WO2019142053A2

WO2019142053A2 - Therapeutic inhibitory compounds

Info

Publication number: WO2019142053A2
Application number: PCT/IB2019/000079
Authority: WO
Inventors: Andrew Mcdonald; Shawn QIAN
Original assignee: Lifesci Pharmaceuticals Inc
Current assignee: Lifesci Pharmaceuticals Inc
Priority date: 2018-01-17
Filing date: 2019-01-17
Publication date: 2019-07-25
Anticipated expiration: 2020-07-17
Also published as: WO2019142053A3

Abstract

Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds that are useful for inhibiting plasma kallikrein. Furthermore, the subject compounds and compositions are useful for the treatment of diseases wherein the inhibition of plasma kallikrein inhibition has been implicated, such as angioedema and the like.

Description

THERAPEUTIC INHIBITORY COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims benefit of U.S. Patent Application No. 62/618,578, filed on January 17, 2018, which is hereby incorporated by reference in its entirety.

BACKGROUND

[0002] A need exists in the medicinal arts for the effective treatment of diseases and disorders related to the vascular system. Such diseases and disorders include, but are not limited to, angioedema, macular edema and brain edema.

BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibiting plasma kallikrein.

[0004] One embodiment provides a compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (I):

wherein,

Ring A is:

(a) 6-amino-2,4-dimethylpyridin-3-yl,

(b) 5-chloro-lH-indazol-3-yl,

(c) 3-chloro-4-fluoro-lH-indol-5-yl,

(d) 3-chloro-6-fluoro-lH-indol-5-yl,

(e) 3 -chloro- 1 H-pyrrol o [2, 3 -b ] pyri din- 5 -yl , or

(f) l-aminoisoquinolin-6-yl; and X is hydrogen, -NH₂, -N0₂, -CN, -NHCOCH₃, -C0₂H, optionally substituted

alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, -CH₂F, -CHF₂, or -CF_3.

[0005] One embodiment provides a compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (II):

wherein,

Ring A is:

(a) 6-amino-2, 4-dimethylpyri din-3 -yl,

(b) 5-chloro-lH-indazol-3-yl,

(c) 3-chloro-4-fluoro-lH-indol-5-yl,

(d) 3-chloro-6-fluoro-lH-indol-5-yl,

(e) 3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl, or

(f) l-aminoisoquinolin-6-yl; and

X is hydrogen, -NH₂, -N0₂, -NHCOCH₃, -C0₂H, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, -CH₂F, -CHF₂, or -CF_3.

[0006] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (la), (II), (Ha), or a pharmaceutically acceptable salt thereof, and a

pharmaceutically acceptable excipient.

[0007] One embodiment provides a method of inhibiting kallikrein enzyme comprising contacting the kallikrein enzyme with a compound of Formula (I), (la), (II), (Ila).

[0008] One embodiment provides a method for treating angioedema in a patient in need thereof comprising administering to the patient a composition comprising a compound of Formula (I), (la), (II), (Ha), or a pharmaceutically acceptable salt thereof. INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.

PET ATT /ED DESCRIPTION OF THE INVENTION

[0010] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of the described features.

Definitions

[0011] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0012] " Amino" refers to the -NH₂ radical.

[0013] "Cyano" refers to the -CN radical.

[0014] "Nitro" refers to the -N0₂ radical.

[0015] " Oxa" refers to the -O- radical.

[0016] " Oxo" refers to the =0 radical.

[0017] " Thioxo" refers to the =S radical.

[0018] " Imino" refers to the =N-H radical.

[0019] " Oximo" refers to the =N-OH radical.

[0020] "Hydrazino" refers to the =N-NH₂ radical. [0021] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms ( e.g ., C₁-C₁₅ alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-C₈ alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅ alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., Ci-C₂ alkyl).

In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other

embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅ alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (//-propyl), 1- m ethyl ethyl (Ao-propyl), 1 -butyl (//-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso- butyl), 1,1 -dimethyl ethyl (/c/V-butyl), 1 -pentyl (//-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -0C(0)-R^a, -N(R^a)₂, -C(0)R^a, - C(0)0R^a, -C(0)N(R^a)₂, -N(R^a)C(0)0R^a, -0C(0)-N(R^a)₂, -N(R^a)C(0)R^a, -N(R^a)S(0)_tR^a (where t is 1 or 2), -S(0)_t0R^a (where t is 1 or 2), -S(0)_tR^a (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0022] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0023] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms.

The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (z.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -C(0)N(R^a)₂, - N(R^a)C(0)OR^a, -OC(0)-N(R^a)₂, -N(R^a)C(0)R^a, -N(R^a)S(0)_tR^a (where t is 1 or 2), -S(0)_tOR^a (where t is 1 or 2), -S(0)_tR^a (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0024] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, - C(0)N(R^a)₂, -N(R^a)C(0)0R^a, -0C(0)-N(R^a)₂, -N(R^a)C(0)R^a, -N(R^a)S(0)_tR^a (where t is 1 or 2), -S(0)_t0R^a (where t is 1 or 2), -S(0)_tR^a (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0025] "Alkylene" or "alkyl ene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, «-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms ( e.g ., Ci-Cx alkylene). In other embodiments, an alkylene comprises one to five carbon atoms ( e.g ., C₁-C₅ alkylene). In other embodiments, an alkylene comprises one to four carbon atoms

(e.g., C₁-C₄ alkylene). In other embodiments, an alkylene comprises one to three carbon atoms

(e.g., C₁-C₃ alkylene). In other embodiments, an alkylene comprises one to two carbon atoms

(e.g., Ci-C₂ alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C₃-C₅ alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -0C(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)0R^a, - C(0)N(R^a)₂, -N(R^a)C(0)0R^a, -OC(O)- N(R^a)₂, -N(R^a)C(0)R^a, -N(R^a)S(0)_tR^a (where t is 1 or 2), -S(0)_t0R^a (where t is 1 or 2), -S(0)_tR^a (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent

hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms ( e.g ., C₂-C₈ alkynylene). In other

embodiments, an alkynylene comprises two to five carbon atoms (e.g., C₂-C₅ alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C₂-C₄

alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C₂-C₃ alkynylene). In other embodiments, an alkynylene comprises two carbon atom (e.g., C₂ alkylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C₅- C₈ alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C₃-C₅ alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR^a, -SR^a, -0C(0)-R^a, -N(R^a)₂, -C(0)R^a, - C(0)0R^a, -C(0)N(R^a)₂, -N(R^a)C(0)0R^a, -0C(0)-N(R^a)₂, -N(R^a)C(0)R^a, -N(R^a)S(0)_tR^a (where t is 1 or 2), -S(0)_t0R^a (where t is 1 or 2), -S(0)_tR^a (where t is 1 or 2) and -S(0)_tN(R^a)₂ (where t is 1 or 2) where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0027] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted

carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-0C(0)- R^a, -R^b-0C(0)-0R^a, -R^b-0C(0)-N(R^a)₂, -R^b-N(R^a)₂, -R^b-C(0)R^a, -R^b-C(0)0R^a, -R^b- C(0)N(R^a)₂, -R^b-0-R^c-C(0)N(R^a)₂, -R^b-N(R^a)C(0)0R^a, -R^b-N(R^a)C(0)R^a, -R^b-N(R^a)S(0)_tR^a (where t is 1 or 2), -R^b-S(0)_tR^a (where t is 1 or 2), -R^b-S(0)_t0R^a (where t is 1 or 2) and -R^b- S(0)_tN(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0028] "Aralkyl" refers to a radical of the formula -R^c-aryl where R^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0029] "Aralkenyl" refers to a radical of the formula -R^d-aryl where R^d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0030] "Aralkynyl" refers to a radical of the formula -R^e-aryl, where R^e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0031] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula - 0-R^c-aryl where R^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0032] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated {i.e., containing single C-C bonds only) or unsaturated {i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbomyl ( i.e ., bicyclo[2.2.l]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-0C(0)-R^a, -R^b-0C(0)-0R^a, - R^b-0C(0)-N(R^a)₂, -R^b-N(R^a)₂, -R^b-C(0)R^a, -R^b-C(0)0R^a, -R^b-C(0)N(R^a)₂, -R^b-0-R^c- C(0)N(R^a)₂, -R^b-N(R^a)C(0)0R^a, -R^b-N(R^a)C(0)R^a, -R^b-N(R^a)S(0)_tR^a (where t is 1 or 2), -R^b- S(0)_tR^a (where t is 1 or 2), -R^b-S(0)_t0R^a (where t is 1 or 2) and -R^b-S(0)_tN(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^b is independently a direct bond or a straight or branched alkylene or alkenyl ene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0033] "Carbocyclylalkyl" refers to a radical of the formula -R^c-carbocyclyl where R^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0034] "Carbocyclylalkynyl" refers to a radical of the formula -R^c-carbocyclyl where R^c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above. [0035] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula

-0-R^c-carbocydyl where R^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0036] As used herein,“carboxylic acid bioisostere” refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,

[0037] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0038] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0039] "Heterocyclyl" refers to a stable 3- to l8-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl,

imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,

octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,

l-oxo-thiomorpholinyl, and l,l-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-0C(0)-R^a, -R^b-0C(0)-0R^a, -R^b-0C(0)- N(R^a)₂, -R^b-N(R^a)₂, -R^b-C(0)R^a, -R^b-C(0)0R^a, -R^b-C(0)N(R^a)₂, -R^b-0-R^c-C(0)N(R^a)₂, -R^b- N(R^a)C(0)0R^a, -R^b-N(R^a)C(0)R^a, -R^b-N(R^a)S(0)_tR^a (where t is 1 or 2), -R^b-S(0)_tR^a (where t is 1 or 2), -R^b-S(0)_tC)R^a (where t is 1 or 2) and -R^b-S(0)_tN(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0040] "A-heterocyclyl" or“N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An A-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such A-heterocyclyl radicals include, but are not limited to, l-morpholinyl, 1- piperidinyl, l-piperazinyl, l-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0041] " C-heterocyclyl" or“C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0042] "Heterocyclylalkyl" refers to a radical of the formula -R^c-heterocyclyl where R^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0043] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -0-R^c-heterocyclyl where R^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the

heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0044] "Heteroaryl" refers to a radical derived from a 3 - to l8-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, l,3-benzodioxolyl, benzofuranyl, benzooxazolyl,

benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, l,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl

(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,

benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl,

6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5.6.7.8.9.10-hexahydrocycloocta[d]pyrimidinyl,

5.6.7.8.9.10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,l0-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl,

naphthyridinyl, l,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,

5,6,6a,7,8,9,l0,l0a-octahydrobenzo[h]quinazolinyl, 1 -phenyl - 1 //-pyrrol yl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,

pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,

5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,

6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,

5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl ( i.e . thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a, -R^b-0C(0)-R^a, -R^b-0C(0)-0R^a, -R^b-0C(0)- N(R^a)₂, -R^b-N(R^a)₂, -R^b-C(0)R^a, -R^b-C(0)0R^a, -R^b-C(0)N(R^a)₂, -R^b-0-R^c-C(0)N(R^a)₂, -R^b- N(R^a)C(0)0R^a, -R^b-N(R^a)C(0)R^a, -R^b-N(R^a)S(0)_tR^a (where t is 1 or 2), -R^b-S(0)_tR^a (where t is 1 or 2), -R^b-S(0)_tC)R^a (where t is 1 or 2) and -R^b-S(0)_tN(R^a)₂ (where t is 1 or 2), where each R^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0045] "/V-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An /V-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0046] " C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0047] "Heteroaryl alkyl" refers to a radical of the formula -R^c-heteroaryl, where R^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0048] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula - 0-R^c-heteroaryl, where R^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0049] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as ( R )- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers ( e.g cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term“positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0050] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0051] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of ²H, ³H, ^UC, ¹³C and/or ¹⁴C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0052] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of the present disclosure.

[0053] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (²H), tritium (³H), iodine-l25 (¹²⁵I) or carbon-l4 (¹⁴C). Isotopic substitution with ²H, ^UC, ¹³C, ¹⁴C, ¹⁵C, ¹²N, ¹³N, ¹⁵N, ¹⁶N, ¹⁶0, ¹⁷0, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S, ³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁵I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0054] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with ²H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0055] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled

Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0056] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available

commerically from chemical vendors, such as Aldrich Chemical Co.

[0057] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d₃ (CD₃I), are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD₃I is illustrated, by way of example only, in the reaction schemes below.

CD₃I

V base

O V O Y D °

[0058] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD₄), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of L1AID₄ is illustrated, by way of example only, in the reaction schemes below.

[0059] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon- carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0060] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0061] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the kallikrein inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0062] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et ah, "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1- 19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0063] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, NN- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, /V-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, /V-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0064] As used herein,“treatment” or“treating,” or“palliating” or“ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0065] "Prodrug" is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

[0066] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. [0067] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo , to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.

Kallikrein Inhibitory Compounds

[0068] Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibiting plasma kallikrein.

[0069] One embodiment provides a compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (I):

wherein,

Ring A is:

(a) 6-amino-2,4-dimethylpyridin-3-yl,

(b) 5-chloro-lH-indazol-3-yl,

(c) 3-chloro-4-fluoro-lH-indol-5-yl,

(d) 3-chloro-6-fluoro-lH-indol-5-yl,

(e) 3 -chloro- 1 H-pyrrol o [2, 3 -b ] pyri din- 5 -yl , or

(f) l-aminoisoquinolin-6-yl; and X is hydrogen, -NH₂, -N0₂, -CN, -NHCOCH₃, -C0₂H, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, -CH₂F, -CHF₂, or -CF_3.

[0070] One embodiment provides a compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (la):

wherein,

Ring A is:

(a) 6-amino-2,4-dimethylpyridin-3-yl,

(b) 5-chloro-lH-indazol-3-yl,

(c) 3-chloro-4-fluoro-lH-indol-5-yl,

(d) 3-chloro-6-fluoro-lH-indol-5-yl,

(e) 3 -chloro- 1 H-pyrrol o [2, 3 -b ] pyri din- 5 -yl , or

(f) l-aminoisoquinolin-6-yl; and

X is H, -CN, -CH₂F, -CHF₂, or -CF_3.

[0071] Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt thereof, wherein X is H. Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt thereof, wherein X is -CN. Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt thereof, wherein X is -CH₂F, -CHF₂, or -CF_3. Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt thereof, wherein X is H, -CH₂F, -CHF₂, or -CF_3.

[0072] Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt thereof, wherein Ring A is 6-amino-2,4-dimethylpyridin-3-yl. Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt thereof, wherein Ring A is 6-amino-2, 4-dimethylpyri din-3 -yl and X is H. [0073] Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt thereof, wherein Ring A is 5-chloro-lH-indazol-3-yl.

[0074] Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt thereof, wherein Ring A is 3-chloro-4-fluoro-lH-indol-5-yl.

[0075] Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt thereof, wherein Ring A is 3-chloro-6-fluoro-lH-indol-5-yl.

[0076] Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt thereof, wherein Ring A is 3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl.

[0077] Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt thereof, wherein Ring A is l-aminoisoquinolin-6-yl.

[0078] Another embodiment provides the compound of Formula (I) or (la), or pharmaceutically acceptable salt thereof, selected from:

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6- yl)methyl)oxazole-5-carboxamide,

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- cy anooxazol e- 5 -carb oxami de,

N-((3 -chloro-6-fluoro- 1 H-indol-5-yl)methyl)-2-((3 -chloro-8-fluoroquinolin-6- yl)methyl)oxazole-5-carboxamide,

N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5- carboxamide,

N-((3-chloro-lH-pynOlo[2,3-b]pyridin-5-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6- yl)methyl)oxazole-5-carboxamide,

N-((5-chloro-lH-indazol-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5- carb oxami de, and

N-((3 -chloro-4-fluoro- 1 H-indol-5-yl)methyl)-2-((3 -chloro-8-fluoroquinolin-6- yl)methyl)oxazole-5-carboxamide.

[0079] One embodiment provides a compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (II):

wherein,

Ring A is:

(a) 6-amino-2, 4-dimethylpyri din-3 -yl,

(b) 5-chloro-lH-indazol-3-yl,

(c) 3-chloro-4-fluoro-lH-indol-5-yl,

(d) 3-chloro-6-fluoro-lH-indol-5-yl,

(e) 3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl, or

(f) l-aminoisoquinolin-6-yl; and

[0080] One embodiment provides a compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (Ila):

wherein,

Ring A is:

(a) 6-amino-2, 4-dimethylpyri din-3 -yl,

(b) 5-chloro-lH-indazol-3-yl,

(c) 3-chloro-4-fluoro-lH-indol-5-yl,

(d) 3-chloro-6-fluoro-lH-indol-5-yl,

(e) 3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl, or

(f) l-aminoisoquinolin-6-yl; and X is C1-C3 hydroxyalkyl, -CH₂F, -CHF₂, or -CF_3.

[0081] Another embodiment provides the compound of Formula (II), or pharmaceutically acceptable salt thereof, wherein X is optionally substituted C1-C6 alkyl.

[0082] Another embodiment provides the compound of Formula (II) or (Ha), or

pharmaceutically acceptable salt thereof, wherein X is C1-C3 hydroxyalkyl.

[0083] Another embodiment provides the compound of Formula (II) or (Ha), or

pharmaceutically acceptable salt thereof, wherein X is -CH₂F, -CHF₂, or -CF_3.

[0084] Another embodiment provides the compound of Formula (II) or (Ha), or

pharmaceutically acceptable salt thereof, wherein Ring A is 6-amino-2,4-dimethylpyridin-3-yl.

[0085] Another embodiment provides the compound of Formula (II) or (Ha), or

pharmaceutically acceptable salt thereof, wherein Ring A is 5-chloro-lH-indazol-3-yl.

[0086] Another embodiment provides the compound of Formula (II) or (Ila), or

pharmaceutically acceptable salt thereof, wherein Ring A is 3-chloro-4-fluoro-lH-indol-5-yl.

[0087] Another embodiment provides the compound of Formula (II) or (Ila), or

pharmaceutically acceptable salt thereof, wherein Ring A is 3-chloro-6-fluoro-lH-indol-5-yl.

[0088] Another embodiment provides the compound of Formula (II) or (Ila), or

pharmaceutically acceptable salt thereof, wherein Ring A is 3-chloro-lH-pyrrolo[2,3-b]pyridin- 5-yl.

[0089] Another embodiment provides the compound of Formula (II) or (Ila), or

pharmaceutically acceptable salt thereof, wherein Ring A is l-aminoisoquinolin-6-yl.

[0090] Another embodiment provides the compound of Formula (II) or (Ila), or

pharmaceutically acceptable salt thereof, selected from:

N-((6-amino-2,4-dimethylpyri din-3 -yl)m ethyl)- 1 -((3 -chl oro-8-fluoroquinolin-6-yl)methyl)-3 - (l-hydroxyethyl)-lH-pyrazole-4-carboxamide,

N-((6-amino-2,4-dimethylpyri din-3 -yl)m ethyl)- 1 -((3 -chl oro-8-fluoroquinolin-6-yl)methyl)-3 - (2-hydroxypropan-2-yl)-lH-pyrazole-4-carboxamide,

N-((6-amino-2, 4-dimethylpyri din-3 -yl)m ethyl)- 1 -((3 -chl oro-8-fluoroquinolin-6-yl)methyl)-3- (hy droxym ethyl )- 1 H-pyrazol e-4-carb oxami de,

N-((6-amino-2, 4-dimethylpyri din-3 -yl)m ethyl)- 1 -((3 -chl oro-8-fluoroquinolin-6-yl)methyl)-3- (fluoromethyl)-lH-pyrazole-4-carboxamide,

N-((6-amino-2, 4-dimethylpyri din-3 -yl)m ethyl)- 1 -((3 -chl oro-8-fluoroquinolin-6-yl)methyl)-3- (difluoromethyl)-lH-pyrazole-4-carboxamide, N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3-

(difluoromethyl)-lH-pyrazole-4-carboxamide,

N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3-

(fluoromethyl)-lH-pyrazole-4-carboxamide,

N-((l-aminoisoquinolin-6-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3-

(fluoromethyl)-lH-pyrazole-4-carboxamide,

N-((5-chloro-lH-indazol-3-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3-

(fluoromethyl)-lH-pyrazole-4-carboxamide,

N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3-

(fluoromethyl)-lH-pyrazole-4-carboxamide,

N-((3-chloro-lH-pynOlo[2,3-b]pyridin-5-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6- yl)methyl)-3 -(fluoromethyl)- lH-pyrazole-4-carboxamide,

(difluoromethyl)-lH-pyrazole-4-carboxamide,

N-((3-chloro-lH-pynOlo[2,3-b]pyridin-5-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6- yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide, and

N-((l-aminoisoquinolin-6-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3- (difluoromethyl)-lH-pyrazole-4-carboxamide.

[0091] One embodiment provides a compound, or pharmaceutically acceptable salt thereof, selected from:

N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)oxazole-

5-carboxamide,

N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)oxazole-5- carboxamide,

N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)oxazole-5- carboxamide,

N-((5-chloro-lH-indazol-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)oxazole-5- carboxamide, and

N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)oxazole-5- carboxamide. [0092] One embodiment provides a compound, or pharmaceutically acceptable salt thereof, selected from:

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3-(2- hydroxypropan-2-yl)-lH-pyrazole-4-carboxamide,

N-((3 -chloro-6-fluoro- 1 H-indol-5-yl)methyl)- 1 -((3 -chloroquinolin-6-yl)methyl)-3 - (fluoromethyl)-lH-pyrazole-4-carboxamide,

N-((3 -chloro-6-fluoro- 1 H-indol-5-yl)methyl)- 1 -((3 -chloroquinolin-6-yl)methyl)-3 - (difluoromethyl)-lH-pyrazole-4-carboxamide,

N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3-

(difluoromethyl)-lH-pyrazole-4-carboxamide,

(fluoromethyl)-lH-pyrazole-4-carboxamide,

N-((5-chloro-lH-indazol-3-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH- pyrazole-4-carboxamide,

N-((3 -chloro-4-fluoro- 1 H-indol-5-yl)methyl)- 1 -((3 -chloroquinolin-6-yl)methyl)-3 - (difluoromethyl)-lH-pyrazole-4-carboxamide,

N-((5-chloro-lH-indazol-3-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)- lH-pyrazole-4-carboxamide,

N-((l-aminoisoquinolin-6-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)- lH-pyrazole-4-carboxamide,

N-(( 1 -aminoisoquinolin-6-yl)m ethyl)- 1 -((3 -chloroquinolin-6-yl)methyl)-3 -(fluorom ethyl)- 1H- pyrazole-4-carboxamide, and

N-((3 -chloro-4-fluoro- 1 H-indol-5-yl)methyl)- 1 -((3 -chloroquinolin-6-yl)methyl)-3 - (fluoromethyl)-lH-pyrazole-4-carboxamide.

[0093] One embodiment provides a compound, or pharmaceutically acceptable salt thereof, selected from:

N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-l,3,4- oxadiazole-2-carboxamide,

N-((5-chloro-lH-indazol-3-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-l,3,4- oxadiazole-2-carboxamide,

N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-l,3,4- oxadiazole-2-carboxamide, N-((l -aminoisoquinolin-6-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)- 1,3,4- oxadiazole-2-carboxamide, and

N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6- yl)methyl)-l,3,4-oxadiazole-2-carboxamide.

[0094] One embodiment provides a compound, or pharmaceutically acceptable salt thereof, selected from:

N-((5-chloro-lH-indazol-3-yl)methyl)-5-((3-chloroquinolin-6-yl)methyl)-4H-l, 2, 4-tri azole-3- carboxamide,

N-((l-aminoisoquinolin-6-yl)methyl)-5-((3-chloroquinolin-6-yl)methyl)-4H-l, 2, 4-tri azole-3- carboxamide,

N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-((3-chloroquinolin-6-yl)methyl)-4H- 1,2, 4-tri azole-3 -carboxamide,

N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-5-((3-chloroquinolin-6-yl)methyl)-4H-l,2,4- tri azol e-3 -carb oxami de,

N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-5-((3-chloroquinolin-6-yl)methyl)-4H-l,2,4- tri azol e-3 -carb oxami de,

N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H-

1.2.4-tri azole-3 -carboxamide,

N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6- yl)methyl)-4H-l,2,4-triazole-3-carboxamide,

N-((l -aminoisoquinolin-6-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H- 1,2,4- tri azol e-3 -carb oxami de,

N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H-

1.2.4-triazole-3 -carboxamide, and

N-((5-chloro-lH-indazol-3-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H-l,2,4- tri azol e-3 -carb oxami de .

[0095] One embodiment provides a compound, or pharmaceutically acceptable salt thereof, selected from:

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-

(difluoromethyl)oxazole-5-carboxamide;

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-4-((3-chloroquinolin-6-yl)methyl)oxazole-2- carboxamide; N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4- methyloxazole-5-carboxamide;

N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-

(difluoromethyl)oxazole-5-carboxamide;

N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-methyloxazole-5- carboxamide;

(fluoromethyl)oxazole-5-carboxamide;

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-4-((3-chloro-8-fluoroquinolin-6- yl)methyl)oxazole-2-carboxamide;

N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-

(fluoromethyl)oxazole-5-carboxamide;

N-((l-aminoisoquinolin-6-yl)methyl)-4-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-2- carboxamide;

(hydroxymethyl)oxazole-5-carboxamide;

N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-

(hydroxymethyl)oxazole-5-carboxamide;

N-((6-amino-2, 4-dimethylpyri din-3 -yl )methyl)-2-(4-((2-oxopyri din- l(2H)- yl)methyl)benzyl)oxazole-5-carboxamide;

N-((6-amino-2, 4-dimethylpyri din-3 -yl)methyl)-2-((3 -chloroquinolin-6-yl)methyl)-4-( 1- hydroxyethyl)oxazole-5-carboxamide;

N-((6-ami no-2, 4-dim ethyl pyridi n-3-yl)m ethyl )-3-(hydroxym ethyl)-! -(4-((2-oxopyridin- l (2H)- yl )m ethyl )benzyl)-l//-pyrazole-4-carboxamide; and

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-(2- hy droxypropan-2-yl )oxazol e- 5 -carb oxami de .

[0096] One embodiment provides a compound, or pharmaceutically acceptable salt thereof, selected from:

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- methyloxazole-5-carboxamide;

N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-

(difluoromethyl)oxazole-5-carboxamide; N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-

(difluoromethyl)oxazole-5-carboxamide;

N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- methyloxazole-5-carboxamide;

N-((6-amino-2, 4-dimethylpyri din-3 -yl)methyl)-2-((3 -chloro-8- fluoroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5-carboxamide;

N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- (fluoromethyl)oxazole-5-carboxamide;

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-

(hydroxymethyl)oxazole-5-carboxamide;

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- (l-hydroxyethyl)oxazole-5-carboxamide; or

(2-hydroxypropan-2-yl)oxazole-5-carboxamide.

[0097] In some embodiments, the kallikrein inhibitory compound described herein has a structure provided in Table 1.

TABLE 1

Preparation of Compounds

[0098] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka),

Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc.

(Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics

(Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd.

(Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0099] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et ak, "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modem Synthetic Reactions", 2nd Ed., W. A.

Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford ETniversity Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic

Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modem Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471- 19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An ETllmanris Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[00100] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details).

Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses ( e.g ., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the kallikrein inhibitory compound described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical Compositions

[00101] In certain embodiments, the kallikrein inhibitory compound as described herein is administered as a pure chemical. In other embodiments, the kallikrein inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 2 I^st Ed. Mack Pub. Co., Easton, PA (2005)).

[00102] Provided herein is a pharmaceutical composition comprising at least one kallikrein inhibitory compound, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers.

The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient ( i.e the subject) of the composition.

[00103] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (la), (II), (Ha), or as disclosed in Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[00104] In certain embodiments, the kallikrein inhibitory compound as described by Formula (I), (la), (II), (Ha), or as disclosed in Table 1, or a pharmaceutically acceptable salt thereof, is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[00105] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.

(See, e.g. , Remington: The Science and Practice of Pharmacy (Gennaro, 2 I^st Ed. Mack Pub. Co., Easton, PA (2005)).

[00106] The dose of the composition comprising at least one kallikrein inhibitory compound as described herein differ, depending upon the patient's (e.g, human) condition, that is, stage of the disease, general health status, age, and other factors. [00107] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit ( e.g an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[00108] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.

[00109] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), (la), (II), (Ha), or Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[00110] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), (la), (II), (Ha), or Table 1, or a

pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Kallikrein-Kinin System

[00111] Modulation of vascular permeability is important in regulating the passage of small molecules or blood cells between blood vessels and surrounding tissues. Vascular permeability depends upon the physiological states of tissues such as during inflammation, changes in blood pressure, and fluctuations in ion and nutrient gradients. The junctions between the endothelial cells that line blood vessels are the immediate controllers of vascular permeability. The strength of these junctions is tightly regulated by the kinin-kallikrein system of polypeptides and enzymes. Abnormalities in the kinin-kallikrein system lead to a range of pathologies including angioedema, macular edema and brain edema. Angi oedema is a potentially fatal blood disorder characterized by swelling that may occur in the face, gastrointestinal tract, extremities, genitals and upper airways. Genetic hereditary angioedema attacks result from the unregulated activation of the kallikrein system with uncontrolled increases in vascular permeability. Currently there is a need for agents that are useful for the treatment of angioedema and for agents that inhibit plasma kallikrein. [00112] The kallikrein-kinin system represents a metabolic cascade that, when activated, triggers the release of vasoactive kinins. The kinin-kallikrein system (KKS) consists of serine proteases involved in the production of kinins, principally bradykinin and Lys-bradykinin (kallidin). The KKS contributes to a variety of physiological processes including

inflammation, blood pressure control and coagulation. The activation of this system is particularly important in blood pressure regulation and in inflammatory reactions, due to the ability of bradykinin to elevate vascular permeability and to cause vasodilatation of arteries and veins of the gut, aorta, uterus and urethra. The kinin-kallikrein system, also referred to as the contact system, consists of three serine proenzymes (factor XII (FXII) or Hageman factor, factor IX (FIX), and prekallikrein), and the kinin precursor high molecular weight kinin (HK). Contact activation is triggered by the binding of FXII to a negatively charged surface and involves the formation of a-FXIIa via autocatalysis. Bound a-FXIIa converts prekallikrein into kallikrein. Kallikrein can further convert a-FXIIa to b-FXIIa by an additional cleavage at R334-N335, a positive feedback mechanism that leads to sufficient kallikrein production to drive downstream processes. a-FXIIa consists of a heavy and light chain that are disulphide linked, whereas b-FXIIa lacks the heavy chain and loses its capacity to bind to negatively charged surfaces (Stavrou E, Schmaier AH., Thrombosis Research , 2010, 125(3) pp. 210-215). The N-terminal region of FXII (a-FXIIa heavy chain) shows strong homology with tissue-type plasminogen activator (tPA), with the presence of fibronectin type I, epidermal growth factor, and Kringle domains (Ny et al Proc Natl Acad Sci USA , 1984, 81(17) pp. 5355-5359; Cool DE, MacGillivray RT, The Journal of Biological Chemistry , 1987, 262(28) pp. 13662-13673). Kallikrein is a trypsin-like serine protease enzyme that cleaves high molecular weight kinin (HK) to produce bradykinin. Bradykinin then binds to the bradykinin 2R receptors (BK2R) on endothelial cells to trigger an increase in vascular permeability.

[00113] Protease inhibitors regulate the activation of the contact system. Several known serpins of plasma are Cl-inhibitor (CllNH), antithrombin III, a2-macroglobulin, al-protease inhibitor, and a2-antiplasmin (Kaplan et al., Advances in Immunology , 1997 (66) pp.225-72; Pixley et al., The Journal of Biological Chemistry , 1985, 260(3) pp. 1723-9). However, CllNH is the major regulator of the intrinsic system, interfering with the activities of factor Xlla and of kallikrein (Cugno et al., The Journal of Laboratory and Clinical Medicine , 1993, 121(1) pp. 38-43). Both CllNH and a2 -macroglobulin account for more than 90% of the kallikrein inhibitory activity of plasma. Thus, the FXII-dependent kallikrein-kinin system is tightly regulated by the CINH and when regulation of the FXII-dependent kallikrein-kinin system fails, in a subject, the subject is believed to suffer from hereditary angioedema (HAE) that is characterized by invalidating edema attacks.

[00114] Angioedema is a potentially fatal blood disorder characterized by swelling that may occur in the face, gastrointestinal tract, extremities, genitals and upper airways.

Angioedema attacks begin in the deeper layers of the skin and mucous membranes with localized blood vessel dilatation and increased permeability. Symptoms of the disease result from the leakage of plasma from blood vessels into surrounding tissues. Genetic hereditary angioedema attacks result from unregulated activation of the kallikrein system with consequent overproduction of bradykinin and uncontrolled increases in vascular permeability. As vascular permeability rises beyond normal, plasma leaks out of the vasculature into surrounding tissue, causing swelling (Mehta D and Malik AB, Physiol. Rev ., 86 (1), 279-367, 2006; Sandoval R et ah, J Physiol ., 533(pt 2), 433-45, 2001; Kaplan AP and Greaves MW, Angioedema. J Am. Acad. Dermatol ., 2005).

[00115] HAE results from mutations in the genes that code for elements of the coagulation and inflammation pathways. The three forms of HAE are distinguished by their underlying causes and levels of the Cl -esterase inhibitor (CllNH, serpin peptidase inhibitor, clade G, member 1) protein in the blood, which inhibits the activity of plasma kallikrein. In type I, patients have insufficient levels of functional CllNH, while type II patients have dysfunctional CllNH. While type I and II affect men and women at equal rates, type III, which primarily affects women, results from a mutation in coagulation factor XII (Hageman factor; HAE-FXII). The underlying causes of type I and II HAE are autosomal dominant mutations in CllNH gene (SERPING1 gene) on chromosome 11 (11 ql2-ql 3.1).

[00116] CllNH accounts for 90% of inhibition of FXIIa and 50% of inhibition of plasma kallikrein (Pixley RA et ak, J. Biol. Chem ., 260, 1723-9, 1985; Schapira M et ah, Biochemistry , 20, 2738-43, 1981). In addition, CllNH also inactivates prekallikrein (Colman RW et al, Blood , 65, 311-8, 1985). When CllNH levels are normal, its activity blocks FXIIa from converting pre-kallikrein to kallikrein and blocks kallikrein's conversion to HK, thus preventing the production of bradykinin and the edemic episodes. When CllNH levels are low, or levels of dysfunctional CllNH are high, this inhibition fails and the pathogenic process ensues.

[00117] In addition to HAE, plasma kallikrein also contributes to non-hereditary angioedema, high altitude cerebral edema, cytotoxic cerebral edema, osmotic cerebral edema, diabetic macular edema (DME), clinically significant macular edema, cystoid macular edema (CME, Gao BB, Nat Med., 13(2), 181-8, 2007), retinal edema, radiation induced edema, lymph edema, glioma-associated edema, allergic edema e.g. airflow obstruction in chronic allergic sinusitis or perennial rhinitis. Other disorders of the plasma kallikrein system include retinopathy and diabetic retinopathy (Liu J and Feener EP, Biol. Chem. 394(3), 319-28, 2013), proliferative and non-proliferative retinopathy (Liu J et al, Invest. Ophthalmol. Vis. Sci., 54(2), 2013), CME following cataract extraction, CME induced by cryotherapy, CME induced by uveitis, CME following vascular occlusion (e.g., central retinal vein occlusion, branch retinal vein occlusion or hemiretinal vein occlusion), complications related to cataract surgery in diabetic retinopathy, hypertensive retinopathy (JA Phillips et al., Hypertension , 53, 175-181, 2009), retinal trauma, dry and wet age-related macular degeneration (AMD), ischemic reperfusion injuries (C Storoni et al., JPET , 381, 849-954, 2006), e.g., in a variety of contexts associated with tissue and/or organ transplantation.

[00118] Current treatments for angioedema, and those under development, target different elements in the HAE pathway. Three classes of therapies are currently available: (a) replacement therapy with C1INH concentrates (e.g., Cinryze, Berinert), (b) administration of selective kallikrein inhibitors (e.g., Ecallantide) and (c) bradykinin receptors antagonists (e.g., Firazyr).

[00119] Replacement therapies have proven useful for both acute attacks, including emergency situations, such as laryngeal edema (Bork K et al., Transfusion , 45, 1774-1784, 2005; Bork K and Barnstedt S E, Arch. Intern. Med., 161, 714-718, 2001) and prophylaxis. Selective C1INH inhibitors inactivate both a-FXIIa and b-FXIIa molecules active early in the HAE pathway that catalyze the production of kallikrein (Muller F and Renne T, Curr. Opin. Hematol., 15, 516-21, 2008; Cugno M et al., Trends Mol. Med. l5(2):69-78, 2009). In addition to HAE, plasma kallikrein inhibitors are considered to be useful in the treatment of other edemas such as macular edema and brain edema, and retinopathy, e.g., retinopathy associated with diabetes and/or hypertension. There is evidence that plasma kallikrein inhibitors are also effective in the treatment of edema formation in diseases, e.g., edema formation related to ischemic reperfusion injuries. The bradykinin receptors antagonists prevent bradykinin from activating the vascular permeability pathway and stop the initiation of swelling.

[00120] One embodiment provides a method of inhibiting kallikrein enzyme comprising contacting the enzyme with a compound of any one of Formula (I), (la), (II), (Ha), or Table 1. [00121] One embodiment provides a method of inhibiting plasma kallikrein in a subject comprising administering to the subject a composition comprising a compound of any one of Formula (I), (la), (II), (Ha), or Table 1, or a pharmaceutically acceptable salt thereof.

Methods of Treatment

[00122] One embodiment provides a compound of any one of Formula (I), (la), (II),

(Ila), or Table 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body.

[00123] Disclosed herein are methods of treating diseases or disorders wherein the inhibition of plasma kallikrein is indicated. Such diseases and disorders include, but are not limited to, angioedema, including hereditary and non-hereditary, or macular edema, including diabetic macular edema.

[00124] In some embodiments, the methods disclosed herein are useful for the treatment of angioedema. In some embodiments, the angioedema is hereditary angioedema (HAE). One embodiment provides a method of treating angioedema in a patient in need thereof comprising administration of a composition comprising a compound of Formula (I), (la), (II), (Ila), or Table 1, or a pharmaceutically acceptable salt thereof. Another embodiment provides the method wherein the angioedema is hereditary angioedema.

[00125] One embodiment provides a compound of any one of Formula (I), (la), (II),

(Ila), or Table 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of angioedema. Another embodiment provides a compound for use wherein the angioedema is hereditary angioedema.

[00126] One embodiment provides the use of a compound of Formula (I), (la), (II), (Ila), or Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of angioedema. Another embodiment provides the use wherein the

angioedema is hereditary angioedema.

[00127] In some embodiments, the methods disclosed herein are useful for the treatment of macular edema. In some embodiments, the macular edema is diabetic macular edema. One embodiment provides a method of treating macular edema in a patient in need thereof comprising administration of a composition comprising a compound of Formula (I), (la), (II), (Ila), or Table 1, or a pharmaceutically acceptable salt thereof. Another embodiment provides the method wherein the macular edema is diabetic macular edema. [00128] One embodiment provides a compound of any one of Formula (I), (la), (II),

(Ila), or Table 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of macular edema. Another embodiment provides a compound for use wherein the macular edema is diabetic macular edema.

[00129] One embodiment provides the use of a compound of Formula (I), (la), (II), (Ila), or Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of macular edema. Another embodiment provides the use wherein the angioedema is diabetic macular edema.

[00130] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.

EXAMPLES

I. Chemical Synthesis

[00131] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer

chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (d) and coupling constants, J are reported in Hertz. For proton spectra the solvent peak was used as the reference peak.

[00132] The following abbreviations and terms have the indicated meanings throughout:

AcOH acetic acid

B₂pin₂ bis(pinacolato)diboron

Boc = tert- butoxy carbonyl

DCC dicyclohexylcarbodiimide

DIEA N,N-diisopropylethylamine

DMAP 4-dimethylaminopyridine

EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide

eq equivalent(s)

Et ethyl

EtO Ac or EA = ethyl acetate EtOH ethanol

g gram

h or hr hour

HBTU 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium

hexafluorophosphate

HOBt hy droxyb enzotriazol e

HPLC high pressure liquid chromatography

kg or Kg kilogram

L or 1 liter

LC/MS LCMS = liquid chromatography-mass spectrometry

LRMS low resolution mass spectrometry

m/z mass-to-charge ratio

Me methyl

MeOH methanol

mg milligram

min minute

mL milliliter

mmol millimole

NaOAc sodium acetate

PE petroleum ether

Ph phenyl

Prep preparative

quant. quantitative

RP-HPLC reverse phase-high pressure liquid chromatography

rt or RT room temperature

THF tetrahydrofuran

UV ultraviolet

Example 1: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)oxazole-5-carboxamide

[00133] To a mixture of 4-amino-3-fluorobenzoic acid (380 g, 2.45 mol, 1.0 eq), glycerol (451 g, 4.90 mol, 2.0 eq) and sodium 3-nitrobenzenesulfonate (829 g, 3.68 mol, 1.5 eq) was added 70% H₂S0₄ (1420 mL) slowly. The reaction mixture was then heated at 140 °C for 20 h. The mixture was cooled to rt, poured into ice-water (5 L) and adjusted to pH 3~4 with 25% aqueous NaOH. The resulting precipitate was collected by filtration and dried at 90 °C overnight to give 8-fluoroquinoline-6-carboxylic acid.

[00134] The solid was dissolved in methanol (8 L), to which was added 98% H₂S0₄ (125 mL) slowly. The mixture was heated at 70 °C overnight, then cooled to rt, adjusted to pH 8-9 with 25% aqueous NaOH. The mixture was extracted with EA and the combined organic layers were dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 2/1, v/v) to give methyl 8-fluoroquinoline-6-carboxylate (352 g, 70%) as a yellow solid.

[00135] A mixture of methyl 8-fluoroquinoline-6-carboxylate (352 g, 1.72 mol, 1.0 eq) and NCS (575 g, 4.3 mol, 2.5 eq) in AcOH (6.0 L) was stirred at 120 °C overnight. The solvent was removed by evaporation and the resulting residue was diluted with DCM, washed with water, dried, and concentrated. The resulting residue was triturated with EA (3 L) to afford a yellow solid. The filtrate was concentrated and purified by chromatography on a silica gel column (PE/EA = 10/1, v/v) to give methyl 3-chloro-8-fluoroquinoline-6-carboxylate (311 g, 75%).

[00136] To a suspension of methyl 3-chloro-8-fluoroquinoline-6-carboxylate (59.0 g, 0.264 mol, 1.0 eq) in THF (1750 mL) was added dropwise a solution of LiAlH₄ in THF (1M, 123 mL, 0.123 mol) at -20 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with water, and extracted with EA (600 mL x 4). The combined organic layers were dried and concentrated. The solid was triturated with PE/EA (1 L, v/v = 3/1) to afford (3- chloro-8-fluoroquinolin-6-yl)methanol (31 g, 30%) as a yellow solid.

[00137] To a solution of (3-chloro-8-fluoroquinolin-6-yl)methanol (135.8 g, 0.642 mol, 1.0 eq) in CHCl₃ (4.0 L) was added dropwise SOCl₂ (117 mL, 1.615 mol, 2.5 eq), then stirred at rt overnight. The reaction was quenched with water (500 mL), adjusted to pH 8 with

25% aq NaOH. The organic layer was separated and the aqueous layer was extracted with

CHCI₃ (350 mL ^x 3 ). The combined organic layers were dried and concentrated. The resulting residue was triturated with PE/EA (800 mL, v/v = 5/1) to give 3-chloro-6-(chloromethyl)-8- fluoroquinoline (126 g, 85%) as a yellow solid.

[00138] A mixture of 3-chloro-6-(chloromethyl)-8-fluoroquinoline (73.7 g, 0.32 mol, 1.0 eq), bis(triphenylphosphine)palladium(II) chloride (11.2 g, 0.016, 0.05 mol) and K₂CO₃ (46.4 g, 0.336 mol, 1.05 eq) in THF/methanol (1400 mL/700 mL) under CO atmosphere was stirred at rt overnight. The solvent was removed and the resulting residue was purified by

chromatography on a silica gel column (PE/EA = 10/1, v/v) to give methyl 2-(3-chloro-8- fluoroquinolin-6-yl)acetate (66.0 g, 81%) as a white solid.

[00139] To a solution of methyl 2-(3-chloro-8-fluoroquinolin-6-yl)acetate (54.0 g, 0.213 mol, 1.0 eq) in THF (800 mL) was added a solution of NaOH (17.0 g, 0.426 mol, 2.0 eq) in H₂0 (400 mL) stirred at rt for 2 h. The mixture was adjusted to pH 3 with 1 N HC1. The resulting precipitate was collected by filtration, washed with water, and dried at 90 °C to give 2-(3-chloro-8-fluoroquinolin-6-yl)acetic acid (47.5 g, 93%).

[00140] A solution of 2-(3-chloro-8-fluoroquinolin-6-yl)acetic acid (6.2 g, 25.9 mmol, 1.0 eq) and CDI (5.5 g, 33.67 mmol, 1.3 eq) in DMF (200 mL) was stirred at 60 °C for 1 h. NH₄Cl (1.7 g, 31.08 mmol, 1.2 eq) and TEA (3.6 mL, 25.9 mmol, 1.0 eq) were added to the mixture. The resulting mixture was stirred at 60 °C for 1 h. The mixture was concentrated and the resulting residue was diluted with sat. NaHC0₃ aqueous solution with stirring. The resulting precipitate was collected by filtration and dried. The solid was triturated in EA to give

2-(3-chloro-8-fluoroquinolin-6-yl)acetamide (4.72 g, 76%) as an off-white solid.

[00141] To a stirred mixture of 2-(3-chloro-8-fluoroquinolin-6-yl)acetamide (7.3 g,

30.67 mmol, 1.0 eq), Pd(OAc)₂ (69 mg, 0.31 mmol, 0.01 eq), NaOAc (5.0 g, 61.34 mmol, 2.0 eq) and TFA (11.4 mL, 153.35 mmol, 5.0 eq) in toluene (200 mL) was added methyl propiolate (5.5 mL, 61.34 mmol, 2.0 eq) at rt. The mixture was stirred at 70 °C under nitrogen for 15 h. The mixture was diluted with EA and washed with sat. Na₂C0₃ aqueous solution. The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 3/1, v/v) to give methyl 3-(2-(3-chloro-8-fluoroquinolin-6- yl)acetamido)acrylate (3.4 g, 34%) as a yellow solid.

[00142] To a stirred mixture of methyl 3-(2-(3-chloro-8-fluoroquinolin-6- yl)acetamido)acrylate (3.4 g, 10.56 mmol, 1.0 eq) and BF₃ OEt₂ (2.66 mL, 21.12 mmol, 2.0 eq) in dry DCM was added (bis(trifluoroacetoxy)iodo)benzene (5.9 g, 13.73 mmol, 1.3 eq) at 40 °C. The mixture was stirred at the same temperature for 10 mins and then quenched with sat. NaHC0₃ aqueous solution. The mixture was extracted with DCM and the organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1, v/v) to give methyl 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole- 5-carboxylate (780 mg, 23%) as a yellow solid.

[00143] To a suspension of methyl 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5- carboxylate (780 mg, 2.4 mmol, 1.0 eq) in MeOH/H₂0 (30 mL, v/v = 1/1) was added NaOH (195 mg, 4.8 mmol, 2.0 eq). The mixture was stirred at 50 °C for 1 h. The mixture was concentrated to remove MeOH. The aqueous layer was extracted with DCM and then acidified to pH 2 with 1 N HC1. The resulting precipitate was collected by filtration and dried at 120 °C for 1 h to give 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxylic acid (672 mg, 90%) as an off-white solid.

[00144] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxylic acid (235 mg, 0.77 mmol, 1.0 eq) and CDI (137 mg, 0.84 mmol, 1.1 eq) in DMF (10 mL) was stirred at 50 °C for 0.5 h. 5-(Aminomethyl)-4,6-dimethylpyridin-2-amine hydrochloride (159 mg, 0.84 mmol, 1.1 eq) was added and the mixture was stirred at 50 °C for another 0.5 h. The mixture was concentrated to remove DMF. The resulting residue was diluted with DCM and washed with 25% NaOH aqueous solution and brine subsequently. The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 30/1, v/v) to give N-((6-amino-2, 4-dimethylpyri din-3 -yl)methyl)-2-((3-chloro- 8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxamide (80 mg, 24%) as an off-white solid. LRMS (M+H⁺) m/z calculated 440.1, found 440.1. 1H NMR (DMSO-r¾, 400 MHz) d 8.92 (d,

1H), 8.64 (s, 1H), 8.43 (t, 1H), 7.73 (s, 1H), 7.72 (s, 1H), 7.63 (dd, 1H), 6.12 (s, 1H), 5.68 (s, 2H), 4.43 (s, 2H), 4.30 (d, 2H), 2.28 (s, 3H), 2.15 (s, 3H).

Example 2: Preparation of N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)oxazole-5-carboxamide

[00145] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxylic acid (90 mg, 0.294 mmol, 1.0 eq) and CDI (55 mg, 0.338 mmol, 1.15 eq) in DMF (3 mL) was stirred at 60 °C for 1 h. (3-Chloro-6-fluoro-lH-indol-5-yl)methanamine hydrochloride (80 mg, 0.338 mmol, 1.15 eq) was added and the mixture was stirred at 60 °C for 1 h. The mixture was concentrated and the resulting residue was purified by prep-HPLC to give N-((3-chloro-6- fluoro-lH-indol-5-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5- carboxamide (30 mg, 21%) as a white solid. LRMS (M-H⁺) m/z calculated 485.1, found 484.9. 1H NMR (DMSO-r¾, 400 MHz) d 11.40 (s, 1H), 9.06 (t, 1H), 8.92 (d, 1H), 8.65 (s, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.65 (dd, 1H), 7.50 (s, 1H), 7.43 (d, 1H), 7.21 (d, 1H), 4.54 (d, 2H), 4.46 (s, 2H).

Example 3: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)oxazole-5-carboxamide

[00146] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxylic acid (80 mg, 0.26 mmol, 1.0 eq), 6-(aminomethyl)isoquinolin-l -amine hydrochloride (66 mg, 0.31 mmol, 1.2 eq), EDCI (65 mg, 0.34 mmol, 1.3 eq), HOBt (46 mg, 0.34 mmol, 1.3 eq) and TEA (0.14 mL, 1.04 mmo, 4 eq) in DMF was stirred at 50 °C overnight. The mixture was concentrated and the resulting residue was diluted with DCM/MeOH (v/v = 10/1) and washed with sat. NaHC0₃ aqueous solution. The organic layer was dried and concentrated. The resulting residue was purified by prep-HPLC to give N-((l-aminoisoquinolin-6-yl)methyl)-2-

((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxamide (25 mg, 21%) as a white solid. LRMS (M-H⁺) m/z calculated 462.1, found 462.1. 1H NMR (DMSO-i¾, 400 MHz) d 9.19 (t, 1H), 8.93 (d, 1H), 8.66 (s, 1H), 8.13 (d, 1H), 7.78 (s, 1H), 7.76 (d, 1H), 7.74 (s, 1H), 7.66 (dd, 1H), 7.54 (d, 1H), 7.37 (dd, 1H), 6.85 (d, 1H), 6.76 (s, 2H), 4.55 (d, 2H), 4.47 (s, 2H).

Example 4: Preparation of N-((5-chloro-lH-indazol-3-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)oxazole-5-carboxamide

[00147] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxylic acid (80 mg, 0.26 mmol, 1.0 eq) and CDI (49 mg, 0.30 mmol, 1.15 eq) in DMF (3 mL) was stirred at 50 °C for 1 h. Then (5-chloro-lH-indazol-3-yl)methanamine hydrochloride (65 mg, 0.30 mmol, 1.15 eq) was added and the mixture was stirred at 50 °C for 1 h. The mixture was concentrated and the resulting residue was purified by prep-HPLC to give N-((5-chloro-lH- indazol-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxamide (23 mg, 19%) as a white solid. LRMS (M+H⁺) m/z calculated 470.1, found 469.9. 1H NMR

(DMSO-£¾, 400 MHz) d 13.08 (s, 1H), 9.18 (t, 1H), 8.93 (d, 1H), 8.64 (s, 1H), 7.89 (d, 1H), 7.76 (s, 1H), 7.74 (d, 1H), 7.67 (dd, 1H), 7.53 (d, 1H), 7.32 (dd, 1H), 4.73 (d, 2H), 4.45 (s, 2H). Example 5: Preparation of N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)oxazole-5-carboxamide

[00148] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxylic acid (80 mg, 0.26 mmol, 1.0 eq) and CDI (49 mg, 0.30 mmol, 1.15 eq) in DMF (3 mL) was stirred at 50 °C for 1 h. (3-Chloro-4-fluoro-lH-indol-5-yl)methanamine hydrochloride (70 mg, 0.30 mmol, 1.15 eq) was added and the mixture was stirred at 50 °C for 1 h. The mixture was concentrated and the resulting residue was purified by prep-HPLC to give N-((3-chloro-4- fluoro-lH-indol-5-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5- carboxamide (50 mg, 40%) as a white solid. LRMS (M-H⁺) m/z calculated 485.1, found 484.9. 1H NMR (DMSO-i¾, 400 MHz) d 11.59 (s, 1H), 9.03 (t, 1H), 8.92 (d, 1H), 8.65 (s, 1H), 7.74 (s, 1H), 7.73 (d, 1H), 7.65 (dd, 1H), 7.51 (s, 1H), 7.19 (d, 1H), 7.11 (d, 1H), 4.53 (d, 2H), 4.44 (s, 2H).

Example 6: Preparation of N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((3- chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxamide

[00149] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxylic acid (80 mg, 0.26 mmol, 1.0 eq) and CDI (49 mg, 0.30 mmol, 1.15 eq) in DMF (4 mL) was stirred at 50 °C for 1 h. (3-Chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methanamine hydrochloride was added and the mixture was stirred at 50 °C for 1.5 h. The reaction mixture was purified by chromatography on a silica gel column (DCM/MeOH = 20/1, v/v ) to give a crude product, which was purified by pre-HPLC to give N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)- 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5-carboxamide (50 mg, 41%). LRMS (M+H⁺) m/z calculated 470.1, found 470.1. 1H NMR (DMSO-r¾, 400 MHz): d 11.96 (s, 1 H), 9.14 (t, 1 H), 8.92 (d, 1 H), 8.65 (s, 1 H), 8.29 (d, 1 H), 7.86 (s, 1 H), 7.64-7.74 (m, 4 H), 4.54 (d, 2 H), 4.45 (s, 2 H).

Example 7: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-cyanooxazole-5-carboxamide

[00150] A mixture of compound 2-(3-chloro-8-fluoroquinolin-6-yl)acetic acid (20.0 g, 83.4 mmol, 1.0 eq), 2-amino-malononitrile toluene-4-sulfonic acid (25.4 g, 100.0 mmol, 1.2 eq), T₃P (50% in DMF) (106.0 g, 167 mmol, 2.0 eq) and Et₃N ( 16.8 g, 167 mmol, 2.0 eq) in DMF (500 mL) was stirred at rt overnight. DMF was removed by evaporation, and the resulting residue was diluted with EA (3 L) and washed with water (1 L ^c 2). The organic layer was dried and concentrated and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 1/1, v/v to PE/EA/THF = 1/2/0.4, v/v/v) to give a crude product, which was triturated with EA, filtered, and dried to provide 5-amino-2-((3-chloro-8-fluoroquinolin-6- yl)methyl)oxazole-4-carbonitrile (14.0 g, 56%) as a yellow solid.

[00151] A mixture of 5-amino-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-4- carbonitrile (13.3 g, 43.9 mmol, 1.0 eq), /ert-butyl nitrite (9.1 g, 87.8 mmol, 2.0 eq) and CuBr₂ (19.6 g, 87.8 mmol, 2.0 eq) in ACN (700 mL) was stirred at rt for 3 h. The solvent was removed under reduced pressure. The resulting residue was diluted with NH_3.H₂0 (25%) (200 mL), H₂0 (400 mL), and EA (500 mL). The mixture was stirred at rt. The aqueous phase was removed and extracted with EA. The combined organic layers were washed with water, dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 20/1 to 10/1, v/v) to give 5-bromo-2-((3-chloro-8-fluoroquinolin-6- yl)methyl)oxazole-4-carbonitrile (4.4 g, 27%).

[00152] A mixture of 5-bromo-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-4- carbonitrile (3.0 g, 8.2 mmol, 1.0 eq), Pd(dppf)Cl₂ (0.82 mmol, 668 mg, 0.1 eq) and TEA (2.48 g, 24.5 mmol, 3.0 eq) in PrOH (150 mL) was refluxed overnight under CO atmosphere. The reaction mixture was concentrated and purified by chromatography on a silica gel column (PE/EA = 20/1 to 5/1, v/v) to give propyl 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- cyanooxazole-5-carboxylate (468 mg, 15 %).

[00153] To a solution of propyl 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- cyanooxazole-5-carboxylate (468 mg, 1.25 mmol, 1.0 eq) in THF (30 mL) was added a solution of NaOH (200 mg, 5 mmol, 4.0 eq) in H₂0 (30 mL) with stirring at rt for 1 h. The mixture was adjusted to pH 7 with 1 N HC1. THF was removed under reduced pressure. The aqueous layer was adjusted to pH 2 with 1 N HC1, fitered, washed with water, triturated with PE/EA (5/1, v/v), and dried at 60 °C to give 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-cyanooxazole-5- carboxylic acid (340 mg, 82%).

[00154] To a mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-cyanooxazole-5- carboxylic acid (270 mg, 0.81 mmol, 1..0 eq), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine (217 mg, 0.97 mmol, 1.2 eq) and HATU ( 369 mg, 0.97 mmol, 1.2 eq ) in DMF ( l5 mL ) was added TEA (246 mg, 2.43 mmol, 3.0 eq) and the mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (300 mL), and washed with sat. NH₄Cl (100 mL X 2). The organic layer was dried, concentrated, and purified on silica gel column chromatography (DCM/MeOH = 100/1 to 20/1, v/v 24 mL) to give a mixture, which was triturated with DCM/MeOH (5/1, v/v) to give the crude product, which was purified by pre-HPLC to give N- ((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- cyanooxazole-5-carboxamide (50 mg, 40%). LRMS (M+H⁺) m/z calculated 465.1, found 464.9. 1H NMR (DMSO-i¾, 400 MHz) d 9.06 (t, 1 H), 8.94 (d, 1 H), 8.64 (s, 1 H), 7.68-7.74 (m, 2 H), 6.12 (s, 1 H), 5.75 (s, 1 H), 4.48 (s, 2 H), 4.34 (d, 2 H), 2.30 (s, 3H), 2.17 (s, 3 H). Example 8: Preparation of N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)oxazole-5-carboxamide

[00155] To a solution of methyl quinoline-6-carboxylate (15.0 g, 80.2 mmol, 1.0 eq) in DMF (200 ml) was added N-chlorosuccinimide (21.4 g, 0.16 mol, 2.0 eq) and the reaction mixture was stirred at 120° C for 20 h. The reaction mixture was allowed to cool to ambient temperature, treated with brine and the mixture was extracted with EA. The organic layer was dried over Na₂S0₄, filtered and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel column (EA/PE = 1/8, v/v) to afford methyl 3- chloroquinoline-6-carboxylate (9.1 g, 51%) as a yellow solid.

[00156] To a solution of methyl 3-chloroquinoline-6-carboxylate (9.0 g, 40.7 mmol, 1.0 eq) in THF (250 mL) was added LiAlH(t-BuO)₃ (31.0 g, 0.122 mol, 3.0 eq). The resulting mixture was stirred at 40 °C for 12 h and then quenched by the addition of water, extracted with EA. The combined extracts were dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 2/1, v/v) to afford (3-chloro-quinolin-6-yl)- methanol (5.9 g, 75%) as a white solid.

[00157] To (3-chloro-quinolin-6-yl)-methanol (3.3 g, 17.1 mmol, 1.0 eq) was added SOCl₂ (50 mL) and the mixture was stirred at rt for 1 h. The volatiles were then removed under vacuum and the residue was dissolved in DCM. The mixture was washed with sat.NaHC0₃, dried and concentrated to give 3-chloro-6-chloromethyl-quinoline (3.4 g, 94%) as a yellow solid.

[00158] To a solution of 3 -chloro-6-chlorom ethyl-quinoline (9.0 g, 42.44 mmol, 1.0 eq) in DMSO (50 mL) was added NaCN (2.3 g, 46.68 mmol, 1.1 eq) at rt. The mixture was stirred at rt overnight, and EA (500 mL) was added and washed with brine (100 mL x 5). The organic layer was dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA/DCM = 5/1/1) to give (3-chloro-quinolin-6-yl)- acetonitrile (6.0 g, 70%) as a white solid.

[00159] A mixture of (3-chloro-quinolin-6-yl)-acetonitrile (4.30 g, 21.22 mmol’ 1.0 eq) in H₂S0₄ (8 mL), AcOH (8 mL) and water (8 mL) was stirred at 110 °C overnight. The mixture was concentrated, and the resulting residue was neutralized with 1 N NaOH to pH 2. The solid was collected, and dried in vacuum to give 2-(3-chloroquinolin-6-yl)acetic acid (4.2 g, 89%) as a white solid.

[00160] To a solution of (3-chloro-quinolin-6-yl)-acetic acid (4.0 g, 18.1 mmol, 1 eq) in DMF (70 mL) was added CDI (3.5 g, 21.7 mmol, 1.2 eq) at rt. The mixture was stirred at rt for 1.5 h and then to this mixture was added NH₃/H₂0 (10 mL). The resulting mixture was stirred at rt for 0.5 h and concentrated under reduced pressure. To the resulting residue was added 100 mL of H₂0 and the mixture was stirred at rt overnight. The resulting precipitate was collected by filtration and washed with water and acetone subsequently to give 2-(3-chloro-quinolin-6- yl)-acetamide (3.2 g, 80%) an off-white solid.

[00161] A mixture of 2-(3-chloro-quinolin-6-yl)-acetamide (3.5 g, 15.9 mmol, 1 eq), 3- iodo-acrylic acid methyl ester (4.0 g, 19.1 mmol, 1.2 eq), N,N,N',N'-tetramethyl-ethane-l,2- diamine (280 mg, 3.18 mmol, 0.2 eq), Cul (302 mg, 1.59 mmol, 0.1 eq) and Cs₂C0₃ (10.4 g, 31.8 mmol, 2 eq) in dry THF (160 mL) was stirred at 70 °C for 6 h under N_2. The mixture was filtered though a pad of Celite. The filtrate was concentrated, and the resulting residue was purified by chromatography on a silica gel column (EA/PE = 1/8, v/v) to give 3-[2-(3-chloro- quinolin-6-yl)-acetylamino]-acrylic acid methyl ester (1.2 g, 25%) as an off white solid.

[00162] To a solution of 3-[2-(3-chloro-quinolin-6-yl)-acetylamino]-acrylic acid methyl ester (540 mg, 1.78 mmol, 1 eq) in dry DCE (10 mL) was added BF_3.OEt₂ (0.45 mL, 3.56 mmol, 2 eq). The mixture was heated to reflux, and then iodobenzene diacetate (744 mg, 2.31 mmmol, 1.3 eq) was added in one portion rapidly. After stirring under reflux for 40 mins, the mixture was cooled to rt, quenched with saturated NaHC0₃ aqueous solution, and then extracted with DCM (25 mL ^c 3). The combined organic layers were washed with brine, dried and concentrated. The resulting residue was purified by chromatography on a silica column (EA/PE = 1/8, v/v) to give 2-(3-chloro-quinolin-6-ylmethyl)-oxazole-5-carboxylic acid methyl ester (223 mg, 42%) as a white solid.

[00163] To a solution of 2-(3-chloro-quinolin-6-ylmethyl)-oxazole-5-carboxylic acid methyl ester (335 mg, 1.11 mmol, 1 eq) in THF/H₂0 (v/v = 1/1, 30 mL) was added NaOH (67 mg, 1.66 mmol, 1.5 eq) at rt. The mixture was stirred at rt for 1 h. The volatile was evaporated, and the aqueous layer was acidified to pH 3 with 1 N HC1. The resulting precipitate was collected by filtration and dried to give 2-(3-chloro-quinolin-6-ylmethyl)-oxazole-5-carboxylic acid (258 mg, 81%) as a white solid.

[00164] A mixture of 2-(3-chloro-quinolin-6-ylmethyl)-oxazole-5-carboxylic acid (69 mg, 0.24 mmol, 1.0 eq) and CDI (45 mg, 0.276 mmol, 1.15 eq) in DMF (10 mL) was stirred at 60 °C for 1 h. To the reaction mixture was added (3-chloro-6-fluoro-lH-indol-5- yl)methanamine hydrochloride (67 mg, 0.287 mmol, 1.2 eq). The resulting reaction mixture was stirred at 60 °C for lh. The mixture was concentrated and the resulting residue was purified by pre-HPLC to give N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)oxazole-5-carboxamide (26 mg, 23%) as a white solid. LRMS (M+H⁺) m/z calculated 469.1, found 468.8. 1H NMR (DMS0-i 400 MHz) d 11.39 (s, 1H), 9.03 (t, 1H), 8.86 (s, 1 H), 8.55 (s, 1 H), 8.03 (d, 1 H), 7.79 (s, 1 H), 7.77 (s, 1 H), 7.75 (d, 1 H), 7.50 (d, 1 H), 7.43 (d, 1H), 7.21 (d, 1H), 4.54 (d, 2 H), 4.45 (s, 2 H).

Example 9: Preparation of N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)oxazole-5-carboxamide

[00165] To a solution of 2-((3-chloroquinolin-6-yl)methyl)oxazole-5-carboxylic acid (70 mg, 0.24mmol, 1.0 eq) in DMF (3 mL) was added CDI (45 mg, 0.279 mmol, 1.15 eq) at rt. The mixture was stirred at 60 °C for 30 min and (3-chloro-lH-pyrrolo[2,3-b]pyridin-5- yl)methanamine hydrochloride (63 mg, 0.29 mmol, 1.2 eq) was added. The mixture was stirred at 60 °C for 30 min. The mixture was purified by chromatography on a silica gel column (DCM/MeOH = 20/1, v/v) to afford N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)oxazole-5-carboxamide (25 mg, 23%) as a white solid.. LRMS (M+H⁺) m/z calculated 452.1, found 452.1. 1H NMR (DMSO-d6, 400 MHz) d 11.94 (br, 1 H), 9.11 (t, 1 H), 8.55 (s, 1 H), 8.28 (d, 1 H), 8.03 (d, 1 H), 7.87-7.85 (m,2 H), 7.76-7.73 (m, 2 H), 7.67(d, 1 H), 7.34 (d, 1 H), 4.53 (d, 2 H), 4.44 (s, 2H).

Example 10: Preparation of N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)oxazole-5-carboxamide

[00166] To a solution of 2-((3-chloroquinolin-6-yl)methyl)oxazole-5-carboxylic acid (70 mg, 0.24 mmol, 1.0 eq), in DMF (3 mL) was added CDI (45 mg, 0.279 mmol, 1.15 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (3-chloro-4-fluoro-lH-indol-5- yl)methanamine hydrochloride (68 mg, 0.291 mmol, 1.2 eq) was added. The mixture was stirred at 60 °C for 30 min. The mixture was purified by prep-HPLC to afford N-((3-chloro-4- fluoro-lH-indol-5-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)oxazole-5-carboxamide (38 mg, 33.6%) as a white solid. LRMS (M+H⁺) m/z calculated 469.1, found 469.1. 1H NMR

(DMSO-i¾, 400 MHz) d 11.58 (br, 1 H), 9.02 (d, 1 H), 8.87 (s, 1 H), 8.55 (s, 1 H), 8.04 (d, 1 H), 7.88 (s, 1 H), 7.76-7.74 (m, 2 H), 7.51 (d, 1 H), 7.19 (d, 1 H), 7.13-7.09 (m, 1 H), 4.52 (d, 2 H), 4.44 (s, 2H).

Example 11: Preparation of N-((5-chloro-lH-indazol-3-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)oxazole-5-carboxamide

[00167] To a solution of 2-((3-chloroquinolin-6-yl)methyl)oxazole-5-carboxylic acid (70 mg, 0.24 mmol, 1.0 eq), in DMF (3 mL) was added CDI (45 mg, 0.279 mmol, 1.15 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (5-chloro-lH-indazol-3-yl)methanamine hydrochloride (63 mg, 0.291 mmol, 1.2 eq) was added. The mixture was stirred at 60 °C for 30 min. The mixture was purified by prep-HPLC to afford N-((5-chloro-lH-indazol-3-yl)methyl)- 2-((3-chloroquinolin-6-yl)methyl)oxazole-5-carboxamide (25 mg, 23%) as a white solid.

LRMS (M+H⁺) m/z calculated 452.1, found 452.1. ^lH NMR (DMSO-r/d, 400 MHz) d 13.08 (brs, 1 H), 9.17 (t, 1 H), 8.86 (d, 1 H), 8.54 (s, 1 H), 8.03 (d, 1 H), 7.89-7.87 (m,2 H), 7.76-7.74 (m, 2 H), 7.52 (d, 1 H), 7.34 (d, 1 H), 4.73 (d, 2 H), 4.44 (s, 2H).

Example 12: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)oxazole-5-carboxamide

[00168] A mixture of 2-(3-chloro-quinolin-6-ylmethyl)-oxazole-5-carboxylic acid (100 mg, 0.35 mmol, 1.0 eq) , 6-aminomethyl-isoquinolin-l-ylamine hydrochloride (110 mg, 0.53 mmol, 1.5 eq), HOBT (72 mg, 0.53 mmol, 1.5 eq), EDCI (102 mg, 0.53 mmol, 1.5 eq) and Et₃N (106 mg, 1.05 mmol, 3.0 eq) in DMF (6 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford N-((l- aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)oxazole-5-carboxamide (10 mg, 6%) as a white solid. LRMS (M+H⁺) m/z calculated 444.1, found 444.2. 1H NMR (DMSO- d₆, 400 MHz) d 9.19 (t, 1 H), 8.87 (d, 1 H), 8.57 (d, 1 H), 8.15 (d, 1 H), 8.04 (d, 1 H), 7.90 (d, 1 H), 7.78-7.75 (m, 3 H), 7.54 (s, 1 H), 7.39-7.37 (d, 1 H), 6.85 (d, 1 H), 6.76 (s, 2 H), 4.54 (d, 2 H), 4.46 (s, 2 H).

Example 13: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(l-hydroxyethyl)-lH-pyrazole-4-carboxamide

[00169] A mixture of 3-chloro-6-(chloromethyl)-8-fluoroquinoline (3.0 g, 13.1 mmol, 1 eq), ethyl 3-iodo-lH-pyrazole-4-carboxylate (3.83 g, 14.4 mmol, 1.1 eq) and K₂C0₃ (3.62 g, 26.2 mmol, 2.0 eq) in DMF (130 mL) was stirred at rt for 3 h. The mixture was concentrated and the resulting residue was diluted with DCM and washed with water. The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1, v/v) to give ethyl l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3-iodo-lEl- pyrazole-4-carboxylate (3.3 g, 55%) as a white solid.

[00170] A mixture of ethyl l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3-iodo-lEl- pyrazole-4-carboxylate (2.0 g, 4.36 mmol, 1.0 eq), tributyl(l-ethoxyvinyl)stannane (1.9 g, 5.23 mmol, 1.2 eq) and Pd(PPh₃)₄ (403 mg, 0.34 mmol, 0.08 eq) in toluene (50 mL) was stirred at 100 °C for 24 h. The mixture was concentrated, and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1, v/v) to give ethyl l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(l-ethoxyvinyl)-lH-pyrazole-4-carboxylate (900 mg, 51% ) as a yellow solid.

[00171] To a stirred mixture of ethyl l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3-(l- ethoxyvinyl)-lH-pyrazole-4-carboxylate (900 mg, 2.23 mmol, 1.0 eq) in MeOH/H₂0 (20 mL, v/v = 1/1) was added NaOH (179 mg, 4.47 mmol, 2.0 eq ). The mixture was stirred at 60 °C for 1 h, and then concentrated to remove MeOH. The aqueous layer was extracted with EA and the resulting aqueous layer was diluted with 10 mL of THF and acidified with 1 mL of cone. HC1. The reaction mixture was stirred at rt for 1 h. Solvent was removed by evaporation, and the resulting precipitate was collected by filtration. The resulting white solid was dried at 120 °C for 1 h to give 3-acetyl-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-lH-pyrazole-4- carboxylic acid (500 mg, 65% for two steps).

[00172] A mixture of 3-acetyl-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-lH-pyrazole- 4-carboxylic acid (500 mg, 1.44 mmol, 1.0 eq) and CDI (280 mg, 1.73 mmol, 1.2 eq) in DMF (15 mL) was stirred at 60 °C for 1.5 h. tert- Butyl (5-(aminomethyl)-4,6-dimethylpyridin-2- yl)carbamate (398 mg, 1.58 mmol, 1.1 eq) was added and the resulting mixture was stirred at 60 °C for 4 h. The mixture was concentrated, and the resulting residue was diluted with DCM and washed with 25% NaOH aqueous solution. The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 1/1, v/v) to give tert- butyl (5-((3-acetyl-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-lH-pyrazole-4- carboxamido)methyl)-4,6-dimethylpyridin-2-yl)carbamate (660 mg, 79% ) as a white solid.

[00173] To a solution of /er/-butyl (5-((3-acetyl-l-((3-chloro-8-fluoroquinolin-6- yl)methyl)-lH-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-yl)carbamate (115 mg, 0.20 mmol, 1.0 eq) in MeOH/DCM (10 mL, v/v = 1/1) was added NaBH₄ (38 mg, 1.0 mmol, 5 eq). The mixture was stirred at rt for 0.5 h and quenched with sat. NH₄Cl solution. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated. The resulting residue was directly used in next step.

[00174] A mixture of tert- butyl (5-((l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3-(l- hydroxyethyl)-lH-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-yl)carbamate (110 mg, 0.19 mmol, 1 eq) in TFA/DCM (5 mL, v/v = 1/1) was stirred at rt for 1 h. The mixture was concentrated and the resulting residue was diluted with DCM and washed with 20% NaOH aqueous solution. The organic layer was washed with brine, dried and concentrated. The resulting residue was purified by trituration in EA/PE (20 mL, v/v = 1/4) under reflux to give N-((6-amino-2,4-dimethylpyri din-3 -yl)m ethyl)- 1 -((3 -chloro-8-fluoroquinolin-6-yl)methyl)-3- (l-hydroxyethyl)-lH-pyrazole-4-carboxamide (45 mg, 50%) as a white solid. LRMS (M+H⁺) m/z calculated 483.2, found 483.2. 1H NMR (DMSO-i¾, 400 MHz) d 8.93 (s, 1H), 8.68 (s, 1H), 8.55 (t, 1H), 8.35 (s, 1H), 7.66 (s, 1H), 7.52 (dd, 1H), 6.28 (d, 1H), 6.11 (s, 1H), 5.66 (s, 2H), 5.48 (s, 2H), 4.83-4.79 (m, 1H), 4.30 (d, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 1.34 (d, 3H).

Example 14: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(2-hydroxypropan-2-yl)-lH-pyrazole-4-carboxamide

[00175] To a solution of 3-acetyl-l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-lH- pyrazole-4-carboxylic acid (6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-amide (100 mg, 0.21 mmol, 1.0 eq) in THF (20 mL) was added MeMgBr (1.4 mL, 4.16 mmol, 20.0 eq) at 0 °C. The mixture was stirred at rt for 1 h, and NH₄Cl aq was added and extracted with EA (20 mL ^c 2). The organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to afford N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-l-((3- chloro-8-fluoroquinolin-6-yl)methyl)-3-(2-hydroxypropan-2-yl)-lH-pyrazole-4-carboxamide (6 mg, 6%) as a white solid. LRMS (M+H⁺) m/z calculated 497.2, found 497.0. 1H NMR (DMSO- d₆, 400 MHz) d 8.94 (d, 1 H), 8.72-8.68 (m, 2 H), 8.35 (s, 1 H), 7.65 (s, 1 H), 7.53-7.50 (m, 1 H), 6.79 (s, 1 H), 6.11 (s, 1 H), 5.65 (s, 2 H), 5.48 (s, 2 H), 4.30 (d, 2 H), 2.29 (s, 3H), 2.16 (s, 3 H), 1.43 (s, 6 H).

Example 15: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide

[00176] A mixture of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-iodo-lH-pyrazole-4- carboxylic acid ethyl ester (10. Og, 21.76 mmol, 1.0 eq), tributyl-vinyl-stannane (7.6 g, 23.93 mmol, 1.1 eq) and Pd(PPh₃)₂Cl₂ (1.5 g, 2.18 mmol, 0.1 eq) in dioxane (150 mL) was stirred at 90 °C overnight under nitrogen. The mixture was concentrated, and the resulting residue was purified by column chromatography (PE/EA/DCM = 5/1/1 v/v/v) to afford l-(3-chloro-8- fluoro-quinolin-6-ylmethyl)-3 -vinyl- lH-pyrazole-4-carboxylic acid ethyl ester (6.5 g, 83%) as a white solid.

[00177] To a solution of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-vinyl-lH-pyrazole- 4-carboxylic acid ethyl ester (6.0g, 16.68 mmol, 1.0 eq) in THF (200 mL) and H₂0 (50 mL) was added Os0₄ (85 mg, 0.33 mmol, 0.02 eq) and NaI0₄ (7.1 g, 33.36 mmol, 2.0 eq) at rt. The mixture was stirred at rt for 2 h. Na₂S0₃aq was added and extracted with EA (100 mL ^c 3). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The residue was purified by column chromatography (DCM/MeOH = 50/1 v/v) to afford l-(3-chloro-8-fluoro- quinolin-6-ylmethyl)-3-formyl-lH-pyrazole-4-carboxylic acid ethyl ester (4.3 g, 72%) as a white solid.

[00178] To a solution of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-formyl-lH- pyrazole-4-carboxylic acid ethyl ester (150 mg, 0.41 mmol, 1.0 eq) in DCM (20 mL) was added DAST (167 mg, 1.04 mmol, 2.5 eq) at 0 °C. The mixture was stirred at rt for 16 h, and aq. NaHC0₃ was added and extracted with DCM (20 mL ^c 2). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by column chromatography (PE/EA = 3/1 v/v) to afford l-(3-chloro-8-fluoro-quinolin-6- ylmethyl)-3-difluoromethyl-lH-pyrazole-4-carboxylic acid ethyl ester (120 mg, 76%) as a white solid. LRMS (M+H⁺) m/z calculated 384.1, found 384.1.

[00179] To a solution of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-difluoromethyl- lH-pyrazole-4-carboxylic acid ethyl ester (120 mg, 0.31 mmol, 1.0 eq) in THF (10 mL) was added a solution of NaOH (25 mg, 0.62 mmol, 2.0 eq) in H₂0 (10 mL) at rt. The mixture was stirred at 60 °C for 16 h. The mixture was cooled to rt and neutralized with 1 N HC1, and concentrated. The resulting residue (120 mg crude) was used in the next step without further purification. LRMS (M+H⁺) m/z calculated 356.0, found 356.1.

[00180] A mixture of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-difluoromethyl-lH- pyrazole-4-carboxylic acid (120 mg crude, 0.31 mmol, 1.0 eq), 5-aminomethyl-4,6-dimethyl- pyridin-2-ylamine hydrochloride (87 mg, 0.46 mmol, 1.5 eq), HATU (175 mg, 0.46 mmol, 1.5 eq) and Et₃N (94 mg, 0.93 mmol, 3.0 eq) in DMF (4 mL) was stirred at rt for 2 h. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford N-((6-amino- 2,4-dimethylpyridin-3-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3- (difluoromethyl)-lH-pyrazole-4-carboxamide (30 mg, 20%) as a white solid. LRMS (M+H⁺) m/z calculated 489.1, found 489.0. 1H NMR (DMSO-i¾, 400 MHz) d 8.95 (d, 1 H), 8.70 (d, 1

H), 8.45 (s, 1 H), 8.10 (s, 1 H), 7.69 (s, 1 H), 7.55 (dd, 1 H), 7.36 (t, 1 H), 5.70 (brs, 2 H), 5.60 (s, 2 H), 4.27 (d, 2 H), 2.29 (s, 3H), 2.15 (s, 3 H).

Example 16: Preparation of N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide

[00181] To a solution of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-difluoromethyl- lH-pyrazole-4-carboxylic acid (100 mg, 0.31 mmol, 1.0 eq) in DMF (4 mL) was added CDI (68 mg, 0.42 mmol, 1.5 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (3-chloro-6- fluoro-lH-indol-5-yl)methanamine hydrochloride (99 mg, 0.42 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C overnight, and then concentrated. The resulting residue was purified by prep-HPLC to afford N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(difluorom ethyl)- lH-pyrazole-4-carboxamide (95 mg, 63%) as a white solid. LRMS (M+H⁺) m/z calculated 536.1, found 535.8. 1H NMR (DMSO-r¾, 400 MHz) d 11.39 (s, 1 H), 8.96 (d, 1 H), 8.72-8.71 (m, 2 H), 8.48 (s, 1 H), 7.71 (s, 1 H), 7.61-7.58 (m, 1 H), 7.50 (d, 1 H), 7.44 (d, 1 H), 7.36-7.20 (m, 2 H), 5.65 (s, 2 H), 4.50 (d, 2H).

Example 17: Preparation of N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide

[00182] A mixture of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-difluoromethyl-lH- pyrazole-4-carboxylic acid (100 mg, 0.28 mmol, 1.0 eq) and CDI (68 mg, 0.42 mmol, 1.5 eq) in DMF (6 mL) was stirred at 60 °C for 30 min, and (3-chloro-4-fluoro-lH-indol-5- yl)methanamine hydrochloride (98 mg, 0.42 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C overnight, and concentrated. The resulting residue was purified by prep-HPLC to afford N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6- yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide (41 mg, 27%) as a white solid. LRMS (M-H⁺) m/z calculated 534.1, found 534.0. 1H NMR (DMSO-r/^, 400 MHz) d 11.57 (s, 1 H), 8.95 (d, 1 H), 8.71-8.70 (m, 2 H), 8.44 (s, 1 H), 7.70 (s, 1 H), 7.60-7.57 (m, 1 H), 7.50 (d, 1 H), 7.36 (s, 1 H), 7.23-7.12 (m, 3 H), 5.63 (s, 2 H), 4.49 (d, 2H).

Example 18: Preparation of N-((5-chloro-lH-indazol-3-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide

[00183] A mixture of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-difluoromethyl-lH- pyrazole-4-carboxylic acid (100 mg, 0.28 mmol, 1.0 eq) , (5-chloro-lH-indazol-3- yl)methanamine hydrochloride (91 mg, 0.42 mmol, 1.5 eq), HOBT (57 mg, 0.42 mmol, 1.5 eq), EDCI (80 mg, 0.42 mmol, 1.5 eq) and Et₃N (85 mg, 0.84 mmol, 3.0 eq) in DMF (6 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford N-((5-chloro-lH-indazol-3-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6- yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide (55 mg, 38%) as a white solid. LRMS (M+H⁺) m/z calculated 519.1, found 518.8. 1H NMR (DMSO-i¾, 400 MHz) d 13.06 (s,

1 H), 8.96 (d, 1 H), 8.87 (t, 1 H), 8.69 (t, 1 H), 8.41 (s, 1 H), 7.86 (d, 1 H), 7.71 (s, 1 H), 7.60- 7.57 (m, 1 H), 7.53-7.51 (m, 1 H), 7.34-7.25 (m, 3 H), 5.63 (s, 2 H), 4.71 (d, 2 H).

Example 19: Preparation of N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-l-((3- chloro-8-fluoroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide

[00184] A mixture of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-difluoromethyl-lH- pyrazole-4-carboxylic acid (100 mg, 0.28 mmol, 1.0 eq), (3-chloro-lH-pyrrolo[2,3-b]pyridin-5- yl)methanamine hydrochloride (91 mg, 0.42 mmol, 1.5 eq), HOBT (57 mg, 0.42 mmol, 1.5 eq), EDCI (80 mg, 0.42 mmol, 1.5 eq) and Et₃N (85 mg, 0.84 mmol, 3.0 eq) in DMF (6 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(difluorom ethyl)- lH-pyrazole-4-carboxamide (35 mg, 24%) as a white solid. LRMS (M-H ) m/z calculated 517.1, found 517.0. 1H NMR (DMSO-r/^, 400 MHz) d 11.95 (s, 1 H), 8.95 (d, 1 H), 8.82 (t, 1 H), 8.70 (s, 1 H), 8.44 (s, 1 H), 8.28 (d, 1 H), 7.84 (d, 1 H), 7.70 (s, 1 H), 7.66 (d, 1 H), 7.61-7.57 (m, 1 H), 7.36 (t, 1 H), 5.64 (s, 2 H), 4.52 (d, 2 H). Example 20: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide

[00185] A mixture of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-difluoromethyl-lH- pyrazole-4-carboxylic acid (100 mg, 0.28 mmol, 1.0 eq) , 6-aminomethyl-isoquinolin-l- ylamine hydrochloride (88 mg, 0.42 mmol, 1.5 eq), HOBT (57 mg, 0.42 mmol, 1.5 eq), EDCI (80 mg, 0.42 mmol, 1.5 eq) and Et₃N (85 mg, 0.84 mmol, 3.0 eq) in DMF (6 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by prep- HPLC to afford N-((l-aminoisoquinolin-6-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6- yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide (30 mg, 21%) as a white solid. LRMS (M+H⁺) m/z calculated 511.1, found 511.2. 1H NMR (DMSO-r/^, 400 MHz): d 8.96 (d,

1 H), 8.88 (t, 1 H), 8.72 (d, 1 H), 8.49 (s, 1 H), 8.13 (d, 1 H), 7.77-7.73 (m, 2 H), 7.63-7.60 (m,

1 H), 7.55 (s, 1 H), 7.50-7.23 (m, 2 H), 6.86 (d, 1 H), 6.74 (s, 2 H), 5.66 (s, 2 H), 4.54 (d, 2 H).

Example 21: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(hydroxymethyl)-lH-pyrazole-4-carboxamide

[00186] To a solution of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-formyl-lH- pyrazole-4-carboxylic acid ethyl ester (200 mg, 0.55 mmol, 1.0 eq) in MeOH (20 mL) was added NaBH₄ (21.0 mg, 0.55 mmol, 1.0 eq) at 0 °C. The mixture was stirred at rt for 16 h, and then concentrated. The resulting residue was purified by column chromatography (PE/EA = 3/1, v/v) to afford l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-hydroxymethyl-lH-pyrazole-4- carboxylic acid ethyl ester (180 mg, 72%) as a white solid. LRMS (M+H⁺) m/z calculated 364.1, found 364.1.

[00187] To a solution of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-hydroxymethyl- lH-pyrazole-4-carboxylic acid ethyl ester (80 mg, 0.22 mmol, 1.0 eq) in THF (10 mL) was added a solution of NaOH (17 mg, 0.44 mmol, 2.0 eq) in H₂0 (10 mL) at rt. The mixture was stirred at 60 °C for 16 h. The mixture was cooled to rt, neutralized with 1 N HC1, and concentrated. The resulting residue was used in the next step directly (80 mg crude). LRMS (M+H⁺) m/z calculated 336.1, found 336.1.

[00188] A mixture of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-hydroxymethyl-lH- pyrazole-4-carboxylic acid (80 mg crude, 0.22 mmol, 1.0 eq), 5-aminomethyl-4,6-dimethyl- pyridin-2-ylamine hydrochloride (62 mg, 0.33 mmol, 1.5 eq), HATU (125 mg, 0.33 mmol, 1.5 eq) and Et₃N (67 mg, 0.66 mmol, 3.0 eq) in DMF (4 mL) was stirred at rt for 2 h. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford N-((6-amino- 2,4-dimethylpyridin-3-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3- (hydroxymethyl)-lH-pyrazole-4-carboxamide (16 mg, 15%) as a white solid. LRMS (M+H⁺) m/z calculated 469.1, found 469.0. 1H NMR (DMSO-i¾, 400 MHz) d 8.93 (d, 1 H), 8.68 (s, 1 H), 8.36 (s, 1 H), 8.33 (t, 1 H), 7.66 (s, 1 H), 7.55-7.52 (m, 1 H), 6.11 (s, 1 H), 5.84 (t, 1 H), 5.65 (s, 2 H), 5.48 (s, 2 H), 4.50 (d, 2 H), 4.30 (d, 2 H), 2.30 (s, 3H), 2.17 (s, 3 H).

Example 22: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide

[00189] To a solution of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-hydroxymethyl- lH-pyrazole-4-carboxylic acid ethyl ester (100 mg, 0.27 mmol, 1.0 eq) in DCM (20 mL) was added DAST (66 mg, 0.41 mmol, 1.5 eq) at 0 °C. The mixture was stirred at rt for 16 h, and aq. NaHC0₃ was added and extracted with DCM (20 mL ^c 2). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by column chromatography (PE/EA = 5/1, v/v) to afford l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3- fluoromethyl-lH-pyrazole-4-carboxylic acid ethyl ester (80 mg, 81%) as a white solid. LRMS (M+H⁺) m/z calculated 366.1, found 366.1.

[00190] To a solution of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-fluoromethyl-lH- pyrazole-4-carboxylic acid ethyl ester (80 mg, 0.22 mmol, 1.0 eq) in THF (6 mL) was added a solution of NaOH (18 mg, 0.44 mmol, 2.0 eq) in H₂0 (6 mL) at rt. The mixture was stirred at 60 °C for 16 h. The mixture was neutralized with 1 N HC1 and concentrated to give the crude product (80 mg) as a yellow solid, which was used in the next step directly. LRMS (M+H⁺) m/z calculated 338.0, found 338.1.

[00191] A mixture of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-fluoromethyl-lH- pyrazole-4-carboxylic acid (80 mg, crude, 0.22 mmol, 1.0 eq), 5-aminomethyl-4,6-dimethyl- pyridin-2-ylamine hydrochloride (62 mg, 0.33 mmol, 1.5 eq), HATU (125 mg, 0.33 mmol, 1.5 eq) and Et₃N (67 mg, 0.66 mmol, 3.0 eq) in DMF (4 mL) was stirred at rt for 2 h, and then concentrated. The resulting residue was purified by prep-HPLC to afford N-((6-amino-2,4- dimethylpyridin-3-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH- pyrazole-4-carboxamide (16 mg, 15%) as a white solid. LRMS (M+H⁺) m/z calculated 471.1, found 471.2. 1H MR (DMSO-i¾, 400 MHz) d 8.94 (d, 1 H), 8.69 (t, 1 H), 8.38 (s, 1 H), 7.95

(t, 1 H), 7.67 (s, 1 H), 7.55-7.52 (m, 1 H), 6.10 (s, 1 H), 5.63-5.50 (m, 6 H), 4.25 (d, 2 H), 2.28 (s, 3H), 2.15 (s, 3 H). Example 23: Preparation of N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide

[00192] To a solution of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-fluoromethyl-lH- pyrazole-4-carboxylic acid (80 mg, 0.22 mmol, 1.0 eq) in DMF (4 mL) was added CDI (53 mg, 0.33 mmol, 1.5 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (3-chloro-6-fluoro- lH-indol-5-yl)methanamine hydrochloride (77 mg, 0.33 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C overnight, and then concentrated. The resulting residue was purified by prep-HPLC to afford N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide (56 mg, 47%) as a white solid. LRMS (M+H⁺) m/z calculated 518.1, found 517.9. 1H NMR (DMSO-i¾, 400 MHz) d 11.38 (s, 1 H), 8.95 (d, 1 H), 8.69 (s, 1 H), 8.58 (t, 1 H), 8.42 (s, 1 H), 7.69 (s, 1 H), 7.59-7.56 (m, 1 H), 7.50 (d, 1 H), 7.43 (d, 1 H), 7.21 (d, 1 H), 5.63-5.51 (m, 4 H), 4.51 (d, 2H).

Example 24: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide

[00193] A mixture of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-fluoromethyl-lH- pyrazole-4-carboxylic acid (100 mg, 0.27 mmol, 1.0 eq) , 6-aminomethyl-isoquinolin-l- ylamine hydrochloride (86 mg, 0.41 mmol, 1.5 eq), HOBT (55 mg, 0.41 mmol, 1.5 eq), EDCI (78 mg, 0.41 mmol, 1.5 eq) and Et₃N (82 mg, 0.81 mmol, 3.0 eq) in DMF (6 mL) was stirred at rt overnight, and then concentrated. The resulting residue was purified by prep-HPLC to afford N-((l-aminoisoquinolin-6-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3- (fluoromethyl)-lH-pyrazole-4-carboxamide (59 mg, 44%) as a white solid. LRMS (M+H⁺) m/z calculated 493.1, found 492.9. 1H NMR (DMS0-i 400 MHz) d 8.95 (d, 1 H), 8.74-8.71 (m, 2 H), 8.42 (s, 1 H), 8.13 (d, 1 H), 7.76 (d, 1 H), 7.71 (s, 1 H), 7.61-7.57 (m, 1 H), 7.54 (s, 1 H), 7.40-7.37 (m, 1 H), 6.84 (d, 1 H), 6.73 (s, 2 H), 5.63-5.51 (m, 4 H), 4.53 (d, 2 H).

Example 25: Preparation of N-((5-chloro-lH-indazol-3-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide

[00194] To a solution of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-fluoromethyl-lH- pyrazole-4-carboxylic acid (100 mg, 0.27 mmol, 1.0 eq) in DMF (6 mL) was added CDI (66 mg, 0.41 mmol, 1.5 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (5-chloro-lH- indazol-3-yl)methanamine hydrochloride (89 mg, 0.41 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C overnight, and then concentrated. The resulting residue was purified by prep-HPLC to afford N-((5-chloro-lH-indazol-3-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6- yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide (33 mg, 24%) as a white solid. LRMS (M-H ) m/z calculated 499.1, found 499.0. 1H NMR (DMSO-r¾, 400 MHz) d 13.03 (s, 1 H), 8.94 (d, 1 H), 8.72-8.68 (m, 2 H), 8.34 (s, 1 H), 7.87 (d, 1 H), 7.68 (s, 1 H), 7.57-7.51 (m, 2 H), 7.34-7.31 (m, 1 H), 5.64-5.52 (m, 4 H), 4.70 (d, 2H). Example 26: Preparation of N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-l-((3-chloro-8- fluoroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide

[00195] A mixture of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-fluoromethyl-lH- pyrazole-4-carboxylic acid (100 mg, 0.27 mmol, 1.0 eq), (3-chloro-4-fluoro-lH-indol-5- yl)methanamine hydrochloride (96 mg, 0.41 mmol, 1.5 eq), HOBT (55 mg, 0.41 mmol, 1.5 eq), EDCI (78 mg, 0.41 mmol, 1.5 eq) and Et₃N (82 mg, 0.81 mmol, 3.0 eq) in DMF (6 mL) was stirred at rt overnight, and then concentrated. The resulting residue was purified by prep-HPLC to afford N-((3-chloro-4-fluoro-lEl-indol-5-yl)inethyl)-l-((3-chloro-8-fluoroquinolin-6- yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide (54 mg, 39%) as a white solid. LRMS (M+H⁺) m/z calculated 518.1, found 517.9. 1H NMR (DMSO-r¾, 400 MHz) d 11.57 (s, 1 H), 8.94 (d, 1 H), 8.69 (s, 1 H), 8.55 (t, 1 H), 8.39 (s, 1 H), 7.68 (s, 1 H), 7.58-7.55 (m, 1 H), 7.50 (d, 1 H), 7.20-7.11 (m, 1 H), 5.62-5.51 (m, 4 H), 4.48 (d, 2 H).

Example 27: Preparation of N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-l-((3- chloro-8-fluoroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide

N-((3-chloro-1 H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1 -((3-chloro- 8-fluoroquinolin-6-yl)methyl)-3-(fluoromethyl)-1H-pyrazole-4-carboxamide

[00196] A mixture of l-(3-chloro-8-fluoro-quinolin-6-ylmethyl)-3-fluoromethyl-lH- pyrazole-4-carboxylic acid (100 mg, 0.27 mmol, 1.0 eq), (3-chloro-lH-pyrrolo[2,3-b]pyridin-5- yl)methanamine hydrochloride (89 mg, 0.41 mmol, 1.5 eq), HOBT (55 mg, 0.41 mmol, 1.5 eq), EDCI (78 mg, 0.41 mmol, 1.5 eq) and Et₃N (82 mg, 0.81 mmol, 3.0 eq) in DMF (6 mL) was stirred at rt overnight, and then concentrated. The resulting residue was purified by prep-HPLC to afford N-((3-chloro- lH-pyrrolo[2,3-b]pyridin-5-yl)m ethyl)- 1 -((3-chl oro-8-fluoroquinolin-6- yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide (25 mg, 18%) as a white solid. LRMS (M+H⁺) m/z calculated 501.1, found 500.9. 1H NMR (DMSO-i¾, 400 MHz) d 11.94 (s, 1 H),

8.94 (d, 1 H), 8.68 (t, 1 H), 8.38 (s, 1 H), 8.28 (d, 1 H), 7.84 (s, 1 H), 7.68-7.66 (m, 2 H), 7.59- 7.55 (m, 1 H), 5.63-5.51 (m, 4 H), 4.51 (d, 2 H).

Example 28: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-l-((3- chloroquinolin-6-yl)methyl)-3-(2-hydroxypropan-2-yl)-lH-pyrazole-4-carboxamide

[00197] To a stirred solution of 3-amino-lH-pyrazole-4-carboxylic acid ethyl ester (50.0 g, 0.322 mol, 1.0 eq) in concentrated HC1 (450 mL) was added a solution of sodium nitrite (44.4 g, 0.644 mol, 2.0 eq) in water (120 mL) over 25 min at 0 °C. To the resulting reaction mixture was added a solution of KI (134 g, 0.805 mmol, 2.5 eq) in water (280 mL) over 20 min. The reaction mixture was stirred for another more 30 min, and then extracted with EA (600 mL x 3). The combined organic layers were washed with Na₂S₂0₃, dried over Na₂S0₄ and concentrated under reduced pressure to give 3-iodo-lH-pyrazole-4-carboxylic acid ethyl ester (52.2 g, 61%) as a light yellow solid.

[00198] A mixture of 3-chloro-6-(chloromethyl)quinolone (11.0 g, 52.1 mmol, 1.0 eq), ethyl 3-iodo-lH-pyrazole-4-carboxylate (15.3 g, 57.3 mmol, 1.1 eq) and K₂C0₃ (14.4 g, 104.2 mmol, 2.0 eq) in DMF (500 mL) was stirred at rt overnight, and then concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1, v/v) to give ethyl l-((3-chloroquinolin-6-yl)methyl)-3-iodo-lH-pyrazole-4-carboxylate (17.9 g, 78%) as a yellow solid.

[00199] A mixture of ethyl l-((3-chloroquinolin-6-yl)methyl)-3-iodo-lH-pyrazole-4- carboxylate (2.0 g, 4.5 mmol, 1.0 eq), tributyl(l-ethoxyvinyl)stannane (1.95 g, 5.4 mmol, 1.2 eq) and Pd(PPh₃)₄ (416 mg, 0.36 mmol, 0.08 eq) in dry toluene (50 mL) was stirred at 100 °C for 20 h under nitrogen atmosphere, and then concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 4/1, v/v) to give ethyl l-((3- chloroquinolin-6-yl)methyl)-3-(l-ethoxyvinyl)-lH-pyrazole-4-carboxylate (1.4 g, 80%) as a yellow oil.

[00200] To a stirred solution of ethyl l-((3-chloroquinolin-6-yl)methyl)-3-(l- ethoxyvinyl)-lH-pyrazole-4-carboxylate (1.4 g, 3.6 mmol, 1.0 eq) in MeOH/H₂0 (30 mL, v/v 1/1) was added NaOH (290 mg, 7.3 mmol, 2.0 eq). The mixture was stirred at 60 °C for 1.5 h, and then concentrated to remove MeOH. The aqueous layer was extracted with EA. The aqueous layer was diluted with 5 mL of THF and acidified to pH 1 with 1 mL of 2 N HCL The reaction mixture was stirred at 50 °C for 1 h. Solvent was removed by evaporation and the aqueous layer was adjusted to pH 5 with NaHC0_3. The resulting white precipitate was collected by filtration and dried at 110 °C for 1 h to give 3-acetyl-l-((3-chloroquinolin-6- yl)methyl)-lH-pyrazole-4-carboxylic acid (940 mg, 78% for two steps) as a white solid.

[00201] A mixture of 3-acetyl-l-((3-chloroquinolin-6-yl)methyl)-lH-pyrazole-4- carboxylic acid (940 mg, 2.86 mmol, 1.0 eq) and CDI (509 mg, 3.14 mmol, 1.1 eq) in DMF (25 mL) was stirred at 65 °C for 1 h, and tert- butyl (5-(aminomethyl)-4,6-dimethylpyridin-2- yl)carbamate (788 mg, 3.14 mmol, 1.1 eq) was added. The reaction mixture was stirred at 50 °C overnight, and then concentrated. The resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 20/1, v/v) to give tert-butyl (5-((3-acetyl-l-((3- chloroquinolin-6-yl)methyl)-lH-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2- yl)carbamate (1.4 g, 90% ) as a white solid.

[00202] To a solution of [5-({[3-acetyl-l-(3-chloro-quinolin-6-ylmethyl)-lH-pyrazole-4- carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert- butyl ester (100 mg, 0.18 mmol, 1.0 eq) in THF (20 mL) was added MeMgBr (0.89 mL, 2.66 mmol, 15.0 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h, and aq. NH₄Cl was added and extracted with EA (20 mL x 2). The combined organic layers were dried over Na₂S0₄, filtered and concentrated to afford [5-({[l -(3-chloro-quinolin-6-ylmethyl)-3-(l -hydroxy- 1 -methyl-ethyl)-lH-pyrazole-4- carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert- butyl ester (100 mg, crude) as a white solid. LRMS (M+H⁺) m/z calculated 579.2, found 579.1.

[00203] To a solution of [5-({[l-(3-chloro-quinolin-6-ylmethyl)-3-(l-hydroxy-l-methyl- ethyl)-lH-pyrazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert- butyl ester (100 mg crude, 0.18 mmol, 1.0 eq) in DCM (3 mL) was added TFA (3 mL) at 0 °C. The mixture was stirred at 0 °C for 4 h, and then concentrated. The resulting residue was diluted with EtOH (1 mL) and neutralized with aq. NaHCO, and concentrated to give the crude product, which was purified by prep-HPLC to give N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3-(2-hydroxypropan-2-yl)-lH-pyrazole-4- carboxamide (5 mg, 6%) as a white solid. LRMS (M+H⁺) m/z calculated 479.2, found 479.0.

1H NMR (DMSO-i¾, 400 MHz) d 8.88 (d, 1 H), 8.69 (t, 1 H), 8.58 (d, 1 H), 8.35 (s, 1 H), 8.04 (d, 1 H), 7.83 (s, 1 H), 7.67-7.64 (m, 1 H), 6.81 (s, 1 H), 6.10 (s, 1 H), 5.63 (d, 2 H), 5.49 (s, 2 H), 4.29 (d, 2 H), 2.29 (s, 3H), 2.16 (s, 3 H), 1.42 (s, 6 H).

Example 29: Preparation of N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-l-((3- chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide

[00204] A mixture of ethyl l-((3-chloroquinolin-6-yl)methyl)-3-iodo-lH-pyrazole-4- carboxylate (9.0 g, 20.4 mmol, 1.0 eq), tributyl(vinyl)stannane (7.2 g, 22.5 mmol, 1.1 eq) and Pd(PPh₃)₄ (1.9 g, 1.63 mmol, 0.08 eq) in toluene (200 mL) was stirred at 100 °C for 24 h, and then concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1, v/v) to give ethyl l-((3-chloroquinolin-6-yl)methyl)-3-vinyl-lH-pyrazole-4- carboxylateethyl (6.1 g, 87% ) as a yellow solid.

[00205] To a stirred solution of ethyl l-((3-chloroquinolin-6-yl)methyl)-3-vinyl-lH- pyrazole-4-carboxylateethyl (6.1 g, 17.89 mmol, 1.0 eq) in THF/H₂0 (400 mL, v/v = 1/1) was added Os0₄ (91 mg, 0.36 mmol, 0.02 eq) followed by NaI0₄ (7.7 g, 35.8 mmol, 2.0 eq). The resulting mixture was stirred at rt for 0.5 h. The mixture was diluted with water and extracted with EA (100 mL ^c 3). The combined organic layers were dried over Na₂S0 , filtered and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 3/1, v/v) to give ethyl l-((3-chloroquinolin-6-yl)methyl)-3-formyl-lH-pyrazole-4- carboxylate (4.0 g, 65%) as a white solid.

[00206] To a solution of ethyl 1 -((3 -chloroquinolin-6-yl)methyl)-3 -formyl- lH-pyrazole- 4-carboxylate (2.0 g, 5.83 mmol, 1.0 eq) in DCM (50 mL) was added DAST (1.56 mL, 11.66 mmol, 2.0 eq) at 0 °C. The mixture was stirred at rt for 18 h and then quenched with sat.

NaHC0₃ aqueous solution and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1, v/v) to give ethyl l-((3- chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxylate (1.1 g, 52%) as a yellow solid.

[00207] To a suspension of ethyl l-((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)- lH-pyrazole-4-carboxylate (1.3 g, 3.56 mmol, 1.0 eq) in MeOH/H₂0 (30 mL, v/v = 1/1) was added NaOH (285 mg, 7.12 mmol, 2.0 eq). The mixture was stirred at 50 °C for 1 h, and then concentrated to remove MeOH. The aqueous layer was washed with DCM and then acidified to pH 2 with 1 N HC1. The resulting precipitate was collected by filtration and dried at 120 °C for 1 h to give l-((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxylic acid (1.15 g, 96%) as a white solid.

[00208] A mixture of l-((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH- pyrazole-4-carboxylic acid (120 mg, 0.356 mmol, 1.0 eq) and CDI (66 mg, 0.41 mmol, 1.15 eq) in DMF (4 mL) was stirred at 60 °C for 1.5 h, and (3-chloro-6-fluoro-lH-indol-5- yl)methanamine hydrochloride (96 mg, 0.41 mmol, 1.15 eq) was added. The reaction mixture was stirred at 80 °C for 3 h, and then concentrated. The resulting residue was diluted with DCM and washed with water. The organic layer was dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 60/1, v/v) to give N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-l-((3-chloroquinolin-6- yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamideethyl (105 mg, 57%) as a white solid. LRMS (M+H⁺) m/z calculated 518.1, found 517.9. 1H NMR (DMSO-i¾, 400 MHz) d 11.38 (s, 1 H), 8.90 (s, 1 H), 8.72 (t, 1 H), 8.61 (d, 1 H), 8.47 (s, 1 H), 8.07 (d, 1 H), 7.89 (s, 1 H), 7.70 (dd, 1 H), 7.50 (d, 1H), 7.42 (d, 1 H), 7.36 (t, 1H), 7.21 (d, 1H), 5.66 (s, 2 H), 4.50 (d, 2H).

Example 30: Preparation of N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-l-((3- chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide

[00209] A mixture of l-((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH- pyrazole-4-carboxylic acid (80 mg, 0.237 mmol, 1.0 eq) and CDI (44 mg, 0.273 mmol, 1.15 eq) in DMF (3 mL) was stirred at 75 °C for 1 h, and (3-chloro-lH-pyrrolo[2,3-b]pyridin-5- yl)methanamine hydrochloride (59 mg, 0.273 mmol, 1.15 eq) was added. The reaction mixture was stirred at 80 °C for 2 h, and then concentrated. The resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 30/1, v/v) to give N-((3-chloro-lH- pyrrolo[2,3-b]pyridin-5-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH- pyrazole-4-carboxamide (48 mg, 40%) as a white solid. LRMS (M-H ) m/z calculated 499.1, found 499.0. 1H NMR (DMSO-r¾, 400 MHz) d 11.94 (s, 1 H), 8.90 (s, 1 H), 8.81 (t, 1 H), 8.61 (d, 1 H), 8.43 (s, 1 H), 8.27 (d, 1 H), 8.06 (d, 1 H), 7.88 (d, 1 H), 7.84 (d, 1H), 7.70 (dd, 1 H), 7.67 (d, 1H), 7.36 (t, 1H), 5.65 (s, 2 H), 4.51 (d, 2H).

Example 31: Preparation of N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-l-((3- chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide

[00210] A mixture of l-((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH- pyrazole-4-carboxylic acid (80 mg, 0.237 mmol, 1.0 eq) and CDI (44 mg, 0.273 mmol, 1.15 eq) in DMF (3 mL) was stirred at 75 °C for 1 h, and (3-chloro-4-fluoro-lH-indol-5-yl)methanamine hydrochloride (64 mg, 0.273 mmol, 1.15 eq) was added. The reaction mixture was stirred at 80 °C for 6 h, and then concentrated. The resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 60/1, v/v) to give N-((3-chloro-4-fluoro-lH-indol-5- yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide (44 mg, 34%) as a white solid. LRMS (M-H ) m/z calculated 516.1, found 515.8. 1H NMR (DMS0-r 400 MHz) d 11.58 (s, 1 H), 8.90 (s, 1 H), 8.71 (t, 1 H), 8.61 (d, 1 H), 8.44 (s, 1 H), 8.07 (d, 1 H), 7.88 (d, 1 H), 7.70 (dd, 1 H), 7.51 (s, 1H), 7.37 (t, 1 H), 7.20 (d, 1H), 7.13 (d, 1H), 5.64 (s, 2 H), 4.48 (d, 2H).

Example 32: Preparation of N-((5-chloro-lH-indazol-3-yl)methyl)-l-((3-chloroquinolin-6- yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide

[00211] A mixture of l-((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH- pyrazole-4-carboxylic acid (80 mg, 0.237 mmol, 1.0 eq) and CDI (44 mg, 0.273 mmol, 1.15 eq) in DMF (3 mL) was stirred at 75 °C for 1 h, and (5-chloro-lH-indazol-3-yl)methanamine hydrochloride (59 mg, 0.273 mmol, 1.15 eq) was added. The reaction mixture was stirred at 80 °C for 2 h, and then concentrated. The resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 30/1, v/v) to give N-((5-chloro-lH-indazol-3-yl)methyl)-l- ((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide (70 mg, 59%) as a white solid. LRMS (M+H⁺) m/z calculated 501.1, found 500.9. ¹H NMR (DMSO-t/g, 400 MHz) d 13.05 (s, 1 H), 8.90 (s, 1 H), 8.87 (t, 1 H), 8.60 (d, 1 H), 8.40 (s, 1 H), 8.06 (d, 1 H), 7.88 (d, 1 H), 7.86 (d, 1 H), 7.68 (dd, 1H), 7.53 (d, 1 H), 7.39 (t, 1H), 7.32 (d, 1H), 5.64 (s, 2 H), 4.70 (d, 2H).

Example 33: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-l-((3-chloroquinolin-6- yl)methyl)-3-(difluoromethyl)-lH-pyrazole-4-carboxamide

[00212] A mixture of l-((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH- pyrazole-4-carboxylic acid (100 mg, 0.30 mmol, 1.0 eq), 6-(aminomethyl)isoquinolin-l-amine hydrochloride (74 mg, 0.36 mmol, 1.2 eq), HOBt (53 mg, 0.39 mmol, 1.3 eq), EDCI (75 mg, 0.39 mmol, 1.3 eq) and TEA (0.17 mL, 1.2 mmol, 4.0 eq) in DMF (3 mL) was stirred at 50 °C overnight, and then concentrated. The resulting residue was diluted with DCM/MeOH (v/v = 10/1) and washed with sat. NaHC0₃ aqueous solution. The organic layer was dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to give N- ((l-aminoisoquinolin-6-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3-(difluoromethyl)-lH- pyrazole-4-carboxamide (45 mg, 31%) as awhite solid. LRMS (M+H⁺) m/z calculated 501.1, found 500.9. 1H NMR (DMSO-r¾, 400 MHz) d 8.91 (s, 1 H), 8.89 (t, 1 H), 8.63 (d, 1 H), 8.48 (s, 1 H), 8.13 (d, 1 H), 8.08 (d, 1 H), 7.91 (d, 1 H), 7.75 (d, 1H), 7.71 (dd, 1 H), 7.54 (s, 1H), 7.39 (t, 1H), 7.37 (d, 1H), 6.84 (d, 1H), 6.73 (s, 2 H), 5.68 (s, 2 H), 4.52 (d, 2H).

Example 34: Preparation of N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-l-((3- chloroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide

[00213] To a solution of l-(3-chloro-quinolin-6-ylmethyl)-3-formyl-lH-pyrazole-4- carboxylic acid ethyl ester (50 mg, 0.14 mmol, 1.0 eq) in MeOH (10 mL) was added NaBH₄ (6.0 mg, 0.14 mmol, 1.0 eq) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, and then DCM (50 mL) and water (30 mL) was added. The organic layer was dried over Na₂S0₄, filtered and concentrated to afford l-(3-chloro-quinolin-6-ylmethyl)-3-hydroxymethyl-lH- pyrazole-4-carboxylic acid ethyl ester (50 mg, 98%) as a white solid.

[00214] To a solution of l-(3-chloro-quinolin-6-ylmethyl)-3-hydroxymethyl-lH- pyrazole-4-carboxylic acid ethyl ester (1.68 g, 4.86 mmol, 1.0 eq) in DCM (50 mL) was added DAST (1.2 g, 7.29 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h, and quenched with aq. NaHCO, and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na₂S0 , filtered and concentrated. The resulting residue was purified by column chromatography (PE/EA = 3/1, v/v) to afford l-(3-chloro-quinolin-6-ylmethyl)-3-fluoromethyl- lH-pyrazole-4-carboxylic acid ethyl ester (l. lg, 65%) as a white solid. LRMS (M+H⁺) m/z calculated 348.1, found 348.1.

[00215] A mixture of l-(3-chloro-quinolin-6-ylmethyl)-3-fluoromethyl-lH-pyrazole-4- carboxylic acid ethyl ester (l. lg, 3.16 mmol, 1.0 eq) and NaOH (253 mg, 6.33 mmol, 2.0 eq) in THF (20 mL) and H₂0 (10 mL) was stirred at 60 °C overnight, and then concentrated to remove THF and neutralized with 1 N HC1. The resulting white precipitate was collected by filtration and dried in vacuo to afford l-(3-chloro-quinolin-6-ylmethyl)-3-fluoromethyl-lH- pyrazole-4-carboxylic acid (960 mg, 95%). LRMS (M+H⁺) m/z calculated 320.1, found 320.1.

[00216] To a solution of l-(3-chloro-quinolin-6-ylmethyl)-3-fluoromethyl-lH-pyrazole- 4-carboxylic acid (100 mg, 0.31 mmol, 1.0 eq) in DMF (6 mL) was added CDI (76 mg, 0.47 mmol, 1.5 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (3-chloro-6-fluoro-lH- indol-5-yl)methanamine hydrochloride (110 mg, 0.47 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C overnight, and then concentrated. The resulting residue was purified by column chromatography (DCM/MeOH = 30/1, v/v) to afford N-((3-chloro-6-fluoro-lH-indol- 5-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide (109 mg, 71%) as a white solid. LRMS (M-H⁺) m/z calculated 498.1, found 498.0. 1H NMR (DMSO-i¾, 400 MHz) d 11.37 (s, 1 H), 8.89 (d, 1 H), 8.61-8.56 (m, 2 H), 8.41 (s, 1 H), 8.05 (d, 1 H), 7.87 (d, 1 H), 7.70-7.68 (m, 1 H), 7.50 (d, 1 H), 7.43 (d, 1 H), 7.20 (d, 1 H), 5.62-5.60 (m, 3 H), 5.50 (s, 1 H), 4.50 (d, 2 H).

Example 35: Preparation of N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-l-((3- chloroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide

[00217] To a solution of l-(3-chloro-quinolin-6-ylmethyl)-3-fluoromethyl-lH-pyrazole- 4-carboxylic acid (100 mg, 0.31 mmol, 1.0 eq) in DMF (6 mL) was added CDI (76 mg, 0.47 mmol, 1.5 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (3-chloro-lH-pyrrolo[2,3- b]pyridin-5-yl)methanamine hydrochloride (102 mg, 0.47 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C overnight, and then concentrated. The resulting residue was purified by prep-HPLC to afford N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-l-((3- chloroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide (15 mg, 10%) as a white solid. LRMS (M+H⁺) m/z calculated 483.1, found 482.9. 1H NMR (DMSO-i¾, 400 MHz) d 11.94 (s, 1 H), 8.89 (d, 1 H), 8.68 (t, 1 H), 8.60 (d, 1 H), 8.37 (s, 1 H), 8.28 (d, 1 H), 8.05 (d,

1 H), 7.85 (d, 2 H), 7.69-7.66 (m, 2 H), 5.62-5.50 (m, 4 H), 4.51 (d, 2H).

Example 36: Preparation of N-((5-chloro-lH-indazol-3-yl)methyl)-l-((3-chloroquinolin-6- yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide

[00218] To a solution of l-(3-chloro-quinolin-6-ylmethyl)-3-fluoromethyl-lH-pyrazole- 4-carboxylic acid (100 mg, 0.31 mmol, 1.0 eq) in DMF (6 mL) was added CDI (76 mg, 0.47 mmol, 1.5 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (5-chloro-lH-indazol-3- yl)methanamine hydrochloride (89 mg, 0.47 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C overnight, and then concentrated. The resulting residue was purified by prep-HPLC to afford N-((5-chloro-lH-indazol-3-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3- (fluoromethyl)-lH-pyrazole-4-carboxamide (63 mg, 42%) as a white solid. LRMS (M+H⁺) m/z calculated 483.1, found 482.9. 1H NMR (DMSO-i¾, 400 MHz) d 13.04 (s, 1 H), 8.89 (d, 1 H),

8.73 (t, 1 H), 8.59 (d, 1 H), 8.34 (s, 1 H), 8.04 (d, 1 H), 7.87-7.86 (m, 2 H), 7.68-7.66 (m, 1 H), 7.51 (d, 1 H), 7.34-7.31 (m, 1 H), 5.64-5.52 (m, 4 H), 4.70 (d, 2H).

Example 37: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-l-((3-chloroquinolin-6- yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide

[00219] A mixture of l-(3-chloro-quinolin-6-ylmethyl)-3-fluoromethyl-lH-pyrazole-4- carboxylic acid (100 mg, 0.31 mmol, 1.0 eq), 6-aminomethyl-isoquinolin-l-ylamine hydrochloride (98 mg, 0.47 mmol, 1.5 eq), HOBT (63 mg, 0.47 mmol, 1.5 eq), EDCI (90 mg, 0.47 mmol, 1.5 eq) and Et₃N (95 mg, 0.94 mmol, 3.0 eq) in DMF (6 mL) was stirred at rt overnight and then concentrated. The resulting residue was purified by prep-HPLC to afford N- ((l-aminoisoquinolin-6-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH- pyrazole-4-carboxamide (65 mg, 44%) as a white solid. LRMS (M+H⁺) m/z calculated 475.1, found 475.2. 1H NMR (DMSO-r¾, 400 MHz) d 8.90 (d, 1 H), 8.74 (t, 1 H), 8.61 (d, 1 H), 8.42 (s, 1 H), 8.13 (d, 1 H), 8.07 (d, 1 H), 7.89 (d, 1 H), 7.76 (d, 1 H), 7.72-7.69 (m, 1 H), 7.54 (s, 1 H), 7.39-7.37 (m, 1 H), 6.84 (d, 1 H), 6.73 (s, 2 H), 5.64-5.52 (m, 4 H), 4.53 (d, 2 H).

Example 38: Preparation of N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-l-((3- chloroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide

[00220] To a solution of l-(3-chloro-quinolin-6-ylmethyl)-3-fluoromethyl-lH-pyrazole- 4-carboxylic acid (100 mg, 0.31 mmol, 1.0 eq) in DMF (6 mL) was added CDI (76 mg, 0.47 mmol, 1.5 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (3-chloro-4-fluoro-lH- indol-5-yl)methanamine hydrochloride (110 mg, 0.47 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C overnight, and then concentrated. The resulting residue was purified by prep-HPLC to afford N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-l-((3-chloroquinolin-6- yl)methyl)-3-(fluoromethyl)-lH-pyrazole-4-carboxamide (23 mg, 15%) as a white solid. LRMS (M-H ) m/z calculated 498.1, found 498.0. 1H NMR (DMSO-i¾, 400 MHz) d 11.57 (s, 1 H),

8.89 (d, 1 H), 8.61 (d, 1 H), 8.56 (t, 1 H), 8.38 (s, 1 H), 8.05 (d, 1 H), 7.86 (s, 1 H), 7.69-7.66 (m, 1 H), 7.50 (d, 1 H), 7.19-7.10 (m, 2 H), 5.62-5.50 (m, 4 H), 4.48 (d, 2 H).

Example 39: Preparation of N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8- fluoroquinolin-6-yl)methyl)-l,3,4-oxadiazole-2-carboxamide

[00221] To a solution of 3-chloro-6-chloromethyl-8-fluoro-quinoline (2.7 g, 11.74 mmol, 1.0 eq) in DMSO (20 mL) was added NaCN (575 mg, 11.74 mmol, 1.0 eq) at rt. The mixture was stirred at rt overnight, and EA (300 mL) was added. The resulting mixture was washed with brine (30 mL ^c 4). The organic layer was dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 3/1, v/v) to give (3-chloro-8-fluoro-quinolin-6-yl)-acetonitrile (800 mg, 31%) as a yellow solid.

[00222] A mixture of (3-chloro-8-fluoro-quinolin-6-yl)-acetonitrile (800 mg, 3.62 mmol, 1.0 eq) in H₂S0₄ (98%, 8 mL), AcOH (8 mL) and water (8 mL) was stirred at 110 °C overnight, and then concentrated. The resulting residue was adjusted to pH 2 with 1 N NaOH. A white solid was formed, which was filtered and dried in vacuo to give (3-chloro-8-fluoro-quinolin-6- yl)-acetic acid (800 mg, 92%) as a white solid.

[00223] A mixture of (3-chloro-8-fluoro-quinolin-6-yl)-acetic acid (800 mg, 3.34 mmol, 1.0 eq), hydrazinecarboxylic acid /er/-butyl ester (661 mg, 5.01 mmol, 1.5 eq), HATU (1.9 g, 5.01 mmol, 1.5 eq) and Et₃N (1.0 g, 10.02 mmol, 3.0 eq) in DMF (15 mL) was stirred at rt for 2 h, and water (30 mL) was added. A white solid was formed, which was filtered and dried in vacuo to give tert- butyl 2-(2-(3-chloro-8-fluoroquinolin-6-yl)acetyl)hydrazinecarboxylate (760 mg, 64%) as a white solid.

[00224] To a solution of /tvV-butyl 2-(2-(3-chloro-8-fluoroquinolin-6- yl)acetyl)hydrazinecarboxylate (760 mg, 2.15 mmol, 1.0 eq) in EA (20 mL) was added HC1/EA (20 mL) at rt. The mixture was stirred at rt overnight. The mixture was filtered and the resulting solid was washed with EA, and then dried in vacuo to give (3-chloro-8-fluoro-quinolin-6-yl)- acetic acid hydrazide (800 mg, crude) as a white solid.

[00225] To a solution of (3-chloro-8-fluoro-quinolin-6-yl)-acetic acid hydrazide (800 mg, 2.76 mmol, 1.0 eq) and K₂C0₃ (1.1 g, 8.28 mmol, 3.0 eq) in ACN (40 mL) was added chloro-oxo-acetic acid ethyl ester (565 mg, 4.14 mmol, 1.5 eq) at rt. The mixture was stirred at rt overnight, and water (20 mL) was added. A white precipitate was formed, which was filtered, and washed with water (20 mL), MeOH (20 mL) and EA (20 mL) subsequently. The resulting solid was dried in vacuo to afford ethyl 2-(2-(2-(3-chloro-8-fluoroquinolin-6- yl)acetyl)hydrazinyl)-2-oxoacetate (650 mg, 67%) as a white solid.

[00226] To a solution of ethyl 2-(2-(2-(3-chloro-8-fluoroquinolin-6- yl)acetyl)hydrazinyl)-2-oxoacetate (650 mg, 1.84 mmol, 1.0 eq) in DCM (30 mL) was added TsCl (455 mg, 2.39 mmol, 1.3 eq) and Et₃N (280 mg, 2.76 mmol, 1.5 eq) at rt. The mixture was stirred at rt overnight, and then concentrated. The resulting residue was purified by

chromatography on a silica gel column (PE/EA = 1/1, v/v) to afford 5-(3-chloro-8-fluoro- quinolin-6-ylmethyl)-[l,3,4]oxadiazole-2-carboxylic acid ethyl ester (400 mg, 65%) as a white solid.

[00227] To a solution of (3-chloro-6-fluoro-lH-indol-5-yl)methanamine hydrochloride (298 mg, 1.27 mmol, 3.0 eq) in toluene (20 mL) was added AlMe₃ (424 mg, 1.47 mmol, 3.5 eq) at 0 °C. The mixture was stirred at rt for 1 h, and ethyl 5-((3-chloro-8-fluoroquinolin-6- yl)methyl)-l,3,4-oxadiazole-2-carboxylate (130 mg, 0.42 mmol, 1.0 eq) was added. The mixture was stirred at 110 °C overnight. The mixture was concentrated and added water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to afford N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-l,3,4- oxadiazole-2-carboxamide (31 mg, 15%) as a white solid. LRMS (M-H⁺) m/z calculated 486.0, found 485.9. 1H NMR (DMSO-i¾, 400 MHz) d 11.39 (s, 1 H), 9.81 (t, 1 H), 8.94 (d, 1 H), 8.66 (t, 1 H), 7.78 (s, 1 H), 7.71-7.67 (m, 1 H), 7.51-7.46 (m, 2 H), 7.21 (d, 1 H), 4.61 (s, 2 H), 4.57 (d, 2 H).

Example 40: Preparation of N-((5-chloro-lH-indazol-3-yl)methyl)-5-((3-chloro-8- fluoroquinolin-6-yl)methyl)-l,3,4-oxadiazole-2-carboxamide

[00228] To a solution of (5-chloro-lH-indazol-3-yl)methanamine hydrochloride (277 mg, 1.27 mmol, 3.0 eq) in toluene (20 mL) was added AlMe₃ (424 mg, 1.47 mmol, 3.5 eq) at 0 °C. The mixture was stirred at rt for 1 h, and ethyl 5-((3-chloro-8-fluoroquinolin-6-yl)methyl)- l,3,4-oxadiazole-2-carboxylate (130 mg, 0.42 mmol, 1.0 eq) was added. The mixture was stirred at 110 °C overnight. The mixture was concentrated and added water (20 mL) and extracted with DCM (20 mL ^c 3). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to afford N-((5- chloro-lH-indazol -3-yl)methyl)-5-((3-chl oro-8-fluoroquinolin-6-yl)m ethyl)- 1,3, 4-oxadiazole- 2-carboxamide (20 mg, 10%) as a white solid. LRMS (M-H⁺) m/z calculated 469.1, found 469.0. 1H NMR (DMSO-dg, 400 MHz) d 13.08 (s, 1 H), 9.92 (t, 1 H), 8.94 (d, 1 H), 8.65 (d, 1 H), 7.97 (s, 1 H), 7.77 (s, 1 H), 7.70-7.67 (m, 1 H), 7.53 (d, 1 H), 7.36-7.33 (m, 1 H), 4.75 (d, 2 H), 4.60 (s, 2 H).

Example 41: Preparation of N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8- fluoroquinolin-6-yl)methyl)-l,3,4-oxadiazole-2-carboxamide

[00229] To a solution of (3-chloro-4-fluoro-lH-indol-5-yl)methanamine hydrochloride (229 mg, 0.97 mmol, 3.0 eq) in toluene (20 mL) was added AlMe₃ (322 mg, 1.12 mmol, 3.5 eq) at 0 °C. The mixture was stirred at rt for 1 h, and ethyl 5-((3-chloro-8-fluoroquinolin-6- yl)methyl)-l,3,4-oxadiazole-2-carboxylate (100 mg, 0.32 mmol, 1.0 eq) was added. The mixture was stirred at 110 °C overnight. The mixture was concentrated and added water (20 mL) , and extracted with DCM (20 mL ^c 3). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to afford N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-l,3,4- oxadiazole-2-carboxamide (28 mg, 18%) as a white solid. LRMS (M-H⁺) m/z calculated 486.0, found 485.9. 1H NMR (DMSO-i¾, 400 MHz) d 11.59 (s, 1 H), 9.80 (t, 1 H), 8.94 (d, 1 H), 8.66 (d, 1 H), 7.77 (s, 1 H), 7.70-7.67 (m, 1 H), 7.51 (d, 1 H), 7.20-7.12 (m, 2 H), 4.60 (s, 2 H), 4.56 (d, 2 H).

Example 42: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-5-((3-chloro-8- fluoroquinolin-6-yl)methyl)-l,3,4-oxadiazole-2-carboxamide

[00230] To a solution of 6-aminomethyl-isoquinolin-l-ylamine (243 mg, 1.16 mmol, 3.0 eq) in toluene (20 mL) was added AlMe₃ (393 mg, 1.36 mmol, 3.5 eq) at 0 °C. The mixture was stirred at rt for 1 h, and ethyl 5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-l,3,4-oxadiazole-2- carboxylate (130 mg, 0.39 mmol, 1.0 eq) was added. The mixture was stirred at 110 oC overnight. The mixture was concentrated and added water (20 mL), and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to afford N-((l-aminoisoquinolin-6- yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-l,3,4-oxadiazole-2-carboxamide (10 mg, 5%) as a white solid. LRMS (M+H⁺) m/z calculated 463.1, found 463.1. 1H NMR (DMSO- d₆, 400 MHz) d 9.91 (t, 1 H), 8.95 (d, 1 H), 8.67 (s, 1 H), 8.13 (d, 1 H), 7.79-7.75 (m, 2 H), 7.71-7.68 (m, 1 H), 7.56 (s, 1 H), 7.41-7.39 (m, 1 H), 6.85 (d, 1 H), 6.75 (br.s, 2 H), 4.62 (s, 2 H), 4.58 (d, 2 H).

Example 43: Preparation of N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-((3- chloro-8-fluoroquinolin-6-yl)methyl)-l,3,4-oxadiazole-2-carboxamide

N-((3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-

6-yl)methyl)-1,3,4-oxadiazole-2-carboxamide

[00231] To a solution of (3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methanamine hydrochloride (194 mg, 0.89 mmol, 3.0 eq) in toluene (20 mL) was added AlMe₃ (302 mg, 1.05 mmol, 3.5 eq) at 0 °C. The mixture was stirred at rt for lh, and ethyl 5-((3-chloro-8- fluoroquinolin-6-yl)methyl)-l,3,4-oxadiazole-2-carboxylate (100 mg, 0.30 mmol, 1.0 eq) was added. The mixture was stirred at 110 °C overnight. The mixture was concentrated and added water (20 mL), and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by prep-HPLC to afford N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6- yl)methyl)-l,3,4-oxadiazole-2-carboxamide (36 mg, 25%) as a white solid. LRMS (M-H⁺) m/z calculated 469.1, found 468.9. 1H NMR (DMSO-i¾, 400 MHz) d 11.97 (s, 1 H), 9.89 (t, 1 H), 8.94 (d, 1 H), 8.65 (t, 1 H), 8.30 (d, 1 H), 7.89 (d, 1 H), 7.77 (s, 1 H), 7.69-7.66 (m, 2 H), 4.60 (s, 2 H), 4.57 (d, 2 H).

Example 44: Preparation of N-((5-chloro-lH-indazol-3-yl)methyl)-5-((3-chloroquinolin-6- yl)methyl)-4H-l,2,4-triazole-3-carboxamide

[00232] A mixture of (3-chloro-quinolin-6-yl)-acetic acid (1.0 g, 4.51 mmol, 1.0 eq), hydrazinecarboxylic acid tert- butyl ester (894 mg, 6.77 mmol, 1.5 eq), HATU (2.6 g, 6.77 mmol, 1.5 eq) and Et₃N (1.4 g, 13.53 mmol, 3.0 eq) in DMF (20 mL) was stirred at rt overnight, and then water (50 mL) was added. The resulting precipitate was filtered and dried in vacuo to afford N'-[2-(3-chloro-quinolin-6-yl)-acetyl]-hydrazinecarboxylic acid tert- butyl ester (1.3 g, crude) as a white solid.

[00233] To a solution of N'-[2-(3-chloro-quinolin-6-yl)-acetyl]-hydrazinecarboxylic acid /er/-butyl ester (1.3 g, 3.87 mmol, 1.0 eq) in MeOH (20 mL) was added HCl/MeOH (20 mL) at rt. The solution was stirred at rt overnight. The resulting precipitate was filtered and dried in vacuo to afford (3-chloro-quinolin-6-yl)-acetic acid hydrazide (1.0 g, 95%) as a white solid.

[00234] A mixture of (3-chloro-quinolin-6-yl)-acetic acid hydrazide (4.0 g, 16.97 mmol, 1.0 eq) and ethoxy-imino-acetic acid ethyl ester (4.9 g, 33.95 mmol, 2.0 eq) in EtOH (200 mL) and AcOH (10 mL) was stirred at rt for 30 min, and then concentrated. The resulting residue was dried in vacuo to afford amino-{[2-(3-chloro-quinolin-6-yl)-acetyl]-hydrazono}-acetic acid ethyl ester (5.0 g, 89%) as a white solid.

[00235] A mixture of amino-{[2-(3-chloro-quinolin-6-yl)-acetyl]-hydrazono}-acetic acid ethyl ester (2.0 g, 5.97 mmol, 1.0 eq) and TsOH (206 mg, 1.19 mmol, 0.2 eq) in xylene (200 mL) was stirred at 140 °C for 16 h and 180 °C for 8 h and then concentrated. The water was separated with separator. The resulting residue was purified by column chromatography (DCM/MeOH = 20/1, v/v) to afford 5-(3-chloro-quinolin-6-ylmethyl)-4H-[l,2,4]triazole-3- carboxylic acid ethyl ester (800 mg, 42%) as a white solid.

[00236] To a solution of 5-(3-chloro-quinolin-6-ylmethyl)-4H-[l,2,4]triazole-3- carboxylic acid ethyl ester (800 mg, 2.52 mmol, 1.0 eq) in THF (20 mL) was added a solution of LiOH (212 mg, 5.05 mmol, 2.0 eq) in water (4 mL) at rt. The mixture was stirred at rt overnight, and then neutralized with 1 N HC1. The resulting white solid was filtered and dried in vacuo to afford 5-(3-chloro-quinolin-6-ylmethyl)-4H-[l,2,4]triazole-3-carboxylic acid (700 mg, 96%) as a white solid. LRMS (M+H⁺) m/z calculated 289.0, found 289.1.

[00237] To a solution of 5-(3-chloro-quinolin-6-ylmethyl)-4H-[l,2,4]triazole-3- carboxylic acid (100 mg, 0.35 mmol, 1.0 eq) in DMF (10 mL) was added CDI (84 mg, 0.52 mmol, 1.5 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (5-chloro-lH-indazol-3- yl)methanamine hydrochloride (113 mg, 0.52 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C overnight, and then concentrated. The resulting residue was purified by column chromatography (DCM/MeOH = 20/1, v/v) to afford N-((5-chloro-lH-indazol-3-yl)methyl)-5- ((3-chloroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxamide (56 mg, 35%) as a white solid. LRMS (M+H⁺) m/z calculated 452.1, found 452.2. 1H NMR (DMSO-i¾, 400 MHz) d 13.01 (s, 1 H), 9.16 (brs, 1 H), 8.84 (d, 1 H), 8.52 (d, 1 H), 8.01-7.98 (m, 2 H), 7.81 (s, 1 H), 7.73-7.70 (m, 1 H), 7.51 (d, 1 H), 7.33-7.30 (m, 1 H), 4.72 (d, 2 H), 4.31 (s, 2H).

Example 45: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-5-((3-chloroquinolin-6- yl)methyl)-4H-l,2,4-triazole-3-carboxamide

[00238] To a solution of 5-(3-chloro-quinolin-6-ylmethyl)-4H-[l,2,4]triazole-3- carboxylic acid (100 mg, 0.35 mmol, 1.0 eq) in DMF (10 mL) was added CDI (84 mg, 0.52 mmol, 1.5 eq) at rt. The mixture was stirred at 60 °C for 30 min, and 6-aminomethyl- isoquinolin-l-ylamine hydrochloride (109 mg, 0.52 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C overnight, and then concentrated. The resulting residue was purified by prep-

HPLC to afford N-((l-aminoisoquinolin-6-yl)methyl)-5-((3-chloroquinolin-6-yl)methyl)-4H- 1, 2, 4-triazole-3 -carboxamide (13 mg, 8%) as a white solid. LRMS (M+H⁺) m/z calculated 444.1, found 443.9. 1H NMR (DMSO-i¾, 400 MHz) d 14.56 (brs, 1 H), 9.22 (brs, 1 H), 8.85 (d, 1 H), 8.55 (d, 1 H), 8.13 (d, 1 H), 8.01 (d, 1 H), 7.83 (s, 1 H), 7.75-7.72 (m, 2 H), 7.53 (s, 1 H),

7.41-7.39 (m, 1 H), 6.85-6.80 (m, 3 H), 4.55 (d, 2 H), 4.34 (s, 2H).

Example 46: Preparation of N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-((3- chloroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxamide

[00239] To a solution of 5-(3-chloro-quinolin-6-ylmethyl)-4H-[l,2,4]triazole-3- carboxylic acid (70 mg, 0.24 mmol, 1.0 eq) in DMF (10 mL) was added CDI (58 mg, 0.36 mmol, 1.5 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (3-chloro-lH-pyrrolo[2,3- b]pyridin-5-yl)methanamine hydrochloride (79 mg, 0.36 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C overnight, and then concentrated. The resulting residue was purified by prep-HPLC to afford N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-((3- chloroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxamide (13 mg, 12%) as a white solid. LRMS (M+H⁺) m/z calculated 452.1, found 451.9. 1H NMR (DMSO-i¾, 400 MHz) d 11.93 (s,

1 H), 8.84 (d, 1 H), 8.54 (d, 1 H), 8.29 (d, 1 H), 8.00 (d, 1 H), 7.87 (d, 1 H), 7.80 (s, 1 H), 7.72- 7.70 (m, 1 H), 7.65 (d, 1 H), 4.53 (d, 2 H), 4.32 (s, 2H).

Example 47: Preparation of N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-5-((3- chloroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxamide

[00240] To a solution of 5-(3-chloro-quinolin-6-ylmethyl)-4H-[l,2,4]triazole-3- carboxylic acid (100 mg, 0.35 mmol, 1.0 eq) in DMF (10 mL) was added CDI (84 mg, 0.52 mmol, 1.5 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (3-chloro-6-fluoro-lH- indol-5-yl)methanamine hydrochloride (122 mg, 0.52 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C for 2 h, and then concentrated. The resulting residue was purified by prep- HPLC to afford N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-5-((3-chloroquinolin-6- yl)methyl)-4H-l,2,4-triazole-3-carboxamide (49 mg, 30%) as a white solid. LRMS (M+H⁺) m/z calculated 469.1, found 469.1. 1H NMR (DMSO-i¾, 400 MHz) d 11.37 (s, 1 H), 8.85 (d, 1 H), 8.54 (d, 1 H), 8.00 (d, 1 H), 7.82 (s, 1 H), 7.74-7.72 (m, 1 H), 7.49 (d, 1 H), 7.41 (d, 1 H), 7.20 (d, 1 H), 4.54 (d, 2 H), 4.34 (s, 2H).

Example 48: Preparation of N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-5-((3- chloroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxamide

[00241] To a solution of 5-(3-chloro-quinolin-6-ylmethyl)-4H-[l,2,4]triazole-3- carboxylic acid (100 mg, 0.35 mmol, 1.0 eq) in DMF (10 mL) was added CDI (84 mg, 0.52 mmol, 1.5 eq) at rt. The mixture was stirred at 60 °C for 30 min, and (3-chloro-4-fluoro-lH- indol-5-yl)methanamine hydrochloride (122 mg, 0.52 mmol, 1.5 eq) was added. The mixture was stirred at 60 °C for 2 h, and then concentrated. The resulting residue was purified by prep- HPLC to afford N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-5-((3-chloroquinolin-6- yl)methyl)-4H-l,2,4-triazole-3-carboxamide (59 mg, 36%) as a white solid. LRMS (M+H⁺) m/z calculated 469.1, found 468.9. 1H NMR (DMSO-i¾, 400 MHz) d 14.53 (brs, 1 H), 11.58 (s, 1 H), 9.05 (brs, 1 H), 8.84 (d, 1 H), 8.54 (s, 1 H), 8.00 (d, 1 H), 7.81 (s, 1 H), 7.73-7.71 (m, 1 H), 7.49 (d, 1 H), 7.17-7.13 (m, 2 H), 4.54 (d, 2 H), 4.32 (s, 2H).

Example 49: Preparation of N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxamide

[00242] To a mixture of 2-(3-chloro-8-fluoroquinolin-6-yl)acetic acid (10.7 g, 44.7 mmol, 1.0 eq), tert- butyl hydrazinecarboxylate (6.2 g, 46.9 g, 1.05 eq) and HATU (19.5 g, 51.4 mmol, 1.15 eq) in DMF (200 mL) was added TEA (11.3 g, 112 mmol, 2.5 eq). The mixture was stirred at rt overnight, and then concentrated to remove DMF. The resulting residue was triturated with DCM (700 mL), filtered, and washed with DCM. The filtrate was washed with sat. NH₄Cl, concentrated, and purified by chromatography on a silica gel column (PE/EA = 1/1, v/v) to give te/V-butyl 2-(2-(3-chloro-8-fluoroquinolin-6-yl)acetyl)hydrazinecarboxylate (1.3 g, 95%).

[00243] A mixture of tert- butyl 2-(2-(3-chloro-8-fluoroquinolin-6- yl)acetyl)hydrazinecarboxylate (15.1 g, 42.8 mmol, 1.0 eq) in HC1/EA (650 mL) was stirred at rt overnight. The solvent was removed by evaporation. The resulting residue was diluted with water, adjusted pH to 9, filtered, washed with EA, and dried to give 2-(3-chloro-8- fluoroquinolin-6-yl)acetohydrazide (10.0 g, 91%)

[00244] To a suspension of 2-(3-chloro-8-fluoroquinolin-6-yl)acetohydrazide (254 mg, 1.0 mmol, 1.0 eq) and ethyl 2-ethoxy-2-iminoacetate (290 mg, 2.0 mmol, 2.0 eq) in ethanol (10 mL) was added AcOH (0.5 mL). The reaction mixture was stirred at rt for 2 h, and then concentrated under reduced pressure to give (Z)-ethyl 2-amino-2-(2-(2-(3-chloro-8- fluoroquinolin-6-yl)acetyl)hydrazono)acetate. (12.0 g, 100%).

[00245] A suspension of (Z)-ethyl 2-amino-2-(2-(2-(3-chloro-8-fluoroquinolin-6- yl)acetyl)hydrazono)acetate (12.0 g, 34 mmol, 1.0 eq) and TsOH.H₂0 (6.5 g, 34 mmol, 1.0 eq) in xylene (1.8 L) was heated to 140 °C overnight. Solvent was removed under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1 to 0/1, v/v) to give ethyl 5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3- carboxylate (4.6 g, 40%) and ethyl 5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-l,3,4- oxadiazole-2-carboxylate (470 mg, 4%).

[00246] To a solution of ethyl 5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H-l,2,4- triazole-3-carboxylate (4.6 g, 13.7 mmol, 1.0 eq) in THF (350 mL) was added a solution of LiOH (2.3 g, 54.8 mmol, 4.0 eq) in water (50 mL) at rt overnight. The mixture was neutralized with 1 N HC1 to pH 2. The resulting precipitate was filtered and dried by hyophilization to afford 5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxylic acid (4.0 g, 95%) as a white solid.

[00247] A mixture of 5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3- carboxylic acid (100 mg, 0.33 mmol, 1.0 eq), (3-chloro-6-fluoro-lH-indol-5-yl)methanamine hydrochloride (92 mg, 0.39 mmol, 1.2 eq), HATH (149 mg, 0.39 mmol, 1.2 eq) and TEA (99 mg, 0.98 mmol, 3.0 eq) in DMF (5 mL) was stirred at rt overnight, and then concentrated. The resulting residue was purified by pre-HPLC to give N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5- yl)methyl)-5 -((3 -chloro-8-fluoroquinolin-6-yl)methyl)-4H-l, 2, 4-triazole-3 -carboxamide (16 mg, 10%) as a white solid. LRMS (M+H⁺) m/z calculated 487.1, found 487.0. 1H NMR

(DMSO-i/d, 400 MHz) d 11.37 (s, 1 H), 8.91 (d, 1 H), 8.63 (s, 1 H), 7.63-7.66 (m, 2 H), 7.49 (d, 1 H), 7.41 (d, 1 H), 7.20 (d, 1 H), 4.54 (d, 2 H), 4.34 (s, 2 H).

Example 50: Preparation of N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-((3- chloro-8-fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxamide

[00248] To a solution of 5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3- carboxylic acid (123 mg, 0.4 mmol, 1.0 eq) in DMF (5 mL) was added CDI (81 mg, 0.5 mmol, 1.25 eq) at rt. The mixture was stirred at 45 °C for 1.5 h, and (3-chloro-lH-pyrrolo[2,3- b]pyridin-5-yl)methanamine hydrochloride (104 mg, 0.48 mmol, 1.2 eq) was added. The mixture was stirred at 45 °C for 4 h, and then concentrated. The resulting residue was purified by pre-HPLC to give N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-5-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxamide (31 mg, 16%) as a white solid. LRMS (M+H⁺) m/z calculated 470.1, found 470.0. 1H NMR (DMS0-i 400 MHz) d 14.55 (s,

1 H), 11.94 (s, 1 H), 9.25 (s, 1 H), 8.90 (d, 1 H), 8.62 (s, 1 H), 8.30 (d, 1 H), 7.88 (d, 1 H), 7.59- 7.66 (m, 3 H), 4.54 (d, 2 H), 4.32 (s, 2 H).

Example 51: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-5-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxamide

[00249] To a mixture of 5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3- carboxylic acid (123 mg, 0.4 mmol, 1.0 eq), 6-aminomethyl-isoquinolin-l-ylamine

hydrochloride (85 mg, 0.48 mmol, 1.2 eq), EDCI (92 mg, 0.48 mmol, 1.2 eq) and HOBt (65 mg, 0.48 mmol, 1.2 eq) in DMF (5 mL) was added TEA (121 mg, 1.2 mmol, 3.0 eq) at 5 °C. The mixture was stirred at rt overnight, and then concentrated. The resulting residue was purified by pre-HPLC to give N-((l-aminoisoquinolin-6-yl)methyl)-5-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxamide (10 mg, 5%) as a white solid. LRMS (M+H⁺) m/z calculated 462.1, found 462.1. 1H NMR (DMSO-r/d, 400 MHz) d 9.16 (s, 1 H), 8.90 (d, 1 H), 8.63 (s, 1 H), 8.1 l(d, 1 H), 7.74 (d, 1 H), 7.60-7.66 (m, 2 H), 7.52 (s, 1 H), 7.39 (d, 2 H), 6.83 (d, 1 H), 6.70 (s, 2H), 4.55 (d, 2H), 4.31 (s, 2 H).

Example 52: Preparation of N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxamide

[00250] A mixture of 5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3- carboxylic acid (123 mg, 0.40 mmol, 1.0 eq) and CDI (81 mg, 0.50 mmol, 1.25 eq) in DMF (5 mL) was stirred at 45 °C for 1.5 h, and (3-chloro-4-fluoro-lH-indol-5-yl)methanamine hydrochloride (113 mg, 0.48 mmol, 1.2 eq) was added. The reaction mixture was stirred at 45 °C for additional 2 h, and then concentrated. The resulting residue was purified by pre-HPLC to give N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)- 4H-l,2,4-triazole-3-carboxamide (21 mg, 11%) as a white solid. LRMS (M+H⁺) m/z calculated 487.1, found 487.1. 1H NMR (DMSO- d, 400 MHz) d 14.57 (brs, 1 H), 11.56 (s, 1 H), 9.01

(brs, 1 H), 8.90 (d, 1 H), 8.63(s, 1 H), 7.59-7.65 (m, 2 H), 7.49 (s, 1 H), 7.13-7.18 (m, 2 H), 4.53 (d, 2 H), 4.30 (s, 2 H).

Example 53: Preparation of N-((5-chloro-lH-indazol-3-yl)methyl)-5-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3-carboxamide

[00251] To a solution of 5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H-l,2,4-triazole-3- carboxylic acid (123 mg, 0.4 mmol, 1.0 eq) in DMF (5 mL) was added CDI (81 mg, 0.5 mmol, 1.25 eq). The reaction mixture was stirred at 45 °C for 1.5 h, and (5-chloro-lH-indazol-3- yl)methanamine hydrochloride (105 mg, 0.48 mmol, 1.2 eq) was added. The mixture was stirred at 45 °C for additional 1.5 h, and then concentrated. The resulting residue was purified by pre-HPLC to give N-((5-chloro-lH-indazol-3-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6- yl)methyl)-4H-l,2,4-triazole-3-carboxamide (12 mg, 6%) as a white solid. LRMS (M+H⁺) m/z calculated 470.1, found 470.1. 1H NMR (DMSO- d, 400 MHz) d 14.56 (s, 1 H), 13.02 (t, 1 H), 9.19 (s, 1 H), 8.91 (s, 1 H), 8.61 (d, 1 H), 7.98 (s, 1 H), 7.50-7.64 (m, 3 H), 7.31 (d, 1 H), 4.73 (d, 2 H), 4.29 (d, 2 H).

Example 54: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)-4-(difluoromethyl)oxazole-5-carboxamide

A/-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-

4-(difluoromethyl)oxazole-5-carboxamide

[00252] To a mixture of ethyl 4,4-difluoro-3-oxobutanoate (12.5 g, 75 mmol, 1.0 equiv) and calcium carbonate (9.0 g, 90 mmol, 1.2 equiv) in methanol (250 mL) dropwise in an ice- bath. The resulting mixture was stirred for 3 h at rt and then filtered. The filtrate was concentrated in vacuo to give ethyl 2-bromo-4,4-difluoro-3-oxobutanoate (10.2 g, 55%), which was used directly in next step without further purification.

o

[00253] A mixture of ethyl 2-bromo-4,4-difluoro-3-oxobutanoate (10.2 g, 41.6 mmol,

1.0 equiv) and urea (10.0 g, 166 mmol, 4.0 equiv) in ethanol (100 mL) was heated to reflux overnight, cooled to rt, and concentrated. The resulting residue was diluted with DCM (600 mL), washed with water (200 mL><2), dried, and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 2/1, v/v) to give ethyl 2-amino-4- (difluoromethyl)oxazole-5-carboxylate (5.2 g, 61%).

[00254] A mixture of ethyl 2-amino-4-(difluoromethyl)oxazole-5-carboxylate (5.15 g, 0.025 mol, 1.0 equiv), CuBr₂ (11.2 g, 0.05 mmol, 2.0 equiv) and tert-butyl nitrite (5.16 g, 0.05 mol, 2.0 equiv) in ACN (250 mL) was stirred at 50 °C overnight. Acetonitrile was removed mostly under reduced pressure, the residue was diluted with water/NH₃H₂0 (200 mL/50 mL) and extracted with DCM (300 mL><2). The combined organic layers were washed with brine, dried, concentrated, and purified by chromatography on a silica gel column (PE/EA = 5/1, v/v) to give ethyl 2-bromo-4-(difluoromethyl)oxazole-5-carboxylate (4.1 g, 61%).

[00255] To a suspension of ethyl 2-bromo-4-(difluoromethyl)oxazole-5-carboxylate (1.0 g, 3.7 mmol, 1.0 equiv) and Zn (364 mg, 5.6 mmol, 1.5 equiv) in DMA (30 mL) with stirring at 80 °C were added TMSC1 (catalytic amount) and l,2-dibromoethane (catalytic amount). After addition, the resulting reaction mixture was stirred at 80 °C for 2 h, and cooled to rt. To a solution of 3-chloro-6-(chloromethyl)quinolone (762 mg, 3.7 mmol, 1.0 equiv) and

Pd(PPh₃)₂Cl₂ (252 mg, 0.37 mmol, 0.1 equiv) in DMA (15 mL) was added the above prepared of Zn reagent under nitrogen. The mixture was stirred at 50 °C for 4 h. The resulting reaction mixture was diluted with water (300 mL), and extracted with EA (300 mL x 2). The combined organic layers were washed with brine, dried, and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1, v/v) to give ethyl 2-((3- chloroquinolin-6-yl)methyl)-4-(difluoromethyl)oxazole-5-carboxylate as a yellow solid (174 mg, 13%).

[00256] To a suspension of ethyl 2-((3-chloroquinolin-6-yl)methyl)-4- (difluoromethyl)oxazole-5-carboxylate (171 mg, 0.466 mmol, 1.0 equiv) in THF/H₂0 (9 mL, v/v = 5/4) was added NaOH (37 mg, 0.932 mmol, 2.0 equiv). The mixture was stirred at rt overnight, and concentrated to remove THF. The aqueous layer was extracted with DCM (10 mL) and acidified to pH 2 with 1 N HC1. The resulting precipitate was collected by filtration and dried at 120 °C for 2 h to give 2-((3-chloroquinolin-6-yl)methyl)-4- (difluoromethyl)oxazole-5-carboxylic acid (110 mg, 70%).

[00257] A mixture of 2-((3-chloroquinolin-6-yl)methyl)-4-(difluoromethyl)oxazole-5- carboxylic acid (110 mg, 0.3 mmol, 1.0 equiv), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine hydrochloride (74 mg, 0.33 mmol, 1.1 equiv), HATU (125 mg, 0.33 mmol, 1.1 equiv) and TEA (91 mg, 0.9 mmol, 3 equiv) in DMF (5 mL) was stirred at rt overnight. The mixture was diluted with DCM/MeOH (v/v = 10/1, 200 mL) and washed with sat. NH₄Cl aqueous solution (50 mL><2). The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 50/1 ~ 25/1, v/v) to give N-((6-amino- 2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4- (difluoromethyl)oxazole-5-carboxamide (10 mg, 7%). LRMS (M+H+) m/z calculated 472.1, found 471.9. 1H NMR (DMSO-d6, 400 MHz) d 8.87-8.90 (m, 1H), 8.53 (s, 1H), 8.03-8.05 (m, 1H), 7.91 (s, 1H), 7.78-7.80 (m, 1H), 7.22-7.49 (t, 1H), 6.16 (s, 1H), 5.79 (s, 2H), 4.48 (s, 2H), 4.35 (s, 2H), 2.32 (s, 3H), 2.19 (s, 3H).

Example 55: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-4-((3- chloroquinolin-6-yl)methyl)oxazole-2-carboxamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-4-((3- chloroquinolin-6-yl)methyl)oxazole-2-carboxamide

[00258] A mixture of 2-(3-chloroquinolin-6-yl)acetic acid (3.0 g, 13.53 mmol, 1.0 eq) in SOCl₂ (20 mL) was stirred at rt for 2 h. The mixture was concentrated to afford 2-(3- chloroquinolin-6-yl)acetyl chloride (3.6 g crude) as a purple solid without further purification. To a solution of 2-(3-chloroquinolin-6-yl)acetyl chloride (3.6 g crude, 13.53 mmol, 1.0 eq) in THF (100 mL) was added TMSCHN₂ (14 mL, 27.06 mmol, 2.0 eq) at 0 °C . The mixture was stirred at 0 °C for 2 h. Then HBr (6 mL) was added. The mixture was stirred at 0 °C for 1 h. NaHC0₃ aq was added and extracted with EA (50 mL><3). The organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 6/1, v/v) to afford l-bromo-3-(3-chloroquinolin-6-yl)propan-2-one (1.2 g, 30%) as a yellow solid.

[00259] A mixture of l-bromo-3-(3-chloroquinolin-6-yl)propan-2-one (530 mg, 1.77 mmol, 1.0 eq), 2-(benzyloxy)acetic acid (354 mg, 2.13 mmol, 1.2 eq) and K₂C0₃ (488 mg, 3.54 mmol, 2.0 eq) in DMF (10 mL) was stirred at rt overnight. The mixture was concentrated and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 3/1, v/v) to afford 3-(3-chloroquinolin-6-yl)-2-oxopropyl 2-(benzyloxy)acetate (550 mg, 81%) as a yellow solid.

[00260] A mixture of 3-(3-chloroquinolin-6-yl)-2-oxopropyl 2-(benzyloxy)acetate (550 mg, 1.43 mmol, 1.0 eq) and AcONH₄ (1.5 g, 20.06 mmol, 4.0 eq) in AcOH (20 mL) was stirred at 120 °C for 2 h. The mixture was concentrated, and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 3/1, v/v) to afford 2-((benzyloxy)methyl)-4- ((3-chloroquinolin-6-yl)methyl)oxazole (400 mg, 77%) as a yellow solid.

[00261] To a solution of 2-((benzyloxy)methyl)-4-((3-chloroquinolin-6- yl)methyl)oxazole (400 mg, 1.10 mmol, 1.0 eq) in DCM (20 mL) was added BBr₃ (2.2 mL, 2.20 mmol, 2.0 eq) at -78 °C. The mixture was stirred at -78 °C for 2 h. NH₄CI aq was added and extracted with DCM (30 mL><2). The organic layers were dried over Na₂S0₄, filtered and concentrated. The residue was purified by chromatography on a silica gel column

(DCM/MeOH = 40/1, v/v) to afford (4-((3-chloroquinolin-6-yl)methyl)oxazol-2-yl)methanol (260 mg, 86%).

[00262] To a solution of (4-((3-chloroquinolin-6-yl)methyl)oxazol-2-yl)methanol (200 mg, 0.73 mmol, 1.0 eq) in DCM (10 mL) and MeOH (10 mL) was added Mn0₂ (949 mg, 10.92 mmol, 15.0 eq) at rt. The mixture was stirred at rt for 10 h. The mixture was filtered and the filtrate was concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 3/1, v/v) to afford 4-((3-chloroquinolin-6-yl)methyl)oxazole-2-carbaldehyde (70 mg, 35%) as a white solid.

[00263] To a solution of 4-((3-chloroquinolin-6-yl)methyl)oxazole-2-carbaldehyde (70 mg, 0.26 mmol, 1.0 eq) in THF (2 mL) and t-BuOH (2 mL) were added 3-methylbut-l-ene (29 mg, 0.51 mmol, 2.0 eq) and a solution of NaH₂P0₄ (93 mg, 0.78 mmol, 3.0 eq) and NaCl0₂ (70 mg, 0.78 mmol, 3.0 eq) in H₂0 (2 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was adjusted the pH~6 with 1N HC1. The mixture was concentrated to afford 4-((3- chloroquinolin-6-yl)methyl)oxazole-2-carboxylic acid (70 mg crude) as a white solid which used in next step directly.

[00264] A mixture of 4-((3-chloroquinolin-6-yl)methyl)oxazole-2-carboxylic acid (100 mg crude, 0.37 mmol, 1.0 eq), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine hydrochloride (103 mg, 0.55 mmol, 1.5 eq), ELATU (209 mg, 0.55 mmol, 1.5 eq) and Et₃N (112 mg, 1.11 mmol, 3.0 eq) in DMF (4 mL) was stirred at rt for 1 h. The mixture was concentrated the resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 20/1 to 10/1, v/v) to afford N-((6-amino-2,4-dimethylpyri din-3 -yl)methyl)-4-((3-chloroquinolin-6- yl)methyl)oxazole-2-carboxamide (40 mg, 26%) as a white solid. LRMS (M+H⁺) m/z calculated 422.1, found 422.2.

1H NMR (DMSO-i¾, 400 MHz): d 8.83 (d, 2 H), 8.52 (d, 1 H), 8.12 (s, 1 H), 7.99 (d, 1 H), 7.79 (s, 1 H), 7.70 (dd, 1 H), 6.10 (s, 1 H), 5.73 (brs, 2 H), 4.30 (d, 2 H), 4.10 (s, 2 H), 2.29 (s, 3 H), 2.16 (s, 3H).

Example 56: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)-4-methyloxazole-5-carboxamide

W-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)-4-methyloxazole-5-carboxamide

[00265] A mixture of 2-(3-chloroquinolin-6-yl)acetamide (200 mg, 0.91 mmol, 1.0 eq) and ethyl 2-chloro-3-oxobutanoate (1 mL) was stirred at 150 °C for 5 h and 140 °C for 4 h. The mixture was purified by chromatography on a silica gel column (PE/EA=3/l, v/v) to afford ethyl 2-((3-chloroquinolin-6-yl)methyl)-4-methyloxazole-5-carboxylate (110 mg, 37%) as a white solid.

[00266] To a solution of ethyl 2-((3-chloroquinolin-6-yl)methyl)-4-methyloxazole-5- carboxylate (110 mg, 0.33 mmol, 1.0 eq) in THF (4 mL) was added a solution of NaOH (26 mg, 0.66 mmol, 2.0 eq) in H₂0 (4 mL) at rt. The mixture was stirred at rt for 2 h. The mixture was adjusted to pH 5 with 1 N HC1. The resulting precipitate was collected by filtration to afford 2-((3-chloroquinolin-6-yl)methyl)-4-methyloxazole-5-carboxylic acid (80 mg, 80%).

[00267] A mixture of 2-((3-chloroquinolin-6-yl)methyl)-4-methyloxazole-5-carboxylic acid (80 mg, 0.26 mmol, 1.0 eq), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine hydrochloride (74 mg, 0.40 mmol, 1.5 eq), HATU (152 mg, 0.40 mmol, 1.5 eq) and Et₃N (79 mg, 0.78 mmol, 3.0 eq) in DMF (4 mL) was stirred at rt for 1 h. The mixture was concentrated, and the resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 15/1 to 10/1, v/v) to afford N-((6-amino-2, 4-dimethylpyri din-3 -yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)-4-methyloxazole-5-carboxamide (55 mg, 49%) as a white solid. LRMS (M+H⁺) m/z calculated 436.2, found 436.0. 1H NMR (DMSO-i¾, 400 MHz): d 8.86 (d, 1 H), 8.54 (d, 1 H), 8.20 (s, 1 H), 8.02 (d, 1 H), 7.87 (s, 1 H), 7.76-7.74 (m, 1 H), 6.10 (s, 1 H), 5.65 (brs, 2 H), 4.34 (s, 2 H), 4.28 (d, 2 H), 2.31 (s, 3 H), 2.29 (s, 3 H), 2.16 (s, 3H).

Example 57: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-methyloxazole-5-carboxamide

A/-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- chloro-8-fluoroquinolin-6-yl)methyl)-4-methyloxazole-5-carboxamide

[00268] To a solution of 2-(3-chloro-8-fluoroquinolin-6-yl)acetic acid (1.0 g, 4.17 mmol, 1.0 eq) in DMF (10 mL) was added CDI (1.0 g, 6.25 mmol, 1.5 eq) at rt. The mixture was stirred at 50 °C for 30 min. NH₄Cl (334 mg, 6.25 mmol, 1.5 eq) and Et₃N (631 mg, 6.25 mmol, 1.5 eq) were added. The mixture was stirred at 60 °C for 1 h, and poured into water, then yellow solid was collected by filtration, and dried in vacuo to afford 2-(3-chloro-8- fluoroquinolin-6-yl)acetamide (800 mg, 81%).

[00269] A mixture of 2-(3-chloro-8-fluoroquinolin-6-yl)acetamide (400 mg, 1.68 mmol, 1.0 eq) and ethyl 2-chloro-3-oxobutanoate (4 mL) was stirred at 150 °C for 6 h. The mixture was purified by chromatography on a silica gel column (PE/EA = 3/1, v/v) to afford ethyl 2- ((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-methyloxazole-5-carboxylate (160 mg, 27%) as a yellow solid.

[00270] To a solution of ethyl 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- methyloxazole-5-carboxylate (160 mg, 0.46 mmol, 1.0 eq) in THF (4 mL) was added a solution of NaOH (37 mg, 0.92 mmol, 2.0 eq) in H₂0 (4 mL) at rt. The mixture was stirred at rt overnight. The mixture was adjusted to pH 6 with 1N HC1, and concentrated. The resulting precipitate was collected by filtration to afford 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- methyloxazole-5-carboxylic acid (130 mg, 88%) as a yellow solid.

[00271] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-methyloxazole-5- carboxylic acid (60 mg, 0.19 mmol, 1.0 eq), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine hydrochloride (53 mg, 0.28 mmol, 1.5 eq), HATU (106 mg, 0.28 mmol, 1.5 eq) and Et₃N (57 mg, 0.57 mmol, 3.0 eq) in DMF (4 mL) was stirred at rt for 1 h. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford N-((6-amino-2,4- dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-methyloxazole-5- carboxamide (18 mg, 21%) as a white solid. LRMS (M+H⁺) m/z calculated 454.1, found 454.2. 1H NMR (DMSO-i¾, 400 MHz): d 8.93 (d, 1 H), 8.64 (t, 1 H), 8.25 (t, 1 H), 7.71 (s, 1 H), 7.66 (dd, 1 H), 6.09 (s, 1 H), 5.66 (s, 2 H), 4.34 (s, 2 H), 4.28 (d, 2 H), 2.31 (s, 3 H), 2.29 (s, 3 H), 2.16 (s, 3H).

Example 58: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-(difluoromethyl)oxazole-5-carboxamide

[00272] To a suspension of ethyl 2-bromo-4-(difluoromethyl)oxazole-5-carboxylate (1.0 g, 3.7 mmol, 1.0 eq) and Zn (485 mg, 7.4 mmol, 2.0 eq) in DMA (30 mL) with stirring at 80 °C was added TMSC1 (catalytic amount) and l,2-dibromoethane (catalytic amount). After addition, the resulting reaction mixture was stirred at 80 °C for 2 h, cooled to rt. To a solution of 3-chloro-6-(chloromethyl)-8-fluoroquinoline (851 mg, 3.7 mmol, 1.0 eq) and Pd(PPh₃)₄ (428 mg, 0.37 mmol, 0.1 eq) in DMA (15 mL) was added above prepared of Zn reagent under nitrogen. The mixture was stirred at 50 °C for 4 h, diluted with water (120 mL), and extracted with EA (150 mL><2), The combined organic layers were washed with brine (100 mL><2), dried, concentrated, and purified by chromatography on a silica gel column (PE/EA = 10/1 ~ 5/1, v/v) to give ethyl 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-(difluoromethyl)oxazole-5- carboxylate (186 mg, 13%) as a yellow solid.

[00273] To a suspension of ethyl 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- (difluoromethyl)oxazole-5-carboxylate (186 mg, 0.48 mmol, 1.0 eq) in LHF/ELO (9 mL, v/v = 5/4) was added NaOH (39 mg, 0.96 mmol, 2.0 eq). The mixture was stirred at rt overnight, and concentrated to remove THF. The aqueous layer was washed with DCM and then acidified to pH 2 with 1 N HC1. The resulting precipitate was collected by filtration and dried at 120 °C for 2 h to give 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-(difluoromethyl)oxazole-5-carboxylic acid (170 mg, 100%) as a yellow solid.

[00274] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- (difluoromethyl)oxazole-5-carboxylic acid (85 mg, 0.24 mmol, 1.0 eq), 5-(aminomethyl)-4,6- dimethylpyridin-2-amine hydrochloride (70 mg, 0.31 mmol, 1.3 eq), HATU (137 mg, 0.33 mmol, 1.5 eq) and TEA (73 mg, 0.72 mmol, 3 eq) in DMF (5 mL) was stirred at rt overnight. The mixture was diluted with DCM/MeOH (v/v = 10/1) and washed with sat. NH₄Cl aqueous solution. The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 25/1, v/v) to give N-((6-amino-2,4- dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- (difluoromethyl)oxazole-5-carboxamide (21 mg, 10%) as a white solid. LRMS (M-H+) m/z calculated 490.1, found 489.9. 1H NMR (DMSO-i¾, 400 MHz) d 8.90-8.94 (m, 2H), 8.65-8.66 (m, 1H), 7.69-7.75 (m, 2H), 7.2l-7.47(t, 1H), 6.13 (s, 1H), 5.75 (s, 1H), 4.46 (s, 2H), 4.32-4.34 (m, 2H), 2.33 (s, 3H), 2.18 (s, 3H).

Example 59: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)-4-(difluoromethyl)oxazole-5-carboxamide

[00275] A mixture of 2-((3-chloroquinolin-6-yl)methyl)-4-(difluoromethyl)oxazole-5- carboxylic acid (140 mg, 0.41 mmol, 1.0 equiv), 6-(aminomethyl)isoquinolin-l -amine hydrochloride (92 mg, 0.53 mmol, 1.3 equiv), EDCI (110 mg, 0.57 mmol, 1.4 equiv), HOBt (77 mg, 0.57 mmol, 1.4 equiv) and TEA (211 mg, 1.64 mmol, 4 equiv) in DMF ( 10 mL) was stirred at rt overnight. The mixture was diluted with DCM/MeOH (v/v = 10/1, 200 mL) and washed with sat. NH₄Cl aqueous solution (50 mL><2). The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 40/1 ~ 10/1, v/v) and pre-HPLC to give N-((6-amino-2, 4-dimethylpyri din-3 - yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-(difluoromethyl)oxazole-5-carboxamide (21 mg, 10%) as an off-white solid. LRMS (M-H+) m/z calculated 494.1, found 494.1. 1H NMR (DMSO-i¾, 400 MHz) d 9.52-9.55 (m„ 1H), 8.89 (s, 1H), 8.59 (s, 1H), 8.06-8.15 (m, 2H), 7.94 (s, 1H), 7.76-7.84 (m, 2H), 7.57 (s, 1H), 7.23-7.49 (m, 2H), 6.78-6.86 (m, 3H), 4.52-4.58 (m, 4H).

Example 60: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-(difluoromethyl)oxazole-5-carboxamide

[00276] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- (difluoromethyl)oxazole-5-carboxylic acid (36 mg, 0.10 mmol, 1.0 eq), 6- (aminomethyl)isoquinolin-l -amine hydrochloride (21 mg, 0.12 mmol, 1.2 eq), HATEG (49 mg, 0.13 mmol, 1.3 eq) and TEA (30 mg, 0.30 mmol, 3 eq) in DMF (4 mL) was stirred at rt overnight. The mixture was diluted with DCM/MeOH (v/v = 10/1, 150 mL) and washed with sat. NH₄Cl aqueous solution (50 mL><2). The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 25/1, v/v) and pre-HPLC to give N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-(difluoromethyl)oxazole-5-carboxamide (10 mg, 20%) as a white solid. LRMS (M-H+) m/z calculated 512.1, found 512.1. 1H NMR (DMSO-r/₆, 400 MHz) d 9.49-9.52 (m„ 1H), 8.94 (s, 1H), 8.66 (s, 1H), 8.12-8.15 (d, 1H), 7.72-7.77 (m, 3H), 7.57 (s, 1H), 7.22-7.49 (m, 2H), 6.84-6.86 (m, 1H), 6.73 (s, 2H), 4.52-4.58 (m, 4H).

Example 61: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-methyloxazole-5-carboxamide

[00277] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-methyloxazole-5- carboxylic acid (70 mg, 0.22 mmol, 1.0 eq), 6-(aminomethyl)isoquinolin-l -amine (57 mg, 0.33 mmol, 1.5 eq), HATU (125 mg, 0.33 mmol, 1.5 eq) and Et₃N (67 mg, 0.66 mmol, 3.0 eq) in DMF (4 mL) was stirred at rt for 1 h. The mixture was concentrated, and the reasulting residue was purified by prep-HPLC to afford N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-methyloxazole-5-carboxamide (17 mg, 16%) as a white solid. LRMS (M+H⁺) m/z calculated 476.1, found 475.9. 1H NMR (DMSO-r/₆, 400 MHz): d 8.98 (t, 1

H), 8.94 (d, 1 H), 8.66 (t, 1 H), 8.12 (d, 1 H), 7.76-7.69 (m, 3 H), 7.53 (s, 1 H), 7.39 (dd, 1 H), 6.84 (d, 1 H), 6.74 (s, 2 H), 4.52 (d, 2 H), 4.40 (s, 2 H), 2.34 (s, 3H).

Example 62: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)-4-methyloxazole-5-carboxamide

[00278] A mixture of 2-((3-chloroquinolin-6-yl)methyl)-4-methyloxazole-5-carboxylic acid (70 mg, 0.23 mmol, 1.0 eq), 6-(aminomethyl)isoquinolin-l -amine (60 mg, 0.35 mmol, 1.5 eq), HATEG (133 mg, 0.35 mmol, 1.5 eq) and Et₃N (70 mg, 0.69 mmol, 3.0 eq) in DMF (4 mL) was stirred at rt for 1 h. The mixture was concentrated, and the residue was purified by prep- HPLC to afford N-((6-amino-2, 4-dimethylpyri din-3 -yl)methyl)-2-((3 -chl oroquinolin-6- yl)methyl)-4-methyloxazole-5-carboxamide (18 mg, 17%) as a white solid. LRMS (M+H⁺) m/z calculated 458.1, found 457.9. 1H NMR (DMSO-i¾, 400 MHz): d 8.93 (t, 1 H), 8.87 (d, 1 H), 8.56 (d, 1 H), 8.12 (d, 1 H), 8.04 (d, 1 H), 7.89 (d, 1 H), 7.80-7.75 (m, 2 H), 7.53 (s, 1 H), 7.39- 7.37 (m, 1 H), 6.84 (d, 1 H), 6.69 (s, 2 H), 4.52 (d, 2 H), 4.39 (s, 2 H), 2.34 (s, 3H).

Example 63: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5-carboxamide

[00279] A mixture of ethyl 2-chloro-3-oxobutanoate (200 g, 1.22 mol, 1.0 equiv) and urea (293 g, 4.88 mol, 4 equiv) in EtOH (1800 mL) was stirred at reflux for 40 h. EtOH was removed by evaporation, the residue was filtered, washed with water, and dried at 110 °C for 3 h to give ethyl 2-amino-4-methyloxazole-5-carboxylate (121 g, 58%) as a white solid.

[00280] To a suspension of CuCl₂ (105 g, 0.78 mol, 1.3 equiv) and tert-butyl nitrite (67 g, 0.66 mol, 1.1 equiv) in ACN (2400 mL) was added ethyl 2-amino-4-methyloxazole-5- carboxylate (102 g, 0.60 mol, 1.0 equiv) below 10 °C and the reaction mixture was stirred at rt overnight. The resulting mixture was quenched with 1N HC1 to pH 2, and ACN was removed under reduced pressure, the residue was diluted with EA (2500 mL), washed with water (1000 mL><2), dried, and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 10/1, v/v) to give ethyl 2-chloro-4-methyloxazole-5-carboxylate (50.0 g, 44%) as a colerless oil.

[00281] A mixture of ethyl 2-chloro-4-methyloxazole-5-carboxylate (50.0 g, 0.264 mol, 1.0 equiv), NBS (51.7 g, 0.290 mol, 1.1 equiv) and AIBN (8.7 g, 0.053 mol, 0.2 equiv) in CCl₄ (750 mL) was stirred at reflux for 40 h. The reaction mixture was quenched with water, separated, and extracted with DCM (500 mL). The combined organic layers were washed with brine, dried, and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 100/1-10/1, v/v) to give ethyl 4-(bromomethyl)-2-chlorooxazole-5- carboxylate as a colerless oil (46.5 g, 66%).

[00282] To a suspension of 4-nitrobenzoic acid (26.4 g, 0.158 mol, 1.05 equiv) in DMF (500 mL) cooled to 0 °C was added NaH (7.0 g, 0.18 mol, 1.2 eq). The reaction mixture was stirred for 1 h. Then 4-(bromomethyl)-2-chlorooxazole-5-carboxylate (40.3 g, 0.15 mol, 1.0 equiv) in DMF (100 mL) was added and the resulting mixture was stirred at rt for 4 h. The reaction mixture was quenched with water (1000 mL), and extracted with EA (800 mL><2). The combined organic layers were washed with water (500 mL><2), dried, and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 30/1-5/1, v/v) to give ethyl 2-chloro-4-(((4-nitrobenzoyl)oxy)methyl)oxazole-5-carboxylate (26.0 g, 49%) as a white solid.

[00283] To a solution of methyl 2-(3-chloro-8-fluoroquinolin-6-yl)acetate (10.4 g, 0.041 mol, 1.00 equiv) in dry DMF (100 mL) cooled to 0 °C was added NaH (7.0 g, 0.18 mol, 1.2 eq) and the reaction mixture was stirred for 5 min at this temperature. Then ethyl 2-chloro-4-(((4- nitrobenzoyl)oxy)methyl)oxazole-5-carboxylate (14.5 g, 0.041 mol, 1.0 equiv) in dry DMF (50 mL) was added and stirred at 0 °C for 2 h. The resulting reaction mixture was quenched with water (500 mL), extracted with EA (800 mL><2). The combined organics was washed with brine (400 mL><2), dried, concentrated, and the resulting residue was purified by

chromatography on a silica gel column eluted with PE/EA (20/1-3/1) to give ethyl 2-(l-(3- chloro-8-fluoroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4-(((4-nitrobenzoyl)oxy)methyl)oxazole- 5-carboxylate

[00284] To a solution of ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy-2- oxoethyl)-4-(((4-nitrobenzoyl)oxy)methyl)oxazole-5-carboxylate (17.6 g, 30.8 mmol, 1.00 equiv) in ethanol (1000 mL) cooled to 0 °C was added LiOH.H₂0 (1.29 g, 30.8 mmol, 1.0 eq) and the reaction mixture was stirred for 2 h at this temperature. The resulting reaction mixture was adjusted to pH 6-7 with 1 N HC1 and purified directly by chromatography on a silica gel column eluted with PE/EA (5/1— 2/3) to give ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2- methoxy-2-oxoethyl)-4-(hydroxymethyl)oxazole-5-carboxylate (11.1 g, 85%).

[00285] To a solution of ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy-2- oxoethyl)-4-(hydroxymethyl)oxazole-5-carboxylate (5.5 g, 13 mmol, 1.0 equiv) in dry DCM (150 mL) cooled to 0 °C was added DAST (4.2 g, 26 mmol, 2.0 eq). The reaction mixture was stirred for 2 h, quenched with sat aq Na₂CO, and extracted with DCM. The organic layer was concentrated and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 10/1-5/1, v/v) to give ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy-2- oxoethyl)-4-(fluoromethyl)oxazole-5-carboxylate (2.02 g, 37%).

[00286] To a stirred solution of ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy- 2-oxoethyl)-4-(fluoromethyl)oxazole-5-carboxylate (2.2 g, 5.2 mmol, 1.0 equiv) in a 2/1 mixture of methnaol/H₂0 (150 mL/75 mL) was added LiOH.H₂0 (1.09 g, 26 mmol, 5.0 eq). The resulting mixture was stirred at rt for 22 h, and adjusted to pH 6-7 with 1N HC1. Most MeOH was removed by evaporation. The aqueous layer was acidified to pH 2 with 1 N HC1. The resulting precipitate was collected by filtration and dried at 110 °C for 3 h to give 2-((3- chloro-8-fluoroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5-carboxylic acid (1.60 g, 91%) as a yellow solid.

[00287] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- (fluoromethyl)oxazole-5-carboxylic acid (1.25 g, 3.7 mmol, 1.0 eq), tert-butyl (5- (aminomethyl)-4,6-dimethylpyridin-2-yl)carbamate (1.11 g, 4.4 mmol, 1.2 eq), E1ATU (1.82 g, 4.8 mmol, 1.3 eq) and TEA (1.12 g, 11.1 mmol, 3 eq) in DMF (40 mL) was stirred at rt overnight. The mixture was diluted with DCM (250 mL) and washed with sat. NH₄Cl aqueous solution (150 mL><2). The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1-2/1, v/v) to give tert-butyl (5- ((2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5-carboxamido)methyl)- 4,6-dimethylpyridin-2-yl)carbamate (1.2 g, 57%) as a white solid.

[00288] To a stirred solution of tert-butyl (5-((2-((3-chloro-8-fluoroquinolin-6- yl)methyl)-4-(fluoromethyl)oxazole-5-carboxamido)methyl)-4,6-dimethylpyridin-2- yl)carbamate (2.3 g, 4.02 mmol, 1.0 equiv) in DCM (100 mL) was added TFA (50 mL). The resulting mixture was stirred at rt overnight. The solvent was removed and the resulting residue was adjusted to pH 10 with sat aq Na₂CO,.The resulting precipitate was collected by filtration and further purified by chromatography on a silica gel column (DCM/MeOH = 40/1-20/1, v/v) to give N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6- yl)methyl)-4-(fluoromethyl)oxazole-5-carboxamide (1.22 g, 64%) as a white solid. LRMS (M- H+) m/z calculated 472.1, found 471.9. 1H NMR (DMSO-i¾, 400 MHz) d 8.93-8.94 (m, 1H), 8.645-8.66 (m, 2H), 7.74 (s, 1H), 7.68-7.7l(d, 1H), 6.14 (s, 1H), 5.80 (s, 2H), 5.47-5.59 (d,

2H), 4.43 (s, 2H), 4.31-4.32 (d, 2H), 2.31 (s, 3H), 2.18 (s, 3H).

Example 64: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5-carboxamide

[00289] A mixture of 2-((3-chloroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5- carboxylic acid (102 mg, 0.30 mmol, 1.0 eq), 6-(aminomethyl)isoquinolin-l -amine

hydrochloride (62 mg, 0.36 mmol, 1.2 eq), HATU (148 mg, 0.39 mmol, 1.3 eq) and TEA (91 mg, 0.9 mmol, 3 eq) in DMF (6 mL) was stirred at rt overnight. The mixture was diluted with DCM (300 mL) and washed with sat. NH₄Cl aqueous solution (50 mL><2). The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 15/1, v/v) to give N-((l-aminoisoquinolin-6-yl)methyl)-2-((3- chloro-8-fluoroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5-carboxamide (20 mg, 14%). LRMS (M-H+) m/z calculated 494.1, found 493.9. 1H NMR (DMSO-i¾, 400 MHz) d 9.29-9.32 (m„ 1H), 8.94 (s, 1H), 8.66 (s, 1H), 8.12-8.15 (d, 1H), 7.71-7.77 (m, 3H), 7.56 (s, 1H), 7.39- 7.41 (m, 1H), 6.85-6.86 (m, 1H), 6.76 (s, 2H), 5.50-5.62 (d, 2H), 4.56-4.57 (m, 2H), 4.48 (s, 2H).

Example 65: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5-carboxamide

[00290] To a stirred solution of methyl 2-(3-chloroquinolin-6-yl)acetate (7.8 g, 0.033 mol, 1.0 equiv) in dry DMF (100 mL) cooled to 0 °C was added NaH (2.6 g, 0.066 mol, 2.0 eq) and the reaction mixture was stirred for 5 min at this temperature. Then ethyl 2-chloro-4-(((4- nitrobenzoyl)oxy)methyl)oxazole-5-carboxylate (11.7 g, 0.033 mol, 1.0 equiv) in dry DMF (50 mL) was added. The reaction mixtue was stirred at 0 °C for 2 h, quenched with water (500 mL), and extracted with EA (800 mL><2). The combined organic layers were washed with brine (400 mLx2), dried, and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 20/1-4/1, v/v) to give ethyl 2-(l-(3-chloroquinolin-6-yl)-2- methoxy-2-oxoethyl)-4-(((4-nitrobenzoyl)oxy)methyl)oxazole-5-carboxylate (14.1 g, 77%).

[00291] To a solution of ethyl 2-(l-(3-chloroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4- (((4-nitrobenzoyl)oxy)methyl)oxazole-5-carboxylate (14.1 g, 25.5 mmol, 1.0 equiv) in ethanol (500 mL) cooled to 0 °C was added LiOH.H₂0 (1.07 g, 25.5 mmol, 1.0 eq) and the mixture was stirred for 2 h at this temperature. The reaction mixture was adjusted to pH 6~7 with 1N HC1 and purified directly by chromatography on a silica gel column (PE/EA = 2/1, v/v) to give ethyl 2-(l-(3-chloroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4-(hydroxymethyl)oxazole-5-carboxylate (8.8 g, 85%).

[00292] To a stirred solution of ethyl 2-(l-(3-chloroquinolin-6-yl)-2-methoxy-2- oxoethyl)-4-(hydroxymethyl)oxazole-5-carboxylate (2.0 g, 5 mmol, 1.0 equiv) in dry DCM (120 mL) cooled to 0 °C was added DAST (1.61 g, 10 mmol, 2.0 eq) and the mixture was stirred for 2 h at this temperature. The reaction mixture was quenched with sat aq NaHC0₃, and separated, the DCM layer was concentrated, and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 10/1-5/1, v/v) to give ethyl 2-(l-(3- chloroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4-(fluoromethyl)oxazole-5-carboxylate (1.25 g, 62%).

[00293] To a stirred solution of ethyl 2-(l-(3-chloroquinolin-6-yl)-2-methoxy-2- oxoethyl)-4-(fluoromethyl)oxazole-5-carboxylate (3.45 g, 8.5 mmol, 1.0 equiv) in a 2/1 mixture of methanol/H₂0 (300 mL/l50 mL) was added LiOH.H₂0 (1.79 g, 42.5 mmol, 5.0 eq). The reaction mixture was stirred at rt for 18 h and adjusted to pH 6~7 with 1N HC1. After concentration, the aqueous layer was acidified to pH 2 with 1 N HC1. The resulting precipitate was collected by filtration and dried at 120 °C for 3 h to give 2-((3-chloroquinolin-6- yl)methyl)-4-(fluoromethyl)oxazole-5-carboxylic acid (2.40 g, 88%).

c

[00294] A mixture of 2-((3-chloroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5- carboxylic acid (2.20 g, 6.9 mmol, 1.0 eq), tert-butyl (5-(aminomethyl)-4,6-dimethylpyridin-2- yl)carbamate (2.16 g, 8.6 mmol, 1.25 eq), HATU (3.53 g, 9.4 mmol, 1.35 eq) and TEA (2.09 g, 20.6 mmol, 3 eq) in DMF (50 mL) was stirred at rt overnight. The mixture was diluted with DCM/MeOH (20/1) (500 mL) and washed with water (200 mL) sat. NH₄Cl aqueous solution (200 mL x 2). The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1-2/1, v/v) to give tert-butyl (5-((2-((3- chloroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5-carboxamido)methyl)-4,6- dimethylpyridin-2-yl)carbamate (2.6 g, 68%).

[00295] To a stirred solution of tert-butyl (5-((2-((3-chloroquinolin-6-yl)methyl)-4- (fluoromethyl)oxazole-5-carboxamido)methyl)-4,6-dimethylpyridin-2-yl)carbamate (2.6 g, 4.7 mmol, 1.0 equiv) in DCM (100 mL) was added CF₃COOH (50 mL) and this reaction mixture was stirred at rt overnight. After concentration, the mixture was adjusted to pH 9-10 with sat aq Na₂C0₃, and filtered. The resulting precipitate was purified by chromatography on a silica gel column (DCM/MeOH = 30/1-20/1, v/v) to give N-((6-amino-2,4-dimethylpyridin-3- yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5-carboxamide (1.39 g, 66%). LRMS (M-H+) m/z calculated 453.1, found 453.9. 1H NMR (DMSO-i¾, 400 MHz) d 8.87-8.88 (m, 1H), 8.64-8.67 (m, 1H), 8.55-8.56 (m, 1H), 8.03-8.05 (d, 1H), 7.90 (s, 1H), 7.76- 7.79 (m, 1H), 6.10 (s, 1H), 5.69 (s, 2H), 5.47-5.59 (d, 2H), 4.42 (s, 2H), 4.31-4.32 (d, 2H), 2.33 (s, 3H), 2.18 (s, 3H).

Example 66: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-4-((3-chloro-8- fluoroquinolin-6-yl)methyl)oxazole-2-carboxamide

A/-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-4-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-2- carboxamide

[00296] To a solution of methyl 3-chloro-8-fluoroquinoline-6-carboxylate (18 g, 70.94 mmol, 1.0 eq) in THF (200 mL) was added LiHMDS (85 mL, 85.13 mmol, 1.2 eq) dropwise at 0°C, under N₂ atmosphere. The mixture was stirred at 0 °C for 1 h. Then, 2-(benzyloxy)acetyl chloride (18.2 g, 99.3 mmol) in THF (150 mL) was added dropwise. The mixture was stirred at rt overnight. The mixture was quenched with aq.NH₄Cl and extracted with EA. The combined organic layers were dried, concentrated and the resulting residue was purified by

chromatography on a silica gel column (PE/EA = 10/1, v/v) to give methyl 4-(benzyloxy)-2-(3- chloro-8-fluoroquinolin-6-yl)-3-oxobutanoate (18 g, 64%).

[00297] To a solution of methyl 4-(benzyloxy)-2-(3-chloro-8-fluoroquinolin-6-yl)-3- oxobutanoate (18 g, 44.9 mol, 1.0 eq) in THF (180 mL) was added HC1 (6 M, 90 mL). The mixture was stirred at 72 °C overnight. The reaction mixture was adjusted to pH 7~8 with K₂C0₃ and extracted with EA. The combined organic layers were dried, concentrated and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1, v/v) to give 1 -(benzyl oxy)-3 -(3 -chloro-8-fluoroquinolin-6-yl)propan-2-one (9 g, 60%).

[00298] To a solution of 1 -(benzyl oxy)-3 -(3 -chloro-8-fluoroquinolin-6-yl)propan-2-on (9 g, 26 mmol, 1.0 eq) in DCM (90 mL) was added BBr₃ (1M in DCM) (80 mL, 80 mmol, 3 eq) at -78 °C. The mixture was stirred at -78 °C for 1 h. Water was added and the reaction mixture was adjusted to pH 7~8 with NaHC0₃ and extracted with DCM (200 mL ^c 2). The organic layers were dried and concentrated in vacuo to give a crude product, which was triturated in DCM to give l-(3-chloro-8-fluoroquinolin-6-yl)-3-hydroxypropan-2-one (5.1 g, 77%).

[00299] A mixture of 2-(benzyloxy)acetic acid (9.19 g, 55.3 mmol, 1.2 eq), HATU (21 g, 55.3 mmol, 1.2 eq) and DIEA (11.9 g, 92.2 mmol, 2.0 eq) in DMF (300 mL) was stirred at 0 °C for 30 min. Then l-(3-chloro-8-fluoroquinolin-6-yl)-3-hydroxypropan-2-one (11.7 g, 46.1 mmol, 1.0 eq) was added. The mixture was stirred at rt overnight. The reaction mixture was added into water dropwise and the resulting solid was collected to afford 3-(3-chloro-8- fluoroquinolin-6-yl)-2-oxopropyl 2-(benzyloxy)acetate (17 g, 90 %).

OBn

[00300] A mixture of 3-(3-chloro-8-fluoroquinolin-6-yl)-2-oxopropyl 2- (benzyloxy)acetate (15 g, 37.4 mmol, 1.0 eq) and AcONH₄ (40.3 g, 523 mmol, 14.0 eq) in AcOH (500 mL) was stirred at 120 °C for 4 h. After concentration in vacuo, the resulting mixture was purified by chromatography on a silica gel column (PE/EA = 3/1, v/v) to give 2- ((benzyloxy)methyl)-4-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole (8 g, 47 %).

[00301] To a solution of 2-((benzyloxy)methyl)-4-((3-chloro-8-fluoroquinolin-6- yl)methyl)oxazole (8 g, 20.9 mmol, 1.0 eq) in DCM (80 mL) was added BBr₃ (1M in DCM) (63 mL, 63 mmol, 3 eq) at -78 °C. The mixture was stirred at -78 °C for 1 h. Water was added and the reaction mixture was adjusted to pH 7~8 with NaHCO, and extracted with DCM (200 mL x 2). The organic layers were concentrated, and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 3/1, v/v) to give (4-((3-chloro-8- fluoroquinolin-6-yl)methyl)oxazol-2-yl)methanol (4.3 g, 71%).

[00302] To a solution of (4-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazol-2- yl)methanol (3.3 g, 11.3 mmol, 1.0 eq) in DCM/MeOH (100 mL / 100 mL) was added Mn0₂ (14.7 g, 169.5 mmol, 5 eq). The mixture was stirred at rt for 8 h. After filtration, the filtrate was concentrated in vacuo. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 3/1, v/v) to give 4-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-2- carbaldehyde (2.1 g, 50%).

[00303] To a solution of 4-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-2- carbaldehyde (2.1 g, 7.24 mmol, 1.0 eq) in THF (60 mL) and t-BuOH (60 mL) were added 3- methylbut-l-ene (l.0l g, 14.48 mmol, 2.0 eq) and a solution ofNaO0₂ (2.43 g, 21.72 mmol, 3.0 eq) and NaH₂P0₄ (1.96 g, 21.72 mmol, 3.0 eq) in H₂0 (60 mL) at rt. The mixture was stirred at 0 °C for 1 h. Then the mixture was adjusted to pH 6 with 1N HC1 and extracted with EA. The organic layer was concentrated to give 4-((3-chloro-8-fluoroquinolin-6- yl)methyl)oxazole-2-carboxylic acid (1.7 g, 77 %).

[00304] A mixture of 4-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-2-carboxylic acid (1.5 g, 4.9 mmol, 1.0 eq), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine HC1 salt (920 mg, 4.9 mmol, 1.0 eq), HATU (2.23 g, 5.88 mmol, 1.2 eq), and DIEA (1.89 g, 14.7 mmol, 3.0 eq) in DMF (50 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 40/1, v/v) to give N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-4-((3-chloro-8-fluoroquinolin-6- yl)methyl)oxazole-2-carboxamide (1.26 g, 60%). LCMS (M+H⁺)m/z calculated 440.1, found 439.9. 1H NMR (DMSO-i¾, 400 MHz): 5 8.88-8.89 (d, 1H), 8.81-8.82 (m, 1H), 8.59-8.60 (m, 1H), 8.13 (s, 1H), 7.64 (s, 1H), 7.56-7.59 (m, 1H), 6.09 (s, 1H), 5.65 (s, 2H), 4.30-4. 31 (d, 2H), 4.10 (s, 2H), 2.28 (s, 3H), 2.16 (s, 3H).

Example 67: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)-4-(fluoromethyl)oxazole-5-carboxamide

[00305] A mixture of 2-((3-chloroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5- carboxylic acid (180 mg, 0.56 mmol, 1.0 eq), 6-(aminomethyl)isoquinolin-l -amine

hydrochloride (127 mg, 0.73 mmol, 1.3 eq), HATU (298 mg, 0.78 mmol, 1.4 eq) and TEA (170 mg, 1.68 mmol, 3 eq) in DMF (10 mL) was stirred at rt overnight. The mixture was diluted with DCM (250 mL) and washed with sat. NH₄Cl aqueous solution (50 mL x 2). The combined organic layers were dried and concentrated. The resulting residue was purified by

chromatography on a silica gel column (DCM/MeOH = 25/1, v/v) and pre-HPLC to give N-((l- aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-(fluoromethyl)oxazole-5- carboxamide (21 mg, 8%). LRMS (M-H⁺) m/z calculated 476.1, found 475.9. 1H NMR

(DMSO-i¾, 400 MHz) d 9.27-9.30 (m„ 1H), 8.88 (s, 1H), 8.56 (s, 1H), 8.04-8.14 (dd, 2H), 7.93 (s, 1H), 7.75-7.83 (m, 2H), 7.55 (s, 1H), 7.38-7.41 (m, 1H), 6.85 (d, 1H), 6.71 (s, 2H), 5.60 (d, 2H), 5.55-5.56 (m, 2H), 4.48 (s, 2H).

Example 68: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-4-((3-chloro-8- fluoroquinolin-6-yl)methyl)oxazole-2-carboxamide

[00306] A mixture of 4-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-2-carboxylic acid (100 mg, 0.33 mmol, 1.0 eq), 6-(aminomethyl)isoquinolin-l -amine (56 mg, 0.33 mmol,

1.0 eq), HATU (140 mg, 0.36 mmol, 1.2 eq), and DIEA (130 mg, 1 mmol, 3.0 eq) in DMF (5 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by pre-HPLC to give N-((l-aminoisoquinolin-6-yl)methyl)-4-((3-chloro-8- fluoroquinolin-6-yl)methyl)oxazole-2-carboxamide (11 mg, 6%). LRMS (M+H⁺) m/z calculated 462.1, found 461.9. 1H NMR (DMSO-i¾, 400 MHz): d 9.49-9.50 (m, 1H), 8.89-8.90 (d, 1H), 8.61-8.62 (m, 1H), 8.19 (s, 1H), 8.10-8.12 (d, 1H), 7.74-7.76 (d, 1H), 7.66 (s, 1H), 7.59-7.63 (m, 1H), 7.53 (s, 1H), 7.37-7.39 (m, 1H), 6.83-6.85 (d, 1H), 6.70 (s, 2H), 4.52- 4.54(d, 2H), 4.14 (s,2H).

Example 69: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-(hydroxymethyl)oxazole-5-carboxamide

[00307] To a stirred solution of ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy- 2-oxoethyl)-4-(hydroxymethyl)oxazole-5-carboxylate (5.45 g, 12.9 mmol, 1.0 equiv) in a 2/1 mixture of methnaol/EEO (300 mL/l50 mL) was added LiOEl.EEO (2.71 g, 64.5 mmol, 5.0 eq) and the mixture was stirred at rt for 22 h. The reaction mixture was adjusted to pH 6~7 with 1N HC1. The resulting precipitate was collected by filtration and dried at 110 °C for 3 h to give 2- ((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-(hydroxymethyl)oxazole-5-carboxylic acid (4.0 g,

93%).

[00308] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- (hydroxymethyl)oxazole-5-carboxylic acid (2.50 g, 7.4 mmol, 1.0 eq), tert-butyl (5- (aminomethyl)-4,6-dimethylpyridin-2-yl)carbamate (2.24 g, 8.9 mmol, 1.2 eq), HATU (3.65 g, 9.6 mmol, 1.3 eq) and TEA (2.25 g, 22.2 mmol, 3 eq) in DMF (50 mL) was stirred at rt overnight. The mixture was diluted with DCM (300 mL) and washed with sat. NH₄Cl aqueous solution (150 mL ^c 2). The organic layer was dried and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1-1/1, v/v) to give tert-butyl (5- ((2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-(hydroxymethyl)oxazole-5- carboxamido)methyl)-4,6-dimethylpyridin-2-yl)carbamate (2.37 g, 56%).

[00309] To a stirred solution of tert-butyl (5-((2-((3-chloro-8-fluoroquinolin-6- yl)methyl)-4-(hydroxymethyl)oxazole-5-carboxamido)methyl)-4,6-dimethylpyri din-2- yl)carbamate (2.37 g, 4.16 mmol, 1.0 equiv) in DCM (150 mL) was added TFA (50 mL) and the mixture was stirred at rt overnight. The reaction mixture was concentrated and the resulting residue was adjusted to pH 9-10 with sat aq Na₂C0_3. The resulting solid was collected by flitration and purified by chromatography on a silica gel column (DCM/MeOH = 30/1-15/1, v/v) to give N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6- yl)methyl)-4-(hydroxymethyl)oxazole-5-carboxamide (1.0 g, 51%). LRMS (M+H⁺) m/z calculated 470.1, found 469.9. 1H NMR (DMSO-i¾, 400 MHz) d 8.92-8.93 (m, 1H), 8.60-8.64 (m, 2H), 7.73 (S, 1H), 7.64-7.67(d, 1H), 6.11 (s, 1H), 5.65-5.69 (m, 3H), 4.56-4.57 (m, 2H), 4.39 (s, 2H), 4.31-4.32 (m,2H), 2.30 (s, 3H), 2.17 (s, 3H).

Example 70: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)-4-(hydroxymethyl)oxazole-5-carboxamide

[00310] To a solution of methyl 2-(3-chloroquinolin-6-yl)acetate (700 mg, 2.97 mmol, 1.0 eq) in DMF (20 mL) was added NaH (178 mg, 4.45 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then ethyl 2-chloro-4-(((4-nitrobenzoyl)oxy)methyl)oxazole-5- carboxylate (950 mg, 2.67 mmol, 0.9 eq) was added. The mixture was stirred at 0 °C for 2 h. Water (20 mL) was added and the reaction mixture was extracted with EA (50 mL ^c 2). The organic layers were dried over Na₂S0₄, filtered and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 6/1, v/v) to afford ethyl 2-(l-(3- chloroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4-(((4-nitrobenzoyl)oxy)methyl)oxazole-5- carboxylate (930 mg, 62%).

[00311] To a solution of ethyl 2-(l-(3-chloroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4- (((4-nitrobenzoyl)oxy)methyl)oxazole-5-carboxylate (930 mg, 1.68 mmol, 1.0 eq) in THF (20 mL) was added a solution of NaOH (269 mg, 6.72 mmol, 4.0 eq) in H₂0 (20 mL) at rt. The mixture was stirred at rt for 4 h. After concentration in vacuo, the aqueous phase was neutralized with 1 N HC1 to pH 5. The resulting precipitate was collected and dried to afford 2- ((3-chloroquinolin-6-yl)methyl)-4-(((4-nitrobenzoyl)oxy)methyl)oxazole-5-carboxylic acid (700 mg, 89%).

[00312] A mixture of 2-((3-chloroquinolin-6-yl)methyl)-4-(((4- nitrobenzoyl)oxy)methyl)oxazole-5-carboxylic acid (100 mg, 0.21 mmol, 1.0 eq), 5- (aminomethyl)-4,6-dimethylpyridin-2-amine hydrochloride (60 mg, 0.32 mmol, 1.5 eq), HATU (122 mg, 0.32 mmol, 1.5 eq) and Et₃N (64 mg, 0.63 mmol, 3.0 eq) in DMF (4 mL) was stirred at rt for 1 h. The mixture was concentrated and the resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 10/1, v/v) to afford (5-(((6-amino-2,4- dimethylpyridin-3-yl)methyl)carbamoyl)-2-((3-chloroquinolin-6-yl)methyl)oxazol-4-yl)methyl 4-nitrobenzoate (60 mg, 48%).

[00313] To a solution of (5-(((6-amino-2,4-dimethylpyridin-3-yl)methyl)carbamoyl)-2- ((3-chloroquinolin-6-yl)methyl)oxazol-4-yl)methyl 4-nitrobenzoate (60 mg, 0.1 mmol, 1.0 eq) in MeOH (6 mL) was added LiOH H₂0 (10 mg, 0.20 mmol, 2.0 eq) at rt. The mixture was stirred at rt for 1 h. The mixture was concentrated and the resulting residue was purified by prep-HPLC to afford N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)-4-(hydroxymethyl)oxazole-5-carboxamide (40 mg, 87%). LRMS (M+H⁺) m/z calculated 452.1, found 452.1. 1H NMR (DMSO-i¾, 400 MHz): d 8.87 (d, 1 H), 8.61 (t, 1 H),

8.54 (d, 1 H), 8.03 (d, 1 H), 7.88 (d, 1 H), 7.76-7.74 (m, 1 H), 6.13 (s, 1 H), 5.76 (brs, 2 H), 5.66 (t, 1 H), 4.55 (d, 2 H), 4.38 (s, 2 H), 4.30 (d, 2 H), 2.30 (s, 3H), 2.18 (s, 3H).

Example 71: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)-4-(hydroxymethyl)oxazole-5-carboxamide

[00314] A mixture of 2-((3-chloroquinolin-6-yl)methyl)-4-(((4- nitrobenzoyl)oxy)methyl)oxazole-5-carboxylic acid (150 mg, 0.32 mmol, 1.0 eq), 6- (aminomethyl)isoquinolin-l -amine (83 mg, 0.48 mmol, 1.5 eq), HATU (182 mg, 0.48 mmol, 1.5 eq) and Et₃N (97 mg, 0.96 mmol, 3.0 eq) in DMF (6 mL) was stirred at rt for 1 h. The mixture was concentrated, and the resulting residue was purified by chromatography on a silica gel column (DCM/MeOH = 10/1, v/v) to afford (5-(((l-aminoisoquinolin-6- yl)methyl)carbamoyl)-2-((3-chloroquinolin-6-yl)methyl)oxazol-4-yl)m ethyl 4-nitrobenzoate (80 mg, 40%).

[00315] To a solution of (5-(((l-aminoisoquinolin-6-yl)methyl)carbamoyl)-2-((3- chloroquinolin-6-yl)methyl)oxazol-4-yl)methyl 4-nitrobenzoate (80 mg, 0.13 mmol, 1.0 eq) in MeOH (10 mL) was added Li0H ¾0 (11 mg, 0.26 mmol, 2.0 eq) at rt. The mixture was stirred at rt for 1 h. The mixture was concentrated and the resulting residue was purified by prep-HPLC to afford N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)- 4-(hydroxymethyl)oxazole-5-carboxamide (18 mg, 29%). LRMS (M+H⁺) m/z calculated 474.1, found 474.1. 1H NMR (DMSO-i¾, 400 MHz): d 9.25 (t, 1 H), 8.88 (d, 1 H), 8.57 (s, 1 H), 8.37 (d, 1 H), 8.16 (brs, 2 H), 8.05 (d, 1 H), 7.92 (s, 1 H), 7.80 (d, 1 H), 7.72-7.68 (m, 2 H), 7.60 (d,

1 H), 7.10 (d, 1 H), 5.46 (t, 1 H), 4.60 (d, 4 H), 4.44 (s, 2H).

Example 72: Preparation of N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-(hydroxymethyl)oxazole-5-carboxamide

[00316] To a solution of ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy-2- oxoethyl)-4-(hydroxymethyl)oxazole-5-carboxylate (300 mg, 0.71 mmol, 1.0 eq) in THF (15 mL) was added a solution of NaOH (142 mg, 3.55 mmol, 5.0 eq) in H₂0 (10 mL) at rt. The mixture was stirred at rt for 6 h. Then it was neutralized with 1N HC1 to pH 6. After concentration in vacuo, the resulting solid was collected and dried to afford 2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-(hydroxymethyl)oxazole-5-carboxylic acid (260 mg, crude).

[00317] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- (hydroxymethyl)oxazole-5-carboxylic acid (260 mg crude, 0.77 mmol, 1.0 eq), 6- (aminomethyl)isoquinolin-l -amine (200 mg, 1.16 mmol, 1.5 eq), HATU (441 mg, 1.16 mmol,

1.5 eq) and Et₃N (233 mg, 2.31 mmol, 3.0 eq) in DMF (6 mL) was stirred at rt for 2 h. The mixture was concentrated and the resulting residue was purified by prep-HPLC to afford N-((l- aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4- (hydroxymethyl)oxazole-5-carboxamide (6 mg, 2%). LRMS (M+H⁺) m/z calculated 492.1, found 492.0. 1H NMR (DMSO-i¾, 400 MHz): d 9.19 (t, 1 H), 8.93 (d, 1 H), 8.65 (t, 1 H), 8.13 (d, 1 H), 7.76-7.69 (m, 3 H), 7.55 (s, 1 H), 7.41-7.38 (m, 1 H), 6.85 (d, 1 H), 6.75 (d, 2 H), 5.44 (t, 1 H), 4.60 (d, 2 H), 4.56 (d, 2 H), 4.44 (s, 2H).

Example 73: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-(l-hydroxyethyl)oxazole-5-carboxamide

[00318] To a solution of ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy-2- oxoethyl)-4-(hydroxymethyl)oxazole-5-carboxylate (1.5 g, 3.5 mol, 1.0 eq) in DCM (30 mL) was added DMP (1.8 g, 4.26 mmol, 1.2 eq) under N₂ atmosphere. The reaction mixture was stirred at rt overnight and washed with aq.NaHC0₃ (15 mL) and aq.Na₂S₂0₃ (10 mL). The combined organic layers were dried, concentrated and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 8/1, v/v) to give ethyl 2-(l-(3-chloro-8- fluoroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4-formyloxazole-5-carboxylate (920 mg, 62%).

[00319] To a solution of ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy-2- oxoethyl)-4-fonnyloxazole-5-carboxylate (700 mg, 1.66 mol, 1.0 eq) in THF (10 mL) was added MeMgBr (3 M, THF) (0.9 mL, 2.5 mmol, 1.5 eq) under N₂ atmosphere at - 50 °C. The reaction mixture was stirred at rt overnight. Then aq.MLCl (5 mL) was added and the mixture was extracted with EA. The combined organic layers were dried, concentrated and the resuting residue was purified by chromatography on a silica gel column (PE/EA = 5/1, v/v) to give ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4-(l-hydroxyethyl)oxazole-5- carboxylate (410 mg, 57%).

[00320] To a solution of ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy-2- oxoethyl)-4-(l-hydroxyethyl)oxazole-5-carboxylate (100 mg, 0.23 mmol, 1.0 eq) in MeOH (3 mL) was added LiOH.H₂0 (39 mg, 0.92 mmol, 4 eq) in H₂0 (3 mL). The mixture was stirred at rt overnight. The reaction mixture was adjusted to pH 5~6 with 1N HC1 and extracted with EA. The organic layers were concentrated to give 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-(l- hydroxyethyl)oxazole-5-carboxylic acid (70 mg, 87%).

[00321] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-(l- hydroxyethyl)oxazole-5-carboxylic acid (70 mg, 0.2 mmol, 1.0 eq), 5-(aminomethyl)-4,6- dimethylpyridin-2-amine HC1 salt (45 mg, 0.24 mmol, 1.2 eq), HATEG (91 mg, 0.24 mmol, 1.2 eq) and DIEA (77 mg, 0.6 mmol, 3.0 eq) in DMF (5 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford N- ((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-(l- hydroxyethyl)oxazole-5-carboxamide (13 mg, 10%). LRMS (M+H⁺) m/z calculated 484.2, found 483.9. 1H MR (DMSO-i¾, 400 MHz): 8.92-8.93 (d, 1H), 8.76-8.77 (m, 1H), 8.63-8.64 (d, 1H), 7.73(s, 1H), 7.63-7.66 (m, 1H), 6. l0(s, 1H), 5.96-5.98 (d, 1H), 5.65 (s, 2H), 4.97-5.00 (m, 1H), 4.39 (s, 2H), 4.31-4.32 (d, 2H), 2.29 (s, 3H), 2.16 (s, 3H), 1.30-1.32 (d, 3H).

Example 74: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-(4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole -5 -carboxamide

[00322] To a solution of pyridin-2(lH)-one (20 g, 210 mmol, 1.0 eq) in MeCN (500 mL) were added l,4-bis(bromomethyl)benzene (83 g, 315 mmol, 1.5 eq) and K₂C0₃ (58 g, 420 mmol, 2.0 eq). The reaction mixture was then stirred at 80 °C overnight. The mixture was cooled to rt and filtered, the filtrate was concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 1/1, v/v) to give l-(4- (bromomethyl)benzyl)pyridin-2(lH)-one (31 g, 54%).

[00323] To a solution of l-(4-(bromomethyl)benzyl)pyridin-2(lH)-one (10 g, 36 mmol, 1.0 eq) in THF/MeOH (200 mL, v/v = 2/1) was added Pd(PPh₃)₂Cl₂ (1.26 g, 1.8 mmol, 0.05 eq) and K₂C0₃ (5.2 g, 37.8 mmol, 1.05 eq). The reaction mixture was stirred at rt overnight under CO atmosphere. The mixture was filtered and the filtrate was concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 1/1, v/v) to give methyl 2-(4-((2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (8.6 g, 93%).

[00324] To a mixture of methyl 2-(4-((2-oxopyridin-l(2H)-yl)methyl)phenyl)acetate (1.0 g, 3.9 mmol, 1.0 eq) and ethyl 2-chlorooxazole-5-carboxylate (684 mg, 3.9 mmol, 1.0 eq) in DMF (50 mL) was added NaH (312 mg, 7.8 mmol, 2.0 eq) at 0 °C. The reaction mixture was stirred at this temperature for 1 h under N_2. Water (20 mL) was added and the mixture was extracted with EA (50 mL x3). The combined organic layers were washed with brine (50 mL), dried over Na₂S0₄ and concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 1/1, v/v) to give ethyl 2-(2-methoxy-2-oxo-l-(4-((2-oxopyridin- l(2H)-yl)methyl)phenyl)ethyl)oxazole-5-carboxylate (1.0 g, 65%).

[00325] To a solution of ethyl 2-(2-methoxy-2-oxo-l-(4-((2-oxopyridin-l(2H)- yl)methyl)phenyl)ethyl)oxazole-5-carboxylate (200 mg, 0.5 mmol, 1.0 eq) in THF/H₂0/MeOH (20 mL, v/v/v = 2/3/1) was added LiOH.H₂0 (84 mg, 2.0 mmol, 4.0 eq). The mixture was stirred at rt overnight. The reaction was monitored by LC-MS. Then dilute HC1 was added and the mixture was adjusted to pH 3, and stirred at rt for 4 h. After concentration in vacuo, the resulting precipitate was collected by filtration and washed with water and acetone

subsequently to give 2-(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxylic acid (100 mg, 59%).

[00326] To a solution of 2-(4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5- carboxylic acid (100 mg, 0.32 mmol, 1.0 eq) in DMF (20 mL) were added 5-(aminomethyl)- 4,6-dimethylpyridin-2-amine hydrochloride (72 mg, 0.38 mmol, 1.2 eq), HATU (182 mg, 0.48 mmol, 1.5 eq) and DIEA (123 mg, 0.96 mmol, 3.0 eq). The reaction mixture was stirred at rt overnight. The mixture was concentrated and the resulting residue was purified by pre-HPLC to give N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-(4-((2-oxopyridin-l(2H)- yl)methyl)benzyl)oxazole-5-carboxamide (65 mg, 64%). LRMS (M+H⁺) m/z calculated 444.2, found 444.0. 1H NMR (DMS0-i 400 MHz) d 8.41 (t, 1H), 7.76 (dd, 1H), 7.68 (s, 1H), 7.38-

7.43 (m, 1H), 7.25 (s, 4H), 6.40 (d, 1H), 6.21-6.24 (m, 1H), 6.11 (s, 1H), 5.68 (s, 2H), 5.06 (s, 2H), 4.28 (d, 2H), 4.14 (s, 2H), 2.27 (s, 3H), 2.14 (s, 3H).

Example 75: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)-4-(l-hydroxyethyl)oxazole-5-carboxamide

[00327] To a solution of ethyl 2-(l-(3-chloroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4- (hydroxymethyl)oxazole-5-carboxylate (1 g, 2.47 mol, 1.0 eq) in DCM (25 mL) was added DMP (1.26 g, 2.97 mmol, 1.5 eq) under N₂ atmosphere and the mixture was stirred at rt overnight. Then aq.NaHCO, (15 mL) and aq. Na₂S₂0₃ (10 mL) were added, and the mixture was extracted with DCM. The combined organic layers were dried, concentrated and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 8/1, v/v) to give ethyl 2-(l-(3-chloroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4-formyloxazole-5-carboxylate (750 mg, 76%).

[00328] To a solution of ethyl 2-(l-(3-chloroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4- formyloxazole-5-carboxylate (750 mg, 1.86 mol, 1.0 eq) in THF (15 mL) was added MeMgBr (3 M in THF) (0.93 mL, 2.8 mmol, 1.5 eq) under N₂ atmosphere at -50 °C. The mixture was stirred at rt overnight and quenched with aq.MLCl (5 mL) and extracted with EA (30 mL x 2). The combined organic layers were dried, concentrated and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 6/1, v/v) to give ethyl 2-(l-(3-chloroquinolin- 6-yl)-2-methoxy-2-oxoethyl)-4-(l-hydroxyethyl)oxazole-5-carboxylate (500 mg, 64%) as a yellow oil.

[00329] To a solution of ethyl 2-(l-(3-chloroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4-(l- hydroxyethyl)oxazole-5-carboxylate (200 mg, 0.48 mmol, 1.0 eq) in MeOH (5 mL) was added LiOH.H₂0 (80 mg, 1.91 mmol, 4 eq) in H₂0 (5 mL). The mixture was stirred at rt overnight. The reaction mixture was adjusted to pH 5~6 with 1N HC1 and extracted with EA. The organic layers were dried and concentarted to give 2-((3-chloroquinolin-6-yl)methyl)-4-(l- hydroxyethyl)oxazole-5-carboxylic acid (150 mg, 94%).

[00330] A mixture of 2-((3-chloroquinolin-6-yl)methyl)-4-(l-hydroxyethyl)oxazole-5- carboxylic acid (150 mg, 0.45 mmol, 1.0 eq), 5-(aminomethyl)-4,6-dimethylpyridin-2-amine HC1 salt (84 mg, 0.45 mmol, 1.0 eq), HATU (205 mg, 0.54 mmol, 1.2 eq) and DIEA (174 mg, 1.35 mmol, 3.0 eq) in DMF (5 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford N-((6-amino-2,4- dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-(l-hydroxyethyl)oxazole-5- carboxamide (60 mg, 29%). LRMS (M+H⁺) m/z calculated 466.2, found 466.1. 1H NMR (DMSO-i¾, 400 MHz): d 8.86-8.87 (d, 1H), 8.78-8.79 (m, 1H), 8.55-8.56(d, 1H), 8.02-8.04(d, 1H), 7.89 (s, 1H), 7.91 (s, 1H), 7.73-7.76 (m, 1H), 6.10 (s, 1H), 5.99-6.00 (d, 1H), 4.97-5.00 (m, 1H), 4.38 (s 2H), 4.30-4.31 (d, 2H) 2.29 (s, 3H), 2.16 (s, 3H), 1.30-1.32 (d, 3H). Example 76: Preparation ofN-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-3- (hydroxym ethyl)- l-(4-((2-oxopyri din- l(2//)-yl)m ethyl )benzyl)-li7-pyrazole-4-carboxamide

[00331] To a solution of l-(4-(bromomethyl)benzyl)pyridin-2(l//)-one (8.0g, 28.8 mmol, 1.0 eq) in DMF (100 mL) were added ethyl 3 -i odo- 1 //-pyrazol e-4-carboxyl ate (7.65 g, 28.8 mmol, 1.0 eq) and K₂C0₃ (7.94 g, 57.5 mmol, 2.0 eq). The mixture was stirred at rt for 4 h and concentrated. The resulting residue was purified by chromatography on a silica gel column (EA/PE = 3/2, v/v) to give ethyl 3 -i odo- 1 -(4-((2-oxopyri di n- 1 (2H)-y\ )methyl )benzyl )- 1 H- pyrazole-4-carboxylate (4.5 g, 34%).

[00332] A mixture of ethyl 3 -i odo- 1 -(4-((2-oxopyri di n- 1 (2//)-yl ) ethyl )benzyl )- 1 H- pyrazole-4-carboxylate (2.9 g, 6.26 mmol, 1.0 eq), tributyl(vinyl)tin (2.38 g, 7.5 mmol, 1.2 eq), Pd(PPh₃)₃Cl₂ (439 mg, 0.63 mmol, 0.1 eq) in dioxane (50 ml) was stirred at 100 °C for 3 d under nitrogen atmosphere. After cooling to rt, water (300 mL) was added and the mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with water, dried over Na₂S0₄ and concentrated. The resulting residue was purified by chromatography on a silica gel column (EA/PE = 1/1, v/v) to give ethyl 1 -(4-((2-oxopyridin- l (2H)- yl )m ethyl )benzyl)-3 -vinyl- liT-pyrazole-4-carboxylate (2.2 g, 97%).

[00333] To a solution of ethyl l-(4-((2-oxopyridin-l(2//)-yl)methyl)benzyl)-3-vinyl-l//- pyrazole-4-carboxylate (2.2 g, 6.05 mmol, 1.0 eq) in THF/water (35 ml / 35 ml) was added Os0₄ (154 mg, 0.605 mmol, 0.1 eq) at 0 °C. After stirring at rt for 30 min, NaI0₄ (2.59 g, 12.1 mmol, 2.0 eq) was added. The reaction mixture was stirred at rt for 3 h and extracted with EA (100 mL x 3). The combined organic layers were washed with water (200 mL) and Na₂SO, aq., dried over Na₂S0₄ and concentrated to give ethyl 3 -formyl- l-(4-((2-oxopyri din- 1(2//)- yl (methyl (benzyl)-! //-pyrazole-4-carboxylate (1.93 g, 87%).

[00334] To a solution of ethyl 3 -formyl- l-(4-((2-oxopyri din- l(2//)-yl (methyl (benzyl)- l//-pyrazole-4-carboxylate (l.8g, 4.93 mmol, 1.0 eq) in MeOH (30 mL) was added NaBH₄ (374 mg, 9.85 mmol, 2.0 eq,) at 0 °C. The mixture was stirred at rt for 16 h under nitrogen atmosphere. After that, water (100 mL) was added and the mixture was extracted with DCM (100 mL x 3). The combined organic layers were washed with water (200 mL), dried over Na₂S0 and concentrated. The resulting residue was purified chromatography on a silica gel column (DCM/MeOH = 30/1, v/v) to give ethyl 3 -(hydroxymethyl)- l-(4-((2-oxopyridin- 1(2/7)- yl)methyl)benzyl)-l//-pyrazole-4-carboxylate (0.5 g, 29%).

[00335] To a solution of methyl 3 -(hydroxymethyl)- l-(4-((2-oxopyri din- 1(2/7)- yl)methyl)benzyl)-l//-pyrazole-4-carboxylate (200 mg, 0.564 mmol, 1.0 eq) in THF / Water (10 ml / 2.5 ml) was added LiOH.H₂0 (95 mg, 2.26 mmol, 4.0 eq). The mixture was stirred at rt for 16 h. The mixture was concentrated, and the aqueous layer was adjusted to pH 3 with 1N HC1. The mixture was extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated to give 3 -(hydroxymethyl)- 1-(4-((2- oxopyridin- 1 (2//(-yl (methyl (benzyl (- 1 //-pyrazole-4-carboxylic acid (280 mg, 94%).

[00336] A mixture of 3 -(hydroxymethyl )- l -(4-((2-oxopyridin- 1 (2//)-yl (methyl (benzyl )- liT-pyrazole-4-carboxylic acid (72 mg, 0.212 mmol, 1.0 eq), 5-(aminomethyl)-4,6- dimethylpyridin-2-amine (40 mg, 0.213 mmol, 1.0 eq), HATU (122.0 mg , 0.32lmmol, 1.5 eq) and DIEA (166 mg , 1.285 mmol, 6.0 eq) in DMF (6 ml) was stirred at rt for 16 h. The reaction mixture was concentrated, and the resulting residue was purified by prep-HPLC to give N-((6- amino-2,4-dimethylpyridin-3-yl)methyl)-3 -(hydroxymethyl)- l-(4-((2-oxopyri din- 1(2//)- yl (methyl (benzyl)-! //-pyrazole-4-carboxamide (47.5 mg, 48%). LRMS (M+H⁺) m/z calculated 473.2 found 473.0. 1H NMR (DMSO-r/₆, 400 MHz): 8.29-8.27 (m , 1H), 8.25 (s, 1H), 7.76-7.74 (dd, J= 1.6 Hz, 1H), 7.43-7.38 (m, 1H), 7.26-7.21 (m, 4H), 7.40-7.38 (m,lH), 6.24-6.20 (m, 1H), 6.10 (s, 1H), 5.84-5.81 (m, 1H), 5.63 (s, 2H), 5.22 (s, 2H), 5.06 (s, 2H), 4.47-4.46 (d, j = 4.0 Hz, 2H), 4.28-4.27 (d, J= 4.0 Hz, 2H), 2.29(s, 3H), . 2.l6(s, 3H).

Example 77: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8- fluoroquinolin-6-yl)methyl)-4-(2-hydroxypropan-2-yl)oxazole-5-carboxamide

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6- yl)methyl)-4-(2-hydroxypropan-2-yl)oxazole-5-carboxamide

[00337] To a solution of ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy-2- oxoethyl)-4-(l-hydroxyethyl)oxazole-5-carboxylate (220 mg, 0.5 mol, 1.0 eq) in DCM (6 mL) was added DMP (254 mg, 0.6 mmol, 1.2 eq) under N₂ atmosphere. The mixture was stirred at rt overnight. Then aq.NaHC0₃ (5 mL) and aq.Na₂S₂0₃ (3 mL) was added and the mixture was extracted with DCM (20 mL ^c 3). The combined organic layers were dried, concentrated and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 7/1, v/v) to give ethyl 4-acetyl-2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy-2-oxoethyl)oxazole-5- carboxylate (150 mg, 70%).

[00338] To a solution of ethyl 4-acetyl-2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy- 2-oxoethyl)oxazole-5-carboxylate (150 mg, 0.35 mol, 1.0 eq) in THF(5 mL) was added MeMgBr (3 M in THF) (0.17 mL, 0.52 mmol, 1.5 eq) under N₂ atmosphere at - 50 °C. The mixture was stirred at rt overnight and quenched with aq.NH₄Cl (5 mL) and extracted with EA. The combined organic layers were dried, concentrated and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1, v/v) to give ethyl 2-(l-(3-chloro-8- fluoroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4-(2-hydroxypropan-2-yl)oxazole-5-carboxylate (30 mg, 20%).

[00339] To a solution of ethyl 2-(l-(3-chloro-8-fluoroquinolin-6-yl)-2-methoxy-2- oxoethyl)-4-(2-hydroxypropan-2-yl)oxazole-5-carboxylate (30 mg, 0.07 mmol, 1.0 eq) in

MeOH (2 mL) was added LiOH.H₂0 (11 mg, 0.27 mmol, 4 eq) in H₂0 (2 mL). The mixture was stirred at rt overnight. The reaction mixture was adjusted to pH 5~6 with 1N HC1 and extracted with EA (20 mL ^c 2). The combined organic layers were dried and concentrated to give 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-(2-hydroxypropan-2-yl)oxazole-5- carboxylic acid (20 mg, 89%).

[00340] A mixture of 2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-(2-hydroxypropan-2- yl)oxazole-5-carboxylic acid (140 mg, 0.38 mmol, 1.0 eq), 5-(aminomethyl)-4,6- dimethylpyridin-2-amine HC1 salt(72 mg, 0.38 mmol, 1.0 eq), HATU (173 mg, 0.46 mmol, 1.2 eq) and DIEA (150 mg, 1.14 mmol, 3.0 eq) in DMF (5 mL) was stirred at rt overnight. The mixture was concentrated, and the resulting residue was purified by prep-HPLC to afford N- ((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4-(2- hydroxypropan-2-yl)oxazole-5-carboxamide (9 mg, 33%). LRMS (M+H⁺) m/z calculated 498.2, found 498.1. 1H NMR (DMSO-i¾, 400 MHz): d 9.23 (s, 1H), 8.92-8.93 (d, 1H), 8.65 (s,

1H), 7.72(s, 1H), 7.62-7.66 (m, 1H), 6.70 (s, 1H), 6.l0(s, 1H), 6.66 (s, 2H), 4.39 (s, 2H), 4.32- 4.33 (d, 2H), 2.29 (s, 3H), 2.16 (s, 3H), 1.42 (s, 6H).

Example 78: Preparation of N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3- chloroquinolin-6-yl)methyl)-4-(2-hydroxypropan-2-yl)oxazole-5-carboxamide

[00341] To a solution of ethyl 2-(l-(3-chloroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4-(l- hydroxyethyl)oxazole-5-carboxylate (1 g, 1.5 mol, 1.0 eq) in DCM (30 mL) was added DMP (1.5 g, 3.58 mmol, 1.5 eq) under N₂ atmosphere with stirring at rt overnight. Then aq.NaHCO, (15 mL) and aq.Na₂S₂0₃ (10 mL) was added and the mixture was extracted with DCM. The combined organic layers were dried, concentrated. The resulting residue was purified by chromatography on a silica gel column (PE/EA = 8/1, v/v) to give ethyl 2-(l-(3-chloroquinolin- 6-yl)-2-methoxy-2-oxoethyl)-4-(2-hydroxypropan-2-yl)oxazole-5-carboxylate (700 mg, 70%).

[00342] To a solution of ethyl 4-acetyl-2-(l-(3-chloroquinolin-6-yl)-2-methoxy-2- oxoethyl)oxazole-5-carboxylate (700 mg, 1.68 mol, 1.0 eq) in THF(lO.O mL) was added MeMgBr (3 M in THF) (0.8 mL, 2.52mmol, 1.5 eq) under N₂ atmosphere at - 50 °C. The mixture was stirred at rt overnight and quenched with aq. NH₄Cl (5 mL) and extracted with EA (20 mL x 2). The combined organic layers were dried, concentrated and the resulting residue was purified by chromatography on a silica gel column (PE/EA = 5/1, v/v) to give ethyl 2-(l- (3-chloroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4-(2-hydroxypropan-2-yl)oxazole-5- carboxylate (200 mg, 27%).

[00343] To a solution of ethyl 2-(l-(3-chloroquinolin-6-yl)-2-methoxy-2-oxoethyl)-4-(2- hydroxypropan-2-yl)oxazole-5-carboxylate (200 mg, 0.46 mmol, 1.0 eq) in MeOH (5 mL) was added LiOH.H₂0 (78 mg, 1.85 mmol, 4 eq) in H₂0 (5 mL). The mixture was stirred at rt overnight. The reaction mixture was adjusted to pH 5~6 with 1N HC1 and extracted with EA (20 mL x 2). The combined organic layers were dried and concentrated to give 2-((3- chloroquinolin-6-yl)methyl)-4-(2-hydroxypropan-2-yl)oxazole-5-carboxylic acid (140 mg, 87%).

[00344] A mixture of 2-((3-chloroquinolin-6-yl)methyl)-4-(2-hydroxypropan-2- yl)oxazole-5-carboxylic acid (140 mg, 0.38 mmol, 1.0 eq), 5-(aminomethyl)-4,6- dimethylpyridin-2-amine HC1 salt (72 mg, 0.38 mmol, 1.0 eq), HATU (173 mg, 0.46 mmol, 1.2 eq) and DIEA (150 mg, 1.14 mmol, 3.0 eq) in DMF (5 mL) was stirred at rt overnight. The mixture was concentrated and the resulting residue was purified by prep-HPLC to afford N-((6- amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-(2- hydroxypropan-2-yl)oxazole-5-carboxamide (43 mg, 24%). LRMS (M+H⁺) m/z calculated 480.2, found 481.0. 1H NMR (DMSO-i¾, 400 MHz): d 9.29 (s, 1H), 8.89-8.90 (d, 1H), 8.59- 8.60 (d, 1H), 8.04-8.07(d, 1H), 7.91 (s, 1H), 7.75-7.78 (d, 1H), 6.75 (s, 1H), 6. l2(s, 1H), 5.71 (s, 2H), 4.41 (s, 2H), 4.34-4.35 (d, 2H), 2.31 (s, 3H), 2.18 (s, 3H), 1.44 (s, 6H).

II. Biological Evaluation

Example 1: In vitro enzyme inhibition

[00345] The ability of the compounds disclosed herein to inhibit human plasma kallikrein activity was quantified according to the procedures below.

[00346] A 10 mM solution of the test compound was made in DMSO. This solution was serially diluted 1 :5 in DMSO to yield 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256 and 0.00512 mM compound test solutions. A control tube containing only DMSO is included. 16 pL of each compound test solution was combined with 384 pL of assay buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.01% Triton X-100) to yield a“4X test compound buffer stock”.

[00347] Separately, a 40 nM solution of human Plasma Kallikrein (Abeam) and a 93.6 pM solution Pro-Phe-Arg-AMC (Bachem) were made using assay buffer. These solutions are hereby refered to as 4X hPK and 2X PFR-AMC, respectively.

[00348] 60 pL of each 4X test compound buffer stock was combined with 60 pL of 4X hPK to yield 120 pL of“2X test compound buffer stock/2X hPK”. 50 pL was removed from this mixture and placed into duplicate wells on a Microfluor lBlack U-bottom microtiter plate (Thermo Scientific). This plate was incubated for 5 minutes at 37 °C. To each well, 50 pL of pre-warmed 2X PFR-AMC was added to start the enzymatic reaction. Cleavage of PFR-AMC was monitored in a Biotek Synergy H4 reader set at 37 °C. Readings are taken every 43 seconds for 1 hour. The highest mean velocity over 20 reads (-15 minutes) is used to calculate the IC_50. The IC₅₀ is calculated using the Gen5 (Biotek Instruments).

[00349] The ability of the compounds listed in Table 2 to inhibit human plasma kallikrein activity was determined.

TABLE 2

Note: Biochemical assay IC₅₀ and HWB EC₅₀ data are designated within the following ranges:

A: < 0.10 mM C: > 1.0 mM to < 10 mM

B: > 0.10 mM to < 1.0 mM D: > 10 mM ΐo 30 mM

Example 2: Human whole blood kallikrein inhibition

[00350] The ability of the compounds disclosed herein to inhibit human plasma kallikrein activity was quantified according to the procedures below.

[00351] All dilutions were prepared in an assay buffer comprising 50 mM Tris-HCl pH 7.2, 150 mM NaCl, and 0.01% Triton X-100.

[00352] Human plasma was thawed on ice and centrifuged for 15 min at 4 °C to remove platelets. A 1 mM stock solution of ellagic acid was diluted to 8 mM and mixed with human plasma, after removing platelets, at a ratio of 1 :0.8. The mixture of human plasma and ellagic acid was further diluted 32-fold in the assay buffer, to yield the final mixture for use in the inhibition assay.

[00353] A 22.5 pL volume of the final mixture of human plasma and ellagic acid was added to a 96-well microwell plate and the plate was incubated for 15 min at 37 °C. [00354] The test compound solution was prepared to provide final concentrations of 20 mM, 5 mM, 1.25 pM, 312.5 nM, 78.125 nM, 19.531 nM, 4.883 nM, 1.221 nM, 0.305 nM, and 0.076 nM. Each test compound concentration was tested in duplicates.

[00355] In addition to the inhibitor control and test wells, the 96 well assay plate included positive control wells which contain the mixture of human plasma and ellagic acid without test compounds, and background wells which contain neither the mixture of human plasma and ellagic acid nor the test compounds. The total volume of liquid in positive control and background wells was brought up to 35 pL using the assay buffer.

[00356] The assay plate containing test compounds mixed with human plasma and ellagic acid and appropriate controls was incubated at 37 °C for 5 min. A 10 mM stock solution of substrate Z-FR-2-AMC was diluted to 133.2 pM in the assay buffer, and 15 pL of the diluted substrate was added to each well, to yield a final substrate concentration of 40 pM in each well. The reagents were mixed by shaking the plate gently for 30 sec.

[00357] The enzyme reaction was quantified by immediate kinetic reading of the assay plate using excitation/emission wavelengths of 330 nm/440 nm respectively. Fluorescence intensity was recorded for 60 min, using a time interval of 43 sec.

[00358] The inhibition activity of the test compounds were evaluated using the IC₅₀ values, calculated according to the dose-response curve of the test compounds, fitted using the “log(inhibitor)-response(variable slope)” equation in GraphPadPrism software (GraphPad Software, Inc.).

[00359] The percentage inhibition (EC₅₀) was calculated using the following equation:

Sample value-Mean(BG)

Inhibition% 100 Mean(PC)-Mean(BG) X 100

where, Mean(BG) is the average value of the fluorescence intensity of the background wells and Mean(PC) is the average value of the fluorescence intensity of the positive control wells. Human whole blood kallikrein inhibition EC₅₀ results for select compounds is provided in Table 2.

III. Pharmacokinetic evaluation

[00360] Pharmacokinetic studies of select compounds were performed to assess the pharmacokinetic properties. Male Sprague-Dawley rats were administered a single oral dose of the test compound at 10 mg/kg (dose concentration: 2 mg/mL, dose volume: 5 ml/kg) via oral gavage. Blood samples were collected via jugular vein at pre-dose, post-dose 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h and 24 h, and centrifuged (8000 rpm for 6 minutes at 2-8 °C). The resulting plasma fractions were analyzed by LC/MS/MS to determine the concentration of the test compound. An analogous protocol was followed for the species of dog (tested at 5 mg/kg) and monkey (tested at 10 mg/kg). Oral exposure data for select compounds described herein are shown in Table 3.

TABLE 3

A: < 100 ng h/mL C: > 1000 ng h/mL to < 10,000 ng h/mL

B: > 100 ng h/mL to < 1000 ng h/mL D: > 10,000 ng h/mL to < 30,000 ng h/mL

BLQ means below level of quantitation

III. Comparison compounds

[00361] Data is provided for comparison compounds in Table 4 and Table 5.

TABLE 4

Note: Biochemical assay IC₅₀ and HWB EC₅₀ data are designated within

following ranges: A: < 0.10 mM C: > 1.0 mM to < 10 mM

B: > 0.10 mM to < 1.0 mM D: > 10 mM ΐo 30 mM

TABLE 5

Note: Pharmacokinetic data are designated within the following ranges:

A: < 100 ngh/mL C: > 1000 ngh/mL to < 10,000 ngh/mL

B: > 100 ng h/mL to < 1000 ng h/mL D: > 10,000 ng h/mL to < 30,000 ng h/mL

BLQ means below level of quantitation

IV. Preparation of pharmaceutical dosage forms

Example 1: Oral Tablet

[00362] A tablet is prepared by mixing 48% by weight of a compound of Formula (I), (II), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, 45% by weight of microcrystalline cellulose, 5% by weight of low-substituted hydroxypropyl cellulose, and 2% by weight of magnesium stearate. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 250-500 mg.

Claims

wherein,

Ring A is:

(a) 6-amino-2, 4-dimethylpyri din-3 -yl,

(b) 5-chloro-lH-indazol-3-yl,

(c) 3-chloro-4-fluoro-lH-indol-5-yl,

(d) 3-chloro-6-fluoro-lH-indol-5-yl,

(e) 3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl, or

(f) l-aminoisoquinolin-6-yl; and

X is hydrogen, -NH₂, -N0₂, -CN, -NHCOCH₃, -C0₂H, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, -CH₂F, -CHF₂, or -CF_3.

2. A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (la):

wherein,

Ring A is:

(a) 6-amino-2, 4-dimethylpyri din-3 -yl,

(b) 5-chloro-lH-indazol-3-yl,

(c) 3-chloro-4-fluoro-lH-indol-5-yl,

(d) 3-chloro-6-fluoro-lH-indol-5-yl, (e) 3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl, or

(f) l-aminoisoquinolin-6-yl; and

X is H, -CN, -CH₂F, -CHF₂, or -CF_3.

3. The compound of claim 1 or 2, or pharmaceutically acceptable salt thereof, wherein X is H.

4. The compound of claim 1 or 2, or pharmaceutically acceptable salt thereof, wherein X is -CN.

5. The compound of claim 1 or 2, or pharmaceutically acceptable salt thereof, wherein X is -

CH₂F, -CHF₂, or -CF_3.

6. A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (II):

wherein,

Ring A is:

(a) 6-amino-2, 4-dimethylpyri din-3 -yl,

(b) 5-chloro-lH-indazol-3-yl,

(c) 3-chloro-4-fluoro-lH-indol-5-yl,

(d) 3-chloro-6-fluoro-lH-indol-5-yl,

(e) 3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl, or

(f) l-aminoisoquinolin-6-yl; and

7. A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula (Ha):

wherein, Ring A is:

(a) 6-amino-2, 4-dimethylpyri din-3 -yl,

(b) 5-chloro-lH-indazol-3-yl,

(c) 3-chloro-4-fluoro-lH-indol-5-yl,

(d) 3-chloro-6-fluoro-lH-indol-5-yl,

(e) 3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl, or

(f) l-aminoisoquinolin-6-yl; and

X is C1-C3 hydroxyalkyl, -CH₂F, -CHF₂, or -CF_3.

8. The compound of claim 6, or pharmaceutically acceptable salt thereof, wherein X is C1-C3 hydroxyalkyl.

9. The compound of claim 6, or pharmaceutically acceptable salt thereof, wherein X is -CH₂F, - CHF₂, or -CF_3.

10. The compound of any one of claims 1-9, or pharmaceutically acceptable salt thereof, wherein Ring A is 6-amino-2,4-dimethylpyridin-3-yl.

11. The compound of any one of claims 1-9, or pharmaceutically acceptable salt thereof, wherein Ring A is 5-chloro-lH-indazol-3-yl.

12. The compound of any one of claims 1-9, or pharmaceutically acceptable salt thereof, wherein Ring A is 3-chloro-4-fluoro-lH-indol-5-yl.

13. The compound of any one of claims 1-9, or pharmaceutically acceptable salt thereof, wherein Ring A is 3-chloro-6-fluoro-lH-indol-5-yl.

14. The compound of any one of claims 1-9, or pharmaceutically acceptable salt thereof, wherein Ring A is 3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl.

15. The compound of any one of claims 1-9, or pharmaceutically acceptable salt thereof, wherein Ring A is l-aminoisoquinolin-6-yl.

16. The compound of claim 1 or 2, or pharmaceutically acceptable salt thereof, selected from:

N-((6-amino-2, 4-dimethylpyri din-3-yl)methyl)-2-((3-chl oro-8-fluoroquinolin-6- yl)methyl)oxazole-5-carboxamide,

N-((3 -chloro-6-fluoro- 1 H-indol-5-yl)methyl)-2-((3 -chloro-8-fluoroquinolin-6- yl)methyl)oxazole-5-carboxamide, N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5- carboxamide,

N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6- yl)methyl)oxazole-5-carboxamide,

N-((5-chloro-lH-indazol-3-yl)methyl)-2-((3-chloro-8-fluoroquinolin-6-yl)methyl)oxazole-5- carboxamide, and

17. The compound of claim 6 or 7, or pharmaceutically acceptable salt thereof, selected from:

N-((6-amino-2, 4-dimethylpyri din-3 -yl)m ethyl)- 1 -((3 -chl oro-8-fluoroquinolin-6-yl)methyl)-3- (l-hydroxyethyl)-lH-pyrazole-4-carboxamide,

N-((6-amino-2, 4-dimethylpyri din-3 -yl)m ethyl)- 1 -((3 -chl oro-8-fluoroquinolin-6-yl)methyl)-3- (2-hydroxypropan-2-yl)-lH-pyrazole-4-carboxamide,

N-((6-amino-2, 4-dimethylpyri din-3 -yl)m ethyl)- 1 -((3 -chl oro-8-fluoroquinolin-6-yl)methyl)-3- (difluoromethyl)-lH-pyrazole-4-carboxamide,

(difluoromethyl)-lH-pyrazole-4-carboxamide,

(fluoromethyl)-lH-pyrazole-4-carboxamide,

N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6- yl)methyl)-3 -(fluoromethyl)- lH-pyrazole-4-carboxamide, N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-l-((3-chloro-8-fluoroquinolin-6-yl)methyl)-3-

(difluoromethyl)-lH-pyrazole-4-carboxamide,

18. A compound, or pharmaceutically acceptable salt thereof, selected from:

N-((3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)oxazole- 5-carboxamide,

N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)oxazole-5- carboxamide.

19. A compound, or pharmaceutically acceptable salt thereof, selected from:

(difluoromethyl)-lH-pyrazole-4-carboxamide,

(fluoromethyl)-lH-pyrazole-4-carboxamide,

N-((5-chloro-lH-indazol-3-yl)methyl)-l-((3-chloroquinolin-6-yl)methyl)-3-(fluoromethyl)-lH- pyrazole-4-carboxamide, N-((3 -chloro-4-fluoro- 1 H-indol-5-yl)methyl)- 1 -((3 -chloroquinolin-6-yl)methyl)-3 - (difluoromethyl)-lH-pyrazole-4-carboxamide,

20. A compound, or pharmaceutically acceptable salt thereof, selected from:

N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-l,3,4- oxadiazole-2-carboxamide,

N-((l -aminoisoquinolin-6-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)- 1,3,4- oxadiazole-2-carboxamide, and

N-((3-chloro-lH-pynOlo[2,3-b]pyridin-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6- yl)methyl)-l,3,4-oxadiazole-2-carboxamide.

21. A compound, or pharmaceutically acceptable salt thereof, selected from:

N-((3-chloro-4-fluoro-lH-indol-5-yl)methyl)-5-((3-chloroquinolin-6-yl)methyl)-4H-l,2,4- tri azol e-3 -carb oxami de, N-((3-chloro-6-fluoro-lH-indol-5-yl)methyl)-5-((3-chloro-8-fluoroquinolin-6-yl)methyl)-4H-

1.2.4-tri azole-3 -carboxamide,

1.2.4-triazole-3 -carboxamide, and

22. A compound, or pharmaceutically acceptable salt thereof, selected from:

(difluoromethyl)oxazole-5-carboxamide;

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-4-((3-chloroquinolin-6-yl)methyl)oxazole-2- carboxamide;

N-((6-amino-2,4-dimethylpyridin-3-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4- methyloxazole-5-carboxamide;

N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-

(difluoromethyl)oxazole-5-carboxamide;

(fluoromethyl)oxazole-5-carboxamide;

N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-

(fluoromethyl)oxazole-5-carboxamide;

(hydroxymethyl)oxazole-5-carboxamide; N-((l-aminoisoquinolin-6-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)-4-

(hydroxymethyl)oxazole-5-carboxamide;

N-((6-amino-2, 4-dimethylpyri din-3 -yl)methyl)-3-(hydroxym ethyl)- l-(4-((2-oxopyri din- 1(2//)- yl )m ethyl )benzyl)-l -pyrazole-4-carboxamide; and

23. A compound, or pharmaceutically acceptable salt thereof, selected from:

(difluoromethyl)oxazole-5-carboxamide;

(hydroxymethyl)oxazole-5-carboxamide;

(2-hydroxypropan-2-yl)oxazole-5-carboxamide.

24. A pharmaceutical composition comprising a compound of any one of the claims 1-23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

25. A method of preparing a pharmaceutical composition comprising mixing a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. A compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body.

27. A compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of angioedema.

28. A compound for use according to claim 27, wherein the angioedema is hereditary angioedema.

29. Use of a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of angioedema.

30. Use according to claim 29, wherein the angioedema is hereditary angioedema.

31. A method of treating angioedema in a patient in need thereof comprising administering a

composition comprising a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof.

32. The method of claim 31, wherein the angioedema is hereditary angioedema.

33. A method of inhibiting kallikrein enzyme comprising contacting the enzyme with a compound of any one of claims 1-23.

34. A method of inhibiting plasma kallikrein in a subject comprising administering to the subject a composition comprising a compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof.