred solution of N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)spiro[chromane-2,1'-cyclopropane]-4-carboxamide (55 mg, 0.1 mmol, 1 eq) in (3 mL) of DCM at 0 °C is added Dess-Martin Periodinane (165.2 mg, 0.4 mmol, 3 eq) and the resulting reaction mixture is stirred for 3 h at rt. The progress of the reaction is monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.45, UV active). After completion of reaction, the reaction mixture is quenched with 20 mL of sodium thiosulphate and 20 mL of sodium bicarbonate, stirred for 15 minutes, and extracted with DCM (2 x 20 mL). The combined organic layer is washed with sodium thiosulphate (20 mL x 2), sodium bicarbonate brine solution (20 mL x 2), and brine (20 mL). The resulting organic layer is dried over sodium sulphate and concentrated under reduced pressure to afford crude product which is triturated with Et2O / n-Pentane mixture (20 mL, 1:1) to afford the product (25.2 mg) as an off-white solid. MS (ESI): m / z: 419.37 [M+H]+. 'H NMR. (400 MHz, DMSO-d6) 8 ppm: 8.82-8.78 (m, 1H), 8.62 (d, J= 7.20 Hz, 1H), 7.36-6.80 (m, 7H), 6.69-6.48 (m, 2H), 5.32-5.22 (m, 1H), 3.91-3.82 (m, 1H), 3.28-3.18 (m, 1H), 2.82-2.74 (m, 2H), 2.35-2.19 (m, 1H), 1.68-1.62 (m, 1H), 0.99-0.42 (m, 8H).Example 65Attorney Docket No. NTG-08-PCT

[0165] May be synthesized by procedures described herein.

[0166] MS by LC-MS: m / z: 435.42 [M+H]+.Example 66Synthesis of N-((S)-4-(cyclopropylamino)-3,4-dioxo-l-phenylbutan-2-yl)-2-methylchromane-4-carboxamide

[0167] To a stirred solution of N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)-2-methylchromane-4-carboxamide (0.1 g, 0.2 mmol, 1 eq) in DCM (2 mL) cooled to 0°C under nitrogen atmosphere is added Dess-Martin periodinane (312 mg, 0.7 mmol, 3 eq) portion wise. After completion, the reaction mixture is stirred for 6 h at rt. The progress of the reaction is monitored by TLC (50% EtOAc in pet ether, Rf: 0.65, UV active). After 6 h, the reaction mixture is quenched with saturated sodium thiosulphate (1 x 50 mL) and sodium bicarbonate solution (2 x 50 mL) extracted with DCM (2 x 50 mL), washed with brine solution (1 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford crude product (0.1 g) as an off-white solid. The crude product is triturated with Et2O (20 mL) and dried under high vacuo to afford the product (50.1 mg) as a white solid. MS (ESI): m / z: 407.1 [M+H]+.1HNMR(400 MHz, DMSO-d6) 5 ppm: 8.81-8.73 (m, 1H), 8.60-8.52 (m, 1H), 7.35-7.22 (m,Attorney Docket No. NTG-08-PCT5H), 7.11-6.68 (m, 4H), 5.30-5.10 (m, 1H), 4.40-3.64 (m, 2H), 3.22-3.15 (m, 1H), 2.82-2.72 (m, 2H), 1.91-1.59 (m, 2H), 1.32-1.20 (m, 3H), 0.67-0.54 (m, 4H).Example 67Synthesis of 2-(tert-butyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxo-l-phenylbutan-2-yl)chromane-4-carboxamide

[0168] To a stirred solution of 2-(tert-butyl)-N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)chromane-4-carboxamide (0.1 g, 0.2 mmol, 1 eq) in DCM (2 mL) cooled to 0 °C under nitrogen atmosphere is added Dess-Martin periodinane (188.3 mg, 0.4 mmol, 2 eq) portion wise. The reaction mixture is stirred for 6 h at rt. The progress of the reaction is monitored by TLC (50% EtOAc in pet ether, Rf: 0.65, UV active). After 6 h, the reaction mixture is quenched with saturated aqueous sodium thiosulphate (1 x 10 mL) and saturated sodium bicarbonate solution (2 x 10 mL) and extracted with DCM (2 x 20 mL). The organic layer is washed with brine solution (1 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford crude product (0.1 g) as an off-white solid. The crude residue is triturated with Et₂O (20 mL) and dried under high vacuo to afford the product (79 mg) as a white solid. MS (ESI): m / z: 449.20 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 ppm: 8.81-8.46 (m, 2H), 7.34-7.22 (m, 5H), 7.11-6.86 (m, 2H), 6.84-6.42 (m, 2H), 5.30-5.09 (m, 1H), 3.93-3.59 (m, 2H), 3.28-3.12 (m, 1H), 2.82-2.72 (m, 2H), 2.00-1.58 (m, 2H), 0.99-0.88 (m, 9H), 0.69-0.54 (m, 4H).Example 68Synthesis of N-((S)-4-(cyclopropylamino)-3,4-dioxo-l -phenylbutan-2-yl)isochromane-4-carboxamideAttorney Docket No. NTG-08-PCT

[0169] To a stirred solution of N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)isochromane-4-carboxamide (60 mg, 0.2 mmol, 1 eq) in DCM (1.2 mL) cooled to 0 °C under nitrogen atmosphere is added Dess-Martin periodinane (194 mg, 0.5 mmol, 3 eq) portion wise. Reaction mixture is stirred for 2 h at it. Progress of the reaction is monitored by TLC (70% EtOAc, Rf: 0.5). After 2 h, the reaction mixture is quenched with saturated sodium thiosulphate (3 x 15 mL) and extracted with DCM (2 x 20mL), washed with saturated sodium bicarbonate solution (2 x 20 mL), extracted with DCM (2 x 20mL), washed with saturated brine solution (1 x 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford crude (0.05 g) as an off-white solid. The crude product is triturated with n-pentane (3 x 10 mL), filtered, and rinsed with n-pentane, dried under high vacuum to afford the product (39 mg) as an off-white solid. MS (ESI): m / z: 393.1 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 ppm: 8.81-8.77 (m, 1H), 8.53-8.51 (m, 1H), 7.35-7.11 (m, 7H), 7.07-6.64 (m, 2H), 5.25-5.22 (m, 1H), 4.65 (s, 2H), 3.99-3.87 (m, 1H), 3.84-3.69 (m, 2H), 3.26-3.14 (m, 1H), 2.87-2.76 (m, 2H), 0.70-0.57 (m, 4H).Example 69Example 70Attorney Docket No. NTG-08-PCTSynthesis of N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)-2,2-dimethylchromane-4-carboxamide

[0170] To a stirred solution of 2,2-dimethylchromane-4-carboxylic acid (2.3 g, 11 mmol, 1 eq) in DMF (60 mL) is added DIPEA (5.8 mL, 33.2 mmol, 3 eq) followed by EDC. HC1 (4.2 g, 22.2 mmol, 2 eq), ethyl cyanohydroxyiminoacetate (3.1 g, 22 mmol, 2 eq) and (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-phenylbutanamide hydrochloride (3.0 g, 11 mmol, 1 eq) at 0 °C. The resulting reaction mixture is stirred at rt for 16 h. The reaction progress is monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.40, Visualization: UV active). After completion, the reaction mixture is quenched with water (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer is washed with cold water (100 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude compound (4.2 g) as a light-yellow solid. The crude compound is purified by combi flash chromatography (product elution with 45 % ethyl acetate in pet ether). The combined pure fractions are concentrated under reduced pressure to afford product (2.5 g) as light-yellow solid.Synthesis of N-((S)-4-(cyclopropylamino)-3,4-dioxo-l-phenylbutan-2-yl)-2,2-dimethylchromane-4-carboxamide

[0171] To a stirred solution of N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)-2,2-dimethylchromane-4-carboxamide (1.9 g, 4.5 mmol, 1 eq) in DCM (60 mL) at 0 °C is added Dess-Martin Periodinane (5.7 g, 13.5 mmol, 3 eq) and the resulting solution is stirred for 3 h at rt. The progress of the reaction is monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.45, UV active). After completion of reaction, the reaction mixture is quenched with (40 mL) of sodium thiosulphate and (40 mL) of sodium bicarbonate, stirred for 15 minutes, and extracted with DCM (2 x 50 mL). The combined organic layer is washed with sodiumAttorney Docket No. NTG-08-PCTthiosulphate (40 mL x 2), sodium bicarbonate (40 mL x 2) and brine (50 mL). The resultant organic layer is dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product (2.7 g) as an off white solid. The crude is triturated in DCM and pentane (10 mL, 1:1) and dried high vacuo to afford product (1.5 g) as an off white solid. MS (ESI): m / z; 421.2 [M+H]+. Isomers separated by chiral SFC prep.Example 69

[0172] Peak 2: Isolated 5.0 mg as an off-white solid. MS (ESI): m / z: 421.1 [M+H]+. Chiral HPLC: RT- 4.54 minute (97.7%). ¹H NMR (400 MHz, DMSO-d6) δ ppm: 88.81-8.77 (m, 2H), 7.33-7.21 (m, 5H), 7.08-7.04 (m, 2H), 6.77-6.73 (m, 1H), 6.67 (d,,7= 7.60 Hz, 1H), 5.27-5.22 (m, 1H), 3.80-3.75 (m, 1H), 3.20-3.16 (m, 1H), 2.82-2.76 (m, 2H), 1.82-1.69 (m, 2H), 1.30 (s, 3H), 1.13 (s, 3H), 0.66-0.61 (m, 4H).Example 70

[0173] Peak-1: Isolated 12.5 mg as an off-white solid. MS (ESI): m / z: 421.2 [M+H]+. Chiral HPLC: RT- 2.77 minute (99.9%). ’H NMR (400 MHz, DMSO) 8 ppm: 88.80-8.75 (m, 2H), 7.38-7.28 (m, 5H), 7.03-6.99 (m, 1H), 6.64 (d, J= 7.20 Hz, 1H), 6.57-6.53 (m, 1H), 6.40 (d, J = 7.60 Hz, 1H), 5.32-5.28 (m, 1H), 3.77-3.71 (m, 1H), 3.28-3.23 (m, 1H), 2.80-2.73 (m, 1H), 1.91-1.79 (m, 1H), 1.38 (s, 3H), 1.24-1.23 (m, 2H), 1.15 (s, 3H), 0.71-0.66 (m, 2H), 0.61-0.57 (m, 2H).Example 71Synthesis of N-((S)-4-(cyclopropylamino)-3,4-dioxo-l-phenylbutan-2-yl)isochromane-l-carboxamide

[0174] To a solution of N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl) isochromane-1 -carboxamide (120 mg, 0.3 mmol, 1 eq) in 7 mL of DCM at 0 °C is added Dess-Martin Periodinane (387.1 mg, 0.9 mmol, 3 eq) and the resulting solution is stirred for 2 h atAttorney Docket No. NTG-08-PCTrt. Progress of the reaction is monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.45, UV active). After completion of the reaction, the reaction mixture is quenched with (20 mL) of sodium thiosulphate and (20 mL) of sodium bicarbonate, stirred for 15 minutes, and extracted with (2 x 30 mL) of DCM. The combined organic extracts are washed with sodium thiosulphate and (30 mL x 2) and sodium bicarbonate brine solution (30 mL x 2) and brine (30 mL). The organic layer is dried over sodium sulphate and concentrated under reduced pressure to give crude product (106 mg) as an off-white solid. The crude product is purified by combi flash chromatography (product elution with 45% ethyl acetate in pet ether). Combined pure fractions are evaporated under reduced pressure to obtain the product (21 mg) as a paleyellow solid. MS (ESI): m / z: 393.16 [M+H]+.JH NMR (400 MHz, DMSO-d6) 8 ppm: 8.79-8.76 (m, 1H), 8.44-8.35 (m, 1H), 7.34-7.10 (m, 8H), 7.07-6.96 (m, 1H), 5.26-5.22 (m, 1H), 5.14- 5.10 (m, 1H), 4.19-4.02 (m, 1H), 3.82-3.74 (m, 1H), 3.22-3.10 (m, 1H), 2.93-2.72 (m, 4H), 0.69-0.61 (m, 2H), 0.59-0.57 (m, 2H).Example 72

[0175] To a solution of 2,3 -dihydrobenzofuran-3 -carboxylic acid (93 mg, 0.6 mmol, 1 eq) in DMF (4 mL) is added N, N-diisopropylethylamine (0.4 mL, 2.3 mmol, 4 eq) EDC. HC1 (146.1 mg, 0.8 mmol, 1.4 eq) and HOBT (103.3 mg, 0.8 mmol, 1.4 eq) followed by (3S)-3-amino-2-hydroxy-4-phenylbutanamide hydrochloride (130.7 mg, 0.6 mmol, 1 eq) at 0 °C. The resulting reaction mixture is stirred at room temperature for 16 hours. Progress of the reaction is monitored by TLC (mobile phase 10% MeOH in DCM. Rf: 0.12, Visualization: UV active). After completion of reaction, the reaction mixture is quenched with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts are washed with brine, dried over sodium sulphate, and concentrated under reduced pressure to afford crude product as a brownAttorney Docket No. NTG-08-PCTsolid. The crude product is purified by combi-flash (product is eluted with 15% MeOH in DCM). Pure fractions are evaporated to afford N-((2S)-4-amino-3-hydroxy-4-oxo-l-phenylbutan-2-yl)-2,3-dihydrobenzofuran-3-carboxamide (101 mg) as a pale-yellow solid. MS (ESI): m / z: 341.24 [M+H]+.

[0176] To a solution of N-((2S)-4-amino-3-hydroxy-4-oxo-l-phenylbutan-2-yl)-2,3-dihydrobenzofuran-3 -carboxamide (100 mg, 0.3 mmol, 1 eq) in DCM (7 mL) is added Dess-Martin Periodinane (373.8 mg, 0.9 mmol, 3 eq) at 0 °C. The resulting mixture is stirred at room temperature for 3 hours. Progress of the reaction is monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.33, Visualization: UV active). After completion of reaction, the reaction mixture is quenched with 15 mL of sodium thiosulphate and 20 mL of sodium bicarbonate, stirred for 15 min, and extracted with (3 x 20 mL) of DCM. The combined organic extracts are washed with brine solution, dried over sodium sulphate, and concentrated under reduced pressure to give crude product as a brown liquid. After washings with DCM in pentane: 65 mg. The crude product is purified by combi-flash column chromatography (product elution with 50% EtOAc in DCM) to afford the product (12 mg) as an off-white solid. MS (ESI): m / z: 339.1 [M+H]+. 'H NMR(400 MHz, DMSO-d6) 5 ppm: 8.81-8.74 (m, 1H), 8.09 (d, J = 10.4 Hz, 1H), 7.83 (d, J = 22.0 Hz, 1H), 7.34-7.23 (m, 6 H), 7.14-7.03 (m, 1H), 6.85-6.62 (m, 2 H), 5.31-5.24 (m, 1H), 4.62-4.49 (m, 2H), 4.32-4.26 (m, 1H), 3.32-3.16 (m, 1H), 2.82-2.73 (m, 1H).Example 73ClExample 74Attorney Docket No. NTG-08-PCTaSynthesis of tert-butyl (S)-(3-(4-chlorophenyl)-l-(methoxy(methyl)amino)-l-oxopropan-2-yl)carbamate

[0177] To a stirred solution of 2-((tert-butoxy carbonyl)amino)-3-(4-chlorophenyl) propanoic acid (10 g, 33.4 mmol) in DMF (100 mL) is added DIPEA (17.4 mL, 100 mmol) dropwise at rt. After 10 min., HATU (15.2g, 40 mmol) and N, O-dimethyl hydroxylamine hydrochloride (3.9 g, 40 mmol) is added at room temperature and stirred for 16 h. Progress of the reaction is monitored by TLC (30% EtOAc-pet ether, Rf: 0.32, UV active). On completion, the reaction mixture is diluted with water (200 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers are washed with brine solution (2 x 120 mL), dried over Na2SO4, and filtered. The filtrate is concentrated under reduced pressure to afford the crude product (15 g). The obtained crude compound is pre-adsorbed onto silica gel and purified via combi-flash and eluted with 60-65% EtOAc in pet ether with flow rate 30 mL / minute. The pure fractions containing product are combined and concentrated under reduced pressure to afford the product (10 g). MS (ESI): m / z; 287.1 [M+H]+.Synthesis of tert-butyl (S)-(l-(4-chlorophenyl)-3-oxopropan-2-yl)carbamate

[0178] To a stirred solution of tert-butyl (S)-(3-(4-chlorophenyl)-l-(methoxy(methyl)amino)-l-oxopropan-2-yl)carbamate (5 g, 15 mmol) in THF (100 mL) is added lithium aluminium hydride, 2.0 M solution in THF (8.8 mL, 18 mmol) dropwise at -5 °C. The resulting reaction mixture is stirred at -5 °C for 1.5 h. The progress of the reaction is monitored on TLC (mobile Phase: 20% EtOAc in pet ether, Rf: 0.44, UV active). After completion of reaction, the reaction mixture is quenched with saturated NH4CI solution (50 mL) and filtered on celite pad. The pad is rinsed with ethyl acetate (3 x 150 mL). The filtrate is extracted with ethyl acetate (2 x 50 mL). The combined organic layer is dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude product (3.6 g) as an off-white solid.Attorney Docket No. NTG-08-PCTSynthesis of tert-butyl ((2S)-3-(4-chlorophenyl)-l-cyano-l-hydroxypropan-2-yl)carbamate

[0179] To a stirred solution of tert-butyl (S)-(l-(4-chlorophenyl)-3-oxopropan-2-yl)carbamate (3.1 g, 11 mmol) in DCM (50 mL) is added triethylamine (1.8 mL, 13 mmol) and 2-hydroxy-2-methylpropanenitrile (3 mL, 33 mmol) subsequently at 0 °C. The resulting reaction mixture is stirred at room temperature for 4 h. The progress of the reaction is monitored by TLC (mobile Phase: 30% EtOAc in pet ether, Rf: 0.39, Visualization: UV active). After completion of reaction, the reaction mixture is diluted with water (150 mL) and extracted with DCM (3 x 150 mL). The combined organic layer is washed with saturated sodium chloride solution (80 mL), dried over anhydrous Na2SC>4. and concentrated under reduced pressure to obtain the crude product (3.2 g) as a pale-yellow gummy material. The crude product is purified by flash chromatography eluting with 30% EtOAc in hexane to afford the product (2.1 g) as an off-white solid. MS (ESI): m / z: 211.07 [M+H]+[M-100], Chiral HPLC: (18.58% + 33.47% + 25.40% + 22.55%, mixture of isomers).Synthesis of tert-butyl ((2S)-4-amino-l-(4-chlorophenyl)-3-hydroxy-4-oxobutan-2-yl) carbamate

[0180] To a stirred solution of tert-butyl ((2S)-3-(4-chlorophenyl)-l-cyano-l-hydroxypropan-2-yl) carbamate (2.1 g, 7 mmol) in a 10:1 mixture of EtOH (46.2 mL) and H2O is added mercury (II) chloride (3.7 g, 14 mmol) and acetaldoxime (4.8 mL, 68 mmol) at 0 °C and stirred for 10 minutes. The resultant reaction mixture is then stirred at rt for 16 h. The reaction progress is monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.2, Visualization: UV active). After completion of reaction, the reaction mixture is quenched with ice cold water (80 mL) and extracted with EtOAc (3 x 120 mL). The combined organic layer is washed with brine, dried over sodium sulphate, and concentrated under reduced pressure to afford the desiredcrude product (2.2 g). The obtained crude product is pre-adsorbed onto silica gel and purified via combi-flash and eluted with 60-65% EtOAc in pet ether with flow rate 30 mL / minute. The pure fractions containing product are combined and concentrated under reduced pressure to afford the product (1.5 g) as a white solid. MS (ESI): m / z: 229.10 [M-100]+. Chiral HPLC: (17.44% + 44.08% + 38.49%, mixture of isomers).Synthesis of (3S)-3-amino-4-(4-chlorophenyl)-2-hydroxybutanamide hydrochloride

[0181] To a stirred solution of tert-butyl ((2S)-4-amino-l-(4-chlorophenyl)-3-hydroxy-4-oxobutan-2-yl) carbamate (1.5 g, 5 mmol) in 1,4-dioxane (15 mL) at 0 °C is added 4 M HC1 inAttorney Docket No. NTG-08-PCTdioxane (15 mL) at same temperature and stirred for 2 h at rt. Progress of the reaction is monitored by TLC (mobile phase: 10% MeOH / DCM, Rf: 0.18, Visualization: UV active). After completion of reaction, the reaction mixture is concentrated under reduced pressure to obtain the crude product (1.4 g) as an off white solid. The crude product is triturated with n-pentane (3 x 30 mL), filtered, and rinsed with n-pentane, dried under high vacuum to afford the product (1.2 g) as a white solid. MS (ESI): m / z: 229.10 [M+H]+. Chiral HPLC: (37.39% + 22.74% + 39.87%, mixture of isomers).Synthesis of (4R)-N-((2S)-4-amino-l-(4-chlorophenyl)-3-hydroxy-4-oxobutan-2-yl)chromane-4-carboxamide

[0182] To a stirred solution of (3S)-3-amino-4-(4-chlorophenyl)-2-hydroxybutanamide hydrochloride (200 mg, 0.8 mmol) in DMF (3.5 mL) are added DIPEA (0.4 mL, 2.3 mmol), EDC. HC1 (174 mg, 0.9 mmol), and HOBt (122 mg, 0.9 mmol) at 0 °C under nitrogen atmosphere. After 10 minutes (R)-chromane-4-carboxylic acid (161 mg, 0.9 mmol) is added at 0 °C. Stirred at RT for 16 h. Progress of the reaction is monitored by TLC (mobile phase: 10% MeOH in DCM, Rf: 0.38, Visualization: UV active.) After completion of reaction, the reaction mixture is diluted with water (60 mL) and extracted with EtOAc (2 x 80 mL). The total organic layer is washed with saturated NaCl solution (2 x 40 mL) and dried over anhydrous Na2SO4 (20 g), filtered, and concentrated under reduced pressure to afford crude product. The reaction mixture is quenched with ice water (60 mL), extracted with EtOAc (2 x 80 mL), and washed with saturated brine solution (1 x 40 mL). The organic layer is again washed with saturated brine solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford crude (250 mg) as an off-white solid. The crude product is triturated with n-pentane and diethyl ether (150 mL) and filtered to yield 200 mg as an off white solid.Synthesis of N-(4-amino-l-(4-chlorophenyl)-3,4-dioxobutan-2-yl)chromane-4-carboxamide

[0183] To a stirred solution of (4R)-N-((2S)-4-amino-l-(4-chlorophenyl)-3-hydroxy-4-oxobutan-2-yl)chromane-4-carboxamide (200 mg, 0.5 mmol) in DCM (10 mL) cooled to 0 °C under nitrogen atmosphere is added Dess-Martin periodinane 97% (654 mg, 1.5 mmol) portion wise. The resulting reaction mixture is stirred for 2 h at rt. The progress of the reaction is monitored by TLC (mobile phase: 10% MeOH-DCM, Rf: 0.65, Visualization: UV active). After 2 h, the reaction mixture is quenched with saturated sodium thiosulphate (1 x 20 mL) and extracted with DCM (2 x 50 mL). The total organic layer is washed with saturated sodiumAttorney Docket No. NTG-08-PCTbicarbonate solution (2 x 20 mL) followed by saturated sodium chloride solution (1 x 20 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford crude (210 mg) as an off-white solid. Crude product is triturated with n-pentane and diethyl ether (150 mL) to afford N-(4-amino-l-(4-chlorophenyl)-3,4-dioxobutan-2-yl)chromane-4-carboxamide (38 mg) as an off-white solid which is purified by prep-SFC.Example 74

[0184] SFC Purification: The pure fractions are combined and concentrated under reduced pressure to afford (R)-N-((S)-4-amino-l-(4-chlorophenyl)-3,4-dioxobutan-2-yl) chromane-4-carboxamide (6.30 mg, Chiral-SFC Purity: 99.7%) as an off-white solid (6.30 mg). MS (ESI): m / z: 387.1 [M+H]+. 'H-NMR (400 MHz, DMSO-d6) 8 ppm 8.65 (d, J = 8.0 Hz, 1 H), 8.09 (s, 1 H), 7.85 (s, 1 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4 Hz, 2 H), 7.03 (t, J = 4.2 Hz, 1 H), 6.71-6.64 (m, 2 H), 6.55 (d, J = 13.6 Hz, 1 H), 5.24-5.18 (m, 1 H), 4.28-4.22 (m, 1 H), 4.07-4.02 (m, 1 H), 3.66 (t, J = 5.8 Hz, 1 H), 3.18-3.12 (m, 1 H), 2.74 (t, J = 6.8 Hz, 1 H), 1.95 (d, J = 1.6 Hz, 2 H).Example 73N-(4-amino-l-(4-chlorophenyl)-3, 4-dioxobutan-2-yl) chromane-4-carboxamide

[0185] 89 mg as an off-white solid. MS (ESI): m / z: 387.1 [M+H]-. 'H-NMR (400 MHz, ) 3 8.65-8.62 (m, 1 H), 8.07 (d, J = 5.2 Hz, 1 H), 7.82 (d, J = 12.8 Hz, 1 H), 7.39-7.36 (m, 2 H), 7.31-7.25 (m, 2 H), 6.82-6.78 (m, 2 H), 6.68-6.57 (m, 2 H), 5.22-5.18 (m, 1 H), 4.25-4.18 (m, 1 H), 4.06-4.01 (m, 1 H), 3.69-3.65 (m, 1 H), 3.21-3.14 (m, 1 H), 2.82-2.73 (m, 1 H), 1.96-1.87 (m, 2H).Example 75Synthesis of N-((S)-4-(cyclopropylamino)-3,4-dioxo-l-phenylbutan-2-yl)-2,2-dimethylchromane-4-carboxamideAttorney Docket No. NTG-08-PCTSynthesis of N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)-2,2-dimethylchromane-4-carboxamide

[0186] To a stirred solution of 2,2-dimethylchromane-4-carboxylic acid (0.2 g, 0.7 mmol, 1 eq) in DMF (10 mL) are added DIPEA (0.4 mL, 2.2 mmol, 3 eq) followed by EDC. HC1 (0.3 g, 1.5 mmol, 2 eq), oxyma (0.2 g, 1.5 mmol, 2 eq) and (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-phenylbutanamide (200 mg, 0.7 mmol, 1 eq) at 0 °C. The resulting reaction mixture is stirred at rt for 16 h. The reaction progress is monitored by TLC (mobile phase: 50% EtOAc in pet ether, Rf: 0.40, Visualization: UV active). After completion of reaction, ice-cold water (50 mL) is added to the reaction mixture and stirred for 20 min. Then the reaction mixture is extracted with EtOAc (3 x 30 mL), the combined organic layer is washed with 0.5 N HC1 solution (2 x 20 mL) and saturated brine solution, and dried over anhydrous Na2SO4 to obtain the crude product (0.2 g). The crude product is triturated in DCM and pentane and dried under reduced pressure to afford the product (0.14 g) as an off white solid. ESI-MS (m / z): 423.25 [M+H]+.Synthesis of N-((S)-4-(cyclopropylamino)-3,4-dioxo-l-phenylbutan-2-yl)-2,2-dimethylchromane-4-carboxamide

[0187] To a stirred solution of N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)-2,2-dimethylchromane-4-carboxamide (140 mg, 0.3 mmol, 1 eq) in DCM (15 mL) is added Dess-Martin periodinane 97% (421.6 mg, 1 mmol, 3 eq) portion wise at 0 °C. The resulting reaction mixture is stirred at rt for 2 h. The progress of the reaction is monitored by TLC (mobile phase: 30% EtOAc in pet ether, Rf: 0.45, Visualization: UV active). After completion of reaction, the reaction mixture is quenched with saturated solution of Na2S2O5 (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layer is washed with saturated solution of Na2S2O5 (5 x 20 mL) and NaHCO3 (3 x 20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product (0.075 g). The crude product is triturated in EtOAc and pentane and dried under reduced pressure to afford the product (0.07 g) as an off-white solid. MS (ESI): m / z: 421.3 [M+H]+. 'H-NMR (400 MHz, DMSO-d6) 8.82-8.74 (m, 2 H), 7.36-7.22 (m, 5 H), 7.06-6.99 (m, 1 H), 6.78-6.67 (m, 1 H), 6.57-6.41 (m, 1 H), 5.30-5.27 (m, 1 H), 3.80-3.70 (m, 1 H), 3.27-3.18 (m, 1 H), 2.89-2.73 (m, 2 H), 1.87-1.74 (m, 2 H), 1.32 (s, 3 H), 1.15 (s, 3 H), 0.69-0.64 (m, 2 H), 0.62-0.57 (m, 2 H). Example 76Attorney Docket No. NTG-08-PCT

[0188] May be synthesized by procedures described herein.Example 77

[0189] May be synthesized by procedures described herein.Example 78

[0190] To a stirred solution of 1 -amino- 1 -oxo-4-phenyl-3-( 1-phenylcy cl opropane-1-carboxamido)butan-2-yl (300 mg, 0.9 mmol) is added DMP (940 mg, 2.2 mmol, 2.5 eq) at 0 °C and stirred at same temperature for 15 minutes. Reaction is monitored by TLC. Quench the reaction with saturated sodium bicarbonate solution (20 mL) and extract the compound to DCMAttorney Docket No. NTG-08-PCT(50 mL x 3). The DCM layer is washed with brine (20 mL), dried over Na2SO4, and the solvent is evaporated under reduced pressure. Product is purified by triturating with ethanol and diethyl ether. Off-white solid is obtained (30 mg). LC-MS (M+l): 336.9, (M-l): 334.9. H NMR (DMSO-de, 400 MHz): 8.02 (bs, 1H), 7.84 (bs, 1H), 7.32-7.20 (m, 8H), 6.98-6.96 (m, 2H), 6.584 (d, J=8.1 Hz, 1H), 5.18-5.15 (m, 1H), 3.09-3.04 (m, 1H), 2.89-2.84 (m, 1H), 1.29-1.24 (m, 2H), 1.01-0.93 (m, 2H).Example 79Synthesis of N-(4-(cyclopropylamino)-3,4-dioxo-l-(pyridin-2-yl)butan-2-yl)-6-methylspiro[chromane-2,l'-cyclopropane]-4-carboxamide

[0191] To a stirred solution of N-(4-(cyclopropylamino)-3-hydroxy-4-oxo-1-(pyridin-2-yl)butan-2-yl)-6-methylspiro[chromane-2,1'-cyclopropane]-4-carboxamide (150 mg, 0.3 mmol, 1 eq) in DCM (5 mL) is added Dess-Martin periodinane (418 mg, 1 mmol, 3 eq) portion wise at 0 °C under nitrogen atmosphere. The reaction mixture is stirred at rt for 2 h. The progress of the reaction is monitored by TLC (100% EtOAc, Rf: 0.5, UV active). On completion, the reaction mixture is quenched with saturated aqueous sodium thiosulphate (3 x 10 mL) at 0 °C and extracted with DCM (2 x 10 mL). The organic layer is washed with saturated aqueous sodium bicarbonate solution (2 x 10 mL) and extracted with DCM (3 x 10 mL), washed with brine solution (1 x 15 mL), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure to afford crude product (120 mg) as an off-white solid. The crude product is triturated with n-pentane (2 x 10 mL), filtered, and rinsed with n-pentane, dried under high vacuum to afford the product (28 mg) as an off-white solid. MS (ESI): m / z: 434.31 [M+H]+. 'H NMR(400 MHz, DMSO-d6) 5 ppm: 8.72 (bs, 1H), 8.52-8.43 (m, 2H), 7.75-7.73 (m, 1H), 7.33-7.25 (m, 2H), 6.88-6.55 (m, 3H), 5.46 (bs, 1H), 3.82 (bs, 1H), 3.22-3.19 (m, 2H), 2.76 (bs, 1H), 2.34-2.28 (m, 1H), 2.17-2.11 (m, 3H), 1.71-1.67 (m, 1H), 0.86 (bs, 1H), 0.71-0.58 (m, 7H).Attorney Docket No. NTG-08-PCTExample 80Synthesis of 6-cyano-N-((S)-4-(cyclopropylamino)-3,4-dioxo-l-phenylbutan-2-yl)spiro[chromane-2,l'-cyclopropane]-4-carboxamideN%

[0192] To a stirred solution of 6-cyano-N-((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-l-phenylbutan-2-yl)spiro[chromane-2,l'-cyclopropane]-4-carboxamide (29 mg, 0.07 mmol, 1 eq) in DCM (3 mL) is added Dess-Martin Periodinane (82.8 mg, 0.2 mmol, 3 eq) at 0 °C. The resulting reaction mixture is stirred at rt for 3 h. The progress of the reaction is monitored by TLC (mobile phase: 70% EtOAc in pet ether, Rf: 0.45, UV active). After completion of the reaction, the reaction mixture is quenched with sodium thiosulphate (10 mL) and sodium bicarbonate (10 mL) and stirred for 15 min and extracted with DCM (2 x 20 mL). The combined organic layer is washed with sodium thiosulphate (20 mL x 2) and sodium bicarbonate (20 mL x 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated under reduced pressure to afford crude compound (25 mg) as an off-white solid. The crude compound is titrated with diethyl ether (2 x 3 mL) and pentane (2 x 3 mL), dried under high vacuo to afford the product (4.3 mg) as an off-white solid. MS (ESI): m / z: 444.35 [M+H]+.JH NMR(400 MHz, DMSO-d6) δ ppm: 8.84-8.78 (m, 1H), 8.74-8.70 (m, 1H), 7.59-7.51 (m, 1H), 7.37-7.24 (m, 6H), 6.88-6.85 (m, 1H), 5.29-5.23 (m, 1H), 3.92-3.89 (m, 1H), 3.28-3.18 (m, 1H), 2.82-2.78 (m, 2H), 2.28-2.16 (m, 1H), 1.84-1.80 (m, 1H), 1.28-1.26 (m, 2H), 0.98-0.80 (m, 2H), 0.68-0.66 (m, 2H), 0.62-0.53 (m, 2H).Example 81Calpain-1 inhibitionGeneral in vitro protocolAttorney Docket No. NTG-08-PCT

[0193] The ability of compounds of Formula I to inhibit the protease activity of Calpain-1 is determined using the Calpain-1 Calpain-Glo Protease assay, which measures the ability of test compounds to inhibit the cleavage of the luminogenic substrate Suc-LLVY-aminoluciferin (Promega, catalog number G8501).

[0194] Briefly, Calpain-1 enzyme isolated from human erythrocytes (Catalog No.: 208713-500UG, Sigma Aldrich) is diluted in assay buffer and added to test wells and negative control wells in the assay plate (final assay concentration 20 nM). DMSO stock of test compounds is added to the test wells, and DMSO is added to the negative control and background control wells to reach a final concentration of 0.1%. The assay plate is incubated at room temperature for 30 minutes. Following incubation, a detection reagent consisting of Calpain-Glo buffer, Suc-LLVY-Glo Substrate, CaCl2(final concentration 1 mM) and luciferin detection reagent is added to each well, and the plate is incubated in the dark for 12 minutes. Following incubation, luminescence is measured using a Promega Gio-Max reader.Data analysis:

[0195] The inhibition of calpain-1 activity is calculated by normalization to the negative control (Calpain-1 plus 0.1% DMSO, 0% inhibition) and the positive control (assay buffer plus 0.1% DMSO, 100% inhibition). The mean percent inhibition values are used to make a concentrationresponse plot and fitted to a four-parameter logistic curve (equation: y= min+(max-min) / (1+10 ((LogIC50-X)*Hill Slope)).

[0196] Examples of compounds of Formula I are tested across a dose range to determine the concentration at which half-maximal inhibition (IC50) is observed. Representative results are provided in Tables 18 and 19.Table 18.In vitro inhibition of calpain-1Example Number CAPN-1 IC50 pM Example Number CAPN-1 IC50 pM 1 0.07 27 2.1 2 0.1 28 1.4 3 0.2 29 1.5 4 0.2 30 0.02, 0.03 5 6.9 31 0.1 6 1.3 32 0.2 7 0.05 33 0.48 0.08 34 0.4Attorney Docket No. NTG-08-PCT9 0.1 35 0.07 10 0.2 36 1.5 11 0.4 37 0.3 12 0.2 38 0.6 13 1.2 39 0.4 14 0.005 40 0.3 15 0.009 41 0.05 16 0.1 42 0.04, 0.05 17 0.2 43 0.002, 0.004 18 0.1 45 0.06 19 0.02 49 0.07 20 0.06 50 0.07 21 0.1 51 0.05 22 0.04, 0.09 52 0.06 23 0.04 53 0.04 24 > 6.6 54 2.4 25 3.0 55 0.08 26 1.8 56 0.0457 0.3Table 19.In vitro inhibition of calpain-1Example Number CAPN-1 IC50μM Example Number CAPN-1 IC50μM 58 0.5 59 0.1 60 2.6 61 0.03 62 0.2 63 0.1 64 0.4 65 0.9 66 1.9 67 >10 68 1.4 69 1 70 0.02 71 1.3 72 0.2 73 0.1 74 0.1 75 0.02, 0.03 76 0.04, 0.09 77 2.6 78 2.6 79 0.380 0.06

Claims

1. Attorney Docket No. NTG-08-PCT2.CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula I:

5.

6. ^2b7.Formula I8.wherein:9.A is C3-7-cycloalkyl substituted with -Ci-4-alkyl, aryl (e.g., phenyl), -O-CH2-aryl (e.g., -O-CH2-phenyl), or -C(O)O-Ci-4-alkyl or A is the fragment:

11. 13.wherein:14.B is a 4- to 8-membered non-aromatic ring, e.g., a 4- to 7-membered non-aromatic ring, which is fused to the benzene ring and which optionally contains one heteroatom selected from O, S, and N,15.the wavy line shows the point of attachment of the fragment to Formula I,16.the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, C3-6-heterocyclyl, -CN, -C(0)NH2, and 5-to 6-membered heteroaryl optionally substituted with Ci-4-alkyl, and17.x is 0 or 1;18.Ri is C3-7-cycloalkyl, aryl, or 5- to 6-membered heteroaryl each of which is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, Ci-4-alkoxy, C1-4-haloalkyl, -CN, and halogen; and Attorney Docket No. NTG-08-PCT19.R2aand R b are independently selected from H, C3-7-cycloalkyl, Ci-4-alkyl, C3.7-cyloalkyl-C1.4-alkyl, and benzyl optionally substituted with Ci-4-alkyl;20.in free or pharmaceutically acceptable salt form.

2. The compound according to claim 1, in free or pharmaceutically acceptable salt form, wherein R2a is H.

3. The compound according to claim 1 or 2, in free or pharmaceutically acceptable salt form, wherein A is C3-7-cycloalkyl mono-substituted with -Ci-4-alkyl, aryl, -O-CH2-aryl, or -C(O)O-Ci-4-alkyl.

4. The compound according to claim 3, in free or pharmaceutically acceptable salt form, wherein A is the fragment:

25. 27.wherein the wavy line shows the point of attachment of the fragment to Formula I.

5. The compound according to claim 1 or 2, in free or pharmaceutically acceptable salt form, wherein A is the fragment:

30. 32.wherein:33.B is a 4- to 7-membered non-aromatic ring which is fused to the benzene ring and which optionally contains one heteroatom selected from O, S, and N, the wavy line shows the point of attachment of the fragment to Formula I, the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, Attorney Docket No. NTG-08-PCT34.C3-6-heterocyclyl, -CN, -C(0)NH2, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl, and x is 0 or 1.

6. The compound according to any one of claims 1, 2, or 5, in free or pharmaceutically acceptable salt form, wherein x is 0, so A is the fragment:

37. 39.wherein B is a 4- to 6-membered non-aromatic ring which is fused to the benzene ring and which optionally contains one heteroatom selected from O, S, and N, the wavy line shows the point of attachment of the fragment to Formula I, and the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, C3-6-heterocyclyl, -CN, -C(0)NH2, and 5- to 6-membered heteroaryl optionally substituted with C i-4- alkyl.

7. The compound according to claim 5 or 6, in free or pharmaceutically acceptable salt form, wherein B is a 6-membered non-aromatic ring which is fused to the benzene ring and which contains one N.

8. The compound according to claim 7, in free or pharmaceutically acceptable salt form, wherein A is the fragment:

43.

9. The compound according to claim 5 or 6, in free or pharmaceutically acceptable salt form, wherein the fragment is optionally substituted with one or more substituentsAttorney Docket No. NTG-08-PCT46.independently selected from Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl, and x is 0 or 1.

10. The compound according to claim 5, 6, or 9, in free or pharmaceutically acceptable salt form, wherein B is a 5- or 6-membered non-aromatic ring which is fused to the benzene ring and which contains one O.

11. The compound according to claim 5, 6, 9, or 10, in free or pharmaceutically acceptable salt form, wherein A is the fragment:

50. 52.wherein the wavy line shows the point of attachment of the fragment to Formula I and the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, halogen, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl.

12. The compound according to claim 11, in free or pharmaceutically acceptable salt form, wherein A is the fragment:

55. 57.wherein the wavy line shows the point of attachment of the fragment to Formula I and the fragment is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, halogen, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl. Attorney Docket No. NTG-08-PCT13. The compound according to claim 12, in free or pharmaceutically acceptable salt form, wherein the fragment is substituted with one or two substituents selected from Ci-4-alkyl, halogen, and 5- to 6-membered heteroaryl optionally substituted with Ci-4-alkyl.

14. The compound according to claim 12 or 13, in free or pharmaceutically acceptable salt form, wherein the fragment is substituted with one substituent selected from halogen.

15. The compound according to claim 14, in free or pharmaceutically acceptable salt form, wherein the fragment is substituted with F or Cl.

16. The compound according to claim 12, in free or pharmaceutically acceptable salt form, wherein the fragment is substituted with one 5- to 6-membered heteroaryl optionally mono- substituted with Ci-4-alkyl.

17. The compound according to claim 16, in free or pharmaceutically acceptable salt form, wherein the fragment is substituted with one pyrazolyl mono-substituted with -CH3.

18. The compound according to claim 12 or 13, in free or pharmaceutically acceptable salt form, wherein the fragment is substituted with one or two substituents selected from Ci-4-alkyl.

19. The compound according to any one of claims 1, 2, or 5-18, in free or pharmaceutically acceptable salt form, wherein the fragment66. 68.is: Attorney Docket No. NTG-08-PCT70.

71. wherein the wavy line shows the point of attachment of the fragment to Formula I. Attorney Docket No. NTG-08-PCT20. The compound according to any one of claims 1-19, in free or pharmaceutically acceptable salt form, wherein Ri is phenyl optionally substituted with one substituent independently selected from halogen (e.g., F or Cl), alkoxy (e.g., methoxy), and -CN or Ri is pyridyl.

21. The compound according to claim 20, in free or pharmaceutically acceptable salt form, wherein Ri is phenyl optionally substituted with F, Cl, methoxy, or-CN.

22. The compound according to any one of claims 1-21, in free or pharmaceutically acceptable salt form, wherein R2b is H.

23. The compound according to any one of claims 1-21, in free or pharmaceutically acceptable salt form, wherein R2b is Ci-4-alkyl (e.g., -CH3).

24. The compound according to any one of claims 1-21, in free or pharmaceutically acceptable salt form, wherein R2b is C3-7-cycloalkyl (e.g., cyclopropyl).

25. A compound of Formula II:

79. 81.Formula II,82.wherein:83.Ri is C3-7-cycloalkyl, aryl, or 5- to 6-membered heteroaryl each of which is optionally substituted with one or more substituents independently selected from Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, -CN, and halogen;84.R2aand R2b are independently selected from H, C3-7-cycloalkyl, Ci-4-alkyl, C3-7-cyloalkyl-Ci-4-alkyl, and benzyl optionally substituted with Ci-4-alkyl; and Attorney Docket No. NTG-08-PCT85.R.3 and R4 are independently bonded to either ring of the chromanyl fragment and are independently selected from H, Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, C3-6-heterocyclyl, -CN, -C(0)NH2, and 5- to 6-membered heteroaryl optionally substituted with C1.4-alkyl;86.in free or pharmaceutically acceptable salt form.

26. The compound according to claim 25, in free or pharmaceutically acceptable salt form, wherein R3 and R4 are independently bonded to either ring of the chromanyl fragment and are independently selected from H, Ci-4-alkyl, Ci-4-alkoxy, Ci-4-haloalkyl, halogen, oxo, and 5-to 6-membered heteroaryl optionally substituted with Ci-4-alkyl.

27. The compound according to claim 25 or 26, free or pharmaceutically acceptable salt form, wherein the compound of Formula II is:89.490.o91.H II N92.H94. 95.R2b28. A compound, in free or pharmaceutically acceptable salt form, wherein the compound is selected from any of those set forth in Table 1.

29. A compound, in free or pharmaceutically acceptable salt form, wherein the compound is selected from any of those set forth in Table 2.

30. A compound, in free or pharmaceutically acceptable salt form, wherein the compound is selected from any of those set forth in Table 3.

31. A compound, in free or pharmaceutically acceptable salt form, wherein the compound is selected from any of those set forth in Table 4.Attorney Docket No. NTG-08-PCT32. A compound, in free or pharmaceutically acceptable salt form, wherein the compound is selected from any of those set forth in Table 5.

33. A compound, in free or pharmaceutically acceptable salt form, wherein the compound is selected from any of those set forth in Table 6.

34. A compound, in free or pharmaceutically acceptable salt form, wherein the compound is selected from any of those set forth in Table 7.

35. A compound, in free or pharmaceutically acceptable salt form, wherein the compound is selected from any of those set forth in Table 8.

36. A compound, in free or pharmaceutically acceptable salt form, wherein the compound is selected from any of those set forth in Table A, Table B, Table C, or Table D.

37. A pharmaceutical composition, wherein the pharmaceutical composition comprises the compound according to any one of claims 1-36, in free or pharmaceutically acceptable salt form, in combination with a pharmaceutically acceptable carrier.

38. A method for prophylaxis or treatment of a calpain-mediated disorder in a patient in need thereof, wherein the method comprises administering an effective amount of the compound according to any one of claims 1-36, in free or pharmaceutically acceptable salt form, or the pharmaceutical composition according to claim 37, to the patient.

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