MASP-2 INHIBITORS AND METHODS OF USE

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Serial Numbers 62677472, filed May 29, 2018, U.S. Provisional Application Serial Numbers 62677538, filed May 29, 2018, U.S. Provisional Application Serial Numbers 62677495, filed May 29, 2018, and U.S. Provisional Application Serial Numbers 62677514, filed May 29, 2018. Each of the foregoing related applications is incorporated herein by reference in its entirety.

STATEMENT REGARDING SEQUENCE LISTING

The sequence listing associated with this application is provided in text format in lieu of a paper copy and is hereby incorporated by reference into the specification. The name of the text file containing the sequence listing is MP_l_0282_PCT_SequenceListing_20l 90528. The text file is 7 KB, was created on May 28, 2019, and is being submitted via EFS-Web with the filing of the specification.

FIELD

The present disclosure is directed generally to compositions and methods that are useful in the field of medicine. More specifically, the disclosure provides small molecule synthetic inhibitors of mannan-binding lectin-associated serine protease-2 (MASP-2), including small molecule inhibitors that are selective for MASP-2 over thrombin,

compositions thereof, and methods for the manufacture and use thereof.

BACKGROUND

The complement system plays a role in the inflammatory response and becomes activated because of tissue damage or microbial infection. Complement activation must be tightly regulated to ensure selective targeting of invading microorganisms and avoid self- inflicted damage (Ricklin et al., Nat. Immunol. 11 :785-797, 2010). Currently, it is widely accepted that the complement system can be activated through three distinct pathways: the classical pathway, the lectin pathway, and the alternative pathway. The classical pathway is usually triggered by a complex composed of host antibodies bound to a foreign particle (i.e., an antigen) and generally requires prior exposure to an antigen for the generation of a specific antibody response. Since activation of the classical pathway depends on a prior adaptive immune response by the host, the classical pathway is part of the acquired immune system. In contrast, both the lectin and alternative pathways are independent of adaptive immunity and are part of the innate immune system.

Mannan-binding lectin-associated serine protease-2 (MASP-2) has been shown to be required for the function of the lectin pathway, one of the principal complement activation pathways (Vorup-Jensen et al, J. Immunol 165:2093-2100, 2000; Ambrus et al, J Immunol. 170: 1374-1382, 2003; Schwaeble et al, PNAS 108:7523-7528, 2011). Importantly, inhibition of MASP-2 does not appear to interfere with the antibody-dependent classical complement activation pathway, which is a critical component of the acquired immune response to infection. As described in U.S. Patent No. 9,011,860 (assigned to Omeros corporation), which is hereby incorporated by reference, discloses a fully human monoclonal antibody targeting human MASP-2 has been generated which binds to human MASP-2 with high affinity and blocks the lectin pathway complement activity and is therefore useful to treat various lectin complement pathway-associated diseases and disorders.

MASP-2-dependent complement activation has been implicated as contributing to the pathogenesis of numerous acute and chronic disease states. Therefore, a need exists for small molecule compounds which are suitable for administration for treatment of subject suffering from MASP-2 complement pathway-associated diseases and disorders.

An important protein for mammalian immunity is the mannan-binding lectin- associated serine protease-2 (MASP-2), which has been shown to be required for the function of the lectin pathway, one of the principal complement activation pathways (Vorup-Jensen et al., J. Immunol 165:2093-2100, 2000; Ambrus et al, J Immunol. 170: 1374-1382, 2003; Schwaeble et al, PNAS 108:7523-7528, 2011). Inhibition of MASP-2 does not appear to interfere with the antibody-dependent classical complement activation pathway, which is a critical component of the acquired immune response to infection. Inhibiting human MASP-2 to block the lectin pathway complement activity is useful to treat various lectin complement pathway-associated diseases and disorders.

Therapeutic compounds and methods of identifying small molecule inhibitors of MASP-2 are needed as they are important to treat various lectin complement pathway- associated diseases and disorders, including diseases that are not suitably or efficiently treated with large molecule biologic inhibitors.

SUMMARY

The present disclosure provides, inter alia, compounds of Formulae (1-1) and (1-2):

or a salt thereof; wherein the variables are as defined below.

The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (1-1) or (1-2), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

The compounds of Formula (1-1) or (1-2) are useful in the treatment of MASP-2- associated diseases and disorders, and in the manufacture of medicaments for treating MASP- 2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (1-1) or (1-2), or a salt thereof.

The present disclosure provides, inter alia, compounds of Formulae (IIA) and (IIB):

or a salt thereof; wherein the variables are as defined below. Various embodiments of the compounds of Formula (IIA) or (IIB), are also described. The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

The compounds of Formula (IIA) or (IIB) are useful in the treatment of MASP-2- associated diseases and disorders, and in the manufacture of medicaments for treating MASP- 2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (IIA) or (IIB), or a salt thereof.

The present disclosure provides, inter alia, compounds of Formula (III):

or a salt thereof; wherein the variables are as defined below. Various embodiments of the compounds of Formula (III), are also described.

The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

The compounds of Formula (III) are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2- associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a

therapeutically effective amount of a compound of Formula (III), or a salt thereof.

The present disclosure provides, inter alia, compounds of Formulae (IV):

or a salt thereof; wherein the variables are as defined below. Various embodiments of the compounds of Formula (IV), are also described.

The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. The compounds of Formula (IV) are useful as MASP-2 inhibitors. The compounds of Formula (IV) are useful in therapy. The compounds of Formula (IV) are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (IV), or a salt thereof.

The present disclosure provides, inter alia, compounds of Formulae (VA) or (VB):

or a salt thereof; wherein the variables are as defined below. Various embodiments of the compounds of Formula (VA) or (VB) are also described.

The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (VA) or (VB), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

The compounds of Formula (VA) and (VB) are useful as MASP-2 inhibitors. The compounds of Formula (VA) and (VB) are useful in therapy. The compounds of Formula (VA) and (VB) are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (VA) or (VB), or a salt thereof.

The present disclosure provides, inter alia, compounds of Formulae (VIA) or (VIB):

or a salt thereof; wherein the variables are as defined below. Various embodiments of the compounds of Formula (VIA) or (VIB) are also described.

The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (VIA) or (VIB), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

The compounds of Formula (VIA) and (VIB) are useful as MASP-2 inhibitors. The compounds of Formula (VIA) and (VIB) are useful in therapy. The compounds of Formula (VIA) and (VIB) are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (VIA) or (VIB), or a salt thereof.

The present disclosure provides, inter alia, compounds of Formulae (VIIA) or

(VIIB):

or a salt thereof; wherein the variables are as defined below. Various embodiments of the compounds of Formula (VIIA) or (VIIB) are also described.

The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (VIIA) or (VIIB), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. The compounds of Formula (VIIA) and (VIIB) are useful as MASP-2 inhibitors. The compounds of Formula (VIIA) and (VIIB) are useful in therapy. The compounds of Formula (VIIA) and (VIIB) are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (VIIA) or (VIIB), or a salt thereof.

These and other aspects, objects and embodiments will become more apparent when read with the detailed description and figures which follow.

DESCRIPTION

I. Definitions

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

In the Summary above, the present Description, and the claims below, reference is made to particular features and aspects of the invention, including method steps. The disclosure of the invention in this specification includes all possible combinations of such particular features within the embodiments of the invention disclosed, at least to the extent that such combinations are non-contradictory. For example, if the description presents aspects A, B, and C of an embodiment, it is understood that this also discloses particular

embodiments including both aspects A and B, both aspects B and C, and both aspects A and C, as well as an embodiment with aspects A, B, and C. a. General Definitions

The terms "a," "an," or "the" not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and reference to "the agent" includes reference to one or more agents known to those skilled in the art. [0001] The terms "about" and "approximately" refer to an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Typical, exemplary degrees of error are within 20 percent (%); preferably, within 10%; and more preferably, within 5% of a given value or range of values. Any reference to "about X" specifically indicates at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X,

1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" is intended to teach and provide written support for a claim limitation of, e.g., "0.98X." Alternatively, in biological systems, the terms "about" and "approximately" may mean values that are within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a given value. Numerical quantities given herein are approximate unless stated otherwise, meaning that the term "about" or "approximately" can be inferred when not expressly stated. When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "from about 5 to 20%" is equivalent to "from about 5% to about 20%. " When "about" is applied to the first value of a set of values, it applies to all values in that set. Thus, "about 7,

9, or 11 mg/kg" is equivalent to "about 7, about 9, or about 11 mg/kg."

The term "MASP-2" refers to mannan-binding lectin-associated serine protease-2. Human MASP-2 protein with UniProt accession code 000187 (SEQ ID NO: l). The Serine Protease Domain ('B-chain' = Mannan-binding lectin serine protease 2 B chain, based on UniProtKB - 000187 (MASP-2_HUMAN)) includes residues 445 to 686 (or consists of residues 445 to 686).

The term "MASP-2-dependent complement activation" refers to MASP-2-dependent activation of the lectin pathway, which occurs under physiological conditions (i.e.. in the presence of Ca ⁺⁺ ) leading to the formation of the lectin pathway C3 convertase C4b2a and upon accumulation of the C3 cleavage product C3b subsequently to the C5 convertase C4b2a(C3b)n.

The term "MASP-2-dependent complement-associated disease or disorder" refers to a disease or disorder that is associated with MASP-2-dependent complement activation.

The term "MASP-2-associated disease or disorder" refers to a disease or disorder that is associated with activation or activity of MASP-2, including MASP-2-dependent complement-associated disease or disorders, and wherein inhibition of MASP-2 is or is expected to be therapeutically beneficial.

The term "lectin pathway" refers to complement activation that occurs via the specific binding of serum and non-serum carbohydrate-binding proteins including mannan-binding lectin (MBL), CL- 11 and the ficolins (H-ficolin, M-ficolin, or L-ficolin). The term "classical pathway" refers to complement activation that is triggered by an antibody bound to a foreign particle and requires binding of the recognition molecule Clq.

Amino acid residues are abbreviated as follows: alanine (Ala; A), asparagine (Asn;

N), aspartic acid (Asp; D), arginine (Arg; R), cysteine (Cys; C), glutamic acid (Glu; E), glutamine (Gln; Q), glycine (Gly; G), histidine (His; H), isoleucine (Ile), leucine (Leu), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

In the broadest sense, the naturally occurring amino acids can be divided into groups based upon the chemical characteristic of the side chain of the respective amino acids. By "hydrophobic" amino acid is meant either His, Leu, Met, Phe, Trp, Tyr, Val, Ala, Cys or Pro. By "hydrophilic" amino acid is meant either Gly, Asn, Gln, Ser, Thr, Asp, Glu, Lys, Arg or His. This grouping of amino acids can be further sub-classed as follows: by "uncharged hydrophilic" amino acid is meant either Ser, Thr, Asn or Gln. By "acidic" amino acid is meant either Glu or Asp. By "basic" amino acid is meant either Lys, Arg or His.

The term "conservative amino acid substitution" is illustrated by a substitution among amino acids within each of the following groups: (1) glycine, alanine, valine, leucine, and isoleucine, (2) phenylalanine, tyrosine, and tryptophan, (3) serine and threonine, (4) aspartate and glutamate, (5) glutamine and asparagine, and (6) lysine, arginine and histidine.

The term "a subject" includes all mammals, including without limitation, humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs and rodents.

The terms "small molecule" and "small organic molecule" refers to a small carbon- containing molecule that has a molecular weight of about 2500 daltons or lower. In some embodiments, a small molecule has a molecular weight of about 2000 daltons or lower. In some embodiments, a small molecule has a molecular weight of about 1500 daltons or lower. In some embodiments, a small molecule has a molecular weight of about 1000 daltons or lower. In some embodiments, a small molecule has a molecular weight of about 750 daltons or lower. In some embodiments, a small molecule has a molecular weight of about 500 daltons or lower. In some embodiments, a small molecule has a molecular weight of about 50 daltons or greater. In some embodiments, a small molecule has a molecular weight of about 75 daltons or greater. In some embodiments, a small molecule has a molecular weight of about 100 daltons or greater. In some embodiments, a small molecule has a molecular weight of about 150 daltons or greater. In some embodiments, a small molecule has a molecular weight of about 250 daltons or greater. In some emboiments, small molecules may have a molecular weight in the range from about 50 daltons to about 500 daltons, from about 50 daltons to about 750 daltons, from about 50 daltons to about 1000 daltons, from about 50 daltons to about 1500 daltons, from about 50 daltons to about 2000 daltons, or from about 50 daltons to about 2500 daltons. When the term "compound" is used herein, the term is explicitly intended to include small molecule compounds as defined herein (including any of the embodiments thereof).

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The terms "disorder," "disease," and "condition" are used interchangeably for a condition in a subject. A disorder is a disturbance or derangement that affects the normal function of the body of a subject. A disease is a pathological condition of an organ, a body part, or a system resulting from various causes, such as infection, genetic defect, or environmental stress that is characterized by an identifiable group of symptoms.

The term "effective amount" or "effective dose" means an amount sufficient to achieve the desired result and accordingly will depend on the ingredient and its desired result. Nonetheless, once the desired effect is identified, determining the effective amount is within the skill of a person skilled in the art.

The term "subcutaneous administration" refers to administration of a formulation under all layers of the skin of a subject.

The term "histidine" specifically includes L-histidine unless otherwise specified.

The term "isotonic" refers to a formulation that has essentially the same osmotic pressure as human blood. Isotonic formulations will generally have an osmotic pressure from about 250 to about 350 mOsmol/L. Isotonicity can be measured using a vapor pressure or freezing point depression osmometer, for example.

The term "hypertonic" refers to a formulation with an osmotic pressure above that of human (i.e., greater than 350 mOsm/L).

The term "hydrogen-bonding" is a partially electrostatic attraction between a hydrogen (H) which is bound to a more electronegative atom such as nitrogen (N) or oxygen (O) and another adjacent atom bearing a lone pair of electrons. For example, when it is stated that the nitrogen acts as a "hydrogen bond donor" it means that a hydrogen (H) bound to a nitrogen (N) is donated by the nitrogen as it electrostatically attracted to or accepted by an adjacent atom bearing a lone pair of electrons such as an oxygen. Similarly, when it is stated that an oxygen acts as a "hydrogen bond acceptor," it means that a hydrogen (H) bound to a more electronegative atom such as nitrogen (N) is electrostatically attracted to or "accepted by" an adjacent atom such as oxygen bearing a lone pair of electrons. Sometimes the hydrogen bonded atoms are called out without explicitly stating the origin and presence of an intermediate hydrogen atom. The term "hydrogen bonding" is used wherever LigPlot+ software predicts a hydrogen bonding interaction using its algorithm and applied parameters of 3.35 A for maximum distance between hydrogen bond donor and acceptor. Not all hydrogen bonds may actually be in place simultaneously; this is evident for atoms that are shown to form 4 putative hydrogen bonds, where however, at any given time only 3 hydrogen bonds are chemically possible. In general, although crystal structures such as the co-crystal structural information herein does not directly show or detect hydrogen bonding, the software used to describe the co-crystal does predict such H-bonding exists. Therefore, throughout the disclosure when a H-bond is present and described, it may be said to be "predicted" by software to be present.

The term ionic bonding includes a type of chemical bond that involves the electrostatic attraction between oppositely charged ions, and is the primary interaction occurring in ionic compounds.

The term "van der Waals" interaction includes weak, short-range electrostatic attractive forces between uncharged molecules, arising from the interaction of permanent or transient electric dipole moments. As determined by LigPlot+ software employing models derived from the corresponding crystallographic MASP-2 compound co-structures, such interactions include all contacts that are computed using non-bonded contact parameters between hydrophobic to any contacts for interactions with a maximum contact distance of 3.90 A.

The term "p-p interaction or p-p stacking" interaction includes attractive, noncovalent interactions between aromatic rings that are oriented either roughly parallel or roughly perpendicular (such as in "edge-face" interactions) to each other, since they contain p bonds.

Typically, the active site of serine proteases such as MASP-2 is shaped as a cleft where the polypeptide substrate or inhibitor binds. Schechter and Berger labeled amino acid residues from the N to C terminus of the polypeptide substrate as follows: Pi,..., P3, P2, Pl, RG, P2', P3',..., Pj) and their respective binding sub-sites Si,..., S3, S2, Sl, ST, S2', S3',..., Sj. The cleavage is catalyzed between Pl and RG (Schechter, I. & Berger, A. On the size of the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun. 27 (1967)). The term "binding site" is an area on the protein wherein a small molecule can interact with such as a region on the surface of MASP-2, which region does not or only partially overlaps with the active site, but nevertheless render the MASP-2 molecule less active or inactive.

The term "or" refers to an alternative and should in general be construed non- exclusively. For example, a claim to "a composition comprising A or B" would typically present an aspect with a composition comprising both A and B. "Or" should, however, be construed to exclude those aspects presented that cannot be combined without contradiction (e.g., a composition pH that is between 9 and 10 or between 7 and 8).

The group "A or B" is equivalent to the group "selected from the group consisting of A and B."

The linking term "comprising" or "comprise" is not closed. For example, "a composition comprising A" must include at least the component A, but it may also include one or more other components (e.g., B; B and C; B, C, and D; and the like). The term "comprising" therefore should in general be construed as not excluding additional ingredients. For example, a claim to "a composition comprising A" would cover compositions that include A and B; A, B, and C; A, B, C, and D; A, B, C, D, and E; and the like.

The term "hypertonic" refers to a formulation with an osmotic pressure above that of human (i.e., greater than 350 mOsm/KglHhO).

The term "agent" refers to a compound or mixture of compounds that, when added to a composition, tend to produce a particular effect on the composition's properties. For example, a composition comprising a thickening agent is likely to be more viscous than an otherwise identical comparative composition that lacks the thickening agent.

[0002] A "subject" includes all mammals, including without limitation, humans, non human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs and rodents.

A "synthetic" compound means a compound that is not naturally occurring and that has been synthesized by humans. Reference to a compound herein may be understood to include reference to synthetic compounds, unless the context indicates otherwise.

The terms "treat," "treating," or "treatment" includes administering or applying a composition (e.g., a composition described herein) in an amount, manner (e.g., schedule of administration), and mode (e.g., route of administration) that is effective to improve a disorder or a symptom thereof, or to prevent, to retard, or to slow the progression of a disorder or a symptom thereof. Such improvements can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable.

"Treating" and "treatment" also include prophylactic treatment. In certain

embodiments, treatment methods comprise administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may comprise a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the subject, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In one aspect, chronic administration may be required. For example, the compositions are administered to the subject in an amount, and for a duration, sufficient to treat the subject.

The expressions, "ambient temperature" and "room temperature," as used herein, are understood in the art, and refer generally to a temperature, e.g. , a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g., a temperature from about 20 °C to about 30 °C. b. Chemical Definitions

At various places in the present specification, certain features of the compounds are disclosed in groups or in ranges. It is specifically intended that such a disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the terms "Ci-6 alkyl" and "C1-C6 alkyl" are specifically intended to individually disclose (without limitation) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and Ce alkyl.

At various places in the present specification, variables defining divalent linking groups are described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CR'R") _n - includes both -NR(CR'R")n- and -(CR'R")nNR- and is intended to disclose each of the forms individually. Where the structure requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl" then it is understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted", unless otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta- substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. The phrase "optionally substituted" means substituted or unsubstituted. The term "substituted" means that a hydrogen atom is formally removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The terms "Cn-m" and "Cn-C _m " where n and m are integers indicates a group that contains from n to m carbon atoms. Examples include Ci-4, Ci-6, and the like. The term is intended to expressly disclose every member in the range, i.e., Cn, Cn+i, Cn+2 ... Cm-2, Cm-1, Cm. For example, Ci-6 is intended to disclose Ci, C2, C3, C4, Cs, and Ce. "Cn-m" means the same as "Cn-Cm".

The term "alkyl" employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched. The terms "Cn-m alkyl" and "Cn-Cm alkyl" refer to an alkyl group having n to m carbon atoms. For example, C1-C12 indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it. If not otherwise indicated, an alkyl group about 1 to about 20 carbon atoms. An alkyl group formally corresponds to an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, «-propyl, isopropyl, «-butyl, tert- butyl, isobutyl, .sec-butyl: higher homologs such as 2-methyl- 1 -butyl, l,l-dimethylpropyl, «-pentyl, 3-pentyl, «-hexyl, 1,2,2- trimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, and the like. The term "lower alkyl" refers to alkyl groups having from 1 to 6 carbon atoms in the chain. A "substituted alkyl" group is an alkyl group that is substituted with one or more substituents.

The term "alkenyl" employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound. The terms "Cn-m alkenyl" and "Cn-Cm alkenyl" refer to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n- propenyl, isopropenyl, «-butenyl. ve -butenyl and the like.

The term "alkynyl" employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. An alkynyl group formally corresponds to an alkyne with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. The term "C _n -m alkynyl" and "Cn-Cm alkynyl" refer to an alkynyl group having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

The term "alkylene", employed alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane with two C-H bonds replaced by points of attachment of the alkylene group to the remainder of the compound. The term "C _n -m alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethan-l,2-diyl, propan-l,3-diyl, propan- 1 ,2-diyl, butan-l,4-diyl, butan-l,3-diyl, butan-l,2-diyl, 2-methyl- propan-l,3-diyl and the like. In some embodiments, "Cn-m alkylene" can refer to chain of from n to m methylene (CH2) groups, -(CH2)n-m-, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, etc.

The term "alkoxy", employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group is as defined above. The term "Cn-m alkoxy" refers to an alkoxy group, the alkyl group of which has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n- propoxy and isopropoxy), t-butoxy and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

The term "alkoxy alkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by an alkoxy group. The term "Cn-m alkoxy-C _P -q alkyl" refers to a C _P - q alkyl group substituted by a Cn-m alkoxy group. In some embodiments, the hydroxyalkyl group has one alkoxy group. In some embodiments, the alkoxyalkyl group has one or two alkoxy groups, each on a different carbon atom. Examples may include, but are not limited to, methoxymethyl, ethoxymethyl, 3-ethoxy ethyl, and 1 -methoxy ethyl.

The term "amino" refers to a group of formula -NH2. The term "carbamyl" refers to a group of formula -C(0)NH2.

The term "carbonyl", employed alone or in combination with other terms, refers to a - C(=0)- group, which also may be written as C(O).

The term "cyano" or "nitrile" refers to a group of formula -CºN, which also may be written as -CN.

The terms "halo" or "halogen", used alone or in combination with other terms, refers to fluoro, chloro, bromo and iodo. In some embodiments, "halo" refers to a halogen atom 10 selected from F, Cl, or Br. In some embodiments, halo is F.

The term "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom. The term " C _n -m haloalkyl" refers to a Cn-m alkyl group having n to m carbon atoms and from at least one up to {2(n to m)+l } halogen atoms, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CCh, CHCh, C2CI5 and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.

The term "haloalkoxy", employed alone or in combination with other terms, refers to a group of formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term "Cn-m haloalkoxy" refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons. Example haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

The term "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a hydroxy. The term "Cn-m hydroxyalkyl" refers to a Cn- m alkyl group having n to m carbon atoms and from at least one hydroxy group. In some embodiments, the hydroxyalkyl group has one alcohol group. In certain aspects, the hydroxyalkyl group has one or two alcohol groups, each on a different carbon atom. In certain aspects, the hydroxyalkyl group has 1, 2, 3, 4, 5, or 6 alcohol groups. Examples may include, but are not limited to, hydroxymethyl, 2-hydroxy ethyl, and 1 -hydroxy ethyl.

The term "oxo" refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an /V-oxide group.

The term "sulfido" refers to a sulfur atom as a divalent substituent, forming a thiocarbonyl group (C=S) when attached to carbon.

The term "n-membered," where n is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. The term "n-m membered" wherein n and m are integers describes a range where the number of ring forming atoms is from n to m. For example, piperidinyl is an example of a 6-membered

heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring and l,2,3,4-tetrahydro-naphthalene is an example of a lO-membered cycloalkyl group.

The term "aromatic" refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e.. having (4n + 2) delocalized p (pi) electrons where n is an integer).

The term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term "Cn-m aryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetracenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms, from 6 to about 18 carbon atoms, from 6 to about 15 carbon atoms, or from 6 to about 10 carbon atoms. In some embodiments, the aryl group is phenyl.

The term "arylalkyl" or "aralkyl" or "alkylaryl" employed alone or in combination with other terms, refers to a group of formula -alkylene-aryl, and refers to an alkyl group as defined herein wherein at least one hydrogen has been replaced by an aryl group as defined herein. In some embodiments, arylalkyl is C6-10 aryl-Ci-3 alkyl. In some embodiments, arylalkyl is C6-10 aryl-Ci-4 alkyl. In some embodiments, arylalkyl is C6-10 aryl-Ci-3 alkyl. In some embodiments, arylalkyl is phenyl-Ci-3 alkyl. Examples include, but are not limited to, benzyl, 1 -phenylethyl, 4-methylbenzyl, and l,l,-dimethyl-l-phenylmethyl. In some embodiments, arylalkyl is benzyl.

The term "heteroaryl" or "heteroaromatic," employed alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen and nitrogen. An "n-membered heteroaryl" or "n-membered heteroaromatic", wherein n is an integer, refers to a heteroaryl having n ring-forming atoms. An "n-m membered heteroaryl" or "n-m membered heteroaromatic", wherein n and m are integers, refers to a heteroaryl having from n to m ring forming atoms. The number of carbon atoms in the ring is fewer than the number of ring forming atoms by the number of heteroatoms. Thus, in some embodiments, an n-membered heteroaryl may have n-l, n-2, n-3 or n-4 ring carbon atoms and an n-m membered heteroaryl may have from n-l, n-2, n-3 or n-4 ring carbon atoms to m-l, m-2, m-3 or m-4 ring carbon atoms. In some embodiments, an n-m membered heteroaryl may have from 1 to m-l ring carbon atoms. In some embodiments, the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, quinoline, isoquinoline, naphthyridine (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6- naphthyridine), indole, azaindole, benzothiophene, benzofuran, benzisoxazole,

benzimidazole, imidazo| 1.2-6 |thiazole. purine, furazane, triazole, tetrazole, l,2,4-thiadiazole, quinazoline, phthalazine, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, or the like.

A five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more ( e.g ., 1, 2 or 3) ring atoms are independently selected from N, O and S.

Exemplary five-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, l,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, l,2,3-oxadiazolyl, 1 ,2,4-triazolyl, l,2,4-thiadiazolyl, 1 ,2,4-oxadiazolyl, 1,3,4- triazolyl, l,3,4-thiadiazolyl and l,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected fromN, O and S.

Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term "heteroarylalkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-heteroaryl. The term "n-membered heteroarylalkyl" wherein n is an integer refers to a heteroarylalkyl group in which the heteroaryl is n-membered. The term "n-m membered-Cp-q-alkyl" wherein n, m, p and q are integers refers to heteroarylalkyl group in which the heteroaryl is n to m membered and the alkyl has from p to q carbon atoms. In some embodiments, heteroarylalkyl is 5-10 membered heteroaryl-Ci-3 alkyl or Ci-9 heteroaryl-Ci-3 alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and has 1, 2, 3, 4 or 5 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, heteroarylalkyl is C 1-9 heteroaryl-Ci-4 alkyl, wherein the heteroaryl portion is monocyclic or bicyclic and has 1, 2, 3, or 4 heteroatom ring members

independently selected from nitrogen, sulfur and oxygen. Examples include pyridylmethyl, such as 2-pyridylmethyl, 3 -pyridylmethyl, or 4-pyridylmethyl.

The term "cycloalkyl", employed alone or in combination with other terms, refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. The term includes cyclized alkyl and alkenyl groups. The term "Cn-m cycloalkyl" refers to a cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C3-7). In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, bicyclo[l. l. l]pentanyl, bicyclo[2. l.l]hexanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term "cycloalkylalkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-cycloalkyl. The term Cn-m cycloalkyl-Cp-q alkyl wherein n, m, p and q are integers, refers to a cycloalkyl group having from n to m carbon atoms attached to an alkyl group having from p to q carbon atoms. In some embodiments, cycloalkylalkyl is C3-7 cycloalkyl-Ci-3 alkyl, wherein the cycloalkyl portion is monocyclic or bicyclic. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentanemethyl, and cyclohexylmethyl.

The term "heterocycloalkyl", employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, and oxygen. An "n-membered heterocycloalkyl" wherein n is an integer, refers to a heteroaryl having n ring-forming atoms. An "n-m membered heterocycloalkyl" wherein n and m are integers, refers to a

heterocycloalkyl having from n to m ring-forming atoms. The number of carbon atoms in the ring is fewer than the number of ring forming atoms by the number of heteroatoms. Thus, in some embodiments, an n-membered heterocycloalkyl may have n-l, n-2, n-3 or n-4 ring carbon atoms and an n-m membered heterocycloalkyl may have from n-l, n-2, n-3 or n-4 ring carbon atoms to m-l, m-2, m-3 or m-4 ring carbon atoms. In some embodiments, an n-m membered heterocycloalkyl may have from 1 to m-l ring carbon atoms. In some

embodiments, a heterocycloalkyl has 4-12 ring members, 4-10 ring members, 4-7 ring members or 4-6 ring members. Included in heterocycloalkyl groups are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic ( e.g ., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfide group or other oxidized linkage (e.g., C(O), S(O), C(S) or S(0) ₂ , /V-oxide etc.) or a nitrogen atom can be quatemized. The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e.. having a bond in common with) to the heterocycloalkyl ring, e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of heterocycloalkyl groups include azetidine, azepane, dihydrobenzofuran, dihydrofuran, dihydropyran, morpholine, 3-oxa-9- azaspiro[5.5]undecane, l-oxa-8-azaspiro[4.5]decane, piperidine, piperazine, pyran, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, l,2,3,4-tetrahydroquinoline, tropane, and thiomorpholine.

As used herein, the term "heterocycloalkylalkyl," employed alone or in combination with other terms, refers to a group of formula -alkylene-heterocycloalkyl. The term "n- membered heterocycloalkylalkyl" wherein n is an integer refers to a hereoarylalkylalkyl group in which the heterocycloalkyl is n-membered. The term "n-m membered-Cp-q-alkyl wherein n, m, p and q are integers refers to heterocycloalkylalkyl group in which the heterocycloalkyl is n to m membered and the alkyl has from p to q carbon atoms. In some embodiments, heterocycloalkylalkyl is 4-10 membered heterocycloalkyl-Ci-3 alkyl or Ci-9 heterocycloalkyl-Ci-3 alkyl, wherein the heterocycloalkyl portion is monocyclic or bi cyclic and has 1, 2, 3, 4 or 5 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, heterocycloalkylalkyl is C2-9 heterocycloalkyl-Ci-4 alkyl or C2-9 heterocycloalkyl-Ci-3 alkyl, wherein the heterocycloalkyl portion is monocyclic or bi cyclic and has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

At certain places, the definitions or embodiments may refer to specific rings (e.g, an azetidine ring, a pyridine ring, etc). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas an azetidin-3-yl ring is attached at the 3 -position.

When any two groups or two instances of the same substituent group are

"independently selected" from a list of alternatives, the groups may be the same or different. For example, if R ^a and R ^b are independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, then a molecule with two R ^a groups and two R ^b groups could have all groups be alkyl group (e.g., four different alkyl groups). Alternatively, the first R ^a could be alkyl, the second R ^a could be fluoro, the first R ^b could be hydroxyalkyl, and the second R ^b could be amino (or any other substituents taken from the group). Alternatively, both R ^a and the first R ^b could be fluoro, while the second R ^b could be alkyl (i.e.. some pairs of substituent groups may be the same, while other pairs may be different). Unless otherwise indicated, if two or more groups having the same definition are present, but the definition provides for alternatives, it should be understood that each occurrence of the same group is independently selected from the possible alternatives. For example, if two or more R ^a groups are present in a compound, and the definition of R ^a provides that R ^a can be A, B or C, then it should be understood that each R ^a group present in the compound is independently chosen from A, B and C, so that the R ^a groups present in the compound can be the same or different.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds described herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as b- camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, l,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

In some embodiments, the compounds of the invention have the (///-configuration. In other embodiments, the compounds have the (^/-configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently (R) or (S), unless otherwise indicated.

Compounds described herein may also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1H- and J//-i midazole. 1H-, 2H- and 4H- 1, 2,4- triazole, 1H- and 2H- isoindole and 1H- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. The disclosure is intended to encompass all such tautomers of the compounds described.

Compounds described herein can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

The term, "compound," as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted.

Compounds described herein may include acidic and/or basic groups and be capable of forming salts. It should be understood that the present disclosure is intended to include all salts of compounds that are capable of forming salts, whether or not the possible existence of salts is expressly described, including both acid and base salts of a compound. Furthermore, when a compound is described that is a salt, it is understood that the disclosure of the compound is intended to include all forms of the compound, including the free base or free acid, as well as alternative salt forms thereof. The term "salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The terms "a salt thereof," "salt thereof," or "salts thereof can be applied to any preceding member of an associated Markush group. For example, a group consisting of A, B, C, and salts thereof would include within its scope embodiments that were a salt of A, embodiments that were a salt of B, and embodiments that were a salt of C.

Salts of the compounds disclosed herein include pharmaceutically acceptable salts.

The term "pharmaceutically acceptable salts" refers to non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17 ^th Ed., (Mack Publishing Company, Easton,

1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66( 1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N-oxide forms. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA, which is incorporated herein by reference.

Compounds, and salts thereof, including pharmaceutically acceptable salts, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein, and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates. The compounds may be in any solid-state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference to compounds and salts thereof should be understood as encompassing any solid-state form of the compound.

In some embodiments, the compounds described herein or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, e.g., a composition enriched in the compounds of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof. c. Abbreviations

The following abbreviations may be used herein and, unless otherwise noted, have the meanings indicated below: m (micro); °C (degrees Celsius); Ac (acetyl); ACN (acetonitrile); anhyd (anhydrous); aq (aqueous); atm (atmosphere(s)); Bn (benzyl); Boc (tert- butoxy carbonyl); Bu (butyl); calcd (calculated); Cbz (benzyloxy carbonyl); chrom.

(chromatography); CPME (cyclopentyl methyl ether); CH2CI2 (dichloromethane); coned (concentrated); cone (concentration); DCC (N A'-dicyclohexylcarbodiimide); DIAD

(Diisopropyl azodicarboxylate); DIEA (A.A-di isopropyl ethyl amine): DMAP (4-(A,A- dimethylamino)pyridine); DMF (dimethylformamide); DMSO (dimethylsulfoxide); EDC (A- (3-dimethylaminopropyl)-A-ethylcarbodiimide hydrochloride); equiv (equivalent); ES (electrospray); Et (ethyl); Et20 (diethyl ether); g (gram(s)); h (hour(s)); HATU (A- [(Dimethy lamino)- \H- 1 ,2,3 -triazolo- [4,5 -b] py ridin- 1 -y lmethy lene] -A-methy lmethanaminium hexafluorophosphate A-oxide); HBTU (<9-(Benzotriazol- 1 -yl)-A, , ', A'-tetramethyl-<9-( 1 - benzotriazol-l-yl)uronium hexafluorophosphate,); HPLC (high-performance liquid chromatography); HOBt (1 -hydroxy benzotriazole hydrate); L (liter(s)); m (milli); in- meta); M (molar); MeCN (acetonitrile); min (minute(s)); mL (milliliter); mol (mole; molecular (as in mol wt)); Ms (methanesulfonyl); MS (mass spectrometry); MW (molecular weight); NBS (N- bromosuccinimide); NCS (V-chlorosuccinimide); NIS (/V-iodosuccinimide); NHS (N- hydroxysuccinimide); NMM (4-methylmorpholine); NMR (nuclear magnetic resonance); o- (ortho); obsd (observed); p- (para); Ph (phenyl); Phth (Phthabmide); ppt (precipitate); Pr (propyl); psi (pounds per square inch); temp (temperature); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TPP (triphenylphosphine); and Tr (trityl). Other abbreviations may also be used and have the meanings that would be understood by the person having skill in the art.

II. Compounds

A. Compounds of Formula 1-1

In certain aspects, the present disclosure provides a compound of Formula (1-1):

or a salt thereof, wherein:

Cy ^1A is unsubstituted or substituted C6-10 aryl or unsubstituted or substituted 5-10 membered heteroaryl; wherein the ring atoms of the 5-10 membered heteroaryl forming Cy ^1A consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S; wherein the substituted C6-10 aryl or substituted 5-10 membered heteroaryl forming Cy ^1A are substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^CylA , halogen, Ci-6 haloalkyl, CN, OR ^a11 , S» ⁸¹¹ , C(0)R ^bn , C(0)NR ^cll R ^dn , C(0)OR ^a11 , 0C(0)R ^bn ,

OC(0)NR ^cll R ^dn , NR ^cll R ^dn , NR ^cll C(0)R ^bn , NR ^cll C(0)NR ^cll R ^dn , NR ^cll C(0)OR ^a11 ,

NR ^cll S(0) ₂ R ^bn , S(0) ₂ NR ^cll R ^dn and oxo;

each R ^CylA is independently selected from Ci-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-lO-membered heterocycloalkyl forming R ^CylA consist of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein each Ci-6 alkyl, C ₂ -6 alkenyl, or C ₂ -6 alkynyl forming R ^CylA is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR ^a11 , SR ^a11 , C(0)R ^bn , C(0)NR ^cll R ^dn , C(0)OR ^a11 , 0C(0)R ^bn , 0C(0)NR ^cll R ^dn , NR ^cii R ^d n NR ^cll C(0)R ^b11 , NR ^cll C(0)NR ^cll R ^dn , NR ^cll C(0)0R ^al1 , C(=NR ^ell )NR ^cll R ^dn , NR ^cll C(=NR ^ell )NR ^cll R ^dn , S(0)R ^bn , S(0)NR ^cll R ^dn , S(0) ₂ R ^bn , NR ^cll S(0) ₂ R ^bn ,

S(0) ₂ NR ^cll R ^dn and oxo, and wherein each Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming R ^{C l A} is independently

unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C ₂ -e alkenyl, C ₂ -e alkynyl, Ci-e haloalkyl, CN, OR ^a11 , SR ^a11 , C(0)R ^bn ,

C(0)NR ^cll R ^dn , C(0)OR ^a11 , OC(0)R ^bn , OC(0)NR ^cll R ^dn , NR ^cll R ^dn , NR ^cll C(0)R ^bn , NR ^cll C(0)NR ^cll R ^dn , NR ^cll C(0)OR ^a11 , C(=NR ^ell )NR ^cll R ^dn , NR ^cll C(=NR ^ell )NR ^cll R ^dn , S(0)R ^bn , S(0)NR ^cll R ^dn , S(0) ₂ R ^bll , NR ^cll S(0) ₂ R ^bn , S(0) ₂ NR ^cll R ^dn and oxo;

R ¹¹ is H or C1-6 alkyl, Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl, wherein the C1-6 alkyl forming R ¹¹ is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, CN, OR ^a11 , SR ^a11 , C(0)R ^bn , C(0)NR ^cll R ^dn ,

C(0)OR ^a11 , OC(0)R ^bn , 0C(0)NR ^cll R ^dn , NR ^cll R ^dn , NR ^cll C(0)R ^bn , NR ^cll C(0)NR ^cll R ^dn , NR ^cll C(0)OR ^a11 , C(=NR ^ell )NR ^cll R ^dn , NR ^cll C(=NR ^ell )NR ^cll R ^dn , S(0)R ^bn , S(0)NR ^cll R ^dn , S(0) ₂ R ^bn , NR ^cll S(0) ₂ R ^bn , S(0) ₂ NR ^cll R ^dn and oxo, and wherein the Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl forming R ¹¹ is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from C1-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C1-6 haloalkyl,

S(0) ₂ NR ^cll R ^dn and oxo;

R ¹² is H or C1-6 alkyl; or

R ¹¹ and R ¹² , together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring;

A ¹¹ is CR ¹³ R ¹⁵ or N;

each R ¹³ is independently Cy ^1B , (CR ^13A R ^13B )n3Cy ^1B , (C1-6 alkylene)Cy ^1B , (C ₂ -6 alkenylene)Cy ^1B , (C ₂ -6 alkynylene)Cy ^1B or OCy ^1B , wherein the C1-6 alkylene, C ₂ -6 alkenylene, or C ₂ -6 alkynylene component of R ¹³ is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of halogen, CN, OR ^a11 , SR ^a11 , C(0)R ^bn , C(0)NR ^cll R ^dn , C(0)OR ^a11 , 0C(0)R ^bn , 0C(0)NR ^cll R ^dn , NR ^cll R ^dn ,

S(0) ₂ NR ^cll R ^dn and oxo;

each R ¹⁴ is independently selected from H and C1-6 alkyl; R ¹⁵ is selected from H, R ¹³ , Ci-6 alkyl and OH;

a pair of R ¹⁴ groups attached to adjacent carbon atoms, or a pairing of R ¹⁴ and R ¹⁵ groups attached to adjacent carbon atoms, may, independently of other occurrences of R ¹⁴ , together be replaced a bond connecting the adjacent carbon atoms to which the pair of R ¹⁴ groups or pairing of R ¹⁴ and R ¹⁵ groups is attached, such that the adjacent carbon atoms are connected by a double bond; or

a pair of R ¹⁴ groups attached to the same carbon atom, or a pairing of R ¹³ and R ¹⁵ groups attached to the same carbon atom, may, independently of other occurrences of R ¹⁴ , and together with the carbon atom to which the pair of R ¹⁴ groups or pairing of R ¹³ and R ¹⁵ groups is attached together form a spiro-fused C3-10 cycloalkyl or 4-10 membered

heterocycloalkyl ring, wherein the ring atoms of the 4-10 membered heterocycloalkyl ring formed consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, wherein the spiro-fused C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring formed is optionally further substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloalkyl, CN, OR ^a11 , SR ^a11 , C(0)R ^bn , C(0)NR ^cll R ^dn ,

S(0) ₂ R ^bn , NR ^cll S(0) ₂ R ^bn , S(0) ₂ NR ^cll R ^dn and oxo; or

pairs of R ¹⁴ groups attached to adjacent carbon atoms, or a pairing of R ¹⁴ and R ¹⁵ groups attached to adjacent carbon atoms, may, independently of other occurrences of R ¹⁴ , together with the adjacent carbon atoms to which the pair of R ¹⁴ groups or pairing of R ¹⁴ and R ¹⁵ groups is attached, form a fused C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the 4-10 membered heterocycloalkyl ring formed consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, wherein the fused C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring formed is optionally further substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloalkyl, CN, OR ^a11 , SR ^a11 , C(0)R ^bn , C(0)NR ^cll R ^dn , C(0)OR ^a11 , 0C(0)R ^bn ,

0C(0)NR ^cll R ^dn , NR ^cll R ^dn , NR ^cll C(0)R ^bn , NR ^cll C(0)NR ^cll R ^dn , NR ^cll C(0)OR ^a11 , C(=NR ^ell )NR ^cll R ^dll , NR ^cll C(=NR ^ell )NR ^cll R ^dn , S(0)R ^bn , S(0)NR ^cll R ^dn , S(0) ₂ R ^bn , NR ^cll S(0) ₂ R ^bl1 , S(0) ₂ NR ^cll R ^dn and oxo; or

a grouping of four R ¹⁴ groups attached to two adjacent carbon atoms, or a grouping of two R ¹⁴ , one R ¹³ and one R ¹⁵ groups attached to two adjacent carbon atoms, may, independently of other occurrences of R ¹⁴ , together with the two adjacent carbon atoms to which the grouping of four R ¹⁴ groups or grouping of two R ¹⁴ , one R ¹³ and one R ¹⁵ groups are attached, form a fused Ce-io aryl or 5-10 membered heteroaryl, C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring formed consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, and wherein the fused Ce-io aryl or 5-10 membered heteroaryl, C3-10 cycloalkyl or 4-10 membered heterocycloalkyl ring formed is optionally further substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloalkyl, CN, OR ^a11 , SR ^a11 , C(0)R ^{b n} , C(0)NR ^{c l l} R ^{d n} ,

C(0)OR ^a11 , OC(0)R ^bn , OC(0)NR ^cll R ^dn , NR ^cll R ^dn , NR ^cll C(0)R ^bn , NR ^cll C(0)NR ^cll R ^dn , NR ^cll C(0)OR ^a11 , C(=NR ^ell )NR ^cll R ^dn , NR ^cll C(=NR ^ell )NR ^cll R ^dn , S(0)R ^bn , S(0)NR ^cll R ^dn , S(0) ₂ R ^bn , NR ^cll S(0) ₂ R ^bn , S(0) ₂ NR ^cll R ^dn and oxo;

nl is 1 or 2;

n2 is 0, 1 or 2;

provided that the sum of nl and n2 is 1, 2 or 3;

provided that if nl is 1 or n2 is 0, then A ¹¹ is CR ¹³ R ¹⁵ ;

n3 is 0, 1 or 2;

each R ^13A is independently H or C1-6 alkyl;

each R ^13B is independently H or C1-6 alkyl; or

or R ^13A and R ^13B attached to the same carbon atom, independently of any other R ^13A and R ^13B groups, together may form -(CH2)2-5-, thereby forming a 3-6 membered cycloalkyl ring;

Cy ^1B is unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy ^1B consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and

wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy ^1B are substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^CylB , halogen, Ci-6 haloalkyl, CN, OR ^a11 , S ^®311 , C(0)R ^bn , C(0)NR ^cll R ^dn , C(0)OR ^a11 , 0C(0)R ^bn ,

0C(0)NR ^cll R ^dn , NR ^cll R ^dn , NR ^cll C(0)R ^bn , NR ^cll C(0)NR ^cll R ^dn , NR ^cll C(0)OR ^a11 ,

NR ^cll S(0) ₂ R ^bn , S(0) ₂ NR ^cll R ^dn and oxo; wherein each R ^{t 1 B} is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming R ^{C 1 B} consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming R ^{C 1 B} is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR ^a11 , SR ^a11 , C(0)R ^bn , C(0)NR ^cll R ^dn , C(0)OR ^a11 , 0C(0)R ^bn ,

0C(0)NR ^cll R ^dn , NR ^cll R ^dn , NR ^cll C(0) ^Rbn , NR ^cll C(0)NR ^cll R ^dn , NR ^cll C(0)OR ^a11 , C(=NR ^ell )NR ^cll R ^dll , NR ^cll C(=NR ^ell )NR ^cll R ^dn , S(0)R ^bn , S(0)NR ^cll R ^dn , S(0) ₂ R ^bn , NR ^cll S(0)2R ^bn , S(0)2NR ^cll R ^dn and oxo; and wherein each Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming R ^{C 1 B} is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, OR ^a11 , SR ^a11 , C(0)R ^bn , C(0)NR ^cll R ^dn , C(0)OR ^a11 , 0C(0)R ^bn , OC(0)NR ^cll R ^dn , NR ^cll R ^dn ,

NR ^cll C(0) ^Rbn , NR ^cll C(0)NR ^cll R ^dn , NR ^cll C(0)OR ^a11 , C(=NR ^ell )NR ^cll R ^dn ,

NR ^cll C(=NR ^ell )NR ^cll R ^dn , S(0)R ^bn , S(0)NR ^cll R ^dn , S(0) ₂ R ^bn , NR ^cll S(0) ₂ R ^bl1 ,

S(0)2NR ^cll R ^dn and oxo;

R ¹⁶ is H, Cy ^ic , Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming R ¹⁶ is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of Cy ^ic , halogen, CN, OR ^a11 , SR ^a11 , C(0)R ^bn , C(0)NR ^cll R ^dn , C(0)OR ^a11 , OC(0)R ^bn , 0C(0)NR ^cll R ^dn , NR ^cll R ^dn , NR ^cll C(0)R ^bn , NR ^cll C(0)NR ^cll R ^dn , NR ^cll C(0)OR ^a11 , C(=NR ^ell )NR ^cll R ^dn , NR ^cll C(=NR ^ell )NR ^cll R ^dn , S(0)R ^bn , S(0)NR ^cll R ^dn , S(0) ₂ R ^bn , NR ^cll S(0) ₂ R ^bn , S(0) ₂ NR ^cll R ^dn and oxo, provided that no more than one of the substituents of R ¹⁶ is Cy ^ic ;

Cy ^ic is unsubstituted or substituted Ce-io aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy ^ic consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and

wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy ^ic are substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cylc , halogen, Ci-6 haloalkyl, C

OC(0)NR ^cl C(=NR ^ell )NR ^cll R ^dn , C(=NOR ^all )NR ^cll R ^dn , C(=N0C(0)R ^bll )NR ^cll R ^dn , C(=NR ^ell )NR ^cll C(0)0R ^al1 , NR ^cll C(=NR ^ell )NR ^cll R ^dn , S(0)R ^bn , S(0)NR ^cll R ^dn , S(0) ₂ R ^bn , NR ^cll S(0) ₂ R ^bn , S(0) ₂ NR ^cll R ^dn and oxo;

wherein each R ^{C 1 c} is independently selected from Ci-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming R ^{C l t} consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each C1-6 alkyl, C ₂ -6 alkenyl, or C ₂ -6 alkynyl forming R ^Cylc is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR ^a11 , SR ^a11 , C(0)R ^bn , C(0)NR ^cll R ^dn , C(0)OR ^a11 , 0C(0)R ^bn , 0C(0)NR ^cll R ^dn , NR ^cll R ^dn , NR ^cll C(0) ^Rbn , NR ^cll C(0)NR ^cll R ^dn , NR ^cll C(0)OR ^a11 , C(=NR ^ell )NR ^cll R ^dll , NR ^cll C(=NR ^ell )NR ^cll R ^dn , S(0)R ^bn , S(0)NR ^cll R ^dn , S(0) ₂ R ^bn , NR ^cll S(0) ₂ R ^bn , S(0) ₂ NR ^cll R ^dn and oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming R ^Cylc is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, C1-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C1-6 haloalkyl, CN, OR ^a11 , SR ^a11 ,

S(0) ₂ NR ^cll R ^dn and oxo;

R ^aii , R ^bn , R ^cl1 and R ^dn are each independently selected from H, C1-6 alkyl, C2-6 alkenyl, C ₂ -6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- C1-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl, wherein said C1-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- C1-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl forming R ^al1 , R ^bn , R ^cl1 and R ^dn are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci-6 alkyl, halo, CN, OR ^a12 , SR ^a12 , C(0)R ^bl2 , C(0)NR ^cl2 R ^dl2 , C(0)OR ^a12 , OC(0)R ^b12 , 0C(0)NR ^cl2 R ^dl2 , NR ^cl2 R ^d12 , NR ^cl2 C(0)R ^bl2 , NR ^cl2 C(0)NR ^cl2 R ^dl2 , NR ^cl2 C(0)0R ^al2 , C(=NR ^el2 )NR ^cl2 R ^d12 , NR ^cl2 C(=NR ^el2 )NR ^cl2 R ^d12 , S(0)R ^bl2 , S(0)NR ^cl2 R ^dl2 , S(0) ₂ R ^bl2 , NR ^cl2 S(0) ₂ R ^bl2 , S(0) ₂ NR ^cl2 R ^dl2 and oxo;

or R ^cl1 and R ^dn attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from Ci-e alkyl, halo, CN, OR ^a12 , SR ^a12 , C(0)R ^bl2 , C(0)NR ^cl2 R ^dl2 , C(0)0R ^al2 ,

S(0) ₂ R ^bl2 , NR ^cl2 S(0) ₂ R ^bl2 , S(0) ₂ NR ^cl2 R ^dl2 and oxo;

R ^{al 2} . R ^bl2 , R ^cl2 and R ^dl2 are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl forming R ^al2 , R ^bl2 , R ^cl2 and R ^dl2 are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl) ₂ , halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo;

or R ^cl2 and R ^dl2 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl) ₂ , halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo; and

R ^{el 1} and Re ¹² are each, independently, H, CN or N0 ₂ .

In some embodiments, the compound is of Formula (1-2):

In some embodiments, Cy ^1A is unsubstituted or substituted aryl.

In some embodiments, Cy ^1A is unsubstituted or substituted phenyl.

In some embodiments, Cy ^1A is substituted phenyl. In some embodiments, Cy ^1A is substituted with at least one OR ^a11 or at least one C(=NR ^ell )NR ^cll R ^dn , C(=NOR ^all )NR ^cll R ^dn , C(=N0C(0)R ^bll )NR ^cll R ^dn , or

C(=NR ^ell )NR ^cll C(0)0R ^al1 .

In some embodiments, Cy ^1A is substituted with at least one OR ^a11 and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

In some embodiments, Cy ^1A is substituted with at least one OH and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

In some embodiments, Cy ^1A is substituted with at least one C(=NR ^ell )NR ^cll R ^dn ,

C(=NOR ^all )NR ^cll R ^dn , C(=N0C(0)R ^bll )NR ^cll R ^dn , C(=NR ^ell )NR ^cll C(0)0R ^al1 , preferably in the 4-position.

In some embodiments, Cy ^1A is substituted with at least one C(=NR ^ell )NR ^cll R ^dn , preferably in the 4-position.

In some embodiments, Cy ^1A is substituted with at least one C(=NH)NH2, preferably in the 4-position.

In some embodiments, Cy ^1A is of any one of the following formulae:

In some embodiments, in the formula defining Cy ^1A , each R ^{C l A} is independently Ci-6 alkyl, such as methyl, or halogen, such as Cl or Br, or amino.

In some embodiments, Cy ^1A is of any one of the following formulae:

In some embodiments, in the formula defining Cy ^1A , R ^al1 is Ci-6 alkyl, such as methyl, R ^bn is Ci-6 alkyl, such as methyl, R ^bn is Ci-6 haloalkyl, such as trifluoromethyl, and R ^cl1 is alkyl such as methyl.

In some embodiments, Cy ^1A is unsubstituted or substituted heteroaryl.

In some embodiments, Cy ^1A is unsubstituted or substituted pyridin-3-yl, 1H- pyrrolo[2,3-b]pyridine-5-yl, or lH-benzo[d]imidazol-6-yl.

In some embodiments, Cy ^1A is of any one of the following formulae:

In some embodiments, each R ^{C 1 L} in the formula defining Cy ^1A is independently Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably Cl, or amino.

In some embodiments, each R ^{t 1 L} attached to nitrogen in the formula defining Cy ^1A is Ci-6 alkyl, such as methyl or ethyl.

In some embodiments, R ¹¹ is Ci-6 alkyl.

In some embodiments, R ¹¹ is methyl.

In some embodiments, R ¹¹ is H.

In some embodiments, R ¹² is H.

In some embodiments, R ¹² is Ci-6 alkyl, such as methyl or ethyl, preferably methyl.

In some embodiments, R ¹¹ and R ¹² , together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring.

In some embodiments, nl is 1.

In some embodiments, nl is 2.

In some embodiments, n2 is 0.

In some embodiments, n2 is 1.

In some embodiments, n2 is 2.

In some embodiments, the compound is according to any of the following Formulae (I-la) to (I- If) and (I-2a) to (I-2r):

(I- la) (I- lb)

(I-2e) (I-2f)

(I-2o) (I-2p)

(I-2q) (I-2r)

In some embodiments, the compound is according to any of the following Formulae (I-lg) to (I-lo) and (I-2aa) to (I-2az):

(I-lo)

(I-2ak) (I-2al)

(I-2au) (I-2av)

(I-2ay) (I-2az)

In some embodiments, the compound is according to any of the following Formulae (1-3) to (1-9):

(1-9) In some embodiments, the compound is according to any of the following Formulae (I-3a) to (I-3k):

In some embodiments, the compound is according to any of the following Formulae

(I-4a) to (I-4bf): (I-4al) (I-4am) (I-4ay) (I-4az)

(I-4be) (I-4bf)

In some embodiments, the compound is according to any of the following Formulae (I-5a) to (I-5u):

(I-5e) (I-5f)

(I-5u)

In some embodiments, the compound is according to any of the following Formulae

(I-6a) to (I-6cw):

(I-6as) (I-6at)

(I-6be) (I-6bf) (I-6cc) (I-6cd)

(I-6co) (I-6cp)

(I-6cv) (I-6cw)

In some embodiments, the compound is according to any of the following Formulae (I-7a) to (I-7co):

(I-7a) (I-7b) (I-7ak) (I-7al)

(I-7)ax

(I-7aw)

(I-7bu) (I-7bv)

(I-7co)

In some embodiments, the compound is according to any of the following Formulae (I-8a) to (I-8z):

(I-80) (I-8p)

(I-8y) (I-8z)

In some embodiments, the compound is according to any of the following Formulae (I-9a) to (I-9z):

(I-9a) (I-9b)

(I-9m) (I-9n)

(i-9y) (I-9z)

In some embodiments, R ¹³ is Cy ^1B . In some embodiments, R ¹³ is (Ci-6 alk lene)Cy ^1B , (C2-6 alkenylene)Cy ^1B , or (C2-6 alkynylene)Cy ^1B . In some embodiments, the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R ¹³ is unsubstituted.

In some embodiments, R ¹³ is (CR ^13A R ^13B )n3Cy ^1B .

In some embodiments, each R ^13A is H.

In some embodiments, each R ^13B is H.

In some embodiments, n3 is 0.

In some embodiments, n3 is 1.

In some embodiments, n3 is 2.

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, Cy ^1B is unsubstituted Ce-io aryl.

In some embodiments, Cy ^1B is unsubstituted phenyl.

In some embodiments, Cy ^1B is unsubstituted naphthyl, such as 1 -naphthyl or 2- naphthyl.

In some embodiments, Cy ^1B unsubstituted 5-10 membered heteroaryl.

In some embodiments, Cy ^1B is unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl or unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl.

In some embodiments, Cy ^1B is substituted Ce-io aryl.

In some embodiments, Cy ^1B is substituted phenyl.

In some embodiments, Cy ^1B is a biphenylyl (i.e., phenyl substituted by phenyl), such as 2-, 3-, or 4-biphenylyl.

In some embodiments, Cy ^1B is substituted naphthyl, such as 1 -naphthyl or 2-naphthyl.

In some embodiments, Cy ^1B substituted 5-10 membered heteroaryl.

In some embodiments, Cy ^1B is substituted pyridyl, such as substituted 2-, 3-, or 4- pyridyl or substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl.

In some embodiments, Cy ^1B is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^CylB , halogen, and C1-6 haloalkyl; wherein each R ^CylB is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and Ce-io aryl or 5-10 membered heteroaryl, wherein each Ce-io aryl or 5-10 membered heteroaryl forming R ^{C 1 B} is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and haloalkyl. In some embodiments, R ¹³ is selected from groups of the following formulae:

In some embodiments, R ^{t 1 B} in the formula representing R ¹³ is Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen, such as fluorine or chlorine, preferably fluorine.

In some embodiments, R ^{C 1 B} in the formula representing R ¹³ is Ci-6 alkyl, such as methyl or ethyl, preferably methyl.

In some embodiments, R ^{C 1 B} in the formula representing R ¹³ is halogen, such as fluorine or chlorine, preferably fluorine.

In some embodiments, no more than one R ¹⁴ is other than hydrogen. In some embodiments, no more than one R ¹⁴ is other than hydrogen and one R ¹⁴ is Ci- 6 alkyl, such as methyl.

In some embodiments, each R ¹⁴ is hydrogen.

In some embodiments, A ¹¹ is N.

In some embodiments, R ¹⁵ is hydrogen.

In some embodiments, R ¹⁵ is Ci-6 alkyl such as methyl.

In some embodiments, R ¹⁵ is hydroxyl.

In some embodiments, R ¹⁶ is hydrogen.

In some embodiments, R ¹⁶ is unsubstituted or substituted Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.

In some embodiments, R ¹⁶ is unsubstituted Ci-6 alkyl such as methyl.

In some embodiments, R ¹⁶ is substituted Ci-6 alkyl.

In some embodiments, the substituted Ci-6 alkyl forming R ¹⁶ is substituted by 1, 2, 3,

4 or 5, such as 1, 2, or 3, or, preferably 1, substituents selected from the group consisting of halogen, CN, C(0)NR ^cll R ^dn and C(0)0R ^al1 .

In some embodiments, R ¹⁶ is (CH2)i-6C(0)0R ^a11 .

In some embodiments, the R ^al1 defining R ¹⁶ is H or Ci-6 alkyl such as methyl.

In some embodiments, the R ^al1 defining R ¹⁶ is H.

In some embodiments, R ^al1 , R ^bn , R ^cl1 and R ^dn , R ^al2 , R ^bl2 , R ^cl2 and R ^dl2 are each independently selected from H and Ci-6 alkyl.

In some embodiments, each R ^el1 and each R ^el2 is H.

In some embodiments, the compounds of Formula (1-1), and embodiments thereof, can be in the form of a salt such as a pharmaceutically acceptable salt.

The compounds of Formula (1-1), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (1-1), and embodiments thereof, are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (1-1), or an embodiment thereof, optionally in the form of a salt.

In some embodiments the compound Formula (1-1) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient. [0003] In certain aspects, the compound is one or more selected from the compounds of Formula (1-1) set forth in the Examples, including the compounds listed in Table 1, (e.g., the compounds with selectivity for MASP-2 over thrombin). In certain aspects, one or more of the variables defining the compounds of Formula (I) (such as Cy ^1A ; R ^CylA ; R ¹¹ ; R ¹² ; A ¹¹ ; R ¹³ ; R ¹⁴ ; R ¹⁵ ; nl; n2; n3; R ^13A ; R ^13B ; Cy ^1B ; R ¹⁶ ; R ^16A ; R ^16B ; Cy ^ic ; R ^Cylc ; R ^{al 1} , R ^bn , R ^{cl 1} ; R ^dn ; R ^{ei i} , R ^al2 , R ^bl2 , R ^cl2 ; R ^dl2 ; and R ^{el 1} ) is selected from the corresponding substituents in the compounds of Formula (1-1) in the Examples including the compounds listed in Table 1, preferably, those of the compounds with selectivity for MASP-2 over thrombin.

[0004] In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (-) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers or

diastereomers.

[0005] In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. et al, J. Pharm. Sci 1977, 66, 1-19. They include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, arylsulfonates, alkylsulfonates, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).

[0006] In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group; hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O- alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like.

[0007] In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin is at least 1.1 : 1, 1.25: 1, 1.5: 1, 1.75: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11 : 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 21 : 1, 22: 1, 23: 1, 24: 1, 25: 1, or 30: 1.

B. Compounds of Formula IIA and IIB

In certain aspects, the present disclosure provides a compound of Formula (IIA) and

(IIB)

or a salt thereof, wherein:

Cy ^2A is unsubstituted or substituted C6-10 aryl or unsubstituted or substituted 5-10 membered heteroaryl; wherein the ring atoms of the 5-10 membered heteroaryl forming Cy ^2A consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S; wherein the substituted C6-10 aryl or substituted 5-10 membered heteroaryl forming Cy ^2A are substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cy2A , halogen, C1-6 haloalkyl, CN, OR ^a21 , S ^®821 , C(0)R ^b21 , C(0)NR ^c21 R ^d21 , C(0)0R ^a21 , 0C(0)R ^b21 ,

C(=NR ^e21 )NR ^c21 C(0)0R ^a21 , NR ^c21 C(=NR ^e21 )NR ^c21 R ^d21 , S(0)R ^b21 , S(0)NR ^c21 R ^d21 , S(0) ₂ R ^b21 , NR ^c21 S(0) ₂ R ^b21 , S(0) ₂ NR ^c21 R ^d21 and oxo;

each R ^Cy2A is independently selected from C1-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-lO-membered heterocycloalkyl forming R ^Cy2A consist of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein each C1-6 alkyl, C ₂ -6 alkenyl, or C ₂ -6 alkynyl forming R ^Cy2A is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR ^a21 , SR ^a21 , C(0)R ^b21 , C(0)NR ^c21 R ^d21 , C(0)0R ^a21 , 0C(0)R ^b21 , 0C(0)NR ^c21 R ^d21 ,

S(0)2NR ^c21 R ^d21 and oxo, and wherein each Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming R ^{C 2A} is independently

unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, CN, OR ³²¹ , SR ^a21 , C(0)R ^b21 ,

C(0)NR ^c21 R ^d21 , C(0)OR ^a21 , OC(0)R ^b21 , 0C(0)NR ^c21 R ^d21 , NR ^c21 R ^d21 , NR ^c21 C(0)R ^b21 , NR ^c21 C(0)NR ^c21 R ^d21 , NR ^c21 C(0)0R ^a21 , C(=NR ^e21 )NR ^c21 R ^d21 , NR ^c21 C(=NR ^e21 )NR ^c21 R ^d21 , S(0)R ^b21 , S(0)NR ^c21 R ^d21 , S(0) ₂ R ^b21 , NR ^c21 S(0) ₂ R ^b21 , S(0) ₂ NR ^c21 R ^d21 and oxo;

R ²¹ is H or C1-6 alkyl, Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl, wherein the C1-6 alkyl forming R ²¹ is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen, CN, OR ^a21 , SR ^a21 , C(0)R ^b21 , C(0)NR ^c21 R ^d21 ,

C(0)OR ^a21 , OC(0)R ^b21 , 0C(0)NR ^c21 R ^d21 , NR ^c21 R ^d21 , NR ^c21 C(0)R ^b21 , NR ^c21 C(0)NR ^c21 R ^d21 , NR ^c21 C(0)0R ^a21 , C(=NR ^e21 )NR ^c21 R ^d21 , NR ^c21 C(=NR ^e21 )NR ^c21 R ^d21 , S(0)R ^b21 , S(0)NR ^c21 R ^d21 , S(0)2R ^b21 , NR ^c21 S(0)2R ^b21 , S(0)2NR ^c21 R ^d21 and oxo, and wherein the Ce-io aryl-Ci-6 alkyl or 5-10 membered heteroaryl-Ci-6 alkyl forming R ²¹ is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, CN, OR ^a21 , SR ^a21 , C(0)R ^b21 , C(0)NR ^c21 R ^d21 , C(0)OR ^a21 , OC(0)R ^b21 , 0C(0)NR ^c21 R ^d21 , _NRC ²ⁱ _R ^d2i NR ^c21 C(0)R ^b21 , NR ^c21 C(0)NR ^c21 R ^d21 , NR ^c21 C(0)0R ^a21 , C(=NR ^e21 )NR ^c21 R ^d21 , NR ^c21 C(=NR ^e21 )NR ^c21 R ^d21 , S(0)R ^b21 , S(0)NR ^c21 R ^d21 , S(0) ₂ R ^b21 , NR ^c21 S(0) ₂ R ^b21 ,

S(0)2NR ^c21 R ^d21 and oxo;

R ²² is H or C1-6 alkyl; or

R ²¹ and R ²² , together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring;

A ²³ is N or NR ²³ ;

A ²⁴ is CR ²⁴ ; N or NR ²⁴ ;

A ²⁶ is CR ²⁶ or S;

provided that

A ²³ , A ²⁴ and A ²⁶ in Formula (IIA) are selected such that the ring comprising A ²³ , A ²⁴ and A ²⁶ is a heteroaryl ring and the symbol = represents an aromatic ring (normalized) bond;

R ²³ is H or C1-6 alkyl;

R ²⁴ is H; C1-6 alkyl or phenyl; R ²⁵ is Cy ^2B , (CR ^25A R ^25B )n25Cy ^2B , (Ci-6 alkylene)Cy ^2B , (C2-6 alkenylene)Cy ^2B , or (C2-6 alkynylene)Cy ^2B , wherein the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R ²⁵ is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of halogen, CN, OR ^a21 , SR ^a21 , C(0)R ^b21 , C(0)NR ^c21 R ^d21 ,

S(0) ₂ R ^b21 , NR ^c21 S(0) ₂ R ^b21 , S(0) ₂ NR ^c21 R ^d21 and oxo;

R ²⁶ is H or C1-6 alkyl;

each R ^25A is H or C1-6 alkyl;

each R ^25B is H or C1-6 alkyl;

n25 is 0, 1 or 2;

Cy ^2B is unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy ^2B consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and

wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy ^2B are substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cy2B , halogen, C1-6 haloalkyl, CN, OR ^a21 , S ^®821 , C(0)R ^b21 , C(0)NR ^c21 R ^d21 , C(0)OR ^a21 , OC(0)R ^b21 ,

C(=NR ^e21 )NR ^c21 C(0)0R ^a21 , NR ^c21 C(=NR ^e21 )NR ^c21 R ^d21 , S(0)R ^b21 , S(0)NR ^c21 R ^d21 , S(0) ₂ R ^b21 , NR ^c21 S(0) ₂ R ^b21 , S(0) ₂ NR ^c21 R ^d21 and oxo;

wherein each R ^{C 2B} is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming R ^{C 2B} consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming R ^{C 2B} is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR ³²¹ , SR ^a21 , C(0)R ^b21 , C(0)NR ^c21 R ^d21 , C(0)OR ^a21 , OC(0)R ^b21 ,

NR ^c21 S(0)2R ^b21 , S(0)2NR ^c21 R ^d21 and oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming R ^tv2B is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, OR ^a21 , SR ^a21 , C(0)R ^b21 , C(0)NR ^c21 R ^d21 , C(0)OR ^a21 , OC(0)R ^b21 , 0C(0)NR ^c21 R ^d21 , NR ^c21 R ^d21 ,

NR ^c21 C(0) ^Rb21 , NR ^c21 C(0)NR ^c21 R ^d21 , NR ^c21 C(0)0R ^a21 , C(=NR ^e21 )NR ^c21 R ^d21 ,

NR ^c21 C(=NR ^e21 )NR ^c21 R ^d21 , S(0)R ^b21 , S(0)NR ^c21 R ^d21 , S(0) ₂ R ^b21 , NR ^c21 S(0) ₂ R ^b21 ,

S(0)2NR ^c21 R ^d21 and oxo;

R ^a2i , R ^b21 , R ^c21 and R ^d21 are each independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl forming R ^a21 , R ^b21 , R ^c21 and R ^d21 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci-6 alkyl, halo, CN, OR ^a22 , SR ^a22 , C(0)R ^b22 , C(0)NR ^c22 R ^d22 , C(0)0R ^a22 , 0C(0)R ^b22 ,

NR ^c22 S(0) ₂ R ^b22 , S(0) ₂ NR ^c22 R ^d22 and oxo;

or R ^c21 and R ^d21 atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from Ci-e alkyl, halo, CN, OR ³²² , SR ^a22 , C(0)R ^b22 , C(0)NR ^c22 R ^d22 , C(0)0R ^a22 ,

S(0) ₂ R ^b22 , NR ^c22 S(0) ₂ R ^b22 , S(0) ₂ NR ^c22 R ^d22 and oxo;

R ^a22 , R ^b22 , R ^c22 and R ^d22 are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl forming R ^a22 , R ^b22 , R ^c22 and R ^d22 are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo;

or R ^c22 and R ^d22 atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl) ₂ , halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo; and

R ^e21 and Re ²² are each, independently, H, CN or NO2.

In some embodiments, Cy ^2A is unsubstituted or substituted aryl.

In some embodiments, Cy ^2A is unsubstituted or substituted phenyl.

In some embodiments, Cy ^2A is substituted phenyl.

In some embodiments, Cy ^2A is substituted with at least one OR ³²¹ or at least one C(=NR ^e21 )NR ^c21 R ^d21 , C(=NOR ^a21 )NR ^c21 R ^d21 , C(=N0C(0)R ^b21 )NR ^c21 R ^d21 , or

C(=NR ^e21 )NR ^c21 C(0)0R ^a21 .

In some embodiments, Cy ^2A is substituted with at least one OR ³²¹ and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

In some embodiments, Cy ^2A is substituted with at least one OH and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

In some embodiments, Cy ^2A is substituted with at least one C(=NR ^e21 )NR ^c21 R ^d21 , C(=NOR ^a21 )NR ^c21 R ^d21 , C(=N0C(0)R ^b21 )NR ^c21 R ^d21 , C(=NR ^e21 )NR ^c21 C(0)0R ^a21 , preferably in the 4-position.

In some embodiments, Cy ^2A is substituted with at least one C(=NR ^e21 )NR ^c21 R ^d21 , preferably in the 4-position.

In some embodiments, Cy ^2A is substituted with at least one C(=NH)NH2, preferably in the 4-position.

In some embodiments, Cy ^2A is of any one of the following formulae:

In some embodiments, in the formula defining Cy ^2A , each R ^c - ^v2A is independently Ci-6 alkyl, such as methyl, or halogen, such as Cl or Br, or amino.

In some embodiments, Cy ^2A is of any one of the following formulae:

In some embodiments, R ^a21 is Ci-6 alkyl and R ^b21 is Ci-6 alkyl.

In some embodiments, Cy ^2A is unsubstituted or substituted heteroaryl, such as pyridin-3-yl, lH-pyrrolo[2,3-b]pyridine-5-yl, or lH-benzo[d]imidazol-6-yl.

In some embodiments, Cy ^2A is of any one of the following formulae:

WO 2019/231935

In some embodiments, each R ^{t 2A} in the formula defining Cy ^2A is independently Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably

Cl.

In some embodiments, each R ^{t 2A} attached to nitrogen in the formula defining Cy ^2A is

Ci-6 alkyl, such as methyl or ethyl.

In some embodiments, R ²¹ is Ci-6 alkyl.

In some embodiments, R ²¹ is methyl.

In some embodiments, R ²¹ is H.

In some embodiments, R ²² is H.

In some embodiments, R ²² is Ci-6 alkyl.

In some embodiments, R ²² is methyl.

In some embodiments, R ²¹ and R ²² , together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring.

In some embodiments, the compound is of Formula (IIA).

In some embodiments, the compound is according to any of the following Formulae (IIA- la) or (IIA-lb):

(IIA-la) (IIA-lb)

In some embodiments, the compound is according to any of the following Formulae (IIA-2) to (IIA-5):

(IIA-4) (IIA-5)

In some embodiments, the compound is according to any of the following Formulae (IIA-2a) to (IIA-5b):

(IIA-3a) (IIA-3b)

(IIA-5a) (IIA-5b)

In some embodiments, the compound is of Formula (IIB).

In some embodiments, the compound is according to any of the following Formulae

(IIB-la) or (IIB-lb):

(IIB-la) (IIB-lb)

In some embodiments, R ²³ is H.

In some embodiments, R ²³ is Ci-6 alkyl.

In some embodiments, R ²⁴ is H.

In some embodiments, R ²⁴ is Ci-6 alkyl.

In some embodiments, R ²⁴ is phenyl.

In some embodiments, R ²⁵ is Cy ^2B .

In some embodiments, R ²⁵ is (Ci-6 alkylene)Cy ^2B , (C2-6 alkenylene)Cy ^2B , or (C2-6 alkynylene)Cy ^2B , wherein the Ci-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R ²⁵ is unsubstituted or substituted.

In some embodiments, R ²⁵ is (Ci-6 alkylene)Cy ^2B , (C2-6 alkenylene)Cy ^2B , or (C2-6 alkynylene)Cy ^2B , wherein the Ci-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R ²⁵ is unsubstituted.

In some embodiments, R ²⁵ is (CR ^25A R ^25B )n25Cy ^2B .

In some embodiments, each R ^25A is H. In some embodiments, each R ^25B is H.

In some embodiments, n25 is 0.

In some embodiments, n25 is 1.

In some embodiments, n25 is 2.

In some embodiments, R ²⁵ is CffeCy ^2® .

In some embodiments, R ²⁵ is CffeCffeCy ^2® .

In some embodiments, Cy ^2B is unsubstituted Ce-io aryl.

In some embodiments, Cy ^2B is unsubstituted phenyl.

In some embodiments, Cy ^2B is unsubstituted naphthyl, such as 1 -naphthyl or 2- naphthyl.

In some embodiments, Cy ^2B unsubstituted 5-10 membered heteroaryl.

In some embodiments, Cy ^2B is unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl or unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl.

In some embodiments, Cy ^2B is substituted Ce-io aryl.

In some embodiments, Cy ^2B is substituted phenyl.

In some embodiments, Cy ^2B is a biphenylyl (i.e., phenyl substituted by phenyl), such as 2-, 3-, or 4-biphenylyl.

In some embodiments, Cy ^2B is substituted naphthyl, such as 1 -naphthyl or 2-naphthyl.

In some embodiments, Cy ^2B is substituted 5-10 membered heteroaryl.

In some embodiments, Cy ^2B is substituted pyridyl, such as substituted 2-, 3-, or 4- pyridyl or substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl.

In some embodiments, Cy ^2B is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cy2B , halogen, and Ci-6 haloalkyl; wherein each R ^{C 2B} is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C6-10 aryl or 5-10 membered heteroaryl, wherein each C6-10 aryl or 5-10 membered heteroaryl forming R ^{C 2B} is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and haloalkyl.

In some embodiments, R ²⁵ is selected from groups of the following formulae:

In some embodiments, R ^{t 2B} in the formula representing R ²⁵ is Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen, such as fluorine or chlorine, preferably fluorine.

In some embodiments, R ^{t 2B} in the formula representing R ²⁵ is Ci-6 alkyl, such as methyl or ethyl, preferably methyl.

In some embodiments, R ^{C 2B} in the formula representing R ²⁵ is halogen, such as fluorine or chlorine, preferably fluorine.

In some embodiments, R ^a21 , R ^b21 , R ^c21 , R ^d21 , R ^a22 , R ^b22 , R ^c22 , R ^d22 are each independently selected from H, Ci-6 alkyl.

In some embodiments, each R ^e21 and each R ^e22 is H.

The compounds of Formula (IIA) and (IIB), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use.

In some embodiments, the compounds of Formula (IIA) and (IIB), and embodiments thereof, can be in the form of a salt such as a pharmaceutically acceptable salt.

The compounds of Formula (IIA) and (IIB), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (IIA) and (IIB), and embodiments thereof, are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (IIA) or (IIB), or an embodiment thereof, optionally in the form of a salt.

In some embodiments the compound Formula (IIA) or (IIB) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

[0008] In certain aspects, the compound is one or more selected from the compounds of Formula (IIA) and (IIB) set forth in the Examples including the compounds listed in Table 1, e.g., the compounds with selectivity for MASP-2 over thrombin. In certain aspects, one or more of the variables defining the compounds of Formula (IIA) and (IIB) (such as Cy ^2A , R ^Cy2A , Cy ^2B , R ^Cy2B , A ²³ , A ²⁴ , A ²⁶ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , n25, R ^a21 , R ^b21 , R ^c21 , R ^d21 , R ^e21 , R ^a22 , R ^b22 , R ^c22 , R ^d22 and R ^e22 ) is selected from the corresponding substituents in the compounds of Formula (IIA) and (IIB) in the Examples, including the compounds listed in Table 1, preferably, those of the compounds with selectivity for MASP-2 over thrombin.

[0009] In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (-) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers or

diastereomers.

[0010] In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. et al, J. Pharm. Sci 1977, 66, 1-19. They include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, arylsulfonates, alkylsulfonates, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).

[0011] In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group; hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O- alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like. [0012] In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin is at least 1.1 : 1, 1.25: 1, 1.5: 1, 1.75: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11 : 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 21 : 1, 22: 1, 23: 1, 24: 1, 25: 1, or 30: 1.

C. Compounds of Formula III

In certain aspects, the present disclosure provides a compound of Formula (III).

or a salt thereof, for use in treating a MASP-2-associated disease or disorder, wherein:

Cy ^3A is unsubstituted or substituted C6-10 aryl or unsubstituted or substituted 5-10 membered heteroaryl; wherein the ring atoms of the 5-10 membered heteroaryl forming Cy ^3A consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S; wherein the substituted C6-10 aryl or substituted 5-10 membered heteroaryl forming Cy ^3A are substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cy3A , halogen, Ci-6 haloalkyl, CN, OR ^a31 , S* ³³¹ , C(0)R ^b31 , C(0)NR ^c31 R ^d31 , C(0)OR ^a31 , OC(0)R ^b31 ,

NR ^c31 S(0) ₂ R ^b31 , S(0) ₂ NR ^c31 R ^d31 and oxo;

each R ^Cy3A is independently selected from Ci-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-lO-membered heterocycloalkyl forming R ^Cy3A consist of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein each Ci-6 alkyl, C ₂ -6 alkenyl, or C ₂ -6 alkynyl forming R ^Cy3A is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen,

S(0) ₂ NR ^c31 R ^d31 and oxo, and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming R ^Cy3A is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, CN, OR ^a31 , SR ^a31 , C(0)R ^b31 ,

R ³² is H or C1-6 alkyl; or

R ³¹ and R ³² , together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring;

R ³³ is Cy ^3B , (CR ^33A R ^33B )n33Cy ^3B , (C1-6 alkylene)Cy ^3B , (C2-6 alkenylene)Cy ^3B , or (C2-6 alkynylene)Cy ^3B , wherein the C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R ³⁵ is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of halogen, CN, OR ^a31 , SR ^a31 , C(0)R ^b31 , C(0)NR ^c31 R ^d31 ,

S(0) ₂ R ^b31 , NR ^c31 S(0) ₂ R ^b31 , S(0) ₂ NR ^c31 R ^d31 and oxo;

each R ^33A is independently H or C1-6 alkyl;

each R ^33B is independently H or C1-6 alkyl; or

or R ^33A and R ^33B attached to the same carbon atom, independently of any other R ^33A and R ^33B groups, together may form -(CH2)2-5-, thereby forming a 3-6 membered cycloalkyl ring;

n33 is 0, 1, 2 or 3; Cy ^3B is unsubstituted or substituted Ce-io aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy ^3B consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and

wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy ^3B are substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cy3B , halogen, Ci-6 haloalkyl, CN, OR ^a31 , S^ ³¹ , C(0)R ^b31 , C(0)NR ^c31 R ^d31 , C(0)OR ^a31 , OC(0)R ^b31 ,

0C(0)NR ^c31 R ^d31 , NR ^c31 R ^d31 , NR ^c31 C(0)R ^b31 , NR ^c31 C(0)NR ^c31 R ^d31 , NR ^c31 C(0)0R ^a31 , C(=NR ^e31 )NR ^{c3 1} R ^{d3 1} . C(=NOR ^a3 ')NR ^{c3 1} R ^d3 C(=NOC(0)R ^b3 ')NR ^c3 ' R ^d31 .

C(=NR ^e31 )NR ^c31 C(0)0R ^a31 , NR ^c31 C(=NR ^e31 )NR ^c31 R ^d31 , S(0)R ^b31 , S(0)NR ^c31 R ^d31 , S(0) ₂ R ^b31 , NR ^c31 S(0) ₂ R ^b31 , S(0) ₂ NR ^c31 R ^d31 and oxo;

wherein each R ^{t 3B} is independently selected from C1-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming R ^{t 3B} consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each C1-6 alkyl, C ₂ -6 alkenyl, or C ₂ -6 alkynyl forming R ^{C 3B} is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR ^a31 , SR ^a31 , C(0)R ^b31 , C(0)NR ^c31 R ^d31 , C(0)OR ^a31 , OC(0)R ^b31 ,

NR ^c31 S(0) ₂ R ^b31 , S(0) ₂ NR ^c31 R ^d31 and oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming R ^{C 3B} is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, Ci-6 haloalkyl, CN, OR ^a31 , SR ^a31 ,

S(0) ₂ NR ^c31 R ^d31 and oxo;

R ³⁴ is selected from H and Ci-6 alkyl;

R ³⁵ is selected from H, unsubstituted or substituted Ci-6 alkyl and Cy ^3C , wherein the substituted Ci-6 alkyl forming R ³⁵ is substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of Cy ^3C , halogen, CN, OR ^a31 , SR ^a31 , C(0)R ^b31 , C(0)NR ^c31 R ^d31 , C(0)0R ^a31 , 0C(0)R ^b31 , 0C(0)NR ^c31 R ^d31 , NR ^c31 R ^d31 , NR ^c31 C(0)R ^b31 , NR ^c31 C(0)NR ^c31 R ^d31 , NR ^c31 C(0)0R ^a31 , C(=NR ^e31 )NR ^c31 R ^d31 , NR ^c31 C(=NR ^e31 )NR ^c31 R ^d31 , S(0)R ^b31 , S(0)NR ^c31 R ^d31 , S(0)2R ^b31 , NR ^c31 S(0)2R ^b31 , S(0)2NR ^c31 R ^d31 and oxo; provided that no more than one of the substituents of R ³⁵ is Cy ^3C ;

Cy ^3C is unsubstituted or substituted C6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming Cy ^3C consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and

wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl, substituted C3-10 cycloalkyl or substituted 4-10 membered heterocycloalkyl forming Cy ^3C are substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cy3C , halogen, Ci-6 haloalkyl, CN, OR ⁸³¹ , S ^®831 , C(0)R ^b31 , C(0)NR ^c31 R ^d31 , C(0)OR ^a31 , OC(0)R ^b31 ,

0C(0)NR ^c31 R ^d31 , NR ^c31 R ^d31 , NR ^c31 C(0)R ^b31 , NR ^c31 C(0)NR ^c31 R ^d31 , NR ^c31 C(0)0R ^a31 , C(=NR ^e31 )NR ^{c3 1} R ^{d3 1} . C(=NOR ^a3 ')NR ^{c3 1} R ^d3 C(=NOC(0)R ^b3 ')NR ^c3 ' R ^d31 .

C(=NR ^e31 )NR ^c31 C(0)0R ^a31 , NR ^c31 C(=NR ^e31 )NR ^c31 R ^d31 , S(0)R ^b31 , S(0)NR ^c31 R ^d31 , S(0) ₂ R ^b31 , NR ^c31 S(0) ₂ R ^b31 , S(0) ₂ NR ^c31 R ^d31 and oxo;

wherein each R ^{t 3t} is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl forming R ^{t 3t} consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; wherein each C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl forming R ^{C 3C} is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR ⁸³¹ , SR ⁸³¹ , C(0)R ^b31 , C(0)NR ^c31 R ^d31 , C(0)OR ^a31 , OC(0)R ^b31 ,

NR ^c31 S(0)2R ^b31 , S(0)2NR ^c31 R ^d31 and oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming R ^{C 3C} is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, CN, OR ⁸³¹ , SR ⁸³¹ ,

R ³⁶ is selected from H and Ci-6 alkyl;

R ^a31 , R ^b31 , R ^c31 and R ^d31 are each independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl forming R ^a31 , R ^b31 , R ^c31 and R ^d31 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci-6 alkyl, halo, CN, OR ^a32 , SR ^a32 , C(0)R ^b32 , C(0)NR ^c32 R ^d32 , C(0)0R ^a32 , 0C(0)R ^b32 ,

NR ^c32 S(0) ₂ R ^b32 , S(0) ₂ NR ^c32 R ^d32 and oxo;

or R ^c31 and R ^d31 atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from Ci-e alkyl, halo, CN, OR ^a32 , SR ^a32 , C(0)R ^b32 , C(0)NR ^c32 R ^d32 , C(0)0R ^a32 , 0C(0)R ^b32 , 0C(0)NR ^c32 R ^d32 , NR ^c32 R ^d32 , NR ^c32 C(0)R ^b32 , NR ^c32 C(0)NR ^c32 R ^d32 ,

NR ^c32 C(0)0R ^a32 , C(=NR ^e32 )NR ^c32 R ^d32 , NR ^c32 C(=NR ^e32 )NR ^c32 R ^d32 , S(0)R ^b32 , S(0)NR ^c32 R ^d32 , S(0) ₂ R ^b32 , NR ^c32 S(0) ₂ R ^b32 , S(0) ₂ NR ^c32 R ^d32 and oxo;

R ^a32 , R ^b32 , R ^c32 and R ^d32 are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl forming R ^a32 , R ^b32 , R ^c32 and R ^d32 are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl)2, halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo;

or R ^c32 and R ^d32 atached to the same N atom, together with the N atom to which they are both atached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl) ₂ , halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo; and

R ^e31 and Re ³² are each, independently, H, CN or NO2.

In some embodiments, Cy ^3A is unsubstituted or substituted aryl.

In some embodiments, Cy ^3A is unsubstituted or substituted phenyl.

In some embodiments, Cy ^3A is substituted phenyl.

In some embodiments, Cy ^3A is substituted with at least one OR ^a31 or at least one C(=NR ^e31 )NR ^c31 R ^d31 , C(=NOR ^a31 )NR ^c31 R ^d31 , C(=N0C(0)R ^b31 )NR ^c31 R ^d31 , or

C(=NR ^e31 )NR ^c31 C(0)0R ^a31 .

In some embodiments, Cy ^3A is substituted with at least one OR ^a31 and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

In some embodiments, Cy ^3A is substituted with at least one OH and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

In some embodiments, Cy ^3A is substituted with at least one C(=NR ^e31 )NR ^c31 R ^d31 , C(=NOR ^a31 )NR ^c31 R ^d31 , C(=N0C(0)R ^b31 )NR ^c31 R ^d31 , C(=NR ^e31 )NR ^c31 C(0)0R ^a31 , preferably in the 4-position.

In some embodiments, Cy ^3A is substituted with at least one C(=NR ^e31 )NR ^c31 R ^d31 , preferably in the 4-position.

In some embodiments, Cy ^3A is substituted with at least one C(=NH)NH2, preferably in the 4-position.

In some embodiments, Cy ^3A is of any one of the following formulae:

In some embodiments, Cy ^3A is of any one of the following formulae:

In some embodiments, in the formula defining Cy ^3A , R ^a31 is Ci-6 alkyl, such as methyl; R ^b31 is Ci-6 alkyl, such as methyl, or R ^b31 is Ci-6 haloalkyl, such as trifluoromethyl' and R ^c31 is alkyl such as methyl.

In some embodiments, Cy ^3A is unsubstituted or substituted heteroaryl.

In some embodiments, Cy ^3A is unsubstituted or substituted pyridin-3-yl, 1H- pyrrolo[2,3-b]pyridine-5-yl, or lH-benzo[d]imidazol-6-yl.

In some embodiments, Cy ^3A is of any one of the following formulae:

In some embodiments, each R ^tv3A in the formula defining Cy ^3A is independently Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably Cl, or amino.

In some embodiments, each R ^Cy3A attached to nitrogen in the formula defining Cy ^3A is Ci-6 alkyl, such as methyl or ethyl.

In some embodiments, R ³¹ is Ci-6 alkyl.

In some embodiments, R ³¹ is methyl.

In some embodiments, R ³¹ is H.

In some embodiments, R ³² is H.

In some embodiments, R ³² is Ci-6 alkyl.

In some embodiments, R ³² is methyl.

In some embodiments, R ³¹ and R ³² , together with the groups to which they are attached, form a 4-6 membered heterocycloalkyl ring.

In some embodiments, the compound is according to any of the following Formulae

(III- la) to (Ill-lh):

(III-le) (Ill-lf)

(Ill-lg) (Ill-lh)

In some embodiments, R ³³ is Cy ^3B .

In some embodiments, R ³³ is. (Ci-6 alkylene)Cy ^3B , (C2-6 alkenylene)Cy ^3B , or (C2-6 alkynylene)Cy ^3B , wherein the Ci-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R ³⁵ is unsubstituted.

In some embodiments, R ³³ is (Ci-6 alk lene)Cy ^3B , (C2-6 alkenylene)Cy ^3B , or (C2-6 alkynylene)Cy ^3B , wherein the Ci-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene component of R ³⁵ is substituted by 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of halogen, CN, OR ^a31 , SR ^a31 , C(0)R ^b31 , C(0)NR ^c31 R ^d31 , C(0)0R ^a31 , 0C(0)R ^b31 , 0C(0)NR ^c31 R ^d31 , NR ^c31 R ^d31 , NR ^c31 C(0)R ^b31 , NR ^c31 C(0)NR ^c31 R ^d31 , NR ^c31 C(0)0R ^a31 , C(=NR ^e31 )NR ^c31 R ^d31 , NR ^c31 C(=NR ^e31 )NR ^c31 R ^d31 , S(0)R ^b31 , S(0)NR ^c31 R ^d31 , S(0) ₂ R ^b31 ,

NR ^c31 S(0) ₂ R ^b31 , S(0) ₂ NR ^c31 R ^d31 and oxo.

In some embodiments, R ³³ is Cy ^3B , (CR ^33A R ^33B )n33Cy ^3B .

In some embodiments, each R ^33A is H.

In some embodiments, each R ^33B is H.

In some embodiments, n33 is 0.

In some embodiments, n33 is 1.

In some embodiments, n33 is 2.

In some embodiments, n33 is 3.

In some embodiments, R ³³ is CFbCy ^3® .

In some embodiments, R ³³ is CFbCFbCy ^3®

In some embodiments, the compound is according to any of the following Formulae

(III-2) to (III-4):

(III-2) (III-3)

(III-4)

In some embodiments, the compound is according to any of the following Formulae

(III-2a) to (III-2h):

(III-2g) (III-2h)

In some embodiments, the compound is according to any of the following Formulae

(III-3a) to (III-3h):

(III-3g) (III-3h)

In some embodiments, the compound is according to any of the following Formulae

(III-4a) to (III-4h):

(III-4a) (III-4b)

(III-4g) (III-4h)

In some embodiments, R ³³ is CH2CH2CH2Cy ^3B .

In some embodiments, Cy ^3B is unsubstituted C6-10 aryl.

In some embodiments, Cy ^3B is unsubstituted phenyl.

In some embodiments, R ³³ is CH2CH2PI1.

In some embodiments, Cy ^3B is unsubstituted naphthyl, such as 1 -naphthyl or 2- naphthyl.

In some embodiments, R ³³ is CH2CH2-I -naphthyl or CH2CH2-2-naphthyl.

In some embodiments, Cy ^3B unsubstituted 5-10 membered heteroaryl.

In some embodiments, Cy ^3B is unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl, unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, unsubstituted benzo[Z>]thiophenyl such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7- ben/o| |thiophenyl. or unsubstituted indolyl, such as unsubstituted indol-2-yl, -3-yl, -4-yl, -

5-yl, -6-yl or -7-yl.

In some embodiments, Cy ^3B unsubstituted C3-10 cycloalkyl.

In some embodiments, Cy ^3B is unsubstituted cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, Cy ^3B unsubstituted 4-10 membered heterocycloalkyl. In some embodiments, Cy ^3B is substituted C6-10 aryl.

In some embodiments, Cy ^3B is substituted phenyl.

In some embodiments, Cy ^3B is substituted naphthyl, such as 1 -naphthyl or 2-naphthyl.

In some embodiments, Cy ^3B substituted 5-10 membered heteroaryl.

In some embodiments, Cy ^3B is substituted pyridyl, such as substituted 2-, 3-, or 4- pyridyl, substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, substituted benzo[Z>]thiophenyl such as substituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or substituted indolyl, such as substituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

In some embodiments, Cy ^3B substituted C3-10 cycloalkyl.

In some embodiments, Cy ^3B is substituted cyclopentyl, cyclohexyl, or cycloheptyl.

In some embodiments, Cy ^3B substituted 4-10 membered heterocycloalkyl

In some embodiments, Cy ^3B is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cy3B , halogen, and C1-6 haloalkyl; wherein each R ^{t 3B} is independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C6-10 aryl or 5-10 membered heteroaryl, wherein each C6-10 aryl or 5-10 membered heteroaryl forming R ^3B is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and haloalkyl.

In some embodiments, R ³³ is selected from the following groups: phenyl; benzyl;, 2- phenylethyl; 2,3-dihydro-lH-inden-2-yl; 2-(2-methylphenyl)ethyl; 2-(3-methylphenyl)ethyl; 2-(4-methylphenyl)ethyl; 2-(2,4-dimethylphenyl)ethyl; 2-(2,5-dimethylphenyl)ethyl; 2-(3,5- dimethylphenyl)ethyl; 2-(2-ethylphenyl)ethyl; 2-(3-ethylphenyl)ethyl; 2-(4- ethylphenyl)ethyl; 2-(2,4-diethylphenyl)ethyl; 2-(2,5-dimethylphenyl)ethyl; 2-(3,5- dimethylphenyl)ethyl; 2-(2-trifluoromethylphenyl)ethyl; 2-(3-trifluoromethylphenyl)ethyl; 2- (4-trifluoromethylphenyl)ethyl; 2-(2-fluorophenyl)ethyl; 2-(3-fluorophenyl)ethyl; 2-(4- fluorophenyl)ethyl; 2-(2,4-difluorophenyl)ethyl; 2-(2,5-difluorophenyl)ethyl; 2-(3,5- difluorophenyl)ethyl; 2-(2-chlorophenyl)ethyl; 2-(3-chlorophenyl)ethyl; 2-(4- chlorophenyl)ethyl; 2-(2,4-dichlorophenyl)ethyl; 2-(2,5-dichlorophenyl)ethyl; 2-(3,5- dichlorophenyl)ethyl; 2-(2-methoxyphenyl)ethyl; 2-(3-methoxyphenyl)ethyl; 2-(4- methoxyphenyl)ethyl; 2-(2,4-dimethoxyphenyl)ethyl; 2-(2,5-dimethoxyphenyl)ethyl; 2-(3,5- dimethoxyphenyl)ethyl; 2-(cyclopentyl)ethyl; 2-(cyclohexyl)ethyl; 2-(cycloheptyl)ethyl; 2- (2-(aminomethyl)phenyl)ethyl; 2-(3-(aminomethyl)phenyl)ethyl; 2-(4- (aminomethyl)phenyl)ethyl; 2-(2-cyanophenyl)ethyl; 2-(3-cyanophenyl)ethyl; and 2-(4- cyanophenyl)ethyl; and groups of the following formulae:

In some embodiments, R ³⁴ is hydrogen.

In some embodiments, R ³⁴ is Ci-6 alkyl, such as methyl.

In some embodiments, R ³⁵ is H.

In some embodiments, R ³⁵ is Cy ^3C .

In some embodiments, R ³⁵ is unsubstituted Ci-6 alkyl.

In some embodiments, R ³⁵ is substituted Ci-6 alkyl.

In some embodiments, the substituted Ci-6 alkyl forming R ³⁵ is substituted by at least one substituent, wherein the substituents of R ³⁵ are independently selected from: 1, 2, or 3 substituents selected from the group consisting of Cy ^3C , halogen, CN, OR ^a31 , SR ^a31 , C(0)R ^b31 ,

S(0)R ^b31 , S(0)NR ^c31 R ^d31 , S(0) ₂ R ^b31 , NR ^c31 S(0) ₂ R ^b31 , S(0) ₂ NR ^c31 R ^d31 and oxo.

In some embodiments, the substituted Ci-6 alkyl forming R ³⁵ is substituted by at least one substituent, wherein the substituents include Cy ^3C .

In some embodiments, the substituted Ci-6 alkyl forming R ³⁵ is substituted by one substituent, wherein the substituent is Cy ^3C .

In some embodiments, R ³⁵ is (CH ₂ )i-5Cy ^3C .

In some embodiments, R ³⁵ is CH ₂ Cy ^3C .

In some embodiments, Cy ^3C is unsubstituted C6-10 aryl.

In some embodiments, Cy ^3C is unsubstituted phenyl or naphthyl, such as 1 -naphthyl or 2-naphthyl.

In some embodiments, Cy ^3C is unsubstituted 5-10 membered heteroaryl.

In some embodiments, Cy ^3C is unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl, unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, unsubstituted benzo[Z>]thiophenyl such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7- benzo| /? I thiophenyl. or unsubstituted indolyl, such as unsubstituted indol-2-yl, -3-yl, -4-yl, - 5-yl, -6-yl or -7-yl.

In some embodiments, Cy ^3C is unsubstituted C3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

In some embodiments, Cy ^3C is unsubstituted 4-10 membered heterocycloalkyl.

In some embodiments, Cy ^3C is substituted C6-10 aryl.

In some embodiments, Cy ^3C is substituted phenyl, or substituted naphthyl, such as substituted 1 -naphthyl or 2-naphthyl.

In some embodiments, Cy ^3C substituted 5-10 membered heteroaryl.

In some embodiments, Cy ^3C is substituted pyridyl, such as substituted 2-, 3-, or 4- pyridyl, substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, substituted benzo[Z>]thiophenyl such as substituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or substituted indolyl, such as substituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

In some embodiments, Cy ^3C is substituted C3-10 cycloalkyl such as substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

In some embodiments, Cy ^3C is substituted 4-10 membered heterocycloalkyl.

In some embodiments, R ³⁶ is H.

In some embodiments, R ³⁶ is C1-6 alkyl such as methyl.

In some embodiments, R ^a31 , R ^b31 , R ^c31 , R ^d31 , R ^a32 , R ^b32 , R ^c32 and R ^d32 are each independently selected from H and C1-6 alkyl.

In some embodiments, each R ^e31 and each R ^e32 is H.

The compounds of Formula (III), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use.

In some embodiments, the compounds of Formula (III), and embodiments thereof, can be in the form of a salt such as a pharmaceutically acceptable salt.

The compounds of Formula (III), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (III), and embodiments thereof, are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (III), or an embodiment thereof, optionally in the form of a salt.

In some embodiments the compound Formula (III) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

[0013] In certain aspects, the compound is one or more selected from the compounds of Formula (III) set forth in the Examples, including the compounds listed in Table 1, e.g., the compounds with selectivity for MASP-2 over thrombin. In certain aspects, one or more of the variables defining the compounds of Formula (III) (such as Cy ^3A , R ^Cy3A , Cy ^3B , R ^Cy3B ,

Cy ^3C R ^Cy3C R ³¹ R ³² R ³³ R ^33A R ^33B R ³⁴ R ³⁵ R ³⁶ n33 R ^a31 R ^b31 R ^c31 R ^d31 R ^e31 R ^a32 R ^b32 R ^c32 , R ^d32 and R ^e32 ) is selected from the corresponding substituents in the compounds of Formula (III) of the Examples, including the compounds listed in Table 1, preferably, those of the compounds with selectivity for MASP-2 over thrombin.

[0014] In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (-) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers or

diastereomers.

[0015] In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. et al, J. Pharm. Sci 1977, 66, 1-19. They include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, arylsulfonates, alkylsulfonates, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).

[0016] In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group; hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O- alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like. [0017] In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin is at least 1.1 : 1, 1.25: 1, 1.5: 1, 1.75: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11 : 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 21 : 1, 22: 1, 23: 1, 24: 1, 25: 1, or 30: 1.

D. Compounds of Formula IV

In certain aspects, the present disclosure provides a compound of Formula (IV).

or a salt thereof, for use in treating a MASP-2-associated disease or disorder, wherein:

Cy ^4A is unsubstituted or substituted C6-10 aryl or unsubstituted or substituted 5-10 membered heteroaryl; wherein the ring atoms of the 5-10 membered heteroaryl forming Cy ^4A consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S; wherein the substituted C6-10 aryl or substituted 5-10 membered heteroaryl forming Cy ^4A are substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cy4A , halogen, Ci-6 haloalkyl, CN, OR ^a41 , S ^®841 , C(0)R ^b41 , C(0)NR ^c41 R ^d41 , C(0)OR ^a41 , 0C(0)R ^b41 ,

NR ^c41 S(0) ₂ R ^M1 , S(0) ₂ NR ^c41 R ^d41 and oxo;

each R ^Cy4A is independently selected from Ci-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-lO-membered heterocycloalkyl forming R ^Cy4A consist of carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein each Ci-6 alkyl, C ₂ -6 alkenyl, or C ₂ -6 alkynyl forming R ^Cy4A is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR ^a41 , SR ^a41 , C(0)R ^M1 , C(0)NR ^c41 R ^d41 , C(0)OR ^a41 , OC(0)R ^b41 , 0C(0)NR ^c41 R ^d41 ,

_{NRc4 iR} d4i NR ^c41 C(0)R ^b41 , NR ^c41 C(0)NR ^c41 R ^d41 , NR ^c41 C(0)0R ^a41 , C(=NR ^e41 )NR ^c41 R ^d41 ,

NR ^c41 C(=NR ^e41 )NR ^c41 R ^d41 , S(0)R ^b41 , S(0)NR ^c41 R ^d41 , S(0) ₂ R ^b41 , NR ^c41 S(0) ₂ R ^b41 ,

S(0) ₂ NR ^c41 R ^d41 and oxo, and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming R ^Cy4A is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e haloalkyl, CN, OR ^a41 , SR ^a41 , C(0)R ^b41 ,

R ⁴² is H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or Cy ^4B ; wherein each of the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, forming R ⁴² is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of Cy ^4B , halogen, CN, OR ^a41 , SR ^a41 , C(0)R ^b41 ,

S(0)R ^M1 , S(0)NR ^c41 R ^d41 , S(0) ₂ R ^M1 , NR ^c41 S(0) ₂ R ^b41 , S(0) ₂ NR ^c41 R ^d41 and oxo; provided that no more than one of the substituents is Cy ^4B ;

Cy ^4B is unsubstituted or substituted Ce-io aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or unsubstituted or substituted 4-10 membered heterocycloalkyl forming Cy ^4B consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl substituted C3-10 cycloalkyl, or 4- 10 membered heterocycloalkyl forming Cy ^4B is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cy4B , halogen, Ci-6 haloalkyl, CN, OR ^a41 , S ¹¹³⁴¹ , C(0)R ^b41 , C(=N0C(0)R ^b41 )NR ^c41 R ^d41 , C(=NR ^e41 )NR ^c41 C(0)0R ^a41 , NR ^c41 C(=NR ^e41 )NR ^c41 R ^d41 , S(0)R ^b41 , S(0)NR ^c41 R ^d41 , S(0) ₂ R ^M1 , NR ^c41 S(0) ₂ R ^b41 , S(0) ₂ NR ^c41 R ^d41 and oxo;

wherein each R ^{C 4B} is independently selected from Ci-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-lO-membered heterocycloalkyl forming R ^{C 4B} consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, and wherein each C1-6 alkyl, C ₂ -6 alkenyl, or C ₂ -6 alkynyl forming R ^{C 4B} is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR ^a41 , SR ^a41 , C(0)R ^b41 , C(0)NR ^c41 R ^d41 , C(0)OR ^a41 , 0C(0)R ^b41 ,

NR ^c41 S(0) ₂ R ^b41 , S(0) ₂ NR ^c41 R ^d41 and oxo; and \each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming each R ^{C 4B} is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C ₂ -e alkenyl, C ₂ -e alkynyl, Ci-e haloalkyl, CN, OR ^a41 , SR ^a41 , C(0)R ^b41 ,

S(0)R ^b41 , S(0)NR ^c41 R ^d41 , S(0) ₂ R ^M1 , NR ^c41 S(0) ₂ R ^b41 , S(0) ₂ NR ^c41 R ^d41 and oxo;

or R ⁴¹ and R ⁴² , together with the atoms to which they are attached and the nitrogen atom linking the atoms to which R ⁴¹ and R ⁴² are attached, form a 4-7 membered

heterocycloalkyl ring; which is optionally further substituted by 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cy4B , halogen, Ci-6 haloalkyl, CN, OR ^a41 , S ¹¹³⁴¹ , C(0)R ^b41 , C(0)NR ^c41 R ^d41 , C(0)OR ^a41 , OC(0)R ^M1 , 0C(0)NR ^c41 R ^d41 , NR ^c41 R ^d41 , NR ^c41 C(0)R ^b41 ,

S(0)R ^b41 , S(0)NR ^c41 R ^d41 , S(0) ₂ R ^M1 , NR ^c41 S(0) ₂ R ^b41 , S(0) ₂ NR ^c41 R ^d41 and oxo;

R ⁴³ is H, Ci-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, or Cy ^4C ; wherein each of the Ci-6 alkyl, C ₂ -6 alkenyl, or C ₂ -6 alkynyl forming R ⁴³ is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents each independently selected from: 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of Cy ^4C , halogen, CN, OR ^a41 , SR ^a41 , C(0)R ^b41 , C(0)NR ^c41 R ^d41 , C(0)OR ^a41 ,

S(0) ₂ R ^b41 , NR ^c41 S(0) ₂ R ^b41 , S(0) ₂ NR ^c41 R ^d41 and oxo, provided that no more than one substituent of the Ci-6 alkyl, C ₂ -6 alkenyl, or C ₂ -6 alkynyl forming R ⁴³ is Cy ^4C ; Cy ^4C is unsubstituted or substituted Ce-io aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C3-10 cycloalkyl, or unsubstituted or substituted 4-10 membered heterocycloalkyl; wherein the ring atoms of the 5-10 membered heteroaryl or unsubstituted or substituted 4-10 membered heterocycloalkyl forming Cy ^4B consist of carbon atoms and 1, 2 or 3 heteroatoms selected from O, N and S; and wherein the substituted C6-10 aryl, substituted 5-10 membered heteroaryl substituted C3-10 cycloalkyl, or 4- 10 membered heterocycloalkyl forming Cy ^4C is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cy4C , halogen, C1-6 haloalkyl, CN, OR ^a41 , S ¹¹³⁴¹ , C(0)R ^M1 ,

S(0)R ^b41 , S(0)NR ^c41 R ^d41 , S(0) ₂ R ^b41 , NR ^c41 S(0) ₂ R ^b41 , S(0) ₂ NR ^c41 R ^d41 and oxo;

each R ^Cy4C is independently selected from C1-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the ring atoms of the 5-10 membered heteroaryl or 4-lO-membered heterocycloalkyl forming R ^Cy4C consist of carbon atoms and 1, 2, or 3 heteroatoms selected from O, N and S, wherein each C1-6 alkyl, C ₂ -6 alkenyl, or C ₂ -6 alkynyl forming R ^Cy4C is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen,

S(0) ₂ NR ^c41 R ^d41 and oxo; and wherein each C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl forming each R ^Cy4A is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halogen, Ci-6 alkyl, C ₂ -e alkenyl, C ₂ -e alkynyl, Ci-e haloalkyl, CN, OR ^a41 , SR ^a41 , C(0)R ^b41 ,

alkenyl, C ₂ -6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, C6-io aryl, C3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-Ci-3 alkyl, 5-10 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl- Ci-3 alkyl and 4-10 membered heterocycloalkyl-Ci-3 alkyl forming R ^a41 , R ^M1 , R ^c41 and R ^d41 are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Ci-6 alkyl, halo, CN, OR ^a42 , SR ^a42 , C(0)R ^b42 , C(0)NR ^c42 R ^d42 , C(0)0R ^a42 , 0C(0)R ^b42 ,

NR ^c42 S(0) ₂ R ^b42 , S(0) ₂ NR ^c42 R ^d42 and oxo;

or R ^c41 and R ^d41 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each optionally substituted with 1, 2 or 3 substituents independently selected from Ci-e alkyl, halo, CN, OR ^a42 , SR ^a42 , C(0)R ^b42 , C(0)NR ^c42 R ^d42 , C(0)0R ^a42 ,

S(0) ₂ R ^b42 , NR ^c42 S(0) ₂ R ^b42 , S(0) ₂ NR ^c42 R ^d42 and oxo;

R ^a42 , R ^b42 , R ^c42 and R ^d42 are each independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C ₂ -6 alkenyl, C ₂ -6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-Ci-3 alkyl, 5-6 membered heteroaryl-Ci-3 alkyl, C3-7 cycloalkyl-Ci-3 alkyl and 4-7 membered heterocycloalkyl-Ci-3 alkyl forming R ^a42 , R ^b42 , R ^c42 and R ^d42 are each optionally substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl) ₂ , halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo;

or R ^c42 and R ^d42 attached to the same N atom, together with the N atom to which they are both attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or 5-membered heteroaryl group, each of which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from OH, CN, amino, NH(CI-6 alkyl), N(CI-6 alkyl) ₂ , halo, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl, Ci-6 haloalkoxy and oxo; and

R ^e41 and Re ⁴² are each, independently, H, CN or N0 ₂ .

In some embodiments, Cy ^4A is unsubstituted or substituted aryl.

In some embodiments, Cy ^4A is unsubstituted or substituted phenyl.

In some embodiments, Cy ^4A is substituted phenyl. In some embodiments, Cy ^4A is substituted with at least one OR ^a41 or at least one C(=NR ^e41 )NR ^c41 R ^d41 , C(=NOR ^a41 )NR ^c41 R ^d41 , C(=N0C(0)R ^b41 )NR ^c41 R ^d41 , or

C(=NR ^e41 )NR ^c41 C(0)0R ^a41 .

In some embodiments, Cy ^4A is substituted with at least one OR ^a41 and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

In some embodiments, Cy ^4A is substituted with at least one OH and by at least one additional substituent selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl and halogen.

In some embodiments, Cy ^4A is substituted with at least one C(=NR ^e41 )NR ^c41 R ^d41 ,

C(=NOR ^a41 )NR ^c41 R ^d41 , C(=N0C(0)R ^b41 )NR ^c41 R ^d41 , C(=NR ^e41 )NR ^c41 C(0)0R ^a41 , preferably in the 4-position.

In some embodiments, Cy ^4A is substituted with at least one C(=NR ^e41 )NR ^c41 R ^d41 , such as C(=NH)NH2, preferably in the 4-position.

In some embodiments, Cy ^4A is of any one of the following formulae:

In some embodiments, in the formula defining Cy ^4A , R ^a41 is Ci-6 alkyl, such as methyl,

R ^b41 is Ci-6 alkyl, such as methyl, R ^b41 is Ci-6 haloalkyl, such as trifluoromethyl, and R ^c41 is alkyl such as methyl.

In some embodiments, Cy ^4A is unsubstituted or substituted heteroaryl.

In some embodiments, Cy ^4A is unsubstituted or substituted pyridin-3-yl, 1H- pyrrolo[2,3-b]pyridine-5-yl, or lH-benzo[d]imidazol-6-yl.

In some embodiments, Cy ^4A is of any one of the following formulae:

In some embodiments, each R ^{C 4A} in the formula defining Cy ^4A is independently Ci-6 alkyl, such as methyl or ethyl, preferably methyl, or halogen such as F, Cl or Br, preferably

Cl. In some embodiments, each R ^{C 4A} attached to nitrogen in the formula defining Cy ^4A is Ci-6 alkyl, such as methyl or ethyl.

In some embodiments, R ⁴¹ is Ci-6 alkyl.

In some embodiments, R ⁴¹ is H.

In some embodiments, R ⁴¹ is methyl.

In some embodiments, R ⁴² is H.

In some embodiments, R ⁴² is unsubstituted Ci-6 alkyl, such as methyl.

In some embodiments, R ⁴² is Cy ^4B .

In some embodiments, R ⁴² is substituted Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.

In some embodiments, R ⁴² is substituted Ci-6 alkyl.

In some embodiments, R ⁴² is substituted Ci-6 alkyl, wherein the Ci-6 alkyl forming R ⁴² is substituted by 1, 2, or 3 substituents selected from the group consisting of Cy ^4B , halogen, CN, OR ^a41 , SR ^a41 , C(0)R ^b41 , C(0)NR ^c41 R ^d41 , C(0)0R ^a41 , 0C(0)R ^b41 ,

0C(0)NR ^c41 R ^d41 , NR ^c41 R ^d41 , NR ^c41 C(0)R ^b41 , NR ^c41 C(0)NR ^c41 R ^d41 , NR ^c41 C(0)0R ^a41 , C(=NR ^e41 )NR ^c41 R ^d41 , NR ^c41 C(=NR ^e41 )NR ^c41 R ^d41 , S(0)R ^b41 , S(0)NR ^c41 R ^d41 , S(0) ₂ R ^b41 , NR ^c41 S(0) ₂ R ^b41 , S(0)2NR ^c41 R ^d41 and oxo; provided that no more than one of the substituents is Cy ^4B .

In some embodiments, the substituted Ci-6 alkyl forming R ⁴² is substituted by at least one substituent, wherein the substituents include Cy ^4B .

In some embodiments, the substituted Ci-6 alkyl forming R ³⁵ is substituted by one substituent, wherein the substituent is Cy ^4B .

In some embodiments, R ⁴² is (CH2)i-5Cy ^4B .

In some embodiments, R ⁴² is CffeCy ^4® .

In some embodiments, Cy ^4B is unsubstituted C6-10 aryl such as unsubstituted phenyl or naphthyl, such as 1 -naphthyl or 2-naphthyl, Cy ^4B is unsubstituted 5-10 membered heteroaryl, such as unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl, unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, unsubstituted

benzo| /) | thiophenyl such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or unsubstituted indolyl, such as unsubstituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl, Cy ^4B is unsubstituted C3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or Cy ^4B is unsubstituted 4-10 membered heterocycloalkyl.

In some embodiments, Cy ^4B is substituted C6-10 aryl such as substituted phenyl or naphthyl, such as 1 -naphthyl or 2-naphthyl, Cy ^4B is substituted 5-10 membered heteroaryl, such as substituted pyridyl, such as substituted 2-, 3-, or 4-pyridyl, substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, substituted benzo[Z>]thiophenyl such as substituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or substituted indolyl, such as substituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl, Cy ^4B is substituted C3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, or Cy ^4B is substituted 4-10 membered heterocycloalkyl.

In some embodiments, R ⁴¹ and R ⁴² , together with the atoms to which they are attached and the nitrogen atom linking the atoms to which R ⁴¹ and R ⁴² are attached, form a 4-7 membered heterocycloalkyl ring; which is optionally further substituted by 1, 2, 3, 4 or 5 substituents each independently selected from R ^Cy4B , halogen, C1-6 haloalkyl, CN, OR ^a41 ,

S(0) ₂ NR ^c41 R ^d41 and oxo.

In some embodiments, R ⁴¹ and R ⁴² , together with the atoms to which they are attached and the nitrogen atom linking the atoms to which R ⁴¹ and R ⁴² are attached, form a 5 or 6 membered heterocycloalkyl ring.

In some embodiments, the compound is according to any of the following Formulae

(IV- 1), (IV-2), (IV-la), (IV-lb), (IV-2a), or (IV-2b),

(IV-la) (IV-lb)

(IV-2a) (IV-2b)

In some embodiments, R ⁴³ is Cy ^4C .

In some embodiments, R ⁴³ is unsubstituted Ci-6 alkyl.

In some embodiments, R ⁴³ is substituted Ci-6 alkyl.

In some embodiments, the substituted Ci-6 alkyl forming R ⁴³ is substituted by at least one substituent independently selected from: 1, 2, or 3 substituents selected from the group consisting of Cy ^4C , halogen, CN, OR ^a41 , SR ^a41 , C(0)R ^M1 , C(0)NR ^c41 R ^d41 , C(0)0R ^a41 , 0C(0)R ^M1 , 0C(0)NR ^c41 R ^d41 , NR ^c41 R ^d41 , NR ^c41 C(0)R ^b41 , NR ^c41 C(0)NR ^c41 R ^d41 ,

NR ^c41 C(0)0R ^a41 , C(=NR ^e41 )NR ^c41 R ^d41 , NR ^c41 C(=NR ^e41 )NR ^c41 R ^d41 , S(0)R ^b41 , S(0)NR ^c41 R ^d41 , S(0) ₂ R ^b41 , NR ^c41 S(0) ₂ R ^M1 , S(0) ₂ NR ^c41 R ^d41 and oxo.

In some embodiments, the substituted Ci-6 alkyl forming R ⁴³ is substituted by at least one substituent, wherein the substituents include Cy ^4C .

In some embodiments, the substituted Ci-6 alkyl forming R ⁴³ is substituted by one substituent, wherein the substituent is Cy ^4C .

In some embodiments, R ⁴³ is (CH ₂ )i-5Cy ^4C .

In some embodiments, R ⁴³ is CH ₂ Cy ^4C .

In some embodiments, R ⁴³ is CH ₂ CH ₂ Cy ^4G .

In some embodiments, R ⁴³ is CF ₂ Cy ^4C or CF ₂ CH ₂ Cy ^4G .

In some embodiments, Cy ^4C is unsubstituted Ce-io aryl, such as phenyl, 1 -naphthyl or 2-naphthyl.

In some embodiments, Cy ^4C is unsubstituted 5-10 membered heteroaryl, such as unsubstituted pyridyl, such as unsubstituted 2-, 3-, or 4-pyridyl, unsubstituted quinolyl, such as unsubstituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, unsubstituted benzo[Z>]thiophenyl such as unsubstituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or unsubstituted indolyl, such as unsubstituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

In some embodiments, Cy ^4C is unsubstituted C3-10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

In some embodiments, Cy ^4C is unsubstituted 4-10 membered heterocycloalkyl. In some embodiments, Cy ^4C is substituted C6-10 aryl, such as substituted phenyl, substituted 1 -naphthyl or substituted 2-naphthyl.

In some embodiments, Cy ^4C is substituted 5-10 membered heteroaryl, such as substituted pyridyl, such as substituted 2-, 3-, or 4-pyridyl, substituted quinolyl, such as substituted 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, substituted benzo[Z>]thiophenyl such as substituted 2-, 3-, 4-, 5-, 6-, or 7- benzo[Z>]thiophenyl, or substituted indolyl, such as substituted indol-2-yl, -3-yl, -4-yl, -5-yl, -6-yl or -7-yl.

In some embodiments, Cy ^4C is substituted C3-10 cycloalkyl such as substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

In some embodiments, Cy ^4C is substituted 4-10 membered heterocycloalkyl.

In some embodiments, the compound is according to any of the following Formulae

(IV-3)-(IV-7), (IV-3a), (IV-3b), (IV-5a), (IV-5b), (IV-7a), or (IV-7b):

(IV-3a) (IV-3b)

(IV-7a) (IV-7b)

In some embodiments, R ^a41 , R ^b41 , R ^c41 , R ^d41 , R ^a42 , R ^b42 , R ^c42 , and R ^d42 are each independently selected from H and Ci-6 alkyl.

In some embodiments, each R ^e41 and each R ^e42 is H.

In some embodiments, the compounds of Formula (IV), and embodiments thereof, can be in the form of a salt such as a pharmaceutically acceptable salt.

The compounds of Formula (Iv), and embodiments thereof, are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (IV), and embodiments thereof, are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (IV), or an embodiment thereof, optionally in the form of a salt.

In some embodiments the compound Formula (IV) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

[0018] In certain aspects, the compound is one or more selected from the compounds of Formula (IV) set forth in the Examples, including the compounds listed in Table 1, ( e.g . , the compounds with selectivity for MASP-2 over thrombin). In certain aspects, one or more of the variables defining the compounds of Formula (IV) (such as Cy ^4A , R ^Cy4A , Cy ^4B , R ^Cy4B , Cy ^4C , R ^Cy4C , R ⁴¹ , R ⁴² , R ⁴³ , R ^a41 , R ^b41 , R ^c41 , R ^d41 , R ^e41 , R ^a42 , R ^b42 , R ^c42 , R ^d42 and R ^e42 ) is selected from the corresponding substituents in the compounds of Formula (IV) of the Examples, including the compounds listed in Table 1, preferably, those of the compounds with selectivity for MASP-2 over thrombin. [0019] In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (-) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers or

diastereomers.

[0020] In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. et al, J. Pharm. Sci 1977, 66, 1-19. They include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, arylsulfonates, alkylsulfonates, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).

[0021] In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group; hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O- alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like.

[0022] In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin is at least 1.1 : 1, 1.25: 1, 1.5: 1, 1.75: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11 : 1, 12:1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 21: 1, 22: 1, 23: 1, 24: 1, 25: 1, or 30: 1. E. Compounds of Formula VA, VB, VIA, VIB, VIIA and VIIB.

1. Additional Chemical Definitions

The following definitions apply herein in the present section (II)(E) and the claims directed to the compounds of Formulae (VA), (VB), (VIA), (VIB), (VIIA) and (VIIB) disclosed herein.

The term "alkoxy" refers to a straight or branched chain saturated or unsaturated hydrocarbon containing at least one oxygen atom in an ether group (e.g., EtO). The chain may contain an indicated number of carbon atoms. For example, "C1-C12 alkoxy" indicates that the group may have from 1 to 12 (inclusive) carbon atoms and at least one oxygen atom. Examples of C1-C12 alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, n-pentoxy, isopentoxy, neopentoxy, and hexoxy.

The term "alkyl" includes an aliphatic hydrocarbon chain that may be straight chain or branched. The chain may contain an indicated number of carbon atoms: For example, C1-C12 indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it. If not otherwise indicated, an alkyl group about 1 to about 20 carbon atoms. In one aspect, alkyl groups have 1 to about 12 carbon atoms in the chain. In another aspect, alkyl groups ("lower alkyl") have 1 to about 6 carbon atoms in the chain. Examples may include, but are not limited to, methyl, ethyl, propyl, isopropyl (iPr), 1 -butyl, 2-butyl, isobutyl (iBu), tert-butyl, pentyl, 2- methylbutyl, l,l-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, cyclopentyl, or cyclohexyl. In one aspect, an alkyl group can exclude methyl (e.g., 2 to 6 carbon atoms in the chain).

The term "aryl" as used herein includes cyclic aromatic carbon ring systems containing from 6 to 18 carbons. Examples of an aryl group include, but are not limited to, phenyl, naphthyl, anthracenyl, tetracenyl, biphenyl and phenanthrenyl.

The terms "arylalkyl" and "aralkyl," which are used interchangeably, include an alkyl group as defined herein where at least one hydrogen substituent has been replaced with an aryl group as defined herein. Examples include, but are not limited to, benzyl, l-phenylethyl, 4-methylbenzyl, and 1,1, -dimethyl- l-phenylmethyl.

[0023] The term "cycloalkyl" as used herein includes a cyclic hydrocarbon group that may contain an indicated number of carbon atoms: For example, C3-C12 indicates that the group may have from 3 to 12 (inclusive) carbon atoms in it. If not otherwise indicated, a cycloalkyl group includes about 3 to about 20 carbon atoms. In one aspect, cycloalkyl groups have 3 to about 12 carbon atoms in the group. In another aspect, cycloalkyl groups have 3 to about 7 carbon atoms in the group. Examples may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, and cycloheptyl.

As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, or iodo. In one aspect, "halo" includes fluoro or chloro (preferably chloro).

The term "heteroaryl" includes mono and bicyclic aromatic groups of about 4 to about 14 ring atoms (e.g., 4 to 10 or 5 to 10 atoms) containing at least one heteroatom. Heteroatom as used in the term heteroaryl refers to oxygen, sulfur and nitrogen. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Examples include, but are not limited to, pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, l,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, l,2,4-triazinyl, and benzothiazolyl.

As used herein, "heterocyclyl" includes a non-aromatic saturated monocyclic or multicyclic ring system of about 4 to about 10 ring atoms (e.g., 5 to about 8 ring atoms, or 5 to about 6 ring atoms), in which one or more of the atoms in the ring system is an element or elements other than carbon, e.g., nitrogen, oxygen or sulfur. A heterocyclyl group optionally comprises at least one sp ² -hybridized atom (e.g., a ring incorporating a carbonyl, endocyclic olefin, or exocyclic olefin). In some embodiments, a nitrogen or sulfur atom of the heterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Examples of monocyclic heterocyclyl rings include, but are not limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, l,3-dioxolanyl, 1,4- dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

As used herein, the term "hydroxyalkyl" includes an alkyl group where at least one hydrogen substituent has been replaced with an alcohol (-OH) group. In certain aspects, the hydroxyalkyl group has one alcohol group. In certain aspects, the hydroxyalkyl group has one or two alcohol groups, each on a different carbon atom. In certain aspects, the hydroxyalkyl group has 1, 2, 3, 4, 5, or 6 alcohol groups. Examples may include, but are not limited to, hydroxymethyl, 2-hydroxy ethyl, and 1 -hydroxy ethyl.

The term "hypertonic" refers to a formulation with an osmotic pressure above that of human (i.e., greater than 350 mOsm/KglHhO).

When any two substituent groups or any two instances of the same substituent group are "independently selected" from a list of alternatives, the groups may be the same or different. For example, if R ^a and R ^b are independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, then a molecule with two R ^a groups and two R ^b groups could have all groups be alkyl group (e.g., four different alkyl groups). Alternatively, the first R ^a could be alkyl, the second R ^a could be fluoro, the first R ^b could be hydroxyalkyl, and the second R ^b could be amino (or any other substituents taken from the group).

Alternatively, both R ^a and the first R ^b could be fluoro, while the second R ^b could be alkyl (i.e.. some pairs of substituent groups may be the same, while other pairs may be different).

As used herein, the term "salt" refers to acid or base salts of a compound, e.g., ZNA or another 2-(acylamino)imidazole. Illustrative examples of pharmaceutically acceptable salts are cationic salts such as alkali and alkaline earth metal (such as sodium, lithium, potassium, calcium, and magnesium) salts, ammonium (ammonium, trimethyl ammonium,

diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium) salts, mineral acid

(hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic carboxylic acid (acetic acid, propionic acid, glutamic acid, citric acid, and the like) salts, organic sulfonic acid (methanesulfonic acid) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's, Pharmaceutical Sciences (current edition), Mack

Publishing Co., Easton, PA, which is incorporated herein by reference.

The terms "a salt thereof," "salt thereof," or "salts thereof' can be applied to any preceding member of an associated Markush group. For example, a group consisting of A, B, C, and salts thereof would include within its scope embodiments that were a salt of A, embodiments that were a salt of B, and embodiments that were a salt of C.

2. Compounds of Formula VA and VB

In certain aspects, the present disclosure provides a compound is of the Formula (VA) or (VB):

or a salt thereof; wherein: A ¹ is a member selected from the group consisting of-(C=NH)-,-(C=NOR ^a )-, -[C=N0(C=0)R ^a ]-, -[C=N[0(C=0)ZR ^b ]}-, a fused 5- or 6-member heterocyclyl, and a fused 5- or 6-member heteroaryl;

when A ¹ is -(C=NH)-, Y ¹ is selected from the group consisting of-Nfh.

-NH(C=0)R ^a , and - NH(C=0)ZR ^b ;

when A ¹ is -(C=NOR ^a )-, -[C=N0(C=0)R ^a ]-, or -{C=N[0(C=0)ZR ^b ]}-, Y ¹ is

-NH ₂ ;

when A ¹ is fused heterocyclyl or heteroaryl, Y ¹ is -NH2 or halo, and A ¹ is substituted with m additional R ¹ groups;

each R ^a and R ^b is independently selected from the group consisting of C1-C6 alkyl, C3- C10 cycloalkyl, C6-C10 aryl, and C7-C12 arylalkyl; wherein R ^a has m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxy alkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, R ^a and R ^b join to form a heterocyclyl ring with m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, and halo;

each Z is independently selected from the group consisting of O and S;

A ² is a member selected from the group consisting of C3-C6 heteroaryl, Ce aryl, and C2-C6 alkyl;

when A ² is C3-C6 heteroaryl, Y ² is selected from the group consisting of -NH2,

- CH2NH2, chloro, -(C=NH)NH ₂ , -(C=NH)NH(C=0)R ^a ,

-(C=NH)NH(C=0)ZR ^b , -(C=NOR ^a )NH ₂ , -[C=N0(C=0)R ^a ]NH ₂ , and

-{C=N[0(C=0)ZR ^b ]}NH2; and A ² is substituted with m additional R ¹ groups;

when A ² is Ce aryl, Y ² is selected from the group consisting of aminomethyl, hydroxy, and halo, and A ² is substituted with m additional R ¹ groups;

when A ² is C2-C6 alkyl, Y ² is selected from the group consisting of

-NH(C=NH)NH ₂ , -NH(C=NH)NH(C=0)R ^a , and -NH(C=NH)NH(C=0)ZR ^b ;

each R ¹ is a member independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;

each m and n is an independently selected integer from 0 to 3;

L is -(0) _P- (C(R ^2a )(R ^2b ))q-,

each R ^2a or R ^2b is a member independently selected from the group consisting of hydrogen and fluoro;

p is an integer from 0 to 1;

q is an integer from 1 to 2; R ³ is a member selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, and carboxy(Ci-C6 alkyl); or, alternatively, R ³ and R ⁴ join to form an azetidine, pyrrolidine, or piperidine ring;

R ⁴ is a member selected from the group consisting of hydrogen and C1-C6 alkyl; or, alternatively, R ⁴ and R ³ join to form an azetidine, pyrrolidine, or piperidine ring;

R ⁵ is a member selected from the group consisting of C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, heteroaryl, and C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R ¹³ substituents; or, alternatively, R ⁵ and R ⁶ join to form a heterocyclic ring with from 0 to 3 R ¹³ substituents;

R ⁶ is a member selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, carboxy(Ci-C6 alkyl), C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R ¹³ substituents, amino(Ci-C8 alkyl); and amido(Ci-C8 alkyl); or, alternatively, R ⁶ and R ⁵ join to form a heterocyclylic ring with from 0 to 3 R ¹³ substituents; and

each R ¹³ is a member independently selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, (C6-C10 aryl)Ci-C6 alkyl, carboxy(Ci-C6 alkyloxy), heteroaryl, (C6-C10 heteroaryl)Ci-C6 alkyl, heterocyclyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxy alkyl, amino, C1-C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R ¹³ groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring.

In certain aspects, the present disclosure provides a compound is of the Formula (VA) or (VB):

or a salt thereof; wherein:

A ¹ is a member selected from the group including -(C=NH)-,-(C=NOR ^a )-,

-[C=N0(C=0)R ^a ]-, -[C=N[0(C=0)ZR ^b ]}-, a fused 5- or 6-member heterocyclyl, and a fused 5- or 6-member heteroaryl;

when A ¹ is -(C=NH)-, Y ¹ is selected from the group including -Nth, -NH(C=0)R ^a , and - NH(C=0)ZR ^b ; when A ¹ is -(C=NOR ^a )-, -[C=N0(C=0)R ^a ]-, or -{C=N[0(C=0)ZR ^b ]}-, Y ¹ is -

NH ₂ ;

when A ¹ is fused heterocyclyl or heteroaryl, Y ¹ is -NH2 or halo, and A ¹ is substituted with m additional R ¹ groups;

each R ^a and R ^b is independently selected from the group including C1-C6 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, and C7-C12 arylalkyl; wherein R ^a has m substituents selected from the group including C1-C6 alkyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxy alkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, R ^a and R ^b join to form an heterocyclyl ring with m substituents selected from the group including C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, and halo;

each Z is independently selected from the group including O and S;

A ² is a member selected from the group including C3-C6 heteroaryl, G, aryl, and C2-C6 alkyl;

when A ² is C3-C6 heteroaryl, Y ² is selected from the group including -NH2,

- CH2NH2, chloro, -(C=NH)NH ₂ , -(C=NH)NH(C=0)R ^a , -(C=NH)NH(C=0)ZR ^b , - (C=NOR ^a )NH ₂ , -[C=N0(C=0)R ^a ]NH ₂ , and -{C=N[0(C=0)ZR ^b ]}NH ₂ ; and A ² is substituted with m additional R ¹ groups;

when A ² is Ce aryl, Y ² is selected from the group including aminomethyl, hydroxy, and halo, and A ² is substituted with m additional R ¹ groups;

when A ² is C2-C6 alkyl, Y ² is selected from the group including -NH(C=NH)NH2, -NH(C=NH)NH(C=0)R ^a , and -NH(C=NH)NH(C=0)ZR ^b ;

each R ¹ is a member independently selected from the group including C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;

each m and n is an independently selected integer from 0 to 3;

L is -(0) _P- (C(R ^2a )(R ^2b ))q-,

each R ^2a or R ^2b is a member independently selected from the group including hydrogen and fluoro;

p is an integer from 0 to 1;

q is an integer from 1 to 2;

R ³ is a member selected from the group including hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, and carboxy(Ci-C6 alkyl); or, alternatively, R ³ and R ⁴ join to form an azetidine, pyrrolidine, or piperidine ring;

R ⁴ is a member selected from the group including hydrogen and C1-C6 alkyl; or, alternatively, R ⁴ and R ³ join to form an azetidine, pyrrolidine, or piperidine ring; R ⁵ is a member selected from the group including C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, heteroaryl, and C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R ¹³ substituents; or, alternatively, R ⁵ and R ⁶ join to form a heterocyclic ring with from 0 to 3 R ¹³ substituents;

R ⁶ is a member selected from the group including hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, carboxy(Ci-C6 alkyl), C7-C12 arylalkyl or heteroarylalkyl with from 0 to 3 R ¹³ substituents, amino(Ci-C8 alkyl); and amido(Ci-C8 alkyl); or, alternatively, R ⁶ and R ⁵ join to form a heterocyclic ring with from 0 to 3 R ¹³ substituents; and

each R ¹³ is a member independently selected from the group including C1-C6 alkyl, C6-C10 aryl, carboxy(Ci-C6 alkyloxy), heteroaryl, heterocyclyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R ¹³ groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring,

with the proviso that the compound is not melagatran.

In certain aspects, the compound is of Formula VA.

In certain aspects, A ¹ is -(C=NH)-. In certain aspects, A ¹ is -NH(C=0)R ^a . In certain aspects, A ¹ is - NH(C=0)ZR ^b . In certain aspects, Z is O, S, or N.

In certain aspects, A ¹ is -(C=NH)-. In certain aspects, Y ¹ is -NH2. In certain aspects, Y ¹ is -NH(C=0)R ^a In certain aspects, Y ¹ is - NH(C=0)ZR ^b

In certain aspects, A ¹ is -(C=NOR ^a )-. In certain aspects, Y ¹ is -NH2. In certain aspects, Y ¹ is -NH(C=0)R ^a . In certain aspects, Y ¹ is - NH(C=0)ZR ^b .

In certain aspects, R ^a or R ^b is C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or t-butyl. In certain aspects, R ^a or R ^b is C3-C10 cycloalkyl, such as cyclohexyl, cyclopentyl, or cyclopropyl. In certain aspects, R ^a or R ^b is C6-C10 aryl, such as phenyl or substituted phenyl (e.g., 4-methoxyphenyl). In certain aspects, R ^a or R ^b is C7-C12 arylalkyl, such as benzyl or 4-methoxybenzyl.

In certain aspects, A ¹ is a fused heteroaryl. In certain aspects, A ¹ is a quinolone. In certain aspects, A ¹ is an isoquinoline. In certain aspects, A ¹ is a benzimidazole. In certain aspects, Y ¹ is -NH2.

In certain aspects, Y ¹ is-NFk.

In certain aspects, the compound is of Formula VB.

In certain aspects, A ² is Ce aryl. In certain aspects, A ² is C3-C6 heteroaryl.

In certain aspects, A ² is substituted with m additional R ¹ groups, such as halo, hydroxyl, C2-C6 alkyl, or C1-C4 methoxy, In certain aspects, Y ² is halo (e.g., chloro). In certain aspects, Y ² is 3-chloro. In certain aspects, Y ² is aminomethyl (e.g., 4-aminomethyl).

In certain aspects, A ² is C2-C6 alkyl.

In certain aspects, Y ² is -NH(C=NH)NH2.

In certain aspects, Y ² is selected from the group consisting of -NH(C=NH)NH2, -NH(C=NH)NH(C=0)R ^a , and -NH(C=NH)NH(C=0)ZR ^b . In certain aspects, Y ² is

-NH(C=NH)NH2. In certain aspects, Y ² is -NH(C=NH)NH(C=0)R ^a . In certain aspects, Y ² is -NH(C=NH)NH(C=0)ZR ^b .

In certain aspects, the compound has an R ³ stereochemistry of

In certain aspects, R ³ is a member selected from the group including hydrogen or methyl. In certain aspects, R ³ is hydrogen. In certain aspects, R ³ is methyl.

In certain aspects, R ⁴ is a member selected from the group including hydrogen or methyl. In certain aspects, R ⁴ is hydrogen.

In certain aspects, R ³ and R ⁴ join to form an azetidine, pyrrolidine, or piperidine ring. In certain aspects, R ³ and R ⁴ join to form a pyrrolidine ring. In certain aspects, R ³ and R ⁴ join to form a piperidine ring.

In certain aspects, R ⁵ is a member selected from the group including 2, 3 -dihydro- 1H- inden-2-yl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenethyl, and phenpropyl with from 0 to 3 R ¹³ substituents.

In certain aspects, R ⁵ is a member selected from the group including phenethyl, 4- methylphenethyl, 4-chlorophenethyl, 4-fluorophenethyl, and phenpropyl. In certain aspects, R ⁵ is a member selected from the group including phenethyl, 4-methylphenethyl, 4- chlorophenethyl, 4-fluorophenethyl, 3-methylphenethyl, 3-chlorophenethyl, 3- fluorophenethyl, 2-methylphenethyl, 2-chlorophenethyl, 2-fluorophenethyl, phenpropyl, 4- methylphenpropyl, 4-chlorophenpropyl, 4-fluorophenpropyl, 3-methylphenpropyl, 3- chlorophenpropyl, 3-fluorophenpropyl, 2-methylphenpropyl, 2-chlorophenpropyl, and 2- fluorophenpropyl.

In certain aspects, R ⁶ is a member selected from the group including amino(Ci-C8 alkyl). and C7-C12 arylalkyl with from 0 to 3 R ¹³ substituents,

In certain aspects, R ⁶ is a member selected from the group including hydrogen and carboxymethyl. In certain aspects, R ⁶ and R ⁵ join to form a pyrrolidine, octahydro-lH-indole, 3- phenylpyrrolidine, piperidine, l,2,3,4-tetrahydroisoquinoline, 2,5-dihydro-lH-pyrrole, or l,2,3,6-tetrahydropyridine ring.

In certain aspects, R ¹ is hydroxyl or C1-C6 alkoxy. In certain aspects, R ¹ is hydroxyl (e.g., 2-hydroxy; 3-hydroxy). In certain aspects, R ¹ is methoxy (e.g, 2-methoxy).

In certain aspects, m is 0. In certain aspects, m is 1. In certain aspects, n is 0. In certain aspects, n is 1. In certain aspects, both m and n are 0.

In certain aspects, p is 0. In certain aspects, p is 1.

In certain aspects, q is 1. In certain aspects, p is 0 and q is 1.

In certain aspects, each R ^2a or R ^2b is hydrogen. In certain aspects, L is methylene. In certain aspects, L is ethylene.

In certain aspects, the compound of Formula (VA) is selected from compounds of Formulae (VC), (VD), (VE) and (VF):

and salts thereof; wherein:

R ⁷ is a member selected from the group including hydrogen, hydroxyl, and C1-C6 alkyl;

R ⁸ is a member selected from the group including hydrogen and C1-C6 alkyl; and each m and n is an independently selected integer from 0 to 2.

In certain aspects, the compound is of Formula (VC). In certain aspects, the compound is of Formula (VD). In certain aspects, the compound is of Formula (VE). In certain aspects, the compound is of Formula (VF).

In certain aspects, R ⁷ is hydrogen. In certain aspects, R ⁸ is hydrogen.

The compounds of Formula (VA) and (VB), and embodiments thereof, including compounds of Formula (VC), (VD), (VE) and (VF), are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (VA) and (VB), and embodiments thereof, are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (VA) or (VB), or an embodiment thereof, optionally in the form of a salt.

In some embodiments the compound Formula (VA) or (VB) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

In certain aspects, the compound is one or more selected from the compounds of Formula (VA) and (VB) in the Examples, including the compounds listed in Table 1, e.g., the compounds with selectivity for MASP-2 over thrombin. In certain aspects, one or more of R ¹ , R ^a , R ^b , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , or R ¹³ is selected from the corresponding substituents in the compounds of (VA) and (VB) in the Examples, including the compounds listed in Table 1 preferably, those of the compounds with selectivity for MASP-2 over thrombin.

In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (— ) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers or

diastereomers.

In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. et al, J. Pharm. Sci 1977, 66, 1-19. They include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, arylsulfonates, alkylsulfonates, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution). In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group;

hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O-alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like.

In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin is at least 1.1 : 1, 1.25: 1, 1.5: 1, 1.75: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11 : 1, 12: 1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 21 : 1, 22: 1, 23: 1, 24: 1, 25: 1, or 30:1.

3. Compounds of Formula (VIA) and (VIB)

In certain aspects, the present disclosure provides a MASP-2 inhibitory compound for therapeutic use, wherein the compound is of the Formula (VIA) or (VIB):

or a salt thereof; wherein:

A ¹ is a member selected from the group consisting of-(C=NH)-,-(C=NOR ^a )-, -[C=N0(C=0)R ^a ]-, -[C=N[0(C=0)ZR ^b ]}-, a fused 5- or 6-member heterocyclyl, and a fused 5- or 6-member heteroaryl;

when A ¹ is -(C=NH)-, Y ¹ is selected from the group consisting of-NFh, - NH(C=0)R ^a , and - NH(C=0)ZR ^b ;

when A ¹ is -(C=NOR ^a )-, -[C=N0(C=0)R ^a ]-, or -{C=N[0(C=0)ZR ^b ]}-, Y ¹ is -

NH ₂ ;

when A ¹ is fused heterocyclyl or heteroaryl, Y ¹ is -NFh or halo, and A ¹ is substituted with m additional R ¹ groups;

each R ^a and R ^b is independently selected from the group consisting of C1-C6 alkyl, C3- C10 cycloalkyl, C6-C10 aryl, and C7-C12 arylalkyl; wherein R ^a has m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxy alkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, R ^a and R ^b join to form an heterocyclyl ring with m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, and halo;

each Z is independently selected from the group consisting of O and S;

A ² is a member selected from the group consisting of C3-C6 heteroaryl and

C2-C6 alkyl;

when A ² is C3-C6 heteroaryl, Y ² is selected from the group consisting of -NH2,

- CH2NH2, chloro, -(C=NH)NH ₂ , -(C=NH)NH(C=0)R ^a ,

-(C=NH)NH(C=0)ZR ^b , -(C=NOR ^a )NH ₂ , -[C=N0(C=0)R ^a ]NH ₂ , and

-{C=N[0(C=0)ZR ^b ]}NH2; and A ² is substituted with m additional R ¹ groups;

when A ² is C2-C6 alkyl, Y ² is selected from the group consisting of-NH(C=NH)NH2, -NH(C=NH)NH(C=0)R ^a , and -NH(C=NH)NH(C=0)ZR ^b ;

each R ¹ is a member independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;

each m and n is an independently selected integer from 0 to 3;

X and X ² are each a member selected from the group consisting of NR ⁸ , CH, and CR ¹⁰ (preferably, NR ⁸ ); or, alternatively, the X and X ² R ¹⁰ groups join to form a fused G, aryl, heteroaryl, or C5-C7 cycloalkyl ring with from 0 to 3 R ¹³ substituents;

each R ⁸ is a member independently selected from the group consisting of hydrogen and C1-C6 alkyl;

each R ¹⁰ is a member independently selected from the group consisting of C1-C6 alkyl, heteroaryl or C6-C10 aryl with from 0 to 3 R ¹³ substituents, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, two R ¹⁰ groups join to form a fused Ce aryl, heteroaryl, or C5-C7 cycloalkyl ring with from 0 to 3 R ¹³ substituents;

r is an integer from 0 to 4; and

each R ¹³ is a member independently selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, carboxy(Ci-C6 alkyloxy), heteroaryl, heterocyclyl, hydroxyl, hydroxyl(Ci- C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R ¹³ groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring or a salt thereof.

In certain aspects, the compound is of Formula (VIA).

In certain aspects, the compound is of Formula (VIB). In certain aspects, the compound is of Formula (VIC) or (VID):

or a salt thereof.

In certain aspects, each R ⁷ is a member selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl; and m is an integer from 0 to 2.

In certain aspects, (i) the compound is of Formula (VIA) or a salt thereof, and m is 0; or (ii) the compound is (VIB) or a salt thereof, and r is 0.

In certain aspects, X is NR ⁸ .

In certain aspects, R ⁸ is hydrogen.

In certain aspects, X ² is CH or CR ¹⁰ .

In certain aspects, R ¹⁰ is a member independently selected from the group consisting of C1-C6 alkyl, C6 aryl with from 0 to 3 R ¹³ substituents, C1-C6 alkoxy, and C2-C9 alkoxy alkyl.

In certain aspects, two R ¹⁰ groups join to form a fused Ce aryl ring with from 0 to 3 R ¹³ substituents.

[0024] In certain aspects, R ⁷ is hydrogen.

[0025] In certain aspects, R ³ is a member selected from the group consisting of hydrogen or methyl. In certain aspects, R ³ is methyl.

[0026] In certain aspects, Z is O.

[0027] In certain aspects, R ¹¹ is (R ¹⁴ )(R ¹⁴ )N(CO)-.

[0028] In certain aspects, R ¹¹ is (R ¹⁴ )(H)N(CO)-.

[0029] In certain aspects, R ¹⁴ is C1-C6 alkyl, C3-C7 cycloalkyl, or C4-C8

cycloalkylalkyl.

[0030] In certain aspects, R ¹² is hydrogen or C7-C14 arylalkyl.

[0031] In certain aspects, R ¹ is hydroxyl or C1-C6 alkoxy.

[0032] In certain aspects, each R ^2a or R ^2b is hydrogen.

[0033] In certain aspects, L is methylene.

[0034] In certain aspects, A ¹ is -(C=NH)-. In certain aspects, Y ¹ is -NH2. In certain aspects, Y ¹ is -NH(C=0)R ^a . In certain aspects, Y ¹ is - NH(C=0)ZR ^b .

[0035] In certain aspects, A ¹ is -(C=NOR ^a )-. In certain aspects, Y ¹ is -NH2. In certain aspects, Y ¹ is -NH(C=0)R ^a . In certain aspects, Y ¹ is - NH(C=0)ZR ^b . [0036] In certain aspects, A ¹ is -(C=NH)-. In certain aspects, A ¹ is -NH(C=0)R ^a . In certain aspects, A ¹ is - NH(C=0)ZR ^b . In certain aspects, Z is O, S, or N.

[0037] In certain aspects, A ¹ is a fused heteroaryl. In certain aspects, A ¹ is a quinolone. In certain aspects, A ¹ is an isoquinoline. In certain aspects, A ¹ is a benzimidazole. In certain aspects, Y ¹ is -NH ₂ .

[0038] In certain aspects, R ^a or R ^b is C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or t-butyl. In certain aspects, R ^a or R ^b is C3-C10 cycloalkyl, such as cyclohexyl, cyclopentyl, or cyclopropyl. In certain aspects, R ^a or R ^b is C6-C10 aryl, such as phenyl or substituted phenyl (e.g., 4-methoxyphenyl). In certain aspects, R ^a or R ^b is C7-C12 arylalkyl, such as benzyl or 4-methoxybenzyl.

[0039] In certain aspects, R ⁷ is hydrogen.

[0040] In certain aspects, the compound is of Formula (VIB).

[0041] In certain aspects, A ² is C3-C6 heteroaryl.

[0042] In certain aspects, A ² is substituted with m additional R ¹ groups, such as halo, C2-C6 alkyl, or C1-C4 methoxy,

[0043] In certain aspects, Y ² is selected from the group consisting of- NH(C=NH)NH ₂ ,

-NH(C=NH)NH(C=0)R ^a , and -NH(C=NH)NH(C=0)ZR ^b . In certain aspects, Y ² is

-NH(C=NH)NH2. In certain aspects, Y ² is -NH(C=NH)NH(C=0)R ^a . In certain aspects, Y ² is -NH(C=NH)NH(C=0)ZR ^b .

[0044] In certain aspects, Y ² is halo (e.g., chloro, such as 3-chloro). In certain aspects, Y ² is aminomethyl (e.g., 4-aminomethyl).

[0045] In certain aspects, A ² is C2-C6 alkyl.

[0046] In certain aspects, X is NR ⁸ (e.g., NH or NMe). In certain aspects, X is CH. In certain aspects, X is CR ¹⁰ (e.g., CMe).

[0047] In certain aspects, each Z is a member independently selected from the group consisting of O and NR ⁸ ; and each R ⁸ is a member independently selected from the group consisting of hydrogen and C1-C6 alkyl. In certain aspects, one Z or each Z is NR ⁸ . In certain aspects, each R ⁸ is hydrogen.

[0048] In certain aspects, X ² is NR ⁸ (e.g., NH or NMe). In certain aspects, B is CH. In certain aspects, X ² is CR ¹⁰ (e.g., CMe).

[0049] In certain aspects, the compound has an R ³ stereochemistry of R ³

[0050] In certain aspects, R ³ is a member selected from the group consisting of hydrogen or methyl. In certain aspects, R ³ is hydrogen. In certain aspects, R ³ is methyl.

[0051] In certain aspects, R ¹ is hydroxyl or C1-C6 alkoxy. In certain aspects, R ¹ is hydroxyl (e.g., 2-hydroxy; 3-hydroxy). In certain aspects, R ¹ is methoxy (e.g., 2-methoxy).

[0052] In certain aspects, m is 0. In certain aspects, m is 1. In certain aspects, n is 0.

In certain aspects, n is 1. In certain aspects, both m and n are 0.

[0053] In certain aspects, p is 0. In certain aspects, p is 1.

[0054] In certain aspects, q is 1. In certain aspects, p is 0 and q is 1.

[0055] In certain aspects, each R ^2a or R ^2b is hydrogen. In certain aspects, L is methylene In certain aspects, L is ethylene.

[0056] In certain aspects, each R ¹⁰ is a member independently selected from the group consisting of C1-C6 alkyl, heteroaryl or C6-C10 aryl with from 0 to 3 R ¹³ substituents, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, two R ¹⁰ groups join to form a fused G, aryl, heteroaryl, or C5-C7 cycloalkyl ring with from 0 to 3 R ¹³ substituents. In certain aspects, an R ¹⁰ is amino. In certain aspects, an R ¹⁰ and an R ¹ are amino.

[0057] In certain aspects, r is an integer from 0 to 5 (i.e., 0, 1, 2, 3, 4, or 5). In certain aspects, r is an integer from 0 to 4 (i.e., 0, 1, 2, 3, and 4). In certain aspects, r is an integer from 0 to 3 (i.e., 0, 1, 2, or 3).

[0058] In certain aspects, each R ¹³ is a member independently selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, carboxy(Ci-C6 alkyloxy), heteroaryl, heterocyclyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, Ci- C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R ¹³ groups join to form a fused C6-C10 aryl, C6-C10 heteroaryl, or C5-C7 cycloalkyl ring or a salt thereof. In certain aspects, R ¹³ is phenyl. In certain aspects, R ¹³ is substituted phenyl.

The compounds of Formula (VIA) and (VIB), and embodiments thereof, including compounds of Formula (VIC) and (VID), are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (VIA) and (VIB), and embodiments thereof, are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (VIA) and (VIB), or an embodiment thereof, optionally in the form of a salt.

In some embodiments the compound Formula (VIA) and (VIB) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

[0059] In certain aspects, the compound is one or more selected from the compounds of Formula (VIA) and (VIB) in the Examples, including the compounds listed in Table 1, e.g., the compounds with selectivity for MASP-2 over thrombin. In certain aspects, one or more of R ¹ , R ^a , R ^b , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , or R ¹³ is selected from the corresponding substituents in the compounds of (VIA) and (VIB) in the Examples, including the compounds listed in Table 1 preferably, those of the compounds with selectivity for MASP-2 over thrombin.

[0060] In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (— ) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers or

diastereomers.

[0061] In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. et al, J. Pharm. Sci 1977, 66, 1-19. They include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, arylsulfonates, alkylsulfonates, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).

[0062] In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group; hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O- alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like.

[0063] In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin is at least 1.1 : 1, 1.25: 1, 1.5: 1,

1.75: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11 : 1, 12:1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 21: 1, 22: 1, 23: 1, 24: 1, 25: 1, or 30: 1.

4. Compounds of Formula VIIA and VIIB

[0064] In certain aspects, the present disclosure provides a MASP-2 inhibitory compound for therapeutic use, wherein the compound is of the Formula (VIIA) or (VIIB):

or a salt thereof; wherein:

A ¹ is a member selected from the group consisting of-(C=NH)-,-(C=NOR ^a )-, -[C=NO(C=0)R ^a ]-, -[C=N[0(C=0)ZR ^b ]}-, a fused 5- or 6-member heterocyclyl, and a fused 5- or 6-member heteroaryl;

when A ¹ is -(C=NH)-, Y ¹ is selected from the group consisting of-NFh, - NH(C=0)R ^a , and - NH(C=0)ZR ^b ;

when A ¹ is -(C=NOR ^a )-, -[C=NO(C=0)R ^a ]-, or -{C=N[0(C=0)ZR ^b ]}-, Y ¹ is -

NH ₂ ;

when A ¹ is fused heterocyclyl or heteroaryl, Y ¹ is -NFk or halo, and A ¹ is substituted with m additional R ¹ groups;

each R ^a and R ^b is independently selected from the group consisting of C1-C6 alkyl, C3- C10 cycloalkyl, C6-C10 aryl, and C7-C12 arylalkyl; wherein R ^a has m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxy alkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, R ^a and R ^b join to form an heterocyclyl ring with m substituents selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, and halo;

each Z is independently selected from the group consisting of O and S;

A ² is a member selected from the group consisting of C3-C6 heteroaryl and

C2-C6 alkyl;

when A ² is C3-C6 heteroaryl, Y ² is selected from the group consisting of -NH2,

- CH2NH2, chloro, -(C=NH)NH ₂ , -(C=NH)NH(C=0)R ^a ,

-(C=NH)NH(C=0)ZR ^b , -(C=NOR ^a )NH ₂ , -[C=N0(C=0)R ^a ]NH ₂ , and

-{C=N[0(C=0)ZR ^b ]}NH2; and A ² is substituted with m additional R ¹ groups;

when A ² is C2-C6 alkyl, Y ² is selected from the group consisting of-NH(C=NH)NH2, -NH(C=NH)NH(C=0)R ^a , and -NH(C=NH)NH(C=0)ZR ^b ;

each R ¹ is a member independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, and halo;

each m and n is an independently selected integer from 0 to 3;

L is -(0) _P -(C(R ^2a )(R ^2b ))q-,

each R ^2a or R ^2b is a member independently selected from the group consisting of hydrogen and fluoro;

p is an integer from 0 to 1;

q is an integer from 1 to 2;

R ³ is a member selected from the group consisting of hydrogen, C1-C6 alkyl, and carboxy(Ci-C6 alkyl);

each R ¹¹ is a member independently selected from the group consisting of C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, halo, and (R ¹⁴ )(R ¹⁴ )N(CO)-; or, alternatively, two R ¹¹ groups join to form a fused Ce aryl, heteroaryl, or C5-C7 cycloalkyl ring with from 0 to 3 R ¹³ substituents;

r is an integer from 0 to 4; and

each Z is a member independently selected from the group consisting of O and NR ⁸ ; each R ⁸ is a member independently selected from the group consisting of hydrogen and C1-C6 alkyl;

each R ¹² is a member independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C7-C14 arylalkyl with from 0 to 3 R ¹³ substituents; each R ¹³ is a member independently selected from the group consisting of C1-C6 alkyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, two R ¹³ groups join to form a fused Ce aryl, heteroaryl, or C5-C7 cycloalkyl ring; and

each R ¹⁴ is a member independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, C7-C14 arylalkyl, and heteroaryl(Ci-C6 alkyl); or, alternatively, two R ¹³ groups join to form a fused heterocyclyl ring.

In certain aspects, the compound is of Formula (VIIA).

In certain aspects, the compound is of Formula (VIIB).

[0065] In certain aspects, the compound is of Formula (VIIC):

in which each R ⁷ is a member selected from the group consisting of hydrogen, hydroxyl, and C1-C6 alkyl.

[0066] In certain aspects, R ⁷ is hydrogen.

[0067] In certain aspects, X is NR ⁸ .

[0068] In certain aspects, R ⁸ is hydrogen.

[0069] In certain aspects, X ² is CH or CR ¹⁰ .

[0070] In certain aspects, R ¹⁰ is a member independently selected from the group consisting of C1-C6 alkyl, C6 aryl with from 0 to 3 R ¹³ substituents, C1-C6 alkoxy, and C2-C9 alkoxy alkyl.

[0071] In certain aspects, two R ¹⁰ groups join to form a fused Ce aryl ring with from 0 to 3 R13 substituents.

[0072] In certain aspects, R ⁷ is hydrogen.

[0073] In certain aspects, R ³ is a member selected from the group consisting of hydrogen or methyl. In certain aspects, R ³ is methyl.

[0074] In certain aspects, Z is O.

[0075] In certain aspects, R ¹¹ is (R ¹⁴ )(R ¹⁴ )N(CO)-.

[0076] In certain aspects, R ¹¹ is (R ¹⁴ )(H)N(CO)-. [0077] In certain aspects, R ¹⁴ is C1-C6 alkyl, C3-C7 cycloalkyl, or C4-C8

cycloalkylalkyl.

[0078] In certain aspects, R ¹² is hydrogen or C7-C14 arylalkyl.

[0079] In certain aspects, R ¹ is hydroxyl or C1-C6 alkoxy.

[0080] In certain aspects, each R ^2a or R ^2b is hydrogen.

[0081] In certain aspects, L is methylene.

[0082] In certain aspects, A ¹ is -(C=NH)-. In certain aspects, Y ¹ is -NH2. In certain aspects, Y ¹ is -NH(C=0)R ^a . In certain aspects, Y ¹ is - NH(C=0)ZR ^b .

[0083] In certain aspects, A ¹ is -(C=NOR ^a )-. In certain aspects, Y ¹ is -Nth. In certain aspects, Y ¹ is -NH(C=0)R ^a . In certain aspects, Y ¹ is - NH(C=0)ZR ^b .

[0084] In certain aspects, A ¹ is -(C=NH)-. In certain aspects, A ¹ is -NH(C=0)R ^a . In certain aspects, A ¹ is - NH(C=0)ZR ^b . In certain aspects, Z is O, S, or N.

[0085] In certain aspects, A ¹ is a fused heteroaryl. In certain aspects, A ¹ is a quinolone. In certain aspects, A ¹ is an isoquinoline. In certain aspects, A ¹ is a benzimidazole. In certain aspects, Y ¹ is -Nth.

[0086] In certain aspects, R ^a or R ^b is C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or t-butyl. In certain aspects, R ^a or R ^b is C3-C10 cycloalkyl, such as cyclohexyl, cyclopentyl, or cyclopropyl. In certain aspects, R ^a or R ^b is C6-C 10 aryl, such as phenyl or substituted phenyl (e.g., 4-methoxyphenyl). In certain aspects, R ^a or R ^b is C7-C12 arylalkyl, such as benzyl or 4-methoxybenzyl.

[0087] In certain aspects, R ⁷ is hydrogen.

[0088] In certain aspects, the compound is of Formula (VIIB).

[0089] In certain aspects, A ² is C3-C6 heteroaryl.

[0090] In certain aspects, A ² is substituted with m additional R ¹ groups, such as halo, C2-C6 alkyl, or C1-C4 methoxy,

[0091] In certain aspects, Y ² is selected from the group consisting of- NH(C=NH)NH ₂ ,

-NH(C=NH)NH(C=0)R ^a , and -NH(C=NH)NH(C=0)ZR ^b . In certain aspects, Y ² is

-NH(C=NH)NH2. In certain aspects, Y ² is -NH(C=NH)NH(C=0)R ^a . In certain aspects, Y ² is -NH(C=NH)NH(C=0)ZR ^b .

[0092] In certain aspects, Y ² is halo (e.g., chloro, such as 3-chloro). In certain aspects, Y ² is aminomethyl (e.g., 4-aminomethyl).

[0093] In certain aspects, A ² is C2-C6 alkyl. [0094] In certain aspects, X is NR ⁸ (e.g., NH or NMe). In certain aspects, X is CH. In certain aspects, X is CR ¹⁰ (e.g., CMe).

[0095] In certain aspects, each Z is a member independently selected from the group consisting of O and NR ⁸ ; and each R ⁸ is a member independently selected from the group consisting of hydrogen and C1-C6 alkyl. In certain aspects, one Z or each Z is NR ⁸ . In certain aspects, each R ⁸ is hydrogen.

[0096] In certain aspects, X ² is NR ⁸ (e.g., NH or NMe). In certain aspects, B is CH. In certain aspects, X ² is CR ¹⁰ (e.g., CMe).

[0097] In certain aspects, the compound has an R ³ stereochemistry of

[0098] In certain aspects, R ³ is a member selected from the group consisting of hydrogen or methyl. In certain aspects, R ³ is hydrogen. In certain aspects, R ³ is methyl.

[0099] In certain aspects, R ¹ is hydroxyl or C1-C6 alkoxy. In certain aspects, R ¹ is hydroxyl (e.g., 2-hydroxy; 3-hydroxy). In certain aspects, R ¹ is methoxy (e.g., 2-methoxy).

[0100] In certain aspects, m is 0. In certain aspects, m is 1. In certain aspects, n is 0.

In certain aspects, n is 1. In certain aspects, both m and n are 0.

[0101] In certain aspects, p is 0. In certain aspects, p is 1.

[0102] In certain aspects, q is 1. In certain aspects, p is 0 and q is 1.

[0103] In certain aspects, each R ^2a or R ^2b is hydrogen. In certain aspects, L is methylene In certain aspects, L is ethylene.

[0104] In certain aspects, each R ¹⁰ is a member independently selected from the group consisting of C1-C6 alkyl, heteroaryl or C6-C10 aryl with from 0 to 3 R ¹³ substituents, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, C1-C6 alkylamino, and halo; or, alternatively, two R ¹⁰ groups join to form a fused Ce aryl, heteroaryl, or C5-C7 cycloalkyl ring with from 0 to 3 R ¹³ substituents. In certain aspects, an R ¹⁰ is amino. In certain aspects, an R ¹⁰ and an R ¹ are amino.

[0105] In certain aspects, r is an integer from 0 to 5 (i.e., 0, 1, 2, 3, 4, or 5). In certain aspects, r is an integer from 0 to 4 (i.e., 0, 1, 2, 3, and 4). In certain aspects, r is an integer from 0 to 3 (i.e., 0, 1, 2, or 3).

[0106] In certain aspects, each R ¹³ is a member independently selected from the group consisting of C1-C6 alkyl, C6-C10 aryl, carboxy(Ci-C6 alkyloxy), heteroaryl, heterocyclyl, hydroxyl, hydroxyl(Ci-C6 alkyl), C1-C6 alkoxy, C2-C9 alkoxyalkyl, amino, Ci- C6 amido, C1-C6 alkylamino, and halo; or, alternatively, two R ¹³ groups join to form a fused C6-C 10 aryl, C6-C 10 heteroaryl, or C5-C7 cycloalkyl ring or a salt thereof. In certain aspects,

R ¹³ is phenyl. In certain aspects, R ¹³ is substituted phenyl.

The compounds of Formula (VIIA) and (VIIB), and embodiments thereof, including compounds of Formula (VIIC) and (VIID), are useful as inhibitors of MASP-2 and for therapeutic use. The compounds of Formula (VIIA) and (VIIB), and embodiments thereof, are useful in the treatment of MASP-2-associated diseases and disorders, and in the manufacture of medicaments for treating MASP-2-associated diseases and disorders. The present disclosure also provides methods of treating a MASP-2-associated disease and disorder comprising administering to a patient a therapeutically effective amount of a compound of Formula (VIIA) and (VIIB), or an embodiment thereof, optionally in the form of a salt.

In some embodiments the compound Formula (VIIA) and (VIIB) or an embodiment thereof is provided in the form of a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient.

[0107] In certain aspects, the compound is one or more selected from the compounds of Formula (VIIA) and (VIIB) in the Examples, including the compounds listed in Table 1, e.g., the compounds with selectivity for MASP-2 over thrombin. In certain aspects, one or more of R ¹ , R ^a , R ^b , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , or R ¹³ is selected from the corresponding substituents in the compounds of (VIIA) and (VIIB) in the Examples, including the compounds listed in Table 1 preferably, those of the compounds with selectivity for MASP-2 over thrombin.

[0108] In certain aspects, the invention sets forth a stereochemically pure enantiomer or diastereomer (e.g., an optically active compound with one or more chiral centers). Unless specifically indicated otherwise, for any inventive compound with one or more stereocenters, the present invention is intended to include and to describe both the pure (+) and (— ) enantiomers, any other diastereomers, mixtures that are enriched in an enantiomer or diastereomer (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70% 75%, 80%, 85, 90%, or 95% enantiomeric or diastereomeric excess), and a racemic mixture of enantiomers or

diastereomers.

[0109] In certain aspects, the invention sets forth a pharmaceutically acceptable salt of the indicated chemical structure (e.g., a hydrohalide, such as a hydrochloride or dihydrochloride). Examples of pharmaceutically acceptable salts are set forth in, e.g., Burge, S. M. et al, J. Pharm. Sci 1977, 66, 1-19. They include chlorides, bromides, iodides, formates, acetates, propionates, oxalates, malonates, succinates, fumarates, maleates, tartrates, citrates, benzoates, phthalates, sulfonates, arylsulfonates, alkylsulfonates, salts of fatty acids, and the like. Salts can be prepared by a variety of methods known to the skilled artisan, including a precipitation with the conjugate acid or base (e.g., treatment with gaseous HC1 or an HC1 solution).

[0110] In certain aspects, the invention sets forth a prodrug. A prodrug is a compound that is converted to a biologically active form under physiological conditions, often by hydrolysis, oxidation, or reduction (e.g., ester to acid form; carbamate to amino or hydroxy group; hydroxyamidine to amidine) Exemplary prodrugs are set forth in, e.g., Tilley, J.W., "Prodrugs of Benzamide," Prodrugs 2007, 191-222; Peterlin-Masic et al. Curr. Pharma. Design 2006, 12, 73-91. Prodrugs for the amidine group include amidoximes, O- alkylamidoximes, acylami dines, carbamates, l,2,4-oxadiazolin-4-ones, and the like.

[0111] In certain aspects, the compound is useful for selectively inhibiting MASP-2 over thrombin, the method comprising administering the compound as described herein. In certain aspects, the selectivity ratio of MASP-2:thrombin is at least 1.1 : 1, 1.25: 1, 1.5: 1, 1.75: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11 : 1, 12:1, 13: 1, 14: 1, 15: 1, 16: 1, 17: 1, 18: 1, 19: 1, 20: 1, 21: 1, 22: 1, 23: 1, 24: 1, 25: 1, or 30: 1.

III. Synthesis

Compounds described herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those illustrated in the Examples below.

The reactions for preparing compounds described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection and

deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al, "Protecting Groups in Carbohydrate Chemistry," J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 'H or ¹³ C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

The particular synthetic methods used in the Examples provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations can be modified or optimized using general knowledge of organic chemistry to prepare various compounds within the scope of the present disclosure.

Starting materials, reagents and intermediates whose synthesis is not described herein are either commercially available, known in the literature, or may be prepared by methods known to one skilled in the art.

It will be appreciated by one skilled in the art that the processes described are not the exclusive means by which compounds of the invention may be synthesized and that a broad repertoire of synthetic organic reactions is available to be potentially employed in synthesizing compounds of the invention. The person skilled in the art knows how to select and implement appropriate synthetic routes. Suitable synthetic methods of starting materials, intermediates and products may be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963- 2012); Journal of Heterocyclic Chemistry, Vols. 1-49 (Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and

Knowledge Updates KU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et al. (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed.); Comprehensive Organic Functional Group Transformations II (Elsevier, 2nd Edition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II

(Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

IV. Methods of Treatment

[0112] In another aspect, the present disclosure provides a method of treating a patient suffering from, or at risk for developing a MASP-2-associated disease or disorder such as a MASP-2-dependent complement-associated disease or disorder comprising administering a small molecule inhibitor of MASP-2.

The compound can be any small molecule inhibitor of MASP-2. In some

embodiments, the compound can be a small molecule inhibitor of MASP-2 that binds to the serine protease domain of MASP-2. In some embodiments, the compound can be a small molecule inhibitor such as a synthetic small molecule inhibitor of MASP-2. In some embodiments, the compound can be a small molecule inhibitor of MASP-2 that binds to the catalytic, substrate-binding region of MASP-2. In some embodiments, the compound selectively inhibits MASP-2 as compared to thrombin.

The compound can be any small molecule inhibitor of MASP-2 as disclosed herein. In some embodiments, the compound can be any of the compounds disclosed above under "II. Compounds" above, or any embodiment thereof.

[0113] As described in U.S. Patent No. 7,919,094; U.S. Patent No. 8,840,893; U.S. Patent No. 8,652,477; U.S. Patent No. 8,951,522, U.S. Patent No. 9,011,860, U.S. Patent No. 9,475,885, U.S. Patent No. 9,644,035, U.S. Patent Application Publication Nos.

US2013/0344073, US2013/0266560, US 2015/0166675, US2017/0137537,

US2017/0166660, US20l7/0l89525,US20l7/026778l, US2017/0283508, US2017/0253667, US2018/0105604, WO2018/045054, W02019/036460 and co-pending U.S. Patent

Application Serial No. 62/688,611 (each of which is assigned to Omeros Corporation, the assignee of the instant application, each of which is hereby incorporated by reference), MASP-2-dependent complement activation has been implicated as contributing to the pathogenesis of numerous acute and chronic disease states. For example, as described in U.S. Patent No. 8,951,522, the primary function of the complement system, a part of the innate immune system, is to protect the host against infectious agents, however, inappropriate or over-activation of the complement system can lead to serious disease, such as thrombotic microangiopathies (TMAs, including aHUS, TTP and HUS) in which endothelial damage as well as fibrin and platelet-rich thrombi in the microvasculature lead to organ damage. The lectin pathway plays a dominant role in activating complement in settings of endothelial cell stress or injury, and preventing the activation of MASP-2 and the lectin pathway halts the sequence of enzymatic reactions that lead to the formation of the membrane attack complex, platelet activation and leukocyte recruitment. As described in U.S. Patent No. 8,652,477, in addition to initiation of the lectin pathway, MASP-2 can also activate the coagulation system and is capable of cleaving prothrombin to thrombin.

[0114] Accordingly, in some embodiments, the method comprises administering to a patient suffering from or at risk for developing a MASP-2-dependent complement-associated disease or disorder an amount of a compound of the disclosure in an amount sufficient to inhibit MASP-2 dependent complement activation in said mammalian subject to thereby treat the disease or disorder. In some embodiments, the method can further comprise, prior to administering a compound of the disclosure to the patient, determining that the patient is afflicted with the lectin complement-associated disease or disorder.

[0115] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is selected from the group consisting of a thrombotic microangiopathy (TMA), a renal condition, an inflammatory reaction resulting from tissue or organ transplantation, an ischemia reperfusion injury, a complication associated with diabetes, a cardiovascular disease or disorder, an inflammatory gastrointestinal disorder, a pulmonary disorder, an ophthalmic disease or disorder, disseminated intravascular coagulation, graft-versus-host disease, veno- occlusive disease and diffuse alveolar hemorrhage.

[0116] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is a thrombotic microangiopathy (TMA) including thrombotic thrombocytopenic purpura (TTP), refractory TTP, Upshaw-Schulman Syndrome (USS), hemolytic uremic syndrome (HUS), atypical hemolytic syndrome (aHUS), non-Factor H-dependent atypical hemolytic syndrome, aHUS secondary to an infection, plasma therapy -resistant aHUS, a TMA secondary to cancer, a TMA secondary to chemotherapy, a TMA secondary to transplantation, or a TMA associated with hematopoietic stem cell transplant.

In some embodiments, the method comprises administering to a patient suffering from or at risk for developing graft-versus-host disease (GVHD), including acute GVHD, chronic GVHD or steroid-resistant GVHD an amount of a compound of the disclosure in an amount sufficient to inhibit MASP-2 dependent complement activation in said mammalian subject to thereby treat the disease or disorder. In some embodiments, the subject suffering from or at risk for developing GVHD has previously undergone, is undergoing, or will undergo a hematopoietic stem cell transplant. In some embodiments, the method comprises administering to a patient suffering from, or at risk for developing diffuse alveolar hemorrhage (DAH) an amount of a compound of the disclosure in an amount sufficient to inhibit MASP-2 dependent complement activation in said mammalian subject to thereby treat the disease or disorder. In some embodiments, the subject suffering from, or at risk for developing DAH has previously undergone, is undergoing, or will undergo a hematopoietic stem cell transplant.

In some embodiments, the method comprises administering to a patient suffering from, or at risk for developing veno-occlusive disease (VOD) an amount of a compound of the disclosure in an amount sufficient to inhibit MASP-2 dependent complement activation in said mammalian subject to thereby treat the disease or disorder. In some embodiments, the subject suffering from, or at risk for developing VOD has previously undergone, is undergoing, or will undergo a hematopoietic stem cell transplant.

[0117] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is a renal condition including, but not limited to, mesangioproliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative

glomerulonephritis (mesangiocapillary glomerulonephritis), acute post infectious

glomerulonephritis (poststreptococcal glomerulonephritis), C3 glomerulopathy,

cryoglobulinemic glomerulonephritis, pauci-immune necrotizing crescentic

glomerulonephritis, lupus nephritis, Henoch-Schonlein purpura nephritis and IgA

nephropathy.

[0118] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is renal fibrosis (e.g., tubulointerstitial fibrosis) and/or proteinuria in a subject suffering from or at risk for developing chronic kidney disease, chronic renal failure, glomerular disease (e.g., focal segmental glomerulosclerosis), an immune complex disorder (e.g., IgA nephropathy, membranous nephropathy), lupus nephritis, nephrotic syndrome, diabetic nephropathy, tubulointerstitial damage and glomerulonepthritis (e.g., C3

glomerulopathy), or a disease or condition associated with proteinuria, including, but not limited to, nephrotic syndrome, pre-eclampsia, eclampsia, toxic lesions of kidneys, amyloidosis, collagen vascular diseases (e.g., systemic lupus erythematosus), dehydration, glomerular diseases (e.g., membranous glomerulonephritis, focal segmental

glomerulonephritis, C3 glomerulopathy, minimal change disease, lipoid nephrosis), strenuous exercise, stress, benign orthostatis (postural) proteinuria, focal segmental glomerulosclerosis, IgA nephropathy (i.e., Berger' s disease), IgM nephropathy, membranoproliferative glomerulonephritis, membranous nephropathy, minimal change disease, sarcoidosis, Alport's syndrome, diabetes mellitus (diabetic nephropathy), drug-induced toxicity (e.g., NSAIDS, nicotine, penicillamine, lithium carbonate, gold and other heavy metals, ACE inhibitors, antibiotics (e.g., adriamycin) or opiates (e.g., heroin) or other nephrotoxins); Fabry's disease, infections (e.g., HIV, syphilis, hepatitis A, B or C, poststreptococcal infection, urinary schistosomiasis); aminoaciduria, Fanconi syndrome, hypertensive nephrosclerosis, interstitial nephritis, sickle cell disease, hemoglobinuria, multiple myeloma, myoglobinuria, organ rejection (e.g., kidney transplant rejection), ebola hemorrhagic fever, Nail patella syndrome, familial Mediterranean fever, HELLP syndrome, systemic lupus erythematosus, Wegener's granulomatosis, Rheumatoid arthritis, Glycogen storage disease type 1, Goodpasture's syndrome, Henoch-Schonlein purpura, urinary tract infection which has spread to the kidneys, Sjogren' s syndrome and post-infections glomerulonepthritis.

[0119] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an inflammatory reaction resulting from tissue or solid organ transplantation including, but not limited to, allotransplantation or xenotransplantation of whole organs (e.g., kidney, heart, liver, pancreas, lung, cornea, and the like) or tissue grafts (e.g., valves, tendons, bone marrow, and the like).

[0120] In some embodiments, the MASP-2-dependent complement-associated disorder is an ischemia reperfusion injury (I/R), including but not limited to, myocardial I/R, gastrointestinal I/R, renal I/R, and I/R following an aortic aneurism repair, I/R associated with cardiopulmonary bypass, cerebral I/R, stroke, organ transplant or reattachment of severed or traumatized limbs or digits; revascularization to transplants and/or replants, and hemodynamic resuscitation following shock and/or surgical procedures.

[0121] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is a complication associated with non-obese diabetes (Type-l diabetes or Insulin- dependent diabetes mellitus) and/or complications associated with Type-l or Type-2 (adult onset) diabetes including, but not limited to diabetic angiopathy, diabetic neuropathy, diabetic retinopathy or diabetic macular edema.

[0122] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is a cardiovascular disease or disorder, including but not limited to, Henoch- Schonlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, vasculitis associated with rheumatoid arthritis (also called malignant rheumatoid arthritis), immune complex vasculitis, and Takayasu's disease; dilated cardiomyopathy; diabetic angiopathy; Kawasaki's disease (arteritis); venous gas embolus (VGE); and inhibition of restenosis following stent placement, rotational atherectomy and/or percutaneous transluminal coronary angioplasty (PTCA).

[0123] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an inflammatory gastrointestinal disorder, including but not limited to, pancreatitis, diverticulitis and bowel disorders including Crohn's disease, ulcerative colitis, irritable bowel syndrome and inflammatory bowel disease (IBD).

[0124] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is a pulmonary disorder, including but not limited to, acute respiratory distress syndrome, transfusion-related acute lung injury, ischemia/reperfusion acute lung injury, chronic obstructive pulmonary disease, asthma, Wegener's granulomatosis, antiglomerular basement membrane disease (Goodpasture's disease), meconium aspiration syndrome, aspiration pneumonia, bronchiolitis obliterans syndrome, idiopathic pulmonary fibrosis, acute lung injury secondary to bum, non-cardiogenic pulmonary edema, transfusion-related respiratory depression and emphysema.

[0125] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an extracorporeal exposure-triggered inflammatory reaction and the method comprises treating a subject undergoing an extracorporeal circulation procedure including, but not limited to, hemodialysis, plasmapheresis, leukopheresis, extracorporeal membrane oxygenation (ECMO), heparin-induced extracorporeal membrane oxygenation LDL precipitation (HELP) and cardiopulmonary bypass (CPB).

[0126] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is selected from inflammatory or non-inflammatory arthritides and other musculoskeletal disorders, including but not limited to, osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, gout, neuropathic arthropathy, psoriatic arthritis, ankylosing spondylitis or other spondyloarthropathies and crystalline arthropathies, muscular dystrophy and systemic lupus erythematosus (SLE).

[0127] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is a skin disorder, including, but not limited to, psoriasis, autoimmune bullous dermatoses, eosinophilic spongiosis, bullous pemphigoid, epidermolysis bullosa acquisita, atopic dermatitis, herpes gestationis and other skin disorders, and for the treatment of thermal and chemical bums including capillary leakage caused thereby.

[0128] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is a peripheral nervous system (PNS) and/or central nervous system (CNS) disorder or injury including, but not limited to, multiple sclerosis (MS), myasthenia gravis (MG), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Guillain Barre syndrome, reperfusion following stroke, degenerative discs, cerebral trauma, Parkinson's disease (PD), Alzheimer's disease (AD), Miller-Fisher syndrome, cerebral trauma and/or hemorrhage, traumatic brain injury, demyelination and meningitis.

[0129] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is sepsis or a condition resulting from sepsis including without limitation severe sepsis, septic shock, acute respiratory distress syndrome resulting from sepsis, hemolytic anemia, systemic inflammatory response syndrome, or hemorrhagic shock.

[0130] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is a urogenital disorder including, but not limited to, painful bladder disease, sensory bladder disease, chronic abacterial cystitis and interstitial cystitis, male and female infertility, placental dysfunction and miscarriage and pre-eclampsia.

[0131] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an inflammatory reaction in a subject being treated with chemotherapeutics and/or radiation therapy, including without limitation for the treatment of cancerous conditions.

[0132] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an angiogenesis-dependent cancer, including but not limited to, a solid tumor(s), blood home tumor(s), high-risk carcinoid tumors and tumor metastases.

[0133] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an angiogenesis-dependent benign tumor, including but not limited to, hemangiomas, acoustic neuromas, neurofibromas, trachomas, carcinoid tumors and pyogenic granulomas.

[0134] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an endocrine disorder including, but not limited to, Hashimoto's thyroiditis, stress, anxiety and other potential hormonal disorders involving regulated release of prolactin, growth or insulin-like growth factor, and adrenocorticotropin from the pituitary.

[0135] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an ophthalmic disease or disorder including, but not limited to, age-related macular degeneration, glaucoma and endophthalmitis.

[0136] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is an ocular angiogenic disease or condition including, but not limited to age- related macular degeneration, uveitis, ocular melanoma, comeal neovascularization, primary pterygium, HSV stromal keratitis, HSV-l-induced comeal lymphangiogenesis, proliferative diabetic retinopathy, diabetic macular edema, retinopathy of prematurity, retinal vein occlusion, comeal graft rejection, neovascular glaucoma, vitreous hemorrhage secondary to proliferative diabetic retinopathy, neuromyelitis optica and rubeosis.

[0137] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is disseminated intravascular coagulation (DIC) or other complement mediated coagulation disorder, including DIC secondary to sepsis, severe trauma, including neurological trauma (e.g., acute head injury, see Kumura et al, Acta Neurochirurgica 55:23- 28 (1987), infection (bacterial, viral, fungal, parasitic), cancer, obstetrical complications, liver disease, severe toxic reaction {e.g., snake bite, insect bite, transfusion reaction), shock, heat stroke, transplant rejection, vascular aneurysm, hepatic failure, cancer treatment by chemotherapy or radiation therapy, bum, or accidental radiation exposure.

In some embodiments, the MASP-2-dependent complement-associated disease or disorder is selected from the group consisting of acute radiation syndrome, dense deposit disease, Degos Disease, Catastrophic Antiphospholipid Syndrome (CAPS), Behcet's disease, cryoglobulinemia; paroxysmal nocturnal hemoglobinuria ("PNH") and cold agglutinin disease.

[0138] In some embodiments, the MASP-2-dependent complement-associated disease or disorder is selected from the group consisting of aHUS, HSCT-TMA, IgAN, and Lupus Nepthritis (LN).

In some embodiments, the method comprises administering to a patient suffering from, or at risk for developing a disease, disorder or condition associated with fibrin-induced activation of the complement system and the associated activation of the coagulation and/or contact systems an amount of a compound of the disclosure in an amount sufficient to inhibit MASP-2 dependent complement activation in said mammalian subject to thereby treat the disease or disorder. In some embodiments, the subject is suffering from, or at risk of developing, a disease, disorder or condition associated with complement-related

inflammation, excessive coagulation or contact system activation initiated by fibrin or activated platelets. In some embodiments, the subject is suffering from a disease or disorder selected from the group consisting of arterial thrombosis, venous thrombosis, deep vein thrombosis, post-surgical thrombosis, restenosis following coronary artery bypass graft and/or an interventional cardiovascular procedure (e.g., angioplasty or stent placement), atherosclerosis, plaque rupture, plaque instability, restenosis, hypotension, acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), disseminated intravascular coagulation (DIC), veno-occlusive disease (VOD), thrombotic microangiopathy, lupus nephritis, superficial thrombophlebitis, Factor V Leiden mutation, ischemic/reperfusion injury, human immunodeficiency virus (HIV) infection, undergoing hormone-replacement therapy (HRT), Alzheimer's disease and/or suffering from a hypercoagulable state. In some embodiments, the subject is suffering from, or at risk for developing an acquired hypercoagulable state due to at least one or more of the following: undergoing therapy with a drug selected from the group consisting of 5-FU, GM-CSF, cisplatin, heparin, COX-2 inhibitor, contrast media, corticosteroids and antipsychotics;

venous stasis (immobilization, surgery, etc.), antiphospholipid syndrome, cancer

(promyelocytic leukemia, lung, breast, prostate, pancreas, stomach and colon tumors), tissue injury due to trauma or surgery, presence of a catheter in a central vein, acquired deficiency of a protein involved in clot formation (e.g., protein C), paroxysmal nocturnal

hemoglobinuria (PNH), elevated levels of homocysteine, heart failure, presence of a mechanical valve, pulmonary hypertension with in-situ thrombosis, atrial fibrillation, heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia and thrombosis (HITT), Kawasaki disease with in-situ thrombus, Takayasu arteritis with in-situ thrombus, thrombophilia of metastatic cancer, elevated Factor VIII levels, pregnancy, inflammatory bowel disease (IBD), or due to a genetic defect that causes or increases the risk of developing, a hypercoagulable state, such as a genetic defect selected from the group consisting of a Prothrombin 20210 gene mutation, an MTHFR mutation, a deficiency of protein C, a deficiency of protein S, a deficiency of protein A, a deficiency of protein Z, an antithrombin deficiency and a genetic disorder producing thrombophilia. In some embodiments, the subject is suffering from, or at risk for developing, a disease or disorder that is amenable to treatment with a kallikrein inhibitor. In some embodiments, the subject is suffering from, or at risk for developing a disease or disorder amenable to treatment with a kallikrein inhibitor is selected from the group consisting of hereditary angioedema, diabetic macular edema and bleeding during cardiopulmonary bypass. In some embodiments, the subject is suffering from, or at risk for developing, a disease or disorder that is amenable to treatment with a thrombin inhibitor, such as arterial thrombosis, venous thrombosis, pulmonary embolism, atrial fibrillation, heparin-induced thrombocytopenia, conversion from one anticoagulant to another, or off-label use for extracorporeal circuit patency of continuous renal replacement therapy (CRRT) in critically ill patients with HIT (maintenance). In some embodiments, the subject has previously experienced, is currently suffering from, or is at risk for developing atrial fibrillation and the MASP-2 inhibitory compound is administered in an amount sufficient to reduce the risk of stroke in said subject. In some embodiments, the subject is suffering from, or at risk for developing, a disease or disorder that is amenable to treatment with a factor XII inhibitor, such as deep vein thrombosis (both primary prophylaxis and extended therapy), pulmonary embolism, nonvalvular atrial fibrillation, prevention of recurrent ischemia after acute coronary syndrome in subjects with or without atrial fibrillation, end-stage renal disease, cerebral ischemia, angina, or to reduce or prevent clotting associated with medical devices (e.g., valves, small caliber grafts, etc.) and/or extracorporeal circuits. In some embodiments, the subject has previously experienced, is currently suffering from, or is at risk for developing nonvalvular atrial fibrillation and the MASP-2 inhibitory compound is administered in an amount sufficient to reduce the risk of stroke and/or embolism in said subject. In some embodiments, the subject has an acquired disease or disorder that increases the propensity for thromboembolism, such as a disease or disorder selected from the group consisting of atherosclerosis, antiphospholipid antibodies, cancer (e.g., promyelocytic leukemia, lung, breast, prostate, pancreatic, stomach and colon), hyperhomocysteinemia, infection, tissue injury, venous stasis (such as due to surgery, orthopedic or paralytic immobilization, heart failure, pregnancy, or obesity) and a subject taking oral contraceptives that contain estrogen. In some embodiments, the subject is in need of anticoagulant therapy and the MASP-2 inhibitory compound is used as a replacement for standard anticoagulant therapy (e.g., Warfarin). In some embodiments, the subject has a condition that normally prohibits standard anticoagulant therapy, such as CNS amyloid angiopathy. In some embodiments of the method, the MASP-2 inhibitory compound is administered as a bridging agent perioperatively in a subject otherwise on standard anticoagulation therapy. In some embodiments, the subject has sickle cell disease which is a vaso-occlusive disorder involving activation of platelets.

Atypical hemolytic uremic syndrome (aHUS).

[0139] Atypical hemolytic uremic syndrome (aHUS) is part of a group of conditions termed "Thrombotic microangiopathies." In the atypical form of HUS (aHUS), the disease is associated with defective complement regulation and can be either sporadic or familial. Familial cases of aHUS are associated with mutations in genes coding for complement activation or complement regulatory proteins, including complement factor H, factor I, factor B, membrane cofactor CD46 as well as complement factor H-related protein 1 (CFHR1) and complement factor H-related protein 3 (CFHR3). (Zipfel, P.F., et al, PloS Genetics 3(3):e4l (2007)). The unifying feature of this diverse array of genetic mutations associated with aHUS is a predisposition to enhanced complement activation on cellular or tissue surfaces. A subject is a risk for developing aHUS upon the onset of at least one or more symptoms indicative of aHUS (e.g., the presence of anemia, thrombocytopenia and/or renal insufficiency) and/or the presence of thrombotic microangiopathy in a biopsy obtained from the subject. The determination of whether a subject is at risk for developing aHUS comprises determining whether the subject has a genetic predisposition to developing aHUS, which may be carried out by assessing genetic information (e.g. from a database containing the genotype of the subject), or performing at least one genetic screening test on the subject to determine the presence or absence of a genetic marker associated with aHUS (i.e., determining the presence or absence of a genetic mutation associated with aHUS in the genes encoding complement factor H (CFH), factor I (CFI), factor B (CFB), membrane cofactor CD46, C3, complement factor H-related protein 1 (CFHR1), or THBD (encoding the anticoagulant protein thrombodulin) or complement factor H-related protein 3 (CFHR3), or complement factor H-related protein 4 (CFHR4)) either via genome sequencing or gene-specific analysis (e.g., PCR analysis), and/or determining whether the subject has a family history of aHUS. Methods of genetic screening for the presence or absence of a genetic mutation associated with aHUS are well established, for example, see Noris M et al. "Atypical Hemolytic-Uremic Syndrome," 2007 Nov 16 [Updated 2011 Mar 10] In: Pagon RA, Bird TD, Dolan CR, et al, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle.

Hematopoietic stem cell transplant-associated TMA (HSCT-TMA)

[0140] Hematopoietic stem cell transplant-associated TMA (HSCT-TMA) is a life- threatening complication that is triggered by endothelial injury. The kidney is the most commonly affected organ, though HSCT-TMA can be a multi-system disease that also involves the lung, bowel, heart and brain. The occurrence of even mild TMA is associated with long-term renal impairment. Development of post-allogeneic HSCT-associated TMA differs in frequency based on varying diagnostic criteria and conditioning and graft-versus- host disease prophylaxis regimens, with calcineurin inhibitors being the most frequent drugs implicated (Ho VT et al, Biol Blood Marrow Transplant, 1 1(8):571-5, 2005).

Immunoglobulin A nephropathy (IgAN)

[0141] Immunoglobulin A nephropathy (IgAN) is an autoimmune kidney disease resulting in intrarenal inflammation and kidney injury. IgAN is the most common primary glomerular disease globally. With an annual incidence of approximately 2.5 per 100,000, it is estimated that 1 in 1400 persons in the U.S. will develop IgAN. As many as 40% of patients with IgAN will develop end-stage renal disease (ESRD). Patients typically present with microscopic hematuria with mild to moderate proteinuria and variable levels of renal insufficiency (Wyatt R.J., et al, NEnglJ Med 36S(25):2402-4, 2013). Clinical markers such as impaired kidney function, sustained hypertension, and heavy proteinuria (over 1 g per day) are associated with poor prognosis (Goto M et al., Nephrol Dial Transplant 24(l0):3068-74, 2009; Berthoux F. et al, J Am Soc Nephrol 22(4):752-6l, 2011). Proteinuria is the strongest prognostic factor independent of other risk factors in multiple large observational studies and prospective trials (Coppo R. et al, J Nephrol 18(5):503-12, 2005; Reich H. N., et al., J Am Soc Nephrol 18(12):3177-83, 2007). It is estimated that 15-20% of patients reach ESRD within 10 years of disease onset if left untreated (D'Amico G., Am J Kidney Dis 36(2):227- 37, 2000). The diagnostic hallmark of IgAN is the predominance of IgA deposits, alone or with IgG, IgM, or both, in the glomerular mesangium.

Lupus Nephritis (LN)

[0142] A main complication of systemic lupus erythematosus (SLE) is nephritis, also known as lupus nephritis, which is classified as a secondary form of glomerulonephritis. Up to 60% of adults with SLE have some form of kidney involvement later in the course of the disease (Koda-Kimble et al, Koda-Kimble and Young's Applied Therapeutics: the clinical use of drugs, lOth Ed, Lippincott Williams & Wilkins: pages 792-9, 2012) with a prevalence of 20-70 per 100,000 people in the US. Lupus nephritis often presents in patients with other symptoms of active SLE, including fatigue, fever, rash, arthritis, serositis, or central nervous system disease (Pisetsky D.S. et al, Med Clin North Am 81(1): 113-28, 1997). Some patients have asymptomatic lupus nephritis; however, during regular follow-up, laboratory abnormalities such as elevated serum creatinine levels, low albumin levels, or urinary protein or sediment suggest active lupus nephritis.

V. Compositions, Dosage and Administration

[0143] The compounds as described herein can be administered in a manner compatible with the dosage formulation, and in such amount as will be effective or suitable for treatment. The quantity to be administered depends on a variety of factors including, e.g., the age, body weight, physical activity, and diet of the individual, and the desired effect. In certain embodiments, the size of the dose may also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of the compound in a particular individual. [0144] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied by a physician and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, hereditary characteristics, general health, sex, diet, mode and time of administration, rate of excretion, drug

combination, the severity of the particular condition, and the host undergoing therapy.

[0145] In certain embodiments, the dose may take the form of solid, semi-solid, or liquid forms, preferably in unit dosage forms suitable for simple administration of precise dosages.

[0146] As used herein, the term "unit dosage form" refers to physically discrete units suitable as unitary dosages for humans and other mammals, each unit containing a predetermined quantity of an active agent calculated to produce the desired onset, tolerability, and/or efficacious effects, in association with a suitable pharmaceutical excipient (e.g., an ampoule). In addition, more concentrated dosage forms may be prepared, from which the more dilute unit dosage forms may then be produced.

[0147] The compounds described herein can be administered to a subject in need of treatment using methods known in the art, such as by oral administration or by injection. The injection can be subcutaneous, intravenous, intraperitoneal, intramuscular. As described herein, parenteral formulations can be prepared in dosage unit form for ease of administration and uniformity of dosage. As used herein the term "unit dosage form" refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect.

[0148] The pharmaceutical compositions of the present application comprise a therapeutically effective amount of a compound of the present application formulated together with one or more pharmaceutically acceptable carriers or excipient. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The pharmaceutical compositions of this application can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.

[0149] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol,

tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0150] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0151] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0152] Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0153] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0154] Dosage forms for topical or transdermal administration of a compound of this application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and any needed preservatives or buffers as may be required.

[0155] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0156] According to the methods of treatment of the present application, disorders are treated or prevented in a subject, such as a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the application, in such amounts and for such time as is necessary to achieve the desired result. The term "therapeutically effective amount" of a compound of the application, as used herein, means a sufficient amount of the compound so as to decrease the symptoms of a disorder in a subject. As is well understood in the medical arts a therapeutically effective amount of a compound of this application will be at a reasonable benefit/risk ratio applicable to any medical treatment.

[0157] In general, compounds of the application will be administered in

therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.

[0158] In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g., humans, is in the range from about 0.5 mg to about 250 mg, about 5 mg to about 150 mg, about 5 mg to about 100 mg, about 10 mg to about 75 mg, about 10 mg to about 50 mg, such as 10, 20, 30, 40, or about 50 mg, conveniently administered, e.g., in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 60 mg active ingredient. [0159] In certain embodiments, a therapeutic amount or dose of the compounds of the present application may range from about 0.1 mg/kg to about 500 mg/kg, alternatively from about 1 to about 50 mg/kg. In general, treatment regimens according to the present application comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this application per day in single or multiple doses. Therapeutic amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.

[0160] Upon improvement of a subject's condition, a maintenance dose of a compound, composition or combination of this application may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. The subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

[0161] It will be understood, however, that the total daily usage of the compounds and compositions of the present application will be decided by the attending physician within the scope of sound medical judgment. The specific inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

[0162] The application also provides for a pharmaceutical combinations, e.g., a kit, comprising a) a first agent which is a compound of the application as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise instructions for its administration.

[0163] Methods for preparing such dosage forms are known to those skilled in the art (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ED., Mack Publishing Co., Easton,

PA (1990)). The dosage forms typically include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents, carriers, adjuvants, diluents, tissue permeation enhancers, solubilizers, and the like. Appropriate excipients can be tailored to the particular dosage form and route of administration by methods well known in the art (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ED., Mack Publishing Co., Easton, PA (1990)).

EXAMPLES

The following examples are provided by way of illustration only and not by way of limitation. Those of skill will readily recognize a variety of noncritical parameters which could be changed or modified to yield essentially similar results.

General Methods

[0164] If not otherwise stated, chromatography refers to flash chromatography conducted on silica gel.

[0165] HPLC purification was performed by one of two methods. Method 1 : on a

Gilson preparative reverse phase HPLC system with the combination of UV/ELS detectors (254 nm and 280 nm) and ThermoFisher Hypersil GOLD Agilent (21.2 x 250 mm) 5 pm C- 18 column. Eluents were a mixture of water and acetonitrile (with 0.05 % trifluoroacetic acid). Flow rate was typically 20 mL/min with a linear gradient of water in acetonitrile from 2-90% in 45 minutes. The injection volume was from 1 to 3 mL with maximum 20 mg per load. Method 2: on a Waters preparative reverse phase HPLC system with the combination of UV/MS detectors (254 nm and 280 nm) and XBridge Prep (19 x 50 mm) C18 IOmM OBD column. Eluents were a mixture of water and acetonitrile (with 0.05 % trifluoroacetic acid). Flow rate was typically 50 mL/min with a linear gradient of water in acetonitrile from 5-95% in 8 minutes. The injection volume was from 0.2 to 1 mL with maximum 20 mg per load.

Example 1: Preparation of ((/?)-2-((iV)-2-((4-Carbamindoylbenzyl(carbamoyl)azetidin- l- ylcyclopropyl-2-oxoethyl)glycine (1028)

[0166] Step 1: To a stirred solution of Boc-D-cyclopropyl glycine (300 mg, 1.4 mmol), methyl (S)-azetidine-2-carboxylate hydrochloride (211 mg, 1.4 mmol) and DMAP (255 mg, 2.4 mmol) in MeCN (5 mL) at 5 °C was added EDC (293 mg, 1.5 mmol). The mixture was stirred for 48 h, then concentrated under vacuum. The residue was dissolved in EtOAc and washed with EhO, 0.5 M KHSCE twice, saturated aqueous NaHCCb, EhO and brine, then dried (Na2SOr) and concentrated under vacuum. Chromatography (EtOAc- hexanes) gave methyl (S -l-((¾)-2-((/er/-butoxycarbonyl)amino)-2- cyclopropylacetyl)azetidine-2-carboxylate (381 mg, 88% yield).

[0167] Step 2: To a solution of methyl (Sj- 1 -(/7 /-2-((/c /-butoxycarbonyl)amino)-2- cyclopropylacetyl)azetidine-2-carboxylate (381 mg) in THF (6 mL) was added 5 equiv of Li OH. The mixture was stirred for 16 h at room temperature, then diluted with EtOAc, and adjusted to pH 3 with the slow addition of 10% KHSO4. The mixture was saturated with NaCl, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 10 mL) and the combined organics were dried (Na2SOr) and concentrated under vacuum to give (S -l-((¾ ⁾ -2-((/er/-butoxycarbonyl)amino)-2-cyclopropylacetyl)az etidine-2-carboxylic acid as a solid foam that was used without further purification (380 mg crude).

[0168] Step 3: (Sj- 1 -( 7i)-2-((/6T/-Butoxycarbonyl)amino)-2- cyclopropylacetyl)azetidine-2-carboxylic acid was coupled with benzyl ((4- (aminomethyl)phenyl)(imino)methyl)carbamate following compound 1028, step 1.

Chromatography (EtOAc-hexanes) gave tert- butyl ((R)-2-((S)-2-((4-(N- ((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamoyl)azetidin -l-yl)-l-cyclopropyl-2- oxoethyl)carbamate as a white foam (180 mg).

[0169] Step 4: A solution of /er/-butyl ((R)-2-((S)-2-((4-(N- ((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamoyl)azetidin -l-yl)-l -cyclopropyl-2- oxoethyl)carbamate (180 mg) in EtOAc was cooled in an ice bath. Hydrogen chloride was bubbled through the solution for approximately 5 min. The mixture was allowed to reach room temp and stirred for 30 min. Et ₂ 0 was added to the solution upon which a ppt formed. After the mixture was left at room temp for 16 h, the product was isolated by filtration, washed with Et ₂ 0 and dried under vacuum. The resulting solid was dissolved in H ₂ 0, made alkaline with 2 M NaOH and extracted with CH ₂ Cl ₂ (3 x 10 mL). The combined organics were washed with brine, dried over Na ₂ SCri and concentrated under vacuum to give benzyl ((4-(((S -l-((¾)-2-amino-2-cyclopropylacetyl)azetidine-2- carboxamido)methyl)phenyl)(imino)methyl)carbamate as a white foam (115 mg, 78% yield over two steps).

[0170] Step 5: To a solution of benzyl ((4-(((S -l-((¾)-2-amino-2- cyclopropylacetyl)azetidine-2-carboxamido)methyl)phenyl)(imi no)methyl)carbamate (103 mg, 0.22 mmol) in MeCN (10 mL) was added bromobenzyl acetate (39 pL, 0.245 mmol) and K ₂ C0 ₃ (77 mg, 0.556 mmol). The mixture was heated to 60 °C and stirred for 16 h. The mixture was concentrated under vacuum and the residue was dissolved in EtOAc, washed with H ₂ 0, dried over Na ₂ SOr and concentrated under vacuum. Chromatography (100% EtOAc then 0-10% MeOH-CH ₂ Ch) gave benzyl ((K 2-((S -2-((4-(N- ((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamoyl)azetidin - 1 -yl)- 1 -cy clopropyl-2- oxoethyl)glycinate (20 mg, 15% yield).

[0171] Step 6: To a degassed solution of benzyl ((¾)-2-((S -2-((4-(N- ((benzyloxy)carbonyl)carbamimidoyl)benzyl)carbamoyl)azetidin - 1 -yl)- 1 -cy clopropyl-2- oxoethyl)glycinate (20 mg, 0.033 mmol) in EtOH was added 10% Pd/C (~ 2 mg). The mixture was stirred under 1 atm H ₂ for 24 h. The mixture was filtered (0.2 pM syringe filter) and the filtrate was concentrated under vacuum to give (fRJ-2-((S)-2-((4- carbamimidoylbenzyl)carbamoyl)azeti din- l-yl)-l-cyclopropyl-2-oxoethyl)gly cine (12 mg). Example 2: Preparation of 0V)- l-((/?)-2-Amino-2-cyclopropylacetyl)-N-(4- carbamimidoylbenzyl)azetidine-2-carboxamide (1002)

[0172] Benzyl ((4-(((5 -l-((7? -2-amino-2-cyclopropylacetyl)azetidine-2- carboxamido)methyl)phenyl)(imino)methyl)carbamate was hydrogenated according to the method for compound 1028, step 6 to provide (S)-l-(/7<! -2-amino-2-cyclopropylacetyl)-N-(4- carbamimidoylbenzyl)azetidine-2-carboxamide.

Example 3: Preparation of (£)-l-(( ?)-2-((2-amino-2-oxoethyl)amino)-2- cyclohexylacetyl)-N-(4-carbamimidoylbenzyl)azetidine-2-carbo xamide (1102)

[0173] Step G. Benzyl ((4-((/Sj- 1 -(i7 /-2-amino-2-cyclohexylacetyl)azetidine-2- carboxamido)methyl)phenyl)(imino)methyl)carbamate was synthesized according to the foregoing procedures with the appropriate starting materials. Reaction of benzyl ((4-(((S -l- ((¾ ⁾ -2-amino-2-cyclohexylacetyl)azetidine-2- carboxamido)methyl)phenyl)(imino)methyl)carbamate with bromoacetamide (1.2 equiv) and K2CO3 (2.5 equiv) according to the procedure for compound 1028, step 5 gave benzyl ((4- (((5 -l-((K -2-((2-amino-2-oxoethyl)amino)-2-cyclohexylacetyl)azetidine- 2- carboxamido)methyl)phenyl)(imino)methyl)carbamate (76% yield).

[0174] Step 2: Deprotection of benzyl ((4-((/Sj- 1 -( 7i)-2-((2-amino-2- oxoethyl)amino)-2-cyclohexylacetyl)azetidine-2- carboxamido)methyl)phenyl)(imino)methyl)carbamate according to compound 1028, step 6 provided fS -l-((¾)-2-((2-amino-2-oxoethyl)amino)-2-cyclohexylacetyl)-N -(4- carbamimidoylbenzyl)azetidine-2-carboxamide (83% yield).

Example 4: Preparation of A)-l-((i?)-2-Acetamido-2-cyclohexylacetyl)-N-(4- carbamimidoylbenzyl)azetidine-2-carboxamide (1154)

[0175] Step 1: To a solution of benzyl ((4-(((S -l-((¾)-2-amino-2- cyclohexylacetyl)azetidine-2-carboxamido)methyl)phenyl)(imin o)methyl)carbamate (170 mg, 0.337 mmol) in anhydrous CH2CI2 (5 mL) at was added Et ₃ N (138 pL, 1.0 mmol), acetic anhydride (41 pL, 0.405 mmol) and DMAP (2 mg). The mixture was stirred at room temp overnight then concentrated under vacuum. The residue was dissolved in EtOAc, washed with H2O and dried (Na2S04). Chromatography (100% EtOAc then 0-10% MeOEl-CEbCk) gave benzyl ((4-(((S -l-((¾)-2-acetamido-2-cyclohexylacetyl)azetidine-2- carboxamido)methyl)phenyl)(imino)methyl)carbamate (125 mg, 68% yield).

[0176] Step 2: Deprotection of benzyl ((4-((/Sj- 1 -( 7i)-2-acetamido-2- cyclohexylacetyl)azetidine-2-carboxamido)methyl)phenyl)(imin o)methyl)carbamate according to compound 1028, step 6 provided f5^-l-((7? ₎ -2-acetamido-2-cyclohexylacetyl)-N- (4-carbamimidoylbenzyl)azetidine-2-carboxamide (70 mg, 74% yield).

Example 5: Preparation of ((/?)-! -((iV)-2-((4-Carbamimidoylbenzy l)carb am oyl)azetidin- l-yl)-l-oxopropan-2-yl)glycine (1009)

[0177] ((¾)-l-((S -2-((4-Carbamimidoylbenzyl)carbamoyl)azetidin-l-yl)-l- oxopropan-2-yl) glycine was synthesized according to the method for compound 1028, except that Boc deprotection was performed in MeOH instead of EtOAc.

Example 6: Preparation of (iV)-l-((7?)-2-Amino-2-(2,3-dihydro-l H-inden-2-yl)acetyl)-IN- (4-carbamimidoylbenzyl)azetidine-2-carboxamide (1058)

[0178] (S)- 1 -((/ /-2-Amino-2-(2.3-dihydro- 1 H-inden-2-yl)acetyl)-N-(4- carbamimidoylbenzyl)azetidine-2-carboxamide was synthesized according to the method for compound 1028 except that methyl ester hydrolysis was conducted with 1.5 equiv of LiOH in

1: 1 THF-H2O. Example 7: Preparation of (A)-l-( K)-2-amino-2-phenylacetyl)-N-(4- carbamimidoylbenzyl)azetidine-2-carboxamide (1011)

[0179] A solution of methyl (S -azetidine-2-carboxylate (100 mg, 0.66 mmol), (R)-2- ((/c /-butoxycarbonyl)amino)-2-phenylacetic acid (150 mg, 0.60 mmol), pyridine (0.16 mL) and EtOAc (0.33 mL) were cooled at -20 to -10 °C. A solution of propylphosphonic anhydride in EtOAc (50% solution, 0.84 mL) was added dropwise at a rate to maintain the internal temperature below 0 °C. The yellow solution was stirred at 0 °C for 18 h, then cooled to -10 °C and 1 M HC1 (~l mL) was added dropwise. The reaction was stirred at room temp for 2 h. EtOAc was added, the aqueous layer separated and dried over Na ₂ S04. Concentration under vacuum followed by chromatography (50% EtOAc-hexanes) gave methyl (S)-\-((R)-2- (ticT/-buto\ycarbonyl)amino)-2-phenylacetyl)a/etidine-2-carb o\ylate (80 mg).

[0180] The remaining steps for the synthesis of compound 1011, (S)-l-((R)-2-mm\o-2- phenylacetyl)-N-(4-carbamimidoylbenzyl)azetidine-2-carboxami de, were conducted according to the procedures for compound 1058.

Example 8: Preparation of (iV)-l-(D-Prolyl)-IN-(4-carbamimidoylbenzyl)azetidine-2- carboxamide (1156)

[0181] (5 -l-(D-prolyl)-N-(4-carbamimidoylbenzyl)azetidine-2-carboxami de was synthesized according to the procedures for compound 1058, except that methyl ester hydrolysis was conducted with 1.1 equiv LiOH and Boc removal was conducted with TFA- CH2CI2 (0.2 M) at 0 °C to room temp. Example 9: Preparation of ((/?)-2-((A)-2-((4-Carbamimidoyl-3- hydroxybenzyl)carbamoyl)azetidin-l-yl)-l-cyclohexyl-2-oxoeth yl)glycine (1116)

[0182] Step G. to an ice-cold solution of (Sj- 1 -((7 i-2-((/6T/-butoxycarbonyl)amino)-2- cyclohexylacetyl)azetidine-2-carboxylic acid (260 mg, 0.76 mmol) and DIEA (0.42 mL, 2.4 mmol) in anhyd MeCN (15 mL) was added EDC (166 mg, 0.87 mmol) and HOBt (112 mg, 0.83 mmol). The mixture was stirred for 5 min then 6-(aminomethyl)benzo[d]isoxazol-3- amine hydrochloride (183 mg, 0.92 mmol, prepared according to WO 2001079195) was added. The mixture was stirred for 18 h, allowed to warm to room temp, then concentrated under vacuum. The residue was dissolved in EtOAc, washed with LEO and brine, dried over Na ₂ S04 and chromatographed with 65-100% EtOAc-hexanes to give 305 mg of /e/V-butyl ((K)-2-((S -2-(((3-aminobenzo[d]isoxazol-6-yl)methyl)carbamoyl)azetidin -l-yl)-l- cyclohexyl-2-oxoethyl)carbamate.

[0183] Step 2. Boc removal was conducted according to the procedure for compound 1028, except using MeOH-EtOAc as the solvent, gave S)-l-((R)-2-amino-2- cyclohexylacetyl)-N-((3-aminobenzo[d]isoxazol-6-yl)methyl)az etidine-2-carboxamide hydrochloride.

[0184] Step 3: To a solution of (5 -l-((K ₎ -2-amino-2-cyclohexylacetyl)-N-((3- aminobenzo [d]isoxazol-6-yl)methyl)azetidine-2-carboxamide hydrochloride (160 mg, 0.38 mmol) in anhyd MeCN (10 mL) under Ar was added DIEA (0.25 mL) and

bromobenzylacetate (0.08 mL, 0.50 mmol). The mixture was stirred at room temp for 15 h then concentrated under vacuum and re-dissolved in EtOAc. The solution was washed with LEO and brine, dried (Na ₂ S04) and chromatographed with 55-100% EtOAc-hexanes to give 144 mg of benzyl ((¾)-2-(fS -2-(((3-aminobenzo[d]isoxazol-6-yl)methyl)carbamoyl)azetidin - l-yl)-l-cyclohexyl-2-oxoethyl)glycinate.

[0185] Step 4: Benzyl ((¾)-2-(fS -2-(((3-aminobenzo[d]isoxazol-6- yl)methyl)carbamoyl) azetidin-l-yl)-l-cyclohexyl-2-oxoethyl)glycinate was converted to compound 1116 following the procedure of compound 1028, step 6.

Example 10: Preparation of (A)-l-((/?)-2-Amino-2-cyclohexylacetyl)-IN-((l- aminoisoquinolin-6-yl)methyl)azetidine-2-carboxamide dihydrochloride (1041)

[0186] Step G. 6-(Aminomethyl)isoquinolin-l -amine and (S)-\- (R)-2- tert- butoxy carbonyl) amino)-2-cyclohexylacetyl)azetidine-2-carboxylic acid were coupled following the procedure of compound 1116, step 1. After 15 h reaction time, additional DIEA (1 equiv) was added and stirring was continued for 24 h. Following concentration under vacuum, the residue was dissolved in EtOAc and washed with NaHCCb solution, EhO, and brine then dried (Na2SC>4). Chromatography (0-10% MeOEl-CEBCh) gave /e/V-butyl (fRj-2- ((S)-2-(((\ -aminoisoquinolin-6-yl)methyl)carbamoyl)azetidin- 1 -yl)- 1 -cy clohexyl-2- oxoethyl)carbamate (51% yield).

[0187] Step 2: To a solution of te/7-butyl ((R)-2-((S)-2-((( 1 -aminoisoquinolin-6- yl)methyl)carbamoyl)azetidin-l-yl)-l-cyclohexyl-2-oxoethyl)c arbamate (0.51 g, 1.0 mmol) in anhyd CH2CI2 under Ar was added NMM (0.5 mL, 4.5 mmol) and benzylchloroformate (0.2 mL, 1.4 mmol) dropwise. After stirring at room temp for 1.5 h, additional

benzylchloroformate ((0.15 mL, 1.0 mmol) was added and the mixture was stirred for 2.5 h. After cone under vacuum, EtOAc and saturated aqueous NaHCCh were added and the layers were separated. The org layer was washed with brine and dried (Na2S04). Chromatography (75-100% EtOAc-hexanes) provided benzyl (6-(((5j-l-((¾ ⁾ -2-((/er/-butoxycarbonyl)amino)- 2-cyclohexylacetyl)azetidine-2-carboxamido)methyl)isoquinoli n-l-yl)carbamate (79% yield).

[0188] Step 3: The Boc group of benzyl ( 6- (S)-\- (R)-2- tert - butoxycarbonyl)amino)-2-cyclohexylacetyl)azetidine-2-carboxa mido)methyl)isoquinolin-l- yl)carbamate was removed according to the procedure for compound 1116, step 2 followed by aqueous extractive work-up (sat aqueous NaHCCh/CELCh) gave benzyl (6-(((S)-l-((R)-2- amino-2-cyclohexylacetyl)azetidine-2-carboxamido)methyl)isoq uinobn-l-yl)carbamate (88% yield).

[0189] Step J. Benzyl (6-(((S -l-((¾)-2-amino-2-cyclohexylacetyl)azetidine-2- carboxamido) methyl)isoquinobn-l-yl)carbamate (163 mg, 0.31 mmol) was subjected to hydrogenolysis in MeOH with 10% Pd/C (24 mg) under 1 atm EL. After the reaction did not proceed to completion with extended reaction time (42 h); 6 M HC1 (0.5 mL, 3 mmol) was added. The mixture was reacted under 1 atm Eh for 21 h then filtered (0.2 mM syringe filter). Chromatography on a 12 g Biotage C-18 column (5-30% MeCN-ELO) gave 49 mg of compound 1041 as a white solid in 40% yield.

Example 11: Preparation of (S -l-(( ?)-2-Amino-2-cyclohexylacetyl)-N-(4- guanidinobutyl)azetidine-2-carboxamide Dihydrochloride (1006)

[0190] Step 1 : To an ice-cold solution of Boc-Agm (Z) (3.0 g, 8.2 mmol, synthesized according to the procedure of W09429335) in EtOAc-MeOH (20 mL, 1 : 1) was added 4 M HCl-dioxane (10 mL). After 10 min, the solution was allowed to warm to room temp and stirred for 3 h. The mixture was concentrated under vacuum and the residue was dissolved in EtOAc-MeOH and concentrated under vacuum. This procedure was repeated to give benzyl N-[N-(4-aminobutyl)carbamimidoyl] carbamate hydrochloride as a foam (2.045 g, 82% yield).

[0191] Step 2: (S)- 1 -((7i)-2-((/e/ /-Butoxycarbonyl)amino)-2- cyclohexylacetyl)azetidine-2-carboxylic acid and benzyl N-[N-(4- aminobutyl)carbamimidoyl] carbamate hydrochloride were coupled according to the procedure for compound 1116, step 1. Chromatography (0-6% MeOEl-CEBCh) provided tert- buty 1 ((//)- 1 -cy clohexy l-2-((ri)-2-((4-(3 -Cbz-guanidino)buty l)carbamoy l)azetidin- 1 -y l)-2- oxoethyl)carbamate as a white foam (435 mg, 84% yield).

[0192] Step 3: Boc removal according to the procedure for compound 1116, step 2 provided intermediate (S)- 1 -((//)-2-amino-2-cyclohe\ylacetyl)-N-(4-(3-Cbz- guanidino)butyl)azetidine-2-carboxamide dihydrochloride as a white foam.

[0193] Step 4: Removal of the Cbz group of (S)- 1 -((//)-2-amino-2-cyclohexylacetyl)-

N-(4-(3-Cbz-guanidino)butyl)azetidine-2-carboxamide dihydrochloride was conducted according to compound 1028, step 6 followed by the addition of coned HC1 (~3 mmol), filtration (0.2 mM syringe filter) and concentrated under vacuum gave an orange oil. A MeOH solution of the crude product was treated with finely divided charcoal and heated at 30 °C for 30 min. After cooling to room temp, the mixture was filtered (0.2 pM syringe filter) and concentrated under vacuum to give (5 -l-((K ₎ -2-amino-2-cyclohexylacetyl)-N-(4- guanidinobutyl)azetidine-2-carboxamide dihydrochloride as a beige foam (306 mg).

Example 12: Preparation of (iV)-l-((7?)-2-Amino-2-cyclohexylacetyl)-IN-(3- guanidinopropyl)azetidine-2-carboxamide Hydrochloride (1004)

[0194] Step G. lO-Oxa-2,4,8-triazadodecanoic acid, 3-imino-l l,l l-dimethyl-9-oxo-, phenylmethyl ester (synthesized according to the procedure of W09429335) was deprotected according to the procedure for compound 1006, step 1 to give carbamic acid, [[(3- aminopropyl)amino]iminomethyl]-, benzyl ester hydrochloride as a white foam.

Step 2: [0195] (S)- 1 -((7i)-2-((/e/ /-Butoxycarbonyl)amino)-2- cyclohexylacetyl)azetidine-2-carboxylic acid and carbamic acid, [[(4- aminopropyl)amino]iminomethyl]-, benzyl ester hydrochloride were coupled and

subsequently deprotected according to the procedure for compound 1006 to give (S)-\-((R)-2- amino-2-cyclohexylacetyl)-N-(3-guanidinopropyl)azetidine-2-c arboxamide hydrochloride as a white foam (279 mg, 74% yield for three steps).

Example 13: Preparation of S -2-(( ? -2-Amino-2-(2, 3-dihydro- lH-inden-2- yl)acetamido)-N-((l-aminoisoquinolin-6-yl)methyl)propanamide Dihydrochloride (1088)

[0196] Step G. Benzyl ((¾)-2-((/er/-butoxycarbonyl)amino)-2-(2,3-dihydro-lH-inden - 2-yl)acetyl)-L-alaninate (3.6 g, 7.96 mmol, prepared according to the procedure for compound 1116, step 1) was hydrogenated with 10% P d/C in MeOH according to the procedure for compound 1028, step 6. The crude material was crystallized from warm EtOH- H2O; the solid that was collected on a fritted funnel and rinsed with H2O to give ((R)-2-((tert- butoxycarbonyl)amino)-2-(2,3-dihydro-lH-inden-2-yl)acetyl)-L -alanine as a white powder (2.45 g, 85 % yield).

[0197] Step 2: To a solution of ((K)-2-((/er/-butoxycarbonyl)amino)-2-(2,3-dihydro- lH-inden-2-yl)acetyl)-L-alanine (291 mg, 0.80 mmol) in anhyd DMF (2.5 mL) was added 6- (aminomethyl)isoquinolin-l -amine dihydrochloride (252 mg, 1.0 mmol) and DIEA (0.54 mL, 3.1 mmol) to give a tan suspension. HBTU (349 mg, 0.92 mmol) was added in two aliquots then additional anhyd DMF (0.4 mL). After stirring for 50 min at room temp, additional HBTU (18 mg, 0.05 mmol) was added. The reaction was stirred for 90 min then concentrated under vacuum. The residue was dissolved in EtOAc-CH2Ch then washed with 5% aqueous NaHCCh and brine, then dried (Na2SC>4). Chromatography (0-10% MeOH-C^Ch) gave tert- butyl ((R)-2-(((S)- 1 -((( 1 -aminoisoquinolin-6-yl)methyl)amino)- 1 -o\opropan-2-yl)amino)- 1 - (2,3-dihydro-lH-inden-2-yl)-2-oxoethyl)carbamate (398 mg, 95% yield).

[0198] Step 3: To an ice-cold solution of /er/-butyl ((R)-2-(((S)-l-(((l- aminoisoquinolin-6-yl)methyl)amino)-l-oxopropan-2-yl)amino)- l -(2, 3-dihydro- lH-inden-2- yl)-2-oxoethyl)carbamate (130 mg, 0.25 mmol) in MeOH (2 mL) was added 4 M HC1- dioxane (3 mL). The mixture was stirred for 40 min then allowed to warm to room temperature. After stirring for 4 h total, the solution was concentrated under vacuum. The residue was dissolved in a minimal amount of MeOH and triturated with Et20. The mixture was warmed for 30 min at 30-40 °C then cooled to room temp. The solid was collected on a fritted funnel and rinsed with Et20. The solid was dried under vacuum at room temp to give 6S -2-(/7(/-2-amino-2-(2.3-dihydro- 1 H-inden-2-yl)acetamido)-N-(( 1 -aminoisoquinolin-6- yl)methyl)propanamide as an off-white solid (107 mg, 93% yield).

Example 14: Preparation of S -2-((7? -2-Amino-2-(2, 3-dihydro- lH-inden-2- yl)acetamido)-N-(4-(N-methylcarbamimidoyl)benzyl)propenamide Dihydrochloride (1062)

[0199] Step G. ( (7i)-2-((tot-Butoxy carbonyl )amino)-2-(2.3-dihydro- 1 H-inden-2- yl)acetyl)-L-alanine was coupled to 4-(aminomethyl)-N-methylbenzimidamide

dihydrochloride (synthesized according to W02003028729, except that one Boc protecting group was used in the synthetic sequence) were coupled according to the procedure of compound 1088, step 2 at 15 °C to room temp for 16 h. After extractive workup with 10% MeOH-CThCh, chromatography (0-10% (7 M NH3-MeOH)-CH2Cl2) provided tot-butyl

((Rj- 1 -(2.3-dihydro- 1 H-inden-2-yl)-2-((6S - 1 -((4-(N-methylcarbamimidoyl)benzyl)amino)- 1 - oxopropan-2-yl)amino)-2-oxoethyl)carbamate that was contaminated with the dimethyl benzamidine derivative. Purification by HPLC (4-45%, then 70% MeCN-fhO) gave moderate separation of the two products. Lyophilization of the purest fractions gave tot- butyl ((¾)-l-(2,3-dihydro-lH-inden-2-yl)-2-(((5 -l-((4-(N- methy lcarbamimidoy l)benzy l)amino)- 1 -oxopropan-2-y l)amino)-2-oxoethy l)carbamate as a white solid (73 mg, 23% yield.

[0200] Step 2: /e/V-Butyl ((H)- 1 -(2.3-dihydro- 1 H-inden-2-yl)-2-((6S)- 1 -((4-(N-methyl carbamimidoy l)benzy l)amino)- 1 -oxopropan-2-y l)amino)-2-oxoethy l)carbamate was deprotected according to the procedure of compound 1088, step 3. The residue was triturated with Et20-EtOAc with sonication to give f¾i-2-((7? ₎ -2-amino-2-(2,3-dihydro-lH-inden-2- yl)acetamido)-N-(4-(N-methylcarbamimidoyl)benzyl)propenamide dihydrochloride as a light yellow solid (62 mg).

Example 15: Preparation of (/?)-2-Amino-IN-((iV)-l-((2-(6-aminopyridin-3- yl)ethyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1015)

[0201] Step 1 : /C /-Butyl N-|(/e/ /-butoxy (carbonyl |-N-(5-methylpyridin-2- yl)carbamate (synthesized according to W02010141406) was brominated following a modified procedure also reported in W02010141406 as follows. 7er/-butyl N-|(/e/V- butoxy)carbonyl]-N-(5-methylpyridin-2-yl)carbamate (2.118 g, 6.87 mmol) was partially dissolved in CCU (60 mL). To this mixture was added NBS (1.22 g, 6.86 mmol) and benzoyl peroxide (0.21 g, 0.65 mmol). The mixture was heated at 80 °C for 20 h. After cooling to room temp, the mixture was diluted with CH2CI2 and washed with saturated aqueous NaHCCh 2x, 5% aqueous NaHCCh and brine then dried (Na2SOr) and concentrated under vacuum to give crude di-te/7-butyl 5-(bromomethyl)pyri din-2 -yliminodicarbonate (2.6 g).

[0202] Step 2: To a solution of crude di-/er/-butyl 5-(bromomethyl)pyridin-2- yliminodicarbonate (2.2 g) in CH2CI2 (40 mL) was added H2O, NaCN (0.85 g, 17.3 mmol) and B NI (6.4 g, 17.3 mmol). The mixture was stirred vigorously at room temp for 19 h then diluted with CH2CI2 and washed with saturated aqueous NaHCCh 2x, H2O and brine. Dried (Na2S04) and concentrated under vacuum then chromatographed (0-40% EtOAc-hexanes) to give di-/cT/-butyl 5-(cyanomethyl)pyridin-2-yliminodicarbonate (0.84 g).

[0203] Step 3: To a solution of di-te/7-butyl 5-(cyanomethyl)pyridin-2- yliminodicarbonate (370 mg, 1.1 mmol) in MeOH (5 mL) was added C0CI2-6H2O (292 mg, 1.2 mmol) and di-/ -butyl dicarbonate (470 mg, 2.2 mmol). The solution was cooled over an ice/EtOH bath for 4 min, then NaBEE (165 mg, 4.4 mmol) was added in three aliquots over 25 min. The mixture was stirred for 20 min then allowed to warm to room temp and stirred for 75 min. The reaction was quenched with 0.5 M KHSO4 in 0.5 mL aliquots until pH = 2. The aqueous mixture was extracted with 5% MeOH-C^Ch several times then the aqueous layer was adjusted to pH 4-5 with the addition of several drops of 2 M NaOH. Additional extractions with CH2CI2 were conducted. The combined organics were washed with brine, dried (Na2SCri) and concentrated under vacuum to give a yellow oil.

Chromatography (0-45% EtOAc-hexanes) gave /er/-butyl (ter/-butoxycarbonyl)(5-(2-((/er/- butoxycarbonyl)amino)ethyl)pyridin-2-yl)carbamate that was contaminated with 10% of the starting material (320 mg, 66% crude yield).

[0204] Step 4: /CT/-Butyl (/er/-butoxycarbonyl)(5-(2-((/er/- butoxycarbonyl)amino)ethyl)pyridin-2-yl)carbamate (320 mg, 0.73 mmol) was reacted with a concentrated solution of HCl-MeOH (4 mL) prepared by saturating MeOH with HC1 (g). After stirring for 4 h, Et20 was added and the mixture was concentrated under vacuum. Trituration with MeOH-Et20 gave a ppt that was collected on a fritted funnel and rinsed with Et20 and hexanes. 5-(Aminoethyl)pyridin-2-amine dihydrochloride was isolated (135 mg, 76% yield).

[0205] Step 5 : ((K ⁾ -2-((/er/-Butoxycarbonyl)amino)-4-phenylbutanoyl)-L-al anine was coupled with 5-(2-aminoethyl)pyridin-2-amine dihydrochloride to provide /er/-butyl ((R)- 1- ((fSj- 1 -((2-(6-aminopyridin-3-yl)ethyl)amino)- 1 -o\opropan-2-yl)amino)- 1 -oxo-4- phenylbutan-2-yl)carbamate following the procedure for compound 1088, step 2 at 10 °C to room temp for 3 h (94% yield). [0206] Step 6: Deprotection of /er/-butyl ((H)- 1 -(((S)- 1 -((2-(6-aminopyridin-3- y l)ethy l)amino)- 1 -oxopropan-2-y l)amino)- 1 -oxo-4-pheny lbutan-2-y l)carbamate with HC1- MeOH afforded (¾ ⁾ -2-amino-N-((S -l-((2-(6-aminopyridin-3-yl)ethyl)amino)-l-oxopropan- 2-yl)-4-phenylbutanamide dihydrochloride after crystallization from MeOH-MeCN (49 mg, 27% yield).

Example 16: Preparation of (/?)-2-Amino-IN-((iV)-l-(((4-aminoquinazolin-7- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1060)

[0207] Step G. 7-(Aminomethyl)quinazolin-4-amine was synthesized from 7- bromoquinazolin-4-amine in two steps by the procedure reported in W02015103317.

[0208] Step 2: tert- Butyl (JR)- 1 -(((S)- 1 -(((4-aminoquinazolin-7-y l)methy l)amino)- 1 - oxopropan-2-yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate was synthesized by coupling 7- (aminomethyl)quinazolin-4-amine and ((K -2-((/er/-butoxycarbonyl)amino)-4- phenylbutanoyl)-L-alanine according to the procedure for compound 1088, step 2 at 0-5 °C.

[0209] Step 3: Deprotection oftert-butyl ((¾ ⁾ -l-(((5 -l-(((4-aminoquinazolin-7- yl)methyl)amino)-l-oxopropan-2-yl)amino)-l-oxo-4-phenylbutan -2-yl)carbamate with MeOH and 3 M HC1-CPME provided (¾ ⁾ -2-amino-N-((5 -l-(((4-aminoquinazolin-7- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide dihydrochloride as a white powder (50 mg, 96% yield).

Example 17: Preparation of (/?)-2-Amino-IN-((iV)-l-(((l-aminoisoquinolin-6- yl)methyl)amino)-l-oxopropan-2-yl)-N-methyl-4-(3- (trifluoromethyl)phenyl)butanamide Dihydrochloride (1139)

[0210] Step G. /¾)-2-((/er/-Butoxycarbonyl)amino)-4-(3- (trifluoromethyl)phenyl)butanoic acid was coupled to methyl methyl-L-alaninate according to the method for compound 1116, step 1 to afford methyl N-((R)-2-((lerl- butoxycarbonyl)amino)-4-(3-(trifluoromethyl)phenyl)butanoyl) -N-methyl-L-alaninate.

[0211] Step 2: N-(f¾)-2-((Yer/-Butoxycarbonyl)amino)-4-(3- (trifluoromethyl)phenyl)butanoyl)-N-methyl-L-alanine was synthesized from methyl N-((R)- 2-((/er/-butoxycarbonyl)amino)-4-(3-(trifluoromethyl)phenyl) butanoyl)-N-methyl-L- alaninate according to the procedure for ester hydrolysis for compound 1058.

[0212] Step 3: N-(f¾)-2-((Yer/-Butoxycarbonyl)amino)-4-(3- (trifluoromethyl)phenyl)butanoyl)-N-methyl-L-alanine was coupled with 6- (aminomethyl)isoquinolin-l -amine dihydrochloride according to the foregoing procedures to provide /er/-buty 1 ((R)- \ -(((S)- \ -((( \ -aminoisoquinolin-6-y l)methy l)amino)- 1 -oxopropan-2- yl)(methyl)amino)-l-oxo-4-(3-(trifluoromethyl)phenyl)butan-2 -yl)carbamate.

[0213] Step 4: /e/V-Butyl ((H)- 1 -(((Sj- 1 -((( 1 -aminoisoquinolin-6-yl)methyl)amino)- 1 - oxopropan-2-yl)(methyl)amino)-l-oxo-4-(3-(trifluoromethyl)ph enyl)butan-2-yl)carbamate was deprotected with MeOH and 3 M HC1-CPME according to the foregoing procedures to give // 2-amino-N-( _f 2y)- 1 -((( l -aminoisoquinolin-6-yl)methyl)amino)- 1 -o\opropan-2-yl)-N- methyl-4-(3-(trifluoromethyl)phenyl)butanamide dihydrochloride. Example 18: Preparation of 2-Amino-N-((S -l-(((2-amino-lH-benzo[d]imidazol-6- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Di-trifluoroacetate salt (1040)

[0214] Step G. ((K -2-((/er/-Butoxycarbonyl)amino)-4-phenylbutanoyl)-L-alanine was coupled with 6-(aminomethyl)-lH-benzo[d]imidazol-2-amine dihydrochloride according to the procedure of compound 1088, step 2 except that the reaction was conducted at room temp and the 6-(aminomethyl)-lH-benzo[d]imidazol-2-amine dihydrochloride was added to the reaction mixture last. The reaction was stirred for 18 h after which the mixture was concentrated under vacuum. The residue was diluted with CH2CI2 and washed with 5% aqueous NaHCCb, dried (Na2S04) and chromatographed with 10% MeOH (containing 7 M NH3)-CH2Cl2 to give /er/-butyl ((K -l-((fS -l-(((2-amino-lH-benzo[d]imidazol-6- yl)methyl)amino)-l-oxopropan-2-yl)amino)-l-oxo-4-phenylbutan -2-yl)carbamate in 32% yield.

[0215] Step 2: /er/-Butyl ((¾)-l-(((S -l-(((2-amino-lH-benzo[d]imidazol-6- yl)methyl)amino)-l-oxopropan-2-yl)amino)-l-oxo-4-phenylbutan -2-yl)carbamate was deprotected with HCl-MeOH as described in foregoing procedures to give 2-amino-N-((S -l- (((2-amino-lH-benzo[d]imidazol-6-yl)methyl)amino)-l-oxopropa n-2-yl)-4- phenylbutanamide dihydrochloride. The compound was purified by HPLC (2-15-35-90% MeCN-fhO) to give 2-amino-N-((S -l-(((2-amino-lH-benzo[d]imidazol-6- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide di-trifluoroacetate salt, isomer 2.

Example 19: Preparation of (/?)-2-Amino-IN-((/V)-l-((2-(2-aminopyridin-4- yl)ethyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1016)

[0216] Step G. ((K -2-((/er/-Butoxycarbonyl)amino)-4-phenylbutanoyl)-L-alanine was coupled with 4-(2-aminoethyl)pyridin-2-amine dihydrochloride to provide tert- butyl ((R)- \ - (((S)-l-((2-(2-aminopyridin-4-yl)ethyl)amino)-l-oxopropan-2- yl)amino)-l -oxo-4- phenylbutan-2-yl)carbamate according to the procedure of compound 1088, step 2, except that the reaction was conducted at 10-15 °C to room temp.

[0217] Step 2: tert-Butyl ((R)- 1 -(({Sj- 1 -((2-(2-aminopyridin-4-yl)ethyl)amino)- 1 - oxopropan-2-yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate was deprotected with HC1- MeOH according to the foregoing procedures to give compound 1016 (80 mg, 89% yield) Example 20: Preparation of (7?)-2-Amino-N-((A)-l-((4-carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-4-(4-(trifluoromethyl)phenyl)butanamide Dihydrochloride (1119)

[0218] Step 1: To a solution of (K)-2-((/er/-butoxycarbonyl)amino)-4-(4- (trifluoromethyl)phenyl)butanoic acid (500 mg, 1.44 mmol) in anhydrous MeCN (30 mL) was added HOBt (1.1 equiv, 1.58 mmol), DIEA (4.0 equiv, 5.76 mmol) and EDC (1.1 equiv, 1.58 mmol) with stirring at room temp for 30 min. Benzyl L-alaninate hydrochloride (1.1 equiv, 1.58 mmol) was added and stirred overnight. The solution was evaporated to dryness and the residue was partitioned with EtOAc (60 mL) and 10% KHSCri (50 mL). The organic layer was separated and washed with LEO (30 mL), saturated Na ₂ C0 ₃ (60 mL), dried (Na ₂ S04) and evaporated leaving benzyl ((¾)-2-((/er/-butoxycarbonyl)amino)-4-(4- (trifluoromethyl)phenyl)butanoyl)-L-alaninate (512 mg, 70%) as an oil pure enough to use in the next step.

[0219] Step 2: A solution of benzyl (f7? ₎ -2-((/er/-butoxycarbonyl)amino)-4-(4- (trifluoromethyl)phenyl)butanoyl)-L-alaninate (512 mg, 1.01 mmol) in MeOH (20 mL) was degassed with a stream of Ar for 2-3 min. 10% Pd/C (50 mg) was added and a vacuum was pulled for approx. 3 min. A balloon of H2 was added and the reaction was monitored for the consumption of starting material (typically 1-4 h). The catalyst was removed by filtration and the solution was evaporated to dryness leaving ( ¾)-2-((fer/-butoxycarbonyl)amino)-4-(4- (trifluoromethyl)phenyl)butanoyl)-L-alanine as a fluffy white solid (420 mg, 100%).

[0220] Step 3: To a solution of ((K -2-((/er/-butoxycarbonyl)amino)-4-(4- (trifluoromethyl)phenyl)butanoyl)-L-alanine (400 mg, 0.956 mmol) in CH2CI2 (15 mL) was added NHS (1.1 equiv, 1.05 mmol) with stirring at room temp until dissolved. DCC (1.1 equiv, 1.05 mmol) was added and stirred for 1.0 h. This mixture was poured into a separatory funnel containing saturated NaHCCb (15 mL), and benzyl ((4-

(aminomethyl)phenyl)(imino)methyl)carbamate hydrochloride (1.2 equiv, 1.15 mmol) and then shaken for 5 min. The organic layer was filtered over a bed of anhyd Na2S04 and evaporated to dryness. Flash chromatography (3% 7 N NH3 in MeOH/CTLCh) gave tert- butyl ((¾ ⁾ -l-(((5 -l-((4-(N-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-l - oxopropan-2-yl)amino)-l-oxo-4-(4-(trifluoromethyl)phenyl)but an-2-yl)carbamate as an oil (477 mg, 73%). [In certain cases, products were able to be collected by filtration after a reduction in volume of the CH2CI2 layer. These products contained a small amount of DCU which was removed in the final step of the synthesis by filtration from H2O.]

[0221] Step 4: To tert- butyl ((R)- \ -(((S)- \ -((4-(S-

((benzy loxy)carbony l)carbamimidoy l)benzy l)amino)- 1 -oxopropan-2-y l)amino)- 1 -oxo-4-(4- (trifluoromethyl)phenyl)butan-2-yl)carbamate (460 mg, 0.673 mmol) was added a solution of MeOH/HCl (5.0 mL, 227 mg HCl/mL) with stirring at room temp while monitoring for the consumption of starting material. The solution was evaporated to dryness and MeOH (!5mL) was added and evaporated to dryness giving benzyl ((4-(( ¾i-2-(/¾)-2-amino-4-(4- (trifluoromethyl)phenyl)butanamido)propanamido)methyl)phenyl )(imino)methyl)carbamate hydrochloride as a white solid pure enough to use in the next step (420 mg, 100%).

[0222] Step 5: A solution of benzyl ((4-((fS -2-((K ₎ -2-amino-4-(4-

(trifluoromethyl)phenyl)butanamido)propanamido)methyl)phe nyl)(imino)methyl)carbamate hydrochloride (420 mg, 0.677 mmol) in MeOH (10 mL) was degassed with a stream of Ar for 2-3 min. 10% Pd/C (50 mg) was added and a vacuum was pulled for approx. 3 min. A balloon of ¾ was applied and the reaction was monitored for the consumption of starting material (typically 1-2 h). The catalyst was removed by filtration then 4 drops of concentrated HC1 was added and the solution was evaporated to dryness. To the residue was added H2O (2-3 mL). The mixture was filtered then and lyophilized, giving (¾)-2-amino-N-((5 -l-((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-4-(4-(trifluoro methyl)phenyl)butanamide dihydrochloride as an off white solid (350 mg, 100%). Example 21: Preparation of (i?)-2-Amino-N-((A)-l-((4-(N- hydroxycarbamimidoyl)benzyl)amino)-l-oxopropan-2-yl)-4-pheny lbutanamide

Dihydrochloride (1157)

[0223] Step 1: To a solution of tert- butyl ((R)- 1 -(((Sj- 1 -((4-cyanobenzyl)amino)- 1 - oxopropan-2-yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate (660 mg, 1.42 mmol, prepared according to compound 1119, step 3 using 4-cyanobenzyl amine HC1 in MeOH (20 mL) was added hydroxylamine HC1 (1.5 equiv, 2.13 mmol) and Et3N (1.5 equiv, 2.13 mmol). This mixture was heated at reflux for 4 h, evaporated to dryness, and then partitioned between H2O (15 mL) and EtOAc (2 x 30 mL.) The combined organic layers were dried over anhyd Na ₂ S04 and evaporated. Chromatography (50% EtOAc-hexanes) gave /e/V-butyl (fRj- 1 -((fSj- l-((4-(N-hydroxycarbamimidoyl)benzyl)amino)-l -oxopropan-2-yl)amino)-l -oxo-4- phenylbutan-2-yl)carbamate as a white solid (417 mg, 59%).

[0224] Step 2: The intermediate was deprotected according to the procedure for compound 1119, step 4, to provide (i?)-2-amino-N-((5 -l-((4-(N- hydroxycarbamimidoyl)benzyl)amino)-l-oxopropan-2-yl)-4-pheny lbutanamide

dihydrochloride (i.e., compound 1157).

Example 22: Preparation of (7?)-IN-(iV)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-4-phenyl-2,5-dihydro-lH-pyrrole-2-carboxamid e Di-trifluoroacetate (1032)

[0225] (2i?,4 _< S -N-((5 -l-((4-Carbamirnidoylbenzyl)amino)-l-oxopropan-2-yl)-4- hydroxy -4-phenylpyrrolidine-2-carboxamide dihydrochloride (45 mg, 0.093 mmol) was stirred in TFA (5.0 mL) for 48 h at room temp. The solution was evaporated to dryness and the residue was subjected to purification using reverse phase HPLC (5-45-75-90% MeCN- H2O). (K)-N-(S)-l-((4-Carbamimidoylbenzyl)amino)-l-oxopropan-2-yl) -4-phenyl-2,5- dihydro- lH-pyrrole-2-carboxamide di-trifluoroacetate was isolated as a white solid (15 mg, 26% yield).

Example 23: Preparation of (2i?)-2-Amino-N-(l-((4-carbamimidoylbenzyl)amino)-3- fluoro-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1050)

[0226] Step 1: tert- Butyl (l-((4-(N-

((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-3-fluoro -l-oxopropan-2-yl)carbamate was synthesized from 2-((tert-butoxycarbonyl)amino)-3-fluoropropanoic acid and benzyl ((4- (aminomethyl)phenyl)(imino)methyl)carbamate hydrochloride according to the procedure for compound 1119, step 3.

[0227] Step 2: tert- Butyl (l-((4-(N-

((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-3-fluoro -l-oxopropan-2-yl)carbamate was deprotected according to the procedure for compound 1119, step 4 to give benzyl ((4-((2- amino-3-fluoropropanamido)methyl)phenyl) (imino)methyl)carbamate hydrochloride.

[0228] Step 3: Benzyl (^-(^-((K^-amino^-phenylbutanamido)^- fluoropropanamido)methyl)phenyl)(imino)methyl)carbamate hydrochloride was synthesized from benzyl ((4-((2-amino-3-fluoropropanamido)methyl)phenyl) (imino)methyl)carbamate hydrochloride and ¾ ⁾ -2-((tert-butoxycarbonyl)amino)-4-phenylbutanoic acid according to the procedure for compound 1119, step 3.

[0229] Step 4: Benzyl ((4-((2-((K ₎ -2-amino-4-phenylbutanamido)-3- fluoropropanamido)methyl)phenyl)(imino)methyl)carbamate hydrochloride was synthesized from benzyl ((4-((2-((¾)-2-amino-4-phenylbutanamido)-3- fluoropropanamido)methyl)phenyl)(imino)methyl)carbamate hydrochloride according to the procedure for compound 1119, step 4.

[0230] Step 5: (2R)-2-Amino-N-(l-((4-carbamimidoylbenzyl)amino)-3-fluoro-l- oxopropan-2-yl)-4-phenylbutanamide dihydrochloride (1050) was synthesized from benzyl ((4-((2-((K ₎ -2-amino-4-phenylbutanamido)-3- fluoropropanamido)methyl)phenyl)(imino)methyl)carbamate hydrochloride according to the procedure for compound 1119, step 5. Example 24: Preparation of (7?)-N-((A)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-2-(cyclohexylamino)-4-phenylbutanamide Dihydrochloride (1130)

[0231] Step G. Benzyl ((4-(((5 -2-((K -2-amino-4-phenylbutanamido)propanamido) methyl)phenyl)(imino)methyl)carbamate (1.9 g, 41% yield in 4 steps) was synthesized by a method similar to that used for compound 1119, except the crude product was purified by chromatography (10% MeOH-CTHCk and then 5% 7 N NH3 in MeOH- CH2CI2).

[0232] Step 2: To a 20-mL scintillation vial, benzyl ((4-(((5 -2-((K -2-amino-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate (55.1 mg, 0.107 mmol) was added and followed by THF (400 pL). The solution was treated with

cyclohexanone (15 pL, 0.145 mmol) at room temp followed by Na(OAc) ₃ solid (32 mg,

0.151 mmol) and HO Ac (10 pL, 0.175 mmol). After purging with N ₂ , the vial was capped. The reaction was stirred at room temp for 4 h and quenched with about 15 mL saturated NaHCOi solution. The resulting mixture was extracted with 15 mL CH2CI2 (3 times). The organic layers were combined, washed with brine, dried (NadSOi) vacuum filtered, and evaporated under vacuum. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-5% MeOH-CTHCh) gave benzyl ((4-(((S)-2-((R)-2- (cyclohexylamino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate (44 mg, 69% yield).

[0233] Step 3: To a solution of benzyl ((4-(((S -2-((K -2-(cyclohexylamino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate (44 mg, 0.0736 mmol) in MeOH (1.0 mL) was treated with 10% Pd/C (8.1 mg, 0.00761 mmol) at room temp. Air was removed from the reaction apparatus by in-house N2 line (5 times). H2 was added via a balloon while stirring overnight. The reaction was filtered through a 0.25 pm syringe filter. Volatiles were evaporated under vacuum to give (¾ ⁾ -N-((5 -l-((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-2-(cyclohexylam ino)-4-phenylbutanamide, compound 1130 (25.3 mg, 69% yield).

Example 25: Preparation of (/?)-IN-((iV)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-2-((4-hydroxybenzyl)amino)-4-phenylbutanamid e Dihydrochloride (1140)

[0234] (¾)-N-((5 -l-((4-Carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-2-((4- hydroxybenzyl)amino)-4-phenylbutanamide (17.7 mg, 30% yield in 2 steps) was synthesized by a method similar to that used for compound 1130, except the crude product was purified by reverse phase HPLC (5-45-75-90% MeCN-ThO).

Example 26: Preparation of (/?)-IN-((iV)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-4-phenyl-2-((4-(piperazin-l-yl)benzyl)amino) butanamide,

Trifluoroacetate Salt (1148)

[0235] Step G. A clear solution of 4-(piperazin-l-yl)benzaldehyde (502 mg, 2.68 mmol) in CH2CI2 (10 mL) was treated with DIEA (0.900 mL, 5.17 mmol) at room temp under N2 and the reaction changed to clear yellow solution. Benzyl chloroformate (0.450 mL, 3.19 mmol) was added. The reaction gradually changed to deep clear red solution. After stirring at room temp overnight, the reaction was washed with 20 mL 1 N HC1 solution (2 times). The organic layer was washed with brine, dried (Na2S0 ₄ ), vacuum filtered, and evaporated under vacuum. Purification by flash chromatography (0-100% EtOAc-hexanes) gave benzyl 4-(4-formylphenyl)piperazine-l-carboxylate (606 mg, 70% yield).

[0236] Step 2: (R)-N-((Sj- 1 -((4-Carbamimidoylbenzyl)amino)- 1 -o\opropan-2-yl)-4- phenyl-2-((4-(piperazin-l-yl)benzyl)amino)butanamide (3.4 mg, 2.8% yield in 2 steps) was synthesized by a method similar to compound 1130, steps 1 and 2, except the crude product was purified by reverse phase HPLC condition (5-15-90% MeCN-LLO) similar to that used for compound 1140.

Example 27: Preparation of (/?)-2-((5-Aminopentyl)amino)-IN-((iV)-l-((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanam ide Trihydrochloride

(1132)

[0237] Step G. tert- Butyl (5-(((Rj- 1 -((fSj- 1 -((4-carbamimidoylbenzyl)amino)- 1 - oxopropan-2-yl)amino)- 1 -oxo-4-pheny lbutan-2-y l)amino)penty l)carbamate was synthesized by a method similar to step 1 that used for compound 1130 (461.4 mg, 63% yield).

[0238] Step 2: Benzyl ((4-((fS -2-((K ₎ -2-((5-aminopentyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate (crude) was synthesized by a method similar to that used for compound 1119.

[0239] Step 3: (¾)-2-((5-Aminopentyl)amino)-N-((S -l-((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanam ide was synthesized by a method similar to step 2 used for compound 1130 (18.4 mg, 21% yield in 2 steps) except the crude product was purified by reverse phase HPLC (5-45-75-90% MeCN-fhO): (18.4 mg, 21% yield in 2 steps).

Example 28: Preparation of (/?)-2-(((/?)-2-Amino-3-phenylpropyl)amino)-IN-((iV)-l-((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanam ide, Tri- trifluoroacetate Salt

[0240] (R) -2-(((R) -2- Amino-3 -phenyl propyl)amino)-N-(fS - 1-((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanam ide was synthesized by a method similar to that used for compound 1132 except the crude product was purified by reverse phase HPLC condition (5-60-90% MeCN-H20); (13.6 mg, 12% yield in 3 steps).

Example 29: Preparation of (iV)-2-(((7?)-2-Amino-4-phenylbutyl)amino)-IN-(4- carbamimidoylbenzyl)propanamide Dihydrochloride (1013)

[0241] Step G. A solution of (K)-2-((/er/-butoxycarbonyl)amino)-4-phenylbutanoic acid (694.9 mg, 2.49 mmol) in THF (1 mL) was treated with 1 M borane-tetrahydrofuran complex solution (4.2 mL, 4.2 mmol) at 0 °C in an ice bath under N ₂ . Gas was produced moderately. The reaction was warmed to room temp while stirring for 4 h. H2O was added slowly via syringe. Gas was produced violently. The resulting mixture was extracted with 30 mL CH2CI2 (3 times) after adding 30 mL saturated NH4CI solution. The organic layers were combined, dried (Na2SCri). vacuum filtered, and evaporated under vacuum. Purification by chromatography (0-100% EtOAc-hexanes) gave /e/7-butyl (R)-( 1 -hydroxy-4-phenylbutan-2- yl)carbamate (263.4 mg, 40% yield).

[0242] Step 2: A solution of /e/7-butyl (R)-( 1 -hydroxy-4-phenylbutan-2-yl (carbamate (263.4 mg, 0.993 mmol) in CH2CI2 (17 mL) was treated with Dess-Martin periodinane (468.9 mg, 1.10 mmol, 1.1 eq) at 0 °C. The reaction was stirred at the same temperature for 2.5 h. The reaction became opaque and was added to a solution of 1 M Na2S2Cb (20 mL) and 1 M NaHCCh (20 mL) at room temp. The resulting mixture was stirred at room temp for 15 min and became colorless. The organic was separated and the aqueous layer was extracted with CH2CI2 (2 x 20 mL). The organic layer was combined, washed once with saturated NaHCCh solution, dried over Na2S0 ₄ , vacuum filtered, and evaporated under vacuum. Purification by chromatography (0-100% EtOAc-hexanes) gave tert-butyl (R)-( 1 -o\o-4-phenylbutan-2- yl)carbamate (199 mg, 76%).

[0243] Step 3: A solution of tert- butyl (R)-( 1 -o\o-4-phenylbutan-2-yl)carbamate (199 mg, 0.756 mmol) in THF (1.8 mL) was treated with benzyl L-alaninate hydrochloride (102.6 mg, 0.476 mmol) followed by DIEA (240 pL, 1.38 mmol). The resulting colorless solution was treated with NaBH(OAc)3 (148.6 mg, 0.701 mmol) and HOAc (85 pL, 1.49 mmol). After purging with N2, the vial was capped. The reaction was stirred at room temp for 4 h and quenched with about 20 mL saturated NaHCCh solution. The resulting mixture was extracted with 20 mL CH2CI2 (3 times). The organic layers were combined, washed with brine, dried (Na2SCri). vacuum filtered, and evaporated under vacuum. The crude product was dissolved in CH2CI2 and adsorbed onto silica gel. Purification by chromatography (0-100% EtOAc- hexanes) gave benzyl ((¾ ⁾ -2-((/er/-butoxycarbonyl)amino)-4-phenylbutyl)-L-alani nate (127 mg, 63% yield).

[0244] Step 4\ ( ¾ ⁾ -2-(( er -Butoxycarbonyl)amino)-4-phenylbutyl)-L-alanine (99 mg,

100% yield) was synthesized by a method similar to step 2, used for compound 1130.

[0245] Step 5 tert- Butyl ( K)-l-(((SH-((4-(N- ((benzy loxy)carbony l)carbamimidoy l)benzy l)amino)- 1 -oxopropan-2-y l)amino)-4- phenylbutan-2-yl)carbamate (66.8 mg, 38% yield) was synthesized by a method similar to that used for compound 1119, except the crude product was purified by chromatography (10% MeOH- CH2CI2).

[0246] Step 6: Benzyl ((4-(((S -2-(((¾)-2-amino-4- phenylbutyl)amino)propanamido)methyl)phenyl)(imino)methyl)ca rbamate was synthesized by a method similar to that used for compound 1119, except the crude product was purified by flash chromatography (10% MeOH- CH2CI2 and then 5% 7 N NH3 in MeOH-C^Ch). This procedure yielded 15.1 mg (27% yield) of material.

[0247] Step 7: (S -2-(((K ₎ -2-Amino-4-phenylbutyl)amino)-N-(4- carbamimidoylbenzyl)propanamide (i.e.. compound 1013) was synthesized by a method similar to step 2 that used for compound 1130, except the crude product was purified by reverse phase HPLC (2-15-35-90% MeCN-H20) similar to that used for compound 1140. This procedure yielded 10.3 mg (72% yield) of material.

Example 30: Preparation of (i?)-2-Amino-N-((A)-l-((5-chloro-2-hydroxybenzyl)amino)- l-oxopropan-2-yl)-4-phenylbutanamide Hydrochloride (1031)

[0248] (i?)-2-Amino-N-(( _< S)-l-((5-chloro-2-hydroxybenzyl)amino)-l-oxopropan-2- yl)-4-phenylbutanamide was prepared following similar protocols as reported for compound 1119, steps 1-4 using the appropriate starting materials. Example 31: Preparation of fV)- l-((/?)-2-Amino-4-phenylbutanoyl)-IN-(5-chloro-2- hydroxybenzyl)pyrrolidine-2-carboxamide Hydrochloride (1079)

[0249] Steps 1-2: ((i?)-2-((/er/-Butoxycarbonyl)amino)-4-phenylbutanoyl)-L-pro line was prepared following similar protocols as compound 1028, but with steps 1-2 using the appropriate starting materials.

[0250] Steps 3-4 : ( _< S)-l-((i?)-2-Amino-4-phenylbutanoyl)-N-(5-chloro-2- hydroxybenzyl)pyrrolidine-2-carboxamide was prepared following similar protocols as reported for compound 1060, step 2 using the appropriate starting materials. Example 32: Preparation of (/?)-2-Amino-IN-((A)-l-((5-chloro-2-(2-(ethylamino)-2- oxoethoxy)benzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide , Trifluoroacetate Salt (1137)

[0251] Step G. tert- Butyl ((i?)-l-(((<S)-l-((5-chloro-2-hydroxybenzyl)amino)-l- oxopropan-2-yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate (436 mg, 0.89 mmol, as prepared for compound 1031) was suspended in DMF (4 mL) and treated with ethyl bromoacetate (148 pL, 1.34 mmol) and CS2CO3 (725 mg, 2.23 mmol). The reaction mixture was allowed to stir for 18 h, then diluted with EtOAc and washed with H2O, 5% aqueous LiCl and brine. The organic layer was dried over MgSOr and concentrated under vacuum, then purified by chromatography (40-80% EtOAc-hexanes) to yield ethyl 2-(4-chloro-2- ((4S,7i?)-4, 11,11 -trimethyl-3, 6, 9-trioxo-7-phenethyl-l 0-oxa-2, 5,8- triazadodecyl)phenoxy)acetate as a white powder (370 mg, 72% yield).

[0252] Step 2: A reaction vessel was charged with ethyl 2-(4-chloro-2-((45' 7//)- 4,11,1 l-trimethyl-3,6,9-trioxo-7-phenethyl-l0-oxa-2,5,8-triazadode cyl)phenoxy)acetate (370 mg, 0.64 mmol), LiOH (31 mg, 1.28 mmol), THF (3 mL) and H2O (3 mL). The reaction mixture was allowed to stir at room temp for 4 h, then THF was removed under vacuum and the residue was treated with 10% aq. KHSO4 (3 mL). The resulting ppt was filtered and washed with water and hexanes to provide 2-(4-chloro-2-((45',7i?)-4,l 1,11 -trimethyl-3, 6,9- trioxo-7-phenethyl-l0-oxa-2,5,8-triazadodecyl)phenoxy)acetic acid as a white solid (281 mg, 80% yield).

Steps 3-4 : 2-(4-Chloro-2-((4»S',7i?)-4, 11,11 -trimethyl-3, 6, 9-tri oxo-7-phenethyl- lO-oxa-

2,5,8-triazadodecyl)phenoxy)acetic acid (24 mg, 0.04 mmol) and HOBt (5.9 mg, 0.044 mmol) were dissolved in DMF (1 mL). EDC (8.4 mg, 0.044 mmol) was then added in a single portion, followed by ethylamine (2 M in THF, 150 pL) and DIEA (21 pL, 0.12 mmol). The resulting solution was allowed to stir at room temp for 60 h. The reaction mixture was then diluted with EtOAc, washed with 10% aqueous KHSCE, 5% aqueous LiCl, saturated NaHCCb (x2) and brine. The crude mixture was treated with HC1 in MeOH and filtered through diatomaceous earth, then purified by preparative HPLC (5% to 95% MeCN in H2O containing 0.1% TFA) to provide (//)-2-amino-N-(fV)- 1 -((5-chloro-2-(2-(ethylamino)-2- oxoethoxy)benzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide as a white solid (2.4 mg, 11% yield).

Example 33. Preparation of (2/?,-/A)-iV-((iV)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide Dihydrochloride (1230)

Step 7: To a solution of (2R, 4S)-\ -(/er/-butoxycarbonyl)-4-phenylpiperidine-2- carboxylic acid (5.0 g, 16.4 mmol) in MeCN (300 mL, 0.05 M) was added HOBt (2.g, 3.77 mmol), DIEA (11.4 mL, 13.7 mmol), and EDC (2.8 g, 3.77 mmol). After stirring for 30 min at room temperature, benzyl /.-alanine hydrochloride (814 mg, 18 mmol) was added and stirred for 16 h. The reaction mixture was cone in vacuo and the residue was partitioned with EtOAc and 10% KHSCri solution. The organic layer was separated and washed with EhO and saturated aq NaHCCh. The organic layer was dried over anhyd Na ₂ S04 and cone under vacuum. The residue was purified by chromatography (0-20% EtOAc-hexanes; the 3 ^rd UV Active material eluting from the column) to give /er/-butyl (2R 4Sj-2-((fSj- 1 -(benzyloxy)- l-oxopropan-2-yl)carbamoyl)-4-phenylpiperi dine- l-carboxy late (2.59 g, 34% yield).

Step 2: A solution of /er/-butyl (2R 4Sj-2-((fSj- 1 -(benzyloxy)- 1 -oxopropan-2- yl)carbamoyl)-4-phenylpiperidine- l-carboxy late (2.59 mg, 5.54 mmol) was degassed with a stream of Ar for 2 min. 10% Pd/C (130 mg) was added and a vacuum was pulled for 1 min. A balloon of Eh was added and the reaction was monitored for the consumption of starting material for 1.5 h. The catalyst was removed by filtration and the solution was evaporated to give ((2R.4L - 1 -(/cT/-buto\ycarbonyl)-4-phenylpiperidine-2-carbonyl)-L-alan ine (1.8 g,

86%).

Step 3 : ter t-Buty 1 (2R, 4S) -2-(((S) - 1 -((4-(7V-

((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-l-oxopro pan-2-yl)carbamoyl)-4- phenylpiperidine-l-carboxylate was synthesized according to the procedure for compound 0194.

Step 4 Benzyl (\mmo(4-(((S)-2-((2R -AS -4-phenylpiperidine-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate hydrochloride was synthesized according to the procedure for compound 0195.

Step 5: (2R 4S)-N-((S)- 1 -((4-carbamimidoylbenzyl)amino)- 1 -o\opropan-2-yl)-4- phenylpiperidine-2-carboxamide dihydrochloride was synthesized according to the procedure for compound 0196.

Example 34. Preparation of (2/?,-/A)-iV-((iV)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-4-(«i-tolyl)piperidine-2-carboxamide Dihydrochloride (1231)

Step 7: To a solution of dioxane: 2 M K2C03 (l: l, 116 ml total) was added methyl 4- bromopicolinate 10.0 g (46.29 mmol) and m-tolylboronic acid (55.6 mmol, 1.2 eq.). The solution was degassed with a stream of Ar for 5 min. Pd(PPh3)4 (0.05 eq.) was added and the solution was refluxed for 48 h. Dioxane was removed by evaporation followed by the addition of H2O (50 ml) and EtOAc (100 ml) with stirring. The aqueous layer was separated, and the pH adjusted to approx. 5 with the addition of solid KHSO4. The product was collected by filtration, washed with H2O and dried giving 4-(/w-toh )picolinic acid (9.07 g, 92% yield).

Step 2: To a solution of 4-(m-tolyl)picolinic acid (9.05 g., 42.4 mmol) in anhyd MeOH (50 ml) was added H2SO4 (5 ml) with refluxing for 24 h. MeOH was removed by evaporation and the residue partitioned between sat. NaHCCh and CH2CI2. The organic layer was dried over Na2SC>4 and evaporated. Column chrom. (40% EtO Ac/hexanes) gave methyl 4-(m-tolyl)picolinate (6.05 g, 63% yield) as a yellow oil.

Step 3: To a solution of acetic acid (40 ml) was added methyl 4-(/w-toh )picolinate (2.4 g, 10.6 mmol) with degassing with Ar for 2 min. PtCh (240 mg) was added and a vacuum pulled for 5 min. A balloon of ¾ was added with stirring for 26 h. The catalyst was removed by filtration followed by evaporation. Purification by chromatography (1% MeOH-CTkCh) gave methyl 4-(m-tolyl)piperidine-2-carboxylate (1.6 g, 65% yield) as an oil.

Step 4: To a solution of THF-sat. NaHCCb (1: 1, 35 ml total) was added methyl 4-(m- tolyl)piperidine-2-carboxylate (1.6 g, 6.9 mmol) and di-/ -butyl dicarbonate (1.05 equiv, 7.25 mmol) with stirring overnight. THF was removed by evaporation with extraction with CH2CI2 (2 x 30 ml). The organic layer was dried over Na2S0 ₄ and evaporated to dryness. 1- (/CT/-Butyl) 2-methyl 4-(m-tolyl)piperi dine- l,2-dicarboxy late (2.34 g, 100% yield) was used in the next step.

Step 5: To a solution of THF-H2O (1: 1, 30 ml) was added l-(/er/-butyl) 2-methyl 4-

(m-toly l )piperidine- 1.2-dicarbo\ylate (2.34 g, 7.0 mmol) and LiOH (35.0 mmol, 5.0 equiv.) with stirring for 6 h. THF was removed by evaporation and the pH adjusted to 5 with 10% KHSO4. The product was collected by filtration, washed with H2O and dried. 1 -(tert- Butoxy carbonyl )-4-(/ft-tolyl)piperidine-2-carboxylic acid (1.81 g, 81% yield) as a pale yellow solid.

Steps 6-11 : (2R, 4S)-N-((S)- 1 -((4-carbamimidoylbenzyl)amino)- 1 -o\opropan-2-yl)-4- (/M-tolyl)piperidine-2-carbo\amide was synthesized according to the procedures for compound (1230). The third UV Active material eluting from the column in step 6 was carried forward.

Example 35. Preparation of (/?)-iV-((/V)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-2-((2-(4-methylpiperazin-l-yl)benzyl)amino)- 4-phenylbutanamide Di- trifluoroacetate salt

Step 7: Benzyl (imino(4-((( _< S)-2-((7?)-2-((2-(4-methylpiperazin-l-yl)benzyl)amino) -4- phenylbutanamido)propanamido)methyl)phenyl)methyl)carbamate was synthesized according to the procedure for compound 1130, step 2.

Step 2: Deprotection of benzyl (imino(4-(((.Y)-2-((/i)-2-((2-(4-methylpiperazin- 1 - yl)benzyl)amino)-4-phenylbutanamido)propanamido)methyl)pheny l)methyl)carbamate according to the procedure for compound 1130, step 3 afforded (R)-N-((S)- 1 -((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-2-((2-(4-methyl piperazin-l- yl)benzyl)amino)-4-phenylbutanamide.

Step 3: (7?)-7V-((5)-l-((4-Carbamimidoylbenzyl)amino)-l-oxopropan-2- yl)-2-((2-(4- methylpiperazin-l-yl)benzyl)amino)-4-phenylbutanamide di-trifluoroacetate salt was formed according to the procedure for compound (1368), step 2.

Example 36. Preparation of (7?)-2-((4-(l//-Tetrazol-5-yl)benzyl)amino)-/V-((A')-l-((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanam ide Di- trifluoroacetate salt (1233)

Step 7: Benzyl ((4-((( _< S)-2-((7?)-2-((4-(l7/-tetrazol-5-yl)benzyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate was synthesized according to the procedure for compound 1130, step 2.

Step 2: Deprotection of benzyl ((4-(((<S -2-((7?)-2-((4-(l7/-tetrazol-5-yl)benzyl)amino)- 4-phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)c arbamate according to the procedure for compound 1130, step 3. Purification by reverse phase HPLC (5-75-90% MeCN-ELO) afforded (7?)-2-((4-(lH-tetrazol-5-yl)benzyl)amino)-7V-((ri -l-((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanam ide di-trifluoroacetate salt.

Example 37. Preparation of (^)-iV-(l-((4-Carbamimidoylbenzyl)amino)-l-oxopropan-2- yl)-4-(naphthalen- l-yl)- l//-pyrrole-2-carboxamide (1234)

Step 7: In a 50 mL round bottom flask equipped with a stir bar and septum was added methyl 4-iodo- l//-pyrrole-2-carbo\ylate (300 mg, 1.19 mmol), 1 -naphthyl boronic acid (246 mg, 1.43), Pd(OAc) ₂ (13 mg, 0.06 mmol), potassium carbonate (330 mg, 2.39 mmol), acetone (2.7 mL) and water (1.3 mL). The resulting mixture was degassed by bubbling N2 through the solution for 5 min. The reaction was then heated to 75 °C for 5 h. Upon cooling to room temperature, the reaction solution was filtered through diatomaceous earth, eluted with EtOAc, concentrated and purified by chromatography using EtOAc-hexanes to afford methyl 4-(naphthalen-l-yl)-l77-pyrrole-2-carboxylate (260 mg, 86% yield) as a colorless solid.

Step 2: 4-(Naphthalen- l -yl)- l//-pyrrole-2-carbo\ylic acid (180 mg, 82%) was synthesized from methyl 4-(naphthalen- 1 -yl)- l//-pyrrole-2-carbo\ylate (260 mg, 1.03 mmol) according to the procedure for compound (1328), step 1.

Step 3: To a solution of (/e/V-butoxy carbonyl )-/,-alanine (300 mg, 1.58 mmol) in CH2CI2 (11 mL) was added NHS (200 mg, 1.74 mmol) with stirring at ambient temperature until dissolution. DCC (359 mg, 1.74 mmol) was added and stirred for 1.0 h. This mixture was poured into a separatory funnel containing sat. NaHCCb (10 mL), and benzyl ((4- (aminomethyl)phenyl)(imino)methyl)carbamate hydrochloride (540 mg, 1.90 mmol) and then shaken for 5 min. The organic layer was filtered over a bed of anhyd Na2S0 ₄ and evaporated to dryness. Flash chromatography using EtOAc-hexanes gave /er/-butyl (S)-( \ -((4-(N- ((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-l-oxopropan -2-yl)carbamate as a solid (560 mg, 80% yield).

Step 4 Benzyl fV)-((4-((2- aminopropanamido)methyl)phenyl)(imino)methyl)carbamate hydrochloride (380 mg, 90%) was synthesized from /er/-butyl (<5)-(l-((4-/7V-

((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-l-oxopro pan-2-yl)carbamate (560 mg, 1.23 mmol) according to the procedure for compound (1304), step 6.

Step 5: Benzyl fV)-(imino(4-((2-(4-(naphthalen- 1 -yl)- 1 //-pyrrole-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate (35 mg, 45% yield) was synthesized from benzyl (S)-((4-((2- aminopropanamido)methyl)phenyl)(imino)methyl)carbamate hydrochloride (60 mg, 0.17 mmol) according to the procedure for compound (1304), step 7.

Step 6: (S)-N-( 1 -((4-Carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-4-(naphtha len- 1 -yl)- 1 //-pyrrole-2-carbo\amide (25.3 mg, 94% yield) was synthesized from benzyl (S)- (imino(4-((2-(4-(naphthalen- 1 -yl)- 1 //-pyrrole-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate (35 mg, 0.06 mmol) according to the procedure for compound (1304), step 4.

Example 38. Preparation of (^)-iV-(l-((4-Carbamimidoylbenzyl)amino)-l-oxopropan-2- yl)-4-(3-fluoro-4-methylphenyl)- l//-pyrrole-2-carboxamide (1235)

(5)-/V-(l-((4-Carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-4 -(3-fluoro-4- methylphenyl)- l//-pyrrole-2-carboxamide was synthesized according to the procedures for compound (1234).

Example 39. Preparation of (7?)-iV-(fV)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-2-((4-(2-hydroxyethoxy)benzyl)amino)-4-pheny lbutanamide Di- trifluoroacetate salt (1236)

Step 7: Benzyl ((4-(((<S)-2-((7?)-2-((4-(2-hydroxy ethoxy )benzyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate was synthesized according to the procedure for compound 1130, step 2.

Step 2: Deprotection of benzyl ((4-((fY)-2-((//)-2-((4-(2- hydroxy ethoxy )benzyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate according to the procedure for compound 1130, step 3. Purification by reverse phase HPLC (5-75-90% MeCN-fhO) afforded (R)-N-((S)- 1 -((4-carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-2- ((4-(2 -hydroxy ethoxy )benzyl)amino)-4-phenylbutanamide di-trifluoroacetate salt.

Example 40. Preparation of (7?)-2-amino-iV-(fV)- l-((5-chloro-2-(2-((3- hydroxypropyl)amino)-2-oxoethoxy)benzyl)amino)-l-oxopropan-2 -yl)-4- phenylbutanamide Hydrochloride (1237)

[0253] Step G. tert- Butyl ((//)- 1 -(((S)- 1 -((5-chloro-2-hydroxybenzyl)amino)- 1 - oxopropan-2-yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate (436 mg, 0.89 mmol, as prepared for compound 1031) was suspended in DMF (4 mL) and treated with ethyl bromoacetate (148 pL, 1.34 mmol) and CS2CO3 (725 mg, 2.23 mmol). The reaction mixture was allowed to stir for 18 h, then diluted with EtOAc and washed with H2O, 5% aqueous LiCl and brine. The organic layer was dried over MgSOr and concentrated under vacuum, then purified by chromatography (40-80% EtOAc-hexanes) to yield ethyl 2-(4-chloro-2- ((4S,7i?)-4, 11,11 -trimethyl-3, 6, 9-trioxo-7-phenethyl-l 0-oxa-2, 5,8- triazadodecyl)phenoxy)acetate as a white powder (370 mg, 72% yield).

[0254] Step 2: A reaction vessel was charged with ethyl 2-(4-chloro-2-((45' 7//)- 4,11,1 l-trimethyl-3,6,9-trioxo-7-phenethyl-l0-oxa-2,5,8-triazadode cyl)phenoxy)acetate (370 mg, 0.64 mmol), LiOH (31 mg, 1.28 mmol), THF (3 mL) and H2O (3 mL). The reaction mixture was allowed to stir at room temp for 4 h, then THF was removed under vacuum and the residue was treated with 10% aq. KHSO4 (3 mL). The resulting ppt was filtered and washed with water and hexanes to provide 2-(4-chloro-2-((45',7i?)-4,l 1,11 -trimethyl-3, 6,9- trioxo-7-phenethyl-l0-oxa-2,5,8-triazadodecyl)phenoxy)acetic acid as a white solid (281 mg, 80% yield).

Step 3: 2-(4-Chloro-2-((4S',7i?)-4,l 1,11 -trimethyl-3, 6, 9-trioxo-7-phenethyl-l0-oxa- 2,5,8-triazadodecyl)phenoxy)acetic acid (51 mg, 0.09 mmol) and NHS (14 mg) were dissolved in ACN (1 mL). DCC (14 mg, 0.1 mmol) was then added in a single portion, followed by 3-aminopropan-l-ol (22 pL, 0.29 mmol) and DIEA (47 pL, 0.27 mmol). The resulting solution was allowed to stir at room temp for 16 h. The reaction mixture was then diluted with EtOAc, washed with 10% aq KHSCri, brine and sat. aq NaHCCh. The organic layer was dried over Na ₂ S04 and concentrated under vacuum, then purified by

chromatography (7-9% MeOEl-CEhCh) to yield tert-butyl ((//)- 1 -(((S)- 1 -((5-chloro-2-(2-((3- hydroxypropyl)amino)-2-oxoethoxy)benzyl)amino)-l -oxopropan-2-yl)amino)-l -oxo-4- phenylbutan-2-yl)carbamate as a colorless oil (25 mg, 44% yield).

Step 4: ((//)- 1 -(((L')- 1 -((5-Chloro-2-(2-((3-hydro\y propyl)amino)-2- oxoethoxy)benzyl)amino)-l-oxopropan-2-yl)amino)-l-oxo-4-phen ylbutan-2-yl)carbamate carbamate was deprotected according to the procedure for compound 1119, step 4 to provide the title compound as a white solid (21 mg, 95% yield).

Example 41. Preparation of (A)-iV-(l-((4-Carbamimidoylbenzyl)amino)-l-oxopropan-2- yl)-4-(4-methoxyphenyl)- l//-pyrrole-2-carboxamide Trifluoroacetate salt (1238)

( S)-N-( 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-4-(4-methoxy phenyl)- 1 H- pyrrole-2-carboxamide trifluoroacetate salt was synthesized according to the procedures for compound (1234), except that the final product was purified using reverse-phase HPLC. Example 42. Preparation of 0V)-iV-(l-((4-Carbamimidoylbenzyl)amino)- l-oxopropan-2- yl)-5-methyl-4-phenyl- l//-pyrrole-2-carboxamide Trifluoroacetate salt (1239)

Step 7: NIS (3.77 g, 16.7 mmol) was added to a stirring solution of methyl 2- acetamidoacrylate (2 g, 13.9 mmol) in 2% TFA in CH2CI2 (74 mL with 1.5 mL TFA). The mixture was stirred at ambient temperature overnight. The mixture was cooled over an ice bath before triethylamine (6 mL) was added slowly. The mixture was allowed to stir for a further 1 h. The mixture was concentrated and taken up in CH2CI2, washed with 1 M KHSO4, water and brine before concentrating and purifying by chromatography on silica

(hexanes/ethyl acetate 1: 1) to obtain methyl (Z)-2-acetamido-3-iodoacrylate as a yellow- brown solid (1.50 g, 40% yield).

Step 2: Methyl (Z)-2-acetamido-3-iodoacrylate (500 mg, 1.86 mmol), LiCl (78.4 mg, 1.86 mmol), K2CO3 (1.28 g, 9.29 mmol) and Pd(OAc)2 (42 mg, 0.18 mmol) were dissolved in DMF (18 mL) and treated with the prop-l-yn-l-ylbenzene (648 mg, 5.57 mmol). The solution was degassed, placed under Argon atmosphere, and heated to 65 °C with stirring for 12 h. The solution was filtered to remove solids, diluted with EtOAc (50 mL), washed with water (25 mL), brine (25 mL), and the organic layer dried over Na2S04. After cone in vacuo, chromatography (EtOAc-hexanes) afforded methyl 5-methyl-4-phenyl- 1 //-py rrole-2- carboxylate (85 mg, 30% yield) and by-product (75 mg, 25% yield).

Step 3: 5-Methyl-4-phenyl- l//-pyrrole-2-carbo\ylic acid (40 mg, 85% yield) was synthesized from methyl 5-methyl-4-phenyl- l//-pyrrole-2-carbo\ylate (45 mg, 0.21 mmol) according to the procedure for compound (1328), step 1.

Step 4 (S)-N-( 1 -((4-Carbamimidoylbenzyl)amino)- 1 -oxopropan-2-yl)-5-methyl-4- phenyl- 1 //-py rrole-2-carboxamide trifluoroacetate salt was synthesized according to the procedures for compound (1234), step 5 to step 6, except that the final product was purified using reverse-phase HPLC. Example 43. Preparation of fV)-iV-(l-((4-Carbamimidoylbenzyl)amino)- l-oxopiOpan-2- yl)-4, 5-diphenyl- l/ -pyrrole-2-carboxamide (1240)

(S)-N-( 1 -((4-Carbamimidoylbenzyl)amino)- l -o\opropan-2-yl)-4.5-diphenyl- 1 //- pyrrole-2-carboxamide was synthesized according to the procedures for compound (1239). Example 44. Preparation of (2i?,4i?)-iV-((^)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-4-(m-tolyl)piperidine-2-carboxamide Dihydrochloride (1241)

(: 2R,4R)-N-((S )- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-4-(m- tolyl)piperidine-2-carboxamide was synthesized according to the procedures for compound (1231) (9). The first UV Active material eluting from the column in step 6 was carried forward.

Example 45. Preparation of (2i?,4i?)- -((A)-l-((5-Chloro-2-hydroxybenzyl)amino)-l- oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide (1242)

Steps 1-2 : To a solution of ((2RAR)- 1 -(/e/V-butoxy carbonyl )-4-phenylpynOlidine-2- carbonyl)-L-alanine (22 mg, 0.06 mmol) and 2-(aminomethyl)-4-chlorophenol hydrobromide (15 mg, 0.06 mmol) in anhyd DMF (1 mL) at 0 °C was added HBTU (349 mg, 0.92 mmol) and DIEA (31 pL, mmol). The reaction mixture was slowly warmed to ambient temperature and stirred for 2 h, then diluted with EtOAc and washed with 10% aq KHSCri and brine. The organic layer was dried over Na ₂ S04 and concentrated under vacuum, then purified by chromatography (70% EtOAc-hexanes) to provide tert-butyl (2RAR)-2-(((S)- 1 -((5-chloro-2- hydroxybenzyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpyr rolidine-l-carboxylate as a colorless oil. The residue was then taken up in MeOH (1 mL) and treated with 3 M HC1 in CPME (2 mL). After 4h, the reaction mixture was concentrated and purified by

chromatography (7% MeOH/CH2CL2 containing 2.5% 7 N NLb-MeOH) to yield the title compound as a white solid (12.2 mg, 51% yield over 2 steps). Example 46. Preparation of (7?)-2-Amino-iV-((iV)-l-(((6-amino-4-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1243)

Step 7: To a solution of ((K -2-((/er/-butoxycarbonyl)amino)-4-phenylbutanoyl)-L- alanine (152 mg, 0.43 mmol) in anhyd DMF (3.5 mL) under Ar was added DIEA (0.10 mL, 0.57 mmol) and 5-(aminomethyl)-4-methylpyridin-2-amine (65 mg, 0.47 mmol). The mixture was cooled over ice then HBTU (172 mg, 0.45 mmol) was added: the reaction was stirred for 30 min then stored at 2-8 °C overnight. The reaction mixture was cone in vacuo then the residue was dissolved in EtOAc and washed with H2O, diluted NaHCCh solution and brine. The solution was dried (Na2SCri) and cone in vacuo. The residue was purified by

chromatography with 0-10% MeOH-CLLCh to give /er/-butyl ((R)- 1 -((/S - 1 -(((6-amino-4- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)amino)-l-o xo-4-phenylbutan-2- yl)carbamate (25 mg, 12% yield).

Step 2: To a solution of /e/V-butyl ((H)- 1 -(((Sj- 1 -(((6-amino-4-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)amino)-l-oxo-4-phenylbutan -2-yl)carbamate (25 mg, 0.05 mol) in MeOH (2 mL) was added a solution of HC1-CPME (3 M, 4 mL). The mixture was stirred for 2 h then cone in vacuo. The residue was dissolved in MeOH and cone in vacuo then partitioned between H2O and CH2CI2. The H2O layer was washed with CH2CI2 and the volatiles removed in vacuo. The aqueous solution was lyophilized to give (R)- 2- amino-/V-((S -l-(((6-amino-4-methylpyri din-3 -yl)methyl)amino)-l-oxopropan-2-yl)-4- phenylbutanamide dihydrochloride as a white powder (22.8 mg, 97% yield; 85: 15 diastereomer mixture). Example 47. Preparation of (/?)-2-Amino-iV-((iV)- l-(((6-amino-5-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1244)

(¾)-2-Amino-/V-((5)-l-(((6-amino-5-methylpyridin-3-yl)methy l)amino)-l-oxopropan-

2-yl)-4-phenylbutanamide dihydrochloride was synthesized according to the procedures for compound (1243).

Example 48. Preparation of (/?)-2-Amino-iV-((iV)- l-(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1245)

/e/V-Butyl ((R)- 1 -(((Sj- 1 -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate was synthesized according to the procedure for compound (1243), step 1, except that additional HBTU (0.34 eq.) was added after stirring for 3.5 h over ice bath. Following purification of the intermediate, deprotection was achieved according to the procedure for compound (1243), step 2. Example 49. Preparation of (i?)-2-Amino-/V-((A)-l-((5-chloro-2-nitrobenzyl)amino)-l- oxopropan-2-yl)-4-phenylbutanamide Hydrochloride (1246)

Step 7: /e/V-Butyl ((H)- 1 -(((S)- 1 -((5-chloro-2-nitrobenzyl)amino)- 1 -oxopropan-2- yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate synthesized according to step 1 of the procedure for compound (1242) using the appropriate starting materials.

Step 2: To /er/-butyl ((//)- 1 -(((S)- 1 -((5-chloro-2-nitrobenzyl)amino)- 1 -oxopropan-2- yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate (12 mg, 0.025 mmol) was added cone HC1 in MeOH (1 mL). The reaction mixture was allowed to stir at ambient temperature overnight, then evaporated to dryness. The residue was taken up in H2O-ACN (~l: l) and lyophilized overnight to yield (7?)-2-amino-/V-(( _< S)-l-((5-chloro-2-nitrobenzyl)amino)-l-oxopropan-2-yl) - 4-phenylbutanamide, hydrochloride as a yellow powder (8.3 mg, 73%). Example 50. Preparation of (2i?,4A)-7V-((A)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-4-(«i-tolyl)pyrrolidine-2-carboxamide Dihydrochloride (1247)

O

Boc O

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Step 7: To a stirred solution of 1 -(te/7-butyl) 2-methyl (7?)-4-oxopyrrolidine-l,2- dicarboxylate (1.50 g, 6.16 mmol) in THF (15 mL) at -78 °C was slowly added lithium bis(trimethylsilyl)amide (7.40 mL, 7.40 mmol, 1 M in THF) under Ar. After stirring for 1 h at -78 °C, Comins' reagent (2.99 g, 7.40 mmol) in THF (5 mL) was added and the stirring continued for an additional 1 h. The reaction mixture was stirred at -20°C for additional 18 h. The reaction mixture was quenched with 20 mL water and extracted with diethyl ether (3 x 60 mL). The combined extracts were washed with 2 N NaOH solution, dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by chromatography (EtOAc-hexanes) to give \-(ter /-butyl) 2-methyl (7?)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5- dihydro- 1 //-pyrrole- 1.2-dicarbo\ylate (1.85 g, 80% yield).

Step 2: In a 50 mL round bottom flask equipped with a stir bar and septum was added l -(/e/7-butyl) 2-methyl (7?)-4-(((trifluoromethyl)sulfonyl)oxy)-2, 5-dihydro- l/7-pyrrole-l, 2- dicarboxylate (400 mg, 1.06 mmol), m-tolyl boronic acid (215 mg, 1.17), Pd(PPh3)4 (123 mg, 0.11 mmol), K2CO3 (442 mg, 3.20 mmol), dioxane (7.1 mL) and water (1.5 mL). The resulting mixture was degassed by bubbling N2 through the solution for 10 min. The reaction was then heated to 80 °C for 2 h. Upon cooling to ambient temperature, the reaction solution was filtered through diatomaceous earth, eluting with EtOAc, concentrated and purified by chromatography using EtOAc-hexanes to afford 1 -(te/7-butyl) 2-methyl (7?)-4-(m-tolyl)-2,5- dihydro- 1 //-pyrrole- 1.2-dicarbo\ylate (330 mg, 86% yield) as a colorless solid.

Step 3: To a stirred solution of 1 -(/e/7-butyl) 2-methyl (/?)-4-(m-tolyl)-2,5-dihydro- 1 //-pyrrole- 1.2-dicarboxylate (317 mg, 1 mmol) in THF (24 mL), MeOH (12 mL), and water (12 mL) was added LiOH (360 mg, 15 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature overnight. 12 mL of 1 M HC1 was added to the reaction mixture and organic volatiles were removed under vacuum. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic extracts were thoroughly dried using Na ₂ S04, filtered, and concentrated to afford (R)- 1 -(/e/ /-butoxycarbonyl)-4-(m-tolyl)- 2.5-dihydro- 1 //-pyrrole-2-carbo\ylic acid (288 mg crude, 95% yield) that was directly used in the next step without further purification.

Step 4 A solution of (R)- 1 -(/c /-butoxycarbonyl)-4-(/w-tolyl)-2.5-dihydro- l //-pyrrole- 2-carboxylic acid (288 mg, 0.95 mmol) in MeOH (8 mL) was bubbled with Ar gas for 5 min. 10% Pd/C (28 mg) was added to the reaction mixture and that was stirred under 1 atm of LL for 4 h. The reaction mixture was filtered (0.2 mhi syringe filter) and the filtrate was concentrated under vacuum to give (2/iAY)- l -(/e/ /-butoxy carbonyl )-4-(/iz-tolyl (pyrrol idine-2- carboxylic acid (265 mg, 92% yield).

Step 5: /e/V-Butyl (2RAS)-2-(((S)- 1 -(benzyloxy)- 1 -oxopropan-2-y 1 (carbamoyl )-4-(/w- tolyl)pyrrolidine-l-carboxylate (404 mg, 74% yield) was synthesized from (2R,4S)-\-(tert- butoxycarbonyl)-4-(/M-tolyl)pyrrolidine-2-carboxylic acid (360 mg, 1.18 mmol) according to the procedure for compound (1304), step 7.

Step 6: (2RAS)- 1 -(/c /-Butoxycarbonyl)-4-(/w-tolyl)pyrrolidine-2-carbonyl (-/.-alanine (300 mg, 92% yield) was synthesized from /er/-butyl (2i?,4S)-2-(((S)-l-(benzyloxy)-l- oxopropan-2-yl)carbamoyl)-4-(m-tolyl)pyrrolidine-l-carboxyla te (404 mg, 0.87 mmol) according to the procedure for compound (1304), step 4.

Step 7: tert- Butyl (2//.45 2-((fS 1 -((4-(N-

((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-l-oxopro pan-2-yl)carbamoyl)-4-(m- tolyl)pyrrolidine-l-carboxylate (154 mg, 75% yield) was synthesized from (2R,4S)-\-(tert- buto\ycarbonyl)-4-(/M-tolyl)pyrrolidine-2-carbonyl (-/.-alanine (100 mg, 0.26 mmol) according to the procedure for compound (1234), step 3.

Step 8: Benzyl (imino(4-((fS')-2-((2//.45')-4-(/w-tolyl)pyrrolidine-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate dihydrochloride (83 mg, 90% yield) was synthesized from /er/-butyl (2RAS)-2-(((S)- 1 -((4-/7V-

((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-l-oxopro pan-2-yl)carbamoyl)-4-(m- tolyl)pyrrolidine-l-carboxylate (110 mg, 0.17 mmol) according to the procedure for compound (1304), step 8.

Step 9: (2RAS)-N-((S)- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-4 -(m- tolyl)pyrrolidine-2-carboxamide dihydrochloride (64 mg, 86%) was synthesized from benzyl (imino(4-(((5)-2-((2i?,4S)-4-(OT-tolyl)pyrrolidine-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate (55 mg, 0.15 mmol) according to the procedure for compound (1304), step 4.

Example 51. Preparation of (2/?,-//?)-iV-((iV)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-4-(/ -tolyl)piperidine-2-carboxamide Dihydrochloride (1248)

(2R, 4R)-N- (S) - 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-yl)-4-( >- tolyl)piperidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1241). The first UV Active material eluting from the column in step 6 was carried forward. Example 52. Preparation of (2/?,-/A)-iV-((iV)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-4-(/;-tolyl)piperidine-2-carboxamide Dihydrochloride (1249)

(: 2R,4S)-N-((S )- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-yl)-4-(/> tolyl)piperidine-2-carboxamide was synthesized according to the procedures for compound (1231) (9). The third UV Active material eluting from the column in step 6 was carried forward. Example 53. Preparation of (7?)-iV-((A)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-2-((4-(4-(methylsulfonyl)piperazin-l-yl)benz yl)amino)-4- phenylbutanamide Di-trifluoroacetate salt (1250)

Step 7: To a solution of 4-(piperazin-l-yl)benzaldehyde (450.0 mg, 2.37 mmol) in THF (6 mL) and CH2CI2 (6 mL), di-/er/-butyl dicarbonate (650 mg, 2.98 mmol) was added. After purging with N2, the reaction was stirred at room temp for 16 h. The reaction was quenched with 50 mL sat. NLLCl solution and extracted with 50 mL CH2CI2 (3 times). The organic layers were combined, dried (Na2S0 ₄ ), vacuum filtered, and evaporated under vacuum. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-100% EtOAc-hexanes) afforded tert- butyl 4-(4- formylphenyl)piperazine-l-carboxylate (632.6 mg, 92% yield).

Step2 : tert- Butyl 4-(4-((((7?)-l-((( _< S)-l-((4-/7V- ((benzy loxy)carbony l)carbamimidoy l)benzy l)amino)- 1 -oxopropan-2-y l)amino)- 1 -oxo-4- phenylbutan-2-yl)amino)methyl)phenyl)piperazine-l-carboxylat e was synthesized according to the procedure for compound 1130, step 2.

Step 3: te/7-Butyl 4-(4-((((benzyloxy)carbonyl)((7?)-l-(((ri -l-((4-/7V- ((benzy loxy)carbony l)carbamimidoy l)benzy l)amino)- 1 -oxopropan-2-y l)amino)- 1 -oxo-4- phenylbutan-2-yl)amino)methyl)phenyl)piperazine-l-carboxylat e was synthesized according to the procedure for compound 1148, step 1.

Step 4: Deprotection of te/7-butyl 4-(4-((((benzyloxy)carbonyl)((7?)-l-(((ri)-l-((4-(?V- ((benzy loxy)carbony l)carbamimidoy l)benzy l)amino)- 1 -oxopropan-2-y l)amino)- 1 -oxo-4- phenylbutan-2-yl)amino)methyl)phenyl)piperazine-l-carboxylat e was conducted according to the procedure for compound 1015, step 4 except the crude product was purified by chromatography (5% 7 N NEE in MeOEl-CEECE) to afford benzyl ((//)- 1 -(((S)- 1 -((4-/7V- ((benzy loxy)carbony l)carbamimidoy l)benzy l)amino)- 1 -oxopropan-2-y l)amino)- 1 -oxo-4- phenylbutan-2-yl)(4-(piperazin-l -yl)benzyl)carbamate.

Step 5: To a solution of benzyl ((i?)-l-(((5 -l-((4-/7V- ((benzy loxy)carbony l)carbamimidoy l)benzy l)amino)- 1 -oxopropan-2-y l)amino)- 1 -oxo-4- phenylbutan-2-yl)(4-(piperazin-l-yl)benzyl)carbamate (54.4 mg, 0.066 mmol) in DCE (500 pL) and TEA (14 pL) was added MsCl (6 pL) at 0 °C. The reaction was warmed to room temp and stirred for 16 h. The reaction was quenched with 1 mL 0.5 M NaOH solution and extracted with 20 mL CH2CI2 (3 times). The organic layers were combined, washed with brine, dried (Na2SCri). vacuum filtered, and evaporated under vacuum. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-10% MeOEl-CEECE) afforded benzyl ((//)- 1 -(((S)- 1 -((4-6V-

((benzy loxy)carbony l)carbamimidoy l)benzy l)amino)- 1 -oxopropan-2-y l)amino)- 1 -oxo-4- phenylbutan-2-yl)(4-(4-(methylsulfonyl)piperazin-l-yl)benzyl )carbamate.

Step 6: Deprotection of benzyl ((//)- 1 -(((S)- 1 -((4-6V- ((benzy loxy)carbony l)carbamimidoy l)benzy l)amino)- 1 -oxopropan-2-y l)amino)- 1 -oxo-4- pheny lbutan-2-y l)(4-(4-(methy lsulfony l)piperazin- 1 -y l)benzy l)carbamate according to the procedure for compound 1130, step 3. Purification by reverse phase HPLC (5-75-90% MeCN-EEO) afforded (R)-N-((S)- 1 -((4-carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-2- ((4-(4-(methy lsulfony l)piperazin- 1 -yl)benzyl)amino)-4-phenylbutanamide di-trifluoroacetate salt. Example 54. Preparation of (7?)-2-amino-iV-((A)-l-((4-carbamimidoyl-2- methoxybenzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Di-trifluoroacetate salt (1251)

Step 7: A dry round bottom flask was charged with 4-(hydroxymethyl)-3- methoxybenzonitrile (950 mg, 5.8 mmol), CBn (2.12 g, 6.4 mmol) and CH2CI2 (20 mL), then cooled to 0 °C. PPI13 (1.68 g, 6.4 mmol) was added and the reaction mixture stirred for 2 h at ambient temperature. Upon completion, the reaction mixture was concentrated and then purified by chromatography (40% EtOAc-hexanes) to furnish 4-(bromomethyl)-3- methoxybenzonitrile as a white powder (1.1 g, 85% yield).

Step 2: In a dry round bottom flask under Ar, NaH (60% in mineral oil; 508 mg, 12.7 mmol) was washed 3x with hexanes. Anhyd THF was added and the suspension cooled to 0 °C. A solution of 4-(bromomethyl)-3-methoxybenzonitrile (1.1 g, 4.88 mmol) was added followed by dropwise addition of di-/er/-butyl-iminodicarboxylate (1.38 g, 6.36 mmol) in THF. Reaction mixture was stirred for 16 h at ambient temperature then quenched with H2O. THF was removed in vacuo and the aqueous layer filtered through a fritted funnel. The crude product was recrystallized with hot EtOAc to furnish tert- butyl (/ -buto\ycarbonyl)(4- cyano-2-methoxybenzyl)carbamate as a white crystalline solid (1.11 g, 63% yield).

Step 3: A 100 mL round bottom flask was charged with tert- butyl (tert- butoxycarbonyl)(4-cyano-2-methoxybenzyl)carbamate (1.11 g, 3.07 mmol) and anhyd MeOH (10 mL), followed by hydroxylamine hydrochloride (1.07 g, 15.3 mmol) and DIEA (2.67 mL, 15.3 mmol). The reaction flask was equipped with a condenser and heated at reflux for 3 h. Upon cooling, the reaction mixture was then concentrated and the product precipitated with LLO. Crude product was collected by suction filtration, dissolved in CH2CI2, washed with brine and dried over Na2S04. Organic layers were collected and concentrated to furnish tert- butyl (/0-(/c _T /-buto _\Y carbonyl)(4-(N'-hydro _\Y carbamimidoyl)-2-metho _\ y benzyl (carbamate as a white powder (1.12 g, 93% yield)

Step 4: A 100 mL round bottom flask was charged with (E)-(tert- butoxycarbonyl)(4- (N'-hydroxycarbamimidoyl)-2-methoxybenzyl)carbamate (1.12 g, 2.83 mmol), AC2O (320 pL, 3.35 mmol) and AcOH (5 mL). The flask was evacuated and backfilled with Arthen charged with 10% Pd/C (cat.). The flask was again evacuated and backfilled with H2 and allowed to stir at ambient temperature for 16 h. Reaction mixture was filtered through a 0.2 pm syringe filter and concentrated in vacuo to give /e/7-butyl (/er/-butoxycarbonyl)(4- carbamimidoyl-2-methoxybenzyl)carbamate as a white solid (1.25 g, quant.)

Step 5: To a solution of (/er/-butoxycarbonyl)(4-carbamimidoyl-2- methoxybenzyl)carbamate (1.25 g, 2.83 mmol) in THF (7 mL) was added sat. aq NaHC03 (7 mL) and /V-(benzyloxycarbonyloxy)succinimide (741 mg, 3 mmol). The reaction mixture was stirred at ambient temperature for 16 h then diluted with EtOAc and washed with brine. The organic layer was dried over IVlgSOr and concentrated. The residue was then triturated with diethyl ether to provide /er/-butyl (4-(7V-((benzyloxy)carbonyl)carbamimidoyl)-2- methoxybenzyl)(/er/-butoxycarbonyl)carbamate as a white powder (704 mg, 48% yield).

Step 6: tert- Butyl (4-/7V-((benzyloxy)carbonyl)carbamimidoyl)-2- methoxybenzyl)(ter/-butoxycarbonyl)carbamate (103 mg, 0.2 mmol) was deprotected according to the procedure for compound 1015, step 4 to provide benzyl ((4-(aminomethyl)- 3-methoxyphenyl)(imino)methyl)carbamate hydrochloride as a mint-green powder (68 mg, 97% yield).

Steps 7-8 : Benzyl ((4-((fY)-2-((//)-2-amino-4- phenylbutanamido)propanamido)methyl)-3-methoxyphenyl)(imino) methyl)carbamate was synthesized according to steps 1-2 of the procedure for compound (1246) using the appropriate starting materials except the crude material was carried on without purification to the following step.

Step 9: Removal of the Cbz group of benzyl ((4-((fS')-2-((//)-2-amino-4- phenylbutanamido)propanamido)methyl)-3-methoxyphenyl)(imino) methyl)carbamate was carried out according to the procedure for compound 1028, step 6. The crude product was purified by reverse-phase HPLC (35-65% MeCN-fhO + TFA) and the fractions lyophilized to furnish the title compound as a white powder. Example 55. Preparation of (2/?,4V)-iV-((/V)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-4-(/ -tolyl)pyrrolidine-2-carboxamide Dihydrochloride (1252)

(: 2R,4S)-N-((S )- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-yl)-4-(/ tolyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1247).

Example 56. Preparation of (27?,4A ^, )-/V-((A ^, )-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpiperidine-2-carb oxamide

Dihydrochloride (1253)

Step 7: To a solution of ((K -2-((/er/-butoxycarbonyl)amino)-4-(4- (trifluoromethyl)phenyl)butanoyl)-L-alanine (100 mg, 0.266 mmol) in CH2CI2 (5 mL) was added NHS (1.1 equiv, 1.05 mmol) with stirring at room temp until dissolved. DCC (1.1 equiv, 1.05 mmol) was added and stirred for 1.0 h then 5-(aminomethyl)-6-methylpyridin-2- amine (0.319 mmol, 1.2 equiv.) was added with sonication and stirred overnight at room temp. The solution was filtered and evaporated to dryness. Flash chromatography (3% 7 N NFb in MeOFl/CFhCh) gave /er/-butyl (27?,45)-2-(((5)-l-(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpiperi dine- l-carboxy late (91 mg 69%) as a white solid.

Step 2: To te/7-butyl (27?,4 _< S)-2-((( _< S)-l-(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpiperi dine- l-carboxy late (84 mg,

0.169 mmol) was added a solution of MeOH-HCl (5.0 mL, 227 mg HCl/mL) with stirring at room temp while monitoring for the consumption of starting material. The solution was evaporated to dryness and MeOH (15 mL) was added and evaporated to dryness giving (2R,4S)-N-((S)- 1 -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2-yl)-4- phenylpiperidine-2-carboxamide as a white solid (80 mg, 100% yield).

Example 57. Preparation of (27?,4A ^, )-/V-((A')-l-((5-Chloro-2-hydroxybenzyl)ainino)-l- oxopropan-2-yl)-4-(«i-tolyl)pyrrolidine-2-carboxamide Hydrochloride (1254)

Step 7: (2/L4.Y)- 1 -(/c /-Butoxycarbonyl)-4-(/w-tolyl)pyrrolidine-2-carbonyl)-/.-ala nine was synthesized from 1 -(te/7-butyl) 2-methyl (7?)-4-oxopyrrolidine-l,2-dicarboxylate according to the procedure for compound (1247), step 1 to step 6.

Step 2: /e/V-Butyl (2RAS)-2-(((S)- 1 -((5-chloro-2-hydroxybenzyl)amino)- 1 -oxopropan- 2-yl)carbamoyl)-4-(m-tolyl)pyrrolidine-l-carboxylate (57 mg, 70% yield) was synthesized from (2RAS)- 1 -(/e/V-butoxy carbonyl )-4-(/n-tolyl)pynOlidine-2-carbonyl)-/,-alanine (60 mg, 0.16 mmol) according to the procedure for compound (1234), step 3.

Step 3: (2RAS)-NA(S)- 1 -((5-Chloro-2-hydroxybenzyl)amino)- 1 -oxopropan-2-yl)-4- (m-tolyl)pyrrolidine-2-carboxamide hydrochloride (50.7 mg, 90% yield) was synthesized from /er/-buty 1 (2/iAY)-2-(((.Y)- 1 -((5-chloro-2-hy droxy benzy l)amino)- 1 -oxopropan-2- yl)carbamoyl)-4-(m-tolyl)pyrrolidine-l-carboxylate (57 mg, 0.11 mmol) according to the procedure for compound (1304), step 8.

Example 58. Preparation of 2i?, S -/V-( S -l-(((6-Aminopyridin-3-yl)methyl)amino)-l- oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide Dihydrochloride (1255)

Step 7: To a solution of (2R SJ- 1 -(/cT/-buto\ycarbonyl)-4-phenylpyrrolidine-2- carboxylic acid (1 g, 3.4 mmol) in MeCN (25 mL) was added EDC (0.786 g, 4.1 mmol), HOBt (0.553 g, 4.1 mmol) and DIEA (3 mL, 17 mmol). The mixture was stirred at ambient temperature for 15 min then benzyl L-alanine hydrochloride (0.884 g, 4.1 mmol) was added. The mixture was stirred overnight then cone in vacuo. The residue was dissolved in EtOAc and washed with 0.5 M KHSCh, sat. NaHCCb 3x, brine and EhO, dried (Na ₂ S04) and cone in vacuo. Purification by chromatography (5-40% EtOAc-hexanes) gave ((2R,4S)-l-(tert- butoxycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine (1.05 g, 70% yield).

Boc Roc

Step 2: To a degassed solution of ((2R 4S)- 1 -(/e/7-butoxycarbonyl)-4- phenylpyrrolidine-2-carbonyl)-L-alanine (1.05 g, 2.3 mmol) in anhyd MeOH (20 mL) was added 10% Pd/C (0.30 g). The mixture was degassed then put under Eh atm. After stirring overnight at ambient temperature, the mixture was filtered (0.20 pm syringe filter) then cone in vacuo to give 0.825 g of ((2i?,4S -l-(/e/7-butoxycarbonyl)-4-phenylpynOlidine-2- carbonyl)-L-alanine which was used without further purification (0.825 g, 98% yield).

Step 3: ((2R SJ- 1 -(/c /-Butoxycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine was coupled to 5-(aminomethyl)pyridin-2-amine according to the procedure for compound (1243), step 1 to give /er/-butyl (2R Sj-2-((fSj- 1 -(((6-aminopyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate (150 mg, 73% yield).

Step 4 tert- Butyl (2R 4Sj-2-(((Sj- 1 -(((6-aminopyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate was deprotected according to the procedure for compound (1243), step 2 except that 5-6 N HC1-IPA was used to give (2R, 4S)-N-((S)- 1 -(((6-aminopyridin-3-yl)methyl)amino)- 1 -oxopropan-2-yl)-4- phenylpyrrolidine-2-carboxamide dihydrochloride (127 mg, 90% yield). Example 59. Preparation of (7?)-iV-(fV)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-2-(((6-hydroxynaphthalen-2-yl)methyl)amino)- 4-phenylbutanamide Di- trifluoroacetate salt (1256)

Step 7: Benzyl ((4-((( _< S)-2-((7?)-2-(((6-hydroxynaphthalen-2-yl)methyl)amino) -4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate was synthesized according to the procedure for compound 1130, step 2.

Step 2: Deprotection of benzyl ((4-((fY)-2-((//)-2-(((6-hydro\ynaphthalen-2- yl)methyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate according to the procedure for compound 1130, step 3. Purification by reverse phase HPLC (5-75-90% MeCN-fhO) afforded (R)-N-((S)- 1 -((4-carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-2- (((6-hydroxynaphthalen-2-yl)methyl)amino)-4-phenylbutanamide di-trifluoroacetate salt.

Example 60. Preparation of (27?,4A ^, )-/V-((A ^, )-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(«i-tolyl)pyrrolidine- 2-carboxamide

Dihydrochloride (1257)

Step 1 : (2i?,45 -l-(/er/-Butoxycarbonyl)-4-(m-tolyl)pyrrolidine-2-carboxylic acid was synthesized from 1 -(/er/-butyl) 2-methyl (7?)-4-oxopyrrolidine-l,2-dicarboxylate according to the procedures for compound (1247), step 1 to step 4.

Step 2: (2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-(m-tolyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304), step 7 to step 8.

Example 61. Preparation of Methyl (imino(4-(((A)-2-((2/?,4/?)-4-phenylpyrrolidine-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate (1258)

CH ₃ C0 ₂ H

Step 7: To a 0 °C solution of /e/V-butyl (4-carbamimidoylbenzyl)carbamate acetate salt (100 mg, 0.32 mmol) in CH2CI2 (8 mL, 0.04 M) was added DIEA (0.23 mL, 1.3 mmol), DMAP (6.3 mg, 0.05 mmol), and methyl chloroformate (0.03 mL, 0.36 mmol). After stirring for 16 h at room temp, the reaction was quenched by addition of sat. aq NaHCCh. The resulting mixture was extracted with CH2CI2, dried over anhyd Na2SCh. and cone under vacuum. The residue was purified by chromatography (0-100% EtOAc-hexanes) to give methyl ((4-(((/er/-butoxycarbonyl)amino)methyl)phenyl)(imino)methyl )carbamate (57 mg, 57% yield) as a white solid.

Step 2: Deprotection of ((4-(((/er/-butoxycarbonyl)amino)methyl)phenyl)

(imino)methyl)carbamate (121 mg, 0.39 mmol) was conducted according to the procedure for compound (1259), step 2 to give methyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (125 mg, 100% yield).

Step 3: Methyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (230 mg, 0.72 mmol) was coupled with ((2RAR)- 1 -(/e/ /-butoxycarbonyl)-4- phenylpyrrolidine-2-carbonyl (-/.-alanine according to the procedure for compound (1259), step 3 to give / - butyl (2RAR)-2-(((S)- 1 -((4-(N-

(methoxycarbonyl)carbamimidoyl)benzyl)amino)-l-oxopropan- 2-yl)carbamoyl)-4- phenylpyrrolidine-l-carboxylate (200 mg, 61% yield).

Step 4 Deprotection of /er/-butyl (2RAR)-2-(((S)- 1 -((4-/7V- (methoxycarbonyl)carbamimidoyl)benzyl)amino)-l-oxopropan-2-y l)carbamoyl)-4- phenylpyrrolidine-l-carboxylate (172 mg, 0.31 mmol) was conducted according to the procedure for compound (1259), step 4 to give methyl (imino(4-((fV)-2-((2//.4//)-4- phenylpyrrolidine-2-carboxamido)propanamido)methyl)phenyl)me thyl)carbamate (98 mg, 70% yield). Example 62. Preparation of Benzyl (imino(4-(((^)-2-((2i?,4i?)-4-phenylpyrrolidine-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate (1259)

CH ₃ C0 ₂ H

Step 7: To a solution of tert- butyl (4-carbamimidoylbenzyl)carbamate acetate salt (100 mg, 0.32 mmol) in DMF (3 mL, 0.1 M) was added DIEA (0.23 mL, 1.3 mmol) and benzyl chloroformate (30% in toluene, 0.31 mL, 0.65 mmol). After stirring for 16 h at room temperature, FLO was added and the solvents were removed under vacuum. The residue was partitioned with EtOAc and FLO. The organic layer was separated and washed with sat. aq NFLCl, FLO, NaHCCh. The organic layer was dried over anhyd Na2SCri and cone under vacuum. The residue was purified by chromatography (50-100% EtOAc-hexanes) to give benzyl ((4-(((/c /-butox> carbonyl)amino)methyl)phenyl)(imino)methyl (carbamate (77 mg, 62% yield) as a white solid.

Step 2: To a 0 °C solution of benzyl ((4 -(((tert- butoxycarbonyl)amino)methyl)phenyl)(imino)methyl)carbamate (66 mg, 0.17 mmol) in CH2CI2 (1.5 mL, 0.1 M) was added 20% TFA in CH2CI2 (1.5 mL). After stirring for 2 h at room temperature, the reaction mixture was concentrated to give benzyl ((4- (aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (48 mg, 100% yield).

Step 3: To a solution of ((2RAR)- 1 -(/e/7-butoxy carbonyl )-4-phenyl pyrrol idine-2- carbonyl)-Z-alanine (93 mg, 0.26 mmol) in CH2CI2 (5 mL, 0.05 M) was added NHS (33 mg, 0.28 mmol) with stirring at room temp until dissolved. DCC (59 mg, 0.28 mmol) was added and stirred for 1 h. The mixture was poured into a separatory funnel containing sat. aq NaHCCb (5 mL) and benzyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate

trifluoroacetate salt (123 mg, 0.31 mmol) and then shaken for 15 min. The organic layer was filtered through over a bed of anhyd NarSCri and evaporated to dryness. The residue was purified by chromatography (50-100% EtOAc-hexanes) to give tert- butyl (2RAR)-2-(((S)- \ - ((4-(7V-((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)- l -oxopropan-2-yl (carbamoyl )-4- phenylpyrrolidine-l-carboxylate (128 mg, 79% yield).

Step 4: To a suspension of te/7-butyl (2RAR)-2-(((S)- 1 -((4-/7V- ((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-l-oxopropan -2-yl)carbamoyl)-4- phenylpyrrolidine-l-carboxylate (128 mg, 0.2 mmol) in methanol (2 mL, 0.1 M), was added a solution of HCl/MeOH (2 mL, 227 mg HCl/mL). After stirring for 4 h at room temperature, the reaction mixture was concentrated. The residue was purified by chromatography (0-100% [5% 7 N ML in MeOH/CTLCLJ-CTLCh) to give benzyl (imino(4-(((.S')-2-((2/L4/f)-4- phenylpyrrolidine-2-carboxamido)propanamido)methyl)phenyl)me thyl)carbamate (60 mg, 56% yield).

Example 63. Preparation of Hexyl (imino(4-(((A)-2-((2i?,4i?)-4-phenylpyrrolidine-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate (1260)

CH ₃ C0 ₂ H

Step 7: To a 0 °C solution of /er/-butyl (4-carbamimidoylbenzyl)carbamate acetate salt (200 mg, 0.65 mmol) in CH2CI2 (8 mL, 0.08 M) was added DIEA (0.23 mL, 1.3 mmol). After stirring for 15 min at the same temperature, hexyl chloroformate (0.13 mL, 0.78 mmol) was added dropwise. After stirring for 1 h at the same temperature, the reaction was quenched by addition of H2O. The resulting mixture was extracted with CH2CI2, dried over anhyd Na2SCh. and cone under vacuum. The residue was purified by chromatography (0- 100% EtOAc-hexanes) to give tert- butyl (4-/7V-

((hexyloxy)carbonyl)carbamimidoyl)benzyl)carbamate (151 mg, 62% yield).

Step 2: Deprotection of /er/-butyl (4-(N-

((hexyloxy)carbonyl)carbamimidoyl)benzyl)carbamate (150 mg, 0.4 mmol) was conducted according to the procedure for compound (1259), step 2 to give hexyl ((4- (aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (155 mg, 100% yield).

Step 3: Hexyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (140 mg, 0.39 mmol) was coupled with ((2R.4R)- 1 -(/e/V-butoxy carbonyl )-4- phenylpyrrolidine-2-carbonyl (-/.-alanine according to the procedure for compound (1259), step 3 to give / -butyl (2RAR)-2-(((S)- 1 -((4-/7V-

((hexyloxy)carbonyl)carbamimidoyl)benzyl)amino)-l-oxoprop an-2-yl)carbamoyl)-4- phenylpyrrolidine-l-carboxylate (230 mg, 96% yield).

Step 4 To a 0 °C solution of /e/V-butyl (2RAR)-2-(((S)- 1 -((4-/7V- ((hexyloxy)carbonyl)carbamimidoyl)benzyl)amino)-l-oxopropan- 2-yl)carbamoyl)-4- phenylpyrrolidine-l-carboxylate (230 mg, 0.37 mmol) in CH2CI2 (3.5 mL, 0.11 M) was added 20% TFA in CH2CI2 (3.5 mL). After stirring for 3 h at room temp, the reaction mixture was concentrated. The residue was purified by chromatography (0-100% [5% 7 N NLb in MeOH/CLLCy-CLLCh) to give hexyl (imino(4-((fV)-2-((2//.4//)-4-phenylpyrrolidine-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate (131 mg, 68% yield).

Example 64. Preparation of ( R , is)-2-Amino-/V-((A)-l-(((6-aminopyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-5-phenylpent-4-enamide Dihydrochloride (1261)

Step 7: To a solution of ( R , £)-2-amino-5-phenylpent-4-enoic acid (0.97 g, 5.07 mmol) in THF (15 mL), di-te/7-butyl dicarbonate (1.1 g, 5.04 mmol) was added followed by a solution of NaHCCb (1.2 g, 14.3 mmol) in FLO (15 mL). The reaction mixture was cooled briefly over an ice bath and stirred for 1.5 h. Additional THF (10 mL) and sat. NaHCCb (1 mL) were added. The mixture was stirred overnight then EtOAc was added and the mixture acidified with 0.5 M KHSO4. The layers were separated, the aq layer was saturated with NaCl and extracted twice with EtOAc. The combined organics were washed with brine, dried (NaiSOr) and cone in vacuo to give (R /i. ^’ )-2-((/ -buto\y carbonyl )amino)-5-pheny lpent-4- enoic acid (1.53 g, quant yield).

Step 2: To a solution of (R £)-2-((/er/-butoxycarbonyl)amino)-5-phenylpent-4-enoic acid (1.53 g, 5.25 mmol) in anhyd MeCN (27 mL) under Ar was added DIEA (2.0 mL, 11.5 mmol). EDC (1.1 g, 5.7 mmol) and HOBt (0.79 g, 5.8 mmol) were added and the mixture was stirred for 35 min. Methyl L-alaninate hydrochloride (0.89 g, 6.4 mmol) was added and the reaction stirred overnight. The mixture was cone in vacuo and the residue was dissolved in EtOAc, washed with 0.5 M KHSCri 2x, EhO, then sat NaHCCb. The solution was dried (Na ₂ S04), cone in vacuo and purified by chromatography (0-35% EtOAc-hexanes) to give a sticky solid which was dissolved in MeCN-EEO and lyophilized. 1.3 g Of methyl ((RE)- 2- ((/cT/-buto\ycarbonyl)amino)-5-phenylpent-4-enoyl)-L-alanina te was isolated (66% yield).

Step 3: Methyl ((R A ^’ )-2-((/c /-butoxycarbonyl)amino)-5-phenylpent-4-enoyl)-L- alaninate was hydrolyzed according to the procedure for compound 1058 to give ((R,E)-2- ((/cT/-buto\ycarbonyl)amino)-5-phenylpent-4-enoyl)-L-alanine (484 mg, quant yield).

Step 4: ((i?,i?)-2-((ter/-Butoxycarbonyl)amino)-5-phenylpent-4-enoyl )-L-alanine was coupled to 5-(aminomethyl)pyridin-2-amine according to the procedure for compound (1243), step 1 to give /er/-butyl ((i?,£)-l-(((5 -l-(((6-aminopyridin-3-yl)methyl)amino)-l- oxopropan-2-yl)amino)-l -oxo-5 -phenylpent-4-en-2-yl)carbamate (116 mg, 91% yield).

Step 5: /e/V-Butyl ((// A ^’ )- 1 -(({Sj- 1 -(((6-aminopyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)amino)-l -oxo-5 -phenylpent-4-en-2-yl)carbamate was deprotected according to the procedure for compound (1255) to give (i?,£)-2-amino-/V-((S -l-(((6-aminopyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-5-phenylpent-4-enamide dihydrochloride (101 mg, 93% yield).

Example 65. Preparation of (2/?,4V)-iV-(fV)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-4-(3-methoxyphenyl)pyrrolidine-2-carboxamide Dihydrochloride (1262)

(: 2R,4S)-N-((S )- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-4-(3- methoxyphenyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1247).

Example 66. Preparation of Propyl (imino(4-((fV)-2-((2/?,4/?)-4-phenylpyrrolidine-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate (1263)

Step 7: /e/V-Butyl (4-/7V-(propoxycarbonyl)carbamimidoyl)benzyl)carbamate (108 mg, 50% yield) was synthesized from /e/V-butyl (4-carbamimidoylbenzyl)carbamate acetate salt (198 mg, 0.64 mmol) and propyl chloroformate according to the procedure for compound (1260), step 1.

Step 2: Deprotection of /er/-butyl (4-(N-( propox> carbony 1 )carbami mi doyl (benzyl )- carbamate (108 mg, 0.32 mmol) was conducted according to the procedure for compound (1259), step 2 to give propyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate

trifluoroacetate salt (112 mg, 100% yield).

Step 3: Propyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (125 mg, 0.32 mmol) was coupled with ((2R.4R)- 1 -(/e/ /-butoxycarbonyl)-4- phenylpyrrolidine-2-carbonyl (-/.-alanine according to the procedure for compound (1259), step 3 to give / - butyl (2RAR)-2-(((S)- 1 -oxo- 1 -((4-/7V- (propoxycarbonyl)carbamimidoyl)benzyl)amino)propan-2-yl)carb amoyl)-4- phenylpyrrolidine-l-carboxylate (176 mg, 95% yield).

Step 4 Deprotection of /er/-butyl (2RAR)-2-(((S)- 1 -oxo- 1 -((4-/77- (propoxycarbonyl)carbamimidoyl)benzyl)amino)propan-2-yl)carb amoyl)-4- phenylpyrrolidine-l-carboxylate (176 mg, 0.3 mmol) was conducted according to the procedure for compound (1260), step 4 to give propyl (imino(4-(((S)-2-((27?,47?)-4- phenylpyrrolidine-2-carboxamido)propanamido)methyl)phenyl)me thyl)carbamate (89 mg, 62% yield).

Example 67. Preparation of (2R,4R)-N-((S)~ 1

Acetoxycarbamimidoyl)benzyl)amino)-l-oxopropan-2-yl)-4-pheny lpyrrolidine-2- carboxamide (1264)

Step 7: To a solution of (2RAR)- 1 -(/c /-butoxy carbonyl )-4-phenyl pyrrol idine-2- carboxylic acid (1.0 g, 3.43 mmol) in MeCN (70 mL, 0.05 M) was added HOBt (577 mg,

3.77 mmol), DIEA (2.39 mL, 13.7 mmol), and EDC (585 mg, 3.77 mmol). After stirring for 30 min at room temperature, benzyl /.-alanine hydrochloride (814 mg, 3.77 mmol) was added and stirred for 16 h. The reaction mixture was cone and the residue was partitioned with EtOAc and 10% KHSCri solution. The organic layer was separated and washed with EhO and sat. aq NaHCCh. The organic layer was dried over anhyd Na ₂ S04 and cone under vacuum to give the crude /er/-butyl (27?,47?)-2-(((5 -l-(benzyloxy)-l-oxopropan-2-yl)carbamoyl)-4- phenylpyrrolidine-l-carboxylate (1.33 g, 86% yield) which was used in the next step without further purification.

Step 2: A solution of the crude /er/-butyl (2RAR)-2-(((S)- 1 -(benzyloxy)- 1 -oxopropan- 2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate (1.55 g, 3.42 mmol) was degassed with a stream of Ar for 2 min. 10% Pd/C (70 mg) was added and a vacuum was pulled for 1 min. A balloon of Eh was added and the reaction was monitored for the consumption of starting material for 1.5 h. The catalyst was removed by filtration and the solution was evaporated to give ((2//.4//)- l -(/ -buto\y carbonyl )-4-phenyl pyrrol idine-2-carbonyl)-L-alanine (1.24 g, 100% yield).

Step 3: To a solution of ((2//.4//)- 1 -(/e/ /-butoxy carbonyl )-4-phenyl pyrrol idine-2- carbonyl)-Z-alanine (1.16 g, 3.2 mmol) in CH2CI2 (50 mL, 0.06 M) was added NHS (405 mg, 3.52 mmol) with stirring at room temp until dissolved. DCC (726 mg, 3.52 mmol) was added and stirred for 1 h. The mixture was poured into a separatory funnel containing sat. aq

NaHCCb (50 mL) and 4-(aminomethyl)benzonitrile hydrochloride (647 mg, 3.84 mmol) and then shaken for 15 min. The organic layer was filtered through over a bed of anhyd NaiSCri and evaporated to dryness. The residue was purified by chromatography (50-100% EtOAc- hexanes) to give /er/-butyl (2//.4//)-2-((fS - 1 -((4-cyanobenzyl)amino)- 1 -oxopropan-2- yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate (1.3 g, 85% yield) as a white solid.

Step 4: To a solution of /e/7-butyl (2//.4//)-2-((fS - 1 -((4-cyanobenzyl)amino)- 1 - oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate (870 mg, 1.83 mmol) in MeOH (20 mL, 0.09 mmol) was added hydroxylamine hydrochloride (507 mg, 7.3 mmol) and DIEA (1.27 mL, 7.3 mmol). After stirring for 4 h at reflux, the reaction mixture was evaporated to dryness. The residue was purified by chromatography (0-100% EtOAc- hexanes) to give /er/-butyl (2RAR)-2-(((S)- 1 -((4-((Z)-A'- hydroxycarbamimidoyl)benzyl)amino)-l-oxopropan-2-yl)carbamoy l)-4-phenylpyrrolidine-l- carboxylate (670 mg, 72% yield).

Step 5: To a suspension of /e/V-butyl (2i?,4i?)-2-(((S)-l-((4-((Z)-iV- hydroxycarbamimidoyl)benzyl)amino)-l-oxopropan-2-yl)carbamoy l)-4-phenylpyrrolidine-l- carboxylate (239 mg, 0.47 mmol) in acetic acid (5 mL) was added acetic anhydride (1 mL). After stirring for 17 h at room temperature, the reaction mixture was coned. The residue was purified by chromatography (0-100% EtOAc-hexanes) to give /e/V-butyl (2RAR)-2-(((S)- \ - ((4-((Z)-/V-acetoxy carbamimidoyl (benzyl )amino)- l -oxopropan-2-yl)carbamoyl)-4- phenylpyrrolidine-l -carboxylate (180 mg, 70% yield).

Step 6: A solution of /e/V-butyl (2RAR)-2-(((S)- 1 -((4-((Z)-/V- acetoxy carbamimidoyl)benzyl)amino)- 1 -oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine- 1 - carboxylate (180 mg, 0.33 mmol) in EtOAc (1.5 mL) and CH2CI2 (1.5 mL) was cooled in an ice bath. Hydrogen chloride was bubbled through the solution for approximately 1 min. White foam was isolated by filtration and purified by chromatography (0-100% 5% 7 N NH3 in MeOH/ CH2CI2-CH2CI2) to give (2RAR)-N-((S)- 1 -((4-((Z)-A- acetoxycarbamimidoyl)benzyl)amino)-l-oxopropan-2-yl)-4-pheny lpynOlidine-2- carboxamide (62 mg, 42% yield).

Example 68. Preparation of (2i?,4i?)-/V-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide

Dihydrochloride (1265)

Step 7: To a solution of ((2//.4//)- 1 -(/cT/-buto\y carbonyl )-4-phenyl pyrrol idine-2- carbonyl)-L-alanine (93 mg, 0.26 mmol, prepared according to the procedure for compound (1255) in CH2CI2 (5 mL) was added NHS (33 mg, 0.28 mmol). The mixture was stirred for 70 min then DCC was added. After stirring for 70 min, 5-(aminomethyl)-6-methylpyridin-2- amine (47 mg, 0.34 mmol) was added. The mixture was stirred for 3 h then cone in vacuo to a smaller volume, filtered through a cotton plug and rinsed with 5% EtOAC-CEECh. The filtrate was cone in vacuo then purified by chromatography (0-10% MeOH-CEhCh) to give /e/V-butyl (2RAR)-2-(((S)- 1 -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate (93 mg, 75% yield).

Step 2: te/7-Butyl (2RAR)-2-(((S)- 1 -(((6-amino-2-methylpyri din-3-yl (methyl )amino)-

1-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxy late was deprotected according to the procedure for compound (1255). The lyophilized solid was dissolved in MeOH, treated with Darco® charcoal (10 mg), warmed, then cooled to ambient temperature and filtered (0.20 pm syringe filter). The filtrate was cone in vacuo to give (2RAR)-N-((S)- 1 -(((6-amino-

2-methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)-4-ph enylpyrrolidine-2-carboxamide (81.8 mg, 93% yield). Example 69. Preparation of (/?)-2-Amino-iV-((iV)-l-(((6-amino-5-methoxypyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1266)

(R) -2- Amino-/V-((S - 1 -(((6-amino-5 -methoxy pyridin-3-y l)methy l)amino)- 1 - oxopropan-2-yl)-4-phenylbutanamide dihydrochloride was synthesized according to the procedure for compound (1243).

Example 70. Preparation of (/?)-2-amino-iV-((iV)- l-(((6-amino-5-fluoropyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1267)

(¾)-2-Amino-/V-((5 -l-(((6-amino-5-fluoropyridin-3-yl)methyl)amino)-l-oxopropan -

2-yl)-4-phenylbutanamide dihydrochloride was synthesized according to the procedure for compound (1243).

Example 71. Preparation of 4-((((i?)-l-(((A)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)amino)-l-oxo-4-phenylbutan-2-yl)amino)methyl) benzamide Di- trifluoroacetate salt (1268)

Step 1 : Benzyl ((4-((( _< S)-2-((i?)-2-((4-carbamoylbenzyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate was synthesized according to the procedure for compound 1130, step 2.

Step 2: Deprotection of benzyl ((4-(((S)-2-((i?)-2-((4-carbamoylbenzyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate according to the procedure for compound 1130, step 3. Purification by reverse phase HPLC (5-75-90% MeCN-tBO) afforded 4-((((i?)- 1 -(((5)- 1 -((4-carbamimidoy lbenzy l)amino)- 1 -oxopropan-2- yl)amino)- 1 -oxo-4-phenylbutan-2-yl)amino)methyl)benzamide di-trifluoroacetate salt.

Example 72. Preparation of (2i?,4i?)-iV-((A)-l-((2-Acetamido-5-chlorobenzyl)amino)-l- oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide Hydrochloride (1269)

Step 1: /C /-Butyl (2RAR)-2-(((S)- 1 -((2-amino-5-chlorobenzyl)amino)- 1 -oxopropan- 2-yl)carbamoyl)-4-phenylpyrrobdine-l-carboxylate was synthesized according to the procedure for compound 1119, step 3 using the appropriate starting materials.

Steps 2-3 : tert- Butyl (2i?,4i?)-2-(((5)-l-((2-amino-5-chlorobenzyl)amino)-l- oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate (30 mg, 0.06 mmol) was dissolved in CH2CI2 (1 mL) and treated with AC2O (28 pL, 0.3 mmol) and Et ₃ N (42 pL, 0.06 mmol) then stirred for 6 h at ambient temperature. The reaction mixture was diluted with CH2CI2 and washed with 10% aq KHSO4, brine and sat. aq NaHCCb. The organic layer was dried over NaiSCri and concentrated, then the residue purified by chromatography (80-95% EtOAc-hexanes) to furnish tert- butyl (2RAR)-2-(((S)- 1 -((2-acetamido-5- chlorobenzyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpyrr olidine-l-carboxylate as a colorless oil. Removal of the Boc protecting group was achieved upon treatment with 3 M HC1 in iPrOH overnight at ambient temperature. Removal of iPrOH and lyophilization in a mixture of 1 : 1 ACN/H2O gave the title compound as a white powder (15.9 mg, 52% yield over 2 steps).

Example 73. Preparation of (/?)-2-Amino-iV-((A)- l-(((6-carbamimidoylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Di-trifluoroacetate salt (1270)

(i?)-2-Amino-/V-(( _< S)-l-(((6-carbamimidoylpyridin-3-yl)methyl)amino)-l-ox opropan- 2-yl)-4-phenylbutanamide di-trifluoroacetate salt was synthesized according to the procedures for compound 1119 except using benzyl ((5-(aminomethyl)pyridin-2- yl)(imino)methyl)carbamate (PCT Int. Appl, 2001087854, 22 Nov 2001) in step 3.

Purification was achieved by using the procedure for compound 1032.

Example 74. Preparation of (2/?,4A)-iV-((A)- l-(benzylamino)- l-oxopropan-2-yl)-4- phenylpiperidine-2-carboxamide Dihydrochloride (1271)

(: 2R,4S)-N-((S )- 1 -(Benzy lamino)- 1 -oxopropan-2-y l)-4-pheny lpiperidine-2- carboxamide was synthesized according to the procedures for compound (1230), except using benzyl amine in step 3. Example 75. Preparation of (2/?,-//?)-iV-((iV)- l-(((6-Carbamimidoylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide Di- trifluoroacetate (1272)

(2R, 4R)-N-((S)-\ -(((6-Carbamimidoylpyridin-3-yl)methyl)amino)-l -oxopropan-2-yl)-

4-phenylpyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound 1119 except using (2R 4R)- 1 -(/e/ /-butoxycarbonyl)-4- phenylpyrrolidine-2-carboxylic acid in step 1 and benzyl ((5-(aminomethyl)pyridin-2- yl)(imino)methyl)carbamate in step 3. Purification was achieved by using the procedure for compound 1032.

Example 76. Preparation of 5-((fV)-2-((2/?,4/?)-4-Phenylpyrrolidine-2- carboxamido)propanamido)methyl)picolinamide Dihydrochloride (1273)

5-(((L')-2-((2/ί.4/ί)-4- Phenyl pyrrolidine-2- carboxamido)propanamido)methyl)picobnamide was isolated as a byproduct in the synthesis of (1272).

Example 77. Preparation of (2i?,4i?)-/V-((A)-l-((5-chloro-2- (methylsulfonamido)benzyl)amino)-l-oxopropan-2-yl)-4-phenylp yrrolidine-2- carboxamide, hydrochloride (1274)

Step 7: tert- Butyl (27?,47?)-2-((( _< S)-l-((2-amino-5-chlorobenzyl)amino)-l-oxopropan- 2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate (30 mg, 0.06 mmol) (as synthesize in Step 1 for compound (1269)) was dissolved in CH2CI2 (1 mL) and treated with MsCl (7 pL, 0.09 mmol) and EbN (25 pL, 0.18 mmol), then stirred for 16 h at ambient temperature. The reaction mixture was diluted with CH2CI2 and washed with 10% aq KHSO4, brine and sat. aq NaHCCb. The organic layer was dried over Na2SCri and concentrated, then the residue purified by chromatography (80-90% EtO Ac/hexanes) to furnish tert- butyl (27?,47?)-2-(((ri)-l- ((5-chloro-2-(methylsulfonamido)benzyl)amino)-l-oxopropan-2- yl)carbamoyl)-4- phenylpyrrolidine-l-carboxylate as a colorless oil. Removal of the Boc protecting group was achieved upon treatment with 3 M HC1 in iPrOH overnight at ambient temperature. Removal of iPrOH and lyophilization in a mixture of 1 : 1 ACN/H2O gave the title compound as a pink- tinged fluffy solid (1.9 mg, 6% yield over 2 steps). Example 78. Preparation of (i?)-2-Amino-iV-((A)-l-(((6-amino-5-chloropyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1275)

(¾)-2-Amino-/V-((5 -l-(((6-amino-5-chloropyridin-3-yl)methyl)amino)-l-oxopropan - 2-yl)-4-phenylbutanamide dihydrochloride was synthesized according to the procedure for compound (1243).

Example 79. Preparation of (2/?,4V)-iV-((V)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-4-(3-(trifluoromethyl)phenyl)pyrrolidine-2-c arboxamide

Dihydrochloride (1276)

(: 2R,4S)-N-((S )- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-4-(3- (trifluoromethyl)phenyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1247).

Example 80. Preparation of (2i?,4A)-4-(3-(Aminomethyl)phenyl)-iV-((A)-l-((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-ca rboxamide

Trihydrochloride (1277)

(2i?,4ri)-4-(3-(Aminomethy l)pheny l)-/V-((»S)- 1 -((4-carbamimidoy lbenzy l)amino)- 1 - oxopropan-2-yl)pyrrolidine-2-carboxamide trihydrochloride was synthesized according to the procedures for compound (1247).

Example 81. Preparation of (2 i,4 _» S)-/V-((>S)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-4-(3-cyanophenyl)pyrrolidine-2-carboxamide Dihydrochloride (1278)

(: 2R,4S)-N-((S )- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-4-(3- cyanophenyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1247). Example 82. Preparation of (/?)-2-amino-iV-(fV)- l-((5-bromo-2-hydroxybenzyl)amino)- l-oxopropan-2-yl)-4-phenylbutanamide, hydrochloride (1279)

Steps 1-2 : (//)-2-amino-V-(fV)- 1 -((5-bromo-2-hydro\ybenzyl)amino)- 1 -oxopropan-2- yl)-4-phenylbutanamide, hydrochloride was synthesized as a white fluffy powder according to steps 1-2 of the procedure for compound (1246) using the appropriate starting materials (31.4 mg, 44% yield over two steps). Example 83. Preparation of (7?)-2-Amino-iV-((iV)-l-(((6-(aminomethyl)pyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1280)

Step 7: To a suspension of 6-(aminomethyl)nicotinonitrile (2.05 g, 9.95 mmol) in THF (50 mL) was added sat. NaHCCb (50 mL). The mixture was stirred 30 min then benzyl chloroformate (1.6 mL, 11.3 mmol) was added. After stirring vigorously for 2 h, the mixture was diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organics were washed with brine, dried (NarSOr) and cone in vacuo. The crude material was crystallized from warm hexanes-Et20. The solid was collected by filtration, rinsed with Et20-hexanes and -10% EtOAc-hexanes and air dried to give benzyl ((5-cyanopyridin-2-yl)methyl)carbamate (805 mg, 30% yield).

Step 2: To a solution of benzyl ((5-cyanopyridin-2-yl)methyl)carbamate (0.80 g, 2.99 mmol) in MeOH (50 mL) was added NiCh (0.43 g, 3.29 mmol) and di-te/7-butyl dicarbonate (2.05 g, 9.4 mmol). The mixture was cooled over an ice bath and NaBEL (0.445 g, 11.8 mmol) was added in two aliquots over 10 min. The reaction was allowed to warm to ambient temperature, stirred overnight, then cone in vacuo. The residue was dissolved in EtOAc and 0.5 M KHSO4. The layers were separated, and the aqueous layer was adjusted to pH 10 with sat. NaHC03 and 2 M NaOH. After extraction with EtOAc, the combined organics were washed with H2O and dilute aqueous NH4OH solution containing brine. The solution was dried (Na2S04) and cone in vacuo. Purification by chromatography (10-80% EtOAc-hexanes) provided benzyl ((5-(((/cT/-buto\ycarbonyl)amino)methyl)pyridin-2-yl (methyl (carbamate (527 mg, 47% yield).

Step 3: To a solution of benzyl ((5-(((/er/-butoxycarbonyl)amino)methyl)pyridin-2- yl)methyl)carbamate (527 mg, 1.42 mmol) in MeOH (10 mL) was added 3 M HC1-CPME (10 mL). After stirring for 3 h, EtOAc was added to the slurry. The solid was collected by filtration, rinsed with EtOAc and hexanes and dried to give benzyl ((5-(aminomethyl)pyridin- 2-yl)methyl)carbamate dihydrochloride (412 mg, 94% yield).

Step 4: To a solution of ((K)-2-((/e/7-butoxycarbonyl)amino)-4-phenylbutanoyl)-L- alanine (122 mg, 0.35 mmol) and NHS (44 mg, 0.38 mmol) in CH2CI2 (8 mL) was added DCC (77 mg, 0.37 mmol) and the mixture was stirred for 1 h. In a separate vial, benzyl ((5- (aminomethyl)pyridin-2-yl)methyl)carbamate dihydrochloride (140 mg, 0.45 mmol) was treated with CH2CI2 (2 mL) and sat. NaHCCh (2.5 mL). This biphasic mixture was added to the reaction and stirred for 70 min. The layers were separated then the organic layers washed with H2O and brine, then dried (Na2S04) and cone in vacuo. Purification by chromatography (50-100%) EtOAc gave te/7-butyl ((¾)-l-(((S -l-(((6-

((((benzyloxy)carbonyl)amino)methyl)pyridin-3-yl)methyl)a mino)-l-oxopropan-2-yl)amino)- l-oxo-4-phenylbutan-2-yl)carbamate (113 mg, 54% yield).

Step 5: te/7-Butyl ((¾)-l-(((S)-l-(((6-((((benzyloxy)carbonyl)amino)methyl)pyr i din-3 - yl)methyl)amino)-l-oxopropan-2-yl)amino)-l-oxo-4-phenylbutan -2-yl)carbamate was deprotected with 3 M HC1-CPME according to the procedure for (1315), except that the reaction mixture was cone in vacuo to give benzyl ((5-(((S)-2-((R)-2-ammo-4- phenylbutanamido)propanamido)methyl)pyridin-2-yl)methyl)carb amate dihydrochloride.

Step 6: To a degassed solution benzyl ((5-(((S -2-((¾)-2-amino-4- phenylbutanamido)propanamido)methyl)pyridin-2-yl)methyl)carb amate from the previous step in MeOH (8 mL) was added 10% Pd/C (18 mg). The mixture was placed under fh atm and stirred at ambient temperature overnight. After degassing the mixture, 1 M HC1 (0.5 mL) was added then the slurry was filtered (0.2 pm syringe filter) and cone in vacuo. The residue was dissolved in H2O, washed with CH2CI2 3x then cone in vacuo. Dissolution of the residue in EtOAc-MeOH followed by cone in vacuo gave (R)-2-&rmno-N-((S)-\-(((6- (aminomethyl)pyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)-4- phenylbutanamide dihydrochloride as an off-white solid (88 mg, quant yield).

Example 84. Preparation of (2R, 4R)-N-((2S)-l-(((2- Amino-4, 5,6,7- tetrahydrobenzo[i/|thiazol-6-yl)methyl)amino)-l-oxopropan-2- yl)-4-phenylpyrrolidine- 2-carboxamide Di-trifluoroacetate salt (1281)

Step 7: To a 25-mL round bottom flask, commercially available 7V-((4- oxocyclohexyl)methyl)acetamide (467.0 mg, 2.76 mmol) was added and followed by CH2CI2 (5 mL). After purging with N2, a solution of Br2 (140 pL, 2.73 mmol) in CH2CI2 (10 mL) was added dropwise at room temp by a syringe pump at the rate of 0.317 mL per min. After the addition, the reaction was heated to reflux for 1 h. Volatiles was evaporated under vacuum to afford the crude 7V-((3-bromo-4-oxocyclohexyl)methyl)acetamide.

Step 2: To a 25-mL round bottom flask, the crude A-((3-bromo-4- oxocyclohexyl)methyl)acetamide was added and followed by EtOH (8 mL) and thiourea at room temp. After purging with N ₂ , the reaction was heated to reflux for 2 h. Volatiles was evaporated under vacuum. The crude product was diluted with water (10 mL) and followed by slow addition of 1M NaOH solution to become basic (pH about 13). The basic solution was extracted with 15 mL EtOAc (3 times). The organic layers were combined, washed with brine, dried (NaiSCri). vacuum filtered, and evaporated under vacuum. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-15% MeOH-CTHCh) gave /V-((2-amino-4.5.6.7-tetrahydrobenzo|6/|thiazol-6-yl (methyl (acetamide (48.5 mg, 8% yield).

Step 3: To a 25-mL round bottom flask, /V-((2-amino-4, 5,6,7- tetrahydrobenzo[ri]thiazol-6-yl)methyl)acetamide (48.5 mg, 0.213 mmol) was added and followed by the addition of commercially available aqueous HBr solution (2 mL, 48% in water). After purging with N ₂ , the reaction was heated to reflux for 18 h. Volatiles was evaporated under vacuum to afford crude 6-(aminomethyl)-4, 5,6,7- tetrahydrobenzo[ri]thiazol-2-amine dihydrobromide salt.

Step 4 ((2RAR)- 1 -(/c /-Butoxycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine (69.0 mg, 0.190 mmol) was coupled with the crude 6-(aminomethyl)-4, 5,6,7- tetrahydrobenzo[ri]thiazol-2-amine dihydrobromide according to the procedure for compound 1116, step 1 to afford te/7-butyl (2RAR)-2-(((2S)- 1 -(((2-amino-4.5.6.7- tetrahy drobenzo|6/|thiazol-6-yl (methyl (ami no)- l -oxopropan-2-yl (carbamoyl )-4- phenylpyrrolidine-l-carboxylate (64.1 mg, 64% yield).

Step 5: Deprotection of te/7-butyl (2//.4//)-2-(((2L'(- 1 -(((2-amino-4.5.6.7- tetrahy drobenzo|6/|thiazol-6-yl (methyl (ami no)- l -oxopropan-2-y l)carbamo> l)-4- phenylpyrrolidine-l-carboxylate (64.1 mg, 0.121 mmol) was done according to the procedure for compound 1119, step 2. Purification by reverse phase HPLC (5-45-75-90% MeCN-H20) afforded (2i?,4i?)-A-((2S)-l-(((2-amino-4,5,6,7-tetrahydrobenzo[<7 ] ^' thiazol-6- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide di-trifluoroacetate salt (16.0 mg, 31% yield).

Example 85. Preparation of (2A,4i?)-ZV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-benzylpyrrolidine-2-car boxamide

Dihydrochloride (1282)

(2S.4R)-N-((S)- 1 -(((6-Ammo-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-benzylpyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304), steps 7 and 8 starting from commercially available (2S,4R)- 4-benzyl- 1 -(/er/-butoxy carbonyl)pyrrolidine-2-carboxylic acid.

Example 86. Preparation of (2/?,4/?)-iV-(fV)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-benzylpyrrolidine-2-car boxamide

Dihydrochloride (1283)

(: 2R,4R)-N-((S )- 1 -(((6- Amino-2-methy lpy ri din-3 -y l)methy l)amino)- 1 -oxopropan-2- yl)-4-benzylpyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304), steps 7 and 8 starting from commercially available (2//.4//)-4-benzyl- 1 -(/ -buto\ycarbonyl)pyrrolidine-2-carbo\ylic acid. Example 87. Preparation of (2/?,4/?)-4-Benzyl-iV-((/V)- l-((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-ca rboxamide Di- trifluoroacetate salt (1284)

(2//.4//)-4-Benzyl- _' V-(CS')- 1 -((4-carbamimidoylbenzyl)amino)- 1 -oxopropan-2- yl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1247), except that the final product was purified using reverse- phase HPLC.

Example 88. Preparation of (2 _t V,4/?)-4-Benzyl-iV-(fV)-l-((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-ca rboxamide

Dihydrochloride (1285)

(2.V.4/i)-4-Benzyl-/V-((.Y)- 1 -((4-carbamimidoylbenzyl)amino)- 1 -oxopropan-2- yl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1247).

Example 89. Preparation of fV)-iV-(l-((4-Carbamimidoylbenzyl)amino)- l-oxopiOpan-2- yl)-4-phenylthiazole-2-carboxamide Hydrochloride (1286)

( _< S)-/V-(l -((4-Carbamimidoylbenzyl)amino)- 1 -oxopropan-2-yl)-4-phenylthiazole-2- carboxamide hydrochloride was synthesized according to the procedures for compound (1234), except that a few drops of cone HC1 was added to the reaction mixture during the benzyl carbamate deprotection step. Example 90. Preparation of (7?)-2-amino-iV-(fV)-l-((5-Chloro-2-

(hydroxymethyl)benzyl)amino)-l-oxopropan-2-yl)-4-phenylbu tanamide Hydrochloride (1287)

Steps 1-2 : The title compound was synthesized as a white powder according to steps

1-2 of the procedure for compound (1246) using the appropriate starting materials (27.5 mg, 31% yield over two steps).

Example 91. Preparation of 2,2,2-Trichloroethyl (imino(4-((fV)-2-((2/?,4/?)-4- phenylpyrrolidine-2-carboxamido)propanamido)methyl)phenyl)me thyl)carbamate

(1288)

CH ₃ C0 ₂ H

Step 7: To a 0 °C solution of tert- butyl (4-carbamimidoylbenzyl)carbamate acetate salt (100 mg, 0.32 mmol) in DMF (2 mL, 0.16 M) was added trichloroethyl chloroformate (0.09 mL, 0.65 mmol) and Et ₃ N (0.18 mL, 1.29 mmol). After stirring for 1 h at the same temperature, the reaction was quenched by addition of H2O. The resulting mixture was extracted with EtOAc, dried over anhyd Na ₂ S04, and cone under vacuum. The residue was purified by chromatography (0-100% EtOAc-hexanes) to give /e/V-butyl (4-(2V-((2,2,2- trichloroethoxy)carbonyl)carbamimidoyl)benzyl)carbamate (82 mg, 60% yield).

Step 2: Deprotection of /e/V-butyl (4-(?V-((2,2,2- trichloroethoxy)carbonyl)carbamimidoyl)benzyl)carbamate (165 mg, 0.39 mmol) was conducted according to the procedure for compound (1259), step 2 to give 2,2,2- trichloroethyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (126 mg, 100% yield).

Step 3: 2,2,2-Trichloroethyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (170 mg, 0.39 mmol) was coupled with ((2R,4R)-\-(tert- buto\ycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-/.-alanine according to the procedure for compound (1259), step 3 to give 2,2,2-trichloroethyl (imino(4-((fV)-2-((2//.4//)-4- phenylpyrrolidine-2-carboxamido)propanamido)methyl)phenyl)me thyl)carbamate (180 mg, 83% yield).

Step 4 Deprotection of (imino(4-((fS')-2-((2//.4//)-4-phenylpyrrolidine-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate (180 mg, 0.27 mmol) was conducted according to the procedure for compound (1260), step 4 to give 2,2,2- trichloroethyl (imino(4-((CS')-2-((2//.4//)-4-phenyl pyrrol idine-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate (112 mg, 73% yield).

Example 92. Preparation of (i?)-2-Amino-iV-((A)-l-((4-carbamimidoylbenzyl)amino)-l- oxobutan-2-yl)-4-phenylbutanamide Dihydrochloride (1289)

(i?)-2-Amino-/V-(( _< S)-l-((4-carbamimidoylbenzyl)amino)-l-oxobutan-2-yl)-4 - phenylbutanamide dihydrochloride was synthesized using (S)-2-((lerl- butoxycarbonyl)amino)butanoic acid in step 1 according to the procedures for compound 1050. Example 93. Preparation of (2i?,4i?)-iV-((A)-l-((4-carbamimidoylbenzyl)amino)-l- oxobutan-2-yl)-4-phenylpyrrolidine-2-carboxamide Dihydrochloride (1290)

(: 2R,4R)-N-((S )- 1 -((4-carbamimidoy lbenzy l)amino)- 1 -oxobutan-2-y l)-4- phenylpyrrolidine-2-carboxamide was synthesized using fS')-2-((tert- butoxycarbonyl)amino)butanoic acid in step 1 and (2//.4//)- 1 -(/cT/-buto\ycarbonyl)-4- phenylpyrrolidine-2-carboxylic acid in step 3 according to the procedures for compound

1050. Example 94. Preparation of (21?,4A ^, )-/V-((A ^, )-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-(aminomethyl)phenyl) pyrrolidine-2- carboxamide Dihydrochloride (1291)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(3-(aminomethyl)phenyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1257).

Example 95. Preparation of (i?)-ZV-(4-(( )-ZV-Hydroxycarbamimidoyl)benzyl)-2-methyl- 4-oxo-4-((2/?,4/?)-4-phenylpyrrolidin-2-yl)butan amide (1292)

Deprotection of te/7-butyl (2i?,4i?)-2-(((ri -l-((4-((Z)-/V- hydroxycarbamimidoyl)benzyl)amino)-l-oxopropan-2-yl)carbamoy l)-4-phenylpyrrolidine-l- carboxylate (173 mg, 0.34 mmol) was conducted according to the procedure for compound (1260), step 4 to give (R)-N-(4-((Z)-N -hydroxy carbamimidoyl)benzyl)-2-methyl-4-oxo-4- ((2//.4//)-4-phenylpyrrolidin-2-yl)butan amide (103 mg, 71% yield). Example 96. Preparation of Isobutyl (imino(4-(((/V)-2-((2/?,4/?)-4-phenylpyrrolidine-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate (1293)

CH ₃ C0 ₂ H

Step 7: /er/-Butyl (4-/7V-(isobutoxycarbonyl)carbamimidoyl)benzyl)carbamate (145 mg, 64% yield) was synthesized from /er/-butyl (4-carbamimidoylbenzyl)carbamate acetate salt (200 mg, 0.65 mmol) and isobutyl chloroformate according to the procedure for compound (1288), step 1.

Step 2: Deprotection of /e/V-butyl (4-/7V-

(isobutoxycarbonyl)carbamimidoyl)benzyl)carbamate (145 mg, 0.42 mmol) was conducted according to the procedure for compound (1259), step 2 to give isobutyl ((4- (aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (150 mg, 100% yield).

Step 3: Isobutyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (150 mg, 0.42 mmol) was coupled with ((27?,47?)-l-(/er/-butoxycarbonyl)-4- phenylpyrrolidine-2-carbonyl)-/.-alanine according to the procedure for compound (1259), step 3 to give / -butyl (2RAR)-2-(((S)- 1 -((4-(N-

(isobutoxycarbonyl)carbamimidoyl)benzyl)amino)-l-oxopropa n-2-yl)carbamoyl)-4- phenylpyrrolidine-l-carboxylate (173 mg, 84% yield).

Step 4 Deprotection of /e/V-butyl (27?,47?)-2-(((S)-l-((4- ?V- (isobutoxycarbonyl)carbamimidoyl)benzyl)amino)-l-oxopropan-2 -yl)carbamoyl)-4- phenylpyrrobdine-l-carboxylate (173 mg, 0.29 mmol) was conducted according to the procedure for compound (1260), step 4 to give isobutyl (imino(4-(((5 -2-((27?,47?)-4- phenylpyrrobdine-2-carboxamido)propanamido)methyl)phenyl)met hyl)carbamate (111 mg, 77% yield).

Example 97. Preparation of Ethyl (imino(4-(((/V)-2-((2/?,4/?)-4-phenylpyrrolidine-2- carboxamido)propanamido)methyl)phenyl)methyl)carbamate (1294)

CH ₃ C0 ₂ H

Step 7: /e/V-Butyl (4-(7V-(ethoxycarbonyl)carbamimidoyl)benzyl)carbamate (142 mg, 68% yield) was synthesized from /e/V-butyl (4-carbamimidoylbenzyl)carbamate acetic acid (200 mg, 0.65 mmol) and ethyl chloroformate according to the procedure for compound (1288), step 1.

Step 2: Deprotection of tert- butyl (4-(N-

(ethoxycarbonyl)carbamimidoyl)benzyl)carbamate (142 mg, 0.44 mmol) was conducted according to the procedure compound (1259), step 2 to give ethyl ((4- (aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (148 mg, 100% yield).

Step 3: Ethyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (130 mg, 0.39 mmol) was coupled with ((2i?,4i?)-l-(/er/-butoxycarbonyl)-4- phenylpyrrolidine-2-carbonyl)-/.-alanine according to the procedure for compound (1259), step 3 to give / - butyl (2RAR)-2-(((S)- 1 -((4-(N-

(ethoxycarbonyl)carbamimidoyl)benzyl)amino)-l-oxopropan-2 -yl)carbamoyl)-4- phenylpyrrobdine-l-carboxylate (168 mg, 91% yield).

Step 4 Deprotection of tert- butyl (2RAR)-2-(((S)- 1 -((4-/7V- (ethoxycarbonyl)carbamimidoyl)benzyl)amino)-l-oxopropan-2-yl )carbamoyl)-4- phenylpyrrobdine-l-carboxylate (168 mg, 0.3 mmol) was conducted according to the procedure for compound (1260), step 4 to give ethyl (imino(4-(((ri)-2-((2i?,4i?)-4- phenylpyrrobdine-2-carboxamido)propanamido)methyl)phenyl)met hyl)carbamate (102 mg, 74% yield).

Example 98. Preparation of 0V)-iV-(l-((4-Carbamimidoylbenzyl)amino)- l-oxopropan-2- yl)-3-phenyl- l//-pyrazole-5-carboxamide (1295)

(S)-N-( 1 -((4-Carbamimidoylbenzyl)amino)- l -o\opropan-2-yl)-3-phenyl- l//-pyra/ole- 5-carboxamide was synthesized according to the procedures for compound (1234).

Example 99. Preparation of (7?)-2-Amino-iV-((iV)-l-(((2-aminopyridin-4- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1296)

Step 7: ((7 i-2-((/e/ /-Butoxy carbonyl )amino)-4-phenylbutanoyl)-L-alanine was coupled with 4-(aminomethyl)pyridin-2-amine according to the procedure for compound (1265) step 1, except that a small amount of sat. NaHCCb was added to the reaction mixture. Following extractive workup, purification by chromatography (0-10% MeOFl-CFkCk) gave tert- butyl ((R) - 1 -(((S) - 1 -(((2-aminopy ridin-4-yl)methy l)amino)- 1 -oxopropan-2-y l)amino)- 1 - oxo-4-phenylbutan-2-yl)carbamate (90 mg, 57% yield).

Step 2: /e/V-Butyl ((R)- 1 -(((S)- 1 -(((2-aminopyridin-4-yl)methyl)amino)- 1 -oxopropan- 2-yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate was deprotected according to the procedure for compound (1243) to give (//>2-amino-iV-(6S - 1 -(((2-aminopy ridin-4-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-phenylbutanamide dihydrochloride (85 mg, quant yield). Example 100. Preparation of (2i?, S)-/V-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(naphthalen-l-yl)piperi dine-2-carboxamide Dihydrochloride (1297)

(2R.4S)-N-((S)- 1 -(((6-Ammo-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(naphthalen-l-yl)piperidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1231) (9) (the third UV Active material eluting from the column in step 6 was carried forward) and compound (1253) steps 1 and 2.

Example 101. Preparation of (2i?,4i?)-/V-((A)-l-((5-chloro-2-hydroxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2- carboxamide

Hydrochloride (1298)

Step 7: A 100 mL round bottom flask was charged with AcOH (18 mL) and H2SO4 (2 mL), then cooled to 0 °C. Cl- _' V-(hydro\y methyl (acetamide (4.32 g, 35 mmol) and 4-chloro-2- methylphenol (5 g, 35 mmol) were added portionwise to the stirring acidic solution, then the reaction mixture allowed to warm to ambient temperature overnight. The reaction mixture was poured into ice-cold H2O then extracted with CH2CI2 x3. Combined organic layers were washed with brine, dried over Na2SCri and concentrated to produce a colorless oil. The intermediate was dissolved in EtOH (10 mL), treated with cone. HC1 (3 mL) and refluxed for 2 h. The resulting yellow suspension was then stored at -10 °C overnight and filtered with EtOH to yield 2-(aminomethyl)-4-chloro-6-methylphenol, hydrochloride as a white fluffy solid (1.67 g, 23% yield).

Steps 2-3 : The title compound was synthesized as a white powder according to steps 1-2 of the procedure for compound (1246) using the appropriate starting materials (36.7 mg,

25% yield over two steps).

Example 102. Preparation of (i?)-2-Amino-iV-((^)-l-((5-chloro-2-hydroxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Hydrochloride (1299)

Steps 1-2: The title compound was synthesized as a white granular solid according to steps 1-2 of the procedure for compound (1246) using the appropriate starting materials (65 mg, 59% yield over two steps).

Example 103. Preparation of (2i?,4i?)-iV-((A)-l-((4-Carbamimidoyl-3- fluorobenzyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2- carboxamide Di- trifluoroacetate salt (1300)

Step 7: To a solution of 4-(aminomethyl)-2-fluorobenzonitrile (986.0 mg, 6.57 mmol) in MeCN (5.5 mL) was added DIEA (1.2 mL, 6.89 mmol) and di-te/7-butyl dicarbonate (1.44 g, 6.60 mmol) at room temp. After purging with N ₂ , the reaction was stirred at room temp for 16 h. Volatiles was evaporated under vacuum. The crude product was diluted with EtOAc

(200mL) and washed with 10% KHSCri solution (100 mL, 2 times). The organic layer was washed with brine, dried (Na ₂ S04), vacuum filtered, and evaporated under vacuum. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-15% MeOEl-CEECh) afforded tert- butyl (4-cyano-3- fluorobenzyl)carbamate (1. l9g, 73% yield).

Step 2: Benzyl ((4-(aminomethyl)-2-fluorophenyl)(imino)methyl)carbamate hydrochloride was synthesized according to the procedure for compound 1251, steps 3-6.

Step 3: Benzyl ((2-fluoro-4-(((ri -2-((27?,47?)-4-phenylpyrrolidine-2- carboxamido)propanamido)methyl)phenyl)(imino)methyl)carbamat e was synthesized according to the procedure for compound (1281), steps 4-5.

Step 4 Deprotection of benzyl ((2-riuoro-4-((fV)-2-((2/ri4//)-4-phenylpyrrolidine-2- carboxamido)propanamido)methyl)phenyl)(imino)methyl)carbamat e according to the procedure for compound 1130, step 3. Purification by reverse phase HPLC (5-75-90% MeCN-EEO) afforded (2RAR)-N-((S)- 1 -((4-carbamimidoyl-3-nuorobenzyl)amino)- 1 - oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide di-trifluoroacetate salt.

Example 104. Preparation of (27?, 4i?)-7V-( A -l-(((5-Chloro-2-oxo-l, 2-dihydro pyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide Hydrochloride (1301)

(2RAR)-N-(fSj- 1 -(((5-Chloro-2-o\o- 1 2-dihydropyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide hydrochloride was synthesized according to the procedure given for compound (1296). Example 105. Preparation of (2/?,4V)-iV-(( _t V)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-4-(3-ethylphenyl)pyrrolidine-2-carboxamide Dihydrochloride (1302)

(: 2R,4S)-N-((S )- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-4-(3- ethylphenyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1247).

Example 106. Preparation of (2/?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-ethylphenyl)pyrrolid ine-2-carboxamide Dihydrochloride (1303)

The first four steps to synthesize (2R, 4ri)-/V-((ri -l-(((6-amino-2-methylpyri din-3 - yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-ethylphenyl)pyrrolid ine-2-carboxamide dihydrochloride was performed according to the procedures for compound (1257).

Example 107. Preparation of (2i?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-benzylpyrrolidine-2-car boxamide

Dihydrochloride (1304)

Step 7: To a stirred solution of 2-benzyl 1 -(te/7-butyl) (7?)-5-oxopyrrolidine-l,2- dicarboxylate (1.50 g, 4.70 mmol) in THF (31 mL) at -78 °C was slowly added lithium bis(trimethylsilyl)amide (5.17 mL, 5.17 mmol, 1 M in THF) under Ar atmosphere. After stirring for 1 h at -78 °C, benzyl bromide (0.653 mL, 5.65 mmol) was added and the stirring continued for an additional 2 h. The reaction mixture was quenched with sat. NH4CI solution and extracted with diethyl ether (3 x 60 mL). The combined extracts were dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by chromatography (EtOAc-hexanes) gave 2-benzyl 1 -(fe/7-butyl) (2//AY)-4-benzyl-5-o\opyrrolidine- 1.2- dicarboxylate (1.60 g, 83% yield).

Step 2: To a solution of 2-benzyl 1 -(te/7-butyl) (2//.4Y')-4-benzyl-5-oxopyrrolidine- l,2-dicarboxylate (1.60 g, 3.91 mmol) in THF (26 mL) at -78 °C was added lithium triethylborohydride solution (4.30 mL, 4.30 mmol, 1 M in THF) under Ar atmosphere. After 30 min, the reaction mixture was quenched with sat. NaHCCh solution (8.60 mL) and warmed to 0 °C. At 0 °C, 30% H2O2 (about 25 drops) was added and the reaction mixture was stirred at same temperature for 30 min. The organic volatiles were removed under vacuum and the aqueous layer was extracted with CH2CI2 (3 x 40 mL). The combined organic extracts were thoroughly dried using Na2SCri. filtered, concentrated to afford 2- benzyl 1 -(te/7-butyl) (2//AY)-4-benzyl-5-hydro\ypyrrolidine- 1.2-dicarbo\ylate (1.70 g crude) that was directly used in the next step without further purification.

Step 3: To a stirred solution of 2-benzyl 1 -(te/7-butyl) (27?,4 _< S)-4-benzyl-5- hydroxypyrrolidine-l,2-dicarboxylate (1.70 g crude) and triethylsilane (0.685 mL, 4.30 mmol) in CH2CI2 (20 mL) at -78 °C was drop wise added boron trifluoride diethyl etherate (0.531 mL, 4.30 mmol) under Ar atmosphere. After 30 min at same temperature additional triethylsilane (0.685 mL, 4.30 mmol) and boron trifluoride diethyl etherate (0.531 mL, 4.30 mmol) were added. After stirring for 2 h at -78 °C, the reaction mixture was quenched with sat. aqueous NaHCCh solution (10 mL) and extracted with CH2CI2 (3 x 40 mL). The combined extracts were dried over Na2S04, filtered and cone under vacuum. The residue was purified by chromatography (EtOAc-hexanes) to afford 2-benzyl l -(7cT/-butyl) (2RAS)-4- benzylpyrrolidine-l,2-dicarboxylate (1.00 g, 65% yield in two steps).

0 Boc O Boc

Step 4 A solution of 2-benzyl 1 -(/er/-butyl) (2//.4S')-4-benzylpyrrolidine- 1. 2- dicarboxylate (1.00 g, 2.53 mmol) in MeOH (20 mL) was bubbled with Ar gas for 5 minutes. 10% Pd/C (100 mg) was added to the reaction mixture and that was stirred under 1 atmosphere of H2 for 3 h. The reaction mixture was filtered (0.2 mM syringe filter) and the filtrate was concentrated under vacuum to give (2//.4S')-4-benzyl- 1 -(terl- butoxycarbonyl)pyrrolidine-2-carboxylic acid (700 mg, 91% yield).

Step 5: To a stirred solution of (/e/V-butoxy carbonyl )-/,-alanine (1.96 g, 10.38 mmol) in CH2CI2 (55 mL) was added NHS (1.25 g, 10.89 mmol) at room temperature. To the reaction mixture DCC (2.25 g 10.9 mmol) was added and the reaction mixture stirred for 1.0 h. 5-(Aminomethyl)-6-methylpyridin-2-amine was added to the reaction mixture and sonicated for 5 min. The 5-(aminomethyl)-6-methylpyridin-2-amine was completely dissolved and stirred the reaction mixture at ambient temperature for 1 h. The crude reaction mixture was filtered and cone under reduced pressure. The crude reaction mixture was purified by chromatography (MeOH/CEhCh) to afford tert- butyl (<S)-(l-(((6-amino-2- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)carbamate (2.35 g, 70% yield) as a white solid.

Step 6: To /e/V-butyl fV)-( I -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)carbamate (2.35 g, 7.62 mmol) was added a solution of MeOH-HCl (19 mL, 2 M) with stirring at ambient temperature while monitoring for the consumption of starting material (typically 1 h). The solution was evaporated to dryness and MeOH (50 mL) was added and evaporated to dryness to remove residual HC1 gas to give (S)-2- am i n 0 -¥-(( 6 - amino-2-methylpyridin-3-yl)methyl)propanamide hydrochloride (1.60 g, 90% yield) as an off white solid (hygroscopic).

Step 7: To a stirred solution of (2i?,45)-4-benzyl-l-(te/ -butoxycarbonyl)pyrrolidine- 2-carboxylic acid (100 mg, 0.33 mmol) in anhydrous DMF (3.3 mL) was added HOBt (50 mg, 0.36 mmol), DIEA (0.23 mL, 1.32 mmol) and EDC (69 mg, 0.36 mmol) at ambient temperature. The reaction mixture was stirred for 30 min at ambient temperature. (S)-2- Amino-'V-((6-amino-2-methylpyridin-3-yl)methyl)propan amide hydrochloride (97 mg, 0.396 mmol) was added to the reaction mixture and stirred overnight. The solution was evaporated to dryness and the residue was partitioned with EtOAc (20 mL) and 10% KHSCri (15 mL). The organic layer was separated and washed with sat. NaHCCh solution (20 ml), dried over anhydrous Na ₂ S04 and cone under vacuum. The crude reaction mixture was purified by chromatography using MeOH-CLLCk to afford tert- butyl (2RAS)-2-(((S)- 1 -(((6-amino-2- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl) -4-benzylpynOlidine-l- carboxylate (124 mg, 76% yield) as a white solid.

Step 8: To te/7-butyl (2i?,4 _< S)-2-((( _< S)-l-(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-benzylpyrroli dine-l -carboxylate (124 mg, 0.25 mmol) was added a solution of MeOH-HCl (2.0 mL, 2 M) with stirring at ambient temperature while monitoring for the consumption of starting material (30 min to lh). The solution was evaporated to dryness and MeOH (10 mL) was added and evaporated to dryness to remove residual HC1 gas to yield (2RAS)-N-((S)- 1 -(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-benzylpyrrolidine-2-car boxamide dihydrochloride (94 mg, 95% yield) as a white solid. Example 108. Preparation of 2,2,2-Trifluoroethyl (imino(4-(((A')-2-((27?,47?)-4- phenylpyrrolidine-2-carboxamido)propanamido)methyl)phenyl)me thyl)carbamate

(1305)

CH ₃ C0 ₂ H

Step 7: /e/V-Butyl (4-(7V-(ethoxycarbonyl)carbamimidoyl)benzyl)carbamate (139 mg, 57% yield) was synthesized from /e/V-butyl (4-carbamimidoylbenzyl)carbamate acetate salt (200 mg, 0.65 mmol) and trifluoroethyl chloroformate according to the procedure for compound (1288), step 1.

Step 2: Deprotection of /e/V-butyl (4-/7V-

(ethoxycarbonyl)carbamimidoyl)benzyl)carbamate (139 mg, 0.37 mmol) was conducted according to the procedure for compound (1259), step 2 to give 2,2,2-trifluoroethyl ((4- (aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (144 mg, 100% yield).

Step 3: 2,2,2-Trifluoroethyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate trifluoroacetate salt (144 mg, 0.37 mmol) was coupled with ((2R,4R)-\-(tert- buto\ycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-/.-alanine according to the procedure for compound (1259), step 3 to give /e/V-butyl (27?,47?)-2-(((5)-l-oxo-l-((4-(2V-((2,2,2- trifluoroethoxy)carbonyl)carbamimidoyl)benzyl)amino)propan-2 -yl)carbamoyl)-4- phenylpyrrolidine-l-carboxylate (168 mg, 88% yield).

Step 4 Deprotection of tert- butyl (2RAR)-2-(((S)- 1 -oxo- 1 -((4-6V-((2.2.2- trifluoroethoxy)carbonyl)carbamimidoyl)benzyl)amino)propan-2 -yl)carbamoyl)-4- phenylpyrrobdine-l-carboxylate (168 mg, 0.27 mmol) was conducted according to the procedure for compound (1260), step 4 to give 2,2,2-trifluoroethyl (imino(4-((fV)-2-((2// 4//)- 4-phenylpyrrobdine-2-carboxamido)propanamido)methyl)phenyl)m ethyl)carbamate (60 mg, 43% yield). Example 109. Preparation of (27?,4A ^, )-4-Benzyl-/V-((A')- 1 -((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-ca rboxamide

Dihydrochloride (1306)

(2/iAY)-4-Benzyl-/V-((.Y)- 1 -((4-carbamimidoylbenzyl)amino)- 1 -oxopropan-2- yl)pyrrobdine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304), step 1 to step 4 and compound (1247), step 5 to step 9.

Example 110. Preparation of (2/?,4 _t V)-4-Benzyl-iV-(fV)- l-((5-chloro-2-hydroxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-carboxami de Hydrochloride (1307)

Step 7: (2//AY)-4-Benzyl- 1 -(/e/V-butoxy carbonyl )pynOlidine-2-carboxylic acid was synthesized from 2-benzyl 1 -(/er/-butyl) (7?)-5-oxopyrrolidine-l,2-dicarboxylate according to the procedures for compound (1304), step 1 to step 4.

Step 2: /e/V-Butyl (2//AY)-4-benzyl-2-((fS')- 1 -(benzyloxy)- 1 -oxopropan-2- yl)carbamoyl)pyrrolidine-l-carboxylate (350 mg, 66% yield) was synthesized from (2RAS)- 4-benzyl- 1 -(/e/V-butoxy carbonyl )pynOlidine-2-carboxylic acid (350 mg, 1.14 mmol) according to the procedures for compound (1304), step 7.

Step 3: ((2//.4Y')-4-Benzyl- 1 -(/e/V-butoxy carbonyl )pynOlidine-2-carbonyl)-/,-alanine (254 mg, 90% yield) was synthesized from /er/-butyl (2//AS')-4-benzyl-2-((fY)- 1 - (benzyloxy)-l-oxopropan-2-yl)carbamoyl)pyrrolidine-l-carboxy late (350 mg, 0.75 mmol) according to the procedures for compound (1304), step 4.

Step 4 tert- Butyl (2R,4S)-4-benzyl-2-(((S)-l-((5-chloro-2-hydroxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)carbamoyl)pyrrolidine-l -carboxylate (66 mg, 70% yield) was synthesized from ((2i?,45 -4-benzyl-l-(ter/-butoxycarbonyl)pyrrolidine-2- carbonyl)- -alanine (67 mg, 0.18 mmol) according to the procedure for compound (1234), step 3.

Step 5 : (2RAS)-4-Ben/\\-N-((S)- 1 -((5-chloro-2-hy droxy-3 -methy lbenzy l)amino)- 1 - oxopropan-2-yl)pyrrolidine-2-carboxamide hydrochloride (41 mg, 80% yield) was synthesized from te/7-butyl (2R,4S)-4-benzyl-2-(((S)-l-((5-chloro-2-hydroxy-3- methy lbenzy l)amino)-l-oxopropan-2-yl)carbamoyl)pyrrolidine-l-carboxy late (66 mg, 0.12 mmol) according to the procedure for compound (1234), step 3.

Example 111. Preparation of (2/?,-//?)-iV-((iV)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpiperidine-2-carb oxamide

Dihydrochloride (1308)

(2R, 4R)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-phenylpiperidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1253). Example 112. Preparation of ?)-/V-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(naphthalen-l-yl)pipera zine-2-carboxamide Dihydrochloride (1309)

Step 7: To a stirred solution of 1 -(/er/-butyl) 2-methyl (K)-piperazine-l,2- dicarboxylate (2.0 g. 8.2 mmol) in CH2CI2 was added naphthalen-l-ylboronic acid (9.8 mmol, 1.2 equiv) and Cu(OAc)2 (500 mg) and stirring continued for 48 h under a balloon of air. The solution was washed with H2O, dried over Na2SCri and evaporated. Column chromatography (20% EtOAc-hexanes) gave 1 -(ter /-butyl) 2-methyl (K -4-(naphthalen-l- yl)piperazine-l,2-dicarboxylate (402 mg, 13 % yield) as an oil.

Step 2: To a stirred solution of l-(/er/-butyl) 2-methyl (K -4-(naphthalen-l- yl)piperazine-l,2-dicarboxylate (390 mg, 1.05 mmol) in MeOH-EhO was added LiOH (3.15 mmol, 3.0 equiv.) with heating at 60° C for 3 h. The solution is evaporated to dryness and H2O was added with swirling. The pH was adjusted to 5 with 10% KHSO4 and the product was collected by filtration, washed with H2O and dried. (R)- 1 -C/-cT/-buto\ycarbonyl)-4- (naphthalen-l-yl)piperazine-2-carboxylic acid was isolated (335 mg, 89% yield) as a tan solid.

Step 3: /er/-Butyl (R)-2-(((S)- 1 -(benzyloxy)- 1 -oxopropan-2-yl (carbamoyl )-4- (naphthalen-l-yl)piperazine-l-carboxylate was synthesized according to the procedure for compound (1230).

Steps 4-6 : (i?)-/V-((5)-5-(6-Amino-2-methylpyridin-3-yl)-3-oxopentan-2- yl)-4- (naphthalen-l-yl)piperazine-2-carboxamide was synthesized according to the procedures for compound (1253).

Example 113. Preparation of (2/?,4/?)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenoxypyrrolidine-2-ca rboxamide

Dihydrochloride (1310)

(: 2R,4R)-N-((S )- 1 -(((6- Amino-2-methy lpy ri din-3 -y l)methy l)amino)- 1 -oxopropan-2- yl)-4-phenoxypyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304). Example 114. Preparation of (2i?,4i?)-iV-((S)-l-(((l /-Pyrrolo[2,3-Z>]pyridin-5- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide

Dihydrochloride (1311)

Step 1 : (( 2R,4R )- 1 -(/er/-Butoxy carbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine was coupled to ( l //-py rrolo| 2.3-/? |pyridin-5-y l)methan amine according to the procedure given for compound (1265), step 1. Purification by chromatography (0-10% MeOH-CfhCh) gave / - butyl (2RAR)-2-((/Sj- 1 -((( 1 //-pyrrolo|2.3-6 |pyridin-5-yl)methyl)amino)- 1 - oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate (100 mg, 69% yield).

Step 2: /e/V-Butyl (2RAR)-2-((fSj- 1 -((( 1 //-pyrrolo| 2.3-6 |py ridin-5-yl (methyl )amino)- l-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylat e was deprotected according to the procedure given for compound (1243) to give (2RAR)-N-((S)- 1 -((( 1 //-pyrrol o| 2.3- Zi]pyridin-5-yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrr olidine-2-carboxamide dihydrochloride (89.9 mg, 95% yield). Example 115. Preparation of (7?)-iV-((A)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-2-((3-(3-hydroxyphenyl)propyl)amino)-4-pheny lbutanamide Di- trifluoroacetate salt (1312)

Step 1 : Benzyl ((4-(((5)-2-((i?)-2-((3-(3-hydroxyphenyl)propyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate was synthesized according to the procedure for compound 1130, step 2.

Step 2: Deprotection of benzyl ((4-((fV)-2-((//)-2-((3-(3- hydroxyphenyl)propyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate according to the procedure for compound 1130, step 3. Purification by reverse phase HPLC (5-45-90% MeCN-FLO) afforded (R)-N-((S)- 1 -((4-carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-2- ((3-(3-hydroxyphenyl)propyl)amino)-4-phenylbutanamide di-trifluoroacetate salt.

Example 116. Preparation of (2i?,5A)-5-Amino-/V-(5-chloro-2-cyanobenzyl)-2-methyl-4- oxo-7-phenylheptanamide Trifluoroacetate salt (1313)

Step 7: A dry 50 mL round botom flask was charged with NaH (60% in mineral oil) (246 mg, 6.16 mmol) and washed with hexanes 3x under Ar. Dry THF (5 mL) was then added and the suspension cooled to 0 °C. 2-(Bromomethyl)-4-chlorobenzonitrile (650 mg, 2.8 mmol) was dissolved in THF (5 mL) and added to the stirring suspension, followed by di- /e/V-butyl-iminodicarboxylate (679 mg, 3.1 mmol) in THF (5 mL) dropwise. The reaction mixture was allowed to warm to ambient temperature overnight, then quenched with H2O, poured into sat. aq NH4CI and extracted with EtOAc 2x. The combined organic layers were washed with brine and dried over Na2S04. The crude product was then loaded onto silica gel and purified by chromatography (0-30% EtO Ac/hexanes) to yield both di -to /-butyl (5- chloro-2-cyanobenzyl)iminodicarbonate (672 mg, 65% yield) and /e/7-butvl (5-chloro-2- cyanobenzyl)carbamate (158 mg, 21% yield).

Step 2: Di-/c /-butyl (5-chloro-2-cyanobenzyl)iminodi carbonate (110 mg, 0.3 mmol) was dissolved in CH2CI2 and treated with TFA (300 pL) at ambient temperature. After 2 hours, the reaction mixture was concentrated in vacuo to yield 2-(aminomethyl)-4- chlorobenzonitrile, trifluoroacetate as a white powder (79 mg, quant yield).

Step 3: /e/T-Butyl ((//)- 1 -((fV)- 1 -((5-chloro-2-cyanobenzyl)amino)- 1 -oxopropan-2- yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate was synthesized according to step 1 of the procedure for compound (1246) using the appropriate starting materials.

Step 4 /e/T-Butyl ((//)- 1 -((fV)- 1 -((5-chloro-2-cyanobenzyl)amino)- 1 -oxopropan-2- yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate (120 mg, 0.24 mmol) was dissolved in CH2CI2 (2 mL) and treated with TFA (-500 pL). After stirring at ambient temperature overnight, the reaction mixture was concentrated, taken up in ACN/H2O and lyophilized to yield the title compound as a white solid (17 mg, 14% yield over two steps).

Example 117. Preparation of (i?)-2-Amino-A-((A)-l-((5-cyano-2-hydroxybenzyl)amino)- l-oxopropan-2-yl)-4-phenylbutanamide Trifluoroacetate salt (1314)

Steps 1-2: The title compound was synthesized as a white solid according to steps 3-4 of the procedure for compound (1313) using the appropriate starting materials (17 mg, 17% yield over two steps). Example 118. Preparation of fV)-l-((4-Carbamimidoylbenzyl)amino)- l-oxopropan-2-yl (i?)-2-amino-4-phenylbutanoate Hydrochloride (1315)

Step 1: To a stirred solution of (i?)-2-((/er/-butoxycarbonyl)amino)-4-phenylbutanoic acid (838 mg, 3 mmol)), benzyl ( _< S)-lactate (507 pL, 3.15 mmol) and DMAP (403 mg, 3.3 mmol) in CH2CI2 (15 mL) was added DCC (681 mg, 3.3 mmol). The mixture was stirred for 18 h, then diluted with CH2CI2 and washed with 10% aq KHSO4, brine and sat. aq. NaHCCb. The organic layer was dried over Na2SCri and concentrated in vacuo. Chromatography (20% EtO Ac/hexanes) gave (S)- 1 -(benzyloxy)- 1 -oxopropan-2-yl (i?)-2-((tert- butoxycarbonyl)amino)-4-phenylbutanoate (1 g, 76% yield).

Step 2: Removal of the benzyl group of (S)- 1 -(benzyloxy)- 1 -oxopropan-2-yl (R)-2- ((tert-butoxycarbonyl)amino)-4-phenylbutanoate was carried out according to the procedure for compound 1028, step 6.

Steps 3-5: ( _< S -l -((4-Carbamimidoy lbenzy l)amino)-l-oxopropan-2-yl (i?)-2-amino-4- phenylbutanoate hydrochloride was synthesized as a white granular solid according to steps 3-5 of the procedure for compound 1119 using the appropriate starting materials.

Example 119. Preparation of (2/?,4V)-iV-((/V)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-4-(3-isopropylphenyl)pyrrolidine-2-carboxami de Dihydrochloride (1316)

(: 2R,4S)-N-((S )- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-4-(3- isopropylphenyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1247).

Example 120. Preparation of (7?)-iV-((iV)- l-((5-Chloro-2-hydroxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)-4-(naphthalen-l-yl)pip erazine-2-carboxamide Hydrochloride (1317)

(R)-N- (S)- 1 -((5-Chloro-2-hy droxy-3-methylbenzyl)amino)- 1 -oxopropan-2-yl)-4-

(naphthalen-l-yl)piperazine-2-carboxamide hydrochloride was synthesized according to the procedures for compound (1230), except using (R)- 1 -(/cT/-buto\ycarbonyl)-4-(naphthalen- 1 - yl)piperazine-2-carboxylic acid in step 1 and 2-(aminomethyl)-4-chloro-6-methylphenol in step 3. Example 121. Preparation of (2/?,4 _t V)-iV-(0V)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-(trifluoromethyl)ben zyl)pyrrolidine-2- carboxamide Dihydrochloride (1318)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304).

Example 122. Preparation of (7?)-iV-(fV)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-2-((3-(3-hydroxyphenyl)pr opyl)amino)-4- phenylbutanamide Dihydrochloride salt (1319)

Step 7: (7?)-2-((/er/-Butoxycarbonyl)amino)-4-phenylbutanoic acid (5.0 g, 17.9 mmol) was coupled with commercially available benzyl L-alaninate hydrochloride (4.8 g, 22.3 mmol) according to the procedure for compound 1119, step 1 to afford benzyl ((R)-2-((terl- butoxycarbonyl)amino)-4-phenylbutanoyl)-L-alaninate (6.9 g, 87% yield).

Step 2: Deprotection of benzyl ((7?)-2-((/er/-butoxycarbonyl)amino)-4- phenylbutanoyl)-L-alaninate (6.9 g, 15.7 mmol) ) according to the procedure for compound 1119, step 2 afforded ((//)-2-((/cT/-buto\y carbonyl )amino)-4-phenylbutanoyl)-L-alanine (5.3 g, 96% yield).

Step 3: ((7?)-2-((/er/-Butoxycarbonyl)amino)-4-phenylbutanoyl)-L-ala nine (470.0 mg, 1.34 mmol) was coupled with commercially available 5-(aminomethyl)-6-methylpyridin-2- amine (560.0 mg, 1.75 mmol) according to the procedure for compound 1088, step 2 except HBTU was added to the reaction at 0 °C afforded tert- butyl ((//)- 1 -(((S)- 1 -(((6-amino-2- methylpyri din-3 -yl)methyl)amino)-l-oxopropan-2-yl)amino)-l-oxo-4-phenylbuta n-2- yl)carbamate (181.6 mg, 29% yield).

Step 4 Deprotection of tert- butyl ((//)- 1 -(((S)- 1 -(((6-amino-2-methylpyridin-3- y l)methy l)amino)- 1 -oxopropan-2-y l)amino)- 1 -oxo-4-pheny lbutan-2-y l)carbamate (181.6 mg, 0.387 mmol) according to the procedure for compound 1119, step 4 afforded (//)-2-amino- V- ((S)- 1 -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- l -oxopropan-2-yl)-4- phenylbutanamide (115.7 mg, 81% yield).

Step 5 : (R)-2-Am\no-N-((S)- 1 -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-phenylbutanamide (115.7 mg, 0.313 mmol) was reacted with 3-(3- hydroxyphenyl)propanal (68.0 mg, 0.453 mmol) according to the procedure for compound 1130, step 2. The crude product was dissolved in CH2CI2 and adsorbed onto silica gel.

Purification by chromatography (0-15% MeOH-CThCh) afforded (R)-N-((S)- 1 -(((6-amino-2- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)-2-((3-(3- hydroxyphenyl)propyl)amino)-4-phenylbutanamide (42.3 mg, 27% yield).

Step 6: To a solution of R)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- l-oxopropan-2-yl)-2-((3-(3-hydroxyphenyl)propyl)amino)-4-phe nylbutanamide in MeOH (1 mL) was added HC1 in MeOH (0.5 mL, ca. 4 M). Volatile was evaporated under vacuum to afford (i?)-/V-((5)-l -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)-l -oxopropan-2-yl)-2- ((3-(3-hydroxyphenyl)propyl)amino)-4-phenylbutanamide dihydrochloride salt. Example 123. Preparation of (2i?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-5-oxo-4-(3-(trifluorometh yl)benzyl)pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1320)

(2RAS)-N-((S)- 1 -(((6-Ammo-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-5-oxo-4-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxa mide di-trifluoroacetate salt was synthesized according to the procedures for compound (1304) except that the final product was purified using reverse-phase HPLC.

Example 124. Preparation of (2i?,4A)-iV-((i?)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-5-oxo-4-(3-(trifluorometh yl)benzyl)pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1321)

(2RAS)-N-((R)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-5-oxo-4-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxa mide di-trifluoroacetate salt was synthesized according to the procedures for compound (1304), except that the final product was purified using reverse-phase HPLC.

Example 125. Preparation of (2i?,4i?)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenethylpyrrolidine-2- carboxamide

Dihydrochloride (1322)

(: 2R,4R)-N-((S )- 1 -(((6- Amino-2-methy lpy ri din-3 -y l)methy l)amino)- 1 -oxopropan-2- yl)-4-phenethylpyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1247).

Example 126. Preparation of (2i?,4i?)-/V-((A)-l-(((6-Amino-2-ethylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide

Dihydrochlorid

Step 7: To a solution of /e/V-butyl (5-cyano-6-ethylpyridin-2-yl)carbamate (370 mg, 1.5 mmol; synthesized according to US 5,668,289) in MeOH (5 mL) was added 7 M NTb- MeOH (25 mL). The solution was briefly degassed then Raney nickel (~0.3 g) was added. The reaction was put under Th atm and stirred 5.5 h. After reduction was complete, part of the mixture was filtered through diatomaceous earth. The remainder was filtered through paper. The combined filtrates were cone in vacuo. The residue was dissolved in 5% H2O- MeOH and filtered (0.2 pm syringe filter) then cone in vacuo to give /e/V-butyl (5- (aminomethyl)-6-ethylpyridin-2-yl)carbamate as a white solid (323 mg, 86% yield).

Step 2: ((27?, 47?)- 1 -(/er/-Butoxy carbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine was coupled to /er/-butyl (5-(aminomethyl)-6-ethylpyri din-2 -yl)carbamate according to the procedure for compound (1265), step 1 to give / -butyl (27?,47?)-2-((fS -l-(((6-amino-2- ethylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)- 4-phenylpyrrolidine-l- carboxylate (134 mg, 77% yield).

Step 3: te/7-Butyl (2RAR)-2-(((S)- 1 -(((6-amino-2-ethylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate was deprotected according to the procedure given for compound (1243), except that the product was not extracted with CH2CI2. The aqueous solution was filtered (0.2 pm syringe filter) then lyophilized to give (2R, R)-N-((S)- 1 -(((6-amino-2-ethylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2-yl)-4- phenylpyrrolidine-2-carboxamide dihydrochloride (114.9 mg, quant yield).

Example 127. Preparation of (2/?,4V)-iV-((/V)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(naphthalen-l-ylmethyl) pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1324)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(naphthalen-l-ylmethyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1304), except that the final product was purified using reverse-phase HPLC.

Example 128. Preparation of (l?)-2-amino-/V-((A ^, )-l-((5-chloro-2-(l//-tetrazol-l- yl)benzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide (1325)

Steps 1-2: The title compound was synthesized as a white solid according to steps 3-4 of the procedure for compound (1313) using the appropriate starting materials (42 mg, 38% yield over two steps).

Example 129. Preparation of (i?)-2-Amino-7V-((A)-l-((4-carbamimidoylbenzyl)amino)-3- (4-hydroxyphenyl)-l-oxopropan-2-yl)-4-phenylbutanamide Di-trifluoroacetate salt (1326)

Step 7: To a solution of Boc-79-homophenylalanine (300 mg, 1.07 mmol) in anhyd

DMF (6 mL, 0.18 M) was added HOBt (214 mg, 1.4 mmol), DIEA (0.75 mL, 4.3 mmol), and EDC (208 mg, 1.34 mmol). After stirring for 30 min at room temperature, /.-tyrosine methyl ester hydrochloride (354 mg, 1.29 mmol) was added and stirred for 16 h. The reaction mixture was cone and the residue was partitioned with EtOAc and 10% KHSCE solution. The organic layer was separated and washed with EhO and sat. aq NaHCCb. The organic layer was dried over anhyd NarSOr and coned. The residue was purified by chromatography (0- 100% EtOAc-hexanes) to give methyl ((i?)-2-((/e/7-butoxycarbonyl)amino)-4- phenylbutanoyl)-Z-tyrosinate (365 mg, 74% yield).

Step 2: To a solution of methyl ((i?)-2-((fer/-butoxycarbonyl)amino)-4- phenylbutanoyl)-/.-tyrosinate (365 mg, 0.8 mmol) in THF (6 mL) and H2O (6 mL) was added LiOH (38 mg, 1.6 mmol). After stirring for 4 h at room temperature, the reaction mixture was cone to remove THF. To the above mixture was added 10% KHSO4 solution, extracted with EtOAc, dried over anhyd Na ₂ S04, and cone under vacuum. The residue was purified by chromatography (0-100% [5% 7 N NH3 in MeOH/CTECbJ-CTHCh) to give ((R)-2-((/erl- buto\ycarbonyl)amino)-4-phenylbutanoyl (-/.-tyrosine (290 mg, 82% yield).

Step 3: To a solution of ((i?)-2-((/e/7-butoxycarbonyl)amino)-4-phenylbutanoyl)-Z- tyrosine (290 mg, 0.65 mmol) in CH2CI2 (18 mL, 0.04 M) was added NHS (83 mg, 0.72 mmol) with stirring at room temp until dissolved. DCC (148 mg, 0.72 mmol) was added and stirred for 1 h. Benzyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate (222 mg, 0.78 mmol) was added to the above mixture and stirred for 1 h. The reaction was quenched by addition of H2O and the resulting mixture was extracted with CH2CI2, dried over anhyd NarSCri. and cone under vacuum. The residue was purified by chromatography (0-100% EtOAc-hexanes) to give /er/-butyl ((//)- 1 -(((S)- 1 -((4-(N-

((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-3-(4-hyd roxyphenyl)-l-oxopropan-2- yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate (244 mg, 52% yield).

Step 4: Deprotection of /e/7-butyl ((//)- 1 -(((S)- 1 -((4-(N- ((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-3-(4-hydrox yphenyl)-l-oxopropan-2- yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate (244 mg, 0.34 mmol) was conducted according to the procedure for compound (1260), step 4 to give benzyl ((4-((fS')-2-((//)-2- amino-4-phenylbutanamido)-3-(4- hydroxyphenyl)propanamido)methyl)phenyl)(imino)methyl)carbam ate (126 mg, 61% yield).

Step 5: Deprotection of benzyl ((4-((fY)-2-((//)-2-amino-4-phenylbutanamido)-3-(4- hydroxyphenyl)propanamido)methyl)phenyl)(imino)methyl)carbam ate (126 mg, 0.21 mmol) was conducted according to the procedure for compound (1264), step 2 except that the crude material was purified using reverse-phase HPLC.

Example 130. Preparation of (7?)-iV-((A)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-2-((4-hydroxyphenethyl)amino)-4-phenylbutana mide dihydrochloride (1327)

Step 7: Benzyl ((4-(((S -2-( 7<! -2-amino-4-phenylbutanamido)propanamido) methyl)phenyl)(imino)methyl)carbamate (1.9 g, 41% yield in 4 steps) was synthesized by a method similar to that used for compound 1119, except the crude product was purified by chromatography (10% MeOH-CLLCk and then 5% 7 N NLb in MeOH-CLLCh).

Step 2: To a 25-mL round bottom flask, 4-(2-hydroxyethyl)phenol (1 g, 7.24 mmol,) was added and followed by DMSO (8 mL). After purging with N ₂ , the reaction was treated with TEA (2.2 mL) and followed by the addition of a solution of sulfur trioxide pyridine complex (2.50 g, 15.7 mmol) in DMSO (9 mL) by cannulation. The reaction was stirred at room temp for 1 h and quenched with ice water. The reaction mixture was diluted with CH2CI2 and washed with ice water (3 times). The organic layer was collected, washed with brine, dried (Na2S0 ₄ ), vacuum filtered, and evaporated under vacuum. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-100% EtOAc-hexanes) afforded 2-(4-hydroxyphenyl)acetaldehyde (227.4 mg, 23% yield).

Step 3: Benzyl ((4-((( _< S)-2-((7?)-2-((4-hydroxyphenethyl)amino)-4

phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl) carbamate was synthesized according to the procedure for compound 1130, step 2.

Step 4 Deprotection of benzyl ((4-((( _< S)-2-((7?)-2-((4-hydroxyphenethyl)amino)-4 phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl) according to the procedure for compound 1130, step 3 afforded (7?)-7V-((S)-l-((4-carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-2-((4-hydroxyphenethyl)amino)-4-phenylbutana mide. Step 5: ( R)-N-((S )- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-2-((4- hydroxyphenethyl)amino)-4-phenylbutanamide dihydrochloride was formed according to the procedure for compound (1319), step 6.

Example 131. Preparation of (2/?,4A)-iV-((A)-l-(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-chlorobenzyl)pyrroli dine-2-carboxamide Dihydrochloride (1328)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methy]pyridin-3-y])methy])amino)- 1 -oxopropan-2- yl)-4-(3-chlorobenzyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304), except that the benzyl deprotection was done by following LiOH conditions as shown below.

Step 7: To a stirred solution of 2-benzyl 1 -(/er/-butyl) (27?,4 _< S)-4-(3- chlorobenzyl)pyrrolidine-l,2-dicarboxylate (329 mg, 1 mmol) in THF (24 mL), MeOH (12 mL), and water (12 mL) was added LiOH (360 mg, 15 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature overnight. Aqueous HC1 (12 mL, 1 M) was added to the reaction mixture and organic volatiles were removed under vacuum. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic extracts were thoroughly dried using Na ₂ S04, filtered, and concentrated to afford (2RAS)- 1 - (tert-butoxycarbonyl)-4-(3-chlorobenzyl)pynOlidine-2-carboxy lic acid (320 mg crude, 0.96 mmol) that was directly used in the next step without further purification. Example 132. Preparation of (2/?,4/?)-iV-((iV)-l-(((3-chloro-l//-pyrrolo[2,3-/;]pyridin- 5- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide

Dihydrochloride (1329)

Step 7: To a solution of 1 //-pyrrolo| 2.3-/>|pyridine-5-carbonitrile (1.04 g, 7.24 mmol) in anhyd DMF (14 mL) under Ar was added NCS (1.06 g, 6.9 mmol). The mixture was heated at 55 °C for 2.5 h, cooled to ambient temperature, then diluted with H2O until the final volume was ~90 mL. The mixture was cooled and the solid was isolated by filtration, rinsed with H2O and dried in a vac oven (at ambient temperature) to give 3-chloro- 1 //-pyrrolo| 2.3- b\ pyridine-5 -carbonitrile (1.2 g, 93% yield).

Step 2: To a suspension of 3-chloro-l77-pyrrolo[2,3-/ ]pyridine-5-carbonitrile (0.50 g, 2.8 mmol) in MeOH (75 mL) was added di-ter /-butyl dicarbonate (1.29 g, 5.9 mmol) and C0CI2 6H2O (0.36 g, 1.5 mmol). NaBLL (0.37 g, 9.8 mmol) was added in 4 aliquots over 20 min. The mixture was stirred for 2 h then additional NaBLL (0.21 g, 5.6 mmol) was added and stirred overnight. The reaction was acidified with 0.5 M KHSO4 until the pH was neutral. Volatiles were removed in vacuo then the aqueous mixture was extracted with 10% MeOH- CH2CI2 twice. The aqueous layer was re-adjusted to neutral pH and extracted with 10% MeOH-CTHCh. The combined organics were cone in vacuo to remove all volatiles and H2O. Purification by chromatography (two runs: with 0-5% MeOH-C^Ch then 0-25% acetone- CH2CI2) gave /e/V-butyl ((3-chloro- l//-pyrrolo| 2.3-6 |pyridin-5-y 1 (methyl (carbamate (307 mg, 39% yield).

Step 3: To a suspension of /e/V-butyl ((3-chloro- l //-pyrrolo| 2.3-6 |pyridin-5- yl)methyl)carbamate (305 mg, 1.08 mmol) in MeOH (6 mL) was added 3 M HC1-CPME (9 mL). The resulting solution was stirred for 2.5 h then additional 3 M HC1-CPME (5 mL) was added. After stirring for 45 min, the solution was cone in vacuo. The residue was dissolved in MeOH and cone in vacuo. The solid was suspended in MeOH-Et20 and the solid was collected by filtration and air dried to give (3-chloro- 1 //-pyrrolo| 2.3-6 |pyridin-5- yl)methanamine hydrochloride (285 mg, quant yield).

Step 4 ((2RAR)- 1 -(/c /-Butoxycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine was coupled to (3-chloro- li/-pynOlo[2,3-6]pyridin-5-yl)methanamine according to the procedure for compound (1265) to give /er/-butyl (2RAR)-2-(((S)- 1 -(((3-chloro- \ H- pyrrolo| 2.3-6 |pyridin-5-yl)methyl)amino)- l -o\opropan-2-yl)carbamoyl)-4- phenylpyrrolidine-l-carboxylate (71.7 mg, 62% yield).

Step 5: /e/V-Butyl (2RAR)-2-(((S)- 1 -(((3-chloro- 1 //-pyrrolo| 2.3-6 |pyridin-5- yl)methyl)amino)-l -oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l -carboxylate was deprotected according to the procedure for compound (1243), except that the reaction mixture was diluted with Et20. The solid was collected by filtration, rinsed with 2% MeOH-Et20 and dried in a vac oven overnight to give (2RAR)-N-((S)- 1 -(((3-chloro- 1 //-pyrrolo| 2.3-6 |pyridin- 5-yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-c arboxamide dihydrochloride (64 mg, 96% yield). Example 133. Preparation of (7?)-iV-(fV)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-2-((3-hydroxyphenethyl)amino)-4-phenylbutana mide Di- trifluoroacetate salt (1330)

Step 7: 2-(3-Hydroxyphenyl)acetaldehyde was synthesized according to the procedure for compound (1327), step 2.

Step 2: Benzyl ((4-((( _< S)-2-((7?)-2-((3-hydroxyphenethyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate was synthesized according to the procedure for compound 1130, step 2.

Step 3: Deprotection of benzyl ((4-((( _< S)-2-((7?)-2-((3-hydroxyphenethyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate was done according to the procedure for compound 1130, step 3. Purification by reverse phase HPLC (5-75% MeCN-fhO) afforded (7?)-/V-((ri)-l-((4-carbamimidoylbenzyl)amino)-l-oxopropan-2 - yl)-2-((3-hydroxyphenethyl)amino)-4-phenylbutanamide di-trifluoroacetate salt. Example 134. Preparation of (27?,4A ^, )-/V-((A ^, )-l-(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3,5-dimethylbenzyl)pyr rolidine-2-carboxamide Dihydrochloride (1331)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(3,5-dimethylbenzyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304). Example 135. Preparation of (7?)-2-Amino-iV-(fV)- l-((4-carbamimidoylbenzyl)amino)-3- (///-imidazol-5-yl)- l-oxopiOpan-2-yl)-4-phenylbutan amide Di-trifluoroacetate (1332)

Step 7: Methyl ((7?)-2-((/er/-butoxycarbonyl)amino)-4-phenylbutanoyl)- -histidinate

(500 mg, 65% yield) was synthesized from Boc-/ homophenylalanine (500 mg, 1.79 mmol) and /.-histidine methyl ester dihydrochloride according to the procedure for compound (1326), step 1.

Step 2: ((7?)-2-((/e/7-Butoxycarbonyl)amino)-4-phenylbutanoyl)-Z-his tidine (320 mg, 66% yield) was synthesized from methyl ((7?)-2-((tot-butoxycarbonyl)amino)-4- phenylbutanoyl)-/.-histidinate (500 mg, 1.16 mmol) according to the procedure for compound (1326), step 2.

Step 3: te/7-Butyl ((//)- 1 -(((S)- 1 -((4-/77-

((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-3-(777-i midazol-5-yl)-l-oxopropan-2- yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate (160 mg, 30% yield) was synthesized from ((/i)-2-((/e/7-butoxy carbonyl )amino)-4-phenylbutanoyl (-/.-histidine (320 mg, 0.77 mmol) according to the procedure for compound (1326), step 3.

Step 4: Deprotection of te/7-butyl ((//)- 1 -(((S)- 1 -((4-/77- ((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)-3-(777-imid azol-5-yl)-l-oxopropan-2- yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate (160 mg, 0.23 mmol) was conducted according to the procedure for compound (1260), step 4 to give benzyl ((4-((fS')-2-((//)-2- amino-4-phenylbutanamido)-3-(777-imidazol-5- yl)propanamido)methyl)phenyl)(imino)methyl)carbamate (49 mg, 36% yield).

Step 5: Deprotection of benzyl ((4-((fV)-2-((//)-2-amino-4-phenylbutanamido)-3-(///- imidazol-5-yl)propanamido)methyl)phenyl)(imino)methyl)carbam ate (49 mg, 0.08 mmol) was conducted according to the procedure for compound (1264), step 2 except that the crude material was purified using reverse-phase HPLC. Example 136. Preparation of (2i?,4i?)-/V-(( ₁ S)-l-((3-Chloro-5-methylbenzyl)amino)-l- oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide Hydrochloride (1333)

Steps 1-2: The title compound was synthesized as a white powder according to steps

1-2 of the procedure for compound (1246) using the appropriate starting materials (46 mg, 53% yield over two steps).

Example 137. Preparation of (2/?,4V)-4-Benzyl-iV-(fV)-l-(((3-chloro-l//-pyrrolo[2,3- b\ pyridin-5-yl)methyl)amino)- l-oxopropan-2-yl)pyrrolidine-2-carboxamide Di- hydrochloride (1334)

Step 7: /e/V-butyl (2/iAY)-4-benzyl-2-(((.Y)- 1 -(((3-chloro- l//-pyrrolo| 2.3-6 |pyridin-5- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)pynOlidine-l-car boxylate (46 mg, 80% yield) was synthesized from ((2/iAY)-4-benzyl- l -(/6T/-butoxy carbonyl (pyrrol idine-2- carbonyl )-/.-al an ine (40 mg, 0.11 mmol) according to the procedure for compound (1234), step 3.

Step 2: (27?,4 _< S)-4-Benzyl-/V-(( _< S)-l-(((3-chloro-l7/-pynOlo[2,3-Z>]pyridin-5- yl)methyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-carboxamide di-hydrochloride (38.2 mg, 80% yield) was synthesized from /e/V-butyl (2//AY)-4-benzyl-2-((fS')- 1 -(((3-chloro- 1 H- pyrrolo[2,3-b]pyridin-5-yl)methyl)amino)-l-oxopropan-2-yl)ca rbamoyl)pynOlidine-l- carboxylate (46 mg, 0.85 mmol) according to the procedure for compound (1234), step 3.

Example 138. Preparation of fV)-2-((/?)-2-Amino-4-phenylbutanamido)-iV ^l -(4- carbamimidoylbenzyl)pentanediamide Di-trifluoroacetate (1335)

Step 7: Methyl ((//)-2-((/cT/-buto\ycarbonyl)amino)-4-phenylbutanoyl)-/.-gl utaminate (149 mg, 41% yield) was synthesized from Boc-79-homophenylalanine (241 mg, 0.86 mmol) and /.-glutamine methyl ester hydrochloride according to the procedure for compound (1326), step 1.

Step 2: ((i?)-2-Amino-4-phenylbutanoyl)-Z-glutamine (112 mg, 78% yield) was synthesized from methyl ((i?)-2-((/er/-butoxycarbonyl)amino)-4-phenylbutanoyl)-Z- glutaminate (149 mg, 0.35 mmol) according to the procedure for compound (1326), step 2 except that the crude material was applied to the next step without further purification.

Step 3: /e/7- Butyl ((//)- 1 -((fV)-5-amino- 1 -((4-(N- ((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)- 1 ,5-dioxopentan-2-yl)amino)- 1 -oxo-4- phenylbutan-2-yl)carbamate (156 mg, 84% yield) was synthesized from ((//)-2-amino-4- phenylbutanoyl (-/.-glutamine (112 mg, 0.28 mmol) according to the procedure for compound (1326), step 3.

Step 4 Deprotection of tert- butyl ((//)- 1 -((fS -5-amino- 1 -((4-/7V- ((benzyloxy)carbonyl)carbamimidoyl)benzyl)amino)- 1 ,5-dioxopentan-2-yl)amino)- 1 -oxo-4- phenylbutan-2-yl)carbamate (156 mg, 0.23 mmol) was conducted according to the procedure for compound (1260), step 4 to give benzyl ((4-(((5 -5-amino-2-((i?)-2-amino-4- phenylbutanamido)-5-oxopentanamido)methyl)phenyl)(imino)meth yl)carbamate (47 mg, 36% yield).

Step 5: Deprotection of benzyl ((4-((( _< S -5-amino-2-((7?)-2-amino-4- phenylbutanamido)-5-oxopentanamido)methyl)phenyl)(imino)meth yl)carbamate (47 mg, 0.08 mmol) was conducted according to the procedure for compound (1264), step 2 except that the crude material was purified using reverse-phase HPLC.

Example 139. Preparation of (2i?,4i?)-/V-((£)-l-(((3-Amino-li/-pyrazol-5- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide

Dihydrochloride (1336)

Step 7: 3-Amino- 1 //-pyra/ole-5-carbonitrile was reduced according to the procedure for compound (1311), step 1 to give 5-(aminomethyl)-l7/-pyrazol-3-amine which was used in the next step without further purification.

Step 2: ((27?, 47?)- 1 -(/er/-butoxy carbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine was coupled with 5-(aminomethyl)-l77-pyrazol-3-amine following the procedure given for compound (1265), step 1 except that the amine was added to the reaction mixture as a solution in DMF. After the reaction was complete, the mixture was diluted with 5% MeOH- CH2CI2 and washed with sat. NaHCCb and brine, dried (Na2S04) and cone in vacuo.

Purification by chromatography (0-10% MeOH-CFhCh) provided /e/V-butyl (2RAR)-2-(((S)- 1 -(((3-amino- l//-pyra/ol-5-yl)methyl)amino)- 1 -oxopropan-2-yl (carbamoyl )-4- phenylpyrrolidine-l-carboxylate (64 mg, 47% yield).

Step 3: /e/V-Butyl (2RAR)-2-(((S)- 1 -(((3-amino- 1 //-pyra/ol-5-yl)methyl)amino)- 1 - oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate was deprotected according to the procedure given for compound (1323), step 3 to give (2RAR)-N-(fSj- 1 -(((3-amino- 1 H- pyrazol-5-yl)methyl)amino)-l -oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide dihydrochloride (60 mg, quant yield).

Example 140. Preparation of (2/?,4A)-iV-((A)- l-(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-methylbenzyl)pyrroli dine-2-carboxamide dihydrochloride (1337)

(27?, 45 -/V-((5 -l-(((6-amino-2-methylpyri din-3 -yl)methy l)amino)-l -oxopropan-2-yl)- 4-(3-methylbenzyl)pynOlidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304).

Example 141. Preparation of (2i?,4A)-/V-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(naphthalen-2-ylmethyl) pyrrolidine-2- carboxamide Dihydrochloride (1338)

Step 7: To a stirred solution of 2-benzyl 1 -(te/7-butyl) (7?)-5-oxopyrrolidine-l,2- dicarboxylate (600 g, 1.88 mmol) in THF (12.5 mL) at -78 °C was slowly added lithium bis(trimethylsilyl)amide (2.06 mL, 2.06 mmol, 1 M in THF) under Ar atmosphere. After stirring for 1 h at -78 °C, 2-(bromomethyl)naphthalene (500 mg, 2.26 mmol) in 1 mL THF was added and the stirring continued for an additional 2 h. The reaction mixture was quenched with sat. NH4CI solution and extracted with diethyl ether (3 x 20 mL). The combined extracts were dried over Na ₂ S04 filtered and concentrated under vacuum. The residue was purified by chromatography (EtOAc-hexanes) gave 2-benzyl 1 -(ter /-butyl) (2//AY)-4-(naphthalen-2-ylmethyl)-5-o\opyrrolidine- 1.2-dicarbo\ylate (600 mg, 70% yield).

Step 2: To a solution of 2-benzyl 1 -(te/7-butyl) (2//.4Y)-4-(naphthalen-2-y 1 methyl )-5- oxopyrrolidine-l,2-dicarboxylate (600 mg, 3.91 mmol) in THF (8.6 mL) at -78 °C was added lithium triethylborohydride solution (1.56 mL, 1.56 mmol, 1 M in THF) under Ar atmosphere. After 30 min, the reaction mixture was quenched with sat. NaHCCh solution (3 mL) and warmed to 0 °C. At 0 °C, 30% H2O2 (about 10 drops) was added and the reaction mixture was stirred at same temperature for 30 min. The organic volatiles were removed under vacuum and the aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic extracts were thoroughly dried using Na ₂ S04, filtered, concentrated to 2-benzyl 1- (tert- butyl) (27?,4ri)-5-hydroxy-4-(naphthalen-2-ylmethyl)pyrrolidine-l,2 -dicarboxylate (550 mg crude) that was directly used in the next step without further purification. 0 Boc 0 Boc

Step 3: To a stirred solution of 2-benzyl 1 -(/er/-butyl) (2/iAY)-5-hydroxy-4- (naphthalen-2-ylmethyl)pyrrolidine-l,2-dicarboxylate (550 mg crude) and triethylsilane (0.25 mL, 1.56 mmol) in CH2CI2 (5.5 mL) at -78 °C was drop wise added boron trifluoride diethyl etherate (0.19 mL, 1.56 mmol) under Ar. After 30 min at same temperature additional triethylsilane (0.25 mL, 1.56 mmol) and boron trifluoride diethyl etherate (0.19 mL, 1.56 mmol) were added. After stirring for 2 h at -78 °C, the reaction mixture was quenched with sat. aqueous NaHCCh solution (5 mL) and extracted with CH2CI2 (3 x 15 mL). The combined extracts were dried over Na2SCri filtered and cone under vacuum. The residue was purified by chromatography (EtOAc-hexanes) to afford 2-benzyl 1 -(/er/-butyl) (2//AY)-4-(naphthalen-2- ylmethyl)pyrrolidine-l,2-dicarboxylate (350 mg, 60% yield in two steps).

W Bon 0 Boc

Step 4 A solution of 2-benzyl 1 -(/er/-butyl) (2//.4S')-4-(naphthalen-2- ylmethyl)pyrrolidine-l,2-dicarboxylate (350 mg, 0.78 mmol) in MeOH (8 mL) was bubbled with Ar gas for 5 minutes. 10% Pd/C (35 mg) was added to the reaction mixture and stirred under 1 atm of H2 for 3 h. The reaction mixture was filtered (0.2 mM syringe filter) and the filtrate was concentrated under vacuum to give (2RAS)- 1 -(/e/ /-butoxycarbonyl)-4- (naphthalen-2-ylmethyl)pyrrolidine-2-carboxylic acid (250 mg, 90% yield).

Step 5: To a stirred solution of (/e/V-butoxy carbonyl )-/,-alanine (1.96 g, 10.38 mmol) in CH2CI2 (55 mL) was added NHS (1.25 g, 10.89 mmol) at room temperature. To the reaction mixture DCC (2.25 g 10.9 mmol) was added and the reaction mixture stirred for 1.0 h. 5-(Aminomethyl)-6-methylpyridin-2-amine was added to the reaction mixture and sonicated for 5 min. The 5-(aminomethyl)-6-methylpyridin-2-amine was completely dissolved and stirred the reaction mixture at ambient temperature for 1 h. The crude reaction mixture was filtered and cone under reduced pressure. Purification by chromatography using MeOH-CTHCh afforded tert- butyl (ri -(l-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-l- oxopropan-2-yl)carbamate (2.35 g, 70% yield) as a white solid.

Step 6: To te/7-butyl (S)-( I -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)carbamate (2.35 g, 7.62 mmol) was added a solution of MeOH-HCl (19 mL,

2 M) with stirring at ambient temperature while monitoring for the consumption of starting material (typically 1 h). The solution was evaporated to dryness and MeOH (50 mL) was added and evaporated to dryness to remove residual HC1 gas to give fY) -2 - am i n o -V-(( 6 - amino-2-methylpyridin-3-yl)methyl)propanamide hydrochloride (1.60 g, 90% yield) as an off white solid (Hygroscopic).

Step 7: To a stirred solution of (2RAS)- 1 -(/e/7-butoxycarbonyl)-4-(naphthalen-2- ylmethyl)pyrrolidine-2-carboxylic acid (75 mg, 0.21 mmol) in anhydrous DMF (1.4 mL) was added HOBt (32 mg, 0.23 mmol), DIEA (0.15 mL, 0.84 mmol) and EDC (45 mg, 0.23 mmol) at ambient temperature. The reaction mixture was stirred for 30 min at ambient temperature. (<S)-2-amino-/V-((6-amino-2-methy lpyri din-3 -yl)methyl)propanamide hydrochloride (61 mg, 0.32 mmol) was added to the reaction mixture and stirred overnight. The solution was evaporated to dryness and the residue was partitioned with EtOAc (15 mL) and 10% KHSCri (10 mL). The organic layer was separated and washed with sat. NaHCCh solution (10 mL), dried over anhydrous Na ₂ S04 and cone under vacuum. The crude reaction mixture was purified by chromatography using MeOH-CTLCh to afford tert- butyl (2//AY)-2-(((S)- 1 -(((6- amino-2-methylpyri din-3 -yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-(naphthalen- 2- ylmethyl)pyrrolidine-l-carboxylate (52 mg, 45% yield) as a white solid.

Step 8: To te/7-butyl (2i?,4 _< S)-2-(((S)-l-(((6-amino-2-methylpyridin-3- y l)methy l)amino)- 1 -oxopropan-2-y l)carbamoy l)-4-(naphthalen-2-y lmethy l)py rrobdine- 1 - carboxylate (52 mg, 0.095 mmol) was added a solution of MeOH-HCl (2.0 mL, 2 M) with stirring at ambient temperature while monitoring for the consumption of starting material (30 min to lh). The solution was evaporated to dryness and MeOH (10 mL) was added and evaporated to dryness to remove residual HC1 gas to yield (2i?,4ri)-/V-((ri)-l-(((6-amino-2- methy lpyridin-3-y l)methyl)amino)-l-oxopropan-2-yl)-4-(naphthalen-2-y lmethy l)pyrrolidine- 2-carboxamide dihydrochloride (29 mg, 74% yield) as a white solid.

Example 142. Preparation of (/?)-iV-(fV)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-2-((4-chlorophenethyl)amino)-4-phenylbutanam ide Di-trifluoroacetate salt (1339)

Step 1 : Benzyl ((4-((( _< S)-2-((i?)-2-((4-chlorophenethyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate was synthesized according to the procedure for compound 1130, step 2.

Step 2: Deprotection of benzyl ((4-((( _< S -2-((i?)-2-((4-chlorophenethyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate carbamate according to the procedure for compound 1130, step 3. Purification by reverse phase HPLC (5-75% MeCN-fLO) to afford (i?)-/V-((ri)-l-((4-carbamimidoylbenzyl)amino)-l-oxopropan- 2-yl)-2-((4-chlorophenethyl)amino)-4-phenylbutanamide di-trifluoroacetate salt.

Example 143. Preparation of (/?)-iV-(fV)- l-((4-Carbamimidoylbenzyl)amino)- l- oxopropan-2-yl)-2-(phenethylamino)-4-phenylbutanamide Dihydrochloride (1340)

Step 1 : Benzyl (imino(4-((fS')-2-((//)-2-(phenethylamino)-4- phenylbutanamido)propanamido)methyl)phenyl)methyl)carbamate was synthesized according to the procedure for compound 1130, step 2.

Step 2: Deprotection of benzyl (imino(4-((fV)-2-((//)-2-(phenethylamino)-4- phenylbutanamido)propanamido)methyl)phenyl)methyl)carbamate according to the procedure for compound 1130, step 3 afforded (//)- V-(fS')- l -((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-2-(phenethylami no)-4-phenylbutanamide.

Step 3: (R)-N-((S)- 1 -((4-Carbamimidoylbenzyl)amino)- 1 -o\opropan-2-yl)-2- (phenethylamino)-4-phenylbutanamide dihydrochloride was formed according to the procedure for compound (1319), step 6.

Example 144. Preparation of (/?)-2-amino-iV-(fV)-l-((5-chloro-2-(l//- l ,2,4-triazol- l- yl)benzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide (1341)

Steps 1-2: The title compound was synthesized as a white solid according to steps 3-4 of the procedure for compound (1313) using the appropriate starting materials (36 mg, 32% yield over two steps). Example 145. Preparation of (2/?,-//?)-iV-((iV)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(naphthalen-l-yl)piperi dine-2-carboxamide Dihydrochloride (1342)

(2R, 4R)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(naphthalen-l-yl)piperidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1231) (the first UV Active material eluting from the column in step 6 was carried forward) and compound (1253), steps 1 and 2.

Example 146. Preparation of (2i?,4A)-ZV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(isoquinolin-5-ylmethyl )pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1343)

(2i?,45 -/V-((5 -l-(((6-amino-2-methylpyri din-3 -yl)methy l)amino)-l -oxopropan-2-yl)- 4-(isoquinolin-5-ylmethyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1304), except that the final product was purified using reverse-phase HPLC.

Example 147. Preparation of (2i?,4A)-/V-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((±)-l-phenylethyl)pyr rolidine-2-carboxamide Dihydrochloride (1344)

(2i?,45 -/V-((5 -l-(((6-Amino-2-methylpyridin-3-yl)methyl)amino)-l-oxopropan -2- yl)-4-((±)-l-phenylethyl)pyrrolidine-2-carboxamide dihydrochloride was followed according to the procedures for compound (1257).

Example 148. Preparation of (i?)-2-((4-acetamidophenethyl)amino)-ZV-((A)-l-((4- carbamimidoylbenzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanam ide dihydrochloride (1345)

Step 1: Benzyl ((4-(((5)-2-((i?)-2-((4-acetamidophenethyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl)car bamate was synthesized according to the procedure for compound 1130, step 2.

Step 2: Deprotection of benzyl ((4-(((5)-2-((i?)-2-((4-acetamidophenethyl)amino)-4- phenylbutanamido)propanamido)methyl)phenyl)(imino)methyl) according to the procedure for compound 1130, step 3 afforded (i?)-2-((4-acetamidophenethyl)amino)-/V-((5)-l-((4- carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-4-pheny lbutanamide.

Step 3: (i?)-2-((4-Acetamidophenethyl)amino)-iV-((5)-l-((4- carbamimidoy lbenzy l)amino)-l-oxopropan-2-yl)-4-pheny lbutanamide dihydrochloride was formed according to the procedure for compound (1319), step 6. Example 149. Preparation of K)-2-Amino-iV-((A)-l-(((2-aminopyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Dihydrochloride (1346)

(K -2-Amino-/V-((5 -l-(((2-aminopyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)-4- phenylbutanamide dihydrochloride was synthesized according to the procedures given for compound (1323), steps 2 and 3.

Example 150. Preparation of (/?)-iV-((iV)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-benzylpiperazine-2-carb oxamide

Dihydrochloride (1347)

(R)-N- (S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2-yl)-4- benzylpiperazine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1253).

Example 151. Preparation of (/?)-iV-((iV)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(2-methylbenzyl)piperaz ine-2-carboxamide Dihydrochloride (1348)

(R)-N- (S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2-yl)-4- (2-methylbenzyl)piperazine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1230), except using (R)- 1 -(/cT/-buto\ycarbonyl)-4-(2- methylbenzyl)piperazine-2-carboxylic acid in step 1 and 5-(aminomethyl)-6-methylpyridin-2- amine in step 3.

Example 152. Preparation of (/?)-iV-(fV)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-2-((3-hydroxyphenethyl)am ino)-4- phenylbutanamide Dihydrochloride (1349)

Stepl·. Deprotection of benzyl ((i?)-2-((/e/7-butoxycarbonyl)amino)-4- phenylbutanoyl)-L-alaninate (789.3 mg, 1.79 mmol) was done according to the procedure for compound 1119, step 2. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-15% MeOH-CELCh) afforded methyl ((//)-2-amino- 4-phenylbutanoyl)-L-alaninate (335.0 mg, 71% yield).

Step 2: 3-(2-Hydroxyethyl)phenol (2.1 g, 15.2 mmol) was dissolved in DMSO (8 mL) under N2. The solution was treated dropwise with a solution of sulfur trioxide pyridine complex (2.5 g, 15.7 mmol) in DMSO (9 mL). The reaction was stirred at room temp for 1 h, quenched with ice water, and diluted with CH2CI2. The organic layer was washed with ice water (3 times), washed with brine, dried (Na2S0 ₄ ), vacuum filtered, and evaporated under vacuum. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-100% EtOAc-hexanes) afforded the crude 2-(3- hydroxyphenyl)acetaldehyde (1.83 g, 88% yield).

Step 3: Methyl ((//)-2-amino-4-phenylbutanoyl)-L-alaninate (335.0 mg, 1.27 mmol) was coupled with crude 2-(3-hydroxyphenyl)acetaldehyde (417 mg, 3.06 mmol) according to the procedure for compound 1130, step 2. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-5% MeOH-CfhCh) afforded methyl ((i?)-2-((3-hydroxyphenethyl)amino)-4-phenylbutanoyl)-L-alan inate (270 mg, 61% yield).

Step 4 A mixture of ((i?)-2-((3-hydroxyphenethyl)amino)-4-phenylbutanoyl)-L- alaninate (270.3 mg, 0.703 mmol) in THF (3.4 mL) and water (3.4 mL) was treated with LiOH (84 mg, 3.51 mmol). The reaction was stirred for 16 h at room temp, adjusted to pH 3 with the slow addition of 10% KHSO4 solution, extracted with EtOAc (3 times). The organic layers were combined, washed with 5% NaHCCb solution, washed with brine, dried

(Na ₂ S04), vacuum filtered, and evaporated under vacuum to afford the crude ((i?)-2-((3- hydroxyphenethyl)amino)-4-phenylbutanoyl)-L-alanine (213.6 mg, 82% yield).

Step 5 : ((//)-2-((3-Hydro\yphenethyl)amino)-4-phenylbutanoyl)-L-alan ine (110.6 mg, 0.299 mmol) was coupled with 5-(aminomethyl)-6-methylpyridin-2-amine (66 mg, 0.481 mmol) according to the procedure for compound 1088, step 2 except HBTU was added to the reaction at 0 °C to afford (i?)-A-((5)-l-(((6-amino-2-methylpyri din-3 -yl)methy l)amino)-l- oxopropan-2-yl)-2-((3-hydroxyphenethyl)amino)-4-phenylbutana mide (97.6 mg, 67% yield).

Step 6: (R)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-2-((3-hydroxyphenethyl)amino)-4-phenylbutanamide dihydrochloride was formed according to the procedure for compound (1319), step 6. Example 153. Preparation of (2/?,4V)-iV-((/V)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-bromobenzyl)pyrrolid ine-2-carboxamide Dihydrochloride (1350)

(27?, 45 -7V-((5 -l-(((6-amino-2-methylpyri din-3 -yl)methy l)amino)-l -oxopropan-2-yl)- 4-(4-bromobenzyl)pynOlidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1328).

Example 154. Preparation of (2/?,4L')-4-([ 1,1’-Biphenyl]-4-ylmethyl)-iV-((A)-l-(((6- amino-2-methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)py rrolidine-2- carboxamide Dihydrochloride (1351)

Step 7: 2-benzyl l-(tert-butyl) (2//AS')-4-(4-bromobenzyl)pyrrolidine- 1.2- dicarboxylate was synthesized according to the procedures for compound (1304), step 1 to step 3.

Step 2: In a 50 mL round bottom flask equipped with a stir bar and septum was added 2-benzyl 1 -(te/7-butyl) (2/L4.Y)-4-(4-bromobenzyl (pyrrolidine- 1.2-dicarboxylate (143 mg, 0.30 mmol), phenyl boronic acid (44 mg, 0.36), Pd(dppf)Cl2 (22 mg, 0.03 mmol), cesium carbonate (293 mg, 0.90 mmol), THF (3 mL) and water (0.3 mL). The resulting mixture was degassed by bubbling N ₂ through the solution for 10 min. The reaction was then heated to 90 °C for 4 h. Upon cooling to room temperature, the reaction solution was filtered through diatomaceous earth, eluting with EtOAc, concentrated and purified by chromatography using EtOAc-hexanes to afford 2-benzyl l -(/e/7-butyl) (2/ri4.Y)-4-(| 1.1 '-biphenyl |-4- ylmethyl)pyrrolidine-l, 2-dicarboxylate (110 mg, 78% yield) as a colorless sticky liquid.

Step 3 : (2//.4Y)-4-(| 1 , G-Bipheny 1] -4-yl methyl )-/V-((.Y)- 1 -(((6-amino-2-methy lpy ridin- 3-yl)methyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-carboxamid e dihydrochloride was synthesized according to the procedures for compound (1304), step 4 to step 8.

Example 155. Preparation of (7?)-iV-(fV)-l-((4-Carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-4-phenyl-2-((3-(trifluoromethoxy)phenethyl)a mino)butanamide Di- trifluoroacetate salt

Step 7: Benzyl (imino(4-(((5)-2-((7?)-4-phenyl-2-((3- (trifluoromethoxy)phenethyl)amino)butanamido)propanamido)met hyl)phenyl)methyl)carbam ate was synthesized according to the procedure for compound 1130, step 2.

Step 2: Deprotection of benzyl (imino(4-((fY)-2-((//)-4-phenyl-2-((3- (trifluoromethoxy)phenethyl)amino)butanamido)propanamido)met hyl)phenyl)methyl)carbam ate according to the procedure for compound 1130, step 3. Purification by reverse phase HPLC (5-75% MeCN-fhO) to afford (R)-N-((S)- 1 -((4-carbamimidoylbenzyl)amino)- 1 - oxopropan-2-yl)-4-phenyl-2-((3-(trifluoromethoxy)phenethyl)a mino)butanamide di- trifluoroacetate salt.

Example 156. Preparation of (2/?,-AV)-iV-((iV)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-benzylpiperidine-2-carb oxamide

Dihydrochloride (1353)

(2R, 4S)-N- (S)- 1 -(((6-Amino-2-methy lpyri din-3 -yl)methyl)amino)-l-oxopropan-2- yl)-4-benzylpiperidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1253).

Example 157. Preparation of (2S,4R)-iV-((iV)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-benzylpiperidine-2-carb oxamide

Dihydrochloride (1354)

(2S,4R)-N-((S)-l -(((6-Amino-2-methy lpyri din-3 -yl)methyl)amino)- 1 -oxopropan-2- yl)-4-benzylpiperidine-2-carboxamide was synthesized according to the procedures for compound (1230), except using 4-benzyl- l -(/cT/-buto\ycarbonyl)piperidine-2-carbo\y lie acid in step 1 and 5-(aminomethyl)-6-methy lpyri din-2-amine in step 3.

Example 158. Preparation of (i?)-2-amino-ZV-((A)-l-((5-bromo-2-hydroxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide Trifluoroacetate salt (1355)

Steps 1-2: The title compound was synthesized as a white hygroscopic solid according to steps 3-4 of the procedure for compound (1313) using the appropriate starting materials (8.3 mg, 17% yield over two steps).

Example 159. Preparation of (2/?,4L')-4-([ 1,1’-Biphenyl]-4-ylmethyl)-iV-(fV)-l-(((3- chloro-l//-pyrrolo[2,3-/ ]pyridin-5-yl)methyl)amino)-l-oxopropan-2-yl)pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1356)

Step 7: 2-Benzyl 1 -(tert-butyl) (2//.4L')-4-(| 1. 1 '-biphenyl |-4-ylmethyl)pyrrolidine- 1.2- dicarboxylate was synthesized according to the procedures for compound (1351) step 1 and step 2.

Step 2: (27?,45 -4-([l,r-Biphenyl]-4-ylmethyl)-7V-((5)-l-(((3-chloro-l77-pyr rolo[2,3- /> | py ridin-5-y 1 )methy 1 )amino)- 1 -o\opropan-2-yl (pyrrol idine-2-carbo\amide di- trifluoroacetate salt was synthesized according to the procedures for compound (1307), step 1 to step 5, followed by purification by reverse-phase HPLC. Example 160. Preparation of (2/?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-(pyridin-3-yl)benzyl )pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1357)

(27?, 45 -7V-((5 -l-(((6-amino-2-methylpyri din-3 -yl)methy l)amino)-l -oxopropan-2-yl)- 4-(4-(pyridin-3-yl)benzyl)pynOlidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1351), except that the final product was purified by chromatography using reverse-phase HPLC.

Example 161. Preparation of (2i?,4i?)-/V-((A)-l-(((2-Amino-5-chloropyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide Di- trifluoroacetate salt (1358)

Step 7: A solution of 2-amino-5-chloropyridine-3-carbonitrile (250 mg, 1.62 mmol) in MeOH (5 mL) and 7 N U in MeOH (25 mL) was degassed with a stream of Ar 2 times. Raney nickel (300 mg) was added and a vacuum was pulled for 1 min. A balloon of ¾ was added and the reaction mixture was stirred for 16 h at room temperature. Upon completion, the reaction mixture was degassed with a stream of Ar 2 times. The catalyst was removed by diatomaceous earth filtration and the solution was cone. The residue was taken up in 5% H2O in MeOH, filtered (0.2 pm syringe filter), and the filtrate was cone under vacuum to give 3- (aminomethyl)-5-chloropyridin-2-amine (189 mg, 74% yield).

Step 2: To a solution of 3-(aminomethyl)-5-chloropyridin-2-amine (47 mg, 0.3 mmol) in DMF (5 mL, 0.06 mmol) was added ((2i?,4i?)-l-(/er/-butoxycarbonyl)-4- phenylpyrrolidine-2-carbonyl )-/.-alanine (84 mg, 0.23 mmol). The resulting mixture was cooled to 0 °C. HBTU (114 mg, 0.3 mmol) and DIEA (0.16 mL) were added to the above mixture. After stirring for 30 min at the same temperature, the reaction was warmed to room temperature. The reaction was stirred for 90 min then cone under vacuum. The residue was dissolved in EtOAc-CEECE then washed with 10% KHSCri, EEO, sat. aq NaHCCE, and brine. The organic layer was dried over anhyd Na ₂ S04 and cone under vacuum. The residue was purified by chromatography (0-100% [5% 7 N NEE in MeOEl/CEECE]-CEECE) to give tot- butyl (2RAR)-2-(((S)- 1 -(((2-amino-5-chloropyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate (104 mg, 90% yield).

Step 3: Deprotection of /er/-butyl (2RAR)-2-(((S)- 1 -(((2-amino-5-chloropyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpyrroli dine-l-carboxylate (104 mg, 0.21 mmol) was conducted according to the procedure for compound (1260), step 4 except that the final product was purified using reverse-phase HPLC.

Example 162. Preparation of (2/?,4/?)-4-([ 1 ,1 '-Biphenyl ]-3-yl)-iV-((A)-l-(((6-amino-2- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)pyrrolidin e-2-carboxamide Di- trifluoroacetate salt (1359)

Step 1 : (i?)-4-([l, 1 '-Biphenyl |-3-yl)- 1 -(tert-buto\ycarbonyl)-2.5-dihydro- 1 //-pyrrol e- 2-carboxylic acid was synthesized from \-(ter /-butyl) 2-methyl (i?)-4-oxopyrroli dine- 1,2- dicarboxylate according to the procedures for compound (1247), step 1 to step 3.

Step 2: Under Ar, (//)-4-(| 1.1 '-biphenyl |-3-yl)- 1 -(tert-buto\ycarbonyl)-2.5-dihydro- li -pyrrole-2-carboxylic acid (347 mg, 0.95 mmol) and

chlorotris(triphenylphosphine)rhodium (88 mg, 0.095 mmol) were dissolved in anhydrous THF (15 mL), MeOH (15 mL), and Et ₃ N (0.13 mL, 0.95 mmol). The atmosphere in the flask was then changed to Th and a slight positive pressure maintained while the solution was stirred 36 h. The volatiles were evaporated, the residue suspended in NaHCCri (60 mL) and the pH adjusted to approximately 10 with 1 M aq. NaOH. EtOAc (60 mL) was added and the mixture was partitioned. The organic layer was washed with another 30 mL of NaHCCh and the combined aqueous layers were brought to pH 3-4 using 1 M aq. HC1; the product subsequently back-extracted with EtOAc (3 x 60 mL). The combined organic layers were dried over Na ₂ S04 and evaporated to furnish (2RAR)-4-(\ 1.1 '-biphenyl |-3-yl)- 1 -(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (175 mg, 50% yield) as an orange colored sticky liquid.

Step 3: (2RAR)-4-(\ 1.1 '-biphenyl |-3-yl)- 1 -(tert-buto\ycarbonyl)pyrrolidine-2- carboxylic acid was coupled to fS')-2-amino- V-((6-amino-2-methylpyridin-3- yl)methyl)propanamide hydrochloride according to the procedure for compound (1304), step 7 to give te/7-butyl (2i?,45)-4-([l,l'-biphenyl]-3-ylmethyl)-2-(((5 -l-(((6-amino-2- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl) pynOlidine-l-carboxylate.

Step 4 Deprotection of tert- butyl (2//.4L -4-(| 1.1 '-biphenyl |-3-ylmethyl)-2-((fV)- 1 - (((6-amino-2-methylpyridin-3-yl)methyl)amino)-l-oxopropan-2- yl)carbamoyl)pyrrolidine-l- carboxylate according to the procedure for compound (1304), step 8, gave (2//.4//)-4-(| 1. G- biphenyl |-3-yl)-/V-((.Y)- 1 -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)pyrrolidine-2-carboxamide which was purified using reverse-phase HPLC and isolated as the di-trifluoroacetate salt.

Example 163. Preparation of (2i?,4i?)-4-([l,l'-Biphenyl]-3-yl)-iV-((i?)-l-(((6-amino-2- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)pyrrolidin e-2-carboxamide Di- trifluoroacetate salt (1360)

tert- Butyl (2i?,4i?)-4-([ 1 , G-bipheny 1] -3-y lmethy l)-2-(((5)- 1 -(((6-amino-2- methylpyri din-3 -yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)pynOlidine-l -carboxylate, isolated from the preparation of te/7-butyl (2/L4.Y)-4-(| 1.1 '-biphenyl |-3-ylmethyl)-2-((fV)- 1 - (((6-amino-2-methylpyridin-3-yl)methyl)amino)-l-oxopropan-2- yl)carbamoyl)pyrrolidine-l- carboxylate (compound (1359), step 3) was deprotected according to the procedure for compound (1304), step 8 to give (2i?,4i?)-4-([l,r-biphenyl]-3-yl)-/V-((i?)-l-(((6-amino-2- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)pyrrolidin e-2-carboxamide di- trifluoroacetate salt after purification using reverse-phase HPLC.

Example 164. Preparation of (2i?,4^)-iV-(( )-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-(thiazol-2-yl)benzyl )pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1361)

(27?, 4 _< S)-/V-(( _< S')- l-(((6-amino-2-methylpyri din-3 -yl)methyl)amino)-l-oxopropan-2-yl)- 4-(4-(thiazol-2-yl)benzyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1304), except that the final product was purified using reverse-phase HPLC. Example 165. Preparation of (2/?,4/?)-iV-((A)-l-(((3-Chloro-l//-indol-5- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide (1362)

Step 1 : (( 2R,4R )- 1 -(/er/-Butoxy carbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine was coupled with (3-chloro- l //-indol-5-yl)methanamine (synthesized according to the procedures reported in W0200002611) according to the procedure for compound (1265), step 1 to give /e/7-butyl (2RAR)-2-(((S)- 1 -(((3-chloro- 1 //-indol-5-yl)methyl)amino)- 1 -oxopropan- 2-yl)carbamoyl)-4-phenylpynOlidine-l-carboxylate (71.7 mg, 62% yield).

Step 2: To a solution of te/7-butyl (2RAR)-2-((fSj- 1 -(((3-chloro- 1 //-indol-5- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpyrroli dine-l-carboxylate (28.7 mg, 0.055 mmol) in anhyd CH2CI2 (5 mL) over an ice bath was added TFA (6 pL), triethylsilane (2 drops). Additional TFA (6 pL) was added. After stirring for 15 min the ice bath was removed and stirring continued for 1 h. Additional TFA (0.25 mL) was added and the mixture was stirred for 75 min. The reaction was quenched with slow addition of 1 M NaOH (3 mL). After stirring for 5 min the mixture was cooled over an ice bath. Sat. NaHCCb was added until the pH was neutral. The mixture was saturated with NaCl and extracted with 10% MeOH-CTHCh. The combined organics were dried (Na2SCh) and cone in vacuo. Purification by chromatography (0-7.5% MeOH-CTHCh) gave (2RAR)-N-(fSj- 1 -(((3-chloro- 1 //-indol-5- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpynOlidine-2-carb oxamide (12.8 mg, 55% yield).

Example 166. Preparation of (2/?,-AV)-4-Benzyl-iV-((iV)- l-((5-chloro-2-hydroxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)piperidine-2-carboxamid e Hydrochloride (1363)

(2R 4S)-4- 2 _>Q X\/X\-N-((S)- 1 -((5-chloro-2-hydroxy-3-methylbenzyl)amino)- 1 - oxopropan-2-yl)piperidine-2-carboxamide hydrochloride was synthesized according to the procedures for compound (1230), except using ((2R. AS%4-benzyl- 1 -(lerl- butoxycarbonyl)piperidine-2-carbonyl)-L-alanine in step 3. Example 167. Preparation of (2i?,4i?)-iV-((»S)-l-((3-Chloro-5-hydroxybenzyl)amino)-l- oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide Hydrochloride (1364)

Steps 1-2: The title compound was synthesized as a white powder according to steps 3-4 of the procedure for compound 1119 using the appropriate starting materials (8.5 mg,

11% yield over two steps). Example 168. Preparation of (2/?,4V)-iV-((/V)- l-((5-ChloiO-2-hydiOxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)-4-phenylpiperidine-2-c arboxamide

Hydrochloride (1365)

Steps 1-2 : The title compound was synthesized as a white powder according to steps

1-2 of the procedure for compound (1246) using the appropriate starting materials (33 mg, 35% yield over two steps). Example 169. Preparation of (2i?,4i?)-iV-((A)-l-((Imidazo[l,2-a]pyridin-7- ylmethyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-carb oxamide

Dihydrochloride (1366)

(2i?,4i?)-/V-((S -l-((Imidazo[l,2-a]pyridin-7-ylmethyl)amino)-l-oxopropan-2-y l)-4- phenylpyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedure given for compound (1323), steps 2 and 3.

Example 170. Preparation of (A)-iV-(l-(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- l-oxopiOpan-2-yl)-3-benzyl-///-pyrazole-5-carboxamide (1367)

(S)-N-( 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2-yl)-3- benzyl-7i/-pyrazole-5-carboxamide was synthesized according to the procedures for compound (1230), except using 3-benzyl-///-pyra/ole-5-carbo\ylic acid in step 1 and 5- (aminomethyl)-6-methylpyridin-2-amine in step 3.

Example 171. Preparation of (/?)-2-((4-Acetamidophenethyl)amino)-iV-(fV)- l-(((6- amino-2-methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)-4 -phenylbutanamide Dihydrochloride (1368)

Step 7: Benzyl ((//)-2-amino-4-phenylbutanoyl)-L-alaninate (403.0 mg, 1.18 mmol) was coupled with A-(4-(2-oxoethyl)phenyl (acetamide (251.0 mg, 1.42 mmol) according to the procedure for compound 1130, step 2. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-10% MeOH-CTHCh) afforded benzyl ((//)-2-((4-acetamidophenethyl)amino)-4-phenylbutanoyl)-L-al aninate (500.1 mg, 84% yield).

Step 2: Deprotection of benzyl ((7?)-2-((4-acetamidophenethyl)amino)-4- phenylbutanoyl)-L-alaninate (500.1 mg, 0.997 mmol) ) according to the procedure for compound 1119, step 2 afforded methyl ((i?)-2-((4-acetamidophenethyl)amino)-4- phenylbutanoyl)-L-alaninate (122.0 mg, 29% yield).

Step 3: Hydrolysis of methyl ((//)-2-((4-acetamidophenethyl)amino)-4- phenylbutanoyl)-L-alaninate (122.0 mg, 0.287 mmol) according to the procedure for compound (1349), step 4 afforded the crude ((//)-2-((4-acetamidophenethyl)amino)-4- phenylbutanoyl)-L-alanine (37.5 mg, 32% yield).

Step 4: ((//)-2-((4-Acetamidophenethyl)amino)-4-phenylbutanoyl)-L-al anine (37.5 mg, 0.091 mmol) was coupled with 5-(aminomethyl)-6-methylpyridin-2-amine (21.0 mg,

0.15 mmol) according to the procedure for compound 1088, step 2 except HBTU was added to the reaction at 0 °C. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-15% MeOH-C^Ch) afforded (7?)-2-((4- acetamidophenethy l)amino)-/V-((S)- 1 -(((6-amino-2-methy lpy ri din-3 -y l)methy l)amino)- 1 - oxopropan-2-yl)-4-phenylbutanamide (31.1 mg, 64% yield).

Step 5: (7?)-2-((4- Acetamidophenethy l)amino)-/V-(( _< S)- 1 -(((6-amino-2-methy lpy ridin- 3-yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylbutanamide dihydrochloride was formed according to the procedure for compound (1319), step 6. Example 172. Preparation of (2/?,4A)-iV-((A)-l-((5-ChloiO-2-hydiOxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)-4-(3-methylbenzyl)pyrr olidine-2-carboxamide Hydrochloride (1369)

Steps 1-2 : A 250 mL round bottom flask was charged with /V-(tert-butoxy carbonyl )-L- alanine (503 mg, 2.66 mmol) and ACN (13 mL) then cooled to 0 °C. Oxyma (435 mg, 3.06 mmol) and EDC (560 mg, 2.92 mmol) were added portion-wise and allowed to stir for 10 min. 2-(Aminomethyl)-4-chloro-6-methylphenol (500 mg, 2.92 mmol) and DIEA (695 pL, 4 mmol) were then added, respectively, and the reaction allowed to slowly warm to ambient temperature overnight. The solvent was removed under reduced pressure and the residue re dissolved in EtOAc before being washed with 10% aq. KHSCL and brine, dried over NaiSOr and concentrated in vacuo. The crude product was purified by chromatography (60-70%

EtO Ac/hexanes). /er/-Butyl (<S -(l-((5-chloro-2-hydroxy-3-methylbenzyl)amino)-l- oxopropan-2-yl)carbamate was dissolved in cone. HC1 in MeOH (10 mL) and stirred at ambient temperature overnight. The reaction mixture was then concentrated and purified by chromatography (MeOH/C^Ch containing 2.5% 7 N L-MeOH) to yield ( _< S -2-amino-/V- (5-chloro-2-hydroxy-3-methylbenzyl)propenamide as a yellow powder (469 mg, 73% yield

over two steps).

Steps 3-4: The title compound was synthesized as a white solid according to steps 1-2 of the procedure for compound (1246) using the appropriate starting materials (11 mg, 15% yield over two steps).

Example 173. Preparation of (2/?,4»S)-/V-((»S)-l-((5-Chloro-2-hydroxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)-4-(naphthalen-2-ylmeth yl)pyrrolidine-2- carboxamide (1370)

Steps 1-2: The title compound was synthesized as a white solid according to steps 3-4 of the procedure for compound (1313) using the appropriate starting materials (17.4 mg, 36% yield over two steps). Example 174. Preparation of (27?,4A ^, )-4-Benzyl-/V-((A')-l-((5-chloro-2-(l//-tetrazol-l- yl)benzyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-carboxamide Hydrochloride (1371)

(2i?,4ri -4-Benzyl-/V-((ri)-l-((5-chloro-2-(li/-tetrazol-l-yl)benzyl) amino)-l- oxopropan-2-yl)pyrrolidine-2-carboxamide hydrochloride was synthesized according to the procedures for compound (1307).

Example 175. Preparation of (2/?,4V)-iV-(fV)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(2-bromobenzyl)pyrrolid ine-2-carboxamide Di- trifluoroacetate salt (1372)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(2-bromobenzyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1328), except that the final product was purified using reverse-phase HPLC. Example 176. Preparation of (2/?,4V)-4-([ l,l’-Biphenyl]-2-ylmethyl)-iV-(fV)-l-(((6- amino-2-methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)py rrolidine-2- carboxamide Di-trifluoroacetate salt (1373)

O Boc

Step 7: To a stirred solution of 2-benzyl 1 -(te/7-butyl) (7?)-5-oxopyrrolidine-l,2- dicarboxylate (2.0 g, 6.28 mmol) in THF (40 mL) at -78 °C was slowly added lithium bis(trimethylsilyl)amide (6.90 mL, 6.90 mmol, 1 M in THF) under Ar. After stirring for 1 h at -78 °C, 2-bromobenzyl bromide (1.88 g, 7.53 mmol) was added and the stirring continued for an additional 2 h. The reaction mixture was quenched with sat. NH4CI solution and extracted with diethyl ether (3 x 60 mL). The combined extracts were dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by chromatography (EtOAc-hexanes) gave 2-benzyl l -(/e/7-butyl) (2//AY)-4-(2-bromobenzyl)-5-o\opyrrolidine- 1.2-dicarbo\ylate (2.63 g, 86% yield).

Step 2: To a solution of 2-benzyl 1 -(te/7-butyl) (2//AY)-4-(2-bromobenzyl)-5- oxopyrrolidine-l,2-dicarboxylate (1.60 g, 3.91 mmol) in THF (22 mL) at -78 °C was added lithium triethylborohydride solution (3.94 mL, 3.94 mmol, 1 M in THF) under Ar atmosphere. After 30 min, the reaction mixture was quenched with sat. NaHCCb solution (8.60 mL) and warmed to 0 °C. At 0 °C, 30% H2O2 (about 25 drops) was added and the reaction mixture was stirred at same temperature for 30 min. The organic volatiles were removed under vacuum and the aqueous layer was extracted with CH2CI2 (3 x 40 mL). The combined organic extracts were thoroughly dried using Na2SCh. filtered, concentrated to afford 2-benzyl 1 -(te/7-butyl) (2//.4Y')-4-(2-bromobenzyl)-5-hydroxy pyrrolidine- 1.2- dicarboxylate (1.60 g crude) that was directly used in the next step without further purification.

Step 3: To a stirred solution of 2-benzyl 1 -(te/7-butyl) (2//.4Y)-4-(2-bromobenzyl)-5- hydroxypyrrolidine-l,2-dicarboxylate (1.60 g crude) and triethylsilane (0.63 mL, 3.94 mmol) in CH2CI2 at -78 °C was dropwise added boron trifluoride diethyl etherate (0.49 mL, 3.94 mmol) under Ar atmosphere. After 30 min at same temperature additional triethylsilane (0.63 mL, 3.94 mmol) and boron trifluoride diethyl etherate (0.49 mL, 3.94 mmol) were added. After stirring for 2 h at -78 °C, the reaction mixture was quenched with sat. aqueous NaHCCh solution (10 mL) and extracted with CH2CI2 (3 x 40 mL). The combined extracts were dried over Na2S04, filtered and cone under vacuum. The residue was purified by chromatography (EtOAc-hexanes) to afford 2-benzyl 1 -(/e/7-butyl) (2//.4Y')-4-(2-bromobenzyl)pyrrolidine- 1.2- dicarboxylate (931 mg, 60% yield in two steps).

Step 4: In a 50 mL round bottom flask equipped with a stir bar and septum was added 2-benzyl 1 -(te/7-butyl) (2//.4Y')-4-(2-bromobenzyl (pyrrolidine- 1.2-dicarboxylate (200 mg, 0.42 mmol), phenyl boronic acid (62 mg, 0.51), Pd(dppf)Cl2 (31 mg, 0.042 mmol), cesium carbonate (413 mg, 1.26 mmol), THF (4.2 mL) and water (0.42 mL). The resulting mixture was degassed by bubbling N2 through the solution for 10 min. The reaction was then heated to 90 °C for 4 h. Upon cooling to room temperature, the reaction solution was filtered through diatomaceous earth, eluted with EtOAc, concentrated and purified by

chromatography using EtOAc-hexanes to afford 2-benzyl 1 -(ter /-butyl) (27?,45)-4-([1,G- biphenyl] -2-ylmethyl)pyrrolidine-l, 2-dicarboxylate (200 mg, 99% yield) as a colorless sticky liquid.

Step 4 A solution of 2-benzyl 1 -(/e/7-butyl) (2//.4L')-4-(| 1.1 '-biphenyl | -2- ylmethyl)pyrrolidine-l, 2-dicarboxylate (200 mg, 0.42 mmol) in MeOH (4.2 mL) was bubbled with Ar gas for 5 minutes. 10% Pd/C (20 mg) was added to the reaction mixture and that was stirred under 1 atm of Lh for 3 h. The reaction mixture was filtered (0.2 pm syringe filter) and the filtrate was concentrated under vacuum to give (2//.4S')-4-(| 1.1 '-biphenyl |-2-ylmethyl)- 1 - (/cT/-buto\Ycarbonyl)pyrrolidine-2-carbo\ylic acid (150 mg, 93% yield).

Step 5: To a stirred solution of (/e/V-butoxy carbonyl )-/,-alanine (1.96 g, 10.38 mmol) in CH2CI2 (55 mL) was added NHS (1.25 g, 10.89 mmol) at room temperature. To the reaction mixture DCC (2.25 g 10.9 mmol) was added and the reaction mixture stirred for 1.0 h. 5-(Aminomethyl)-6-methylpyridin-2-amine was added to the reaction mixture and sonicated for 5 min. The 5-(aminomethyl)-6-methylpyridin-2-amine was completely dissolved and the reaction mixture was stirred at ambient temperature for 1 h. The crude reaction mixture was filtered and cone under reduced pressure. Purified the crude reaction mixture by chromatography using MeOH-CLLCh to afford tert- butyl (<S)-(l-(((6-amino-2- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)carbamate (2.35 g, 70% yield) as a white solid.

Step 6: To /e/V-butyl (S)-( 1 -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)carbamate (2.35 g, 7.62 mmol) was added a solution of MeOH-HCl (19 mL,

2 M) with stirring at ambient temperature while monitoring for the consumption of starting material (typically 1 h). The solution was evaporated to dryness and MeOH (50 mL) was added and evaporated to dryness to remove residual HC1 gas to give fY) -2 - am i n 0 -V-(( 6 - amino-2-methylpyridin-3-yl)methyl)propanamide hydrochloride (1.60 g, 90% yield) as an off white solid (hygroscopic).

Step 7: To a stirred solution of (2//.4Y)-4-(| 1.1 '-biphenyl |-2-yl methyl)- 1 -(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (38 mg, 0.1 mmol) in anhydrous DMF (1 mL) was added HOBt (24 mg, 0.11 mmol), DIEA (0.1 mL, 0.52 mmol) and EDC (28 mg, 0.11 mmol) at ambient temperature. The reaction mixture was stirred for 30 min at ambient temperature. (<S)-2-amino-/V-((6-amino-2-methylpyridin-3-yl)methyl)pro panamide hydrochloride (23 mg, 0.12 mmol) was added to the reaction mixture and stirred overnight. The solution was evaporated to dryness and the residue was partitioned with EtOAc (10 mL) and 10% KHSCri (5 mL). The organic layer was separated and washed with sat. NaHCCh solution (10 ml), dried over anhydrous Na2S04 and cone under vacuum. The crude reaction mixture was purified by chromatography using MeOH-CLLCh to afford /e/V-butyl (2//AY)-4- ([1,1 '-biphenyl] -2-y lmethy l)-2-((( _< S - 1 -(((6-amino-2-methy lpyridin-3-y l)methy l)amino)- 1 - oxopropan-2-yl)carbamoyl)pyrrolidine-l-carboxylate (40 mg, 70% yield) as a white solid.

Step 8: To /e/V-butyl (2//.4L -4-(| 1.1 '-biphenyl |-2-ylmethyl)-2-((fY)- 1 -(((6-amino-2- methy lpy ridin-3 -y l)methy l)amino)- 1 -oxopropan-2-y l)carbamoyl)py rrolidine- 1 -carboxy late

(40 mg, 0.07 mmol) in 1 mL CH2CI2 was added TFA (0.11 mL, 1.39 mmol) with stirring at ambient temperature while monitoring for the consumption of starting material (30 min to lh). The solution was evaporated to dryness and MeOH (10 mL) was added and evaporated to dryness to remove residual TFA. The resulting crude reaction mixture was purified using reverse-phase HPLC to afford (2//.4L -4-(| 1.1 '-biphenyl |-2-ylmethyl)- V-(fS')- 1 -(((6-amino-2- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)pyrrolidin e-2-carboxamide di- trifluoroacetate salt (22.2 mg, 67% yield) as a white solid. Example 177. Preparation of (2/?,4 _t V)-4-(4-biOmobenzyl)-iV-(fV)-l-((5-chloro-2-hydroxy- 3-methylbenzyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-carboxa mide Hydrochloride (1374)

Steps 1-2 : tert- Butyl (2i?,45 -4-(4-bromobenzyl)-2-(((5)-l-((5-chloro-2-hydroxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)carbamoyl)pyrrolidine-l -carboxylate was synthesized according to step 3 of the procedure for compound 1119 using the appropriate starting materials. Removal of the Boc group was achieved using the procedure from step 4 for compound (1313). The crude product was purified by chromatography (MeOH/CfhCh containing 2.5% 7 N Nfb-MeOH), then the collected fractions were concentrated, treated with 1 N HC1 and lyophilized to yield the title compound as a white powder (28 mg, 47% yield over 2 steps). Example 178. Preparation of (/?)-iV-((A)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-2-((4-chlorobenzyl)amino) -4-phenylbutanamide

(1375)

(i?)-2-Amino-/V-(( _< S)-l-(((6-amino-2-methylpyri din-3 -yl)methyl)amino)-l-oxopropan- 2-yl)-4-phenylbutanamide (148.5 mg, 0.246 mmol) was coupled with 4-chlorobenzaldehyde (45 mg, 0.320 mmol) according to the procedure for compound 1130, step 2. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-5% MeOH-CThCh) afforded (R)-N-((S)- 1 -(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-2-((4-chlorobenzyl)amino) -4-phenylbutanamide (57.3 mg, 44% yield).

Example 179. Preparation of (AJ-Ari-^e-Amino^-methylpyridin-S-ylJmethyl^-^i?)^- amino-4-phenylbutanamido)pentanediamide Di-trifluoroacetate (1376)

Step 7: /e/V-Butyl ((//)- 1 -((fY)-5-amino- 1 -(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l,5-dioxopentan-2-yl)amino)-l-oxo-4-phenylb utan-2-yl)carbamate (49 mg, 17% yield) was synthesized from ((//)-2-amino-4-phenylbutanoyl (-/.-glutamine (230 mg,

0.56 mmol, prepared according to the procedure for compound (1335), step 1-2 and 5- (aminomethyl)-6-methylpyridine-2-amine according to the procedure for compound (1326), step 3.

Step 2: Deprotection of /er/-butyl ((//)- 1 -(((S)-5-amino- 1 -(((6-amino-2-methylpyridin- 3-yl)methyl)amino)- 1 ,5-dioxopentan-2-yl)amino)- 1 -oxo-4-phenylbutan-2-yl)carbamate (49 mg, 0.09 mmol) was conducted according to the procedure for compound (1260), step 4 except that the final product was purified using reverse-phase HPLC.

Example 180. Preparation of (7?)-iV-(fV)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-2-(pentylamino)-4-phenylb utanamide Di- trifluoroacetate salt

Step 1: (//)-2-Amino-'V-(fS - 1 -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-phenylbutanamide (99.0 mg, 0.224 mmol) was coupled with pentanal (30 pL. 0.282 mmol) according to the procedure for compound 1130, step 2. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-5% MeOH-CTLCh) afforded (R)-N-((S)- 1 -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- l - oxopropan-2-yl)-2-(pentylamino)-4-phenylbutanamide (12.5 mg, 13% yield).

Step 2: To a solution of (R)-N-((S)- 1 -(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-2-(pentylamino)-4-phenylb utanamide in CH2CI2 (1 mL) was added TFA (0.5 mL). Volatile was evaporated under vacuum to afford of (R)-N-((S)- 1- (((6-amino-2-methylpyridin-3-yl)methyl)amino)-l-oxopropan-2- yl)-2-(pentylamino)-4- phenylbutanamide di-trifluoroacetate salt.

Example 181. Preparation of (2/?,4A)-iV-((A)- l-(((3-Chloro-l//-pyrrolo|2,3-/;]pyridin-5- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-cyclobutylbenzyl)pyr rolidine-2-carboxamide Di-trifluoroacetate salt (1378)

(2RAS)-N-((S)- 1 -(((3-Chloro- 1 //-pyrrolo| 2.3- |pyridin-5-yl (methyl )amino)- 1 - oxopropan-2-yl)-4-(4-cyclobutylbenzyl)pyrrolidine-2-carboxam ide di-trifluoroacetate salt was synthesized according to the procedures for compound (1356). Example 182. Preparation of (2/?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-cyclobutylbenzyl)pyr rolidine-2-carboxamide Di-trifluoroacetate salt (1379)

Step 7: 2-Benzyl 1 -(ter /-butyl) (2//AY)-4-(4-bromobenzyl)pyrrolidine- 1.2- dicarboxylate was synthesized according to the procedures for compound (1304), step 1 to step 3.

Step 2: In a 50 mL round bottom flask equipped with a stir bar and septum was added 2-benzyl 1 -(te/7-butyl) (2/L4.Y)-4-(4-bromobenzyl (pyrrolidine- 1.2-dicarboxylate (200 mg,

0.42 mmol), cyclobutyl boronic acid (84 mg, 0.84), Pd(dppf)Cl2 (31 mg, 0.042 mmol), K3PO4 (180 mg, 0.84 mmol), Toluene (3 mL) and water (0.3 mL). The resulting mixture was degassed by bubbling N2 through the solution for 10 min. The reaction was then heated to 90 °C for 16 h. Upon cooling to room temperature, the reaction solution was filtered through diatomaceous earth, eluting with EtOAc, concentrated and purified by chromatography using EtO Ac/hexanes to afford 2-benzyl 1 -(tert-butyl) (2//AY)-4-(4-cy clobutylbenzyl (pyrrol idine- 1, 2-dicarboxylate (30 mg, 16% yield) as a colorless sticky liquid.

Step 3: (2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-(4-cyclobutylbenzyl)pyrrolidine-2-carboxam ide di-trifluoroacetate salt was synthesized according to the procedures for compound (1304), step 4 to step 8, except that the final product was purified using reverse-phase HPLC.

Example 183. Preparation of (2i?, S -iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-(fe/Z-butyl)benzyl)p yrrolidine-2-carboxamide Dihydrochloride (1380)

(2R, 4S)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(4-(/cT/-butyl)benzyl)pyrrolidine-2-carbo\amide dihydrochloride was synthesized according to the procedures for compound (1304).

Example 184. Preparation of (i?)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-2-((4-(morpholine-4-carbo nyl)benzyl)amino)-4- phenylbutanamide Di-trifluoroacetate salt (1381)

Step 1: (7?)-2-Arnino-/V-((<S)-l-(((6-amino-2-methylpyridin-3-yl) methyl)arnino)-l- oxopropan-2-yl)-4-phenylbutanamide (42.5 mg, 0.115 mmol) was coupled with 4- (morpholine-4-carbonyl)benzaldehyde (37.5 mg, 0.171 mmol) according to the procedure for compound 1130, step 2. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-10% MeOH-CThCh) afforded (//)- V-(fS')- l -(((6- amino-2-methy lpyri din-3 -yl)methyl)amino)- l-oxopropan-2-y l)-2-((4-(morpholine-4- carbonyl)benzyl)amino)-4-phenylbutanamide (21.4 mg, 32% yield).

Step 2: (R)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-2-((4-(morpholine-4-carbonyl)benzyl)amino)-4-phenylbutan amide di-trifluoroacetate salt was formed according to the procedure for compound (1368), step 2.

Example 185. Preparation of (A)-7V ¹ -((6-Amino-2-methylpyridin-3-yl)methyl)-2- ((2/?,4A)-4-benzylpyrrolidine-2-carboxamido)pentanediamide Di-trifluoroacetate salt (1382)

Step 7: Methyl ((2//. S')-4-benzylpyrrolidine-2-carbonyl)-/.-glutaminate (130 mg, 84% yield) was synthesized from (2/iAY)-4-benzyl- l -(/e/7-butoxy carbonyl (pyrrol idine-2- carboxybc acid (106 mg, 0.35 mmol) and /.-glutamine methyl ester hydrochloride according to the procedure for compound (1326), step 1.

Step 2: ((2//.45')-4-Benzylpyrrolidine-2-carbonyl (- .-glutamine (l23mg, 96% yield) was synthesized from methyl ((2//.4.S')-4-benzylpyrrolidine-2-carbonyl)-/.-glutaminate (130 mg, 0.29 mmol) according to the procedure for compound (1326), step 2 except that the crude material was applied to the next step without further purification.

Step 3: /e/V-Butyl (2//.4.Y)-2-((fS')-5-amino- 1 -(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l,5-dioxopentan-2-yl)carbamoyl)-4-benzylpyr rolidine-l-carboxylate (125 mg, 81% yield) was synthesized from ((2//. S')-4-benzylpyrrolidine-2-carbonyl (-/.-glutamine (l23mg, 0.28 mmol) and 5-(aminomethyl)-6-methylpyridine-2-amine according to the procedure for compound (1326), step 3.

Step 4 Deprotection of /er/-butyl (2//.4Y')-2-((fS')-5-amino- 1 -(((6-amino-2- methylpyridin-3-yl)methyl)amino)-l,5-dioxopentan-2-yl)carbam oyl)-4-benzylpyrrolidine-l- carboxylate (125 mg, 0.23 mmol) was conducted according to the procedure for compound (1260), step 4 except that the final product was purified using reverse-phase HPLC.

Example 186. Preparation of (2/?,4/?)-,V-(fV)- l-((2-Hydroxy-3,5-dimethylbenzyl)amino)- l-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide Hydrochloride (1383)

Steps 1-2 : tert- Butyl (2//.4Y)-4-(4-bromobenzyl)-2-(((S)- 1 -((5-chloro-2-hydroxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)carbamoyl)pyrrolidine-l -carboxylate was synthesized according to step 3 of the procedure for compound 1119 using the appropriate starting materials. Removal of the Boc group was achieved using the procedure from step 4 for compound (1313) to yield the title compound as a beige solid (17.4 mg, 39% over two steps).

Example 187. Preparation of (2/?,4/?)-iV-((iV)-l-(((3-Chloro-l//-pyrazolo[3,4-/ ]pyridin-5- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide

Dihydrochloride (1384)

Step 1 : To a solution of li/-pyrazolo[3,4-Z>]pyridine-5-carbonitrile (303 mg, 2.1 mmol) in anhyd DMF (5 mL) under Ar was added NCS (280 mg, 2.1 mmol). The mixture was heated at 40 °C for 18 h after which the heat was increased to 55 °C. After heating for 5 h, additional NCS (134 mg, 1.0 mmol) was added and heating continued for 30 min. The mixture was slowly cooled to ambient temperature then H2O was added. The mixture was extracted with EtOAc and the combined organics were washed with H2O, sat. NaHCCh and brine then dried (Na2SCri) and cone in vacuo. The solid was chromatographed (0-40% EtOAc-hexanes) to give 3-chloro- 1 //-pyrazolo|3.4-Z> |pyridine-5-carbonitrile (216 mg, 58% yield).

Step 2: 3-Chloro- l//-pyrazolo| 3.4-6 |pyridine-5-carbonitrile was reduced according to the procedure given for compound (1323), step 1. Following filtration of the reaction mixture through diatomaceous earth and cone in vacuo, the solid was dissolved in 1 M HC1 and washed with EtOAc 3x. The aq layer was cone in vacuo to give (3-chloro- 1 //-pyra/olo| 3.4- 6]pyridin-5-yl)methanamine as a tan solid (184 mg, 60% yield).

Step 3: ((2i?,4i?)-l-(/er/-Butoxycarbonyl)-4-phenylpyrrolidine-2-car bonyl)-L-alanine was coupled to (3-chloro- li/-pyrazolo[3,4-6]pyridin-5-yl)methanamine according to the procedure given for (1280). Purification by chromatography (0-5% MeOEl-CEhCh) gave the product contaminated with acid starting material. The product was dissolved in EtOAc, washed with sat. NaHC03 3x, brine then dried over NaiSOr and cone in vacuo to give tot- butyl (2//.4//)-2-((6S - l -(((3-chloro- l//-pyra/olo| 3.4-6 |pyri din-5-yl )methyl)amino)- 1 - oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate (81 mg, 61% yield).

Step 4 tot-Butyl (2RAR)-2-(((S)- 1 -(((3-chloro- l//-py razolo| 3.4-6 |pyridin-5- yl)methyl)amino)-l -oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l -carboxylate was deprotected according to the procedure given for compound (1311), step 3 to give (IRAR)-N- (fSj- 1 -(((3-chloro- 1 //-pyra/olo| 3.4-6 |pyridin-5-yl)methyl)amino)- 1 -o\opropan-2-yl)-4- phenylpyrrolidine-2-carboxamide dihydrochloride (67.6 mg, 88% yield). Example 188. Preparation of (2/?,4V)-iV-(( _t V)- 1 -((5-chloro-2-( 1 //-tetrazol- 1 - yl)benzyl)amino)-l-oxopropan-2-yl)-4-(naphthalen-2-ylmethyl) pyrrolidine-2- carboxamide Trifluoroacetate salt (1385)

Steps 1-2 : tert-Butyl (S)-( I -((5-chloro-2-( I //-tetrazol- 1 -yl)benzyl)amino)- 1 - oxopropan-2-yl)carbamate was synthesized according to steps 3-4 of the procedure for compound (1313) using the appropriate starting materials (3.54 g, 76% yield over two steps).

Steps 3-4: The title compound was synthesized as a white powder according to steps 3-4 of the procedure for compound (1313) using the appropriate starting materials (15 mg, 40% yield over two steps). Example 189. Preparation of (2i?,4i?)-iV-((^)-l-((3-Chloro-5-cyanobenzyl)amino)-l- oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide Trifluoroacetate salt (1386)

Step 7: /e/7- Butyl ((//)- 1 -(((S)- 1 -((3-chloro-5-cyanobenzyl)amino)- 1 -oxopropan-2- yl)amino)-l-oxo-4-phenylbutan-2-yl)carbamate was synthesized as a colorless oil (95 mg, 62% yield) according to step 1 of the procedure for compound (1246) using the appropriate starting materials.

Step 2: Removal of the Boc group was achieved using procedure from step 4 for compound (1313) to yield the title compound as a white powder (21 mg, 67% yield).

Example 190. Preparation of (2i?,4i?)-iV-((^)-l-((3-Carbamoyl-5-chlorobenzyl)amino)-l- oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide Trifluoroacetate salt (1387)

Step 7: /e/V-Butyl (2RAR)-2-(((S)- 1 -((3-chloro-5-cyanobenzyl)amino)- 1 -oxopropan-2- yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate (65 mg, 0.13 mmol) was dissolved in EtOH (0.5 mL) and added dropwise to a stirring mixture of urea hydrogen peroxide (72 mg, 0.76 mmol) and NaOH (18 mg, 0.46 mmol) in H2O (1.2 mL) at 0 °C, then allowed to warm to ambient temperature over 2 h. Upon completion, the reaction mixture was diluted in EtOAc, washed with 10% aq. KHSO4 and brine. The organic layer was dried over Na ₂ S04, concentrated and purified by chromatography. The intermediate was then dissolved in CH2CI2 (2 mL) and treated with TFA (0.5 mL) at ambient temperature for 2 h, before being concentrated to furnish the title compound as a white powder (28 mg, 40% yield over two steps).

Example 191. Preparation of iV-((iV)- l-(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- l-oxopropan-2-yl)-7,7-dimethyl-5-oxo-4-phenyl-l,4,5,6,7,8-he xahydroquinoline-2- carboxamide (1388)

N-((S)-\ -(((6-amino-2-methy lpy ridin-3 -y l)methy l)amino)- 1 -oxopropan-2-y l)-7,7 - dimethyl-5-oxo-4-phenyl-l,4,5,6,7,8-hexahydroquinoline-2-car boxamide was synthesized according to the procedure for compound (1304), step 7 using 7,7-dimethyl-5-oxo-4-phenyl- l,4,5,6,7,8-hexahydroquinoline-2-carboxylic acid. Example 192. Preparation of ?)-/V-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-2,3,4,9-tetrahydro-///-py rido[3,4-/ ]indole-3- carboxamide Hydrochloride (1389)

(R)-N- (S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2-yl)- 2.3.4.9-tetrahydro-///-pyrido| 3.4- 1 indole-3 -carboxamide hydrochloride was synthesized according to the procedures for compound (1304), steps 7 and 8 using (3R)-2-(tert- butoxycarbonyl)-2,3,4,4a,9,9a-hexahydro-77/-pyrido[3,4-6]ind ole-3-carboxylic acid.

Example 193. Preparation of (2i?,4i?)-/V-((A)-l-(((3-Aminobenzo[</]isoxazol-6- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide Di- trifluoroacetate salt (1390)

Step 7: To a solution of 4-aminomethyl-2-fluoro-benzonitrile hydrochloride (1.0 g, 5.35 mmol) in MeOH (10 mL) and MeCN (10 mL) was added Et ₃ N (2.2 mL, 16.05 mmol), di-/c /-butyl dicarbonate (1.4 g, 6.43 mmol) and DMAP (653 mg, 5.35 mmol). After stirring for 16 h, the reaction mixture was cone and the residue was partitioned with EtOAc and H2O. The organic layer was separated, washed with brine, dried over anhyd Na ₂ S04, and cone under vacuum. The residue was purified by chromatography (0-100% EtOAc-hexanes) to give /er/-butyl (4-cyano-3-fluorobenzyl)carbamate (1.13 g, 88% yield).

Step 2: To a solution of acetohydroxamic acid in anhyd DMF was added KO'Bu (1 M in THF, 7.1 mL, 7.1 mmol). After stirring for 30 min at ambient temperature, tert- butyl (4- cyano-3-fluorobenzyl)carbamate (1.13 g, 4.73 mmol) was added to the above mixture. After stirring for 19 h at the same temperature, the reaction was quenched by addition of FhO and extracted with EtOAc. The organic layer was washed with brine, dried over anhyd Na ₂ S04, and cone under vacuum. The residue was purified by chromatography (0-100% EtOAc- hexanes) to give /er/-butyl ((3-aminobenzo[ri]isoxazol-6-yl)methyl)carbamate (925 mg, 74% yield).

Step 3: Deprotection of te/7-butyl ((3-aminobenzo[< ]isoxazol-6-yl)methyl)carbamate (125 mg, 0.48 mmol) was conducted according to the procedure for compound (1259), step 2 to give 6-(aminomethyl)benzo[ri|isoxazol-3 -amine di-trifluoroacetate salt (186 mg, 100% yield).

2TFA

Step 4 tert- Butyl (2i?,4i?)-2-(((»5)-l-(((3-aminobenzo[< ]isoxazol-6-yl)methyl)amino)- l-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylat e (153 mg, 84% yield) was synthesized from 6-(aminomethyl)benzo[ri]isoxazol-3-amine di-trifluoroacetate salt (130 mg, 0.47 mmol) according to the procedure for compound (1358), step 2.

Step 5: Deprotection of tert- butyl (27?,47?)-2-(((ri -l-(((3-aminobenzo[i7]isoxazol-6- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpyrroli dine-l-carboxylate (153 mg, 0.3 mmol) was conducted according to the procedure for compound (1260), step 4 except that the final product was purified using reverse-phase HPLC.

Example 194. Preparation of (2i?,4A)-/V-((A)-l-(((6-Aiiiino-2-iiiethylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-(2-oxopyrrolidin-l-y l)benzyl)pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1391)

Step 7: 2-Benzyl l-(tert-butyl) (2//.45')-4-(4-bromobenzyl)pyrrolidine- 1.2- dicarboxylate was synthesized according to the procedures for compound (1304), step 1 to step 3.

Step 2: In a 50 mL round bottom flask equipped with a stir bar and septum was added 2-benzyl 1 -(tert-butyl) (2//AY)-4-(4-bromobenzyl (pyrrolidine- 1.2-dicarbo\ylate (120 mg, 0.25 mmol), 2-pyridone (43 mg, 0.51), BrettPhos palladacycle (4.2 mg, 0.005 mmol), K3PO4 (108 mg, 0.51 mmol), /e/7-butanol (1.2 mL). The resulting mixture was degassed by bubbling N2 through the solution for 5 min. The reaction was then heated to 100 °C for 12 h. Upon cooling to room temperature, the reaction solution was filtered through diatomaceous earth, eluting with EtOAc, concentrated and purified by chromatography using EtOAc-hexanes to afford 2-benzyl 1 -(/er/-butyl) (2//.45')-4-(4-(2-oxopyrrolidin- 1 -yl)benzyl)pyrrolidine- 1.2- dicarboxylate (30 mg, 25% yield) as a colorless oil.

Step 3: (2RAS)-N-((S)- 1 -(((6-Ammo-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-(4-(2-oxopy rrolidin- 1 -y l)benzy l)py rrolidine-2-carboxamide di- trifluoroacetate salt was synthesized according to the procedures for compound (1304), step 4 to step 8, except that the final product was purified using reverse-phase HPLC.

Example 195. Preparation of (2i?,4^)-iV-((^)-l-(((3-Chloro-li -pyrrolo[2,3- »]pyridin-5- yl)methyl)amino)-l-oxopropan-2-yl)-4-(naphthalen-2-ylmethyl) pyrrolidine-2- carboxamide Di-Trifluoroacetate salt (1392)

(2RAS)-N-((S)- 1 -(((3-Chloro- 1 //-pyrrolo| 2.3-/ |pyridin-5-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-(naphthalen-2-ylmethyl)pyrrolidine-2-carbo xamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1334).

Example 196. Preparation of (2/?,4L)-4-([ 1,1’-Biphenyl]-2-ylmethyl)-iV-(fV)-l-(((3- chloro-l//-pyrrolo[2,3-/ ]pyridin-5-yl)methyl)amino)-l-oxopropan-2-yl)pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1393)

(2RAS)A-(\ 1. 1 '-Biphenyl |-2-yl methyl )-/V-((.Y)- 1 -(((3-Chloro- 1 //-pyrrolo|2.3- 6 |p> ridin-5-yl)methyl)amino)- l -oxopropan-2-yl)pyrrolidine-2-carboxamide di- trifluoroacetate salt was synthesized according to the procedures for compound (1356). Example 197. Preparation of (2R,4R)-N-((S)-l-((5-chloro-2-(2H-tetrazol-2- yl)benzyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide

Trifluoroacetate (1394)

Step 7: 2-Amino-5-chlorobenzonitrile (lg, 6.55 mmol) was dissolved in EtOH (5 mL) and H2O (10 mL), then treated with tetrafluoroboric acid (48% in H2O; 1.7 mL, 13.1 mmol) and cooled to 0 °C. Sodium nitrite (497 mg, 7.2 mmol) in H2O (10 mL) was added dropwise to the stirring mixture. After 1 h, the suspension was filtered using cold Et ₂ 0 and H2O then dried under vacuum to yield the diazonium tetrafluoroborate salt as a yellow solid (502 mg, 31% yield).

Step 2: The diazonium salt (502 mg, 2 mmol) and CFsCC Ag (530 mg, 2.4 mmol) were suspended in dry THF (20 mL) and cooled to -78 °C under Ar. EbN (418 pL, 3 mmol) was added dropwise followed by TMSCHN2 (2 M in hexanes; 1.1 mL, 2.2 mmol) after 10 minutes. The reaction mixture was allowed to stir for 1 h before slowly warming to ambient temperature and quenched with CsF (304 mg, 2 mmol) in MeOH. After 30 minutes, EtOAc and brine were added, then the organic layer separated and dried over Na ₂ S04 and concentrated. Purification by chromatography (30-40% EtO Ac/hexanes) furnished 5-chloro- 2-(2//-tetra/ol-2-yl)benzonitrile as a brown solid (86 mg, 21% yield).

Step 3: A solution of 5-chloro-2-(2//-tetrazol-2-yl)benzonitrile (86 mg, 0.42 mmol) in 7 N NFL in MeOH (5 mL) was degassed with an Ar balloon. Raney nickel (~40 mg) was added and a vacuum was pulled for 0.5 min prior to backfilling with a balloon of H2. The reaction mixture was stirred for 16 h at ambient temperature. Upon completion, the catalyst was removed by filtration through diatomaceous earth and the solution concentrated in vacuo to give (5-chloro-2-(2//-tetra/ol-2-yl)phenyl)methan amine (78 mg, 89% yield) as a brown oil.

Steps 4-5 : The title compound was synthesized as a white powder according to steps 3-4 of the procedure for compound (1313) using the appropriate starting materials, except with purification by prep HPLC (2.3 mg, 3% yield over two steps).

Example 198. Preparation of (2/?,4/?)-iV-(fV)- l-((3,5-dichloro-2-hydroxybenzyl)amino)- l-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide Trifluoroacetate (1395)

Steps 1-2 : tert- Butyl (2i?,4i?)-2-(((5)-l-((3,5-dichloro-2-hydroxybenzyl)amino)-l- oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate synthesized according to step 1 of the procedure for compound (1242) using the appropriate starting materials. Removal of the Boc group was achieved according to step 4 of compound (1313) to yield the title compound as a white crystalline solid (23 mg, 35% yield over two steps). Example 199. Preparation of (2/?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((2'-cyano-4'-fluoro-[l ,l ^, -biphenyl]-4- yl)methyl)pyrrolidine-2-carboxamide (1396)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-((2'-cyano-4'-fluoro-[l,r-biphenyl]-4-yl)methyl)pyrrol idine-2-carboxamide was synthesized according to the procedures for compound (1351), except that the free base was isolated after purification by column chromatography (0-10% [7 N Nfb-MeOHJ-CfhCh).

Example 200. Preparation of (2i?,4A)-iV-((A)-l-(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((2'-carbamoyl-4'-fluor o-[l,r-biphenyl]-4- yl)methyl)pyrrolidine-2-carboxamide Di-trifluoroacetate salt (1397)

(2i?,4 _< Y)-/V-((»Y)- 1 -(((6-Amino-2-methylpyri din-3 -yl)methyl)amino)- 1 -oxopropan-2- yl)-4-((2'-carbamoyl-4'-fluoro-[l,r-biphenyl]-4-yl)methyl)py nOlidine-2-carboxamide di- trifluoroacetate salt was synthesized according to the procedures for compound (1351), except that the final product was purified using reverse-phase HPLC.

Example 201. Preparation of 2-((2i?,4A)-2-(((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpiperid in-l-yl)acetic acid Trifluoroacetate salt (1398)

To a stirred solution of (2/ri4.Y)-/V-((.Y)- l -(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpiperidine-2-carb oxamide dihydrochloride (1253) (10 mg, 0.021 mmol) in CH2CI2 (1 mL) and NEt3 (0.3 mL) was added benzyl 2- bromoacetate (48 mg, 0.21 mmol) under Ar atmosphere. After stirring for 24 h at ambient temperature the reaction mixture was concentrated and dissolved in MeOH. To the solution was added 10% Pd/C (50 mg) and stirred under H2 atmosphere at room temperature for 18 h. The reaction mixture was filtered over diatomaceous earth and washed with MeOH. The organic washes were concentrated and purified by reverse-phase HPLC to yield 2-((2//AY)-2- (((5)- 1 -(((6-amino-2-methy lpyri din-3 -y l)methy l)amino)- 1 -oxopropan-2-y l)carbamoy l)-4- phenylpiperidin-l-yl)acetic acid trifluoroacetate salt (6.2 mg, 52% yield over 2 steps).

Example 202. Preparation of (2/?,-//?)-iV-((iV)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((4-phenylthiophen-2-yl )methyl)pyrrolidine-2- carboxamide Dihydrochloride (1399)

Step 7: 2-Benzyl 1 -(7m- butyl) (2R -//i)-4-((4-bromothiophen-2-yl)methyl)-5- oxopyrrolidine-l,2-dicarboxylate was synthesized according to the procedure for compound (1304).

Step 2: A solution of 2-benzyl 1 -(te/7-butyl) 27?,47? -4-((4-bromothiophen-2- yl)methyl)-5-oxopyrrolidine-l,2-dicarboxylate (270 mg, 0.55 mmol) and phenylboronic acid (0.66 mmol, 1.2 equiv.) in THF/2M K2CO3 (1: 1) was degassed with a stream of Ar for 5 min. Pd(PPh3)4 (0.05 equiv.) was added and the solution was heated at 60 ⁰ C overnight. THF was removed by evaporation and the solution was extracted with EtOAc. The organic layer was dried over Na ₂ S04 and evaporated. Column chromatography (10% EtOAc-hexanes) gave 2- benzyl 1 -(/e/7-butyl) (2R 4/ H5-o\o-4-((4-phenylthiophen-2-yl)methyl (pyrrolidine- 1.2- dicarboxylate (141 mg, 53% yield) as an oil.

Step 3: 2-Benzyl 1 -(/ - butyl) (2R 4/ /-4-((4-phenylthiophen-2- yl)methyl)pyrrolidine-l,2-dicarboxylate was synthesized according to the procedure for compound (1304).

Step 4 To a solution of 2-benzyl 1 -(/e/7-butyl) ^2i?,4i? ₎ -4-((4-phenylthiophen-2- yl)methyl)pynOlidine-l,2-dicarboxylate (100 mg, 0.21 mmol) in THF (2.0 ml) and MeOH (1.0 ml) was added LiOH (3.14 mmol, 15.0 equiv.) in H2O (1.0 ml) with stirring at room temp overnight. The solution was evaporated to dryness and H2O (5.0 ml) was added to the residue with swirling. The aqueous layer was extracted with ether, separated, pH adjusted to 5 with 10% KHSO4 and extracted with CH2CI2. The organic layer was dried over Na2SOr and evaporated giving (2R, 4R)-l -(/cT/-buto\ycarbonyl)-4-((4-phenylthiophen-2- yl)methyl)pyrrolidine-2-carboxylic acid (75 mg, 93% yield) as a foamy white solid.

Steps 5-6 : (2R 4R)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-((4-phenylthiophen-2-yl)methyl)pyrrolidine -2-carboxamide

dihydrochloride was synthesized according to the procedures for compound (1304).

Example 203. Preparation of (7?)-iV-((iV)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-l,2,3,4-tetrahydrobenzo[4 ,5]thieno[2,3-c]pyridine- 3-carboxamide Hydrochloride (1400)

(R)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2-yl)- 1.2.3.4-tetrahydrobenzo|4.5 |thieno|2.3-cj pyridine-3 -carboxamide hydrochloride was synthesized according to the procedures for compound (1304), steps 7 and 8 using (R)-2- (/er/-butoxy carbonyl)-!, 2, 3, 4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridine-3-carboxy lie acid. Example 204. Preparation of (2/?,4L')-4-([ 1,1’-Biphenyl]-2-ylmethyl)-iV-(fV)-l-((5-chloro- 2-hydroxy-3-methylbenzyl)amino)-l-oxopropan-2-yl)pyrrolidine -2-carboxamide Hydrochloride (1401)

Step 1-2 : The title compound was synthesized as a white powder (7.4 mg, 27% yield) according to steps 3-4 of the procedure for compound (1313) using the appropriate starting materials, except with purification of the crude product by chromatography (MeOH/C^Ch containing 2.5% 7 N NH3-MeOH), followed by treatment with 1 N HC1 and lyophilization overnight.

Example 205. Preparation of (2/?,4L')-4-([ 1,1’-Biphenyl]-2-ylmethyl)-iV-(fV)-l-((5-chloro- 2-(l//-tetrazol-l-yl)benzyl)amino)-l-oxopropan-2-yl)pyrrolid ine-2-carboxamide Trifluoroacetate (1402)

Steps 1-2: The title compound was synthesized as a white solid according to steps 3-4 of the procedure for compound (1313) using the appropriate starting materials (11 mg, 33% yield over two steps). Example 206. Preparation of (2/?,4V)-iV-(fV)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((2 ^, -(aminomethyl)-4'-fluoro-[l,l ^, -biphenyl]-4- yl)methyl)pyrrolidine-2-carboxamide (1403)

(2i?,45)-iV-((5)-l-(((6-Amino-2-methylpyridin-3-yl)methyl)am ino)-l-oxopropan-2- yl)-4-((2'-(aminomethyl)-4'-fluoro-[l,r-biphenyl]-4-yl)methy l)pyrrolidine-2-carboxamide was synthesized from (1396) according the procedure given for compound (1304), step 4.

Example 207. Preparation of (21?,4A')-/V-((A ^, )-l-((5-Chloro-2-(l//-tetrazol-l- yl)benzyl)amino)-l-oxopropan-2-yl)-4-(4-(pyridin-3-yl)benzyl )pyrrolidine-2- carboxamide Hydrochloride (1404)

Step 7: tot-Butyl (2/?,4<S)-2-(((<S)-l-((5-chloro-2-(l//-tetrazol-l-yl)b enzyl)amino)-l- oxopropan-2-yl)carbamoyl)-4-(4-(pyridin-3-yl)benzyl)pyrrolid ine-l-carboxylate (47 mg, 80% yield) was synthesized from (S)-2-amino-7V-(5-chloro-2-(li/-tetrazol-l- yl)benzyl)propanamide trifluoroacetate (28 mg, 0.10 mmol) according to the procedure for compound (1304), step 7.

Step 2: (2RAS)-N-((S)- 1 -((5-Chloro-2-( 1 H-tetrazol- 1 -yl)benzyl)amino)- 1 -oxopropan- 2-yl)-4-(4-(pyridin-3-yl)benzyl)pyrrobdine-2-carboxamide hydrochloride (43 mg, 90% yield) was synthesized from tot-butyl (2RAS)-2-(((S)- 1 -((5-chloro-2-( 1 //-tetrazol- 1 - y l)benzy l)amino)- 1 -oxopropan-2-y l)carbamoy l)-4-(4-(py ri din-3 -y l)benzy l)py rrolidine- 1 - carboxylate (47 mg, 0.07 mmol) according to the procedure for compound (1304), step 8.

Example 208. Preparation of (2/?,4V)-4-((2'-Carbamoyl-4’-fluoro-[ l,l '-biphenyl]-4- yl)methyl)-iV-(fV)-l-((5-chloiO-2-(l//-tetrazol-l-yl)benzyl) amino)-l-oxopropan-2- yl)pyrrolidine-2-carboxamide Hydrochloride (1405)

(27?,4<S -4-((2'-Carbamoyl-4'-fluoro-[l , l'-biphenyl]-4-yl)methyl)-7V-((5)-l -((5-chloro-

2-( 1 //-tetrazol- 1 -> l)benzyl)amino)- l -oxopropan-2-yl)pyrrolidine-2-carboxamide

hydrochloride was synthesized according to the procedures for compound (1404). Example 209. Preparation of (2/?,4V)-4-([ l,l '-Biphenyl]-3-ylmethyl)-iV-((A)-l-(((6- amino-2-methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)py rrolidine-2- carboxamide Dihydrochloric acid (1406)

Step 7: To a stirred solution of 2-benzyl 1 -(te/7-butyl) (7?)-5-oxopyrrolidine-l,2- dicarboxylate (3.25 g, 10.2 mmol) in THF (60 mL) at -78 °C was slowly added lithium bis(trimethylsilyl)amide (11.25 mL, 11.25 mmol, 1 M in THF) under Ar atmosphere. After stirring for 1 h at -78 °C, 3-bromobenzyl bromide (2.80 g, 11.25 mmol) was added and the stirring continued for an additional 2 h. The reaction mixture was quenched with sat. NH4CI solution and extracted with diethyl ether (3 x 100 mL). The combined extracts were dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by chromatography (EtOAc-hexanes) gave 2-benzyl \-(ter /-butyl) (27?,4ri)-4-(3-bromobenzyl)-5- oxopyrrolidine-l,2-dicarboxylate (3.47 g, 70% yield).

Step 2: To a solution of 2-benzyl 1 -(te/7-butyl) (2/L4.Y)-4-(3-bromobenzyl)-5- oxopyrrolidine-l,2-dicarboxylate (3.47 g, 7.12 mmol) in THF (47 mL) at -78 °C was added lithium triethylborohydride solution (7.83 mL, 7.83 mmol, 1 M in THF) under Ar atm. After 30 min, the reaction mixture was quenched with sat. NaHCCh solution (20 mL) and warmed to 0 °C. At 0 °C, 30% H2O2 (about 60 drops) was added and the reaction mixture was stirred at same temperature for 30 min. The volatiles were removed under vacuum and the aqueous layer was extracted with CH2CI2 (3 x 60 mL). The combined organic extracts were thoroughly dried using Na2SC>4, filtered, concentrated to afford 2-benzyl l-(/er/-butyl) (27?,4ri -4-(3-bromobenzyl)-5-hydroxypyrrolidine-l,2-dicarboxylate (3.30 g crude) that was directly used in the next step without further purification. O Boc O Boc

Step 3: To a stirred solution of 2-benzyl 1 -(te/7-butyl) (2i?,45)-4-(3-bromobenzyl)-5- hydroxypyrrolidine-l, 2-dicarboxylate (3.30 g crude) and triethylsilane (1.25 mL, 7.80 mmol) in CH2CI2 (36 mL) at -78 °C was drop wise added boron trifluoride diethyl etherate (0.95 mL, 7.80 mmol) under Ar atm. After 30 min at same temperature additional triethylsilane (1.25 mL, 7.80 mmol) and boron trifluoride diethyl etherate (0.95 mL, 7.80 mmol) were added. After stirring for 2 h at -78 °C, the reaction mixture was quenched with sat. aqueous NaHCCh solution (20 mL) and extracted with CH2CI2 (3 x 60 mL). The combined extracts were dried over Na2S04, filtered and cone under vacuum. The residue was purified by chromatography (EtOAc-hexanes) to afford 2-benzyl 1 -(/e/7-butyl) (2//AY)-4-(3-bromobenzyl)pyrrolidine- 1.2- dicarboxylate (1.60 g, 47% yield in two steps).

Step 4: In a 50 mL round bottom flask equipped with a stir bar and septum was added 2-benzyl 1 -(Ye/7-butyl) (2//.4Y)-4-(3-bromobenzyl /pyrrolidine- 1.2-dicarboxylate (200 mg, 0.42 mmol), phenyl boronic acid (62 mg, 0.51), Pd(dppf)Cl2 (31 mg, 0.042 mmol), cesium carbonate (413 mg, 1.26 mmol), THF (4.2 mL) and water (0.42 mL). The resulting mixture was degassed by bubbling N2 through the solution for 10 min. The reaction was then heated to 90 °C for 4 h. Upon cooling to ambient temperature, the reaction solution was filtered through diatomaceous earth, eluting with EtOAc, concentrated and purified by

chromatography using EtOAc-hexanes to afford 2-benzyl 1 -(ter /-butyl) (2//.4L')-4-(| 1. G- biphenyl]-3-ylmethyl)pyrrolidine-l, 2-dicarboxylate (167 mg, 83% yield) as a colorless sticky liquid.

Step 4 A solution of 2-benzyl 1 -(/e/7-butyl) (2//.4L')-4-(| 1.1 '-biphenyl | -3- ylmethyl)pyrrolidine-l, 2-dicarboxylate (167 mg, 0.35 mmol) in MeOH (3 mL) was bubbled with Ar gas for 5 minutes. 10% Pd/C (17 mg) was added to the reaction mixture and that was stirred under 1 atm of Lh for 3 h. The reaction mixture was filtered (0.2 mhi syringe filter) and the filtrate was concentrated under vacuum to give (2//.4S')-4-(| I . I '-biphenyl |-3-ylmethyl)- 1 - (/e/V-butoxy carbonyl )pynOlidine-2-carboxy lie acid (130 mg, 96% yield).

Step 5: To a stirred solution of (/cT/-buto\y carbonyl)-/. -alanine (1.96 g, 10.38 mmol) in CH2CI2 (55 mL) was added NHS (1.25 g, 10.89 mmol) at room temperature. To the reaction mixture DCC (2.25 g 10.9 mmol) was added and the reaction mixture stirred for 1.0 h. 5-(Aminomethyl)-6-methylpyridin-2-amine was added to the reaction mixture and sonicated for 5 min. The 5-(aminomethyl)-6-methylpyridin-2-amine was completely dissolved and stirred the reaction mixture at ambient temperature for 1 h. The crude reaction mixture was filtered and cone under reduced pressure. The crude reaction mixture was purified by chromatography using MeOH-CLLCh to afford tert- butyl ( _< S)-(l-(((6-amino-2- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)carbamate (2.35 g, 70% yield) as a white solid.

Step 6: To /e/V-butyl (S)-( I -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)carbamate (2.35 g, 7.62 mmol) was added a solution of MeOH-HCl (19 mL,

2 M) with stirring at ambient temperature while monitoring for the consumption of starting material (typically 1 h). The solution was evaporated to dryness and MeOH (50 mL) was added and evaporated to dryness to remove residual HC1 gas to give (S)-2- am i n o -V-(( 6 - amino-2-methylpyridin-3-yl)methyl)propanamide hydrochloride (1.60 g, 90% yield) as an off white solid (hygroscopic).

Step 7: To a stirred solution of (2//.4Y)-4-(| 1.1 '-biphenyl |-3-ylmethyl)- 1 -(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (40 mg, 0.10 mmol) in anhydrous DMF (1 mL) was added HOBt (16 mg, 0.11 mmol), DIEA (0.07 mL, 0.42 mmol) and EDC (22 mg, 0.11 mmol) at ambient temperature. The reaction mixture was stirred for 30 min at ambient temperature. (<S)-2-amino-/V-((6-amino-2-methylpyridin-3-yl)methyl)pro panamide hydrochloride (26 mg, 0.12 mmol) was added to the reaction mixture and stirred overnight. The solution was evaporated to dryness and the residue was partitioned with EtOAc (10 mL) and 10% KHSCri (5 mL). The organic layer was separated and washed with sat. NaHCCh solution (10 ml), dried over anhydrous Na2S04 and cone under vacuum. The crude reaction mixture was purified by chromatography using MeOH-CLLCh to afford /e/V-butyl (2//AY)-4- ([1,1 '-biphenyl] -3 -y lmethy l)-2-((( _< S - 1 -(((6-amino-2-methy lpyridin-3-y l)methy l)amino)- 1 - oxopropan-2-yl)carbamoyl)pyrrolidine-l-carboxylate (48 mg, 80% yield) as a white solid.

Step 8: To /e/V-butyl (2/iAY)-4-(| 1. 1 '-biphenyl | -3 -yl methyl )-2-(((.Y)- 1 -(((6-amino-2- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl) pynOlidine-l-carboxylate (48 mg, 0.08 mmol) was added a solution of MeOH-HCl (2.0 mL, 2 M) with stirring at ambient temperature while monitoring for the consumption of starting material (30 min to lh). The solution was evaporated to dryness and MeOH (10 mL) was added and evaporated to dryness to remove residual HC1 gas to yield (2//AY)-4-(| 1. 1 '-biphenyl |-3-ylmethyl)- V-(fS')- l-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-l-oxopropan- 2-yl)pyrrolidine-2- carboxamide dihydrochloride (48 mg, 95%) as a white solid.

Example 210. Preparation of (2/?,4A)-iV-((A)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3,5-dimethoxybenzyl)py rrolidine-2- carboxamide Di-trifluoroacetate salt (1407)

OMe

Stepl·. 2-Benzyl \- ter /-butyl) (2/iAY)-4-(3.5-dimethoxy benzyl )-5-oxopyrrolidine- 1.2- dicarboxylate (619 mg, 85% yield) was synthesized from 2-benzyl \-(ter /-butyl) (R)- 5- oxopyrrolidine-l,2-dicarboxylate (500 mg, 1.56 mmol) and 3,5-dimethoxybenzyl bromide according to the procedure for compound (1304), step 1.

Step 2: 2-Benzyl 1 -(tert-butyl) (2//AY)-4-(3.5-dimetho\y benzyl )-5- hydroxypyrrolidine-l,2-dicarboxylate was synthesized from 2-benzyl l-(tert-butyl) (2RAS)- 4-(3,5-dimethoxybenzyl)-5-oxopyrrolidine-l,2-dicarboxylate (619 mg, 1.32 mmol) according to the procedure for compound (1304), step 2.

Step 3: 2-Benzyl 1 -(tert-butyl) (2//AY)-4-(3.5-dimetho\ybenzyl)pyrrolidine- 1.2- dicarboxylate (322 mg, 54% for 2 steps) was synthesized from 2-benzyl 1 -(/er/-butyl) (2//AY)-4-(3.5-dimetho\ybenzyl)-5-hydro\ypyrrolidine- 1.2-dicarbo\ylate according to the procedure for compound (1304), step 3.

Step 4: (2RAS)- 1 -(/c /-butoxy carbonyl )-4-(3.5-di methoxy benzyl )py rrolidine-2- carboxylic acid (232 mg, 90% yield) was synthesized from 2-benzyl 1 -(/e/7-butyl) (2//AY)-4- (3,5-dimethoxybenzyl)pyrrolidine-l,2-dicarboxylate (322 mg, 0.71 mmol) according to the procedure for compound (1304), step 4.

Step 5: /e/V-Butyl (2RAS)-2-(((S)- 1 -(((6-arnino-2-rnethylpyridin-3-yl)rnethyl)arnino)- l-oxopropan-2-yl)carbamoyl)-4-(3,5-dimethoxybenzyl)pyrrolidi ne-l-carboxylate (61 mg, 76% yield) was synthesized from (2i?,4S)-l-(/er/-butoxycarbonyl)-4-(3,5- dimethoxybenzyl)pyrrolidine-2-carboxylic acid (53 mg, 0.15 mmol) according to the procedure for compound (1304), step 5.

Step 6: Deprotection of /e/V-butyl (2//.4L')-2-(((L - 1 -(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-(3,5-dimethox ybenzyl)pyrrolidine-l- carboxylate (61 mg, 0.11 mmol) was conducted according to the procedure for compound (1260), step 4 except that the final product was purified using reverse-phase HPLC.

Example 211. Preparation of (2/?,4 _t V)-iV-(fV)- l-((5-ChloiO-2-hydiOxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)-4-(2-(5-chlorothiophen -2- yl)benzyl)pyrrolidine-2-carboxamide Hydrochloride (1408)

Step 7: A 20 mL pressure vial was charged with 2-benzyl l-(ter /-butyl) (2//.4S')-4-(2- bromobenzyl)pyrrolidine-l,2-dicarboxylate (121 mg, 0.26 mmol), (5-chlorothiophen-2- yl)boronic acid (83 mg, 0.51 mmol), Pd(dppf)Ch (19 mg, 0.026 mmol) and K2CO3 (108 mg, 0.78 mmol) before being sparged with Ar. Dioxane (3 mL) and H2O (0.3 mL) were added by syringe, and the reaction mixture was sealed and allowed to stir at 90 °C for 18 h. Upon completion, the reaction mixture was concentrated and purified by chromatography (0-30% EtO Ac/hexanes) to yield 2-benzyl \-(ter /-butyl) (27?,4S)-4-(2-(5-chlorothiophen-2- yl)benzyl)pyrrobdine-l,2-dicarboxylate (82 mg, 62% yield) as ayellow oil.

Step 2: A 50 mL round bottom flask was charged with 2-benzyl 1 -(ter /-butyl) (27?, 45)- 4-(2-(5-chlorothiophen-2-yl)benzyl)pynOlidine-l,2-dicarboxyl ate (82 mg, 0.16 mmol), LiOH (58 mg, 2.4 mmol) and a mixture of TFlF/MeOFl/FbO (2: 1 : 1). Upon completion, the reaction mixture was concentrated, acidified to pH ~3 with 1 M HC1 and extracted with EtO Ac 2x. Concentration in vacuo gave (2/? AY)- 1 -(/e/7-butoxy carbonyl )-4-(2-(5-chlorothiophen-2- yl)benzyl)pyrrolidine-2-carboxylic acid as ayellow oil.

Step 3: (2RAS)- 1 -(/e/7-Butoxycarbonyl)-4-(2-(5-chlorothiophen-2- yl)benzyl)pyrrobdine-2-carboxybc (17 mg, 0.04 mmol) and HOBt (5.9 mg, 0.044 mmol) were dissolved in DMF (1 mL). EDC (8.4 mg, 0.044 mmol) was then added in a single portion, followed by ethylamine (2 M in THF, 150 pL) and DIEA (21 pL, 0.12 mmol). The resulting solution was allowed to stir at room temp for 16 h. The reaction mixture was then diluted with EtO Ac, washed with 10% aqueous KHSO4 and brine. Purification by chromatography (70-80% EtO Ac/hexanes) gave tert- butyl (2/i AY)-2-(((.Y)- 1 -((5-chloro-2- hydroxy-3-methylbenzyl)amino)-l-oxopropan-2-yl)carbamoyl)-4- (2-(5-chlorothiophen-2- yl)benzyl)pyrrolidine-l-carboxylate as a colorless oil.

Step 4: The title compound was synthesized as an off-white powder (10 mg, 46% yield over two steps) according to step 4 of the procedure for compound (1313), except with purification by chromatography (5% MeOH/CEhCh containing 2.5% 7 N NEE-MeOEl) followed by treatment with 1 N HC1 and lyophilization overnight.

Example 212. Preparation of (2/?,4A)-iV-((A)-l-((5-Chloro-2-(l//-tetrazol-l- yl)benzyl)amino)-l-oxopropan-2-yl)-4-(2-(5-chlorothiophen-2- yl)benzyl)pyrrolidine-2- carboxamide Trifluoroacetate (1409)

Steps 1-2 : The title compound was synthesized as a beige powder (10 mg, 43% yield over two steps) according to steps 3-4 of the procedure for compound (1408) except with purification by prep-HPLC (ACN/EEO + TFA). Example 213. Preparation of (2i?,4^)-iV-(( )-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(2-(5-chlorothiophen-2- yl)benzyl)pyrrolidine-2- carboxamide Trifluoroacetate (1410)

Steps 1-2 : The title compound was synthesized as a beige powder (7.6 mg, 37% yield over two steps) according to steps 3-4 of the procedure for compound (1408) except with purification by prep-HPLC (ACN/H2O + TFA).

Example 214. Preparation of 3-((2i?,4A)-2-(((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpiperid in-l-yl)propanoic acid Trifluoroacetate salt (1411)

Steps 1 and 2: To a stirred solution of (2/ri4.Y)-/V-((S)- 1 -(((6-amino-2-methylpyridin- 3-yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpiperidine-2-ca rboxamide dihydrochloride (10 mg, 0.021 mmol) in CH2CI2 (2 mL) and NEt3 (0.1 mL) was added ethyl 3- bromopropanoate (0.026 ml, 0.21 mmol) under Ar atmosphere. After stirring for 24 h at ambient temperature the reaction mixture was concentrated and dissolved in THF (2 mL). To the solution was added LiOH (10 mg, 0.21 mmol) dissolved in 2 ml of water at room temperature and stirred at ambient temperature for 18 h. The reaction mixture was acidified with TFA and purified by reverse-phase HPLC to yield 3-((2//.4L')-2-(((L')- 1 -(((6-amino-2- methy lpy ridin-3 -y l)methy l)amino)- 1 -oxopropan-2-y l)carbamoy l)-4-pheny lpiperidin- 1 - yl)propanoic acid trifluoroacetate salt (8.0 mg, 81% yield over two steps).

Example 215. Preparation of 6-((2/?,4A)-2-(((A)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpiperid in-l-yl)hexanoic acid Trifluoroacetate salt (1412)

6-((2//.4L')-2-(((L')- 1 -(((6- Amino-2-methy lpy ridin-3-y l)methy l)amino)- 1 -oxopropan- 2-yl)carbamoyl)-4-phenylpiperidin-l-yl)hexanoic acid trifluoroacetate salt was synthesized according to the procedures for compound (1411) using the corresponding bromoester. Example 216. Preparation of (2i?,4A,5i?)-A-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-benzyl-5-ethylpyrrolidi ne-2-carboxamide Di- trifluoroacetate salt (1413)

To a solution of 2-benzyl 1 -(te/7-butyl) (2//.4S')-4-benzyl-5-o\opyrrolidine- 1.2- dicarboxylate (0.2 g, 0.49 mmol) in THF (20 mL) at -78 °C was added ethyl magnesium bromide solution (0.53 mL, 0.53 mmol, 1 M in THF) under Ar atmosphere. After 30 min, the reaction mixture was quenched with saturated NaHCCb solution (5 mL) and warmed to 0 °C. The organic volatiles were removed under vacuum and the aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic extracts were thoroughly dried using Na2S0 ₄ , filtered, and concentrated to afford 2-benzyl 1 -(tert-butyl) (2R,4S)-4-benzyl-5-ethyl-5- hydroxypyrrolidine-l,2-dicarboxylate (220 mg crude). This material was directly used in the next step without further purification. Subsequent steps were followed according to the procedures for compound (1304).

Example 217. Preparation of (2/?,4A)-iV-((A)-l-((5-Chloro-2-(l H-tetrazol-1- yl)benzyl)amino)-l-oxopropan-2-yl)-4-(naphthalen-l-ylmethyl) pyrrolidine-2- carboxamide Hydrochloride (1414)

(2RAS)-N-((S)- 1 -((5-Chloro-2-( I //-tetrazol- 1 -yl)benzyl)amino)- 1 -oxopropan-2-yl)-4- (naphthalen-l-ylmethyl)pyrrolidine-2-carboxamide hydrochloride was synthesized according to the procedures for compound (1404). Example 218. Preparation of (2i?,4S)-ZV-((»S')-l-(((3-Chloro-li/-pyrrolo[2,3-Z>]pyri din-5- yl)methyl)amino)-l-oxopropan-2-yl)-4-(naphthalen-l-ylmethyl) pyrrolidine-2- carboxamide Hydrochloride (1415)

(2RAS)-N-((S)- 1 -(((3-Chloro- 1 //-pyrrolo| 2.3-6|pyridin-5-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-(naphthalen-l -ylmethyl)pyrrolidine-2-carboxamide hydrochloride was synthesized according to the procedures for compound (1334).

Example 219. Preparation of (2i?,4»S)-ZV-((»S)-l-((5-Chloro-2-(l//-tetrazol-l- yl)benzyl)amino)-l-oxopropan-2-yl)-4-(3,5-dimethylbenzyl)pyr rolidine-2-carboxamide Hydrochloride (1416)

(2RAS)-N-((S)- 1 -((5-Chloro-2-( I //-tetra/ol- 1 -yl)benzyl)amino)- 1 -o\opropan-2-yl)-4- (3,5-dimethylbenzyl)pyrrolidine-2-carboxamide hydrochloride was synthesized according to the procedures for compound (1404).

Example 220. Preparation of (2/?,4/?)-iV-(fV)- l-(((7-Chloro-///-benzo[r/]imidazol-5- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide

Trifluoroacetate salt (1417)

Step 7: /e/V-Butyl (2RAR)-2-(((S)- 1 -(((7-chloro-///-benzo|6/|imida/ol-5- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpyrroli dine-l-carboxylate (102 mg, 92% yield) was synthesized from l-(7-chloro-777-benzimidazole-5-yl)methanamine (50 mg, 0.28 mmol) according to the procedure for compound (1358), step 2.

Step 2: Deprotection of /e/V-butyl (27?,47?)-2-(((<S)-l-(((7-chloro-777-benzo[<7]imidazol - 5-y l)methy l)amino)- 1 -oxopropan-2-y l)carbamoy l)-4-pheny lpy rrobdine- 1 -carboxy late (102 mg, 0.19 mmol) was conducted according to the procedure for compound (1260), step 4 except that the final product was purified using reverse-phase HPLC.

Example 221. Preparation of (2/?,4/?)-iV-(fV)- l-(((7-Chloro-2-methyl-///- benzo[r/]imidazol-5-yl)methyl)amino)-l-oxopropan-2-yl)-4-phe nylpyrrolidine-2- carboxamide Trifluoroacetate salt (1418)

Step 7: (7-Chloro-2-methyl-777-benzo[<7]imidazol-5-yl)methanamine was synthesized from 7-chloro-2-methyl-777-benzo[<7]imidazole-5-carbonitrile (100 mg, 0.52 mmol) according to the procedure for compound (1358), step 1.

Step 2: tot-Butyl (27?,47?)-2-(((»S)-l-(((7-chloro-2-methyl-777-benzo[ _< 7]imidazol-5- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpyrrobd ine-l-carboxylate (98 mg, 35% for 2 steps) was synthesized from (7-Chloro-2-methyl-777-benzo[ _< 7]imidazol-5- yl)methanamine (102 mg, 0.52 mmol) according to the procedure for compound (1358), step 2

Step 3: Deprotection of tot-butyl (27?,47?)-2-((( _< S)-l-(((7-chloro-2-methyl-777- benzo[<7|imidazol-5-yl)methyl)amino)-l-oxopropan-2-yl)car bamoyl)-4-phenylpyrrobdine-l- carboxylate (98 mg, 0.18 mmol) was conducted according to the procedure for compound (1260), step 4 except that the final product was purified using reverse-phase HPLC. Example 222. Preparation of (27?,4A ^, )-/V-((A')-l-((5-Chloro-2-(///-tetrazol-l- yl)benzyl)amino)-l-oxopropan-2-yl)-4-(3,5-dimethoxybenzyl)py rrolidine-2-carboxamide Trifluoroacetate salt (1419)

Step 1 : tert- Butyl (S)-( 1 -((5-chloro-2-( ///-tetra/ol- 1 -yl)benzyl)amino)- 1 -oxopropan- 2-yl)carbamate (3.54 g, 76% yield) was synthesized from 5-chloro-2-( ///-tetra/ol e- 1 - yl)benzenemethamine (3.0 g, 12.2 mmol) according to the procedure for compound (1259), step 3.

Step 2: Deprotection of te/7-butyl (S)-( I -((5-chloro-2-( ///-tetrazol- 1 - yl)benzyl)amino)-l-oxopropan-2-yl)carbamate (3.54 g, 9.3 mmol) was conducted according to the procedure for compound (1259), step 2.

Step 3: /e/7- Butyl (2RAS)-2-(((S)- 1 -((5-chloro-2-( ///-tetrazol- 1 -yl)benzyl)amino)- 1 - oxopropan-2-yl)carbamoyl)-4-(3,5-dimethoxybenzyl)pynOlidine- l-carboxylate (85 mg, 76% yield) was synthesized from fV)-2-amino- V-(5-chloro-2-( ///-tetrazol- 1 - yl)benzyl)propenamide trifluoroacetate salt (99 mg, 0.23 mmol) according to the procedure for compound (1358), step 2.

Step 4 Deprotection of tert- butyl (27?,4<5)-2-(((<5)-l-((5-chloro-2-(777-tetrazol-l- yl)benzyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-(3,5-dimethox ybenzyl)pynOlidine-l- carboxylate (85 mg, 0.14 mmol) was conducted according to the procedure for compound (1260), step 4 except that the final product was purified using reverse-phase HPLC.

Example 223. Preparation of (2/?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-(azetidine-l-carbony l)benzyl)pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1420)

Step 7: 2-Benzyl 1 -(ter /-butyl) (2//AY)-4-(3-bromobenzyl)pyrrolidine- 1.2- dicarboxylate was synthesized according to the procedures for compound (1304), step 1 to step 3.

Step 2: A 25 mL vial equipped with a stir bar was charged with (C0 ₂ H H ₂ 0) ₂ (80 mg, 0.63 mmol), Pd(OAc) ₂ (1 mg, 0.0042), xantphos (2.5 mg, 0.0042), benzyl (27?,4 _< S)-4-(3- bromobenzyl)pyrrolidine-2-carboxylate (200 mg, 0.42 mmol), Ac ₂ 0 (60 pL, 0.633 mmol), DIEA (0.11 mL, 0.63 mmol), and DMF (2.0 mL) in air. The tube was quickly sealed with a Teflon® high pressure valve, frozen in liquid nitrogen, evacuated and backfilled with N ₂ (5 times). After the reaction mixture was stirred in a preheated oil bath (100 °C) for 6 h, it was allowed to cool down to ambient temperature. The reaction mixture was diluted with EtOAc (10 mL), acidified with 2 M HC1 (5 mL, once), and washed with brine (5 mL, twice). The organic phase was dried over anhydrous NaiSCri and concentrated in vacuo to afford 3- (((3S,5i?)-5-((benzyloxy)carbonyl)pyrrolidin-3-yl)methyl)ben zoic acid (45 mg, 25% yield) that was directly used in the next step without further purification.

Step 3: To a stirred solution of 3-(((3ri',5i?)-5-((benzyloxy)carbonyl)pyrrolidin-3- yl)methyl)benzoic acid (45 mg, 0.10 mmol) and triethylamine (0.10 mL, 0.70 mmol) in CH2CI2 (1 mL) at 0 °C was added oxalyl chloride (0.34 pL, 0.40 mmol), azetidine (30 mg, 0.50mmol) followed by DMF (2 drops) under Ar atm. The reaction mixture was stirred at ambient temperature overnight and the solvents were removed under reduced pressure. The residue was purified by chromatography (EtOAc-hexanes) to afford benzyl (2/L4.Y)-4-(3- (azetidine- l-carbonyl)benzyl)pyrrolidine-2-carboxy late (31 mg, 61% yield).

Step 4 (2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-(3-(azetidine-l-carbonyl)benzyl)pynOlidine -2-carboxamide di- trifluoroacetate salt was synthesized according to the procedures for compound (1304), step 4 to step 8, except that the final product was purified using reverse-phase HPLC.

Example 224. Preparation of (2i?,4i?)- -((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((3-bromoisoxazol-5-yl) methyl)pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1421)

( 2R,4R)-N-((S )- 1 -(((6- Amino-2-methy lpy ridin-3 -y l)methy l)amino)- 1 -oxopropan-2- yl)-4-((3-bromoisoxazol-5-yl)methyl)pyrrolidine-2-carboxamid e di-trifluoroacetate salt was synthesized according to the procedures for compound (1328), except that the final product was purified using reverse-phase HPLC.

Example 225. Preparation of (2/?,-AV)-iV-((iV)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3,4-dichlorobenzyl)pyr rolidine-2-carboxamide Dihydrochloride (1422)

(2R, 4S)-N- (S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(3,4-dichlorobenzyl)pynOlidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304), except that the benzyl deprotection (Step 4) was done by following LiOH conditions as described for compound (1399).

Example 226. Preparation of (2/?,-AV)-iV-((iV)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((4-fluoronaphthalen-l- yl)methyl)pyrrolidine-2- carboxamide Dihydrochloride (1423)

(2R, 4S)-N- (S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-((4-fluoronaphthalen- 1 -yl)methyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304). Example 227. Preparation of (2/?,4A)-iV-((A)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3,5-bis(trifluoromethy l)benzyl)pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1424)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(3,5-bis(trifluoromethyl)benzyl)pynOlidine-2-carboxami de di-trifluoroacetate salt was synthesized according to the procedures for compound (1304), except for the final Boc deprotection:

To /e/7-butyl (2RAS)-2-(((S)- 1 -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)carbamoyl)-4-(3,5-bis(trifluoromethyl)benzyl) pyrrolidine-l-carboxylate (27.7 mg, 0.04 mmol) in CH2CI2 (200 pL, 0.2 M) was added TFA (67 pL, 0.88 mmol) with stirring at ambient temperature while monitoring for the consumption of starting material (1-2 h). The solution was evaporated to dryness and was purified using reverse-phase HPLC to yield (2RAS)-N-((S)- 1 -(((6-amino-2-methy lpyri din-3 -y l)methy l)amino)- 1 -oxopropan-2-y l)-4- (3,5-bis(trifluoromethyl)benzyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt (12.8 mg, 39% yield) as a white solid.

Example 228. Preparation of (2/?,4/?)-iV-(fV)- l-(((3-Amino-///-indazol-6- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide

Trifluoroacetate salt (1425)

Step 1 : tert- Butyl (2R.4R)-2-(((S)- 1 -(((3-amino-///-inda/ol-6-yl)methyl)amino)- 1 - oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate (147 mg, 88% yield) was synthesized from 6-(aminomethyl)-///-inda/ol-3-amine (70 mg, 0.43 mmol) according to the procedure for compound (1358), step 2.

Step 2: Deprotection of te/7-butyl (2RAR)-2-(((S)- 1 -(((3-amino-///-indazol-6- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpyrroli dine-l-carboxylate (147 mg, 0.29 mmol) was conducted according to the procedure for compound (1260), step 4 except that the final product was purified using reverse-phase HPLC.

Example 229. Preparation of (2i?,4^)-iV-((^)-l-((5-Chloro-2-(l//-tetrazol-l- yl)benzyl)amino)-l-oxopropan-2-yl)-4-phenylpiperidine-2-carb oxamide

Trifluoroacetate (1426)

Steps 1-2 : The title compound was synthesized as a white powder (11 mg, 16% yield over two steps) according to steps 1-2 of the procedure for compound (1246) using the appropriate starting materials, except with purification by prep-HPLC (ACN/H2O + TFA). Example 230. Preparation of (2i?,4A)-7V-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-bromobenzyl)pyrrolid ine-2-carboxamide Di- trifluoroacetate salt (1427)

Step 7: (2RAS)-N-((S)- 1 -(((6-Ammo-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-(4-bromobenzyl)pyrrolidine-2-carboxamide was synthesized according to the procedure for compound (1304) (30% yield in 3 steps).

Step 2: A solution of (27?, 4ri -7V-((ri)-l-(((6-amino-2-methylpyri din-3 - yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-bromobenzyl)pynOlidi ne-2-carboxamide (503.3 mg, 1.06 mmol) in THF (11 mL) and water (1.1 mL) was treated with potassium

benzyltrifluoroborate (287.0 mg, 1.45 mmol), CsCCb (1.05 g, 3.22 mmol), and PdCl2(pddf) (78 mg, 0.11 mmol). After purging with N2, the reaction was heated at 90 °C for 16 h and quenched with water. The reaction mixture was extracted with EtOAc (3 times). The organic layers were combined, washed with brine, dried (Na ₂ S04), vacuum filtered, and evaporated under vacuum. The crude product was dissolved in CH2CI2 and adsorbed on silica gel.

Purification by chromatography (0-100% EtOAc-hexanes) afforded 2-benzyl \-(ter /-butyl) (2/ri4Y)-4-(4-benzylbenzyl)pyrrolidine- 1.2-dicarbo\ylate (425.8 mg, 83% yield).

Step 3: Deprotection of 2-benzyl \-(ter /-butyl) (2//.4L')-4-(4- benzylbenzyl)pyrrolidine-l,2-dicarboxylate according to the procedure for compound (1304), step 4 afforded the crude (2/iAY)-4-(4-benzylbenzyl)- l -(/e/ /-butoxy carbonyl (pyrrol idine-2- carboxylic acid.

Step 4: /e/V-Butyl fY)-( 1 -(((6-((/c /-butoxy carbonyl )amino)-2-methy lpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamate was obtained according to the procedure for compound (1304), step 5 (87% yield).

Step5: Deprotection of /e/7-butyl (ri)-(l-(((6-((/er/-butoxycarbonyl)amino)-2- methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)carbamate was done according to the procedure for compound (1304), step 6 except the crude product was purified by

chromatography (0-10% 7 N NEE in MeOEl-CEECE) afforded (ri -2-amino-/V-((6-amino-2- methylpyridin-3-yl)methyl)propanamide (92% yield).

Step 6: CY)-2-Amino-/V-((6-amino-2-methylpyridin-3-yl (methyl (propan amide was coupled with the crude (2/iAY)-4-(4-benzylbenzyl)- l -(/e/ /-butoxy carbonyl (pyrrol idine-2- carboxylic acid according to the procedure for compound 1119, step 1 to afford tert- butyl (2RAS)-2-(((S)- 1 -(((6-amino-2-methy lpy ridin-3-y l)methy l)amino(- 1 -oxopropan-2- y l)carbamoy l)-4-(4-benzy lbenzy l)py rrolidine- 1 -carboxy late.

Step 7: A solution of /e/V-butyl (2RAS)-2-(((S)- 1 -(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-(4-benzy lbenzy l)pyrrolidine-l -carboxy late (45.0 mg, 0.0768 mmol) in CH2CI2 (1.0 mL) and TES (50 pL) was treated with TFA (500 pL) at 0 °C. The reaction was stirred at room temp for 2 h and concentrated under reduced pressure. The crude product was dissolved in CH2CI2 and adsorbed on silica gel. Purification by chromatography (0-5% 7 N NEE in MeOEl-CEECE) afforded (2RAS)-N-((S)- 1 -(((6-amino- 2-methylpyridin-3-yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-be nzylbenzyl)pyrrolidine-2- carboxamide (33.0 mg, 88% yield). Step 8: (2RAS)-N-((S)- 1 -(((6-Amino-2-methy lpy ridin-3 -y l)methy l)amino)- 1 - oxopropan-2-yl)-4-(4-benzylbenzyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was formed according to the procedure for compound (1368), step 2.

Example 231. Preparation of (2 ?,4S)-/V-(( _» S)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-cyanobenzyl)pyrrolid ine-2-carboxamide Di- trifluoroacetate salt (1428)

(2i?,45 -/V-((5 -l -(((6-Amino-2-methy lpy ridin-3 -yl)methy l)amino)-l -oxopropan-2- yl)-4-(4-cyanobenzyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1424).

Example 232. Preparation of (2/?,4A)-iV-((A)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-cyanobenzyl)pyrrolid ine-2-carboxamide Di- trifluoroacetate salt (1429)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(3-cyanobenzyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1424). Example 233. Preparation of (2i?,4^)-iV-(( )-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-phenoxybenzyl)pyrrol idine-2-carboxamide Di-trifluoroacetate salt (1430)

(2i?, 4 _< S)-/V-(( _< S')- l-(((6-amino-2-methylpyri din-3 -yl)methyl)amino)-l-oxopropan-2-yl)-

4-(4-phenoxybenzyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1424).

Example 234. Preparation of (2/?,-AV)-iV-((iV)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((4-cyanonaphthalen-l-y l)methyl)pyrrolidine-2- carboxamide Dihydrochloride (1431)

(2R, 4S)-N- (S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-((4-cyanonaphthalen- 1 -yl)methyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304).

Example 235. Preparation of 2i?, S -/V-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((3-chloronaphthalen-l- yl)methyl)pyrrolidine-2- carboxamide Dihydrochloride (1432)

(2R, 4S)-N- (S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-((3-chloronaphthalen- 1 -yl)methyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304), except that the benzyl deprotection (Step 4) was done by following LiOH conditions as described in compound (1399).

Example 236. Preparation of (2/?,4A)-iV-((A)-l-(((3-Chloro-///-pyrrolo[2,3-/ ]pyridin-5- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpiperidine-2-carb oxamide (1433)

Step 7: To a solution of (2RAS)- 1 -(/e/ /-butoxycarbonyl)-4-phenylpiperidine-2- carboxylic acid (5.0 g, 16.4 mmol) in MeCN (300 mL, 0.05 M) was added HOBt (2.g, 3.77 mmol), DIEA (11.4 mL, 13.7 mmol), and EDC (2.8 g, 3.77 mmol). After stirring for 30 min at ambient temperature, benzyl /.-alanine hydrochloride (814 mg, 18 mmol) was added and stirred for 16 h. The reaction mixture was cone and the residue was partitioned with EtOAc and 10% KHSCri solution. The organic layer was separated and washed with EhO and sat. aq NaHCCb. The organic layer was dried over anhyd NaiSOr and cone under vacuum. The residue was purified by chromatography (0-20% EtOAc-hexanes) to give /e/V-butyl (2//.4L - 2-(((S)- 1 -(benzyloxy)- 1 -oxopropan-2-y l)carbamoy l)-4-pheny lpiperidine- 1 -carboxy late (2.59 mg, 34% yield).

Step 2: A solution of /e/V-butyl (2RAS)-2-(((S)- 1 -(benzyloxy)- 1 -oxopropan-2- y l)carbamoyl)-4-phenylpiperi dine- l-carboxy late (2.59 mg, 5.54 mmol) was degassed with a stream of argon for 2 min. 10% Pd/C (130 mg) was added and a vacuum was pulled for 1 min. A balloon of Eh was added and the reaction was monitored for the consumption of starting material for 1.5 h. The catalyst was removed by filtration and the solution was evaporated to give ((2RAS)- 1 -(/e/V-butoxy carbonyl )-4-phenylpiperidine-2-carbonyl)-L- alanine (1.8 g, 86% yield).

Step 3: /e/V-Butyl (2RAS)-2-(((S)- 1 -(((3-chloro-///-pyrrolo| 2.3-6 |pyridin-5- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-pheny lpiperidine- l-carboxy late (75 mg,

93% yield) was synthesized from (3-chloro-///-pyrrolo|2.3-Z> |pyridin-5-yl)methanamine dihydrochloride (50 mg, 0.2 mmol) and ((2//AY)- l -(/cT/-buto\ycarbonyl)-4-phenylpiperidine- 2-carbonyl (-/.-alanine (57 mg, 0.15 mmol) according to the procedure for compound (1358), step 2

Step 4 Deprotection of /e/V-butyl (2//AS')-2-((fV)- 1 -(((3-chloro-///-pyrrolo| 2.3- Z>]pyridin-5-yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl) -4-phenylpiperidine-l- carboxylate (75 mg, 0.14 mmol) was conducted according to the procedure for compound (1260), step 4 except that the final product was purified using reverse-phase HPLC. Example 237. Preparation of (2/?,4/?)-iV-((iV)-l-((Imidazo[ l,2-«]pyridin-6- ylmethyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-carb oxamide

Dihydrochloride (1434)

Step 7: ((2RAR)- 1 -(/c /-Butoxycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine was coupled to imidazo[l,2-a]pyridin-6-ylmethanamine dihydrochloride according to the procedure for (1280), step 4 to give /e/V-butyl (27?,47?)-2-(((5 -l-((imidazo[l,2-a]pyridin-6- ylmethyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolid ine-l-carboxylate (80 mg, 74% yield).

Step 2: /e/V-Butyl (27?,47?)-2-(((S -l-((imidazo[l,2-a]pyridin-6-ylmethyl)amino)-l- oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate was deprotected according to the procedure for compound (1323), step 3 to give (27?,47?)-7V-((5 -l-((imidazo[l,2-a]pyridin- 6-ylmethyl)amino)- 1 -oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide dihydrochloride (86 mg, quant yield). Example 238. Preparation of (2/?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3,5-dichlorobenzyl)pyr rolidine-2-carboxamide Dihydrochloride (1435)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(3,5-dichlorobenzyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1328).

Example 239. Preparation of (2i?,4A)-4-Benzyl-/V-((A)-l-((5-bromo-3-methyl-2-(l//- tetrazol-l-yl)benzyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-c arboxamide

Trifluoroacetate (1436) and (2/?,4A)-4-Benzyl-iV-((A)-l-((3-methyl-2-(2//-tetrazol-2- yl)benzyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-carboxamide (1437)

Step 7: A 100 mL round bottom flask was charged with 5-bromo-2-fluoro-3- methylbenzonitrile (428 mg, 2 mmol), l//-tetra/ole (0.45 M in CAN; 5 mL), K2CO3 (318 mg, 2.3 mmol), and DMF (15 mL), then sealed under Ar and stirred at 80 °C for 72 h. Reaction mixture was then diluted with EtOAc, washed with H20, 5% aq. LiCl and brine. The organic layer was dried over Na2SCh. concentrated and purified by chromatography (20-60%

EtO Ac/hexanes) to give 5-bromo-3-methyl-2-(277-tetrazol-2-yl)benzonitrile as a white solid (78 mg, 80% yield based on recovered starting material).

Step 2: A solution of 5-bromo-3-methyl-2-(2//-tetra/ol-2-yl)benzonitrile (49 mg, 0.19 mmol) in 7 M NEE in MeOH (5 mL) was degassed with an Ar balloon. Raney nickel (~40 mg) was added and a vacuum was pulled for 0.5 min prior to backfilling with a balloon of EU The reaction mixture was stirred for 16 h at ambient temperature. Upon completion, the catalyst was removed by filtration through diatomaceous earth and the solution concentrated in vacuo to give an inseparable mixture of (5-bromo-3-methyl-2-(2//-tetrazol-2- yl)phenyl)methanamine and (3-methyl-2-(2//-tetra/ol-2-yl)phenyl)methanamine.

Step 3: DCC-mediated coupling was accomplished according to step 3 of the procedure for compound (1313) using the appropriate starting materials. Purification by chromatography (EtO Ac/hexanes) furnished both tert- butyl (2//.45')-4-benzyl-2-((fV)- 1 -((5- bromo-3-methyl-2-(2//-tetrazol-2-yl)benzyl)amino)- 1 -oxopropan-2- yl)carbamoyl)pyrrolidine-l-carboxylate (44 mg, 35% yield) and tert- butyl (2//AY)-4-benzyl- 2-(((S)- 1 -((3 -methyl-2-(2//-tetrazol-2-yl)benzyl)amino)- 1 -oxopropan-2- yl)carbamoyl)pyrrolidine-l-carboxylate (66 mg, 60% yield).

Step 4 Removal of the Boc group from tert- butyl (2//.4Y')-4-benzyl-2-((fS')- 1 -((5- bromo-3-methyl-2-(2//-tetrazol-2-yl)benzyl)amino)- 1 -oxopropan-2- yl)carbamoyl)pyrrolidine-l-carboxylate was achieved using procedure from step 4 for compound (1313) except with purification by prep-HPLC (ACN/H2O + TFA) to yield the title compound as a beige powder (7 mg, 19% yield).

Step 4 Removal of the Boc group from te/7-butyl (2i?,4S)-4-benzyl-2-(((»S)-l-((3- methy l-2-(2i/-tetrazol-2-y l)benzy l)amino)- 1 -oxopropan-2-y l)carbamoy l)py rrobdine- 1 - carboxylate was achieved using procedure from step 4 for compound (1313) except with purification by prep HPLC (ACN/H2O + TFA) to yield the title compound as a white powder (7 mg, 13% yield).

Example 240. Preparation of (A)-iV-((6-Amino-2-methylpyridin-3-yl)methyl)- l-((2/?,4A)- 4-(4-bromobenzyl)pyrrolidine-2-carbonyl)azetidine-2-carboxam ide Di-trifluoroacetate salt (1438)

fS')-iV-((6-Amino-2-methylpyridin-3-yl (methyl)- 1 -((2//AY)-4-(4- bromobenzyl)pyrrobdine-2-carbonyl)azetidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1451), except that in step 5, a solution of 6 N HC1 in /PrOH was used to deprotect the Boc group and the amide coupling was performed using HATU.

To (.Y)-/V-((6-amino-2- methyl pyridin-3-yl (methyl )azetidine-2-carboxamide hydrochloride (27 mg, 0.11 mmol), (2//AS')-4-(4-bromobenzyl)- 1 -(lerl- butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.11 mmol), DIEA (100 pL, 0.55 mmol) in DMF (370 pL, 0.3 M) was added a HATU (63 mg, 0.17 mmol) with stirring at ambient temperature while monitoring for the consumption of starting material (16 h). The solution was diluted with EtOAc, extracted with sat. aq NH4CI. The aqueous layer was extracted 2 additional times, then the organic layer was washed with H2O, then brine, dried over Na2SCri and evaporated to dryness. The resulting residue was purified on an amine column using EtOAc, then MeOH/CEhCh to yield /e/ /-butyl (2//.4V)-2-(hV)-2-(((6-amino-2-methylpyridin- 3-yl)methyl)carbamoyl)azetidine- 1 -carbonyl)-4-(4-bromobenzyl)pyrrobdine- 1 -carboxylate (33 mg, 54% yield) as an off-white film.

Example 241. Preparation of 4-((2 ?,4 _» S)-2-((( _» S)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpiperid in-l-yl)butanoic acid Trifluoroacetate salt (1439)

4-((2RAS)-2-(((S)- 1 -(((6- Amino-2-methy lpy ridin-3-y l)methy l)amino)- 1 -oxopropan- 2-yl)carbamoyl)-4-phenylpiperidin-l-yl)butanoic acid trifluoroacetate salt was synthesized according to the procedures for compound (1411) using the corresponding bromoester.

Example 242. Preparation of Ethyl 4-((2/?,4A)-2-(((A)- l-(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpiperid in-l-yl)butanoate

(1439)

Ethyl 4-((2RAS)-2-(((S)- 1 -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)carbamoyl)-4-phenylpiperidin-l-yl)butanoate was synthesized according to the procedures for compound (1411), step 1, using the corresponding bromoester except that the final product was purified on an amine column (100% EtOAc). Example 243. Preparation of (2i?,4A)-7V-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-l-methyl-4-phenylpiperidi ne-2-carboxamide

To a stirred solution of (2/L4.Y)-/V-((.Y)- l -(((6-amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpiperidine-2-carb oxamide di-trifluoroacetate salt (100 mg, 0.16 mmol) in CH2CI2 (2 mL) and NEt3 (0.1 mL) was added methyl iodide (0.048 ml, 0.8 mmol) under Ar atmosphere. After stirring for 18 h at ambient temperature the reaction mixture was concentrated and purified on an amine column (100% EtOAc) to yield (: 2R,4S)-N-((S )- 1 -(((6-amino-2-methy lpy ridin-3-y l)methy l)amino)- 1 -oxopropan-2-y 1)- 1 - methyl-4-phenylpiperidine-2-carboxamide (22 mg, 34% yield).

Example 244. Preparation of (2/?,4/?)-iV-( IV - l-(((3-Chloro- l-methyl- l//-pyrrolo[2,3- /;]pyridin-5-yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrr olidine-2-carboxamide Dihydrochloride (1441)

Step 7: A solution of 3-chloro-l77-pyrrolo[2,3-/ ]pyridine-5-carbonitrile (215 mg, 1.21 mmol; described for compound (1329)) in anhyd DMF (7 mL) was added to an ice-cold suspension of NaH (60% in oil; 538 mg, 13.4 mmol) in anhyd DMF (2 mL) under Ar. The mixture was allowed to warm to ambient temperature. After stirring for 30 min, the mixture was cooled over an ice bath and iodomethane (0.22 pl, 3.5 mmol) was added over 5 min. The mixture was slowly warmed to ambient temperature, stirred 3 h, then cooled over an ice bath. The reaction was quenched with H2O then EtOAc was added. The layers were separated. The aq layer was extracted with EtOAc and the combined organics were washed with brine, dried (Na ₂ S04) and cone in vacuo. Purification by chromatography (10-35% EtOAc-hexanes) gave 3-chloro-l -methyl- li/-pyrrolo[2,3-/ ]pyridine-5-carbonitrile (226 mg, 97% yield).

Steps 2-3 : 3-Chloro- 1 -methyl- 1 //-pyrrolo| 2.3-6 |pyridine-5-carbonitrile was reduced using the two-step procedure described for compound (1329)) to give (3-chloro- 1 -methyl- IH- pyrrolo| 2.3-6 |pyridin-5-yl)methan amine dihydrochloride (75 mg, 54% for two steps).

Step 4 ((2RAR)- 1 -(/c /-Butoxycarbonyl)-4-phenylpyrrolidine-2-carbonyl)-L-alanine was coupled to (3-chloro- 1 -methyl- l//-py rrolo| 2.3- |py ridin-5-y l)methan amine

dihydrochloride following the procedure given for (1280), step 4 to give / -butyl (2RAR)-2- ((fSj- 1 -(((3-chloro- 1 -methyl- 1 //-py rrolo| 2.3-61 py ridin-5-yl (methyl )amino)- 1 -oxopropan-2- yl)carbamoyl)-4-phenylpynOlidine-l-carboxylate (35 mg, 64% yield).

Step 5: /e/V-Butyl (2//.4//)-2-((6S)- 1 -(((3-chloro- 1 -methyl- 1 //-pyrrolo| 2.3-6 |pyridin-5- yl)methyl)amino)-l -oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l -carboxylate was deprotected according to the procedure given for compound (1323), step 3 to give (2R,4R)-N- (fSj- 1 -(((3-chloro- 1 -methyl- l//-pyrrolo| 2.3-/> |pyridin-5-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-phenylpyrrolidine-2-carboxamide dihydrochloride (30.9 mg, 93% yield).

Example 245. Preparation of (2i?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(2,4-dichlorobenzyl)pyr rolidine-2-carboxamide Dihydrochloride (1443)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(2,4-dichlorobenzyl)pynOlidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1328). Example 246. Preparation of (2/?,4A)-iV-((A)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(2,5-dichlorobenzyl)pyr rolidine-2-carboxamide Dihydrochloride (1444)

(2i?,45)-iV-((5)-l-(((6-Amino-2-methylpyridin-3-yl)methyl)am ino)-l-oxopropan-2- yl)-4-(2,5-dichlorobenzyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1328).

Example 247. Preparation of (2i?,4^)-iV-(( )-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-bromophenoxy)pyrroli dine-2-carboxamide Dihydrochloride (1445)

Step 7: To a stirred solution of 2-benzyl 1 -(/er/-butyl) (2//.4///-4-hydroxy pyrrol idine- l,2-dicarboxylate (410 mg, 1.27 mmol), 4-bromophenol (242 mg, 1.39 mmol) and TPP (367 mg, 1.39 mmol) in THF (6.35 mL) was added DIAD (0.27 mL, 1.39 mmol) at ambient temperature under Ar. The mixture was stirred at ambient temperature overnight. After removal of the solvent, the resulting residue was purified by chromatography using EtOAc- hexanes to afford 2-benzyl 1 -(ter /-butyl) (27?, 4 _< S)-4-(4-bromophenoxy /pyrrolidine- 1,2- dicarboxylate (533 mg, 88% yield) as a colorless solid.

Step 2: (2/ AY)-4-(4-Bromophenoxy)- 1 -(/c /-butoxy carbonyl )pyrrolidine-2-carboxy lie acid was synthesized from 2-benzyl 1 -(tert-butyl) (2//AS')-4-(4-bromophenoxy /pyrrol idine- l,2-dicarboxylate according to the procedures for compound (1328), step 1.

Step 3: (2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-(4-bromophenoxy)pyrrolidine-2-carboxamide dihydrochloride was synthesized from (2/ AY)-4-(4-bromophenoxy)- 1 -(/c /-butoxy carbonyl /pyrrol idine-2- carboxylic acid according to the procedures for compound (1304), step 7 and step 8. Example 248. Preparation of (2i?,4A)-/V-((A)-l-(((6-Ainino-2-inethylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenoxypyrrolidine-2-ca rboxamide

Dihydrochloride (1446)

(2RAS)-N-((S)- 1 -(((6-Ammo-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-phenoxypyrrolidine-2-carboxamide dihydrochloride was synthesized from (2RAS)-N- (( _< S -l-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-l-oxopropan -2-yl)-4-(4- bromophenoxy)pynOlidine-2-carboxamide dihydrochloride according to the procedures for compound (1304), step 4.

Example 249. Preparation of (2i?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-fluorobenzyl)pyrroli dine-2-carboxamide Di- trifluoroacetate salt (1447)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(4-fluorobenzyl)pynOlidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1304). Example 250. Preparation of (2/?,4V)-4-benzyl-iV-((/V)- l-((3,5-dichloro-2- hydroxybenzyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-carboxam ide, hydrochloride (1448)

Steps 1-2: The title compound was synthesized according to steps 1-2 of the procedure for compound (1246) using the appropriate starting materials, except with purification by column (MeOH/CThCh containing 2.5% 7 N NTb-MeOH), then treatment with 1 M HC1 and lyophilization (10 mg, 19% yield over two steps). Example 251. Preparation of (27?,4A ^, )-/V-((A ^, )-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(benzo[c] [l,2,5]thiadiazol-5- ylmethyl)pyrrolidine-2-carboxamide Di-trifluoroacetate salt (1449)

Step 7: 2-Benzyl 1 -(tert-butyl) (2//AY)-4-(benzo|c || 1.2.5 |thiadiazol-5- ylmethyl)pyrrolidine-l,2-dicarboxylate was synthesized according to the procedure for compound (1304).

Step 2: To a solution of 2-benzyl 1 -(te/7-butyl) (2//.4V)-4-(benzo| || 1.2.5 |thiadia/ol- 5-ylmethyl)pyrrolidine-l,2-dicarboxylate (141.4 mg, 0.311 mmol) in THF (7.2 mL) and MeOH (3.6 mL) was added water (3.6 mL) followed by the addition of LiOH (117.0 mg,

4.89 mmol). After purging with N ₂ , the reaction was stirred at room temp for 16 h, diluted with water, and washed with EtOAc. The organic layer was discarded. The aqueous layer was adjusted to pH 3 with the slow addition of 1 M KHSCri solution and extracted with EtOAc (3 times). The organic layers were combined, washed with 5% NaHC03 solution, washed with brine, dried (Na ₂ S04), vacuum filtered, and evaporated under vacuum to afford the crude (2//AY)-4-(benzo|cj| 1.2.5 |thiadiazol-5-ylmethyl)- l -(/c /-butox> carbonyl)pyrrolidine-2- carboxylic acid.

Step 3: To the crude (2/L4Y')-4-(benzo|cj| 1.2.5 |thiadia/ol-5-yl methyl)- 1 -(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid in DMF (5.2 mL) was added NHS (45.0 mg, 0.391 mmol) and DCC (72.0 mg, 0.349 mmol). After purging with N ₂ , the reaction was stirred at room temp for 45 min and ( _< S)-2-amino-/V-((6-amino-2-methylpyridin-3- yl)methyl)propanamide (81.0 mg, 0.389 mmol) was added. The reaction was stirred at room temp for 16 h and evaporated under reduced pressure to dryness. The crude product was dissolved in CH2CI2 and adsorbed onto silica gel. Purification by chromatography (0-10% MeOH-CTHCh) afforded tert- butyl (2//.4L')-2-(((L)- l -(((6-amino-2-methylpyridin-3- y l)methy l)amino)- 1 -oxopropan-2-y l)carbamoy l)-4-(benzo |cj [ 1 ,2,5] thiadiazol-5 - y lmethy l)py rrolidine- 1 -carboxy late.

Step 4 Deprotection of tert- butyl (2RAS)-2-(((S)- 1 -(((6-amino-2-methylpyridin-3- y l)methy l)amino)- 1 -oxopropan-2-y l)carbamoy l)-4-(benzo [c] [ 1 ,2,5] thiadiazol-5 - y lmethy l)py rrolidine- 1 -carboxy late according to the procedure for compound (1427), step 7 except purification by reverse phase HPLC (5-75% MeCN-H20) afforded (2R,4S)-N-((S)-\- (((6-amino-2-methylpyridin-3-yl)methyl)amino)-l-oxopropan-2- yl)-4-

(benzofc] [l,2,5]thiadiazol-5-ylmethyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt.

Example 252. Preparation of (2i?, S -4-Benzyl-/V-((A)-l-(((3-chloro- 1-methyl- 1/7- pyrrolo [2,3-Z>] pyridin-5-yl)methyl)amino)- l-oxopropan-2-yl)pyrrolidine-2-carboxamide Dihydrochloride (1450)

Step 7: To a solution of ( 27?,45 -4-benzylpyrrolidine-2-carbonyl)-L-alanine (70.2 mg, 0.187 mmol) and NHS (25 mg, 0.22 mmol) in CH2CI2 (3.5 mL) was added DCC (24 mg, 0.12 mmol). After stirring for 30 min, a mixture of (3-chloro- 1 -methyl- 1 //-pyrrolo| 2.3-7» | pyridin- 5-yl)methanamine dihydrochloride (55 mg, 0.24 mmol) in CH2CI2 (2 mL) and sat. NaHCCh (3 mL) was added to the reaction mixture. After stirring for 30 min, the reaction was diluted with 5% MeOH-CLLCh and washed with sat. NaHCCh 3x, dried (Na2SCh) and cone in vacuo. Purification (0-10% MeOH-CTLCh; then 50-100% EtOAc-hexanes) gave tert- butyl (2R 4S)-4-b _QX\/ x\-2-(((S)- 1 -(((3-chloro- 1 -methyl- 1 //-py rrolo| 2.3-7» |pyridin-5- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)pyrrolidine-l-ca rboxylate (67.8 mg, 66% yield).

Step 2: To a solution of /e/V-butyl (2R 4S)-4-b _QX\/ x\-2-(((S)- 1 -(((3-chloro- 1 -methyl- li/-pyrrolo [2,3 -Z ]pyri din-5 -yl)methy l)amino)-l -oxopropan-2-yl)carbamoyl)pyrrolidine-l- carboxylate (66 mg, 0.12 mmol) in MeOH (2 mL) was added 3 M HCl-MeOH (5 mL). The mixture was stirred for 2 h then 6-7 M HCl-iPrOH (3 mL) was added. After stirring for 45 min, the reaction mixture was cone in vacuo. The residue was dissolved in MeCN-TLO, filtered (0.2 pm syringe filter) and lyophilized to give (2i?,4ri -4-benzyl-/V-(fS -l-(((3-chloro- 1 -methyl- 1 //-pyrrolo| 2.3-6 |pyridin-5-yl)methyl)amino)- 1 -o\opropan-2-yl)pyrrolidine-2- carboxamide dihydrochloride (55 mg, 85% yield).

Example 253. Preparation of (2/?,4V)-iV-((/V)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-bromo-4-chlorobenzyl )pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1451)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(3-bromo-4-chlorobenzyl)pynOlidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1424), except that in step 4, the ester was deprotected following the procedure below. Additionally, the title compound was not purified by prep HPLC.

To 2-benzyl 1 -(/er/-butyl) (2/iAY)-4-(3-bromo-4-chlorobenzyl (pyrrolidine- 1.2-dicarboxylate (50 mg, 0.1 mmol) in THF (2 mL, 0.05 M), MeOH (1 mL, 0.1 M), H ₂ 0 (1 mL, 0.1 M) was added a LiOH ftO (66 mg, 1.5 mmol) with stirring at ambient temperature while monitoring for the consumption of starting material (16 h). The solution was brought to pH 3 with 1 N HC1, extracted 3x with EtOAc then dried over NarSOr and evaporated to dryness. The resulting residue was carried forward without further purification. Example 254. Preparation of (2i?,4A)-/V-((A)-l-(((6-Ainino-2-inethylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-bromobenzyl)pyrrolid ine-2-carboxamide Dihydrochloride (1452)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(3-bromobenzyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1328).

Example 255. Preparation of (2/?,-AV -iV-( IV - l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((6-methoxynaphthalen-2 -yl)methyl)pyrrolidine- 2-carboxamide Dihydrochloride (1453)

(2R, 4S)-N- (S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-((6-methoxynaphthalen-2-yl)methyl)pyrrolidine-2-carbox amide dihydrochloride was synthesized according to the procedures for compound (1304).

Example 256. Preparation of (2/?,-//?)-iV-((iV)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((5-chlorothiophen-2-yl )methyl)pyrrolidine-2- carboxamide Dihydrochloride (1454)

(2R, 4R)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-((5-chlorothiophen-2-yl)methyl)pyrrolidine-2-carboxami de dihydrochloride was synthesized according to the procedures for compound (1304), except that the benzyl deprotection (Step 4) was done by following LiOH conditions as described for compound (1399). Example 257. Preparation of (2/?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-chloro-4-

(trifluoromethoxy)benzyl)pyrrolidine-2-carboxamide Di-trifluoroacetate salt (1455)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(3-chloro-4-(trifluoromethoxy)benzyl)pyrrolidine-2-car boxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1328).

Example 258. Preparation of (2/?,-//?)-iV-((iV)-l-((5-ChloiO-2-hydroxy-3- methylbenzyl)amino)-l-oxopropan-2-yl)-4-((5-chlorothiophen-2 -yl)methyl)pyrrolidine- 2-carboxamide Dihydrochloride (1456)

(2R 4R)-N-((S)- 1 -((5-Chloro-2-hydroxy-3-methylbenzyl)amino)- 1 -o\opropan-2-yl)-4-

((5-chlorothiophen-2-yl)methyl)pyrrolidine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304), except (S -2-amino-/V-(5-chloro-2- hydroxy-3-methylbenzyl)propenamide was used in step 7 and the benzyl deprotection (Step 4) was done by following LiOH conditions as described for compound (1399).

Example 259. Preparation of (2i?,4i?)-iV-((»S)-l-(((5-chloroquinolin-3-yl)methyl)amino) - l-oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide (1457)

Steps 1-2: The title compound was synthesized as a beige powder according to steps 3-4 of the procedure for compound 1119 using the appropriate starting materials (8.1 mg, 12% yield over two steps). Example 260. Preparation of (2i?,4i?)-ZV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(benzo[/ ]thiophen-2-ylmethyl)pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1458)

(: 2R,4R)-N-((S )- 1 -(((6- Amino-2-methy lpy ri din-3 -y l)methy l)amino)- 1 -oxopropan-2- yl)-4-(benzo[Z>]thiophen-2-ylmethyl)pyrrolidine-2-carboxa mide di-trifluoroacetate salt was synthesized according to the procedures for compound (1451).

Example 261. Preparation of (2i?,4^)-iV-(( )-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzy l)pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1459)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1328). Example 262. Preparation of (2i?,4i?)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((5-chlorobenzo[r/]thia zol-2- yl)methyl)pyrrolidine-2-carboxamide Di-trifluoroacetate salt (1460)

(: 2R,4R)-N-((S )- 1 -(((6- Amino-2-methy lpy ri din-3 -y l)methy l)amino)- 1 -oxopropan-2- yl)-4-((5-chlorobenzo[ci]thiazol-2-yl)methyl)pyrrolidine-2-c arboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1328), except that the final product was purified using reverse-phase HPLC. Example 263. Preparation of (2i?, S -/V-( A -l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((5-chlorothiophen-3-yl )methyl)pyrrolidine-2- carboxamide Dihydrochloride (1461)

(2R, 4S)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-((5-chlorothiophen-3-yl)methyl)pyrrolidine-2-carboxami de dihydrochloride was synthesized according to the procedures for compound (1304), except that the benzyl deprotection (Step 4) was done by following LiOH conditions as described for compound (1399).

Example 264. Preparation of (2/?,4/?)-iV-((A)-l-(((5-bromo-l//-indazol-7- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide (1462)

Step 7: (5-Bromo- l//-indazol-7-yl)methanol (62 mg, 0.2 mmol) was dissolved in CH2CI2 (2 mL) and treated with PBn (20 pL, 0.21 mmol), then stirred at ambient temperature overnight. The reaction mixture was diluted with CH2CI2 and washed with H2O and brine, then dried over Na ₂ S04 and concentrated to furnish 5-bromo-7-(bromomethyl)- l//-inda/ole as a white solid (58 mg, quant yield).

Step 2: A 50 mL round bottom flask was charged with 5-bromo-7-(bromomethyl)- l//- indazole (58 mg, 0.2 mmol), potassium phthalimide (37 mg, 0.2 mmol) and DMF (2 mL), then stirred at ambient temperature overnight. Upon completion, the reaction mixture was concentrated and purified by chromatography to give 2-((5-bromo- 1 //-indazol-7- yl)methyl)isoindoline-l,3-dione as a white solid (13 mg, 18% yield).

Step 3: 2-((5-Bromo-li/-indazol-7-yl)methyl)isoindoline-l,3-dione (13 mg, 0.04 mmol) was dissolved in EtOH (1 mL) and treated with hydrazine hydrate. After 4 h at ambient temperature, the reaction mixture was concentrated, dissolved in 3 N HC1 and filtered through a syringe filter (0.2 pm) and concentrated in vacuo to give (5-bromo- l //- indazol-7-yl)methanamine, hydrochloride as a white solid (10 mg, quant yield).

Step 4: The title compound was synthesized as a white solid (6.2 mg, 35% yield over two steps) according to steps 1-2 of the procedure for compound (1246) using the appropriate starting materials, except with purification by prep HPLC (ACN/FhO +TFA). Example 265. Preparation of (27?,47?)-/V-((A ^, )-l-(((///-Pyrrolo[3,2-c|pyridin-2- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide Di- trifluoroacetate salt (1463)

Step 7: /e/V-Butyl (27?,47?)-2-(((5)-l-(((777-pyrrolo[3,2-c]pyridin-2-yl)methyl )amino)- l-oxopropan-2-yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylat e (49 mg, 48% yield) was synthesized from (///-pyrrolo| 3.2-c |pyridin-2-yl)methanamine according to the procedure for compound (1358), step 2.

Step 2: Deprotection of /e/ /-butyl (27?,47?)-2-(((5 -l-(((777-pyrrolo[3,2-c]pyridin-2- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpyrroli dine-l-carboxylate (49 mg, 0.1 mmol) was conducted according to the procedure for compound (1260), step 4.

Example 266. Preparation of (2/?,4V)-iV-(( _t V)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-bromo-4-chlorobenzyl )-l-ethylpyrrolidine-2- carboxamide (1464)

To (2RAS)-N-((S)- 1 -(((6-ammo-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(3-bromo-4-chlorobenzyl)pyrrolidine-2-carboxamide ditrifluoroacetate (20 mg, 0.027 mmol) in NEt3 (20 pL, 1.6 M) and CH2CI2 (340 pL, 0.08 M) was added ethyl bromide (10 pL, 0.135 mmol) with stirring at ambient temperature while monitoring for the consumption of starting material (3 d). The solution was concentrated and evaporated to dryness. The resulting residue was purified on an amine column using EtOAc, then MeOEl/CEhCh to yield (2i?,4ri -/V-((ri -l-(((6-amino-2-methylpyridin-3-yl)methyl)amino)-l-oxopropan -2-yl)-4-(3- bromo-4-chlorobenzyl)-l-ethylpynOlidine-2-carboxamide (4.6 mg, 32% yield) as an off- white solid.

Example 267. Preparation of fV)-iV-((6-Amino-2-methylpyridin-3-yl)methyl)- l-((2/?,4A)- 4-(4-bromobenzyl)pyrrolidine-2-carbonyl)pyrrolidine-2-carbox amide Di- trifluoroacetate salt (

(.Y)-/V-((6-Amino-2-methylpyridin-3-yl (methyl)- 1 -((2//.4Y)-4-(4- bromobenzyl)pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide ditrifluoroacetate was synthesized according to the procedures for compound (1438) except that in step 5, DMF was used as the solvent in place of CH2CI2 for the DCC coupling and TFA (20 eq.) in CH2CI2 (0.2 M) was used to deprotect the Boc group. Example 268. Preparation of (2/?,4A)-iV-((A)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-bromo-3-chlorobenzyl )pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1466)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(4-bromo-3-chlorobenzyl)pynOlidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1451).

Example 269. Preparation of fV)-iV-( l-(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- l-oxopropan-2-yl)-4-benzyl- l//-pyrrole-2-carboxamide trifluoroacetic acid (1467)

To a solution consisting of 4-benzyl- 1 //-pyrrole-2-carbo\ylic acid (25 mg, 0.13 mmol) and HATU (53 mg, 0.14 mmol) in anhydrous DMF (1 mL) was added DIEA (60 pL, 0.34 mmol). The reaction mixture was stirred for 30 min at ambient temperature before (S)-2- amino-N-((6-amino-2-methylpyridin-3-yl)methyl)propanamide hydrochloride (28 mg, 0.11 mmol) was added to the reaction mixture and stirred overnight. The reaction mixture was made acidic by adding TFA (100 pL) and the crude reaction mixture purified by reverse- phase HPLC to afford fS')-A-( l -(((6-amino-2-methylpyridin-3-yl)methyl)amino)- l - oxopropan-2-yl)-4-benzyl-l7/-pyrrole-2-carboxamide trifluoroacetic acid (17.2 mg, 30%) as a light tan solid.

Example 270. Preparation of (2/?,4A)-iV-((S)-l-(((3-Chloro-l//-pyrrolo[2,3-/;]pyridin-5- yl)methyl)amino)-l-oxopropan-2-yl)-4-((2-methylpyridin-4-yl) methyl)pyrrolidine-2- carboxamide Trifluoroacetate (1468)

Step 7: 2-Benzyl 1 -(tert-butyl) (2//AY)-4-((2-methy lpyridin-4-y 1 (methyl )-5- oxopyrrolidine-l,2-dicarboxylate was synthesized according step 1 of the procedure for compound (1304) using the appropriate starting materials (113 mg, 24% yield).

Step 2: 2-Benzyl 1 -(ter/-butyl) (2//.4V)-5-hydroxy-4-((2-methylpyridin-4- yl)methyl)pyrrolidine-l,2-dicarboxylate was synthesized as a colorless oil according to step 2 of the procedure for compound (1304), except the crude product was filtered through diatomaceous earth (101 mg, 87% yield).

Step 3: 2-Benzyl 1 -(tert-butyl) (2/iAY)-4-((2-methyl pyridin-4-yl /methyl /pyrrolidine- l,2-dicarboxylate was synthesized as a colorless oil according step 3 of the procedure for compound (1304) (52 mg, 62% yield).

Step 4 (2RAS)- 1 -(/e/7-butoxy carbonyl )-4-((2-methylpyridin-4-yl /methyl /pyrrolidine- 2-carboxylic acid was synthesized as a colorless oil according to step 4 of the procedure for compound (1304) (41 mg, 98% yield).

Steps 5-6 : The title compound was synthesized as a light pink solid according to steps 5-6 of the procedure for compound (1304), except for purification by prep HPLC (ACN/H2O +TFA) (16.8 mg, 40% yield over two steps). Example 271. Preparation of (2/?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((2-methylpyridin-4-yl) methyl)pyrrolidine-2- carboxamide Dihydrochloride (1469)

Steps 1-2 : The title compound was synthesized as a beige powder according to steps 5-6 of the procedure for compound (1304) (15.4 mg, 75% yield over two steps).

Example 272. Preparation of (2i?,4A)-/V-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(benzo[c] [l,2,5]oxadiazol-5- ylmethyl)pyrrolidine-2-carboxamide Di-trifluoroacetate salt (1470)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(benzo[c] [l,2,5]oxadiazol-5-ylmethyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedure for compound (1449), step 1-4. Example 273. Preparation of (2/?,4/?)-iV-((/V)-l-oxo- l-((Thieno[2,3-/ ]pyridin-5- ylmethyl)amino)propan-2-yl)-4-phenylpyrrolidine-2-carboxamid e Trifluoroacetate salt (1471) (69)

Step 7: Thieno| 2.3-7» |pyridin-5-ylmethan amine (97 mg, 95% yield) was synthesized from thieno| 2.3-7»|pyridine-5-carbonitrile (100 mg, 0.62 mmol) according to the procedure for compound (1358), step 1.

Step 2: /e/V-Butyl (2RAR)-2-(((S)- 1 -oxo- 1 -((thieno| 2.3-7» |pyridin-5- ylmethyl)amino)propan-2-yl)carbamoyl)-4-phenylpyrrolidine-l- carboxylate (120 mg, 91% yield) was synthesized from thieno| 2.3-/)|pyridin-5-ylmethanamine (50 mg, 0.34 mmol) according to the procedure for compound (1358), step 2.

Step 3: Deprotection of /e/V-butyl (2RAR)-2-(((S)- 1 -oxo- 1 -((thieno| 2.3-7» |pyridin-5- ylmethyl)amino)propan-2-yl)carbamoyl)-4-phenylpyrrobdine-l-c arboxylate (120 mg, 0.29 mmol) was conducted according to the procedure for compound (1260), step 4 except that the final product was purified using reverse-phase HPLC. Example 274. Preparation of (2/?,4V)-iV-(fV)-l-(((///-Pyrrolo[3,2-c]pyridin-2- yl)methyl)amino)-l-oxopropan-2-yl)-4-benzylpyrrolidine-2-car boxamide Di- trifluoroacetate salt (1472)

Step 7: te/7-Butyl (2/ri4.Y)-2-(((.Y)- 1 -(((///-pyrrolo| 3.2- |py ridin-2-yl (methyl )amino)- l-oxopropan-2-yl)carbamoyl)-4-benzylpyrroli dine- 1 -carboxylate (36 mg, 33% yield) was synthesized from (777-pyrrolo[3,2-c]pyridin-2-yl)methanamine and (2/i AY)-4-benzyl- 1 -(lerl- butoxycarbonyl)pyrrolidine-2-carboxylic acid (80 mg, 0.21 mmol, prepared according to the procedure for compound (1304), step 1-4 according to the procedure for compound (1358), step 2.

Step 2: Deprotection of te/7-butyl (2i?,45)-2-(((5)-l-(((7i/-pyrrolo[3,2-c]pyridin-2- yl)methyl)amino)-l -oxopropan-2-yl)carbamoyl)-4-benzylpyrrolidine-l -carboxylate (36 mg, 0.07 mmol) was conducted according to the procedure for compound (1260), step 4 except that the final product was purified using reverse-phase HPLC. Example 275. Preparation of 3-((2i?,4^)-2-((( )-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-(3-chloro-4-f luorobenzyl)pyrrolidin- l-yl)propanoic acid Trifluoroacetate salt (1473)

3-((2RAS)-2-(((S)- 1 -(((6- Amino-2-methy lpy ridin-3-y l)methy l)amino)- 1 -oxopropan- 2-yl)carbamoyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidin-l-yl)p ropanoic acid was synthesized according to the procedures for compound (1411) using the corresponding bromoester.

Example 276. Preparation of (2i?,4A)-iV-((A)-l-(((3-Chloro-l-methyl-Li -pyrrolo[2,3- Z»]pyridin-5-yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-chloro -4- fluorobenzyl)pyrrolidine-2-carboxamide Trifluoroacetate salt (1474)

(2RAS)-N-((S)- 1 -(((3-chloro- 1 -methyl- l//-pyrrolo| 2.3-6|pyridin-5-yl)methyl)amino)- l-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzyl)pyrrolidine-2-c arboxamide trifluoroacetate salt was synthesized according to the procedures for compound (1476).

Example 277. Preparation of (2/?,4A)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-chloro-4-methoxybenz yl)pyrrolidine-2- carboxamide Di- trifluoroacetate salt (1475)

(2i?, 4 _< Y)-/V-((»Y)-l-(((6-Amino-2-methylpyri din-3 -yl)methyl)amino)-l-oxopropan-2- yl)-4-(3-chloro-4-methoxybenzyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1328).

Example 278. Preparation of (2i?,4A)-/V-((A)-l-(((3-Chloro- 1-methyl- Iff- pyrrolo [2,3- Z»]pyridin-5-yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-methyl benzyl)pyrrolidine-2- carboxamide Hydrochloride (1476)

(2RAS)-N-((S)- 1 -(((3-Chloro- 1 -methyl- l//-pyrrolo| 2.3-6 |pyridin-5-yl)methyl)amino)- l-oxopropan-2-yl)-4-(3-methylbenzyl)pyrrolidine-2-carboxamid e hydrochloride was synthesized according to the procedures for compound (1450).

Example 279. Preparation of (2i?,4A)-iV-((A)-l-(((3-Chloro-l-methyl-lff-pyrrolo[2,3- Z»]pyridin-5-yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-chloro benzyl)pyrrolidine-2- carboxamide Trifluoroacetate salt (1477)

(2RAS)-N-((S)- 1 -(((3-chloro- 1 -methyl- 1 //-pyrrolo| 2.3-5|pyridin-5-yl)methyl)amino)- l-oxopropan-2-yl)-4-(3-chloroben/yl)pyrrolidine-2-carboxamid e trifluoroacetate salt was synthesized according to the procedures for compound (1450).

Example 280. Preparation of (2i?, S -iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((3-methoxynaphthalen-2 -yl)methyl)pyrrolidine- 2-carboxamide Dihydrochloride (1478)

(2R, 4S)-N- (S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-((3-methoxynaphthalen-2-yl)methyl)pyrrolidine-2-carbox amide dihydrochloride was synthesized according to the procedures for compound (1304).

Example 281. Preparation of (2/?,-AV)-iV-((IV)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((4-methylnaphthalen-l- yl)methyl)pyrrolidine-2- carboxamide Dihydrochloride (1479)

(2R, 4S)-N- (S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-((4-methylnaphthalen- 1 -yl)methyl)pyrrobdine-2-carboxamide dihydrochloride was synthesized according to the procedures for compound (1304). Example 282. Preparation of (7?)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4,4-bis(4-fluorobenzyl)py rrolidine-2-carboxamide Di-trifluoroacetate salt (1480)

( R)-N-((S )- 1 -(((6- Amino-2-methy lpy ridin-3-y l)methy l)amino)- 1 -oxopropan-2-y l)-4,4- bis(4-fluorobenzyl)pyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1304).

Example 283. Preparation of (2i?,4i?)-/V-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(l-phenylcyclopropyl)py rrolidine-2-carboxamide Di-trifluoroacetate salt (1481)

O

Boc

MeO

Step 7: (R)- l-(/er/-Butoxycarbonyl)-4-(l-pheny ley cl opropyl)-2, 5-dihydro- l77-pyrrole- 2-carboxylic acid was synthesized from \-(ter /-butyl) 2-methyl (7?)-4-oxopyrroli dine- 1,2- dicarboxylate according to the procedures for compound (1247), steps 1 to 3, utilizing potassium trifluoro(l-phenylcyclopropyl)borate as the coupling partner in the first step.

Steps 2-4 : (2RAR)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 - oxopropan-2-yl)-4-(l-phenylcyclopropyl)pyrrolidine-2-carboxa mide di-trifluoroacetate salt was synthesized according to the procedures for compound (1359), steps 2-4. Example 284. Preparation of (2i?,4A)-4-(2-bromobenzyl)- -((A)-l-(((3-chloro-l-methyl- l//-pyrrolo [2,3-/ ]pyridin-5-yl)methyl)amino)- l-oxopropan-2-yl)pyrrolidine-2- carboxamide Hydrochloride (1482)

(2i?,4 _< S)-4-(2-bromobenzy l)-/V-((5 - 1 -(((3 -chloro- 1 -methyl- l //-pyrrolo [2,3 -Z>]py ridin-

5-yl)methyl)amino)-l-oxopropan-2-yl)pyrrolidine-2-carboxa mide Hydrochloride was synthesized according to the procedures for compound (1450).

Example 285. Preparation of (2i?,4i?)-iV-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-((4-bromo-5-chlorothiop hen-2- yl)methyl)pyrrolidine-2-carboxamide Di-trifluoroacetate salt (1483)

(: 2R,4R)-N-((S )- 1 -(((6- Amino-2-methy lpy ridin-3 -y l)methy l)amino)- 1 -oxopropan-2- yl)-4-((4-bromo-5-chlorothiophen-2-yl)methyl)pyrrolidine-2-c arboxamide di-trifluoroacetate salt was synthesized according to the procedure for compound (1449). Example 286. Preparation of 2-((2R,4S)-2-(((S)- l-(((3-Chloro- 1-methyl- l//-pyrrolo [2,3- / ]pyridin-5-yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-(3 -chloro-4- fluorobenzyl)pyrrolidin-l-yl)acetic acid Trifluoroacetate salt (1484)

2-((2/i AY)-2-(((.Y)- 1 -(((3-Chloro- 1 -methyl- 1 //-pyrrolo|2.3-Y |pyridin-5- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-(3-chloro-4-f luorobenzyl)pynOlidin-l- yl)acetic acid trifluoroacetate salt was synthesized according to the procedures for compound (1411). Example 287. Preparation of (2R,4R)-N-((S)-l-((4-carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide Dihydrochloride (1485)

(: 2R,4R)-N-((S )- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y l)-4 -{m- tolyl)piperidine-2-carboxamide was synthesized according to the procedures for compound 6. The first UV Active material eluting from the column in step 1.

Example 288. Preparation of (2S,4S)-N-((S)-l-((4-carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide Dihydrochloride (1486)

(: 2R,4R)-N-((S )- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y \)-A-(m- tolyl)piperidine-2-carboxamide was synthesized according to the procedures for compound 6. The second UV Active material eluting from the column in step 1. Example 289. Preparation of (2S,4R)-N-((S)-l-((4-carbamimidoylbenzyl)amino)-l- oxopropan-2-yl)-4-phenylpiperidine-2-carboxamide Dihydrochloride (1487)

(: 2R,4R)-N-((S )- 1 -((4-Carbamimidoy lbenzy l)amino)- 1 -oxopropan-2-y \)-A-(m- tolyl)piperidine-2-carboxamide was synthesized according to the procedures for compound 6. The fourth UV Active material eluting from the column in step 1.

Example 290. Preparation of iV-(5-Chloro-2-( l//-tetrazol- l-yl)benzyl)-2-(6-methyl-2- oxo-3-(phenethylamino)pyrazin-l(2//)-yl)acetamide (1489)

Step 7: The title compound was prepared according to step 3 of the procedure for compound (1365), using the appropriate starting materials except with purification by chromatography (95% EtO Ac/hexanes; 42 mg, 88% yield).

Example 291. Preparation of iV-((3-Chloro-l//-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-(6- methyl-2-oxo-3-(phenethylamino)pyrazin- l(2//)-yl)acetamide Acetate salt (1490)

Step 7: The title compound was prepared according to step 3 of the procedure for compound (1365), using the appropriate starting materials except with purification by chromatography (MeOH/ CH2CI2 + AcOH; 10 mg, 22% yield). Example 292. Preparation of 7V-((l-Aminoisoquinolin-6-yl)methyl)-2-(6-methyl-2-oxo-3-

(phenethylamino)pyrazin- l(2//)-yl)acetamide Trifluoroacetamide salt (1491)

Step 7: The title compound was prepared according to step 3 of the procedure for compound (1365), using the appropriate starting materials (9 mg, 20% yield).

Example 293. Preparation of iV-((2-Amino- l//-benzo[r/]imidazol-6-yl)methyl)-2-(6- methyl-2-oxo-3-(phenethylamino)pyrazin- l(2//)-yl)acetamide Trifluoroacetamide salt (1492)

Step 7: A solution of ethyl 2-(3-bromo-6-methyl-2-oxopyrazin-l(277)-yl)acetate (411 mg, 1.5 mmol) and phenethylamine (189 pL, 1.5 mmol) in 1: 1 toluene/EtOH (10 mL) was heated at 125 °C for 18 h in a sealed flask. Upon cooling, the reaction mixture was concentrated then taken up in EtOAc and washed with sat. aq. NaHC03, brine and dried over Na ₂ S04 then concentrated. The crude product was purified by chromatography (60%

EtO Ac/hexanes) to furnish ethyl 2-(6-methyl-2-o\o-3-(phenethylamino)pyra/in- 1 (2H)- yl)acetate as a beige solid (390 mg, 82% yield).

Step 2: Ethyl 2-(6-methyl-2-o\o-3-(phenethylamino)pyra/in- 1 (2//)-yl (acetate (390 mg, 1.24 mmol) was dissolved in 1 : 1 THF/MeOH (6 mL) and treated with 1 N aq. NaOH (3 mL). After 2 h, the organic solvents were removed in vacuo and cooled to 0 °C before being acidified with 1 N HC1. The precipitated product was collected by filtration to give 2-(6- methyl-2-o\o-3-(phenethylamino)pyrazin- l (2//)-yl (acetic acid as a pale yellow powder (285 mg, 81% yield).

Step 3: A 50 mL round bottom flask was charged with 2-(6-methyl-2-oxo-3- (phenethylamino)pyrazin- l (2//)-yl)acetic acid (29 mg, 0.1 mmol), EDC (21 mg, 0.11 mmol), HOBt (16 mg, 0.12 mmol) and DMF (1 mL). After 5 min, 6-(aminomethyl)-li - benzo| c/| i mi da/ol -2-ami ne dihydrochloride (26 mg, 0.11 mmol) and DIEA (52 pL, 0.3 mmol) were added and the reaction stirred for 16 h at ambient temperature. Upon completion, the reaction mixture was diluted with EtOAc and washed with sat. NaHCCk and brine, then dried over Na ₂ S04 and concentrated. Purification by prep-HPLC (ACN/EEO + TFA) gave the title compound as a white powder (19 mg, 35 % yield).

Example 294. Preparation of (2/?,4/?)-iV-((/V)- l-(((4-Bromo- l//-pyrrolo[2,3-c]pyridin-2- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide Di- trifluoroacetate salt (1493)

Step 7: To a 0 °C solution of methyl 4-bromo- 1 //-pyrrolo|2.3-c |pyridine-2- carboxylate (1.0 g, 3.92 mmol) in THF (20 mL, 5.1 M) was added lithium aluminum hydride (1 M in THF, 6.3 mL, 6.3 mmol). After stirring for 1 h at the same temperature, the reaction was quenched by addition of H2O. The resulting mixture was extracted with EtOAc, dried over anhyd Na ₂ S04, and cone under vacuum. The residue was purified by chromatography (0-100% EtOAc-hexanes) to give (4-bromo- l77-pyrrolo[2,3-c]pyridin-2-yl)methanol (206 mg, 23% yield).

Step 2: To a solution of (4-bromo- 1 //-pyrrolo| 2.3-c|pyridin-2-yl)methanol (206 mg, 0.91 mmol) in CH2CI2 (1.5 mL, 0.6 M) was added 4.0 M HC1 in dioxane (2.2 mL). After stirring for 15 min, the reaction mixture was cone under vacuum. To this residue was added thionyl chloride (1 mL) at 0 °C. After stirring for 2 min at reflux, the reaction mixture was concentrated to give the crude 4-bromo-2-(chloromethyl)-l77-pyrrolo [2,3 -c] pyridine hydrochloride salt (256 mg, 99% yield).

Step 3: To a solution of di-/e/7-butyl iminodicarboxylate (295 mg, 1.36 mmol ) in DMF (5 mL, 0.27 M) was added sodium hydride (60% dispersion in mineral oil). After stirring for 30 min, the crude 4-bromo-2-(chloromethyl)- 1 //-pyrrolo| 2.3 - | pyridine hydrochloride salt (256 mg, 0.9 mmol) in DMF (1.0 mL, 0.9 M) was added drop-wise. After stirring for 2 h at room temperature, another 0.5 eq of sodium hydride was added. After stirring for 16 h at the same temperature, the reaction was quenched by addition of H2O. The resulting mixture was extracted with EtOAc, dried over anhyd Na ₂ S04, and cone under vacuum. The residue was dissolved in CH2CI2 (5 mL) and 4.0 M HC1 in dioxane was added. After stirring for 22 h, the reaction mixture was concentrated to the crude (4-bromo- \H- pyrrolo[2,3-c]pyridin-2-yl)methanamine hydrochloride salt (233 mg, 86% yield).

Step 4 : tert- Butyl (2RAR)-2-(((S)- 1 -(((4-bromo- 1 //-pyrrolo| 2.3-c |pyridin-2- yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-phenylpyrroli dine-l-carboxylate (13 mg, 4% yield) was synthesized from the crude (4-bromo- 1 //-py rrolo| 2.3- |pyridin-2- yl)methanamine hydrochloride salt (217 mg, 0.6 mmol) according to the procedure for compound , step 2.

Step 5: Deprotection of te/7-butyl (2//.4//)-2-((fY)- 1 -(((4-bromo- 1 //-py rrolo| 2.3- c]pyridin-2-yl)methyl)amino)-l-oxopropan-2-yl)carbamoyl)-4-p henylpyrrolidine-l- carboxylate (13 mg, 0.02 mmol) was conducted according to the procedure for compound , step 4 except that the final product was purified using reverse-phase HPLC.

Example 295. Preparation of (2/?,4A)-iV-(fV)- l-((( l//-Pyrrolo[3,2-c]pyridin-2- yl)methyl)amino)-l-oxopropan-2-yl)-4-(3-chloro-4-fluorobenzy l)pyrrolidine-2- carboxamide Di-trifluoroacetate salt (1494)

Step 7: To a -78 °C solution of 2-benzyl 1 -(/e/7-butyl) (7?)-5-oxopyrrolidine-l,2- dicarboxylate (500 mg, 1.57 mmol) in THF (10 mL, 0.16 M) was slowly added lithium bis(trimethylsilyl)amide (1 M in THF, 1.72 mL, 1.72 mmol). After stirring for 1 h at the same temperature, 4-(bromomethyl)-2-chloro-l-fluorobenzene (420 mg, 1.88 mmol) in THF (2 mL) was added. After stirring for 2 h at the same temperature, the reaction was quenched by addition of sat. aq NH4CI. The resulting mixture was extracted with EtOAc, dried over anhyd Na ₂ S04, and cone under vacuum. The residue was purified by chromatography (0-100% EtOAc-hexanes) to give 2-benzyl 1 -(te/7-butyl) (27?,4 _< S)-4-(3-chloro-4-fluorobenzyl)-5- oxopyrrolidine-l,2-dicarboxylate (450 mg, 62% yield).

Step 2: To a -78 °C solution of 2-benzyl l-(/er/-butyl) (27?,4 _< S)-4-(3-chloro-4- fluorobenzyl)-5-oxopyrrolidine-l,2-dicarboxylate (450 mg, 0.97 mmol) in THF (7 mL, 0.14 M) was added lithium triethylborohydride (1 M in THF, 1.07 mL, 1.07 mmol). After stirring for 30 min, the reaction was quenched by addition of sat. aq NaHCCh and warmed to 0 °C. 30% H2O2 (about 8 drops) was added and the reaction mixture was stirred for 30 min at same temperature. The organic volatiles were removed under vacuum and the aqueous layer was extracted with CH2CI2. The combined extracts were dried over anhyd Na ₂ S04, and cone under vacuum to give 2-benzyl l -(/e/7-butyl) (27?,4ri)-4-(3-chloro-4-fluorobenzyl)-5- hydroxypyrrolidine-l,2-dicarboxylate (450 mg, 100%) which was used in the next step without further purification.

Step 3: To a -78 °C solution of 2-benzyl l-(Ye/7-butyl) (27?,4 _< S)-4-(3-chloro-4- fluorobenzyl)-5-hydroxypynOlidine-l,2-dicarboxylate (450 mg, 0.97 mmol) in CH2CI2 (6 mL, 0.16 M) was added triethylsilane (0.38 mL, 2.13 mmol) and boron trifluoride diethyl etherate (0.65 mL, 2.13 mmol). After stirring for 2 h at the same temperature, the reaction was quenched by addition of sat. aq NaHCCh solution. The resulting mixture was extracted with CH2CI2, dried over anhyd Na2S0 ₄ , and cone under vacuum. The residue was purified by chromatography (0-100% EtOAc-hexanes) to give 2-benzyl l -(/e/7-butyl) (2/ AY)-4-(3- chloro-4-fluorobenzyl)pyrrolidine-l,2-dicarboxylate (220 mg, 51% yield for two steps).

Step 4 A solution of 2-benzyl 1 -(/e/7-butyl) (2/ AY)-4-(3-chloro-4- fluorobenzyl)pyrrolidine-l,2-dicarboxylate (220 mg, 0.49 mmol) was degassed with a stream of Ar for 2 min. 10% Pd/C (10 mg) was added and a vacuum was pulled for 1 min. A balloon of H2 was added and the reaction was monitored for the consumption of starting material for 1.5 h. The catalyst was removed by filtration and the solution was evaporated to give (27?, 45)- l-(/er/-butoxycarbonyl)-4-(3-chloro-4-fluorobenzyl)pyrrolidi ne-2-carboxylic acid (175 mg, 100% yield).

Step 5: To a solution of (/e/V-butoxy carbonyl )-/,-alanine (467 mg, 2.47 mmol) in CH2CI2 (15 mL) and MeOH (5 mL) was added NHS (313 mg, 2.72 mmol) with stirring at room temp until dissolved. DCC (561 mg, 2.72 mmol) was added and stirred for 1 h. (177- pyrrolo[3,2-c]pyridin-2-yl)methanamine (400 mg, 2.72 mmol) was added to the above mixture and stirred for 1 h. The reaction was quenched by addition of H2O and the resulting mixture was extracted with CH2CI2, dried over anhyd NaiSCri. and cone under vacuum. The residue was purified by chromatography (0-100% EtOAc-hexanes) to give tert- butyl (<S)-(l- ((( l //-py rrolo| 3.2-c|py ridin-2-yl (methyl (ami no)- l -o\opropan-2-yl (carbamate (129 mg, 15% yield).

Step 6: To a 0 °C solution of /e/V-butyl (S)-( 1 -((( l //-pyrrolo|3.2- |pyridin-2- yl)methyl)amino)-l-oxopropan-2-yl)carbamate (129 mg, 0.4 mmol) in CH2CI2 (10 mL, 0.04 M) was added 20% TFA in CH2CI2 (10 mL). After stirring for 3 h at room temperature, the reaction mixture was concentrated to give 0Y)-/V-(( l //-pyrrolo| 3.2-6 |pyri din-2-yl (methyl )-2- aminopropanamide di-trifluoroacetate salt (180 mg, 100% yield).

Step 7: To a solution of 2-benzyl 1 -(/er/-butyl) (2i?,4 _< S)-4-(3-chloro-4- fluorobenzyl)pyrrolidine-l,2-dicarboxylate (25 mg, 0.07 mmol) in anhyd DMF (2 mL, 0.04 M) was added HOBt (14 mg, 0.09 mmol), DIEA (0.05 mL, 0.28 mmol), and EDC (14 mg, 0.09 mmol). After stirring for 30 min at ambient temperature, (S)-N-(( l //-pyrrolo| 3.2- c]pyri din-2 -yl)methyl)-2-aminopropanamide di-trifluoroacetate salt (38 mg, 0.08 mmol) was added and stirred for 16 h. The reaction mixture was cone and the residue was partitioned with EtOAc and 10% KHSO4 solution. The organic layer was separated and washed with H2O and sat. aq NaHCCh. The organic layer was dried over anhyd Na2SCri and coned. The residue was purified by chromatography (0-100% [5% 7 N NFL in MeOFl/CFhChJ-CFhCh) to give /e/V-butyl (2//.4L')-2-(((L')- 1 -((( l //-pyrrolo| 3.2-c|pyndin-2-y 1 (methyl (amino)- 1 - oxopropan-2-yl)carbamoyl)-4-(3-chloro-4-fluorobenzyl)pyrroli dine-l-carboxylate (27 mg, 68% yield).

Step 8: To a 0 °C solution of /e/7-butyl (2/ AY)-2-(((.Y)- 1 -((( 1 //-pyrrolo| 3.2-c |pyridin- 2-yl)methyl)amino)- 1 -oxopropan-2-yl)carbamoyl)-4-(3-chloro-4-fluorobenzyl)pyrrol idine- 1 - carboxylate (27 mg, 0.05 mmol) in CH2CI2 (1 mL, 0.05 M) was added 20% TFA in CH2CI2 (1 mL). After stirring for 3 h at room temperature, the reaction mixture was concentrated to give (27?, 45)-A-((5)-l-((( l77-pyrrolo[3,2-c]pyri din-2 -yl)methyl)amino)-l -oxopropan-2-yl)-4- (3-chloro-4-fluorobenzyl)pynOlidine-2-carboxamide di-trifluoroacetate salt (33 mg, 100% yield).

Example 296. Preparation of (2/?,4/?)-iV-((A)-l-(((l//-Pyrrolo|2,3-c]pyridin-2- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide Di- trifluoroacetate salt (1495)

Step 7: (27?,47?)-/V-((<S)-l-(((l77-PynOlo[2,3-c]pyridin-2-yl)met hyl)amino)-l- oxopropan-2-yl)-4-phenylpyrrolidine-2-carboxamide di-trifluoroacetate salt (2.0 mg, 80% yield) was synthesized from (27?,47?)-7V-((5)-l-(((4-Bromo-l77-pyrrolo[2,3-c]pyridin-2- yl)methyl)amino)-l-oxopropan-2-yl)-4-phenylpyrrolidine-2-car boxamide di-trifluoroacetate salt (prepared according to the procedure for compound (1493), step 1-5) according to the procedure for compound (1264), step 2. Example 297. Preparation of (2/?,4V)-iV-(( _t V)- l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-l-ethyl-4-phenylpiperidin e-2-carboxamide (1496)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-l-ethyl-4-phenylpiperidine-2-carboxamide was synthesized according to the procedures for compound (1464).

Example 298. Preparation of (2i?,4A)-/V-((A)-l-(((6-Amino-2-methylpyridin-3- yl)methyl)amino)-l-oxopropan-2-yl)-4-(4-bromobenzyl)-iV-meth ylpyrrolidine-2- carboxamide Di-trifluoroacetate salt (1497)

(2RAS)-N-((S)- 1 -(((6-Amino-2-methylpyridin-3-yl)methyl)amino)- 1 -oxopropan-2- yl)-4-(4-bromobenzyl)-/V-methylpyrrolidine-2-carboxamide di-trifluoroacetate salt was synthesized according to the procedures for compound (1438), except that the title compound was not purified by prep HPLC.

Example 299. Preparation of 2-(Pyridin-2-yl)-lH-benzo[d]imidazole-5- carboximidamide Dihydrochloride (2001)

[0255] This method is a modification of the general procedure of W. B. Young et al, Bioorg. Med. Chem. Lett. 16 (2006) 710-713. A mixture of 3,4-diaminobenzimidamide HC1 (0.5 g, 2.6 mmol), picolinaldehyde (0.22 mL, 2.3 mmol), benzoquinone (0.28 g, 2.6 mmol) and ethanol (15 mL) was heated at reflux. After stirring for 3 h, the mixture was allowed to warm to room temp and the volatiles removed under reduced pressure. The residue was dissolved in methanol (5 mL) then added to cold MeCN (100 mL) while stirring to yield a precipitate that was isolated by filtration. The precipitate was dissolved in 6 N HC1 (20 mL) and poured into stirring acetone (150 mL) to give a precipitate. The precipitate was isolated by filtration, washed with acetone and dried under reduced pressure to provide 2-(pyridin-2- yl)-lH-benzo[d]imidazole-5-carboximidamide, dihydrochloride salt (0.53 g, 65%).

[0256] Proceeding similarly to the procedure for compound 2001, but with the appropriate starting materials, the following compounds were made: 2-( l//-imidazol-4-yl)- 1 //-benzo| d|imidazole-5-carbo\imidamide dihydrochloride (2000); 2-(6-methylpyridin-2-yl)- lH-benzo[d]imidazole-5-carboximidamide; 2-(6-methylpyridin-2-yl)-lH-benzo[d]imidazole- 5-carboximidamide (2003); 2-(3- inelhylpyridin-2-yl) - ///-benzo | d | i mi dazol e-5- carboximidamide dihydrochloride (2004); 2-(4-methylpyridin-2-yl)-lH- benzo[d]imidazole- 5-carboximidamide dihydrochloride (2005); 2-(5-ethylpyridin-2-yl)-lH-bm/o[d]imida/o\ _Q -5- carboximidamide dihydrochloride (2007); 2-(6- elhylpyridin-2-y/J - ///-benzo | d | i mi dazol e-5- carboximidamide dihydrochloride (2008); I H /7/-/2 2'-Z>/benzo|d|imida/ole-5- carboximidamide dihydrochloride (2009); 2-(5-meihylpyridin-2-yl) - ///-benzo | d | i mi dazol e-5- carboximidamide dihydrochloride (2010); 2-(6-(methoxymethyl)pyridin-2-yl)-lH- benzo[d]imidazole-5-carboximidamide dihydrochloride (2011); 2-(4-ethoxypyridin-2-yl)-lH- benzo[d]imidazole-5-carboximidamide dihydrochloride (2012); 2-(quinolin-2-yl)-lH- benzo[d]imidazole-5-carboximidamide dihydrochloride (2013); 2-(isoquinolin-3-yl)-lH- benzo[d]imidazole-5-carboximidamide dihydrochloride (2014); and 2-(6-(4-

//i/ ;ra/;/7em'///n7 /6///i-2-i7/-benzo|d|imidazole-5-carboximidamide dihydrochloride (2016).

Example 300. Preparation of 2-(Pyridin-2-ylmethyl)-Li/-benzo[d]imidazole-5- carboximidamide Dihydrochloride (2002)

3,4-diaminobenzimidamide

[0257] This method is a modification of the general procedure of W. B. Young et al, Bioorg. Med. Chem. Lett. 16 (2006) 710-713. An oven-dried flask was charged with 3,4- diaminobenzimidamide HC1 (0.99 g, 5.3 mmol), ethyl 2-(pyridin-2-yl)acetate (0.9 mL, 5.9 mmol) and polyphosphoric acid (8 mL). The mixture was heated to 180 °C. After stirring for 2 h, the mixture was allowed to warm to room temp. The mixture was diluted with LLO (50 mL) and then cooled over an ice bath. After the mixture was cooled, an aq solution of 50% NaOH was added to adjust the pH to 8, and the mixture was allowed to warm to room temp. To the gummy mixture was added MeOH (10 mL); the volatiles were removed under reduced pressure. Aqueous saturated NaHCCb was added with vigorous stirring until a precipitate was obtained,. The precipitate was then isolated by filtration and rinsed with H2O. The precipitate was dissolved in 6 N HC1 (15 mL). The solution was poured into stirring acetone (150 mL) to give a precipitate, which was isolated by filtration, washed with acetone, and dried to provide 2-(pyridin-2-ylmethyl)- l //-benzo| d|imida/ole-5-carbo\i midamide dihydrochloride salt (0.24 g, 14%).

Example 301. Preparation of 2-((l//-Benzo[d]imidazol-2-yl)methyl)-lH- benzo[d]imidazole-5-carboximidamide Dihydrochloride (2015)

[0258] This method is a modification of the general procedure of W. B. Young et al, Bioorg. Med. Chem. Lett. 16 (2006) 710-713. An oven-dried flask was charged with 3,4- diaminobenzimidamide HC1 (0.98 g, 5.2 mmol), ethyl 2-(l//-benzo[d]imidazol-2-yl)acetate (1.2 g, 5.8 mmol) and polyphosphoric acid (8 mL). The mixture was heated to 185 °C. After stirring for 2 h, the mixture was allowed to cool to room temp. After 8 h, the mixture was diluted with H2O (50 mL) and then cooled over an ice bath. After the mixture was cooled, a solution of 50% NaOH was added to adjust the pH to 9. The mixture was vigorously stirred and gradually warmed to room temp; the solids were isolated by vacuum filtration and rinsed with H2O. The solids were then stirred for 30 min with saturated aq NaHCCb, filtered, and rinsed with H2O. The precipitate was collected and dissolved in 6 N HC1 (15 mL). The solution was poured into stirring acetone (150 mL) to give a precipitate. The precipitate was isolated by filtration, washed with acetone and dried to provide 2-((lH-benzo[d]imidazol-2- yljmethyl)- 1 //-benzo| d|imidazole-5-carboximidamide. dihydrochloride salt (1.6 g, 85%).

Example 302. Preparation of ((4-((2-(3-Benzyl-7-carbamoyl-2,4-dioxo-3,4- dihydroquinazolin-l(2//)-yl)acetamido)methyl)phenyl)(imino)m ethyl)- ⁵ -azaneyl Acetate (2017)

[0259] Step /: A reaction vessel was charged with 2-aminoterephthalic acid (600 mg, 3.31 mmol) and THF (10 mL). To this was added benzyl isocyanate (485 mg, 3.64 mmol), and the mixture was refluxed at 70 °C for 4 h. The reaction mixture was then cooled, and the solvent was evaporated under vacuum and replaced with EtOH (10 mL). The reaction was treated with H2SO4 (2 mL) and stirred at 70 °C for 2 h. Upon completion, the reaction was cooled to 5 °C and treated with water, whereupon a slurry was formed. The precipitate was filtered and washed with H2O and hexanes, then collected as an off-white solid that was then re suspended in THF (10 mL) and H2O (10 mL). LiOH (2 equiv, 159 mg) was added in one portion and the reaction stirred at ambient temperature for 2 h. After completion, THF was removed under vacuum and the reaction then acidified with 1 N HC1. The resulting slurry was filtered to yield 3-benzyl-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-7-carboxyli c acid as a white powder (650 mg, 66% yield over 3 steps).

[0260] Step 2: A mixture of 3-benzyl-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-7- carboxylic acid (297 mg, 1 mmol), tritylamine (285 mg, 1.1 mmol), Et3N (418 pL, 3 mmol) in DMF (10 mL) was treated with PyBOP (513 mg, 1.1 mmol). The reaction mixture was allowed to stir at ambient temperature overnight, then diluted with EtOAc and washed with 10% aq KHSO4, brine, and saturated aq NaHCCh. The organic layer was dried over Na2SC>4, filtered, concentrated under vacuum, and then purified by chromatography (10-30% EtOAc- hexanes) to yield 3-benzy 1-2.4-dioxo-A-trityl- 1.2.3.4-tetrahydroquina/oline-7-carboxamide as a white crystalline solid (126 mg, 23% yield).

[0261] Step 3: A reaction vessel was charged with 3-benzyl-2,4-dioxo-/V-trityl- l,2,3,4-tetrahydroquinazoline-7-carboxamide (120 mg, 0.22 mmol), K2CO3 (76 mg, 0.55 mmol) and DMF (2 mL). To this stirring solution was added ethyl bromoacetate (28 pL, 0.25 mmol) and the mixture was allowed to stir at room temp overnight. Upon completion, the reaction mixture was treated with H2O, whereupon ethyl 2-(3-benzyl-2,4-dioxo-7- (tri tylcarbamoyl)-3.4-dihydroquina/ol in- l (2//)-yl (acetate precipitated as a white solid (62 mg, quant yield) which was collected by filtration.

[0262] Step 4: To a stirring suspension of ethyl 2-(3-benzyl-2,4-dioxo-7- (tri tylcarbamoyl)-3.4-dihydroquina/ol in- l (2//)-yl (acetate (137 mg, 0.22 mmol) in THF (2.5 mL) and H2O (2.5 mL) was added LiOH (11 mg, 0.44 mmol) in one portion. The reaction mixture was stirred at ambient temp overnight. After completion, the reaction mixture was neutralized with 10% aq KHSO4, and extracted with EtOAc (10 mL x 3). The combined organics were washed with brine, dried (Na2S04), filtered and concentrated under vacuum to provide 2-(3-benzyl-2.4-dioxo-7-(tritylcarbamoyl)-3.4-dihydroquinazo lin- 1 (2//)-yl (acetic acid as a white powder (59 mg, 45% yield).

[0263] Step 5: To the reaction vessel was added 2-(3-benzyl-2,4-dioxo-7- (tritylcarbamoyl)-3,4-dihydroquinazolin-l(277)-yl)acetic acid (59 mg, 0.1 mmol), DMAP (24.4 mg, 0.2 mmol) and CH2CI2 (1 mL). To this stirring mixture was added EDC (23 mg, 0.12 mmol) followed by benzyl ((4-(aminomethyl)phenyl)(imino)methyl)carbamate (35.2 mg, 0.11 mmol). The reaction mixture was stirred at ambient temp overnight, after which time it was washed successively with 10% aq KHSO4, H2O, saturated aq NaHCCh, and brine. The organic layer was dried (Na2SCri) and concentrated under vacuum to provide benzyl ((4- ((2-(3-benzyl-2,4-dioxo-7-(tritylcarbamoyl)-3,4-dihy droquinazolin- 1(277)- yl)acetamido)methyl)phenyl)(imino)methyl)carbamate as a white solid (86 mg, quant yield).

[0264] Step 6: Benzyl ((4-((2-(3-benzyl-2,4-dioxo-7-(tritylcarbamoyl)-3,4- dihydroquina/olin- l (2//)-yl )acetamido)methyl (phenyl )(imino)methyl (carbamate (86 mg, 0.1 mmol) was dissolved in CH2CI2 (1 mL) and treated with TFA (600 pL). The resulting yellow solution was stirred for 3 h and then treated with MeOH (150 pL), whereupon the solution immediately became colorless. The reaction mixture was evaporated to dryness and purified by chromatography (10% MeOH-CTBCh + 1% 7 M B-MeOH to yield benzyl ((4-((2-(3- benzy 1-7 -carbamoy l-2,4-dioxo-3 ,4-dihy droquinazolin- 1 (277)- yl)acetamido)methyl)phenyl)(imino)methyl)carbamate as a white solid (42 mg, 68% yield).

[0265] Step 7: Benzyl ((4-((2-(3-benzyl-7-carbamoyl-2,4-dioxo-3,4- dihy droquinazolin- 1 (2//)-yl)acetamido)methyl)phenyl)(imino)methyl /carbamate (14 mg, 0.023 mmol) was dissolved in a mixture of MeOH (6 ml) and HO Ac (3 mL). The resulting solution was degassed with a stream of nitrogen for 2-3 min. 10% Pd/C (5 mg) was added, and the mixture was put under vacuum for approximately 1 minute. A balloon of hydrogen was applied, and the reaction was monitored for the consumption of starting material. The reaction mixture was filtered through a 0.2 pm syringe filter and evaporated to dryness to give compound 2017 as a white solid (11 mg, 99% yield).

Example 303. Preparation of 3-Benzyl-l-(2-((4-carbamimidoylbenzyl)amino)-2- oxoethyl)-iV-methyl-2,4-dioxo-l,2,3,4-tetrahydroquinazoline- 7-carboxamide (2018)

[0266] Step 1: 3-Benzyl-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-7-carboxyli c acid (330 mg, 1.1 mmol) was suspended in CH2CI2 (15 mL). To the stirred mixture was added methylamine (2 M in THF, 660 pL, 1.32 mmol) and DIEA (570 pL, 3.3 mmol). After 5 min at ambient temp, the reaction mixture became a clear solution. To this solution was added HATU (550 mg, 1.32 mmol). Upon completion of reaction after 4 h, the reaction mixture was washed with 1 M HC1, H2O, and saturated aq NaHCCh, then filtered through a glass fritted funnel to yield 3-benzyl-N-methyl-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-7- carboxamide as a white solid (340 mg, quant).

[0267] Steps 2-5: 3-Benzyl-l-(2-((4-carbamimidoylbenzyl)amino)-2-oxoethyl)-N- methyl-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-7-carboxamide was prepared from 3-benzyl- N-methyl-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-7-carboxami de following similar protocols as described in steps 3-5, and 7 in Example 4 (i.e., for compound 2017).

Example 304. Preparation of 3-Benzyl-l-(2-((4-carbamimidoylbenzyl)amino)-2- oxoethyl)-iV-cyclohexyl-2,4-dioxo-l,2,3,4-tetrahydoroquinazo line-7-carboxamide (2021)

[0268] Step 1: 3-Benzyl-2,4-dioxo-l,2,3,4-tetrahydroquinazobne-7-carboxybc acid (300 mg, 1.0 mmol) was suspended in CH2CI2 (10 mL). To this stirring mixture was added cyclohexylamine (140 pL, 1.2 mmol), DIEA (529 pL, 3 mmol), HOBt (165 mg, 1.2 mmol) and EDC (234 mg, 1.2 mmol) in sequential order. The mixture was stirred for 24 h. Upon completion, the reaction mixture was washed with 1 N HC1, and saturated aq NaHCCb. The organic layer was dried over Na2SOr and concentrated under vacuum to provide 3-benzyl-N- cyclohexyl-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-7-carboxa mide as a white solid (200 mg, 52% yield).

[0269] Steps 2-5: 3-Benzyl-l-(2-((4-carbamimidoylbenzyl)amino)-2-oxoethyl)-n- cyclohexyl-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-7-carboxa mide was prepared from 3- benzyl-N-cyclohexyl-2,4-dioxo-l,2,3,4-tetrahydroquinazoline- 7-carboxamide following similar protocols to those described in steps 3-5, and 7 in Example 4 (i.e., for compound 2017).

Table 1 lists compounds of the Examples described above, as well as additional compounds that may be prepared according to methods analogous to those described for the compounds above and other methods known to a person having skill in the art.

Table 1. Compound List

Example 305. Enzymatic Assay for MASP-2

[0270] The MASP-2 assay utilizes a fluorogenic substrate, based on the cleavage site for its natural substrate C2. The assay was run at room temperature in an assay buffer containing 20 mM Hepes, pH 7.4, 140 mM NaCl and 0.1% Tween 20. Assay parameters were adjusted such that the assay was linear with respect to time, enzyme and substrate concentrations. Under these optimized assays conditions, IC50 values were equivalent to Ki values, except in a few cases of "tight binding" inhibitors. Cases of "tight binding" or possible "slow binding" inhibitors were handled by the methods described in Copeland R.A. (2013) Evaluation of Enzyme Inhibitors in Drug Discovery. 2nd Ed., John Wiley and Sons, Inc., Chapters 5-7.

[0271] The MASP-2 assay protocol was carried out as follows. Test compounds were serially diluted in DMSO and then 100 nL of each dilution was transferred to the assay plate(s). 10 pL of Assay Buffer was added, followed by 15 pL of Enzyme (MASP-2 (CCP1- CCP2-SP) in Assay Buffer. 15 pL of Substrate in Assay Buffer was then added and mixed to start the reactions. After 20 min at room temperature, 15 pL of a stop solution (0.1 M acetic acid) was added, mixed and the plates were read on a SpectraMax i3x Microplate Reader and exported as Excel files. Each assay plate included a "no inhibitor" (DMSO Only) control, a "no enzyme" control and a reference inhibitor control. % Activity values = l00*(ave. test comp fluorescence - ave. "no enz" fluorescence) / (ave. "DMSO only" fluorescence - ave."no enz" fluorescence). IC50 and Ki values were very reproducible, falling well within ± 2-fold.

Example 306. Lectin pathway activation assay in human serum treated with small compounds

[0272] Microtiter ELISA plate was coated with mannan from Saccharomyces cerevisiae (Sigma- Aldrich, M7504) for overnight at 4 °C in coating buffer [15 mM Na ₂ C03, 35 mM NaHC03]. Plate was blocked with 1% bovine serum albumin (BSA) (Sigma-Aldrich, A3294) in Tris-buffered Saline (TBS) [10 mM Tris-HCl, 140 mM NaCl] for 2 hours at room temperature. 1% human serum was incubated with serial dilutions of small compounds in GVB++ [4 mM Barbital, 145 mM NaCl, 0.2 mM MgCh, 0.2 mM CaCh, 1% Gelatin] and incubated for 15 minutes at room temperature. 100 pL of this mixture were then added to the plate and plate was incubated at 37°C for up to an hour with gentle shaking, 200 rpm. After that, plate was washed thrice in wash buffer [TBS containing 5 mM CaCh and 0.05% Tween- 20] and 100 pL of rabbit anti human C3c (Dako, A0062) diluted 1:5000 in wash buffer were added and incubated at 37°C for 30 minutes. Plate was washed and 100 pL of HRP goat anti rabbit IgG (Southern Biotech, 4050-05) diluted 1 :8000 in wash buffer were added and incubated at room temperature for 30 minutes. After that, plate was washed three times and 100 pL /well of TMB Colorimetric substrate (Thermo Scientific, 34029) were added and incubated at room temperature for 5 minutes and the reaction was stop by adding 100 pL /well of 0.1 N sulfuric acid (BDH7230) and the absorbance was measured at 450 nm.

Example 307. Enzymatic Assay for Thrombin

The thrombin assay utilizes a fluorogenic peptide substrate (Boc-VPR-AMC (R&D Systems) and was run at room temperature in an assay buffer containing 20 mM Hepes, pH 7.4, 140 mM NaCl and 0.1% Tween 20. Assay parameters were adjusted such that the assay was linear with respect to time, enzyme and substrate concentrations. Under these optimized assays conditions, ICso values were equivalent to Ki values, except in a few cases of "tight binding" inhibitors. Cases of "tight binding" or possible "slow binding" inhibitors were handled by the methods described in Copeland R.A. (2013) Evaluation of Enzyme Inhibitors in Drug Discovery. 2nd Ed. John Wiley and Sons, Inc., Chapters 5-7.

The thrombin assay protocol was carried out as follows. Test compounds were serially diluted in DMSO and then 100 nl of each dilution was transferred to the assay plate(s). 10 pL of Assay Buffer was added, followed by 15 pL of enzyme (human a-thrombin (BioPharm Lab.)) in assay buffer. 15 pL of substrate in assay buffer were then added and mixed to start the reactions. After 20 min at room temperature, 15 pL of a stop solution (0.1 M acetic acid) was added, mixed and the plates were read on a SpectraMax i3x Microplate Reader and exported as Excel files. Each assay plate included a "no inhibitor" (DMSO Only) control, a "no enzyme" control and a reference inhibitor control. % Activity values = l00*(ave. test comp fluorescence - ave."no enz" fluorescence) / (ave. "DMSO only" fluorescence - ave. "no enz" fluorescence). IC50 and Ki values were very reproducible, falling well within ± 2-fold.

The results of biological assays for the compounds listed in Table 1 are listed in Tables 2, 3 and 4 below.

Table 2: MASP-2 / Thrombin / Lectin Pathway Inhibition for Compounds 1000-1229

MASP-2 Inhibition and Thrombin Inhibition Ki Values:

* Ki of less than 25 mM

** Ki of less than 10 mM

*** Ki of less than 2.5 mM

**** Ki of less than 0.5 mM

Ki of >25 mM

Lectin Pathway Inhibition

IC50 value > 50 mM

+ ICso value in the range of 5 mM to 50 mM

++ ICso value in the range of 0.5 mM to 5 mM

+++ ICso value in the range of 0.05 mM to 0.5 mM

++++ ICso value < 0.05 mM

Selectivity of compound for MASP-2 inhibition versus thrombin:

less than 1.0-fold

* 1.0 to 5.0-fold

** 5.0 to 25-fold

*** 25 to lOO-fold

**** >l00-fold

ND Not determined Table 3. MASP-2 / Thrombin / Lectin Pathway Inhibition for Compounds 1230-1497

MASP-2 Inhibition and Thrombin Inhibition Ki Values:

* 10 mM<K _ί <25 mM

** 2.5 mM < K _ί < 10 mM

*** 0.5 mM < Ki < 2.5 mM

**** Ki < 0.5 mM

Ki of >25 mM

ND Not determined

Lectin Pathway Inhibition

+ 5 pMMCso <50 mM

+4- 0.5 mM < IC50 < 5 mM

-H-4- 0.05 mM < Ki < 0.5 mM

++++ Ki < 0.05 mM

IC50 >50 mM

Selectivity of compound for MASP-2 inhibition versus thrombin:

< 1.0-fold

* >1.0 to <5.0-fold

** >5.0 to <25-fold

*** >25 _l0 <l00-fold

**** > 100-fold

ND Not determined

Table 4. MASP-2 / Thrombin / Lectin Pathway Inhibition

MASP-2 Inhibition and Thrombin Inhibition Ki values:

* Ki of less than 25 mM

** Ki of less than 10 mM

*** Ki of less than 2.5 mM

**** Ki of less than 0.5 mM

***** Ki of less than 0.05 mM

Ki of >25 mM

Lectin Pathway Inhibition:

IC value > 50 mM

+ IC u value in the range of 5 mM to 50 mM

Selectivity of compound for MASP-2 versus thrombin.

less than 1.0-fold

+ 1.0 to 5.0-fold

++ 5.0 to 25-fold

+++ 25 to 100-fold

++++ >100-fold

ND Not determined

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. Each reference, including without limitation all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety for all purposes.