Modulators of coronavirus 3c-like protease and uses thereof

Abstract

The present disclosure provides modulators, such as inhibitors, of 3C-like (3CL) protease and formulations thereof, wherein said modulators and formulations thereof are useful for treating diseases and disorders associated with a coronavirus 3CL protease and inhibiting the replication of coronaviruses.

Description

MODULATORS OF CORONAVIRUS 3C-LIKE PROTEASE AND USES THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No.63 / 537,751 filed September 11, 2023, which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION

[0002] The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease, is the main protease found in coronaviruses.3C- like (3CL) proteases are widely found in (+)ssRNA viruses. All of them are cysteine proteases with a chymotrypsin-like fold (PA clan), using a catalytic dyad or triad. The Enzyme Commission refers to this family as SARS coronavirus main proteinase. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019).3C-like protease is present in the SARS-CoV-2 virus. Very few drugs are known to effectively inhibit (e.g., inhibit the replication of) SARS‑CoV‑2, such as by modulating (e.g., inhibiting) the activity of 3C-like protease. Accordingly, there is a need for new compounds that modulate coronaviruses, or modulate the activity of 3C-like protease. SUMMARY OF THE INVENTION

[0003] In one aspect, provided herein is a compound represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1aand R1bare each independently selected from: hydrogen; and C1-4 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, - N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, -S(O)2R11, - NO2, =O, =S, =N(R11), and -CN;R2is selected from: hydrogen; and C1-4alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, - N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, - NO2, =O, =S, =N(R12), and -CN; R3is absent; or selected from C6-10 carbocyclene and 5- to 10-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, - N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, - NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, - N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, - NO2, =O, =S, =N(R13), and -CN; or R2and R3come together with the nitrogen to which they are each bound to form a 4- to 6- membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR13A, -SR13A, -N(R13A)2, -C(O)R13A, -C(O)N(R13A)2, -C(O)OR13A, - OC(O)R13A, -N(R13A)C(O)R13A, -N(R13A)C(O)OR13A, -N(R13A)S(O)2R13A, -S(O)2N(R13A)2, - S(O)R13A, -S(O)2R13A, -NO2, =O, =S, =N(R13A), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13A, -SR13A, -N(R13A)2, -C(O)R13A, -C(O)N(R13A)2, -C(O)OR13A, - OC(O)R13A, -N(R13A)C(O)R13A, -N(R13A)C(O)OR13A, -N(R13A)S(O)2R13A, -S(O)2N(R13A)2, - S(O)R13A, -S(O)2R13A, -NO2, =O, =S, =N(R13A), and -CN; Ring A is C6carbocycle; L1is absent or C1-2 alkylene; Ring B is 5- to 10-membered heterocyclene; R4and R5are each independently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, - N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, - NO2, =O, =S, =N(R14), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, - NO2, =O, =S, =N(R14), and -CN; L2is selected from: -(C1-10alkylene)-, -O-(C1-10alkylene)-, -O-(C2-10alkenylene)-, -C(=O)N(R6)- (C1-10alkylene)-, -C(=O)N(R6)-(C2-10alkenylene)-, -(C1-10alkylene)-O-C(=O)N(R6)-(C1-10alkylene)-, -(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-, -(5- to 6-membered heterocyclene)-(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-, -(C1-10alkylene)-N(R6)C(=O)- (C1-10carbocyclene)-, and -(C1-10alkylene)-N(R6)C(=O)-(C6-10 carbocyclene)-(C1-10alkylene)-, wherein each alkylene, alkenylene, carbocyclene, and heterocyclene is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, - N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, -S(O)2R15, - NO2, =O, =S, =N(R15), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, - N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, -S(O)2R15, - NO2, =O, =S, =N(R15), and -CN; R6is selected from: hydrogen; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -C(O)OR16, -OC(O)R16, - N(R16)C(O)R16, -N(R16)C(O)OR16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -S(O)R16, -S(O)2R16, - NO2, =O, =S, =N(R16), and -CN; R11, R12, R13, R13A, R14, R15, and R16are each independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle, and 3- to 10- membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2,-NO2, =O, and -CN; n is selected from 0, 1, 2, 3, and 4; and m is selected from 0, 1, 2, 3, and 4.

[0004] In some embodiments, for a compound or salt of Formula (I), the compound or salt is represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L1, L2, R2, R3, R4, R5, n, and m are as defined for a compound or salt of Formula (I).

[0005] In some embodiments, for a compound or salt of Formula (I) or Formula (II), the compound or salt is represented by the structure of Formula (III):or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L1, L2, R3, R4, R5, n, and m are as defined for a compound or salt of Formula (I).

[0006] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the compound or salt is represented by the structure of Formula (IV):or a pharmaceutically acceptable salt thereof; wherein Ring B, L1, L2, R3, R4, R5, n, and m are as defined for a compound or salt of Formula (I).

[0007] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the compound or salt is represented by the structure of Formula (V):, or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L2, R3, R4, R5, n, and m are as defined for a compound or salt of Formula (I).

[0008] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the compound or salt is represented by the structure of Formula (VI):or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L2, R3, R4, R5, n, and m are as defined for a compound or salt of Formula (I).

[0009] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), and at least one pharmaceutically acceptable excipient.

[0010] In one aspect, provided herein is a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). In some embodiments, the disease or disorder associated with a coronavirus 3CL protease is a coronavirus infection. Insome embodiments, the disease or disorder associated with a coronavirus 3CL protease is a SARS-CoV-2 infection.

[0011] In one aspect, provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). In some embodiments, the coronavirus is SARS-CoV-2. INCORPORATION BY REFERENCE

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. DETAILED DESCRIPTION OF THE INVENTION

[0013] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. Definitions

[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0015] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0016] "Alkyl" refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-C12 alkyl). The alkyl is attached to the remainder of the molecule through a single bond. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C1-C12 alkyl). In certain embodiments, an alkyl comprises one to eight carbonatoms (i.e., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1- C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5alkyl). For example, the alkyl group may be attached to the rest of the molecule by a single bind, such as, methyl, ethyl, 1-propyl (n-propyl), 1- methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso- butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), and the like.

[0017] "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 preferably having from two to twelve carbon atoms (i.e., C2-C12alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

[0018] "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, and preferably having from two to twelve carbon atoms (i.e., C2-C12alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0019] "Alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably 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 radical group can be attached to the alkylene group and simultaneously be attached to the rest of the molecule. Thepoints of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C10 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5alkylene).

[0020] "Alkenylene" refers to a straight 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 double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The radical group can be attached to the alkenylene group and simultaneously be attached to the rest of the molecule. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-C10alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene).

[0021] "Alkynylene" refers to a straight 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 preferably 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 radicalgroup through a single bond. The radical group can be attached to the alkynylene group and simultaneously be attached to the rest of the molecule. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. Alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-C10alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5alkynylene).

[0022] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term -Cx-y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example, -C1-6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0023] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -Cx-y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, - C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain. For example, -C2-6 alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0024] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle include 3- to 10-membered monocyclic ringsand 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiro- ring systems. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0025] The term “carbocyclene” as used herein refers to a divalent saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. The carbocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. A carbocyclene may be optionally substituted by one or more substituents such as those substituents described herein. Carbocyclene includes divalent 3- to 10-membered monocyclic rings and divalent polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic carbocyclene may be selected from saturated, unsaturated, and aromatic rings. Polycyclic carbocyclenes may be fused, bridged or spiro-ring systems. Polycyclic carbocyclenes may be fused, bridged or spiro-ring systems. The single bond connecting the carbocyclene to the rest of the molecule and the single bond connecting the carbocyclene to the radical group may be located on the same ring or different rings of a polycyclic carbocyclene. In some embodiments, the carbocyclene is an arylene, for example, a phenylene. A “phenylene” as used herein refers to a divalent benzene group. The phenylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. A phenylene may be optionally substituted by one or more substituents such as those substituents described herein.

[0026] "Cycloalkyl" refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl). In certain embodiments, a cycloalkyl comprises three to ten carbon atoms (i.e., C3-10cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkyl). The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and thelike. Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0027] "Cycloalkenyl" refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond (i.e., C3-12cycloalkenyl). In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms (i.e., C3-10cycloalkenyl). In other embodiments, a cycloalkenyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkenyl). The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0028] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel 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. Aryl may be optionally substituted by one or more substituents such as those substituents described herein.

[0029] A “Cx-ycarbocycle” is meant to include groups that contain from x to y carbons in a ring. For example, the term “C3-6 carbocycle” can be a saturated, unsaturated or aromatic ring system that contains from 3 to 6 carbon atoms―any of which is optionally substituted as provided herein.

[0030] The term “heterocycle” as used herein refers to a saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12- membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from nitrogen, sulfur, or any combinationthereof. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein. Bicyclic heterocycles may be fused, bridged or spiro-ring systems. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.

[0031] The term “heterocyclene” as used herein refers to a divalent saturated, unsaturated, non- aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. The heterocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The single bond attaching the heterocyclene group to the rest of the molecule and the single bond attaching the heterocyclene group to the radical group may be each independently connected through any atom of the heterocyclene as valency permits, including a carbon atom in the heterocyclene ring or a heteroatom in the heterocyclene ring. A heterocyclene may be optionally substituted by one or more substituents such as those substituents described herein. Heterocyclenes include 3- to 10- membered monocyclic rings and polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic heterocyclene may be selected from saturated, unsaturated, and aromatic rings. Polycyclic heterocyclenes may be fused, bridged or spiro-ring systems. The single bond connecting the heterocyclene to the rest of the molecule and the single bond connecting the heterocyclene to the radical group may be located on the same ring or different rings of a polycyclic heterocyclene and may be attached to the rest of the molecule or the radical group through any atom of the heterocyclene, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocyclene comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocyclene comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocyclene comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocyclene comprises at least one heteroatom selected from nitrogen, sulfur, or anycombination thereof. In some embodiments, the heterocyclene is a heteroarylene. In some embodiments, the heterocyclene is a heterocycloalkylene.

[0032] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]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, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0033] The term “heteroaryl” refers to a radical derived from a 5- to 12-membered aromatic ring radical whose ring structure comprise at least one heteroatom, preferably between one to four heteroatoms. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of themolecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.

[0034] As used herein, the heteroaryl ring may be selected from monocyclic or polycyclic (bicyclic and fused or bridged) systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. Heteroaryl includes aromatic single ring structures, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein. Heteroaryl also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic.

[0035] An “X-membered heterocycle” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0036] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.

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

[0038] As used herein, the term "haloalkyl" or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, and I). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected for example, 1-chloro,2-fluoroethane.

[0039] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0040] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb- N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo(=N-OH), hydrazine(=N-NH2), -Rb-ORa, -Rb-OC(O)- Ra, -Rb-OC(O)- ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb- C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine(=N-NH2), -Rb-ORa, -Rb-OC(O)- Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0041] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0042] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0043] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0044] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0045] As used herein, the phrase "a subject in need thereof" refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0046] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms ““administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0047] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0048] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0049] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset ofsymptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. Compounds

[0050] In some aspects, provided herein is a compound represented by the structure of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1aand R1bare each independently selected from: hydrogen; and C1-4 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, - N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, -S(O)2R11, - NO2, =O, =S, =N(R11), and -CN; R2is selected from: hydrogen; and C1-4alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, - N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, - NO2, =O, =S, =N(R12), and -CN; R3is absent; or selected from C6-10 carbocyclene and 5- to 10-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, - N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, - NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, -N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, - NO2, =O, =S, =N(R13), and -CN; or R2and R3come together with the nitrogen to which they are each bound to form a 4- to 6- membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR13A, -SR13A, -N(R13A)2, -C(O)R13A, -C(O)N(R13A)2, -C(O)OR13A, - OC(O)R13A, -N(R13A)C(O)R13A, -N(R13A)C(O)OR13A, -N(R13A)S(O)2R13A, -S(O)2N(R13A)2, - S(O)R13A, -S(O)2R13A, -NO2, =O, =S, =N(R13A), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13A, -SR13A, -N(R13A)2, -C(O)R13A, -C(O)N(R13A)2, -C(O)OR13A, - OC(O)R13A, -N(R13A)C(O)R13A, -N(R13A)C(O)OR13A, -N(R13A)S(O)2R13A, -S(O)2N(R13A)2, - S(O)R13A, -S(O)2R13A, -NO2, =O, =S, =N(R13A), and -CN; Ring A is C6carbocycle; L1is absent or C1-2 alkylene; Ring B is 5- to 10-membered heterocyclene; R4and R5are each independently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, - N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, - NO2, =O, =S, =N(R14), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, - N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, - NO2, =O, =S, =N(R14), and -CN; L2is selected from: -(C1-10alkylene)-, -O-(C1-10alkylene)-, -O-(C2-10alkenylene)-, -C(=O)N(R6)- (C1-10alkylene)-, -C(=O)N(R6)-(C2-10alkenylene)-, -(C1-10alkylene)-O-C(=O)N(R6)-(C1-10alkylene)-, -(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-, -(5- to 6-membered heterocyclene)-(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-, -(C1-10alkylene)-N(R6)C(=O)- (C1-10carbocyclene)-, and -(C1-10alkylene)-N(R6)C(=O)-(C6-10 carbocyclene)-(C1-10alkylene)-, wherein each alkylene, alkenylene, carbocyclene, and heterocyclene is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, - N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, -S(O)2R15, - NO2, =O, =S, =N(R15), and -CN; andC1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, - N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, -S(O)2R15, - NO2, =O, =S, =N(R15), and -CN; R6is selected from: hydrogen; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -C(O)OR16, -OC(O)R16, - N(R16)C(O)R16, -N(R16)C(O)OR16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -S(O)R16, -S(O)2R16, - NO2, =O, =S, =N(R16), and -CN; R11, R12, R13, R13A, R14, R15, and R16are each independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle, and 3- to 10- membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; n is selected from 0, 1, 2, 3, and 4; and m is selected from 0, 1, 2, 3, and 4.

[0051] In some embodiments, for a compound or salt of Formula (I), R1aand R1bare each independently hydrogen or C1-4 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, - S(O)2N(R11)2, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), and -CN. In some embodiments, R1ais hydrogen. In some embodiments, R1bis hydrogen. In some embodiments, R1aand R1bare each hydrogen. In some embodiments, R1ais C1-4alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, - S(O)2N(R11)2, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), and -CN. In some embodiments, R1bis C1-4 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), and -CN. In some embodiments, R1aand R1bare each independently hydrogen or C1-4alkyl. In some embodiments, R1aand R1bare each independently C1-4alkyl. In some embodiments, R1ais C1-4 alkyl. In some embodiments, R1bis C1-4 alkyl. In some embodiments, R1aand R1bare each independently hydrogen, methyl, or ethyl.

[0052] In some embodiments, for a compound or salt of Formula (I), the compound or salt is represented by the structure of Formula (II):or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L1, L2, R2, R3, R4, R5, n, and m are as defined for a compound or salt of Formula (I).

[0053] In some embodiments, for a compound or salt of Formula (I) or Formula (II), R3is absent; or selected from C6-10 carbocyclene and 5- to 10-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, -N(R13)C(O)R13, - N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, -N(R13)C(O)R13, - N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN. In some embodiments, R3is absent. In some embodiments, R3is selected from C6-C10arylene and 5- to 10-membered heteroarylene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -C(O)OR13, -OC(O)R13, -N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)S(O)2R13, - S(O)2N(R13)2, -S(O)R13, -S(O)2R13, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -C(O)OR13, -OC(O)R13, -N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)S(O)2R13, - S(O)2N(R13)2, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN. In some embodiments, R3is selected from C6-C10arylene. In some embodiments, R3is selected from 5- to 10-memberedheteroarylene. In some embodiments, R3is selected from C6 arylene and 9-membered heteroarylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, and C1-6alkyl optionally substituted with one or two substituents independently selected from halogen and -OR13. In some embodiments, is selected from C6 arylene. In some embodiments, R3is selected from 9-membered heteroarylene. In some embodiments, R3is optionally substituted with one or more substituents independently selected from halogen, -OR13, and C1-6alkyl optionally substituted with one or two substituents independently selected from halogen and -OR13. In some embodiments, R3is optionally substituted with one or two or three substituents independently selected from halogen, -OR13, and C1-6alkyl optionally substituted with one or two substituents independently selected from halogen and -OR13. In some embodiments, R3is selected from phenylene, benzoxazolene, andthe point of connection between R3and L2.

[0054] In some embodiments, for a compound or salt of Formula (I) or Formula (II), R2and R3come together with the nitrogen to which they are each bound to form a 4- to 6-membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR13A, -SR13A, -N(R13A)2, -C(O)R13A, -C(O)N(R13A)2, -C(O)OR13A, -OC(O)R13A, - N(R13A)C(O)R13A, -N(R13A)C(O)OR13A, -N(R13A)S(O)2R13A, -S(O)2N(R13A)2, -S(O)R13A, - S(O)2R13A, -NO2, =O, =S, =N(R13A), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13A, -SR13A, -N(R13A)2, -C(O)R13A, - C(O)N(R13A)2, -C(O)OR13A, -OC(O)R13A, -N(R13A)C(O)R13A, -N(R13A)C(O)OR13A, - N(R13A)S(O)2R13A, -S(O)2N(R13A)2, -S(O)R13A, -S(O)2R13A, -NO2, =O, =S, =N(R13A), and -CN. In some embodiments, R2and R3come together with the nitrogen to which they are each bound to form a 6-membered heterocycloalkylene optionally substituted with one or two or three substituents independently selected from: C1-6alkyl. In some embodiments, R2and R3come together with the nitrogen to which they are each bound to form a pyrrolidine ring or a 3-azabicyclo[3.1.0]hexane group, each of which is optionally substituted with one or two or three substituents independently selected from: C1-6alkyl. In some embodiments, R2and R3come together with the nitrogen to which they are each bound to form, wherein x denotes the point of connection to L2.

[0055] In some embodiments, for a compound or salt of Formula (I) or Formula (II), the compound or salt is represented by the structure of Formula (III):or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L1, L2, R3, R4, R5, n, and m are as defined for a compound or salt of Formula (I).

[0056] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), Ring A is C6carbocycle. In some embodiments, Ring A is phenyl.

[0057] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the compound or salt is represented by the structure of Formula (IV):or a pharmaceutically acceptable salt thereof; wherein Ring B, L1, L2, R3, R4, R5, n, and m are as defined for a compound or salt of Formula (I).

[0058] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (III), or Formula (IV), R4is independently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, - OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN. In some embodiments, R4is independently selected at each occurrence from: halogen, - OR14, -CN, and C1-6alkyl. In some embodiments, R4is independently selected at each occurrence from: halogen and -CN. In some embodiments, R4is independently selected at each occurrence from: halogen and -CN; and n is 0 or 1 or 2 or 3. In some embodiments, R4is independently selected at each occurrence from: fluoro and -CN. In some embodiments, R4is independently selected at each occurrence from: fluoro and -CN; and n is 2 or 3. In some embodiments, each occurrence of R4is fluoro. In some embodiments, each occurrence of R4is fluoro; and n is 3. In some embodiments,

[0059] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (III), or Formula (IV), n is selected from 0, 1, 2, 3, and 4. In some embodiments, n is selected from 0, 1, 2, and 3. In some embodiments, n is selected from 0, 1, and 2. In some embodiments, n is selected from 1, 2, 3, and 4. In some embodiments, n is selected from 2, 3, and 4. In some embodiments, n is selected from 2 and 3. In some embodiments, n is 2. In some embodiments, n is 3.

[0060] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula

[0061] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (III), or Formula (IV), L1is absent or C1-2 alkylene. In some embodiments, L1is absent or methylene. In some embodiments, L1is absent. In some embodiments, L1is methylene.

[0062] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the compound or salt is represented by the structure of Formula (V):, or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L2, R3, R4, R5, n, and m are as defined for a compound or salt of Formula (I).

[0063] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), the compound or salt is represented by the structure of Formula (VI):or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L2, R3, R4, R5, n, and m are as defined for a compound or salt of Formula (I).

[0064] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), Ring B is 5- to 10-membered heterocyclene. In some embodiments, Ring B is 5- to 10-membered heteroarylene. In some embodiments, Ring B is selected from triazolylene, pyridylene, quinolinylene, and pyrrolopyridylene. In some embodiments, Ring B is selected from triazolylene. In some embodiments, Ring B is selected from pyridylene. In some embodiments, Ring B is selected from quinolinylene. In some embodiments, Ring B is selected from pyrrolopyridylene.

[0065] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), R5is independently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, - N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, - S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN. In some embodiments, R5is independently selected at each occurrence from halogen, -OR14, -CN, and C1-6alkyl. In some embodiments, R5is independently selected at each occurrence from halogen. In some embodiments, R5is independently selected at each occurrence from halogen; and m is 0 or 1 or 2 or 3. In some embodiments, R5is independently selected at each occurrence from chloro. In some embodiments, R5is independently selected at each occurrence from chloro; and m is 0 or 1.

[0066] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), m is selected from 0, 1, 2, 3, and 4. In some embodiments, m is selected from 0, 1, 2, and 3. In some embodiments, m is selected from 0, 1, and 2. In some embodiments, m is selected from 0 and 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0067] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (IV),is selected fromwherein y denotes the point ofconnection to L2.

[0068] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), L2is selected from: -(C1-10alkylene)-, -O-(C1-10alkylene)-, -O-(C2-10alkenylene)-, -C(=O)N(R6)-(C1-10alkylene)-, -C(=O)N(R6)-(C2-10alkenylene)-, -(C1-10alkylene)-O-C(=O)N(R6)-(C1-10alkylene)-, -(C1-10alkylene)-C(=O)N(R6)- (C1-10alkylene)-, -(5- to 6-membered heterocyclene)-(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-, -(C1-10alkylene)-N(R6)C(=O)-(C1-10carbocyclene)-, and -(C1-10alkylene)- N(R6)C(=O)-(C6-10carbocyclene)-(C1-10alkylene)-, wherein each alkylene, alkenylene, carbocyclene, and heterocyclene is optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -C(O)OR15, -OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, - S(O)2N(R15)2, -S(O)R15, -S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, - N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, -S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; and R6is selected from: hydrogen; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, - C(O)N(R16)2, -C(O)OR16, -OC(O)R16, -N(R16)C(O)R16, -N(R16)C(O)OR16, -N(R16)S(O)2R16, - S(O)2N(R16)2, -S(O)R16, -S(O)2R16, -NO2, =O, =S, =N(R16), and -CN. In some embodiments, L2is selected from: -(C1-10alkylene)-, -O-(C1-10alkylene)-, -O-(C2-10alkenylene)-, -C(=O)N(R6)- (C1-10alkylene)-, -C(=O)N(R6)-(C2-10alkenylene)-, -(C1-10alkylene)-O-C(=O)N(R6)-(C1-10alkylene)-, -(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-, -(5- to 6-membered heteroarylene)- (C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-, -(C1-10alkylene)-N(R6)C(=O)-(C6-10 arylene)-, and -(C1-10alkylene)-N(R6)C(=O)-(C6-10 arylene)-(C1-10alkylene)-, wherein each alkylene, alkenylene, arylene, and heteroarylene are optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -C(O)OR15, -OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, - S(O)2N(R15)2, -S(O)R15, -S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, - N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, - N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, -S(O)2R15, -NO2, =O, =S, =N(R15), and -CN. In some embodiments, L2is selected from: -(C1-10alkylene)-t, -O-(C1-10alkylene)-t, -(C1-10alkylene)-O-t, -O-(C2-10alkenylene)-t, -C(=O)N(R6)-(C1-10alkylene)-t, -C(=O)N(R6)-(C2-10alkenylene)-t, -(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-t, -(5- to 6-membered heteroarylene)-(C1-10alkylene)- C(=O)N(R6)-(C1-10alkylene)-t, -(C1-10alkylene)-O-C(=O)N(R6)-(C1-10alkylene)-t, -(C1-10alkylene)-N(R6)C(=O)-t, -(C1-10alkylene)-N(R6)C(=O)-(C1-10alkylene)-t, -(C1-10alkylene)- N(R6)C(=O)-(C6-10 arylene)-t, and -(C1-10alkylene)-N(R6)C(=O)-(C6-10 arylene)-(C1-10alkylene)-t; wherein t denotes the point of connection to Ring B. In some embodiments, L2is selected from: -(C1-10alkylene)-t, -O-(C1-10alkylene)-t, -(C1-10alkylene)-O-t, -O-(C2-10alkenylene)-t, - C(=O)N(R6)-(C1-10alkylene)-t, -C(=O)N(R6)-(C2-10alkenylene)-t, -(C1-10alkylene)-C(=O)N(R6)- (C1-10alkylene)-t, -(5- to 6-membered heteroarylene)-(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-t, -(C1-10alkylene)-O-C(=O)N(R6)-(C1-10alkylene)-t, -(C1-10alkylene)-N(R6)C(=O)-t, - (C1-10alkylene)-N(R6)C(=O)-(C1-10alkylene)-t, -(C1-10alkylene)-N(R6)C(=O)-(C6-10 arylene)-t, and -(C1-10alkylene)-N(R6)C(=O)-(C6-10 arylene)-(C1-10alkylene)-t; wherein t denotes the point of connection to Ring B; and R6is selected from hydrogen and C1-6alkyl. In some embodiments, L2is selected from: -(C1-10alkylene)-t, -O-(C1-10alkylene)-t, -(C1-10alkylene)-O-t, -O-(C2-10alkenylene)-t, -C(=O)N(R6)-(C1-10alkylene)-t, -C(=O)N(R6)-(C2-10alkenylene)-t, -(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-t, -(5- to 6-membered heteroarylene)-(C1-10alkylene)- C(=O)N(R6)-(C1-10alkylene)-t, -(C1-10alkylene)-O-C(=O)N(R6)-(C1-10alkylene)-t, -(C1-10alkylene)-N(R6)C(=O)-t, -(C1-10alkylene)-N(R6)C(=O)-(C1-10alkylene)-t, -(C1-10alkylene)- N(R6)C(=O)-(C6-10 arylene)-t, and -(C1-10alkylene)-N(R6)C(=O)-(C6-10 arylene)-(C1-10alkylene)- t; wherein t denotes the point of connection to Ring B; and R6is selected from hydrogen and methyl. In some embodiments, L2is selected from:; wherein t denotes the point of connection to Ring B.

[0069] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), R6is selected from: hydrogen; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -C(O)OR16, -OC(O)R16, -N(R16)C(O)R16, - N(R16)C(O)OR16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -S(O)R16, -S(O)2R16, -NO2, =O, =S, =N(R16), and -CN. In some embodiments, R6is selected from hydrogen and C1-6alkyl. In some embodiments, R6is hydrogen. In some embodiments, R6is C1-6alkyl. In some embodiments, R6is selected from hydrogen, methyl, and ethyl. In some embodiments, R6is selected from hydrogen and methyl. In some embodiments, R6is methyl.

[0070] In some embodiments, for the compound or salt of Formula (I), R3is absent and the structure of Formula (I) is represented by the structure of Formula (VII):or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L1, L2, R1a, R1b, R2, R4, R5, n, and m are as defined for a compound or salt of Formula (I).

[0071] In some embodiments, for the compound or salt of Formula (I), L1is absent and the structure of Formula (I) is represented by the structure of Formula (VIII):or a pharmaceutically acceptable salt thereof; wherein Ring A, Ring B, L2, R1a, R1b, R2, R3, R4, R5, n, and m are as defined for a compound or salt of Formula (I).

[0072] In some embodiments, for a compound or salt of Formula (I), Formula (II), Formula (III),

[0073] In some embodiments, for a compound or salt of Formula (V), the compound or salt is,,

[0074] In some embodiments, for a compound or salt of Formula (VI), the compound or salt is,acceptable salt thereof.

[0075] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0076] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salts of Formula (I), are intended to include all Z-, E- and tautomeric forms as well.

[0077] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system.When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined. “Atropisomers” are different compounds displaying different conformations due to hindered rotation at a single bond.

[0078] The compounds or salts for Formula (I), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0079] In certain embodiments, compounds or salts for Formula (I), may comprise two or more enantiomers or diatereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers exist. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers usingoptically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.

[0080] 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. In certain embodiments, the compounds or salts for Formula (I), exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non–limiting examples of tautomeric equilibrium include:

[0081] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. 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 inU.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.

[0082] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds include, by way of non-limiting example only, the following synthetic methods.

[0083] 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.

[0084] 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 commercially from chemical vendors, such as Aldrich Chemical Co.

[0085] Unless otherwise stated, compounds described 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 by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0086] 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-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br, and125I 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.

[0087] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds of Formula (I). The compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0088] The methods and compositions of Formula (I), include the use of amorphous forms as well as crystalline forms (e.g., polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0089] Compounds of Formula (I), also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0090] In certain embodiments, compounds or salts of Formula (I), may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0091] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0092] In certain embodiments, the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell. In certain embodiments, the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell. In particular embodiments, the prodrug isconverted to the parent compound once it has passed through the cell membrane into a cell. In certain embodiments, the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity.

[0093] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0094] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Pharmaceutical Formulations

[0095] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (II) and at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (III) and at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (IV) and at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (V) and at least one pharmaceutically acceptableexcipient. In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (VI) and at least one pharmaceutically acceptable excipient.

[0096] Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions can also include the compounds, salts or conjugates in a free- base form or pharmaceutically-acceptable salt form.

[0097] Methods for formulation of the conjugates can include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Alternatively, the compounds, salts or conjugates can be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0098] Pharmaceutical compositions can comprise at least one active ingredient (e.g., a compound, salt or conjugate). The active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.

[0099] Pharmaceutical compositions as often further can comprise more than one active compound (e.g., a compound, salt or conjugate and other agents) as necessary for the particular indication being treated. The active compounds can have complementary activities that do not adversely affect each other. For example, the composition can also comprise a chemotherapeutic agent, cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and / or cardioprotectant. Such molecules can be present in combination in amounts that are effective for the purpose intended.

[0100] The compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.

[0101] The compositions can be formulated for administration as an injection. Non-limiting examples of formulations for injection can include a sterile suspension, solution or emulsion in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. Injections can be formulated for bolus injection or continuous infusion. Alternatively, the compositions can be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0102] For parenteral administration, the compounds, salts or conjugates can be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently non-toxic, and non-therapeutic. Vehicles can be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0103] Sustained-release preparations can also be prepared. Examples of sustained-release preparations can include semipermeable matrices of solid hydrophobic polymers that can contain the compound, salt or conjugate, and these matrices can be in the form of shaped articles (e.g., films or microcapsules). Examples of sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly (vinyl alcohol)), polylactides, copolymers of L-glutamic acid and γ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTM(i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly- D-( –)-3-hydroxybutyric acid.

[0104] Pharmaceutical formulations can be prepared for storage by mixing a compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient, and / or a stabilizer. This formulation can be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and / or stabilizers can be nontoxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and / or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol,trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and / or non- ionic surfactants or polyethylene glycol.

[0105] A compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) may be formulated in any suitable pharmaceutical formulation. A pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and adjuvants.

[0106] In certain embodiments, a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) is formulated with a chelating agent or other material capable of binding metal ions, such as ethylene diamine tetra acetic acid (EDTA) and its salts are capable of enhancing the stability of a compound or salt of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI).

[0107] Pharmaceutical formulations may be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein can be formulated in dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and / or intraperitoneal administration. In some embodiments, the dosage form is formulated for oral administration. For example, the pharmaceutical composition can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder. In some embodiments, the pharmaceutical composition can be formulated as a unit dosage in liquid, gel, semi-liquid, semi- solid, or solid form.

[0108] The amount of compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) and the discretion of the prescribing physician.

[0109] In some embodiments, the disclosure provides a pharmaceutical composition for oral administration containing at least one compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) and a pharmaceutical excipientsuitable for oral administration. The composition may be in the form of a solid, liquid, gel, semi- liquid, or semi-solid. In some embodiments, the composition further comprises a second agent.

[0110] Pharmaceutical compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, or dispersible powders or granules, or syrups or elixirs. Such dosage forms can be prepared by any of the methods of pharmacy, which typically include the step of bringing the active ingredient(s) into association with the carrier. In general, the composition are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) moistened with an inert liquid diluent.

[0111] In some embodiments, the disclosure provides a pharmaceutical composition for injection containing a compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) disclosed herein and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the composition are as described herein.

[0112] In certain embodiments, the compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) may be formulated for injection as aqueous or oil suspensions, emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0113] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention ofthe action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0114] Pharmaceutical compositions may also be prepared from a compound or salt of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions, by way of non-limiting example only, may be found in, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999). Methods of Treatment

[0115] The compounds and salts described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

[0116] The compositions containing the compound(s) described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0117] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0118] In some aspects, the present disclosure provides a method for treatment, comprising administering to a subject in need thereof an effective amount of a compound or salt of Formula (I).

[0119] In certain embodiments, provided herein is a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or salt of Formula (I). In certain embodiments, provided herein is a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or salt of Formula (II). In certain embodiments, provided herein is a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or salt of Formula (III). In certain embodiments, provided herein is a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or salt of Formula (IV). In certain embodiments, provided herein is a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or salt of Formula (V). In certain embodiments, provided herein is a method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or salt of Formula (VI). In some embodiments, the disease or disorder associated with a coronavirus 3CL protease is a coronavirus infection. In some embodiments, the disease or disorder associated with a coronavirus 3CL protease is a SARS-CoV-2 infection. In some embodiments, the disease or disorder associated with a coronavirus 3CL protease is a MERS (e.g., MERS-CoV) infection, a SARS (e.g., SARS-CoV, SARS-CoV-1) infection, a 229E (e.g., HCoV-229E) infection, a NL63 (e.g., HCoV-NL63) infection, a OC43 (e.g., HCoV-OC43) infection, or a HKU1 (e.g., HCoV-HKU1) infection.

[0120] In certain embodiments, provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (I). In certain embodiments, provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula(II). In certain embodiments, provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (III). In certain embodiments, provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (IV). In certain embodiments, provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (V). In certain embodiments, provided herein is a method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of Formula (VI). In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the coronavirus is MERS-CoV, SARS-CoV-1, HCoV-229E, HCoV-NL63, HCoV-OC43, or HCoV-HKU1. EXAMPLES

[0121] The disclosure now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure, and are not intended to limit the disclosure in any way.

[0122] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or be synthesized or be prepared as described herein.

[0123] Example 1: Synthesis of Intermediates

[0124] All oxygen and / or moisture sensitive reactions were carried out under N2 atmosphere. All reagents and solvents were purchased from commercial vendors and used as received.1H NMR spectra were recorded on a 400 MHz or 500 MHz spectrometer.1H, and19F NMR spectra were recorded in CDCl3 or DMSO-d6, CD3OD, CD3CN or AcOH-d4. Chemical shifts are reported in parts per million (ppm) and are referenced to the residual solvent resonance as the internal standard. Data are reported as follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, quint. = quintet, m = multiplet or combinations thereof), couplingconstants (Hz), and integration. Waters Acquity UPLC was used for the reaction monitoring and MS determination, 10 mM aq. NH4HCO2or 10 mM aq. NH4HCO3and MeCN were used as a mobile phases. Silica gel column chromatography or C18column chromatography was used for purifications, in some cases prep-MS purification or chiral separation of enantiomers and / or atropisomers were performed.

[0125] Synthesis of methyl 3-(4-aminoisoquinolin-5-yl)benzoate:

[0126] Step 1: A mixture of (3-methoxycarbonylphenyl)boronic acid (709 mg, 3.94 mmol, 1.5 eq), N-(5-chloroisoquinolin-4-yl)-1,1-diphenylmethanimine (900 mg, 2.63 mmol, 1 eq), Pd2(dba)3 (120 mg, 131 μmol, 0.05 eq), PCy3 (88 mg, 315 μmol, 102 μL, 0.12 eq) and K3PO4 (947.34 mg, 4.46 mmol, 1.7 eq) in dioxane (9 mL) and Water (4.5 mL) was degassed and purged with N2for 3 times, and then the mixture was was heated to 90°C and stirred at 90°C for 12h under N2 atmosphere. LCMS analysis showed the reaction was completed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 3 / 1) to give methyl 3- (4-((diphenylmethylene)amino)isoquinolin-5-yl)benzoate (0.7 g, 1.58 mmol, 60% yield). LCMS (ESI+): m / z 443.2 [M+H]+

[0127] Step 2: To a solution of methyl 3-(4-((diphenylmethylene)amino)isoquinolin-5- yl)benzoate (650 mg, 1.47 mmol, 1 eq) in THF (19 mL) and EtOH (19 mL) was added HCl (2 M, 3.08 mL, 4.19 eq). The mixture was stirred at 20°C for 12 h. LCMS analysis showed the reaction was completed. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (5 mL) for 30 min to give methyl 3-(4- aminoisoquinolin-5-yl)benzoate: (362 mg, 1.15 mmol, 78.29% yield, HCl salt. LCMS (ESI+):m / z 279.1 [M+H]+,1H NMR (400 MHz, DMSO-d6): δ ppm: 9.09 (s, 1H), 8.41 (dd, J = 1.2, 8.4 Hz, 1H), 8.12 (td, J = 1.6, 7.6 Hz, 1H), 7.99 (t, J = 1.2 Hz, 1H), 7.97 - 7.89 (m, 2H), 7.80 (dd, J = 1.2, 7.2 Hz, 1H), 7.78 - 7.74 (m, 1H), 7.73 - 7.68 (m, 1H), 5.56 (br s), 3.88 (s, 3H).

[0128] Synthesis of 5-allylisoquinolin-4-amine:

[0129] Step 1: A mixture of N-(5-chloroisoquinolin-4-yl)-1,1-diphenylmethanimine (4.2 g, 12.25 mmol, 1 eq), LiCl (1.56 g, 36.75 mmol, 3 eq), allyltributylstannane (8.11 g, 36.75 mmol, 7.52 mL, 2 eq) and Pd(PPh3)2Cl2 in DMF (40 mL) were degassed and purged with N2 for 3 times, then the resulting mixture was heated to 90°C and stirred at 90 °C for 12 h under N2 atmosphere. LCMS analysis showed the starting material was consumed completely and one main peak with desired mass was detected. The resulting mixture was quenched by addtion Potassium fluoride aqueous solution (40 mL) and extracted with ethyl acetate (3 × 70 mL). The combined organic layers was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1) to give N-(5-allylisoquinolin- 4-yl)-1,1-diphenylmethanimine (2.8 g, 8.04 mmol, 66% yield). LCMS (ESI+): m / z 349.2 [M+H]+.

[0130] Step 2: To a solution of N-(5-allylisoquinolin-4-yl)-1,1-diphenylmethanimine in MeCN (20 mL) was added TFA (4 mL) and H2O (4 mL) at 20°C. The mixture was stirred at 20°C for 4 h. The resulting mixture was diluted with H2O (30 mL) and extracted with petroleum ether (3 × 30 mL). The water layer was lyophilization to give 5-allylisoquinolin-4-amine (1922 mg, 34.68 mmol, 74% yield). LCMS (ESI+): m / z 185.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.94 (s, 1H), 8.20 - 8.14 (s, 1H), 7.90 (s, 1H), 8.84 – 7.78 (s, 1H), 7.76 – 7.72 (m, 1H), 6.48 – 6.24 (s, 2H), 6.23 – 6.15 (m, 1H), 5.20 (dd, J = 1.6, 10 Hz, 1H), 4.90 (dd, J = 1.6, 17.2 Hz, 1H), 4.10 (d, J = 5.2 Hz, 2H).

[0131] Synthesis of 2-(But-3-en-1-yloxy)-4-methoxyaniline:

[0132] Step 1.2-(But-3-en-1-yloxy)-4-methoxy-1-nitrobenzene. A mixture of 2-fluoro-4- methoxy-1-nitrobenzene (1000 mg, 5.84 mmol), 3-buten-1-ol (570 mg, 0.677 mL, 7.9 mmol), 7.9 mL of a 1 M solution of NaHMDS in THF (7.9 mmol) in 20 mL of DMF was heated at 100C for 1 h, then cooled and diluted with ether and water, partitioned, the organic layer washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by chromatography (24 g SiO2, 0-30% EtOAc to hexanes over 20 min) to provide 2-(but-3-en-1-yloxy)-4-methoxy- 1-nitrobenzene as an oil: 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 9.6 Hz, 1H), 6.57 – 6.43 (m, 2H), 5.93 (ddt, J = 17.1, 10.3, 6.8 Hz, 1H), 5.20 (dq, J = 17.2, 1.6 Hz, 1H), 5.14 (ddt, J = 10.1, 1.9, 1.1 Hz, 1H), 4.11 (t, J = 6.6 Hz, 2H), 3.87 (s, 3H), 2.62 (qt, J = 6.7, 1.3 Hz, 2H); LCMS observed M+H = 224.0.

[0133] Step 2.2-(But-3-en-1-yloxy)-4-methoxyaniline. A mixture of 2-(but-3-en-1-yloxy)-4- methoxy-1-nitrobenzene (950 mg, 0.18 mmol), SnCl2 (4.00 g, 21.3 mmol), and 1.07 mL of conc. HCl in 43 mL of EtOH was heated at 100 C for 90 min, then cooled to rt and 5.3 mL of 10 M NaOH was added with ice bath cooling and the mixture stirred 5 min. The mixture was diluted with EtOAc, water and then filtered. The filtrate was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on SiO2 (12 g, 10-100% EtOAc in hexanes over 20 min) to provide 638 mg (77%) of 2-(but-3-en-1-yloxy)-4-methoxyaniline as an oil: 1H NMR (400 MHz, CDCl3) δ 6.65 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 2.6 Hz, 1H), 6.35 (dd, J = 8.4, 2.6 Hz, 1H), 5.90 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.18 (dq, J = 17.2, 1.7 Hz, 1H), 5.13 – 5.05 (m, 1H), 4.02 (t, J = 6.6 Hz, 2H), 3.74 (s, 3H), 3.54 (d, J = 16.4 Hz, 2H), 2.57 (qt, J = 6.6, 1.4 Hz, 2H); LCMS M+H observed = 194.0.

[0134] Synthesis of 2-(allyloxy)-6-chloro-4-methoxyaniline:

[0135] Step 1: NaHMDS (1 M, 16.89 mL, 1.5 eq) was added dropwise to a stirred solution of prop-2-en-1-ol (7.5 mL) at 0°C under N2atmosphere. The resulting mixture was stirred at 0°C for 1 h. Then a solution of 1,3-dichloro-5-methoxy-2-nitrobenzene (2.5 g, 11.26 mmol, 1 eq) in THF (10 mL) was added dropwise to the mixture at 0°C. Then the resulting mixture was heated to 65°C and stirred at 65°C over a period of 11 h.1H-NMR showed desired product was formed. The resulting mixture was quenched by addition of ammonium chloride (10 mL) at 0°C, and then diluted with water (5 mL) and extracted with Ethyl acetate (3 × 5 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 98 / 2) to give 1-(allyloxy)-3-chloro-5-methoxy-2- nitrobenzene (900 mg, 3.69 mmol, 27% yield).1H NMR: (400 MHz, CHLOROFORM-d) δ ppm: 6.93 (s, 2H), 6.59 - 6.41 (m, 2H), 6.03 - 5.90 (m, 1H), 5.41 (d, J = 17.6 Hz, 1H), 5.32 (br d, J = 10.8 Hz, 1H), 4.61 (d, J = 4.8 Hz, 2H), 3.87 (s, 2H), 3.83 - 3.82 (m, 1H), 3.83 (s, 2H), 0.97 - 0.79 (m, 3H).

[0136] Step 2: To a solution of 1-(allyloxy)-3-chloro-5-methoxy-2-nitrobenzene (900.00 mg, 3.69 mmol, 1 eq) in EtOH (10 mL) and H2O (2 mL) was added NH4Cl (1.98 g, 36.94 mmol, 10 eq) at 20°C. The resulting mixture was heated to 80°C and stirred at 80°C for 5 min. Then Fe (1.24 g, 22.16 mmol, 6 eq) was added, and then mixture was stirred at 80°C for 12 h. LCMS analysis showed the starting material was consumed completely and desired product was formed. Another vial was set up as described above. Both two reaction mixtures were combined for work up and purification. The resulting mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 50 / 1) to give 2-(allyloxy)-6-chloro-4-methoxyaniline (605 mg, 2.83 mmol, 77% yield). LCMS (ESI+): m / z 214.2 [M+H]+.1H NMR:(400 MHz, DMSO-d6)δ ppm:6.57 - 6.43 (m, 2H), 6.13 - 5.97 (m, 1H), 5.43 (qd, J = 1.6, 17.2 Hz, 1H), 5.26 (d, J = 1.6, 10.6 Hz, 1H), 4.58 (td, J = 1.6, 5.2 Hz, 2H), 4.35 (s, 2H), 3.65 (s, 3H).

[0137] Synthesis of 2-(but-3-en-1-yloxy)-6-chloro-4-methoxyaniline:

[0138] 2-(but-3-en-1-yloxy)-6-chloro-4-methoxyaniline was prepared analogously to 2- (allyloxy)-6-chloro-4-methoxyaniline, replacing prop-2-en-1-ol with but-3-en-1-ol.

[0139] Synthesis of 2-chloro-4-methoxy-6-(pent-4-en-1-yloxy)aniline:

[0140] 2-chloro-4-methoxy-6-(pent-4-en-1-yloxy)aniline was prepared analogously to 2- (allyloxy)-6-chloro-4-methoxyaniline, replacing prop-2-en-1-ol with pent-4-en-1-ol

[0141] Synthesis of tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4- yl)methyl)(methyl)carbamate

[0142] Step 1: tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4-yl)methyl)carbamate. To a solution of potassium;(tert-butoxycarbonylamino)methyl-trifluoro-boranuide (20.1 g, 84.8 mmol) and 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine (9.0 g, 34.8 mmol) in dioxane (800mL) and H2O (160 mL) was added Pd(dppf)Cl2 (2.5 g, 3.4 mmol) and K2CO3 (14.5 g, 105 mmol) at 25 °C under N2protection. The resulting mixture was stirred at 105°C for 12 h. After cooled to room temperature. The reaction mixture was diluted with 100 mL of water, extracted with ethyl acetate (500 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE:EtOAc (petroleum ether:ethyl acetate) = 20:1-2:1 to afford crude compound. The residue was purified by C18 column (0.5% NH3•H2O- MeCN system) to afford tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4- yl)methyl)carbamate (4.7 g, 43.6% yield).

[0143] Step 2: 6-chloro-2-methyl-4-((methylamino)methyl)-2H-indazol-5-amine. To a mixture of tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4-yl)methyl)carbamate (4.7 g, 15.2 mmol) in BH3-THF (40 mL, 1.0 M in THF) was stirred at 50 °C for 12 h under N2protection. After cooled to room temperature. The reaction mixture was quenched with 80 mL of MeOH and 30 mL of HCl (1.0 N). The mixture was stirred at 50 °C for 2 h. After cooled to room temperature, and added 500 mL of saturated aqueous NaHCO3, extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to afford 6-chloro-2-methyl-4-((methylamino)methyl)-2H- indazol-5-amine (2.4 g, crude).

[0144] Step 3: tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4- yl)methyl)(methyl)carbamate. To a solution of 6-chloro-2-methyl-4-((methylamino)methyl)-2H- indazol-5-amine (2.4 g, 10.7 mmol) in DCM (35 mL) was added (Boc)2O (4.1 g, 18.8 mmol) and TEA (2.9 g, 28.7 mmol) at 25oC under N2protection. The resulting mixture was stirred at 25 °C for 1 h. The mixture was concentrated and purified by silica gel chromatography eluted with PE:THF = 30:1-1:1 to afford tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4- yl)methyl)(methyl)carbamate (2.5 g, 72.0% yield) . LC-MS m / z (ESI): [M+H]+325.2,1H-NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.61 (s, 1H), 5.11 (br, 2H), 4.56 (s, 2H), 4.07 (s, 3H), 2.66 (s, 3H), 1.45 (s, 9H).

[0145] Synthesis of tert-butyl (2-(5-amino-6-chloro-2-methyl-2H-indazol-4- yl)ethyl)carbamate:

[0146] Step 1: tert-butyl (2-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)ethyl)carbamate. To a solution of 4-bromo-6-chloro-2-methyl-indazol-5-amine (300 mg, 1.16 mmol), potassium(2- ((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (581.2 mg, 2.31 mmol) and K2CO3(353.1 mg, 2.56 mmol) in toluene (8 mL) and water (0.8 mL) was added Pd(dppf)Cl2(169.6 mg, 0.23 mmol) at 25 °C under N2 protection. The resulting mixture was stirred at 95 °C for 12 h. The reaction was repeated 4 times. After cooled to room temperature. These reactions mixture was diluted with 50 mL of water, extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with PE: EtOAc = 10: 1 to afford 1.3 g (crude). The crude product was purified by Prep-HPLC (0.1% NH3•H2O / MeCN system) to afford 770 mg (41.0% yield) of tert-butyl (2-(5-amino-6-chloro-2- methyl-2H-indazol-4-yl)ethyl)carbamate. LC-MS m / z (ESI): [M+H]+325.2.1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.49 (s, 1H), 6.86-6.83 (m, 1H), 4.77 (br, 2H), 4.07 (s, 3H), 3.13-3.07 (m, 2H), 2.88-2.83 (m, 2H), 1.37 (s, 9H).

[0147] Synthesis of methyl 4-(4-aminoisoquinolin-5-yl)benzoate:

[0148] Step 1: To a solution of N-(5-chloroisoquinolin-4-yl)-1,1-diphenylmethanimine (1.8 g, 5.25 mmol, 1 eq) in dioxane (18 mL) and H2O (3.6 mL) was added (4- (methoxycarbonyl)phenyl)boronic acid (1.89 g, 10.50 mmol, 2 eq), K3PO4 (1.89 g, 8.93 mmol, 1.7 eq), Pd2(dba)3(240.40 mg, 262.53 μmol, 0.05 eq), PCy3(176.69 mg, 630.07 μmol, 204.26 μL, 0.12 eq) under N2. Then the mixture was stirred at 90°C for 12 h under N2. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 10: 1) to give methyl 4-(4-((diphenylmethylene)amino)isoquinolin-5-yl)benzoate (1.3 g, 2.79 mmol, 53% yield). LCMS (ESI+): m / z 443.3 [M+H]+.1H NMR: (400 MHz, CHLOROFORM - d) δ ppm 8.94 (s, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.60 - 7.55 (m, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.42 - 7.33 (m, 2H), 7.29 - 7.11 (m, 7H), 7.01 - 6.92 (m, 2H), 3.74 (s, 3H).

[0149] Step 2: To a solution of methyl methyl 4-(4-((diphenylmethylene)amino)isoquinolin-5- yl)benzoate (1.25 g, 2.82 mmol, 1 eq) in THF (32.5 mL) and MeOH (32.5 mL) was added HCl (2 M, 5.65 mL, 4 eq). Then the mixture was stirred at 20°C for 12 h. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was added into MTBE (5 mL). Then the mixture was filtered and the filter cake was concentrated under reduced pressure to give methyl 4-(4-aminoisoquinolin-5-yl)benzoate (750 mg, 2.20 mmol, 78% yield, 92.4% purity, HCl). LCMS (ESI+): m / z 279.2 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ ppm, 8.93 (s, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 8.0 Hz, 2H), 7.97 (t, J = 7.6 Hz, 1H), 7.85 (d, J = 6.4 Hz, 1H), 7.80 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 3.98 (s, 3H).

[0150] Synthesis of tert-butyl (5-bromoisoquinolin-4-yl)carbamate:

[0151] A solution of 5-bromoisoquinoline-4-carboxylic acid (122 g, 484.00 mmol, 1 eq) in t- BuOH (1220 mL) was added TEA (146.93 g, 1.45 mol, 202.10 mL, 3 eq) and DPPA (173.16 g, 629.21 mmol, 135.81 mL, 1.3 eq). Then the mixture was stirred at 80°C for 12 h. LCMS analysis showed the starting material was consumed completely and desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 1) to give tert-butyl (5-bromoisoquinolin-4-yl)carbamate (135 g, 418 mmol, 86% yield). LCMS (ESI+): m / z 323.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ = 9.29 (s, 1H), 9.04 (br s, 1H), 8.36 (s, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.10 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 1.77 - 1.13 (m, 9H).

[0152] Synthesis of methyl 4-(4-aminoisoquinolin-5-yl)picolinate:

[0153] Step 1: A mixture of tert-butyl (5-bromoisoquinolin-4-yl)carbamate (8 g, 24.75 mmol, 1 eq), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (9.77 g, 37.13 mmol, 1.5 eq), Pd(dppf)Cl2(3.62 g, 4.95 mmol, 0.2 eq), K3PO4(7.88 g, 37.13 mmol, 1.5 eq) in dioxane (80 mL) and H2O (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 6 h under N2 atmosphere. The suspension was filtered through a pad of silica gel and the filter cake was washed with ethyl acetate (50 mL × 3). The combined filtrates werewashed with water (100 mL × 2) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 1 / 100) to give methyl 4-(4-((tert- butoxycarbonyl)amino)isoquinolin-5-yl)picolinate (7.9 g, 20 mmol, 82% yield, 98% purity). LCMS (ESI+): m / z 380.2 [M+H]+.1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 9.21 (s, 1H), 8.84 (d, J = 4.9 Hz, 1H), 8.68 (s, 1H), 8.20 (d, J = 0.9 Hz, 1H), 8.12 (dd, J = 0.9, 8.2 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.58 - 7.49 (m, 2H), 5.76 (br s, 1H), 4.04 (s, 3H), 1.30 (s, 9H).

[0154] Step 2: To a solution of methyl 4-(4-((tert-butoxycarbonyl)amino)isoquinolin-5- yl)picolinate (9.55 g, 25.17 mmol, 1 eq) in DCM (40 mL) was added HCl / dioxane (4 M, 95 mL, 15.10 eq). The mixture was stirred at 25°C for 3 h. The reaction mixture was concentrated under reduced pressure, the residual product was diluted with water (100 mL) and basified with 1N NaOH to pH=7-8, the resulting solution was extracted with DCM (50 mL × 3), the combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to get methyl 4-(4-aminoisoquinolin-5-yl)picolinate (5.2 g, 18 mmol, 71% yield, 96% purity). LCMS (ESI+): m / z 280.2 [M+H]+,1H NMR (400 MHz, METHANOL- d4) δ ppm: 9.10 (s, 1H), 9.03 (d, J = 5.8 Hz, 1H), 8.67 (d, J = 1.6 Hz, 1H), 8.54 (dd, J = 2.1, 7.5 Hz, 1H), 8.36 - 8.31 (m, 1H), 8.13 - 8.08 (m, 2H), 8.06 (s, 1H), 4.13 (s, 3H).

[0155] Synthesis of tert-butyl (5-(3-hydroxypropyl)isoquinolin-4-yl)carbamate:

[0156] Step 1: A mixture of tert-butyl (5-bromoisoquinolin-4-yl)carbamate (0.5 g, 1.55 mmol, 1 eq), trimethyl(prop-2-ynoxy)silane (496.02 mg, 3.87 mmol, 594.03 μL, 2.5 eq), Pd(PPh3)2Cl2(217.18 mg, 309.42 μmol, 0.2 eq), CuI (370.36 mg, 437.55 μmol, 0.1 eq), TEA (3.71 g, 11.38 mmol, 2.6 eq) in THF (2 mL) was degassed and purged with N2 for 3 times, and then theresulting mixture was heated to 90°C and stirred at 90°C for 12 h under N2 atmosphere. Six additional vials were set up as described above. All seven reaction mixtures were combined for work up and purification. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (5×3 mL). The combined organic phase was washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 3 / 1) to give tert-butyl (5-(3-hydroxyprop-1-yn-1-yl)isoquinolin-4-yl)carbamate (2 g, 6.7 mmol, 72% yield). LCMS (ESI+): m / z 399.2 [M+H]+.

[0157] Step 2: To a solution of Pd / C (1.61 g, 1.51 mmol, 10% purity, 0.3 eq), Pd(OH)2(423.66 mg, 301.67 μmol, 10% purity, 0.06 eq) in EtOH (5 mL) was added tert-butyl (5-(3-hydroxyprop- 1-yn-1-yl)isoquinolin-4-yl)carbamate (1.5 g, 5.03 mmol, 1 eq) and the mixture was purged with H2for 3 times, the resulting mixture was stirred at 25°C for 2 h under H2atmosphere. An identical reaction was run and the two reaction mixtures were combined for work up and purification. The resulting mixture was concentrated under reduced pressure to give tert-butyl (5- (3-hydroxypropyl)isoquinolin-4-yl)carbamate (2.6 g, 8.6 mmol, 86% yield).

[0158] Synthesis of 2-(4-((diphenylmethylene)amino)isoquinolin-5-yl)ethan-1-ol:

[0159] Step 1: A mixture of N-(5-chloroisoquinolin-4-yl)-1,1-diphenylmethanimine (5 g, 14.58 mmol, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.04 g, 26.25 mmol, 4.45 mL, 1.8 eq), K3PO4(4.64 g, 21.88 mmol, 1.5 eq), Pd(OAc)2(163.72 mg, 729.25 μmol, 0.05 eq) andXPhos (695.29 mg, 1.46 mmol, 0.1 eq) in dioxane (30 mL) and H2O (3 mL) was degassed and purged with N2for 3 times, and then The resulting mixture was heated to 80°C and stirred at 80°C for 8 h. LCMS analysis showed the starting material was consumed completely and desired product was formed. The resulting mixture was diluted with water (90 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 4 / 1) to give 1,1- diphenyl-N-(5-vinylisoquinolin-4-yl)methanimine (4 g, 12 mmol, 82% yield). LCMS (ESI+): m / z 335.1 [M+H]+.

[0160] Step 2: A mixture of 1,1-diphenyl-N-(5-vinylisoquinolin-4-yl)methanimine (2 g, 5.98 mmol, 1 eq) in THF (2 mL) was degassed and purged with N2 for 3 times, and then added 9- BBN (0.5 M, 40 mL, 3.34 eq) at 0°C, the mixture was stirred at 35°C for 12 h under N2atmosphere. After which time a mixture of NaOH (0.5 M, 20.00 mL, 1.67 eq) and H2O2(17.70 g, 156.11 mmol, 15 mL, 30% purity, 26.10 eq), the mixture was stirred at 25°C for 0.5 h under N2 atmosphere. The resulting mixture was quenched by addition potassium carbonate (50 mL) at 0°C, and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with brine (2×10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The resulting mixture was concentrated under reduced pressure to give 2-(4- ((diphenylmethylene)amino)isoquinolin-5-yl)ethan-1-ol (1.5 g, 4.3 mmol, 72 % yield). LCMS (ESI+): m / z 353.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm: 8.79 (s, 1H), 7.93 - 7.89 (m, 1H), 7.80 - 7.75 (d, J = 7.2 Hz,), 7.61 - 7.56 (m, 3H), 7.55 - 7.49 (m, 2H), 7.44 (s, 1H), 7.30 - 7.25 (m, 3H), 7.15 - 7.10 (m, 2H), 4.54 (t, J = 5.2 Hz, 1H), 3.79 - 3.72 (m, 2H), 3.35 (s, 2H).

[0161] Synthesis of tert-butyl 3-(4-aminoisoquinolin-5-yl)propanoate:

[0162] Step 1: A mixture of N-(5-chloroisoquinolin-4-yl)-1,1-diphenylmethanimine (16 g, 46.67 mmol, 1eq), tert-butyl acrylate (6.58 g, 51.34 mmol, 7.45 mL, 1.1 eq), palladium bis(tri-tert- butylphosphine) (715.55 mg, 1.40 mmol, 0.03 eq) and N-cyclohexyl-N-methyl-cyclohexanamine (10.03 g, 51.34 mmol, 10.89 mL, 1.1 eq) in Tol. (160 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100°C for 12 h under N2 atmosphere. LCMS showed the reaction was completed. The reaction mixture was worked up with another 2 g scale reaction. The reaction mixture was diluted with H2O (100 mL) and extracted with MTBE (200 mL×2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to10 / 1) to give tert-butyl (E)-3-(4- ((diphenylmethylene)amino)isoquinolin-5-yl)acrylate (19 g, 44 mmol, 94% yield). LCMS (ESI+): m / z 435.2 [M+H]+.

[0163] Step 2: To a solution of Pd / C (19.00 g, 17.85 mmol, 10% purity) in EtOH (200 mL) was added tert-butyl (E)-3-(4-((diphenylmethylene)amino)isoquinolin-5-yl)acrylate (19 g, 43.73 mmol, 1eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25°C for 2 h. LCMS showed the reaction mixture was completed. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 3-(4-((diphenylmethylene)amino)isoquinolin-5-yl)propanoate (21 g, 38 mmol,88% yield, 80% purity), which was used in the next step without further purification. LCMS (ESI+): m / z 437.1 [M+H]+.

[0164] Step 3: To a solution of tert-butyl 3-(4-((diphenylmethylene)amino)isoquinolin-5- yl)propanoate (1.2 g, 2.75 mmol, 1eq) in MeOH (10 mL) was added NaOAc (1.98 g, 24.19 mmol, 8.8 eq) and hydroxylamine;hydrochloride (2.29 g, 32.99 mmol, 12 eq). The mixture was stirred at 20°C for 12 h. LCMS showed the reaction mixture was completed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% NH3•H2O) to give tert-butyl 3-(4- aminoisoquinolin-5-yl)propanoate (440 mg, 59% yield). LCMS (ESI+): m / z 273.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm: 8.53 (s, 1H), 7.97 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.45 - 7.37 (m, 2H), 5.34 (s, 2H), 3.48 (t, J = 7.6 Hz,2H), 2.63 (t, J = 7.6 Hz,2H), 1.33 (s, 9H).

[0165] Synthesis of 7-nitro-1H-pyrrolo[3,2-c]pyridine:

[0166] Step 1: A mixture of 3-bromo-5-nitropyridin-4-amine (20 g, 91.74 mmol, 1 eq), ethynyl(trimethyl)silane (27.03 g, 275.22 mmol, 38.13 mL, 3 eq) and Et3N (58.48 g, 577.96 mmol, 80.44 mL, 6.3 eq) in dioxane (300 mL) was degassed and purged with N2 for 3 times, then PdCl2(PPh3)2(3.22 g, 4.59 mmol, 0.05 eq) and CuI (873.59 mg, 4.59 mmol, 0.05 eq) was added to above mixture. The resulting mixture was degassed and purged with N2for 3 times, then it was heated to 70°C and stirred at 70°C for 12 h under N2 atmosphere. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 95 / 5) to give 3-nitro-5-((trimethylsilyl)ethynyl)pyridin-4-amine (13.7 g, 58.2 mmol, 63.5% yield). LCMS (ESI+): m / z 236.3 [M+H]+.

[0167] Step 2: To a solution of 3-nitro-5-((trimethylsilyl)ethynyl)pyridin-4-amine (30 g, 127.49 mmol, 1 eq) in MeOH (400 mL) was added K2CO3 (52.86 g, 382.47 mmol, 3 eq) at 25°C. The resulting mixture was stirred at 25°C for 2 h. The resulting mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 75 / 25) to give 3-ethynyl-5-nitropyridin-4-amine (14.8 g, 90.7 mmol, 71.2% yield). LCMS (ESI+): m / z 164.3 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm: 8.98 (s, 1H), 8.41 (s, 1H), 8.10 - 7.32 (m, 2H), 4.83 (s, 1H).

[0168] Step 3: A mixture of 3-ethynyl-5-nitropyridin-4-amine (9.5 g, 58.23 mmol, 1 eq) and pyrrolidine (8.28 g, 116.47 mmol, 9.72 mL, 2 eq) in H2O (500 mL) was heated 150°C and stirred at 150°C for 1 h. Three vial was set up as described above. All four reaction mixtures were combined for work up and purification. LCMS analysis showed 10% starting material remained and 84% of desired compound was detected. The resulting mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (200 mL) at 25°C for 30 min to give 7-nitro-1H-pyrrolo[3,2-c]pyridine (33.9 g, 166 mmol, 71.4% yield, 80% purity). LCMS (ESI+): m / z 164.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm: 12.40 (br s, 1H), 9.17 (s, 1H), 9.08 (s, 1H), 7.63 (d, J = 3.1 Hz, 1H), 6.89 (d, J = 3.1 Hz, 1H).

[0169] Synthesis of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrrolo[3,2-c]pyridin-7- amine:

[0170] Step 1: To a solution of 7-nitro-1H-pyrrolo[3,2-c]pyridine (21 g, 128.73 mmol, 1 eq) in DMF (450 mL) were added Cs2CO3 (125.83 g, 386.19 mmol, 3 eq) and 2-bromoethoxy-tert- butyl-dimethyl-silane (92.39 g, 386.19 mmol, 3 eq) at 25°C. The resulting mixture was heated to 60°C and stirred at 60°C for 12 h. The reaction mixture was poured into ice water (2000 mL) and extracted with ethyl acetate (3 × 1000 mL). The combined organic layers were washed with water (2 × 800 mL) and brine (1000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 7 / 3) to give 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7- nitro-1H-pyrrolo[3,2-c]pyridine (31 g, 96 mmol, 75% yield). LCMS (ESI+): m / z 322.2 [M+H]+.

[0171] Step 2: To a solution of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-nitro-1H-pyrrolo[3,2- c]pyridine (46 g, 143.10 mmol, 1 eq) in EtOH (450 mL) and H2O (90 mL) was added NH4Cl (76.55 g, 1.43 mol, 10 eq) at 20°C. The resulting mixture was heated to 90°C and stirred at 90°C for 5 min. Then Fe (47.95 g, 858.62 mmol, 6 eq) was added, and the mixture was stirred at 90°C for 12 h. The crude product was filtered and filter layer was concentrated and triturated with THF (5 mL) at 25°C for 30 min to give 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrrolo[3,2- c]pyridin-7-amine (36 g, 124 mmol, 86% yield). LCMS (ESI+): m / z 292.2 [M+H]+.

[0172] Synthesis of 1-allyl-1H-pyrrolo[3,2-c]pyridin-7-amine:

[0173] Step 1: To a solution of 7-nitro-1H-pyrrolo[3,2-c]pyridine (8 g, 49.04 mmol, 1 eq) in DMF (80 mL) was added 3-bromoprop-1-ene (11.87 g, 98.08 mmol, 2 eq) and K2CO3(13.56 g, 98.08 mmol, 2 eq). The mixture was heated to 50°C and stirred at 50°C for 8 h. LCMS analysis showed the reaction was completed. The resulting mixture was diluted with H2O (300 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-allyl-7-nitro-1H-pyrrolo[3,2-c]pyridine (6 g, 29.53 mmol, 60.21% yield), which was used for the next step without further purification. LCMS (ESI+): m / z 204.2 [M+H]+.

[0174] Step 2: To a solution of 1-allyl-7-nitro-1H-pyrrolo[3,2-c]pyridine (2 g, 9.84 mmol, 1 eq) in EtOH (10 mL) and H2O (2 mL) was added NH4Cl (5.26 g, 98.43 mmol, 10 eq), then Fe (3.30 g, 59.06 mmol, 6 eq) was added at 80°C to the mixture, the mixture was stirred at 80°C for 12 h. LCMS analysis showed desired product was formed. The reaction mixture was filtered before cold. Then the resulting mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (TFA condition).1-allyl-1H-pyrrolo[3,2-c]pyridin-7-amine (1.5 g, 8.66 mmol, 88% yield) was obtained. LCMS (ESI+): m / z 174.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm: 8.63 (s, 1H), 7.77 - 7.66 (m, 2H), 6.93 (d, J = 3.2 Hz, 1H), 6.17 - 6.04 (m, 1H), 5.93 (s, 2H), 5.21 - 5.17 (m, 2H), 5.15 (dd, J = 1.2, 10.4 Hz, 1H), 4.75 (dd, J = 1.2, 17.2 Hz, 1H).

[0175] Synthesis of 1-(but-3-en-1-yl)-1H-pyrrolo[3,2-c]pyridin-7-amine:

[0176] 1-(but-3-en-1-yl)-1H-pyrrolo[3,2-c]pyridin-7-amine was prepared analogously 1-allyl- 1H-pyrrolo[3,2-c]pyridin-7-amine replacing 3-bromoprop-1-ene with 4-bromobut-1-ene.

[0177] Synthesis of 4-(allyloxy)-5-chloropyridin-3-amine:

[0178] Step 1: To a solution of 3-chloro-5-nitropyridin-4-ol (12 g, 68.75 mmol, 1 eq) in acetone (50 mL) was added K2CO3 (14.25 g, 103.13 mmol, 1.5 eq) and allyl bromide (12.48 g, 103.13 mmol, 1.5 eq) at 20°C. The resulting mixture was heated to 40°C and stirred at 40°C for 12 h. LCMS analysis showed the starting material was consumed completely. The resulting mixture was filtered, the filter liquor concentrated under reduced pressure to give a residue. The crude product 4-(allyloxy)-3-chloro-5-nitropyridine (13.5 g, 63 mmol, 92% yield) was used into the next step without further purification. LCMS (ESI+): m / z 215.0 [M+H]+.

[0179] Step 2: To a solution of 4-(allyloxy)-3-chloro-5-nitropyridine (13.5 g, 62.91 mmol, 1 eq) in EtOH (100 mL) and H2O (20 mL) was added NH4Cl (33.65 g, 629.06 mmol, 10 eq) at 25°C. The resulting mixture was heated to 80°C, then Fe (21.08 g, 377.44 mmol, 6 eq) was slowly added into the mixture at 80°C. The resulting mixture was stirred at 80°C for 12 h. LCMS analysis showed starting material was consumed completely and one main peak with desired m / z or desired mass was detected. The reaction mixture was filtered, the filter liquor and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 10:1) to give 4-(allyloxy)-5-chloropyridin-3-amine (5.4g, 29 mmol, 46% yield). LCMS (ESI+): m / z 185.0 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm: 7.84 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.03 - 5.91 (m, 1H), 5.31 - 5.16 (m, 2H), 4.92 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H).

[0180] Synthesis of 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine and 6-chloro-2-methyl- 4-vinyl-2H-indazol-5-amine:

[0181] Step 1: To a solution of 6-chloro-2-methyl-2H-indazol-5-amine (10 g, 55.06 mmol, 1 eq) in ACN (100 mL) was slowly added NBS (9.8 g, 55.06 mmol, 1 eq) at 0°C. The resulting mixture was heated to 25°C and stirred at 25°C for 1 h. LCMS analysis showed starting material was consumed completely and one main peak with desired mass was detected. The resulting mixture was filtered, the filter liquor concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (petroleum ether: ethyl acetate=100:1 to 1:1) to give 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine (3.0 g, 11.5 mmol, 21% yield).

[0182] Step 2: To a solution of 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine (3 g, 11.51 mmol, 1 eq) in dioxane (24 mL) and H2O (6 mL) was added potassium; trifluoro (vinyl) boranuide (3.08 g, 23.02 mmol, 2 eq), Cs2CO3(7.5 g, 23.02 mmol, 2 eq) and Pd(dppf)Cl2.CH2Cl2(0.94 g, 1.15 mmol, 0.1 eq) at 25°C. The resulting mixture was heated to 80°C and stirred at 80°C for 12 h. LCMS analysis showed the starting material was consumed completely and one main peak with desired Ms was detected. The reaction mixture was filtered, the filter liquor and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (basic condition) to give 6-chloro-2-methyl-4-vinyl-2H-indazol-5-amine (1.93 g, 9.3 mmol, 81% yield).

[0183] Synthesis of tert-butyl (3-(5-amino-6-chloro-2-methyl-2H-indazol-4- yl)propyl)carbamate:

[0184] Step 1: To a solution of 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine (10 g, 38.38 mmol, 1 eq) and NaHCO3(3.55 g, 42.22 mmol, 1.1 eq) in THF / H2O (1:1, 80 mL) was added CbzCl (7.2 g, 42.22 mmol, 1.1 eq) at 0°C. The resulting mixture was heated to 25°C and stirred at 25°C for 12 h. The resulting mixture was filtered, the filter liquor concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (5 mL) at 25°C for 10 min to give benzyl (4-bromo-6-chloro-2-methyl-2H-indazol-5-yl)carbamate (4 g, 10.18 mmol, 26% yield). LCMS (ESI+): m / z 396.0 [M+H]+.

[0185] Step 2: To a solution of benzyl (4-bromo-6-chloro-2-methyl-2H-indazol-5-yl)carbamate (4 g, 10.14 mmol, 1 eq) and tert-butyl prop-2-yn-1-ylcarbamate (3.93 g, 25.32 mmol, 2.5 eq) in DMF (50 mL) and TEA (25 mL) was added CuI (0.27 g, 2.03 mmol, 0.2 eq) and Pd(PPh3)2Cl2 (0.94 g, 1.15 mmol, 0.1 eq) at 25°C. The resulting mixture was heated to 70°C, the resulting mixture was stirred at 70°C for 12 h. The reaction mixture was filtered, the filter liquor and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (basic condition) to give benzyl (4-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-6-chloro-2- methyl-2H-indazol-5-yl)carbamate (2 g, 4.3 mmol, 42% yield). LCMS (ESI+): m / z 469.3 [M+H]+.

[0186] Step 3: To a solution of 5% Pd / C (1 g) in EA (20 mL) was added benzyl (4-(3-((tert- butoxycarbonyl)amino)prop-1-yn-1-yl)-6-chloro-2-methyl-2H-indazol-5-yl)carbamate (2 g, 42.65 mmol, 1 eq) under N2atmosphere. The suspension was degassed and purged with H2for 5times. The mixture was stirred under H2 (15 Psi.) at 50°C for 12 h. The reaction mixture was filtered, the filter liquor and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition) to give tert-butyl (3-(5-amino-6-chloro-2-methyl- 2H-indazol-4-yl)propyl)carbamate (1.1 g, 3.25 mmol, 76% yield).

[0187] Synthesis of methyl (3,4,5-trifluorobenzyl)carbamimidothioate hydroiodide:

[0188] Step 1: A mixture of (3,4,5-trifluorophenyl)methanamine (20 g, 124 mmol, 1 eq) and benzoyl isothiocyanate (22.3 g, 136 mmol, 18.4 mL, 1.1 eq) in DCM (200 mL) was degassed and purged with N2for 3 times, and then the resulting mixture was stirred at 25°C for 3 h under N2atmosphere. The resulting mixture was concentrated under reduced pressure to give N'- benzoyl-N-(3,4,5-trifluorobenzyl)carbamimidothioic acid (40 g, 123 mmol, 99% yield). LCMS (ESI+): m / z 325.2 [M+H]+.

[0189] Step 2: To a solution of N'-benzoyl-N-(3,4,5-trifluorobenzyl)carbamimidothioic acid (40 g, 123.33 mmol, 1 eq) in EtOH (400 mL) was added NaOH (1 M, 400 mL) at 25°C. The resulting mixture was stirred at 25°C for 2 h. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (50 mL) and adjusted to pH=7 with saturated citric acid solution. Then the resulting mixture was filtered and the filter cake was dried under vacuum to give N-(3,4,5-trifluorobenzyl)carbamimidothioic acid (26.6 g, 121 mmol, 97.9% yield). LCMS (ESI+): m / z 221.2 [M+H]+.

[0190] Step 3: To a solution of N-(3,4,5-trifluorobenzyl)carbamimidothioic acid (34 g, 154 mmol, 1 eq) in EtOH (350 mL) were added NaHCO3 (14.27 g, 169.83 mmol, 6.61 mL, 1.1 eq) and MeI (21.91 g, 154.39 mmol, 9.61 mL, 1 eq) at 25°C. The resulting mixture was heated to50°C and stirred at 50°C for 1 h. The resulting mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with MTBE (15 mL) 20°C for 30 min, then it was filtered and washed with ethyl acetate (5 mL). The filter cake was dried under vacuum to give methyl (3,4,5-trifluorobenzyl)carbamimidothioate hydroiodide (45 g, 124.26 mmol, 80% yield). LCMS (ESI+): m / z 235.1 [M+H]+.

[0191] Synthesis of methyl (2,4,5-trifluorobenzyl)carbamimidothioate hydroiodide:

[0192] Step 1: A mixture of (2,4,5-trifluorophenyl)methanamine (30 g, 186.19 mmol, 1 eq), benzoyl isothiocyanate (33.42 g, 204.81 mmol, 27.56 mL, 1.1 eq) in DCM (300 mL) was degassed and purged with N2for 3 times, and then the resulting mixture was stirred at 25°C for 2 h under N2 atmosphere. LCMS showed the desired product was formed. The resulting mixture was concentrated under reduced pressure to remove DCM (300 mL) to give N'-benzoyl-N- (2,4,5-trifluorobenzyl)carbamimidothioic acid (45 g, 140 mmol, 75% yield). LCMS (ESI+): m / z 325.1 [M+H]+.

[0193] Step 2: A mixture of N'-benzoyl-N-(2,4,5-trifluorobenzyl)carbamimidothioic acid (35 g, 107.92 mmol, 1 eq), NaOH (1 M, 175 mL, 1.62 eq) in EtOH (175 mL) was degassed and purged with N2for 3 times, and then the resulting mixture was heated to 80°C and stirred at 80°C for 2 h under N2 atmosphere. LCMS analysis showed the desired product was formed. The resulting mixture was concentrated under reduced pressure to remove EtOH (250 mL). After cooling, to the resulting mixture was added an aqueous solution 1N HCl to give a neutral solution (pH 6.9- 7). N-(2,4,5-trifluorobenzyl)carbamimidothioic acid (20 g, 91 mmol, 84% yield) was precipitated from the neutral solution and collected by filtration and drying. LCMS (ESI+): m / z 221.1 [M+H]+.

[0194] Step 3: A mixture of N-(2,4,5-trifluorobenzyl)carbamimidothioic acid (20 g, 91 mmol, 1 eq), CH3I (12.9 g, 91 mmol, 5.68 mL, 1 eq) in EtOH (200 mL) was degassed and purged with N2for 3 times at 20°C, and then the resulting mixture was heated to 50°C and stirred at 50°C for 0.5h under N2 atmosphere. LCMS analysis showed the desired product was formed. The resulting mixture was concentrated under reduced pressure to remove EtOH (100 mL). The crude product was triturated with MTBE 100 ml at 25°C for 15 min to give methyl (2,4,5- trifluorobenzyl)carbamimidothioate hydroiodide (16.29 g, 45 mmol, 50% yield).

[0195] Synthesis of 3-((1-allyl-1H-1,2,4-triazol-3-yl)methyl)-6-(methylthio)-1-(2,4,5- trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione and 3-((1-allyl-1H-1,2,4-triazol-5- yl)methyl)-6-(methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione:y)

[0196] Step 1: To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (20 g, 157.35 mmol, 1eq) in acetone (2 L) was added K2CO3 (57.41 g, 415.42 mmol, 2.64 eq) and allyl bromide (23.80 g, 196.69 mmol, 1.25 eq). The resulting mixture was stirred at 20°C for 16 h under N2 atmosphere. LCMS analysis showed the reaction mixture was completed. The resulting mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 20 / 80) to give methyl 1- allyl-1H-1,2,4-triazole-3-carboxylate (13 g, 78 mmol, 49% yield) and methyl 1-allyl-1H-1,2,4- triazole-5-carboxylate (8 g, 48 mmol, 30% yield). LCMS (ESI+): m / z 168.3.

[0197] Step 2: To a solution of methyl 1-allyl-1H-1,2,4-triazole-3-carboxylate (5 g, 29.91 mmol, 1 eq) in THF (25 mL) was added LiAlH4 (1.14 g, 29.91 mmol, 1 eq) under N2 atmosphere at 0°C. The resulting mixture was stirred at 0°C for 1 h. The resulting mixture was quenched by adding NaSO4·10H2O at 0°C, and then filtered and concentrated under reduced pressure to give(1-allyl-1H-1,2,4-triazol-3-yl)methanol (2 g, 14 mmol, 48% yield). Similarly, reduction of methyl 1-allyl-1H-1,2,4-triazole-5-carboxylate with LAH gave (1-allyl-1H-1,2,4-triazol-5- yl)methanol. LCMS (ESI+): m / z 140.3 [M+H]+.

[0198] Step 3: To a solution of 6-(methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine- 2,4(1H,3H)-dione (5.5 g, 18.14 mmol, 1 eq) in THF (50 mL) was added (1-allyl-1H-1,2,4- triazol-3-yl)methanol (5.05 g, 36.27 mmol, 2 eq), PPh3(9.61 g, 36.64 mmol, 2.02 eq) and DIAD (4.51 g, 22.31 mmol, 1.23 eq) at 0°C. The resulting mixture was stirred at 25°C for 1 h. LCMS analysis showed one main peak with desired mass was detected. The resulting mixture was diluted with water 50 mL and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition) to give 3-((1-allyl-1H-1,2,4-triazol-3-yl)methyl)-6-(methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5- triazine-2,4(1H,3H)-dione (2.8 g, 5.75 mmol, 31.72% yield, 87% purity). LCMS (ESI+): m / z 425.1 [M+H]+, rt: 1.609 min.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.41 (s, 1H), 7.66 - 7.60 (m, 1H), 7.48 - 7.39 (m, 1H), 6.04 - 5.92 (m, 1H), 5.21 (dd, J = 1.2, 10.4 Hz, 1H), 5.15 - 5.13 (m, 2H), 5.13 - 5.10 (m, 1H), 5.00 (s, 2H), 4.77 (d, J = 6.0 Hz, 2H), 2.52 (s, 3H). Similarly, coupling of 6-(methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione and (1-allyl-1H-1,2,4-triazol-5-yl)methanol gave 3-((1-allyl-1H-1,2,4-triazol-5-yl)methyl)-6-(methylthio)-1- (2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione. LCMS (ESI+): m / z 425.1 [M+H]+, rt: 0.690 min.1H NMR (400 MHz, DMSO-d6)δ ppm: 7.83 (s, 1H), 7.64 (dt, J = 6.8, 10.3 Hz, 1H), 7.55 - 7.42 (m, 1H), 6.06 - 5.93 (m, 1H), 5.23 (dd, J = 0.8, 10.0 Hz, 1H), 5.13 (br s, 2H), 5.13 (s, 2H), 5.07 (dd, J = 1.6, 17.6 Hz, 1H), 4.92 (br d, J = 5.6 Hz, 2H), 2.52 (s, 3H).

[0199] Synthesis of methyl 3-(4-(3-(2-chloro-5-cyanobenzyl)-4-(methylthio)-2,6-dioxo-3,6- dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate:

[0200] Step 1: A mixture of 4-chloro-3-methylbenzonitrile (25 g, 164.92 mmol, 1 eq), NBS (35.22 g, 197.90 mmol, 1.2 eq) and AIBN (13.54 g, 82.46 mmol, 0.5 eq) in isopropyl acetate (250 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80°C for 3 h under N2atmosphere. TLC indicated ~30% of 4-chloro-3-methylbenzonitrile remained, and one major new spot with larger polarity was detected. Another reaction was set up as described above. Both reaction mixtures were combined for work up and purification. The reaction mixture was washed water (500 mL) and brine (500 mL). The organic layer was driedover Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 5 / 1) to give 3-(bromomethyl)-4-chlorobenzonitrile (60 g, 208.25 mmol, 63.14% yield, 80% purity).1H NMR: (400 MHz, CHLOROFORM-d):δ ppm: 7.76 (d, J = 1.8 Hz, 1H), 7.58 - 7.49 (m, 2H), 4.56 (s, 2H).

[0201] Step 2: To a solution of NH3 / MeOH (7 M, 371.88 mL, 30 eq) in MeOH (2 L) was added 3-(bromomethyl)-4-chlorobenzonitrile (20 g, 86.77 mmol, 1 eq) at 25°C. The mixture was heated to 40°C and stirred at 40°C for 12 h. TLC showed the reaction mixture was completed. Another both reaction were set up as described above. All three reaction mixtures were combined for work up and purification. The reaction mixture was concentrated to afford crude product. The crude product was triturated with MTBE (100 mL) at 20oC for 30 min to give 3-(aminomethyl)- 4-chlorobenzonitrile (60 g, 230 mmol, 88% yield, 95% purity, HBr salt).1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.09 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 2.0, 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 4.19 (s, 2H)

[0202] Step 3: A mixture of 3-(aminomethyl)-4-chlorobenzonitrile (20 g, 80.80 mmol, 1 eq, HBr) and TEA (12.26 g, 121.20 mmol, 16.87 mL, 1.5 eq) in DCM (200 mL) was degassed and purged with N2for 3 times, Then benzoyl isothiocyanate (13.85 g, 84.84 mmol, 11.41 mL, 1.05 eq) in DCM (100 mL) was added dropwise and then the mixture was stirred at 25°C for 3 h under N2 atmosphere. LCMS showed the reaction was completed. Another two reactions were set up as described above. All three reaction mixtures were combined for work up and purification. The reaction mixture was concentrated and filtered to give (Z)-N'-benzoyl-N-(2- chloro-5-cyanobenzyl)carbamimidothioic acid (62 g, 179 mmol, 75% yield, 95% purity).1H NMR: (400 MHz, DMSO-d6) δ ppm: 8.0911.51 - 10.84 (m, 1H), 9.73 - 8.54 (m, 1H), 8.01 - 7.93 (m, 2H), 7.85 - 7.78 (m, 2H), 7.75 - 7.69 (m, 1H), 7.68 - 7.61 (m, 1H), 7.55 - 7.46 (m, 2H), 4.96 (s, 2H)

[0203] Step 4: A mixture of (Z)-N'-benzoyl-N-(2-chloro-5-cyanobenzyl)carbamimidothioic acid (20 g, 60.64 mmol, 1 eq) in EtOH (200 mL) was added NaOH (1 M, 200.00 mL, 3.30 eq). Then the mixture was stirred at 25°C for 3 h under N2 atmosphere. LCMS showed the reaction mixture was completed. Another two reactions were set up as described above. All three reaction mixtures were combined for work up and purification. The residue was diluted with water (50 mL) and adjusted to pH=7 with saturated citric acid solution. Then the resulting mixture was filtered and the filter cake was dried under vacuum to give a residue. The crude product was purified by reversed-phase HPLC (neutral condition) to give N-(2-chloro-5- cyanobenzyl)carbamimidothioic acid (27.5 g, 121.84 mmol, 67% yield).1H NMR: (400 MHz,DMSO-d6) δ ppm:8.09 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.50 - 7.21 (m, 2H), 4.77 - 4.65 (m, 2H.

[0204] Step 5: A mixture of N-(2-chloro-5-cyanobenzyl)carbamimidothioic acid (11 g, 48.74 mmol, 1 eq) in EtOH (150 mL) was added NaHCO3 (4.09 g, 48.74 mmol, 1.90 mL, 1 eq) and MeI (6.92 g, 48.74 mmol, 3.03 mL, 1 eq). Then the mixture was stirred at 50°C for 1 h under N2 atmosphere. LCMS showed the reaction mixture was completed. The resulting mixture was filtered and concentrated under reduced pressure to give a residue. Then it was filtered and washed with MTBE (15 mL) to give methyl (2-chloro-5-cyanobenzyl)carbamimidothioate (15 g, 40.80 mmol, 84% yield, HI salt).1H NMR: (400 MHz, DMSO-d6) δ ppm: 9.72 - 8.49 (m, 3H), 7.97 - 7.90 (m, 2H), 7.89 - 7.83 (m, 1H), 7.75 (d, J = 8.4 Hz, 1H), 4.57 (s, 2H), 3.07 (s, 3H).

[0205] Step 6: A mixture of methyl 3-(4-aminoisoquinolin-5-yl)benzoate (5.26 g, 18.90 mmol, 1eq), methyl (2-chloro-5-cyanobenzyl)carbamimidothioate (9.73 g, 26.46 mmol, 1.4 eq, HI), TEA (14.54 g, 143.69 mmol, 20 mL, 7.60 eq) in MeCN (100 mL) was added DSC (48.42 g, 189.00 mmol, 10 eq) and DMAP (461.81 mg, 3.78 mmol, 0.2 eq). The reaction mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 12 h under N2atmosphere. LCMS showed the reaction mixture was completed. The reaction mixture was filtered and the filter layer was concentrated. The crude product was poured into water (100 mL), extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine (50 mL) and dried over Na2SO4and concentrated. The residue was purified by prep-HPLC (FA condition) to give methyl 3-(4-(3-(2-chloro-5-cyanobenzyl)-4-(methylthio)-2,6-dioxo-3,6-dihydro-1,3,5- triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (2.4 g, 3.82 mmol, 20% yield, 98% purity, FA). (ESI+): m / z 570.0 [M+H]+,1H NMR: (400 MHz, DMSO-d6) δ ppm: 12.90 - 12.51 (m, 1H), 9.54 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 4.4 Hz, 1H), 8.42 - 8.36 (m, 1H), 8.13 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.96 (br d, J = 9.2 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.78 - 7.70 (m, 2H), 7.68 - 7.59 (m, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.43 (br d, J = 7.6 Hz, 1H), 5.09 (d, J = 18.0 Hz, 1H), 4.94 (d, J = 18.0 Hz, 1H), 4.60 (d, J = 18.0 Hz, 1H), 4.42 (d, J = 18.0 Hz, 1H), 3.94 (s, 2H), 3.86 (s, 1H), 2.43 (s, 2H), 2.34 (s, 1H).

[0206] Synthesis of (R)- and (S)- 3-((3-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H- pyrrolo[3,2-c]pyridin-7-yl)-6-(methylthio)-2,4-dioxo-3,4-dihydro-1,3,5-triazin-1(2H)- yl)methyl)-4-chlorobenzonitrile:

[0207] A mixture of methyl (2-chloro-5-cyanobenzyl)carbamimidothioate (7.5 g, 20.40 mmol, 1.19 eq, HI) in ACN (75 mL) and TEA (15 mL) was added 1-(2-((tert- butyldimethylsilyl)oxy)ethyl)-1H-pyrrolo[3,2-c]pyridin-7-amine (5 g, 17.15 mmol, 1 eq), DSC (21.97 g, 85.77 mmol, 5 eq), DMAP (209.58 mg, 1.72 mmol, 0.1 eq) and purged with N2for 3 times, and then the mixture was stirred at 25°C for 12 h under N2 atmosphere. LCMS showed the reaction mixture was completed. The reaction mixture was filtered and filter layer was concentrated. The crude product was added into water (5 mL), extracted with ethyl acetate (5 mL×2). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC (neutral condition) to give 3-((3-(1-(2-((tert- butyldimethylsilyl)oxy)ethyl)-1H-pyrrolo[3,2-c]pyridin-7-yl)-6-(methylthio)-2,4-dioxo-3,4- dihydro-1,3,5-triazin-1(2H)-yl)methyl)-4-chlorobenzonitrile (3.5 g, 5.70 mmol, 16.62% yield, 95% purity). m / z 583.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm: 8.84 (s, 1H), 8.22 (s, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.87 (dd, J = 2.0, 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 3.2 Hz, 1H), 6.68 (d, J = 3.2 Hz, 1H), 5.29 - 5.17 (m, 2H), 4.27 - 4.07 (m, 2H), 3.82 - 3.71 (m, 1H), 3.30 -2.60 (m, 1H), 2.62 (s, 3H), 0.72 (s, 9H), -0.30 (d, J = 7.2 Hz, 6H). The final target waspurified by SFC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:55%-85% B over 8.0 min) to give peak 1 (2.3 g, 3.89 mmol, 45.40% yield, 98.7% purity) and peak 2 (2.26 g, 3.85 mmol, 44.88% yield, 99.3% purity).

[0208] Synthesis of methyl 3-(4-(4-(methylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate:

[0209] A solution of methyl (2,4,5-trifluorobenzyl)carbamimidothioate hydroiodide (6.25 g, 17.25 mmol, 1.2 eq, HI) in ACN (75 mL) and TEA (15 mL) was stirred at 25°C for 10 min. Then the resulting mixture were added methyl 3-(4-aminoisoquinolin-5-yl)benzoate (4 g, 14.37 mmol, 1 eq), DSC (36.82 g, 143.73 mmol, 10 eq) and DMAP (351.17 mg, 2.87 mmol, 0.2 eq) at 25°C. The resulting mixture was stirred at 25 °C for 12 h. The resulting mixture was filtered and concentrated under reduced pressure to give a residue. The residue was diluted with water (300 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition) to give methyl 3-(4-(4- (methylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin- 5-yl)benzoate (3.33 g, 5.90 mmol, 41% yield). LCMS (ESI+): m / z 565.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm: 9.53 (d, J = 2.4 Hz, 1H), 8.59 (d, J = 3.6 Hz, 1H), 8.42 - 8.33 (m, 1H), 8.03 - 7.95 (m, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.66 - 7.51 (m, 4H), 7.40 (t, J = 7.2 Hz, 1H), 5.09 - 4.89 (m, 1H), 4.57 - 4.29 (m, 1H), 3.90 (d, J = 24.8 Hz, 3H), 2.40 (d, J = 37.6 Hz, 3H).

[0210] Synthesis of methyl 4-(4-(4-(methylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)picolinate:

[0211] A solution of methyl (2,4,5-trifluorobenzyl)carbamimidothioate hydroiodide (6.22 g, 17.19 mmol, 2 eq, HI) in ACN (45 mL) and TEA (9 mL) was stirred at 25°C for 10 min. Then the resulting mixture was added methyl 4-(4-aminoisoquinolin-5-yl)picolinate (2.4 g, 8.59 mmol, 1 eq), DSC (22.01 g, 85.93 mmol, 10 eq) and DMAP (209.96 mg, 1.72 mmol, 0.2 eq) at 0°C. The resulting mixture wasstirred at 25°C for 39 h. LCMS analysis showed the desired product was detected. Two batches work up together. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was diluted with water (200 mL) and extracted with ethyl acetate (100 × 3 mL). The combined organic layers was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 100), then the crude was purified by reversed-phase HPLC (0.2% FA condition), the mixture was lyophilized directly to give methyl 4-(4-(4-(methylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)picolinate (1 g, 1.6 mmol, 9.4% yield). LCMS (ESI+): m / z 566.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) ppm: 9.56 (d, J = 2.3 Hz, 1H), 8.73 (dd, J = 4.8, 13.6 Hz, 1H), 8.63 (d, J = 6.1 Hz, 1H), 8.44 (br d, J = 8.1 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.78 (dd, J = 1.0, 4.5 Hz, 1H), 7.69 - 7.53 (m, 3H), 7.42 (dd, J = 1.6, 4.9 Hz, 1H), 5.19 - 4.99 (m, 1H), 4.70 - 4.37 (m, 1H), 3.99 - 3.86 (m, 3H), 2.45 - 2.32 (m, 3H).

[0212] Synthesis of tert-butyl 3-(2-(5-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate:

[0213] Step 1: tert-butyl 3-vinylbenzoate. To a solution of tert-butyl 3-bromobenzoate (24.0 g, 93.3 mmoL), potassium vinyltrifluoroborate (18.8 g, 140.0 mmoL) and potassium carbonate (38.7 g, 280.0 mmoL) in dioxane (600 mL) and water (100 mL) was added Pd(dppf)Cl2 (3.9 g, 4.7 mmoL) at 25 °C under N2 protection. The resulting mixture was stirred at 85 °C for 12 h. The reaction was cooled to room temperature, diluted with 100 mL of water, extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 100: 1 to afford 16.7 g (87.4% yield) of tert-butyl 3-vinylbenzoate.

[0214] Step 2: tert-butyl 3-(2-hydroxyethyl)benzoate. To a mixture of tert-butyl 3-vinylbenzoate (16.7 g, 81.8 mmoL) in 9-BBN (350 mL, 0.5 M in THF) was stirred at 50 °C for 15 h under N2 protection. The reaction was cooled to room temperature, poured into ice water (200 mL) and stirred for 10 min. The pH value of the solution was adjusted to 9~10 with aqueous NaOH (30%). Then H2O2 (30%, 20 mL) was added slowly at 5 °C. The resulting mixture was stirred at 25 °C for 2 h, extracted with ethyl acetate (150 mL × 3). The combined organic layer werewashed with brine (100 mL × 3), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE:EtOAc = 10:1-2:1 to afford 14.5 g (79.7% yield) of tert-butyl 3-(2-hydroxyethyl)benzoate.

[0215] Step 3: tert-butyl 3-(2-bromoethyl)benzoate. To a solution of tert-butyl 3-(2- hydroxyethyl)benzoate (14.5 g, 65.3 mmoL) in DCM (200 mL) was added NBS (16.5 g, 92.8 mmoL) and PPh3(17.1 g, 65.3 mmoL) at 25 °C under N2protection. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with 300 mL of water, extracted with DCM (150 mL × 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 100: 1 to afford 12.1 g (65.5% yield) of tert-butyl 3-(2-bromoethyl)benzoate.

[0216] Step 4: methyl 1-(3-(tert-butoxycarbonyl)phenethyl)-1H-1,2,4-triazole-5-carboxylate and methyl 1-(3-(tert-butoxycarbonyl)phenethyl)-1H-1,2,4-triazole-3-carboxylate. To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (5.4 g, 42.5 mmol) and tert-butyl 3-(2- bromoethyl)benzoate (12.0 g, 42.3 mmol) in CH3CN (150 mL) was added K2CO3 (11.7 g, 84.8 mmol) at 25oC under N2protection. The resulting mixture was stirred at 100 °C for 12 h. After cooled to room temperature. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography eluted with PE: EtOAc =10: 1-4: 1 to afford 3.8 g (27.2% yield) of methyl 1-(3-(tert-butoxycarbonyl)phenethyl)-1H- 1,2,4-triazole-5-carboxylate and 5.7 g (40.8% yield) of methyl 1-(3-(tert- butoxycarbonyl)phenethyl)-1H-1,2,4-triazole-3-carboxylate. Methyl 1-(3-(tert- butoxycarbonyl)phenethyl)-1H-1,2,4-triazole-5-carboxylate: LC-MS m / z (ESI): [M+H]+332.3. Methyl 1-(3-(tert-butoxycarbonyl)phenethyl)-1H-1,2,4-triazole-3-carboxylate: LC-MS m / z (ESI): [M+H]+332.3.

[0217] Step 5: tert-butyl 3-(2-(5-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate. To a solution of methyl 1-(3-(tert-butoxycarbonyl)phenethyl)-1H-1,2,4-triazole-5-carboxylate (4.7 g, 14.2 mmoL) in methanol (50 mL) and water (5 mL) was added NaBH4 (2.2 g, 56.7 mmoL) in 5 portions at 0oC under N2protection. The resulting mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with 100 mL of water, extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 1: 1 to afford 2.1 g (48.8% yield) of tert-butyl 3-(2-(5- (hydroxymethyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate.

[0218] Step 6: tert-butyl 3-(2-(5-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate. To a solution of 6- (ethylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (2.3 g, 7.3 mmoL) and tert- butyl 3-(2-(5-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate (2.2 g, 7.3 mmoL) and PPh3 (2.9 g, 10.9mmol) in THF (40 mL) was added DIAD (2.2 g, 10.9 mmol) at 25oC under N2protection. The resulting mixture was stirred at 25 °C for 14 h. The reaction mixture was added 150 mL of water, extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc =1: 1 to give crude product (4.1 g, crude). The crude product was purified by Prep-HPLC (0.5% NH4HCO3-MeCN system) to afford 2.0 g (45.8% yield) of tert-butyl 3-(2-(5-((4-(ethylthio)-2,6- dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1- yl)ethyl)benzoate. LC-MS m / z (ESI): [M+H]+603.2.

[0219] Synthesis of tert-butyl 3-(2-(3-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate:

[0220] Step 1: tert-butyl 3-(2-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate. To a solution of methyl 1-(3-(tert-butoxycarbonyl)phenethyl)-1H-1,2,4-triazole-3-carboxylate (5.0 g, 15.1mmol) in methanol (80 mL) and water (8 mL) was added NaBH4(2.6 g, 68.8 mmol) in 6 portions at 0oC under N2protection. The resulting mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with 200 mL of water, extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 1: 1 to afford 2.7 g (59.0% yield) of tert-butyl 3-(2-(3- (hydroxymethyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate.

[0221] Step 2: tert-butyl 3-(2-(3-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate. To a solution of 6- (ethylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (2.8 g, 8.9 mmol) and tert-butyl 3-(2-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate tert-butyl 3-(2-(3- (hydroxymethyl)-1H-1,2,4-triazol-1-yl)ethyl)benzoate (2.7 g, 8.9 mmol) and PPh3(3.5 g, 13.4 mmol) in THF (50 mL) was added DIAD (2.7 g, 13.4 mmol) at 25oC under N2protection. The resulting mixture was stirred at 25 °C for 14 h. The reaction mixture was added 150 mL of water, extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE:EtOAc = 1:1 to give crude product (4.6 g, crude). The crude product was purified by Prep-HPLC (0.5% NH4HCO3-MeCN system) to afford 2.3 g (42.9% yield) of tert-butyl 3-(2-(3-((4-(ethylthio)-2,6-dioxo-3-(2,4,5- trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1- yl)ethyl)benzoate. LC-MS m / z (ESI): [M+H]+603.2.

[0222] Synthesis of 3-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrrolo[3,2-c]pyridin-7- yl)-6-(methylthio)-1-(3,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione:3-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)- 1H-pyrrolo[3,2-c]pyridin-7-yl)-6- (methylthio)-1-(3,4,5-trifluorobenzyl)- 1,3,5-triazine-2,4(1H,3H)-dione

[0223] A solution of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrrolo[3,2-c]pyridin-7-amine (7.5 g, 21 mmol, 1.2 eq, HI salt) in ACN (75 mL) and TEA (15 mL) was stirred at 25°C for 10 min. Then the resulting mixture was added methyl (3,4,5-trifluorobenzyl)carbamimidothioate hydroiodide (5 g, 17.15 mmol, 1 eq), DSC (21.97 g, 85.77 mmol, 5 eq) and DMAP (209.58 mg, 1.72 mmol, 0.1 eq) at 25°C. The resulting mixture was stirred at 25°C for 12 h. The resulting mixture was filtered and concentrated under reduced pressure to give a residue. The residue was diluted with water (300 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition) to give 3-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrrolo[3,2-c]pyridin-7-yl)-6-(methylthio)-1-(3,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (7.98 g, 13.8 mmol, 40% yield). LCMS (ESI+): m / z 578.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm: 8.83 (s, 1H), 8.21 (s, 1H), 7.48 (dd, J = 6.8, 8.8 Hz, 2H), 7.36 (d, J = 3.6 Hz, 1H), 6.68 (d, J = 3.2 Hz, 1H), 5.25 - 5.10 (m, 2H), 4.19 - 4.00 (m, 2H), 3.75 - 3.49 (m, 2H), 2.61 (s, 3H), 0.72 (s, 9H), -0.28 (s, 6H).

[0224] Synthesis of tert-butyl 3-(4-(4-(methylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)propanoate:

[0225] To a solution of methyl (2,4,5-trifluorobenzyl)carbamimidothioate hydroiodide (13.30 g, 36.72 mmol, 2 eq, HI) in triethylamine (TEA) (30 mL) and acetonitrile (ACN) (150 mL) were added tert-butyl 3-(4-aminoisoquinolin-5-yl)propanoate (5 g, 18.36 mmol, 1 eq), DSC (23.52 g, 91.80 mmol, 5 eq) and DMAP (224.30 mg, 1.84 mmol, 0.1 eq). The resulting mixture filtered and concentrated under reduced pressure to give a residue. The residue was diluted with water (120 mL) and extracted with ethyl acetate (3×40 mL). The combined organic phase was washed with brine (2×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition) to give tert-butyl 3- (4-(4-(methylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)- yl)isoquinolin-5-yl)propanoate (4.4 g, 7.88 mmol, 43% yield). LCMS (ESI+): m / z 559.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm: 9.40 (s, 1H), 8.61 (s, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.78 - 7.59 (m, 4H), 5.31 - 5.10 (m, 2H), 3.12 - 2.92 (m, 2H), 2.60 (s, 3H), 2.49 - 2.45 (m, 2H), 1.37 (s, 9H).

[0226] Synthesis of 3-(5-bromoisoquinolin-4-yl)-6-(methylthio)-1-(2,4,5-trifluorobenzyl)- 1,3,5-triazine-2,4(1H,3H)-dione, atropisomer 1 and 3-(5-bromoisoquinolin-4-yl)-6- (methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione, atropisomer 2:

[0227] A solution of methyl (2,4,5-trifluorobenzyl)carbamimidothioate hydroiodide (6.76 g, 18.7 mmol, 1.2 eq, HI salt) in ACN (200 mL) and TEA (40 mL) was stirred at 25°C for 10 min. Then the resulting mixture were added 5-bromoisoquinolin-4-amine (10.5 g, 47.07 mmol, 1 eq), N,N’- disuccinimidyl carbonate (DSC) (60.29 g, 235.35 mmol, 5 eq) and DMAP (575.05 mg, 4.71 mmol, 0.1 eq) at 25°C. The resulting mixture was stirred at 25°C for 12 h. The resulting mixture was filtered and concentrated under reduced pressure to give a residue. The residue was diluted with water (300 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (neutral condition) to give 3- (5-bromoisoquinolin-4-yl)-6-(methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)- dione (14 g, 27.5 mmol, 29.2% yield). LCMS (ESI+): m / z 508.9 [M+H]+, 510.9 [M+2+H]+. The two atropiosmers were separated by SFC (ChiralPak IH, ACN). Peak 1 retention time = 1.926 min. Peak 2 retention time 2.275 min. Peak 1 LCMS (ESI+): m / z 508.9 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm: 9.53 (s, 1H), 8.68 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 7.2 Hz,1H), 7.71 - 7.58 (m, 3H), 5.29 - 5.14 (m, 2H), 2.62 (s, 3H). Peak 2 LCMS (ESI+): m / z 508.9 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm: 9.53 (s, 1H), 8.68 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.70 - 7.58 (m, 3H), 5.29 - 5.12 (m, 2H), 2.62 (s, 3H). The 2ndpeak was crystallized to assign the absolute conformation drawn above using the method described below.2 mg of this material was dissolved in 200 microliters isopropyl acetate / methanol (1:1) and kept in a 1 mL vial. The solution evaporates slowly at room temperature. Crystals were observed on the second day. The crystal was a colourless block with the following dimensions: 0.20 × 0.10 × 0.05 mm3. The symmetry of the crystal structure was assigned the monoclinic space group P21with the following parameters: a = 8.42370(10) Å, b = 8.36760(10) Å, c = 17.08770(10) Å, α = 90°, β = 101.6220(10)°, γ = 90°, V = 1179.75(2) Å3, Z = 2, Dc = 1.434 g / cm3, F(000) = 508.0, μ(CuKα) = 3.623 mm-1, and T = 293(2) K.

[0228] Table 1. Atomic coordinates ( x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for 3-(5-bromoisoquinolin-4-yl)-6-(methylthio)-1-(2,4,5- trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (atropisomer 2, peak 2).

[0229] Synthesis of 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine:

[0230] Step 1: 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine. To a solution of 6-chloro-2- methyl-2H-indazol-5-amine (25.0 g, 13.8 mmol) in i-PrOAc (375 mL) and AcOH (125 mL) was added NBS (24.8 g, 139.3 mmol) at 0 °C under N2 protection. The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with 300 mL of water and adjusted to 8 with saturated aqueous NaHCO3.The resulting solution was extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=10: 1-1: 1 to afford 4-bromo-6-chloro-2-methyl-2H- indazol-5-amine (12.1 g, 33.8% yield). LC-MS m / z (ESI): [M+H]+260.0, 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.69 (s, 1H), 5.09 (br, 2H), 4.09 (s, 3H).

[0231] Synthesis of 4-(but-3-en-1-yl)-6-chloro-2-methyl-2H-indazol-5-amine:

[0232] Step 1: 6-chloro-4-(methoxymethyl)-2-methyl-2H-indazol-5-amine. To a solution of (5- amino-6-chloro-2-methyl-2H-indazol-4-yl)methanol (750 mg, 3.55 mmol) in MeOH (9 mL) wasadded Sulfuric acid (300 mg, 3.0 mmol). The mixture was stirred at 50 °C for 0.5 h. The mixture was quenched with aqueous solution NaHCO3(30 mL), extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 5: 1 to afford 6-chloro-4-(methoxymethyl)-2-methyl- 2H-indazol-5-amine (350 mg, 43.7% yield).

[0233] Step 3: 6-chloro-4-(methoxymethyl)-2-methyl-2H-indazol-5-amine: To a solution of potassium; trifluoro(methoxymethyl)boranuide (2.6 g, 17.1 mmol), K2CO3 (3.4 g, 24.6 mmol) and 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine (2.1 g, 8.1 mmol) in dioxane (200 mL) and H2O (40 mL) was added Pd(dppf)Cl2 (650 mg, 0.9 mmol) at 25 °C under N2 protection. The resulting mixture was stirred at 100 °C for 16 h. After cooled to room temperature. The reaction mixture was diluted with 40 mL of water, extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with PE: EtOAc = 20: 1 - 2: 1 to afford crude product. The crude product was purified by C18 column (0.5% NH3•H2O-MeCN system) to afford 6-chloro-4-(methoxymethyl)-2-methyl- 2H-indazol-5-amine (600 mg, 32.9% yield).

[0234] Step 2: 4-(but-3-en-1-yl)-6-chloro-2-methyl-2H-indazol-5-amine. To a solution of 6- chloro-4-(methoxymethyl)-2-methyl-2H-indazol-5-amine (950 mg, 4.05 mmol) in THF (15 mL) was added allyl(bromo)magnesium (9.5 mL, 9.5 mmol, 1 M in THF) dropwise at 0 °C under N2 protection. The resulting mixture was stirred at 25 °C for 14 h. After cooled to 0 °C. The reaction mixture was quenched with 30 mL of saturated aqueous NH4Cl, extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=20: 1-2: 1 to afford crude product. The crude product was purified by C18 column (0.5% NH3•H2O-MeCN system) to afford 4-(but-3-en-1-yl)-6- chloro-2-methyl-2H-indazol-5-amine (452 mg 48% yield). LC-MS m / z (ESI): [M+H]+236.1, 1H-NMR (400 MHz, CHLOROFORM-D) δ 7.66 (s, 1H), 7.59 (s, 1H), 5.94-5.84 (m, 1H), 5.12- 4.99 (m, 2H), 4.14 (s, 3H), 3.81 (s, br, 1H), 2.83-2.80 (m, 2H), 2.41-2.35(m, 2H).

[0235] Synthesis of (2-(aminomethyl)-4,5-difluorophenyl)methanol:

[0236] Step 1: 2-carbamoyl-4,5-difluorobenzoic acid. To a solution of 5, 6- difluoroisobenzofuran-1, 3-dione (20 g, 109 mmol, 1.0 eq) in THF (80 mL) was added NH3•H2O (80 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (100 mL) and the pH value of the solution was adjusted to 2-3 with aqueous HCl (1M). The reaction mixture was filtered and the precipitated solid was washed with water (50 mL x 3) and dried under vacuum to afford 16.0 g (73.4% yield) of 2-carbamoyl-4,5- difluorobenzoic acid.

[0237] Step 2: (2-(aminomethyl)-4,5-difluorophenyl)methanol.To a solution of 2-carbamoyl- 4,5-difluorobenzoic acid (16.0 g, 81.5 mmol, 1.0 eq) in THF (330 mL), and then BH3-THF (1M, 408 ml, 408 mmol, 5.0 eq) was added dropwise at 20 °C. The resulting mixture was stirred at 60 °C for 14 h. After cooled to 0 °C. The reaction mixture was quenched with 100 mL of MeOH. The reaction mixture was concentrated to dryness. The residue was purified by C18 column (H2O-ACN system) to afford 4.0 g (29.2% yield) of (2-(aminomethyl)-4,5- difluorophenyl)methanol. LC-MS m / z (ESI): [M+H]+174.1,1H NMR (400 MHz, DMSO-d6) δ 7.47-7.30 (m, 2H), 4.47 (s, 2H), 3.68 (s, 2H), 3.25 (br, 2H).

[0238] Synthesis of 3-(4-(allyloxy)-5-chloropyridin-3-yl)-6-(methylthio)-1-(2,4,5- trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione:

[0239] Step 1: 3-(4-(allyloxy)-5-chloropyridin-3-yl)-6-(methylthio)-1-(2,4,5-trifluorobenzyl)- 1,3,5-triazine-2,4(1H,3H)-dione. To a solution of 4-(allyloxy)-5-chloropyridin-3-amine (4.0 g,21.7 mmol, 1.0 eq), diisopropyl ethyl amine (DIPEA) (8.4 g, 65.2 mmol, 3.0 eq) and methyl (2,4,5-trifluorobenzyl)carbamimidothioate (5.1 g, 21.7 mmol, 1.0 eq) in DMF (50 mL) was added carbonyl di(imidazole) (CDI) (7.0 g, 43.5 mmol, 2 eq) at 25 °C under N2protection. The resulting mixture was stirred at 50 °C for 14 h. After cooled to room temperature. The reaction mixture was diluted with 200 mL of ice / water, extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with PE: THF = 1: 1 to afford 2.1 g (20.6% yield) of 3-(4-(allyloxy)-5-chloropyridin-3- yl)-6-(methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione. LC-MS m / z (ESI): [M+H]+471.3

[0240] Synthesis of tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4- yl)methyl)carbamate

[0241] Step 1: tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4-yl)methyl)carbamate. To a solution of (tert-butoxycarbonylamino)methyl-trifluoro-boranuide (1.8 g, 7.7 mmol), 4-bromo-6- chloro-2-methyl-2H-indazol-5-amine (1.0 g, 3.9 mmol) and aqueous solution K2CO3(13 mL, 11.6 mmol) in dioxane (66 mL) was added Pd(dppf)Cl2(283.0 mg, 0.4 mmol) at 25 °C under N2protection. The resulting mixture was stirred at 95 °C for 12 h. After cooled to room temperature. The reaction mixture was diluted with 50 mL of water, extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 20:1 - 2:1 to afford crude compound. The crude product was purified Prep-HPLC column (0.5% NH3•H2O-MeCN system) to provide tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4-yl)methyl)carbamate (520 mg, 43.6% yield). LC-MS m / z (ESI): [M+H]+311.1, 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.56 (s, 1H), 7.46- 7.43 (br, m, 1H), 4.98 (br, 1H), 4.23 (d, J = 6.4 Hz, 2H), 4.07 (s, 3H), 1.38 (s, 9H).

[0242] Synthesis of tert-butyl (3-(5-amino-6-chloro-2-methyl-2H-indazol-4- yl)propyl)carbamate:

[0243] Step 1: benzyl (4-bromo-6-chloro-2-methyl-2H-indazol-5-yl)carbamate. To a solution of 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine (10 g, 38.38 mmol, 1 eq) and NaHCO3(3.55 g, 42.22 mmol, 1.1 eq) in THF / H2O (1:1, 80 mL) was added CbzCl (7.2 g, 42.22 mmol, 1.1 eq) at 0°C. The resulting mixture was heated to 25°C and stirred at 25°C for 12 h. LCMS showed 8.9% of remaining and 60% of desired compound was detected. The resulting mixture was filtered, the filter liquor concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (5 mL) at 25°C for 10 min to give benzyl (4-bromo-6-chloro-2-methyl-2H- indazol-5-yl)carbamate (4 g, 10.18 mmol, 26.4% yield). LCMS of reaction (ESI+): m / z 396.0 [M+H]+, Rt: 0.460 min.

[0244] Step 2: benzyl (4-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-6-chloro-2-methyl- 2H-indazol-5-yl)carbamate. To a solution of benzyl (4-bromo-6-chloro-2-methyl-2H-indazol-5- yl)carbamate (4 g, 10.14 mmol, 1 eq) and tert-butyl prop-2-yn-1-ylcarbamate (3.93 g, 25.32 mmol, 2.5 eq) in DMF (50 mL) and TEA (25 mL) was added CuI (0.27 g, 2.03 mmol, 0.2 eq) and Pd(PPh3)2Cl2 (0.94 g, 1.15 mmol, 0.1 eq) at 25°C. The resulting mixture was heated to 70°C, The resulting mixture was stirred at 70°C for 12 h. The reaction mixture was filtered, the filter liquor and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (basic condition) to give benzyl (4-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)- 6-chloro-2-methyl-2H-indazol-5-yl)carbamate (2 g, 4.3 mmol, 42.08% yield). Instrument: Agela- 600 Preparative HPLC system. Column: Welch Xtimate C18250 × 100 mm × 10 um. Mobile phase: A: H2O(0.05% NH3H2O+10 mM NH4HCO3); B: ACN. Gradient: B from 30.00% to65.00% in 30.00 min. Flow rate: 270.00 mL / min. Monitor wavelength: 220&254 nm. LCMS of reaction (ESI+): m / z 469.3 [M+H]+, Rt: 0.509 min.

[0245] Step 3: tert-butyl (3-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)propyl)carbamate. To a solution of palladium (1 g, 93.83 μmol, 2.2 eq) in EA (20 mL) was added benzyl (4-(3-((tert- butoxycarbonyl)amino)prop-1-yn-1-yl)-6-chloro-2-methyl-2H-indazol-5-yl)carbamate (2 g, 42.65 mmol, 1 eq) under N2atmosphere. The suspension was degassed and purged with H2for 5 times. The mixture was stirred under H2 (15 Psi.) at 50°C for 12 h. LCMS analysis showed benzyl (4-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-6-chloro-2-methyl-2H-indazol-5- yl)carbamate was consumed completely and one main peak with desired m / z was detected. The reaction mixture was filtered, the filter liquor and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition) to give tert-butyl (3-(5-amino- 6-chloro-2-methyl-2H-indazol-4-yl)propyl)carbamate (1.1 g, 3.25 mmol, 76.12% yield). Instrument: Auno-600 Preparative HPLC system. Column: Phenomenex luna C18 (250 × 70mm × 15 um). Mobile phase: A: H2O (0.1%TFA); B: ACN. Gradient: B from 20.00% to 50.00% in 20.00 min. Flow rate: 130.00 mL / min. Monitor wavelength: 220&254 nm Monitor wavelength: 220&254 nm. LCMS of reaction (ESI+): m / z 339.2 [M+H]+, Rt: 1.445 min. LCMS of tert-butyl (3-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)propyl)carbamate (ESI+): m / z 339.1 [M+H]+, Rt: 2.121 min.1H NMR: (400 MHz, MeOD –d4) δ ppm 8.23 (s, 1H), 7.58 (s, 1H), 4.18 (s, 3H), 3.13 (t, J = 5.2 Hz, 2H), 2.94 - 2.88 (m, 2H), 1.82 (m, 2H), 1.44 (s, 9H).

[0246] Synthesis of 3-(1-(but-3-en-1-yl)-1H-pyrrolo[3,2-c]pyridin-7-yl)-6-(methylthio)-1- (2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione:

[0247] Step 1: 3-(1-(but-3-en-1-yl)-1H-pyrrolo[3,2-c]pyridin-7-yl)-6-(methylthio)-1-(2,4,5- trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione. To a solution of 1-(but-3-en-1-yl)-1H- pyrrolo[3,2-c]pyridin-7-amine (4.4 g, 15.5 mmol, TFA salt), methyl (2,4,5-trifluorobenzyl)carbamimidothioate (4.4 g, 18.6 mmol) and DIPEA (11 mL) in DMF (45 mL) was added CDI (12.6 g, 77.5 mmoL) at 25oC under N2protection. The resulting mixture was stirred at 80 °C for 24 h. After cooled to room temperature. The reaction mixture was diluted with 200 mL of water, extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (70 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 10: 1 - 0: 1 to afford 3-(1-(but-3-en-1-yl)-1H-pyrrolo[3,2-c]pyridin-7-yl)-6- (methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (2.2 g, 24.7% yield). LC- MS m / z (ESI): [M+H]+474.3,1H-NMR (400 MHz, DMSO-D6) δ 8.84 (s, 1H), 8.22 (s, 1H), 7.70-7.60 (m, 2H), 7.46 (d, J = 3.2 Hz, 1H), 6.70 (d, J = 3.2 Hz, 1H), 5.69-5.59 (m, 1H), 5.28- 5.11 (m, 2H), 4.95-4.83 (m, 2H), 4.08-3.93 (m, 2H), 2.62 (s,3H), 2.34-2.22 (m, 2H).

[0248] Synthesis of 3-(4-(but-3-en-1-yloxy)-5-chloropyridin-3-yl)-6-(methylthio)-1-(2,4,5- trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione:

[0249] Step 1: 3-(4-(but-3-en-1-yloxy)-5-chloropyridin-3-yl)-6-(methylthio)-1-(2,4,5- trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione. To a solution of 4-(but-3-en-1-yloxy)-5- chloropyridin-3-amine (1.8 g, 9.1 mmol), methyl (2,4,5-trifluorobenzyl)carbamimidothioate (2.6 g, 10.9 mmol) and DIPEA (6.5 mL) in DMF (15 mL) was added CDI (7.4 g, 45.5 mmol) at 25oC under N2 protection. The resulting mixture was stirred at 80 °C for 24 h. After cooled to room temperature. The reaction mixture was diluted with 100 mL of water, extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=10: 1-0: 1 to afford 3-(4-(but-3-en-1- yloxy)-5-chloropyridin-3-yl)-6-(methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)- dione (1.5 g, 27.9% yield). LC-MS m / z (ESI): [M+H]+485.21H-NMR (400 MHz,METHANOL-D4) δ 8.30 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.46-7.39 (m, 1H), 7.27- 7.20 (m, 1H), 5.85-5.75 (m, 1H), 5.24 (s, 2H), 5.13-5.08 (m, 2H), 4.12 (t, J = 7.2 Hz, 2H), 2.62 (s, 3H), 2.61-2.56 (m, 2H).

[0250] Synthesis of tert-butyl (2-(5-amino-6-chloro-2-methyl-2H-indazol-4- yl)ethyl)(methyl)carbamate

[0251] Step 1: tert-butyl (2-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)ethyl)carbamate. To a mixture of potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (5.8 g, 23.1 mmol) and 4-bromo-6-chloro-2-methyl-indazol-5-amine (3.0 g, 11.6 mmol) in toluene (80 mL) and water (9 mL) was added potassium carbonate (4.8 g, 34.8 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.7 g, 2.3 mmol) at 25 °C under N2 protection. The resulting mixture was stirred at 95 °C for 12 h. After cooled to room temperature. The reaction mixture was diluted with 50 mL of water, extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 20: 1-1: 1 to give crude compound. The residue was purified by C18 column (0.5% NH3•H2O-MeCN system) to afford tert-butyl (2-(5-amino-6- chloro-2-methyl-2H-indazol-4-yl)ethyl)carbamate (1.0 g, 22.6% yield).

[0252] Step 2: 6-chloro-2-methyl-4-(2-(methylamino)ethyl)-2H-indazol-5-amine. To a mixture of tert-butyl (2-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)ethyl)carbamate (1.0 g, 3.1 mmol) in BH3-THF (20 mL, 1.0 M in THF) was stirred at 50 °C for 12 h under N2 protection. After cooled to room temperature. The reaction mixture was quenched with 30 mL of MeOH and 10mL of HCl (1.0 N). The mixture was stirred at 50 °C for 2 h. After cooled to room temperature. The mixture was diluted with 200 mL of saturated aqueous NaHCO3, extracted with ethyl acetate (150 mL × 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to afford 6-chloro-2-methyl- 4-(2-(methylamino)ethyl)-2H-indazol-5-amine (500 mg crude). LC-MS m / z (ESI): [M+H]+239.1

[0253] Step 3: tert-butyl (2-(5-amino-6-chloro-2-methyl-2H-indazol-4- yl)ethyl)(methyl)carbamate. To a solution of 6-chloro-2-methyl-4-(2-(methylamino)ethyl)-2H- indazol-5-amine (500 mg, 2.09 mmol) in DCM (8 mL) was added (Boc)2O (915 mg, 4.19 mmol) and TEA (0.5 g, 4.6 mmol) at 25oC under N2 protection. The resulting mixture was stirred at 25 °C for 1 h. The mixture was concentrated and purified by silica gel chromatography eluted with PE: THF=30: 1-1: 1 to afford tert-butyl (2-(5-amino-6-chloro-2-methyl-2H-indazol-4- yl)ethyl)(methyl)carbamate (510 mg, 71.8% yield). LC-MS m / z (ESI): [M+H]+339.2, 1H-NMR (400 MHz, DMSO-D6) δ 8.03 (d, J = 16.0 Hz, 1H), 7.51 (s, 1H), 4.73 (d, J = 57.2 Hz, 2H), 4.07 (s, 3H), 3.41-3.34 (m, 1H), 3.30-3.25 (m, 1H), 2.94-2.90 (m, 2H), 2.80 (s, 3H), 1.32 (d, J = 74.8 Hz, 9H).

[0254] Synthesis of 3-((3-(4-(allyloxy)-5-chloropyridin-3-yl)-6-(methylthio)-2,4-dioxo-3,4- dihydro-1,3,5-triazin-1(2H)-yl)methyl)-4-methylbenzonitrile:3-chloro-5- nitropyridin-4-ol4-(allyloxy)-3-chloro-5-nitropyridine 4-(allyloxy)-5-chloropyridin-3-aminemethyl (5-cyano-2- methylbenzyl)carbamimidothioate3-((3-(4-(allyloxy)-5-chloropyridin-3-yl)-6-(methylthio)-2,4-dioxo-3,4-dihydro-1,3,5- triazin-1(2H)-yl)methyl)-4-methylbenzonitrile

[0255] Step 1: 4-(allyloxy)-3-chloro-5-nitropyridine. To a solution of 3-chloro-5-nitropyridin-4- ol (25 g, 143.2 mmoL) and 3-bromoprop-1-ene (70 g, 573 mmoL) in ACN (500 mL) wasadded K2CO3 (59.4 g, 429.7 mmoL) at 25 °C under N2 protection. The resulting mixture was stirred at 70 °C for 16 h. After cooled to room temperature. The suspension was filtered and filter cake was washed with EtOAc (100 mL x 2). The combined filtrates were concentrated and purified by silica gel chromatography eluted with DCM: THF = 10: 1 to 4: 1 to afford 21.2 g (68.9% yield) of 4-(allyloxy)-3-chloro-5-nitropyridine. LC-MS m / z (ESI): [M+H]+215.0

[0256] Step 2: 4-(allyloxy)-5-chloropyridin-3-amine. To a solution of 4-(allyloxy)-3-chloro-5- nitropyridine (21.0 g, 97.9 mmoL) and Fe powder (32.5 g, 582.5 mmoL) in methanol (250 mL) and water (60 mL) was added aqueous solution NH4Cl. The resulting mixture was stirred at 75 °C for 2 h. After cooled to room temperature. The suspension was filtered and filter cake was washed with EtOAc (100 mL x 2). The mixture solution was diluted with 600 mL of water, extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: THF =10: 1-1: 3 to afford 14.8 g (81.9% yield) of 4-(allyloxy)-5-chloropyridin-3-amine.

[0257] Step 3: 3-((3-(4-(allyloxy)-5-chloropyridin-3-yl)-6-(methylthio)-2,4-dioxo-3,4-dihydro- 1,3,5-triazin-1(2H)-yl)methyl)-4-methylbenzonitrile. To a solution of methyl (5-cyano-2- methylbenzyl)carbamimidothioate (4.8 g, 21.9 mmoL) and 4-(allyloxy)-5-chloropyridin-3-amine (4.5 g, 24.4 mmol) in DMF (10 mL) and TEA (3 mL) was added CDI (17.1 g, 105.5 mmol) at 25oC under N2protection. The resulting mixture was stirred at 50 °C for 14 h. After cooled to room temperature. The reaction mixture was diluted with 100 mL of water, extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product purified by silica gel chromatography eluted with PE: THF=30: 1-0: 1 to give crude product. The crude product was slurry with EtOH (10 mL x 3) to afford 3.7 g (37.1% yield) of 3-((3-(4-(allyloxy)-5- chloropyridin-3-yl)-6-(methylthio)-2,4-dioxo-3,4-dihydro-1,3,5-triazin-1(2H)-yl)methyl)-4- methylbenzonitrile. LC-MS m / z (ESI): [M+H]+456.1, 1H-NMR (400 MHz, DMSO-D6) δ 8.34 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 6.10-6.00 (m, 1H), 5.36-5.22 (m, 3H), 5.05 (d, J = 17.6 Hz, 1H), 4.73-4.64 (m, 2H), 2.53 (s, 3H), 2.43 (s, 3H).

[0258] Synthesis of 3-((3-(4-(but-3-en-1-yloxy)-5-chloropyridin-3-yl)-6-(methylthio)-2,4- dioxo-3,4-dihydro-1,3,5-triazin-1(2H)-yl)methyl)-4-chlorobenzonitrile:

[0259] Step 1: 3-((3-(4-(but-3-en-1-yloxy)-5-chloropyridin-3-yl)-6-(methylthio)-2,4-dioxo-3,4- dihydro-1,3,5-triazin-1(2H)-yl)methyl)-4-chlorobenzonitrile To a solution of methyl (2-chloro-5- cyanobenzyl)carbamimidothioate (3.3 g, 13.8 mmol, 1.0 eq) and 4-(but-3-en-1-yloxy)-5- chloropyridin-3-amine (3.0 g, 15.1 mmol, 1.1 eq) in DMF (40 mL) was added CDI (4.5 g, 27.5 mmol, 2.0 eq) and DIPEA (3.6 g, 27.5 mmol, 2.0 eq) at 0 °C under N2protection. The resulting mixture was stirred at 50 °C for 14 h. After cooled to room temperature. The reaction mixture was diluted with 80 mL of water, extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with PE: EtOAc = 1: 1 to afford 1.7 g (25.2% yield) of 3-((3-(4-(but-3-en-1-yloxy)-5- chloropyridin-3-yl)-6-(methylthio)-2,4-dioxo-3,4-dihydro-1,3,5-triazin-1(2H)-yl)methyl)-4- chlorobenzonitrile. LC-MS m / z (ESI): [M+H]+490.1,1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.66 (s, 1H), 7.78-7.70 (m, 2H), 7.61 (s, 1H), 5.90-5.78 (m, 1H), 5.63-5.50 (m, 2H), 5.33- 5.27 (m, 1H), 5.18-5.13 (m, 1H), 4.65-4.58 (m, 2H), 2.87-2.80 (m, 2H), 2.73 (m, 3H).

[0260] Synthesis of methyl 3-((3-chloro-5-(4-(methylthio)-2,6-dioxo-3-(2,4,5- trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)pyridin-4-yl)methyl)benzoate: hmethyl 3- step 2 100 °C, 2 h (bromomethyl) methyl 3-((4,4,5,5- benzoate Step 1 tetramethyl-1,3,2- dioxaborolan-2- yl)methyl)benzoatestep 3 methyl 3-((3-amino-5- methyl 3-((3-chloro-5- chloropyridin-4- nitropyridin-4-yl)methyl)benzoate yl)methyl)benzoatemethyl 3-((3-chloro-5-(4-(methylthio)-2,6-dioxo-3- (2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)- yl)pyridin-4-yl)methyl)benzoate

[0261] Step 1: methyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)benzoate. To a solution of methyl 3-(bromomethyl)benzoate (30 g, 130.9 mmol, 1.0 eq), B2Pin2(36.6 g, 144 mmol, 1.1 eq) and KOAc (25.7 g, 261.9 mmol, 2.0eq) in dioxane (300 mL) was added Pd(dppf)Cl2 (4.8 g, 6.6 mmol, 0.05 eq) at 25 °C under N2 protection. The resulting mixture was stirred at 100 °C for 2 h. After cooled to room temperature. The reaction mixture was diluted with 300 mL of water, extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: THF = 3: 1 to afford 28.5 g (78.8% yield) of methyl 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)methyl)benzoate.

[0262] Step 2: methyl 3-((3-chloro-5-nitropyridin-4-yl)methyl)benzoate. To a solution of 4- bromo-3-chloro-5-nitropyridine (24.1 g, 101.4 mmol, 1.0 eq), methyl 3-((4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)methyl)benzoate (28.0 g, 101.4 mmol, 1.0 eq), Na2CO3(32.2 g, 304.2 mmol, 3.0 eq) in dioxane (2400 mL) and H2O (240 mL) was added Pd(dppf)Cl2 (3.7 g, 5.07 mmol, 0.05 eq) at 25 °C under N2 protection. The resulting mixture was stirred at 80 °C for 14 h. After cooled to room temperature. The reaction mixture was diluted with 300 mL of water, extracted with ethyl acetate (200 mL x 3). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: THF = 1: 1 to afford 8.2 g (26.4% yield) of methyl 3-((3-chloro-5-nitropyridin-4- yl)methyl)benzoate.

[0263] Step 3: methyl 3-((3-amino-5-chloropyridin-4-yl)methyl)benzoate. To a solution of methyl 3-((3-chloro-5-nitropyridin-4-yl)methyl)benzoate (8.2 g, 26.74 mmol, 1.0 eq) and Fe powder (7.5 g, 133.7 mmol, 5.0 eq) in MeOH (100 mL) was added aqueous solution NH4Cl (20 mL) at 25 °C. The resulting mixture was stirred at 60 °C for 2 h. After cooled to room temperature. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography eluted with PE: THF = 1: 1 to afford 4.5 g (60.8% yield) of methyl 3-((3-amino-5-chloropyridin-4-yl)methyl)benzoate. LC-MS m / z (ESI): [M+H]+277.1

[0264] Step 4: methyl 3-((3-chloro-5-(4-(methylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)pyridin-4-yl)methyl)benzoate. To a solution of methyl 3-((3- amino-5-chloropyridin-4-yl)methyl)benzoate (3.6 g, 13.0 mmol, 1.0 eq), methyl (2,4,5- trifluorobenzyl)carbamimidothioate (3.1 g, 13.0 mmol, 1.0 eq) and CDI (10.6 g, 65.0 mmol, 5.0 eq) in DMF (72 mL) was added DIPEA (8.4 g, 65.0 mmol, 5.0 eq) at 25 °C under N2protection. The resulting mixture was stirred at 50 °C for 14 h. The reaction mixture was diluted with 144 mL of water and extracted with ethyl acetate (72 mL x 3). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: THF = 1: 1 to afford 2.2 g (30.0% yield) of methyl 3-((3- chloro-5-(4-(methylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)- yl)pyridin-4-yl)methyl)benzoate. LC-MS m / z (ESI): [M+H]+563.2,1H NMR (400 MHz, Methanol-d4) δ 8.73 (s, 1H), 8.45 (s, 1H), 7.86-7.82 (m, 1H), 7.71 (s, 1H), 7.35-7.15 (m, 4H), 5.10-4.98 (m, 2H), 4.28-4.15 (m, 2H), 3.87 (s, 3H), 2.58 (s, 3H).

[0265] Synthesis of 4-bromo-6-chloro-2-(2-methoxyethyl)-2H-indazol-5-amine

[0266] Step 1: 6-chloro-2-(2-methoxyethyl)-5-nitro-2H-indazole.To a solution of 6-chloro-5- nitro-1H-indazole (200 g, 1.0 mol, 1.0 eq) and K2CO3(207 g, 1.5 mol, 1.5 eq) in DMF (2000 mL) was added 1-bromo-2-methoxyethane (207 g, 1.5 mol, 1.5 eq) at 25oC under N2protection. The resulting mixture was stirred at 95 °C for 16 h. After cooled to room temperature. The mixture was diluted with 1000 mL of water, extracted with DCM (1000 mL x 3). The combined organic layers were washed with brine (1000 mL x 3), dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with PE: EtOAc = 1: 1 to afford 84.0 g (32.44% yield) of 6-chloro-2-(2-methoxyethyl)-5- nitro-2H-indazole. LC-MS m / z (ESI): [M+H]+256.2

[0267] Step 2: 6-chloro-2-(2-methoxyethyl)-2H-indazol-5-amine. To a solution of 6-chloro-2- (2-methoxyethyl)-5-nitro-2H-indazole (84.0 g, 0.33 mol, 1.0 eq) in MeOH (850 ml) and Fe powder (92.4 g, 1.65 mol, 5.0 eq) was added aqueous solution NH4Cl (200 mL) at 25oC under N2protection. The resulting mixture was stirred at 80 °C for 24 h. After cooled to room temperature. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was diluted with 1000 mL of water, extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with PE: EtOAc = 1: 1 to afford 58.0 g (78% yield) of 6-chloro-2-(2-methoxyethyl)-2H-indazol-5-amine.

[0268] Step 3: 4-bromo-6-chloro-2-(2-methoxyethyl)-2H-indazol-5-amine. To a solution of 6- chloro-2-(2-methoxyethyl)-2H-indazol-5-amine (58 g, 0.26 mol, 1.0 eq) in i-PrOAc (440 mL) and AcOH (145 mL) was added NBS (46.3 g, 0.26 mol, 1.0 eq) at -30oC under N2 protection. The resulting mixture was stirred at 5 °C for 4 h. The resulting mixture was diluted with 500 mLof water, extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with PE: EtOAc = 1: 1 to afford 28.3 g (36% yield) of 4-bromo-6-chloro-2-(2-methoxyethyl)-2H-indazol-5-amine. LC-MS m / z (ESI): [M+H]+304.0, 1H-NMR (400 MHz, Chloroform-D) δ 7.78 (s, 1H), 7.66 (s, 1H), 4.51 (t, J = 5.0 Hz, 2H), 3.84 (t, J=5.0 Hz, 2H), 3.34 (s, 3H).

[0269] Synthesis of 4-(but-3-en-1-yl)-6-chloro-2-methyl-2H-indazol-5-amine:

[0270] Step 1: 6-chloro-4-(methoxymethyl)-2-methyl-2H-indazol-5-amine. To a solution of potassium; trifluoro(methoxymethyl)boranuide (2.6 g, 17.1 mmol), 4-bromo-6-chloro-2- methyl-2H-indazol-5-amine (2.0 g, 7.7 mmol) and K2CO3(3.4 g, 24.6 mmol) in dioxane (200 mL) and in H2O (40 mL) was added Pd(dppf)Cl2(650 mg, 0.9 mmol) at 25 °C under N2protection. The resulting mixture was stirred at 95 °C for 12 h. The same reaction was repeated 8 times. After cooled to room temperature. The reaction mixture was diluted with 40 mL of water, extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 2:1 to give crude compound and then the crude product was purified by C18 column (0.5% NH3•H2O-ACN system) to afford 3.65 g (31.6% yield) of 6-chloro-4-(methoxymethyl)-2-methyl-2H-indazol-5- amine.

[0271] Step 2: 4-(but-3-en-1-yl)-6-chloro-2-methyl-2H-indazol-5-amine. To solution of 6- chloro-4-(methoxymethyl)-2-methyl-2H-indazol-5-amine (3.6 g, 16.0 mmol) in THF (40 mL) was added allyl(bromo)magnesium (25 mL, 1 M in THF) dropwise at 0 °C under N2 protection. The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with 100mL of saturated aqueous NH4Cl, extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc = 2:1 to give crude compound. The crude product was purified by C18 column (0.5% NH3•H2O-ACN system) to afford 2.1 g (57.5% yield) of 4-(but-3- en-1-yl)-6-chloro-2-methyl-2H-indazol-5-amine. LC-MS m / z (ESI): [M+H]+236.1, 1H-NMR (400 MHz, CHLOROFORM-D) δ 7.67 (s, 1H), 7.60 (s, 1H), 5.93-5.86 (m, 1H), 5.13-5.12 (m, 1H), 5.03-5.00 (m, 1H), 4.16 (s, 3H), 3.68 (br, s, 1H), 2.85-2.80 (m, 2H), 2.42-2.36 (m, 2H).

[0272] Synthesis of tert-butyl 3-((5-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)methyl)benzoate:

[0273] Step 1: tert-butyl 3-(bromomethyl)benzoate. To a solution of 3-(bromomethyl)benzoic acid (10.0 g, 46.5 mmol) in DCM (100 mL) and cyclohexane (185 mL) was added tert-butyl 2,2,2-trichloroethanimidate (20.3 g, 93.0 mmol) in cyclohexane (60 mL)，then boron trifluoride diethyl etherate (1.4 g, 9.4 mmol) was added dropwise in sequence at 0oC under N2protection. The resulting mixture was stirred at 25 °C for 5 h. Then solid NaHCO3(10 g) was added and stirred at 25 °C for 5 h. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=100: 1 to 20: 1 to afford tert-butyl 3-(bromomethyl)benzoate (11.1 g, 87.9% yield).

[0274] Step 2: methyl 1-(3-(tert-butoxycarbonyl)benzyl)-1H-1,2,4-triazole-5-carboxylate and methyl 1-(3-(tert-butoxycarbonyl)benzyl)-1H-1,2,4-triazole-3-carboxylate. To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (6.1 g, 47.9 mmol) and tert-butyl 3-(bromomethyl)benzoate (10 g, 36.9 mmol) in CH3CN (150 mL) was added K2CO3 (6.1 g, 44.3 mmol) at 25oC under N2protection. The resulting mixture was stirred at 110 °C for 1 h. After cooled to room temperature. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was purified by C18 column (0.5% FA-MeCN system) to afford methyl 1- (3-(tert-butoxycarbonyl)benzyl)-1H-1,2,4-triazole-5-carboxylate (1.9 g, 16.2% yield) as colorless oil and methyl 1-(3-(tert-butoxycarbonyl)benzyl)-1H-1,2,4-triazole-3-carboxylate (6.9 g, 58.8% yield).

[0275] Step 3: tert-butyl 3-((5-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)methyl)benzoate. To a solution of methyl 1-(3-(tert-butoxycarbonyl)benzyl)-1H-1,2,4-triazole-5-carboxylate (4.3 g, 13.6 mmol) in THF (30 mL), methanol (35 mL) and water (3.5 mL) was added NaBH4(2.1 g, 55.2 mmol) in 5 portions at 0oC under N2 protection. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with 100 mL of water, extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: THF = 1: 1 to afford tert-butyl 3-((5- (hydroxymethyl)-1H-1,2,4-triazol-1-yl)methyl)benzoate (2.5 g, 63.8% yield). LC-MS m / z (ESI): [M+H]+290.2.

[0276] Step 4: tert-butyl 3-((5-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)methyl)benzoate. To a solution of tert-butyl 3-((5-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)methyl)benzoate (2.5 g, 8.6 mmol) and 6-ethylsulfanyl-1-[(2,4,5- trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione (2.7 g, 8.6 mmol) and TBUP (2.6 g, 12.9 mmol) in THF (30 mL) was added TMAD (2.3 g, 13.3 mmol) at 0oC under N2protection. The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with 100 mL of H2O, extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: THF = 30: 1- 0:1 to give crude product (4.0 g, crude). The crude product was purified by Prep- HPLC (0.5% NH4HCO3-MeCN system) to afford tert-butyl 3-((5-((4-(ethylthio)-2,6-dioxo-3- (2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1- yl)methyl)benzoate (2.03 g, 39.9% yield). LC-MS m / z (ESI): [M+H]+589.3, 1H-NMR (400 MHz, CHLOROFORM-D) δ 7.94 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.86 (s, 1H), 7.43-7.39 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H),7.15-7.08 (m, 1H), 6.99-6.92 (m, 1H), 5.55 (s, 2H), 5.16 (s, 2H), 5.11 (s, 2H), 3.21-3.16 (m, 1H), 1.59 (s, 9H), 1.35 (t, J = 7.2 Hz, 3H).

[0277] Synthesis of tert-butyl 3-((3-((4-(methylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)methyl)benzoate:

[0278] Step 1: tert-butyl 3-((3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)methyl)benzoate. To a solution of methyl 1-(3-(tert-butoxycarbonyl)benzyl)-1H-1,2,4-triazole-3-carboxylate (5.0 g, 15.8 mmol) in THF (40 mL), methanol (40 mL) and water (4.5 mL) was added NaBH4(2.5 g,66.1 mmol) in 5 portions under N2 protection. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with 80 mL of water, extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: THF=5:1 - 0:1 to afford tert-butyl 3-((3-(hydroxymethyl)-1H- 1,2,4-triazol-1-yl)methyl)benzoate (3.1 g, 67.9% yield). LC-MS m / z (ESI): [M+H]+290.1.

[0279] Step 2: tert-butyl 3-((3-((4-(methylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)methyl)benzoate. To a solution of tert-butyl 3-((3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)methyl)benzoate (3.0 g, 10.4 mmol), 6- ethylsulfanyl-1-[(2,4,5- trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione (3.3 g, 10.4 mmol) and TBUP (3.2 g, 15.6 mmol) in THF (40 mL) was added TMAD (2.7 g, 15.6 mmol) at 0oC h under N2protection. The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was added 100 mL of water, extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: THF=30: 1- 0: 1 to give 4.9 g (crude). The crude product was purified by Prep-HPLC (0.5% NH4HCO3-MeCN system) to afford tert-butyl 3-((3-((4-(methylthio)-2,6-dioxo-3-(2,4,5- trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1- yl)methyl)benzoate (2.31 g, 38% yield). LC-MS m / z (ESI): [M+H]+589.3, 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.00-7.97 (m, 2H), 7.91 (s, 1H), 7.45-7.37 (m, 2H), 7.19-7.12 (m, 1H), 6.99-6.92 (m, 1H), 5.33 (s, 2H), 5.28 (s, 2H), 5.19 (s, 2H), 3.26-3.20 (m, 1H), 1.59 (s, 9H), 1.36 (t, J = 7.2 Hz, 3H).

[0280] Synthesis of tert-butyl 4-(5-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)butanoate:

[0281] Step 1: methyl 1-(4-(tert-butoxy)-4-oxobutyl)-1H-1,2,4-triazole-5-carboxylate. To a solution of methyl 1H-1,2,4-triazole-3-carboxylate (25 g, 196.7 mmol, 1.0 eq) and tert-butyl 2- bromoacetate (43.9 g, 196.7 mmol, 1.0 eq) in CH3CN (250 mL) was added K2CO3(54.4 g, 393.4 mmol, 2.0 eq) at 25 °C under N2 protection. The reaction mixture was stirred at 25 °C for 14 h.The reaction mixture was diluted with 500 mL of water, extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by chromatography column with PE: THF = 10: 1 to afford 6.1 g (11.5% yield) of methyl 1-(4-(tert-butoxy)-4- oxobutyl)-1H-1,2,4-triazole-5-carboxylate and 9.5 g (17.9% yield) of methyl 1-(4-(tert-butoxy)- 4-oxobutyl)-1H-1,2,4-triazole-3-carboxylate.ep methyl 1-(4-(tert-butoxy)-4- tert-butyl 4-(5-(hydroxymethyl)-1H- oxobutyl)-1H-1,2,4-triazole-5- 1,2,4-triazol-1-yl)butanoate carboxylatetert-butyl 4-(5-((4-(ethylthio)-2,6-dioxo-3-(2,4,5- trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)- yl)methyl)-1H-1,2,4-triazol-1-yl)butanoate

[0282] Step 2: tert-butyl 4-(5-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)butanoate. To a solution of methyl 1-(4-(tert-butoxy)-4-oxobutyl)-1H-1,2,4-triazole-5-carboxylate (6.1 g, 22.7 mmol 1.0 eq) in MeOH (60 mL) and H2O (6 mL) was added NaBH4(1.3 g, 34 mmol, 1.5 eq) at 0 °C under N2 protection. The resulting mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with 120 mL of water, extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by chromatography column with PE: THF = 5: 1 to afford 3.5 g (64.0% yield) of tert-butyl 4-(5-(hydroxymethyl)-1H-1,2,4-triazol-1- yl)butanoate.

[0283] Step 3: tert-butyl 4-(5-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)butanoate. To a solution of tert-butyl 4-(5-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)butanoate (3.5 g, 14.5 mmol, 1.0 eq), 6-(ethylthio)-1- (2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (4.6 g, 14.5 mmol, 1.0 eq) and TBUP (5.9 g, 29 mmol, 2.0 eq) in THF (40 mL) was added TMAD (5.0 g, 29 mmol, 2.0 eq) dropwise at 20 °C under N2 protection. The resulting mixture was stirred at 65 °C for 14 h. After cooled to room temperature. The resulting mixture was quenched with 100 mL of water, extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by chromatography column with PE: THF = 1: 1 to give 4.1 g (crude). The crude product was purified by Prep-HPLC (0.5% NH4HCO3-MeCN system) to afford 2.04 g (26.0% yield) of tert-butyl 4-(5-((4-(ethylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5- triazin-1(2H)-yl)methyl)-1H-1,2,4-triazol-1-yl)butanoate. LC-MS m / z (ESI): [M+H]+541.3,1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.36-7.30 (m, 1H), 7.27-7.20 (m, 1H), 5.21 (s, 2H), 5.16 (s, 2H), 4.21 (t, J = 6.8 Hz, 3H), 3.23 (q, J = 7.4 Hz, 3H), 2.23 (t, J = 7.2 Hz, 1H), 2.09 (q, J = 7.2 Hz, 2H), 1.42 (s, 10H), 1.36 (t, J = 7.4 Hz, 4H).

[0284] Synthesis of tert-butyl ((4-(4-(methylthio)-2,6-dioxo-3-(3,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)methyl)carbamate:

[0285] Step 1. N-(5-chloroisoquinolin-4-yl)-1,1-diphenylmethanimine hydrobromide. To 4- bromo-5-chloroisoquinoline (48.0 g, 198 mmol) and benzophenone imine (35.7 mL, 202 mmol) in dioxane (480 mL) were added Cs2CO3(130.0 g, 396 mmol), Pd2(dba)3(16.6 g, 17.8 mmol), and Xantphos (21.7 g, 35.6 mmol) and the reaction mixture was purged with N2 for 5 min. The reaction vessel was placed in an oil bath and the reaction was stirred at 90 °C for 20 h. The reaction mixture was cooled down to rt, water (460 mL) was added, stirred for 30 min and the product was collected by filtration. The solid was washed with water (3 x 100 mL), dried, and triturated in MeOH (2 x 250 mL) to obtain N-(5-chloroisoquinolin-4-yl)-1,1- diphenylmethanimine (85.0 g, quant.) (HBr salt assumed):1H NMR (400 MHz, DMSO-d6): δ=8.90 (s, 1H), 8.04 (dd, J = 8.2, 0.9 Hz, 1H), 7.87 (dd, J = 7.5, 1.1 Hz, 1H), 7.80 – 7.73 (m, 2H), 7.67 (s, 1H), 7.65 – 7.56 (m, 2H), 7.56 – 7.49 (m, 2H), 7.32 – 7.25 (m, 3H), 7.24 – 7.16 (m, 2H); MS (ES+, m / z): [M+H]+ = 343.2 / 345.2 (free base).

[0286] Step 2.5-Chloroisoquinolin-4-amine. To a suspension of N-(5-chloroisoquinolin-4-yl)- 1,1-diphenylmethanimine (75.0 g, 177 mmol) in THF (885 mL) was added HCl (177 mL, 177 mmol) (1M solution in water), and the suspension was stirred at rt for 16 h, more HCl (1M solution in water, 88.5 mL, 88.5 mmol) was added and stirring was continued for another 24 h (40 h in total), The reaction mixture was concentrated down, the residue was acidified with aq. 1M HCl (300 mL) and EtOAc (200 mL) was added. The biphasic (water / THF and EtOAc) mixture was filtered through fritted glass funnel to remove solid residue. The layers of the filtrate solution were separated. The aq. layer was washed with EtOAc (2 x 150 mL), the water layer was cooled to 0°C and basified with solid K2CO3to pH 9. The desired product precipitated from water. It was collected by filtration, dissolved in DCM (1 L), washed with brine (300 mL), dried over Na2SO4, filtered, DCM was evaporated and the solid was triturated in MTBE to obtain 5- chloroisoquinolin-4-amine (24.5 g, 77 %):1H NMR (400 MHz, DMSO-d6): δ = 8.51 (s, 1H), 7.97 (s, 1H), 7.88 (dd, J = 8.2, 1.1 Hz, 1H), 7.64 (dd, J = 7.4, 1.2 Hz, 1H), 7.54 – 7.42 (m, 1H), 6.07 (s, 2H); MS (ES+, m / z): [M+H]+ = 179.0 / 180.9.

[0287] Step 3. tert-Butyl ((4-aminoisoquinolin-5-yl)methyl)carbamate. To a mixture of 5- chloroisoquinolin-4-amine (2.30 g, 12.70 mmol) and potassium (((tert-butoxy- carbonyl)amino)methyl)trifluoroborate (9.54 g, 38.20 mmol), dioxane (120 mL) and H2O (12 mL) were added. N2 was bubbled through the reaction for 5 min, Cs2CO3 (17.0 g, 51.00 mmol), Pd(OAc)2(286.0 mg, 1.27 mmol) and cataCXium A (962.0 mg, 2.55 mmol) were added to the mixture, N2was bubbled for another 5 min, the mixture was heated at 110°C for 16 h. The solvent was evaporated, the mixture was partitioned between EtOAc and brine, the organic layer was separated, dried over Na2SO4, and purified by silica gel chromatography (0-100% EA in heptanes) to provide tert-butyl ((4-aminoisoquinolin-5-yl)methyl)carbamate (1.44 g, 41 %):1H NMR (400 MHz, CDCl3): δ = 8.67 (s, 1H), 7.97 (s, 1H), 7.81 (dd, J = 8.0, 1.4 Hz, 1H), 7.53 – 7.40 (m, 2H), 5.37 (s, 1H), 4.80 (d, J = 5.7 Hz, 2H, 4.43 (s, 2H), 1.44 (s, 9H); MS (ES+, m / z): [M+H]+ = 274.1.

[0288] Step 4. tert-butyl (E)-((4-(3-((methylthio)((3,4,5- trifluorobenzyl)amino)methylene)ureido)isoquinolin-5-yl)methyl)carbamate. To a solution of tert-butyl ((4-aminoisoquinolin-5-yl)methyl)carbamate (1.44 g, 5.16 mmol) in THF (100 mL) was added TEA (2.2 mL, 15.50 mmol) and then triphosgene (625.0 mg, 2.07 mmol) solution in THF (100 mL) at 0 ºC. The resulting mixture was degassed with N2 for 5 min and then stirred at0 ºC for 1 h under N2 atm. To the mixture was added methyl 3,4,5- trifluorobenzylcarbamimidothioate (1.35 g, 5.16 mmol) in THF (100 mL), and the mixture was stirred for an additional 1 h at 0 ºC under N2. The reaction was quenched with water, the mixture was partitioned between EtOAc and brine, the organic layer was separated, dried over Na2SO4, and the solvent was evaporated to obtain tert-butyl (E)-((4-(3-((methylthio)((3,4,5- trifluorobenzyl)amino)methylene)ureido)isoquinolin-5-yl)methyl)carbamate (3.11 g, quant.). The material was used for the next step without purification: MS (ES+, m / z): [M+H]+ = 534.0.

[0289] Step 5. tert-Butyl ((4-(4-(methylthio)-2,6-dioxo-3-(3,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)methyl)carbamate. To a solution of tert-butyl (E)-((4- (3-((methylthio)((3,4,5-trifluorobenzyl)amino)methylene)ureido)isoquinolin-5-yl)methyl)- carbamate (3.11 g, 5.19 mmol) in MeCN (60 mL), was added DIPEA (2.7 mL, 15.60 mmol) and the reaction mixture was stirred for 15 min at rt. Then, CDI (1.33 g, 7.78 mmol) was added and the reaction was stirred at 80 ºC for 1 h. The solvent was evaporated and the crude material was purified by silica gel column chromatography (0-100% EA in heptanes) to provide tert-butyl ((4- (4-(methylthio)-2,6-dioxo-3-(3,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)- yl)isoquinolin-5-yl)methyl)carbamate (2.30 g, 75 %):1H NMR (400 MHz, CDCl3): δ = 9.35 (s, 1H), 8.40 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.72 – 7.63 (m, 1H), 7.22 – 7.08 (m, 2H), 5.26 – 5.05 (m, 2H), 4.74 (s, 1H), 4.53 – 4.40 (m, 2H), 2.75 – 2.69 (m, 3H), 1.45 (s, 9H);19F NMR (376 MHz, CDCl3): δ = -132.02 – -132.33 (m, 1F), -159.10 – -159.66 (m, 1F); MS (ES+, m / z): [M+H]+ = 560.0.

[0290] Synthesis of tert-butyl 3-(4-(methylthio)-2,6-dioxo-3-(3,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)isonicotinate:

[0291] Step 1. tert-Butyl (E)-3-(3-((methylthio)((3,4,5- trifluorobenzyl)amino)methylene)ureido)isonicotinate. To a solution of tert-butyl 3- aminoisonicotinate (500.0 mg, 2.450 mmol) in dry THF (13.6 mL), cooled to 0 °C, was added TEA (1.03 mL, 7.340 mmol) followed by a solution of triphosgene (296.0 mg, 0.978 mmol) in dry THF (8.2 mL). The resulting mixture was purged with N2 for 5 min then stirred at 0 °C for 1 h under N2 atmosphere. Methyl (3,4,5-trifluorobenzyl)carbamimidothioate (624.0 mg, 2.490 mmol) was then added and the reaction mixture was stirred at 0 °C for 2.5 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (2 x 20 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude tert-butyl (E)-3-(3-((methylthio)((3,4,5-trifluorobenzyl)amino)methylene)ureido)isonicotinate (1.20 g, 95 %). The product was used directly in next step without further purification:1H NMR (400 MHz, CD3OD): δ = 9.75 (br. s, 1H), 8.23 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 5.2 Hz, 1H), 7.19 – 7.10 (m, 2H), 4.57 (s, 2H), 2.48 (s, 3H), 1.63 (s, 9H), 2H are exchanged with CD3OD;19F NMR (376MHz, CD3OD): δ = -136.37 – -137.41 (m, 2F), -165.08 – -166.60 (m, 1F); MS (ES+, m / z): [M+H]+ = 455.3.

[0292] Step 2. tert-Butyl 3-(4-(methylthio)-2,6-dioxo-3-(3,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)isonicotinate. To a solution of tert-butyl (E)-3-(3-((methylthio)((3,4,5- trifluorobenzyl)amino)methylene)ureido)isonicotinate (1.08 g, 2.090 mmol) in dry toluene (8.4 mL), was added TEA (0.88 mL, 6.270 mmol) and the reaction mixture was stirred 15 min at rt. Triphosgene (253.0 mg, 0.836 mmol) was then added portionwise and the reaction was stirred at 100 °C for 3 h. The reaction mixture was cooled down to rt, more TEA (0.29 mL, 2.090 mmol) and triphosgene (190.0 mg, 0.627 mmol) were added (portionwise) and reaction was stirred again at 100 °C for 2 h. The reaction mixture was cooled down to rt and concentrated under reduced pressure. Residue was purified by C18 column chromatography (5- 100% MeCN in 10 mM aq. NH4HCO3) to provide tert-butyl 3-(4-(methylthio)-2,6-dioxo-3-(3,4,5-trifluorobenzyl)- 3,6-dihydro-1,3,5-triazin-1(2H)-yl)isonicotinate (213.0 mg, 17 %):1H NMR (400 MHz, CD3OD): δ = 8.81 (d, J = 5.1 Hz, 1H), 8.68 (d, J = 0.4 Hz, 1H), 8.00 (dd, J = 5.1, 0.5 Hz, 1H), 7.26 (dd, J = 8.5, 6.6 Hz, 2H), 5.41 (d, J = 16.8 Hz, 1H), 5.10 (d, J = 16.8 Hz, 1H), 2.65 (s, 3H), 1.50 (s, 9H);19F NMR (376 MHz, CD3OD): δ = -136.01 – -136.14 (m, 2F), -164.33 (m, 1F); MS (ES+, m / z): [M+H]+ = 481.3.

[0293] Example 2: Synthesis of (Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacyclodecaphane-22,24-dione (Compound 1)

[0294] Step 1.6-{[2-(But-3-en-1-yloxy)-6-chloro-4-methoxyphenyl]amino}-3-[5-(prop-2-en- 1-yl)isoquinolin-4-yl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione. To a solution of 6-(methylsulfanyl)-3-[5-(prop-2-en-1-yl)isoquinolin-4-yl]-1-[(2,4,5- trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione (75 mg, 0.16 mmol) and 2-(but-3-en-1-yloxy)- 6-chloro-4-methoxyaniline (45 mg, 0.20 mmol) in 1.3 mL THF at -78C was added 0.36 mL of a 1 M solution of LiHMDS in THF (0.36 mmol) and the mixture stirred for 4 h at -78oC then diluted with 1 M NH4Cl and EtOAc, partitioned and the organic layer dried (MgSO4) and evaporated. The residue was subjected to chromatography (12 g SiO2, 5% EtOAc for 3 min then 5-15% EtOAc in hexanes over 12 min) to provide 14 mgs (13%) of 6-{[2-(but-3-en-1-yloxy)-6- chloro-4-methoxyphenyl]amino}-3-[5-(prop-2-en-1-yl)isoquinolin-4-yl]-1-[(2,4,5- trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione: [M+H]+ 650.3.

[0295] Step 2. (25Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro- 5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclodecaphan-8-ene-22,24- dione. A solution of 6-{[2-(but-3-en-1-yloxy)-6-chloro-4-methoxyphenyl]amino}-3-[5-(prop-2- en-1-yl)isoquinolin-4-yl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione (15 mg, 0.023 mmol) in 1.2 mL toluene was added dropwise to a solution of Grubbs catalyst M204 (2.9 mg, 0.003 mmol) in 1.0 mL toluene with a constant flow of N2 bubbling into it at 100 ℃. Then the mixture was stirred at 100 ℃ with N2bubbling into it for 60 min. Then more Grubbs catalyst M204 (2.9 mg, 0.003 mmol) was added and the mixture continued heating at 100 ℃ for 1h. Thesolvent was evaporated and the residue subjected to SiO2 chromatography (12 g, 5-70% EtOAc in hexanes) to provide 3 mg (21%) of (25Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacyclodecaphan-8-ene-22,24-dione: [M+H]+ 622.3.

[0296] Step 3. (Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-5- oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclodecaphane-22,24-dione (Compound 1). A mixture of (25Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclodecaphan-8-ene- 22,24-dione (3 mg, 0.005 mmol) and 10% Pd / C (5 mgs, 0.005 mmol) in 2 mL EtOAc was stirred under balloon pressure H2 for 2 h. Then the mixture was filtered through Celite, the solvent evaporated and the residue dissolved in 1:1 ACN / MeOH, filtered and the filtrate subjected to preparative HPLC eluting with 20-100% ACN in 0.1% TFA in water over 20 min to provide 0.6 mg (20%) of (Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-5-oxa-3- aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclodecaphane-22,24-dione (Compound 1): 1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.46 (s, 1H), 8.04 (s, 1H), 7.69 (s, 3H), 7.56 (s, 1H), 6.91 (q, J = 8.7 Hz, 1H), 6.67 (s, 1H), 6.52 (d, J = 2.6 Hz, 1H), 5.51 (d, J = 14.8 Hz, 1H), 5.38 (d, J = 14.5 Hz, 1H), 4.21 (d, J = 8.5 Hz, 1H), 3.94 (t, J = 9.5 Hz, 1H), 3.81 (s, 3H), 2.97 – 2.86 (m, 1H), 2.84 – 2.69 (m, 1H), 1.71 – 1.52 (m, 2H), 1.29 (d, J = 2.0 Hz, 2H), 0.85 (dt, J = 21.2, 6.6 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ -117.89, -132.05 – -135.55 (m), -142.49 (d, J = 17.4 Hz); [M+H]+ = 624.3.

[0297] Example 3: Synthesis of (Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacycloundecaphane-22,24-dione (Compound 2)

[0298] Step 1.6-{[2-Chloro-4-methoxy-6-(pent-4-en-1-yloxy)phenyl]amino}-3-[5-(prop-2- en-1-yl)isoquinolin-4-yl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione. To a solution of 6-(methylsulfanyl)-3-[5-(prop-2-en-1-yl)isoquinolin-4-yl]-1-[(2,4,5- trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione (65 mg, 0.14 mmol) and 2-chloro-4-methoxy-6- (pent-4-en-1-yloxy)aniline (42 mg, 0.17 mmol) in 1.3 mL THF at -78C was added 0.35 mL of a 1 M solution of LiHMDS in THF (0.35 mmol) and the mixture stirred for 4 h at -78 ℃ then diluted with 1 M NH4Cl and EtOAc, partitioned and the organic layer dried (MgSO4) and evaporated. The residue was subjected to chromatography (12 g SiO2, 5% EtOAc for 3 min then 5-15% EtOAc in hexanes over 12 min) to provide 21 mgs (22%) of 6-{[2-chloro-4-methoxy-6- (pent-4-en-1-yloxy)phenyl]amino}-3-[5-(prop-2-en-1-yl)isoquinolin-4-yl]-1-[(2,4,5- trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione: 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.37 (s, 1H), 7.97 (dd, J = 7.1, 2.5 Hz, 1H), 7.69 – 7.43 (m, 4H), 6.92 (td, J = 9.6, 6.5 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 6.48 (d, J = 2.6 Hz, 1H), 6.07 – 5.77 (m, 2H), 5.42 (q, J = 15.0 Hz, 2H), 5.30 (s, 1H), 5.10 – 4.97 (m, 3H), 4.89 (dd, J = 17.2, 1.6 Hz, 1H), 4.07 – 3.95 (m, 2H), 3.81 (s, 3H), 3.57 (t, J = 6.9 Hz, 1H), 2.19 (d, J = 7.8 Hz, 2H), 1.89 (ddt, J = 13.6, 6.5, 3.2 Hz, 2H); [M+H] = 664.2.

[0299] Step 2. (25Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro- 5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacycloundecaphan-9-ene-22,24- dione. A solution of 6-{[2-chloro-4-methoxy-6-(pent-4-en-1-yloxy)phenyl]amino}-3-[5-(prop-2- en-1-yl)isoquinolin-4-yl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione (21 mg, 0.032 mmol) in 1.5 mL toluene was added dropwise to a solution of Grubbs catalyst M204 (4.0 mg, 0.005 mmol) in 1.8 mL with a constant flow of N2bubbling into it at 100 °C. Then the mixture was stirred at 100 °C with N2 bubbling into it for 60 min. Then more Grubbs catalyst M204 (4.4 mg, 0.005 mmol) was added and the mixture continued heating at 100 °C for 1 further h. The solvent was evaporated and the residue subjected to SiO2chromatography (12 g, 5-70% EtOAc in hexanes) to provide 6.6 mg (33%) of (25Z)-46-chloro-44-methoxy-21-(2,4,5- trifluorobenzyl)-21,22,23,24-tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacycloundecaphan-9-ene-22,24-dione: [M+H]+ 636.2.

[0300] Step 3. (Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-5- oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacycloundecaphane-22,24-dione (Compound 2). A mixture of (25Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacycloundecaphan-9- ene-22,24-dione (6.6 mg, 0.001 mmol) and 10% Pd / C (5 mgs, 0.005 mmol) in 2 mL EtOAc was stirred under ballon pressure H2 for 2 h. Then the mixture was filtered through Celite, the solvent evaporated and the residue dissolved in 1:1 ACN / MeOH, filtered and the filtrate subjected to preparative HPLC eluting with 20-100% ACN in 0.1% TFA in water over 20 min to provide 1.4 mg (21%) of (Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-5-oxa-3- aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacycloundecaphane-22,24-dione (Compound 2): 1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.52 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.84 – 7.52 (m, 4H), 6.93 (s, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.44 (s, 1H), 5.58 (d, J = 15.0 Hz, 1H), 5.32 (d, J = 17.7 Hz, 1H), 3.85 (d, J = 10.8 Hz, 1H), 3.82 (s, 3H), 3.16 – 3.00 (m, 1H), 2.70 – 2.61 (m, 3H), 2.00 – 1.58 (m, 5H), 1.38 – 1.29 (m, 2H).; 19F NMR (376 MHz, CDCl3) δ - 117.98, -131.44 – -135.55 (m), -141.71; [M+H]+ = 638.3.

[0301] Example 4: Synthesis of (Z)-46-chloro-42-methyl-21-(2,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-42H-3-aza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacyclononaphane-22,24-dione (Compound 3)

[0302] Step 1.6-{[4-(But-3-en-1-yl)-6-chloro-2-methylindazol-5-yl]amino}-3-[5-(prop-2-en- 1-yl)isoquinolin-4-yl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione. To a solution of 6-(methylsulfanyl)-3-[5-(prop-2-en-1-yl)isoquinolin-4-yl]-1-[(2,4,5- trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione (75 mg, 0.16 mmol) and 4-(but-3-en-1-yl)-6- chloro-2-methylindazol-5-amine (4-(but-3-en-1-yl)-6-chloro-2-methyl-2H-indazol-5-amine (39 mg, 0.17 mmol) in 1.5 mL THF at -78C was added 0.34 mL of a 1 M solution of LiHMDS in THF (0.34 mmol) and the mixture stirred for 15 min at -78C then stirred at 0 C for 30 min and finally diluted with 1 M NH4Cl and EtOAc, partitioned and the organic layer dried (MgSO4) and evaporated. The residue was subjected to chromatography (12 g SiO2, 25% EtOAc for 4 min then 25-50% EtOAc in hexanes over 12 min, then 50-100% over 10 min, then 100% for 10 min) to provide 30 mgs (29%) of 6-{[4-(but-3-en-1-yl)-6-chloro-2-methylindazol-5-yl]amino}-3-[5- (prop-2-en-1-yl)isoquinolin-4-yl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione: 1H NMR (400 MHz, CDCl3) δ 9.28 (d, J = 5.5 Hz, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 5.9 Hz, 1H), 7.85 (d, J = 3.8 Hz, 1H), 7.73 (d, J = 0.9 Hz, 1H), 7.65 – 7.38 (m, 3H), 7.03 – 6.87 (m, 1H), 6.11 – 5.68 (m, 1H), 5.57 – 5.34 (m, 2H), 5.11 (t, J = 9.1 Hz, 1H), 4.98 (td, J = 17.1, 10.0 Hz, 3H), 4.22 (s, 3H), 3.73 – 3.54 (m, 2H), 2.74 (dd, J = 15.3, 7.3 Hz, 2H), 2.31 (dq, J = 35.3, 7.2Hz, 2H), 0.96 – 0.77 (m, 2H); 19F NMR (376 MHz, CDCl3) δ -117.35 – -119.74 (m), -133.20 – -134.23 (m), -141.96 (tdd, J = 15.9, 10.0, 5.3 Hz); [M+H]+ 658.3.

[0303] Step 2. (25Z)-46-chloro-42-methyl-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro- 42H-3-aza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacyclononaphan-7-ene-22,24- dione. A solution of 6-{[4-(but-3-en-1-yl)-6-chloro-2-methylindazol-5-yl]amino}-3-[5-(prop-2- en-1-yl)isoquinolin-4-yl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione (30 mg, 0.046 mmol) in 2 mL toluene was added dropwise to a solution of Grubbs catalyst M204 (5.4 mg, 0.006 mmol) in 2.5 mL toluene with a constant flow of N2 bubbling into it at 100 C. Then the mixture was stirred at 100 C with N2 bubbling into it for 60 min. Then more Grubbs catalyst M204 (4.4 mg, 0.005 mmol) was added and the mixture continued heating at 100C for 1h. Then more Grubbs catalyst M204 (4.4 mg, 0.005 mmol) was added and the mixture continued heating at 100C for 1h. The solvent was evaporated and the residue subjected to SiO2 chromatography (12 g, 5-70% EtOAc in hexanes) to provide 9 mg (21%) of a mixture with 33% pure (25Z)-46- chloro-42-methyl-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-42H-3-aza-1(4,5)-isoquinolina- 4(5,4)-indazola-2(3,6)-triazinacyclononaphan-7-ene-22,24-dione: [M+H]+ = 630.3.

[0304] Step 3. (Z)-46-chloro-42-methyl-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-42H- 3-aza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacyclononaphane-22,24-dione (Compound 3) (Compound 3). A 35% pure sample of (25Z)-46-chloro-42-methyl-21-(2,4,5- trifluorobenzyl)-21,22,23,24-tetrahydro-42H-3-aza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacyclononaphan-7-ene-22,24-dione (3 mg, 0.005 mmol) and 10% Pd / C (5 mgs, 0.005 mmol) in 2 mL EtOAc was stirred under ballon pressure H2 for 2 h. Then the mixture was filtered through Celite, the solvent evaporated and the residue dissolved in 1:1 ACN / MeOH, filtered and the filtrate subjected to preparative HPLC eluting with 20-100% ACN in 0.1% TFA in water over 20 min to provide a residue which was concentrated by rotary evaporation and diluted with EtOAc and 1 M NaHCO3, partitioned and the aqueous layer extracted with EtOAc (2X). The combined EtOAc extracts were dried (MgSO4) and evaporated. The residue was subjected to SiO2 purification (4 g SiO2, 50-100% EtOAc in hexanes over 10 min, then EtOAc for 10 min) to provide 1 mg (29%) of (Z)-46-chloro-42-methyl-21-(2,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-42H-3-aza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacyclononaphane-22,24-dione (Compound 3): 1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 8.50 (s, 1H), 8.00 – 7.91 (m, 1H), 7.88 (s, 1H), 7.75 (d, J = 0.9 Hz, 1H), 7.66 – 7.55 (m, 3H), 6.98 – 6.87 (m, 1H), 5.56 (d, J = 14.6 Hz, 1H), 5.38 (d, J = 14.7 Hz, 1H), 4.71 (d, J = 19.8 Hz, 3H), 4.23 (s, 3H), 3.28 – 3.16 (m, 1H), 2.85 (td, J = 12.3, 7.6 Hz, 1H), 2.61 (t, J = 13.5 Hz, 1H),2.47 (t, J = 12.0 Hz, 1H), 2.01 (t, J = 7.3 Hz, 2H), 1.02 (t, J = 7.3 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ -117.0 (m), -133.2 (m), -142.3 (m); M+H found 632.4.

[0305] Example 5: Synthesis of (Z)-15,46-dichloro-42-methyl-21-(2,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-42H-10-oxa-3-aza-4(5,4)-indazola-2(3,6)-triazina-1(3,4)- pyridinacyclodecaphane-22,24-dione (Compound 4)

[0306] Step 1.6-{[4-(But-3-en-1-yl)-6-chloro-2-methylindazol-5-yl]amino}-3-[5-chloro-4- (prop-2-en-1-yloxy)pyridin-3-yl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione. To a solution of 3-[5-chloro-4-(prop-2-en-1-yloxy)pyridin-3-yl]-6-(methylsulfanyl)-1-[(2,4,5- trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione (140 mg, 0.30 mmol) and 4-(but-3-en-1-yl)-6- chloro-2-methylindazol-5-amine (4-(but-3-en-1-yl)-6-chloro-2-methyl-2H-indazol-5-amine (74 mg, 0.31 mmol) in 3.0 mL THF at -78C was added 0.63 mL of a 1 M solution of LiHMDS in THF (0.63 mmol) and the mixture stirred for 15 min at -78 ℃ then stirred at 0 ℃ for 30 min and finally diluted with 1 M NH4Cl and EtOAc, partitioned and the organic layer dried (MgSO4) and evaporated. The residue was subjected to chromatography (24 g SiO2, 50-100% EtOAc to hexane over 15 min then 100% EtOAc for 10 min) to provide 119 mgs (58%) of 6-{[4-(but-3-en- 1-yl)-6-chloro-2-methylindazol-5-yl]amino}-3-[5-chloro-4-(prop-2-en-1-yloxy)pyridin-3-yl]-1- [(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione: 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 6.9 Hz, 1H), 7.69 – 7.61 (m, 2H), 7.61 – 7.52 (m, 1H), 7.43 (p, J = 9.0 Hz, 1H), 6.92 (td, J =9.6, 6.4 Hz, 1H), 5.97 (ddt, J = 16.5, 10.2, 6.1 Hz, 1H), 5.69 (ddt, J = 16.9, 12.2, 6.7 Hz, 1H), 5.49 (d, J = 10.2 Hz, 1H), 5.41 (d, J = 17.0 Hz, 1H), 5.35 (s, 2H), 5.02 – 4.85 (m, 2H), 4.46 (d, J = 6.1 Hz, 2H), 4.20 (s, 3H), 2.64 (dt, J = 16.9, 8.7 Hz, 2H), 2.23 (dh, J = 13.3, 6.7 Hz, 1H), 1.66 (s, 1H), 1.29 – 1.22 (m, 1H); 19F NMR (376 MHz, CDCl3) δ -118.74 (ddd, J = 16.2, 10.5, 5.7 Hz), -133.79 – -135.58 (m), -141.96 (dddd, J = 21.7, 16.2, 10.6, 6.6 Hz); [M+H]+ = 630.3.

[0307] Step 2. (25Z)-15,46-dichloro-42-methyl-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-42H-10-oxa-3-aza-4(5,4)-indazola-2(3,6)-triazina-1(3,4)-pyridinacyclodecaphan- 7-ene-22,24-dione. A solution of 6-{[4-(but-3-en-1-yl)-6-chloro-2-methylindazol-5-yl]amino}-3- [5-chloro-4-(prop-2-en-1-yloxy)pyridin-3-yl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine- 2,4-dione (119 mg, 0.18 mmol) in 9 mL DCE was added dropwise to a solution of Grubbs catalyst M204 (23 mg, 0.027 mmol) in 9 mL DCE with a constant flow of N2 bubbling into it at 90C. Then the mixture was stirred at 90C with N2 bubbling into it for 60 min. Then more Grubbs catalyst M204 (12 mg, 0.013 mmol) was added and the mixture continued heating at 90C for 1h. The solvent was evaporated and the residue subjected to SiO2 chromatography (24 g SiO2, 50% polar solvent (5% MeOH in EtOAc) to hexane, 5 min then 50-100% polar solvent over 10 min, then 100% for 10 min; followed by 10% methanol in DCM for 20 min) to provide 31 mg (27%) of (25Z)-15,46-dichloro-42-methyl-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro- 42H-10-oxa-3-aza-4(5,4)-indazola-2(3,6)-triazina-1(3,4)-pyridinacyclodecaphan-7-ene-22,24- dione: [M+H]+ =631.5.

[0308] Step 3. (Z)-15,46-dichloro-42-methyl-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro- 42H-10-oxa-3-aza-4(5,4)-indazola-2(3,6)-triazina-1(3,4)-pyridinacyclodecaphane-22,24-dione (Compound 4). A mixture of (25Z)-15,46-dichloro-42-methyl-21-(2,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-42H-10-oxa-3-aza-4(5,4)-indazola-2(3,6)-triazina-1(3,4)- pyridinacyclodecaphan-7-ene-22,24-dione (31 mg, 0.044 mmol) and 10% Pd / C (15 mgs, 0.014 mmol) in 1.5 mL EtOAc and 1.5 mL MeOH was stirred under balloon pressure H2 for 2 h. Then the mixture was filtered through Celite, the solvent evaporated and the residue dissolved in 1:1 ACN / MeOH, filtered and the filtrate subjected to preparative HPLC eluting with 40-65% ACN in 0.1% TFA in water over 20 min to provide 5.6 mg (20%) of 6,21-dichloro-17-methyl-28- [(2,4,5-trifluorophenyl)methyl]-8-oxa-1,4,17,18,23,25,28- heptaazapentacyclo[22.2.2.0²,⁷.0¹⁴,²².0¹⁵,¹⁹]octacosa-2,4,6,14(22),15,18,20,24-octaene-26,27- dione. This sample was diluted with EtOAc and 1 M NaHCO3, partitioned and the aqueous layer extracted with EtOAc (2X). The combined EtOAc extracts were dried (MgSO4) and evaporated to provide 4.7 mg (16%) of (Z)-15,46-dichloro-42-methyl-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-42H-10-oxa-3-aza-4(5,4)-indazola-2(3,6)-triazina-1(3,4)-pyridinacyclodecaphane-22,24-dione (Compound 4) as a neutral compound: 1H NMR (400 MHz, DMSO+NEt3) δ 8.32 – 8.11 (m, 2H), 8.02 (s, 1H), 7.64 – 7.44 (m, 2H), 7.41 (s, 1H), 5.26 (d, J = 15.7 Hz, 1H), 5.15 (d, J = 15.3 Hz, 1H), 4.09 (s, 3H), 3.79 – 3.57 (m, 2H), 1.81 – 1.56 (m, 4H), 0.88 – 0.83 (m, 2H); 19F NMR (376 MHz, DMSO+NEt3) δ -73.41 (TFA, 1 / 50 F), -119.78 (1F), -137.53 (1F), -144.07 (1F); [M+H] found 633.5 (100%), 632.5 (91%).

[0309] Example 6: Synthesis of (Z)-46-fluoro-44-methoxy-21-(2,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacyclononaphane-22,24-dione (Compound 5)

[0310] Step 1.3-(5-allylisoquinolin-4-yl)-6-((2-(allyloxy)-6-fluoro-4-methoxyphenyl)amino)- 1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione To a mixture of 3-(5- allylisoquinolin-4-yl)-6-(methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (50 mg, 0.106 mmol) and 2-(allyloxy)-6-fluoro-4-methoxyaniline (23.1 mg, 0.117 mmol) in dry THF (1.00 mL) under nitrogen at -78°C was added dropwise LiHMDS (231 uL, 0.213 mmol) (1M in THF) and the mixture was stirred at 78°C for 4h. The mixture was quenched by adding sat. NH4Cl (0.2 mL). The residue was directly purified by C18column Gilson chromatography (19.5 mm x 150 mm, Gemini Column 25% to 100% Water / MeCN modified with 0.1% TFA over 20 min, flow rate 20 mL / min). The fractions were collected and lyophilized to provide 3-(5- allylisoquinolin-4-yl)-6-((2-(allyloxy)-6-fluoro-4-methoxyphenyl)amino)-1-(2,4,5- trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (16 mg, 72 %): MS (ES+, m / z): [M+H]+ = 620.1.

[0311] Step 2. (25Z,7Z)-46-fluoro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclononaphan-7- ene-22,24-dione. A solution of 3-(5-allylisoquinolin-4-yl)-6-((2-(allyloxy)-6-fluoro-4- methoxyphenyl)amino)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione ( 16.2 mg, 0.026 mmol) dissolved in 1 mL Toluene was added to Grubbs catalyst M204 ( 3 mg, 0.004 mmol) in 0.3 mL toluene at 110C, the mixture stirred for 1 h at 110oC then cooled and the solvent was removed in vacuo. The residue was then purified via Gilson (19.5 mm x 150 mm, Gemini Column 35% to 100% Water / MeCN modified with 0.1% TFA over 20 min, flow rate 20 mL / min) to provide (3.4 mg, 21%) (25Z,7Z)-46-fluoro-44-methoxy-21-(2,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacyclononaphan-7-ene-22,24-dione: [M+H]+ =592.1.

[0312] Step 3. (Z)-46-Fluoro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-5- oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclononaphane-22,24-dione (Compound 5).To a (25Z,7Z)-46-fluoro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclononaphan-7-ene- 22,24-dione (3.4 mg, 0.007 mmol) and 10% Pd / C (3.4mg, 0.026mmol) in 2 mL EtOAc was stirred under an H2 balloon for 1 h. The mixture was then filtered and concentrated in vacuo and the residue was purified by C18 column chromatography Gilson (19.5 mm x 150 mm, Gemini Column 35% to 100% Water / MeCN modified with 0.1% TFA over 20 min, flow rate 20 mL / min) to provide (1mg), (Z)-46-fluoro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclononaphane-22,24- dione: [M+H]+ = 594.1.

[0313] Example 7: Synthesis of (25Z,7Z)-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclononaphan-7- ene-22,24-dione (Compound 6)

[0314] In a similar way as (Z)-46-fluoro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclononaphane-22,24-dione, (25Z,7Z)-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-5-oxa-3-aza-1(4,5)- isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclononaphan-7-ene-22,24-dione was synthesized from 3-(5-allylisoquinolin-4-yl)-6-(methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine- 2,4(1H,3H)-dione (50 mg, 0.106 mmol) and 2-(but-3-en-1-yloxy)-4-methoxyaniline (21 mg, 0.117 mmol) to provide (25Z,7Z)-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-5- oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclononaphan-7-ene-22,24-dione:1H NMR (400 MHz, MeOD) δ 9.36 (d, J = 2.4 Hz, 2H), 8.40 (d, J = 15.4 Hz, 2H), 8.17 – 8.09 (m, 2H), 7.73 – 7.61 (m, 4H), 7.56 (q, J = 9.1 Hz, 2H), 7.25 – 7.06 (m, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.70 (d, J = 2.6 Hz, 1H), 6.46 (ddd, J = 8.5, 5.8, 2.6 Hz, 2H), 5.53 – 5.33 (m, 3H), 5.29 – 5.10 (m, 4H), 4.28 – 4.15 (m, 3H), 3.70 (d, J = 5.6 Hz, 6H), 3.46 (d, J = 35.0 Hz, 3H), 3.25 (s, 22H), 2.63 – 2.47 (m, 2H), 2.37 (s, 1H); MS (ES+, m / z): [M+H]+ = 588.2.

[0315] Example 8: Synthesis of (Z)-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclodecaphane- 22,24-dione (Compound 7)

[0316] In a similar way as (Z)-46-fluoro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-5-oxa-3-aza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclononaphane-22,24- dione, (Z)-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-5-oxa-3-aza-1(4,5)- isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclodecaphane-22,24-dione was synthesized from 3- (5-allylisoquinolin-4-yl)-6-(methylthio)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)- dione (50 mg, 0.106 mmol) and 2-(but-3-en-1-yloxy)-4-methoxyaniline in dry THF (1.00 mL)to provide (Z)-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-5-oxa-3-aza-1(4,5)- isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclodecaphane-22,24-dione:1H NMR (400 MHz, MeOD) δ 9.97 (s, 1H), 9.03 (s, 1H), 8.77 (t, J = 8.1 Hz, 1H), 8.39 – 8.24 (m, 2H), 7.95 – 7.84 (m, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.20 (dd, J = 8.6, 2.6 Hz, 1H), 6.06 (d, J = 16.7 Hz, 1H), 5.97 (d, J = 16.9 Hz, 1H), 4.83 (s, 1H), 3.98 (s, 3H), 3.76 (t, J = 1.7 Hz, 2H), 3.76 (d, J = 6.7 Hz, 3H), 3.37 (s, 2H), 2.66 (s, 1H), 2.51 (s, 1H), 2.27 (s, 5H); MS (ES+, m / z): [M+H]+ = 590.1.

[0317] Example 9: Synthesis of (Z)-5-((46-chloro-42-methyl-22,24,8-trioxo-21,22,23,24- tetrahydro-42H-3,7-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacyclodecaphane-21-yl)methyl)-2-fluorobenzonitrile (Compound 8)

[0318] Step 1. tert-butyl 3-(8-(4-((4-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-2- methyl-2H-indazol-5-yl)amino)-3-(3-cyano-4-fluorobenzyl)-2,6-dioxo-3,6-dihydro-1,3,5- triazin-1(2H)-yl)naphthalen-1-yl)propanoate. To a mixture of tert-butyl 3-(4-(3-(3-cyano-4- fluorobenzyl)-4-(methylthio)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5- yl)propanoate (30 mg, 0.052 mmol) and tert-butyl (2-(5-amino-6-chloro-2-methyl-2H-indazol-4- yl)ethyl)carbamate (16.2 mg, 0.0052 mmol) in dry THF (1.70 mL) under nitrogen at -78°C was added dropwise LiHMDS (0.104 mL, 0.104 mmol) (1M in THF) and the mixture was stirred at 0°C for 1 h. The mixture was quenched by adding sat. NH4Cl (0.1 mL). The residue was directly purified by C18column Gilson (19.5 mm x 150 mm, Gemini Column 30% to 100% Water / MeCN modified with 0.1% TFA over 20 min, flow rate 20 mL / min). The fractions were collected and lyopholized.to provide tert-butyl 3-(8-(4-((4-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-2- methyl-2H-indazol-5-yl)amino)-3-(3-cyano-4-fluorobenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin- 1(2H)-yl)naphthalen-1-yl)propanoate (2 mg, 1 %): MS (ES+, m / z): [M+H]+ = 825.1.

[0319] Step 2.3-(8-(4-((4-(2-aminoethyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)-3-(3- cyano-4-fluorobenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)naphthalen-1- yl)propanoic acid. TFA (1.89 mL, 24.4 mmol) was added to tert-butyl 3-(8-(4-((4-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)-3-(3-cyano-4- fluorobenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)naphthalen-1-yl)propanoate (2 mg, 0.0057 mmol) and the solution was stirred at rt for 15 min. TFA was evaporated, the residue was dissolved in a minimal amount of MeOH and basified with solid NH4HCO3. The material was purified by C18 column chromatography Gilson (19.5 mm x 150 mm, Gemini Column 30% to 100% Water / MeCN modified with 0.1% TFA over 20 min, flow rate 20 mL / min). The fractions were collected and lyophilized to provide 3-(8-(4-((4-(2-aminoethyl)-6-chloro-2-methyl-2H- indazol-5-yl)amino)-3-(3-cyano-4-fluorobenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)- yl)naphthalen-1-yl)propanoic acid (0.8 mg, 99 %): MS (ES+, m / z): [M+H]+ = 683.1.

[0320] Step 3. (Z)-5-((46-chloro-42-methyl-22,24,8-trioxo-21,22,23,24-tetrahydro-42H-3,7- diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacyclodecaphane-21-yl)methyl)-2- fluorobenzonitrile (Compound 8). To a solution of 3-(8-(4-((4-(2-aminoethyl)-6-chloro-2- methyl-2H-indazol-5-yl)amino)-3-(3-cyano-4-fluorobenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin- 1(2H)-yl)naphthalen-1-yl)propanoic acid (0.8 mg, 0.104 mmol) in DMF (4.00 mL) at 0°C was added DIPEA (0.091 mL, 0.518 mmol) and HATU (80.4 mg, 0.207 mmol) and the mixture was stirred at 0°C for 15 min. The crude mixture was directly purified by C18column chromatography Gilson (19.5 mm x 150 mm, Gemini Column 35% to 100% Water / MeCN modified with 0.1% TFA over 20 min, flow rate 20 mL / min). The fractions were collected and lyophilized to provide (Z)-5-((46-chloro-42-methyl-22,24,8-trioxo-21,22,23,24-tetrahydro-42H-3,7- diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacyclodecaphane-21-yl)methyl)-2- fluorobenzonitrile (48.0 mg, 68 %):1H NMR (400 MHz, CDCl3) δ 9.58 (s, 2H), 8.46 (s, 1H), 8.04 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.71 (s, 1H), 7.51 (s, 1H), 5.47 (s, 1H), 4.24 (d, J = 2.2 Hz, 2H), 4.18 (s, 1H), 3.08 – 2.82 (m, 2H), 2.47 (s, 1H), 2.37 (s, 1H), 2.19 (s, 1H), 2.02 (s, 1H), 1.62 (s, 1H), 1.39 – 1.26 (m, 3H); MS (ES+, m / z): [M+H]+ = 651.1.

[0321] Example 10: Synthesis of (Z)-5-((46-chloro-42,7-dimethyl-22,24,8-trioxo-21,22,23,24- tetrahydro-42H-3,7-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacyclodecaphane-21-yl)methyl)-2-fluorobenzonitrile (Compound 9)

[0322] In a similar way as (Z)-5-((46-chloro-42-methyl-22,24,8-trioxo-21,22,23,24-tetrahydro-42H- 3,7-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacyclodecaphane-21-yl)methyl)-2- fluorobenzonitrile, (Z)-5-((46-chloro-42,7-dimethyl-22,24,8-trioxo-21,22,23,24-tetrahydro-42H-3,7- diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacyclodecaphane-21-yl)methyl)-2- fluorobenzonitrile was made from tert-butyl (2-(5-amino-6-chloro-2-methyl-2H-indazol-4- yl)ethyl)carbamate and tert-butyl 3-(4-(3-(3-cyano-4-fluorobenzyl)-4-(methylthio)-2,6-dioxo- 3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)propanoate (30 mg, 0.052 mmol) to afford (Z)-5-((46-chloro-42,7-dimethyl-22,24,8-trioxo-21,22,23,24-tetrahydro-42H-3,7-diaza-1(4,5)- isoquinolina-4(5,4)-indazola-2(3,6)-triazinacyclodecaphane-21-yl)methyl)-2-fluorobenzonitrile:1H NMR (400 MHz, MeOD) δ 9.36 (s, 1H), 8.56 (s, 2H), 8.20 – 8.13 (m, 1H), 8.08 (d, J = 6.1 Hz, 1H), 7.97 (s, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.75 – 7.65 (m, 2H), 7.49 (s, 1H), 5.48 (s, 1H), 5.39 (d, J = 17.0 Hz, 1H), 4.44 – 4.36 (m, 1H), 4.24 (s, 2H), 3.68 (d, J = 15.0 Hz, 1H), 3.03 (t, J = 13.3 Hz, 1H), 2.93 (d, J = 9.4 Hz, 1H), 2.73 (t, J = 15.3 Hz, 1H), 2.52 (s, 3H); [M+H=664.1].

[0323] Example 11: Synthesis of 56-chloro-52-methyl-31-(2,4,5-trifluorobenzyl)-31,32,33,34- tetrahydro-52H-4,8-diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)- benzenacyclononaphane-32,34,9-trione (Compound 10)

[0324] Step 1. Methyl 3-(4-(4-((4-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-2-methyl- 2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)- yl)isoquinolin-5-yl)benzoate. To a solution of methyl 3-(4-(4-(methylthio)-2,6-dioxo-3-(2,4,5- trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (16.9 mg, 0.03 mmol) and tert-butyl (2-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)ethyl)carbamate (15 mg, 0.045 mmol) in 0.5 mL THF at -78oC was added LiHMDS (1M in THF, 0.06 mmol, 0.6 mL) and then the mixture was stirred at -78oC for 1 h. Upon completion, the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered, and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 85% CH3CN in water) to give methyl 3-(4-(4-((4-(2-((tert-butoxycarbonyl)amino)ethyl)-6- chloro-2-methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5- triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (20%, 5.1 mg, 0.006 mmol). [M+H]+ = 841.3.

[0325] Step 2.3-(4-(4-((4-(2-Aminoethyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6- dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoic acid To a solution of methyl 3-(4-(4-((4-(2-((tert-butoxycarbonyl)amino)ethyl)-6-chloro-2- methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (5.1 mg, 0.006 mmol) in 0.5 mL THF at room temperature was added LiOH (1M in water, 0.1 mmol, 0.1 mL) and then the mixture was stirred at 60oC for 5 h. Upon completion, the mixture was neutralized with HCl and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and evaporated. To the residue was added 0.5 mL THF and HCl (1M in water, 0.25 mmol, 0.25 mL) and then the mixture was stirred at room temperature for 15 h. Upon completion, the mixture was neutralized with NaOH aqueous solution (1 M) and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 65% CH3CN in water) to give 3-(4-(4-((4-(2-aminoethyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6-dioxo- 3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoic acid (83%, 3.7 mg, 0.005 mmol): [M+H]+ = 727.1.

[0326] Step 3.56-chloro-52-methyl-31-(2,4,5-trifluorobenzyl)-31,32,33,34-tetrahydro-52H-4,8- diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)-benzenacyclononaphane- 32,34,9-trione (Compound 10). To a solution of 3-(4-(4-((4-(2-aminoethyl)-6-chloro-2-methyl- 2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)- yl)isoquinolin-5-yl)benzoic acid (3.7mg, 0.005 mmol) and HATU (7.6mg, 0.02 mmol) in 1.0 mL DMF at 0oC was added DIPEA (4 mg, 0.03 mmol) and then the mixture was stirred at 0oC for 0.5 h. Upon completion, the mixture was quenched with water (1 mL) and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered, and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 65% CH3CN in water) to give 56-chloro-52-methyl-31- (2,4,5-trifluorobenzyl)-31,32,33,34-tetrahydro-52H-4,8-diaza-2(5,4)-isoquinolina-5(5,4)-indazola- 3(3,6)-triazina-1(1,3)-benzenacyclononaphane-32,34,9-trione (Compound 10) (60%, 2.1 mg, 0.003 mmol): [M+H]+ = 709.2.

[0327] Example 12: Synthesis of 56-chloro-52-methyl-31-(2,4,5-trifluorobenzyl)-31,32,33,34- tetrahydro-52H-4,7-diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)- benzenacyclooctaphane-32,34,8-trione (Compound 11)

[0328] Step 1. Methyl 3-(4-(4-((4-(((tert-butoxycarbonyl)amino)methyl)-6-chloro-2-methyl- 2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)- yl)isoquinolin-5-yl)benzoate. To a solution of methyl 3-(4-(4-(methylthio)-2,6-dioxo-3-(2,4,5- trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (16.9 mg, 0.03 mmol) and tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4-yl)methyl)carbamate (15 mg, 0.045 mmol) in 0.5 mL THF at -78oC was added LiHMDS (1M in THF, 0.06 mmol, 0.6 mL) and then the mixture was stirred at -78oC for 1 h. Upon completion, the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered, and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 85% CH3CN in water) to give methyl 3-(4-(4-((4-(((tert-butoxycarbonyl)amino)methyl)-6- chloro-2-methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5- triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (30%, 7.4 mg, 0.009 mmol): [M+H]+ = 827.2.

[0329] Step 2.3-(4-(4-((4-(Aminomethyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6- dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoic acid To a solution of Methyl 3-(4-(4-((4-(((tert-butoxycarbonyl)amino)methyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin- 1(2H)-yl)isoquinolin-5-yl)benzoate (7.4 mg, 0.009 mmol) in 0.5 mL THF at room temperature was added LiOH (1M in water, 0.1 mmol, 0.1 mL) and then the mixture was stirred at 60oC for 5 h. Upon completion, the mixture was neutralized with HCl and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and evaporated. To the residue was added 0.5 mL THF and HCl (1M in water, 0.25 mmol, 0.25 mL) and then the mixture was stirred at room temperature for 15 h. Upon completion, the mixture was neutralized with NaOH aqueous solution (1 M) and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 65% CH3CN in water) to give 3-(4-(4-((4-(Aminomethyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6-dioxo- 3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoic acid (75%, 4.8 mg, 0.007 mmol): [M+H]+ = 713.1.

[0330] Step 3.56-chloro-52-methyl-31-(2,4,5-trifluorobenzyl)-31,32,33,34-tetrahydro-52H-4,7- diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)-benzenacyclooctaphane- 32,34,8-trione (Compound 11). To a solution of 3-(4-(4-((4-(Aminomethyl)-6-chloro-2-methyl- 2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)- yl)isoquinolin-5-yl)benzoic acid (7.8 mg, 0.007 mmol) and HATU (7.6mg, 0.02 mmol) in 1.0 mL DMF at 0oC was added DIPEA (4 mg, 0.03 mmol) and then the mixture was stirred at 0oC for 0.5 h. Upon completion, the mixture was quenched with water (1 mL) and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered, and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 65% CH3CN in water) to give 56-chloro-52- methyl-31-(2,4,5-trifluorobenzyl)-31,32,33,34-tetrahydro-52H-4,7-diaza-2(5,4)-isoquinolina- 5(5,4)-indazola-3(3,6)-triazina-1(1,3)-benzenacyclooctaphane-32,34,8-trione (Compound 11) (55%, 2.7 mg, 0.0038 mmol): [M+H]+ = 695.2.

[0331] Example 13: Synthesis of 56-chloro-52,7-dimethyl-31-(2,4,5-trifluorobenzyl)- 31,32,33,34-tetrahydro-52H-4,7-diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina- 1(1,3)-benzenacyclooctaphane-32,34,8-trione (Compound 12)Step 3

[0332] Step 1. Methyl 3-(4-(4-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-chloro-2- methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5- triazin-1(2H)-yl)isoquinolin-5-yl)benzoate To a solution of methyl 3-(4-(4-(methylthio)-2,6- dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (16.9 mg, 0.03 mmol) and tert-butyl ((5-amino-6-chloro-2-methyl-2H-indazol-4- yl)methyl)(methyl)carbamate (15 mg, 0.045 mmol) in 0.5 mL THF at -78oC was added LiHMDS (1M in THF, 0.06 mmol, 0.6 mL) and then the mixture was stirred at -78oC for 1 h. Upon completion, the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered, and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 85% CH3CN in water) to give methyl 3-(4-(4- ((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)- 2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (15%, 4.2 mg, 0.005 mmol): [M+H]+ = 841.3.

[0333] Step 2.3-(4-(4-((6-Chloro-2-methyl-4-((methylamino)methyl)-2H-indazol-5- yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoic acid To a solution of methyl 3-(4-(4-((4-(((tert- butoxycarbonyl)(methyl)amino)methyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3- (2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (4.2 mg, 0.005 mmol) in 0.5 mL THF at room temperature was added LiOH (1M in water, 0.1 mmol, 0.1 mL) and then the mixture was stirred at 60oC for 5 h. Upon completion, the mixture was neutralized with HCl and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and evaporated. To the residue was added 0.5 mL THF and HCl (1M in water, 0.25 mmol, 0.25 mL) and then the mixture was stirred at room temperature for 15 h. Upon completion, the mixture was neutralized with NaOH aqueous solution (1 M) and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 65% CH3CN in water) to give 3-(4-(4-((6- Chloro-2-methyl-4-((methylamino)methyl)-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5- trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoic acid (90%, 2.9 mg, 0.004 mmol): [M+H]+ = 727.1.

[0334] Step 3.56-chloro-52,7-dimethyl-31-(2,4,5-trifluorobenzyl)-31,32,33,34-tetrahydro-52H- 4,7-diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)-benzenacyclooctaphane- 32,34,8-trione (Compound 12). To a solution of 3-(4-(4-((6-chloro-2-methyl-4- ((methylamino)methyl)-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoic acid (2.9 mg, 0.004 mmol) and HATU (7.6mg, 0.02 mmol) in 1.0 mL DMF at 0oC was added DIPEA (4 mg, 0.03 mmol) and then the mixture was stirred at 0oC for 0.5 h. Upon completion, the mixture was quenched with water (1 mL) and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered, and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 65% CH3CN in water) to give 56-chloro-52,7-dimethyl-31-(2,4,5-trifluorobenzyl)-31,32,33,34-tetrahydro-52H-4,7- diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)-benzenacyclooctaphane-32,34,8- trione (Compound 12) (85%, 2.4 mg, 0.0034 mmol): [M+H]+ = 709.1.

[0335] Example 14: Synthesis of 56-Chloro-52,8-dimethyl-31-(2,4,5-trifluorobenzyl)- 31,32,33,34-tetrahydro-52H-4,8-diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina- 1(1,3)-benzenacyclononaphane-32,34,9-trione (Compound 13)

[0336] Step 1. Methyl 3-(4-(4-((4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)-6-chloro-2- methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5- triazin-1(2H)-yl)isoquinolin-5-yl)benzoate. To a solution of methyl 3-(4-(4-(methylthio)-2,6- dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (16.9 mg, 0.03 mmol) and tert-butyl (2-(5-amino-6-chloro-2-methyl-2H-indazol-4- yl)ethyl)(methyl)carbamate (15 mg, 0.045 mmol) in 0.5 mL THF at -78oC was added LiHMDS (1M in THF, 0.06 mmol, 0.6 mL) and then the mixture was stirred at -78oC for 1 h. Upon completion, the mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered, and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 85% CH3CN in water) to give methyl 3-(4-(4-((4-(2-((tert- butoxycarbonyl)(methyl)amino)ethyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3- (2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (30%, 7.6 mg, 0.009 mmol): [M+H]+ = 855.3.

[0337] Step 2.3-(4-(4-((6-Chloro-2-methyl-4-(2-(methylamino)ethyl)-2H-indazol-5- yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)- yl)isoquinolin-5-yl)benzoic acid To a solution of methyl 3-(4-(4-((4-(2-((tert- butoxycarbonyl)(methyl)amino)ethyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3- (2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (7.6 mg, 0.009 mmol) in 0.5 mL THF at room temperature was added LiOH (1M in water, 0.1 mmol, 0.1 mL) and then the mixture was stirred at 60oC for 5 h. Upon completion, the mixture was neutralized with HCl and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and evaporated. To the residue was added 0.5 mL THF and HCl (1M in water, 0.25 mmol, 0.25 mL) and then the mixture was stirred at room temperature for 15 h. Upon completion, the mixture was neutralized with NaOH aqueous solution (1 M) and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 65% CH3CN in water) to give 3-(4-(4-((6- Chloro-2-methyl-4-(2-(methylamino)ethyl)-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5- trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoic acid (90%, 5.9 mg, 0.008 mmol): [M+H]+ = 741.1.

[0338] Step 3.56-Chloro-52,8-dimethyl-31-(2,4,5-trifluorobenzyl)-31,32,33,34-tetrahydro-52H- 4,8-diaza-2(5,4)-isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)- benzenacyclononaphane-32,34,9-trione To a solution of 3-(4-(4-((6-chloro-2-methyl-4-(2- (methylamino)ethyl)-2H-indazol-5-yl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoic acid (5.9 mg, 0.008 mmol) and HATU (22.8 mg, 0.06 mmol) in 1.0 mL DMF at 0oC was added DIPEA (12 mg, 0.09 mmol) and then the mixture was stirred at 0oC for 0.5 h. Upon completion, the mixture was quenched with water (1 mL) and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered, and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 65% CH3CN in water) to give 56- chloro-52,8-dimethyl-31-(2,4,5-trifluorobenzyl)-31,32,33,34-tetrahydro-52H-4,8-diaza-2(5,4)- isoquinolina-5(5,4)-indazola-3(3,6)-triazina-1(1,3)-benzenacyclononaphane-32,34,9-trione (74%, 4.3 mg, 0.006 mmol): [M+H]+ = 723.1.

[0339] Example 15: Synthesis of 5-methyl-11-(2,4,5-trifluorobenzyl)-11,12,13,14- tetrahydro-5,9-diaza-2(4,5)-isoquinolina-1(3,6)-triazina-3(1,3)-benzenacyclononaphane- 12,14,4-trione (Compound 14)

[0340] Step 1. Methyl 3-(4-(4-((3-((tert-butoxycarbonyl)(methyl)amino)propyl)amino)-2,6- dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5- yl)benzoate. To a mixture of methyl 3-(4-(4-(methylthio)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)- 3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (14.1 mg, 0.025 mmol) and tert- butyl (3-aminopropyl)(methyl)carbamate (0.25 mL, 0.015 mmol) was added 0.25 mL DIPEA at rt. The mixture was stirred at 60oC for 2 h. Upon completion, the DIPEA was evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 85% CH3CN in water) to give methyl 3-(4-(4-((3-((tert-butoxycarbonyl)(methyl)amino)propyl)amino)-2,6-dioxo-3-(2,4,5- trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (64%, 11.1 mg, 0.015 mmol): [M+H]+ = 704.7.

[0341] Step 2. tert-Butyl (3-aminopropyl)(methyl)carbamate 3-(4-(4-((3- (methylamino)propyl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin- 1(2H)-yl)isoquinolin-5-yl)benzoate. To a solution of methyl 3-(4-(4-((3-((tert- butoxycarbonyl)(methyl)amino)propyl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro- 1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (11.1 mg, 0.015 mmol) in 0.5 mL THF at roomtemperature was added LiOH (1M in water, 0.1 mmol, 0.1 mL) and then the mixture was stirred at 60oC for 5 h. Upon completion, the mixture was neutralized with HCl and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and evaporated. To the residue was added 0.5 mL THF and HCl (1M in water, 0.25 mmol, 0.25 mL) and then the mixture was stirred at room temperature for 15 h. Upon completion, the mixture was neutralized with NaOH aqueous solution (1 M) and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 65% CH3CN in water) to give tert-butyl (3-aminopropyl)(methyl)carbamate 3-(4-(4-((3- (methylamino)propyl)amino)-2,6-dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin- 1(2H)-yl)isoquinolin-5-yl)benzoate (80%, 7.4 mg, 0.013 mmol). [M+H]+ = 590.5.

[0342] Step 3.5-Methyl-11-(2,4,5-trifluorobenzyl)-11,12,13,14-tetrahydro-5,9-diaza-2(4,5)- isoquinolina-1(3,6)-triazina-3(1,3)-benzenacyclononaphane-12,14,4-trione. To a solution of tert-butyl (3-aminopropyl)(methyl)carbamate 3-(4-(4-((3-(methylamino)propyl)amino)-2,6- dioxo-3-(2,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)benzoate (7.4 mg, 0.013 mmol) and HATU (22.8 mg, 0.06 mmol) in 1.0 mL DMF at 0oC was added DIPEA (12 mg, 0.09 mmol) and then the mixture was stirred at 0oC for 0.5 h. Upon completion, the mixture was quenched with water (1 mL) and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered, and evaporated. The residue was purified by prep-HPLC (5% CH3CN in water to 65% CH3CN in water) to give 5-methyl-11-(2,4,5-trifluorobenzyl)- 11,12,13,14-tetrahydro-5,9-diaza-2(4,5)-isoquinolina-1(3,6)-triazina-3(1,3)- benzenacyclononaphane-12,14,4-trione (80%, 6 mg, 0.01 mmol): [M+H]+ = 572.6.

[0343] Example 16: Synthesis of 46-chloro-42-(2-methoxyethyl)-21-(2,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-11H,42H-3-aza-1(7,1),4(5,4)-dipyrrolo[3,2-c]pyridina-2(3,6)- triazinacyclononaphane-22,24-dione (Compound 15)

[0344] Step 1.4-Allyl-6-chloro-2-(2-methoxyethyl)-2H-indazol-5-amine. Degassed mixture of 4-bromo-6-chloro-2-(2-methoxyethyl)-2H-indazol-5-amine (300.0 mg, 0.985 mmol), PdCl2(PPh3)2(70.5 mg, 0.099 mmol), allyltri-n-butyltin (0.5 mL, 1.480 mmol), and DMF (1.6 mL) was stirred at 80 °C for 18 h under N2. The reaction mixture was purified by C18 column chromatography (0-60% MeCN in 10 mM aq. NH4HCO2) to provide 4-allyl-6-chloro-2-(2- methoxyethyl)-2H-indazol-5-amine (219.0 mg, 83 %):1H NMR (500 MHz, CD3OD): δ = 8.06 (d, J = 1.0 Hz, 1H), 7.52 (d, J = 1.0 Hz, 1H), 6.08 – 5.87 (m, 1H), 5.12 – 5.04 (m, 2H), 4.57 –4.48 (m, 2H), 3.86 – 3.81 (m, 2H), 3.57 (dt, J = 6.1, 1.6 Hz, 2H), 3.31 (s, 3H), 2H are exchanged with CD3OD; MS (ES+, m / z): [M+H]+ = 266.2 / 268.2.

[0345] Step 2.6-((4-Allyl-6-chloro-2-(2-methoxyethyl)-2H-indazol-5-yl)amino)-3-(1-(but-3- en-1-yl)-1H-pyrrolo[3,2-c]pyridin-7-yl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)- dione. To a solution of 4-allyl-6-chloro-2-(2-methoxyethyl)-2H-indazol-5-amine (76.2 mg, 0.287 mmol) and 3-(1-(but-3-en-1-yl)-1H-pyrrolo[3,2-c]pyridin-7-yl)-6-(methylthio)-1-(2,4,5- trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (106.0 mg, 0.224 mmol) in THF (2.6 mL) was added 1 M LiHMDS in THF (0.7 mL, 0.700 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with 1 mL sat. aq. NH4Cl and concentrated down. The product was purified by C18 column chromatography (0-100% MeCN in 10 mM aq. NH4HCO2) to provide 6-((4-allyl-6-chloro-2-(2-methoxyethyl)-2H-indazol-5-yl)amino)-3-(1- (but-3-en-1-yl)-1H-pyrrolo[3,2-c]pyridin-7-yl)-1-(2,4,5-trifluorobenzyl)-1,3,5-triazine- 2,4(1H,3H)-dione (41.9 mg, 22 %): MS (ES+, m / z): [M+H]+ = 691.5 / 693.5.

[0346] Step 3.46-Chloro-42-(2-methoxyethyl)-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-11H,42H-3-aza-1(7,1),4(5,4)-dipyrrolo[3,2-c]pyridina-2(3,6)- triazinacyclononaphan-6-ene-22,24-dione. To a degassed solution of 6-((4-allyl-6-chloro-2-(2- methoxyethyl)-2H-indazol-5-yl)amino)-3-(1-(but-3-en-1-yl)-1H-pyrrolo[3,2-c]pyridin-7-yl)-1- (2,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione (41.7 mg, 0.060 mmol) in DCE (36 mL) under N2was added (1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)di- chloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (41.0 mg, 0.048 mmol). Then the reaction was placed under constant N2 bubbling and stirred at 55 °C for 9 h. The reaction mixture was cooled down to rt and purified by C18 column chromatography (0-100% MeCN in 10 mM NH4HCO3) to provide 46-chloro-42-(2-methoxyethyl)-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-11H,42H-3-aza-1(7,1),4(5,4)-dipyrrolo[3,2-c]pyridina-2(3,6)-triazinacyclononaphan- 6-ene-22,24-dione (12.0 mg, 30 %): MS (ES+, m / z): [M+H]+ = 663.5 / 665.4.

[0347] Step 4.46-Chloro-42-(2-methoxyethyl)-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-11H,42H-3-aza-1(7,1),4(5,4)-dipyrrolo[3,2-c]pyridina-2(3,6)- triazinacyclononaphane-22,24-dione. To a solution of 46-chloro-42-(2-methoxyethyl)-21-(2,4,5- trifluorobenzyl)-21,22,23,24-tetrahydro-11H,42H-3-aza-1(7,1),4(5,4)-dipyrrolo[3,2-c]pyridina- 2(3,6)-triazinacyclononaphan-6-ene-22,24-dione (12.0 mg, 0.018 mmol) in MeOH (0.5 mL) and THF (0.8 mL) was added PtO2 (5.4 mg, 0.023 mmol) portion-wise. The reaction mixture was purged with N2, evacuated and stirred under H2(via balloon) at rt for 30 min. The mixture was filtered through a pad Celite and the residue was purified by C18 column chromatography (0- 60% MeCN in 10 mM aq. NH4HCO3) to provide 46-chloro-42-(2-methoxyethyl)-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-11H,42H-3-aza-1(7,1),4(5,4)-dipyrrolo[3,2-c]pyridina- 2(3,6)-triazinacyclononaphane-22,24-dione (3.4 mg). The material was re-purified by Prep- LCMS (see method below), affording 46-chloro-42-(2-methoxyethyl)-21-(2,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-11H,42H-3-aza-1(7,1),4(5,4)-dipyrrolo[3,2-c]pyridina-2(3,6)- triazinacyclononaphane-22,24-dione (1.1 mg, 9 %), as a formate salt:1H NMR (400 MHz, CD3OD): δ = 8.82 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 7.70 – 7.63 (m, 1H), 7.62 (s, 1H), 7.43 (d, J = 3.3 Hz, 1H), 7.30 – 7.18 (m, 1H), 6.78 (d, J = 3.3 Hz, 1H), 5.65 – 5.49 (m, 1H), 5.47 – 5.26 (m, 1H), 4.58 (t, J = 5.1 Hz, 3H), 4.20 – 4.06 (m, 1H), 4.05 – 3.92 (m, 1H), 3.86 (t, J = 5.1 Hz, 2H), 3.01 – 2.89 (m, 1H), 2.68 – 2.55 (m, 1H), 2.25 – 2.09 (m, 1H), 2.07 – 1.94 (m, 2H), 1.69 – 1.43 (m, 3H), 1.41 – 1.32 (m, 2H).1H is exchanged with CD3OD, Formate salt;19F NMR (376 MHz, CD3OD): δ = -119.18 – -120.42 (m, 1F), -137.58 – -138.47 (m, 1F), -145.84 – -146.08 (m, 1F); MS (ES+, m / z): [M+H]+ = 665.50 / 667.49; Prep-QDA: General description: Instrumentation: Waters Prep LC-MS; LC: Autopurification LC-MS (2545 Quaternary, Solvent heater, 3767, SFO, 515, 515, 2998, QDA); MassLynx 4.2 SCN 1036 / FractionLynx; UV Detection: Waters PDA 2998 (198-360nm); MS Detection: Waters QDA, ESI (ES (+), 120-1200 amu; Mobile Phase @40°C; ACD: CAN; Eluent B: CAN; Eluent A: 10 mM NH4HCO2, pH 3.8; Precolumn: XBridge Prep C18, 5µm 19 x 10 mm; Column: CSH C18, 5 µm, 30 x 75 mm; 515 Pump (for ACD): Flow: 4 mL / min; 2545 Quaternary Gradient Module: Prerun: Isocratic at 25% B for 1min; Gradient: 25% B isocratic for 1 minute, 25% B to 45% B in 8 minutes, 45% B to 100% B for 0.1 minute, hold 100% B for 2.9 minutes; Flow: 45 mL / min; Run Time: 12 minutes; Triggered by: MS (664.2); ACD: At-Column Dilution.

[0348] Example 17: Synthesis of (Z)-46-chloro-44-methoxy-21-(3,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-3,10-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacycloundecaphane-22,24,9-trione (Compound 16)

[0349] Step 1. Methyl pent-4-ynoate. To a solution of 4-pentynoic acid (1.00 g, 9.68 mmol) in MeOH (50.0 mL), cooled to 0 °C, was added dropwise SOCl2(0.87 mL, 11.9 mmol) then the resulting mixture was warmed to rt and was stirred overnight. Reaction mixture was diluted with DCM (150 mL) and washed with water (100 mL). Organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure (using rotavap bath at 25 °C) to afford methyl pent-4-ynoate (1.01 g, 93 %), used directly in the next step without purification:1H NMR (400 MHz, CDCl3): δ = 3.70 (s, 3H), 3.63 (s, 1H), 2.60 – 2.44 (m, 4H).

[0350] Step 2. Methyl 5-(2-amino-3-chloro-5-methoxyphenyl)pent-4-ynoate. To a degassed mixture of 2-bromo-6-chloro-4-methoxy-phenylamine (150.0 mg, 0.615 mmol), methyl pent-4- ynoate (96.6 mg, 0.861 mmol), CuI (6.0 mg, 0.031 mmol), PdCl2(PPh3)2(22.0 mg, 0.031 mmol) and PPh3 (16.3 mg, 0.062 mmol). THF (1.25 mL) and TEA (1.25 mL) were added. The reaction was stirred at 65 °C for 7 h. After cooling to rt, reaction mixture was concentrated under reduced pressure then the crude residue was purified by silica gel column chromatography (0 to 100% EtOAc in heptanes) to provide methyl 5-(2-amino-3-chloro-5-methoxyphenyl)pent-4-ynoate (66.0 mg, 34 %): MS (ES+, m / z): [M+H]+ = 268.1 / 270.0.

[0351] Step 3. Methyl 5-(2-amino-3-chloro-5-methoxyphenyl)pentanoate. Methyl 5-(2- amino-3-chloro-5-methoxyphenyl)pent-4-ynoate (66.0 mg, 0.247 mmol) was dissolved in MeOH (2.5 mL), purged with N2 and PtO2 (5.9 mg, 0.025 mmol) was added. The reaction was stirred at rt for 20 h under H2balloon pressure, partial conversion was observed by LC-MS. The solid residue was filtered off and the MeOH solution was degassed with N2, PtO2 (5.9 mg, 0.025 mmol) was added and the mixture was stirred for 9 h under H2 balloon pressure. The reaction mixture was filtered through a syringe filter and solvent was evaporated to obtain methyl 5-(2- amino-3-chloro-5-methoxyphenyl)pentanoate (55.0 mg, 74 %). Used for the next step without purification: MS (ES+, m / z): [M+H]+ = 272.1 / 274.1.

[0352] Step 4. Methyl 5-(2-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)- 4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro-5- methoxyphenyl)pentanoate. A solution of tert-butyl ((4-(4-(methylthio)-2,6-dioxo-3-(3,4,5- trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)methyl)carbamate (50.0 mg, 0.090 mmol) and methyl 5-(2-amino-3-chloro-5-methoxyphenyl)pentanoate (29.1 mg, 0.107 mmol) in dry THF (1.1 mL) was cooled to -78 °C and LiHMDS (1 M in THF, 0.31 mL, 0.310 mmol) was added dropwise. The reaction was stirred at -78 °C for 1 h. More methyl 5-(2-amino- 3-chloro-5-methoxyphenyl)pentanoate (24.3 mg, 0.090 mmol) and LiHMDS (1 M in THF, 0.09 mL, 0.090 mmol) were added at -78 °C and the mixture was stirred at this temperature for 30 min. The reaction mixture was quenched with few drops of sat. aq. solution of NH4Cl andpurified by C18 column chromatography (0-100% MeCN in 10 mM aq. NH4HCO3) to provide methyl 5-(2-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)-4,6-dioxo-1-(3,4,5- trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro-5- methoxyphenyl)pentanoate (17.0 mg, 23 %): MS (ES+, m / z): [M+H]+ = 783.4 / 785.3.

[0353] Step 5. Lithium 5-(2-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)- 4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro-5- methoxyphenyl)pentanoate. To a solution of methyl 5-(2-((5-(5-(((tert-butoxycarbonyl)- amino)methyl)isoquinolin-4-yl)-4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5- triazin-2-yl)amino)-3-chloro-5-methoxyphenyl)pentanoate (17.0 mg, 0.022 mmol) in a (1:1) mixture of THF (0.11 mL) and H2O (0.11 mL) was added LiOH (1.6 mg, 0.065 mmol). The reaction mixture was stirred at rt overnight then concentrated under reduced pressure to afford crude lithium 5-(2-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)-4,6-dioxo-1- (3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro-5- methoxyphenyl)pentanoate. Product was used in the next step without purification, assuming quantitative yield: MS (ES+, m / z): [M+H]+ = 769.4 / 771.4.

[0354] Step 6.5-(2-((5-(5-(Aminomethyl)isoquinolin-4-yl)-4,6-dioxo-1-(3,4,5- trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro-5- methoxyphenyl)pentanoic acid. A mixture of crude lithium 5-(2-((5-(5-(((tert- butoxycarbonyl)amino)methyl)isoquinolin-4-yl)-4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6- tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro-5-methoxyphenyl)pentanoate (17.0 mg, 0.022 mmol) and HCl (4 M in dioxane) (0.14 mL, 0.548 mmol) was stirred at rt, under N2 for 30 min, then concentrated under reduced pressure to afford crude 5-(2-((5-(5-(aminomethyl)isoquinolin- 4-yl)-4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro- 5-methoxyphenyl)pentanoic acid. Product was used in the next step without any purification, assuming quantitative yield: MS (ES+, m / z): [M+H]+ = 669.3 / 671.3.

[0355] Step 7. (Z)-46-chloro-44-methoxy-21-(3,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro- 3,10-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacycloundecaphane-22,24,9- trione. To crude 5-(2-((5-(5-(aminomethyl)isoquinolin-4-yl)-4,6-dioxo-1-(3,4,5-trifluorobenzyl)- 1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro-5-methoxyphenyl)pentanoic acid (15.0 mg, 0.225 mmol) in solution in DMF (2.25 mL), cooled to 0 °C, were successively added DIPEA (0.025 mL, 0.135 mmol) and HATU (17.4 mg, 0.045 mmol). The resulting mixture was stirred at rt for 15 min. The reaction mixture was purified by C18 column chromatography (0-100% MeCN in 10 mM aq. NH4HCO3). Desired fractions were combined and lyophilized. Residue was purified again by C18 column chromatography (0-100% MeCN in 10 mM aq. NH4HCO2) toprovide (Z)-46-chloro-44-methoxy-21-(3,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-3,10-diaza- 1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacycloundecaphane-22,24,9-trione (6.00 mg, 41 %):1H NMR (400 MHz, CD3OD): δ = 9.34 (s, 1H), 8.53 (s, 1H), 8.25 (d, J = 7.4 Hz, 1H), 7.86 (d, J = 6.3 Hz, 1H), 7.81 – 7.71 (m, 1H), 7.49 – 7.37 (m, 2H), 6.90 (s, 1H), 6.79 (s, 1H), 5.62 – 5.21 (m, 2H), 4.69 (d, J = 14.9 Hz, 1H), 4.36 (d, J = 13.4 Hz, 1H), 3.78 (s, 3H), 2.86 (br.s, 1H), 2.48 (br. s, 1H), 2.39 – 2.27 (m, 1H), 2.23 – 2.09 (m, 1H), 1.95 – 1.67 (m, 3H), 1.58 (br.s, 1H), 2H are exchanged with CD3OD; MS (ES+, m / z): [M+H]+ = 651.3 / 653.1.

[0356] Example 18: Synthesis of 46-chloro-42-methyl-21-(3,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-42H-3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacycloundecaphane-22,24,9-trione, atropisomer 1 (Compound 17) and atropisomer 2 (Compound 18)

[0357] Step 1. Methyl 5-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)pent-4-ynoate. To a degassed mixture of CuI (74.6 mg, 0.384 mmol), Pd(PPh3)4(226.0 mg, 0.192 mmol), 4-bromo-6- chloro-2-methyl-2H-indazol-5-amine (1.00 g, 3.84 mmol) and TEA (0.77 mL) was added methyl 4-pentynoate (906.0 mg, 7.68 mmol), and the reaction was stirred at 80 °C for 16 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure then the crude residue was purified by silica gel column chromatography (0-100% EtOAc in heptane) to provide methyl 5-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)pent-4-ynoate (787.0 mg, 67 %): MS (ES+, m / z): [M+H]+ = 292.0 / 293.9.

[0358] Step 2. Methyl 5-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)pentanoate. To a stirred solution of methyl 5-(5-amino-6-chloro-2-methyl-2H-indazol-4-yl)pent-4-ynoate (787.0 mg, 2.700 mmol) in anhydrous MeOH (27 mL) was added PtO2 (64.5 mg, 0.270 mmol) portion- wise. The reaction mixture was purged with N2, then H2was bubbled in the stirring solution for 5 min. The reaction was stirred under an H2atmosphere at rt for 90 min. The reaction mixture was purged with N2, filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (0-50% EtOAc in DCM) to provide methyl 5-(5-amino-6-chloro-2-methyl-2H- indazol-4-yl)pentanoate (767.0 mg, 94 %):1H NMR (400 MHz,CDCl3 ): δ = 7.66 (s, 1H), 7.57 (d, J = 3.1 Hz), 1H, 4.13 (d, J = 2.8 Hz, 3H), 3.76 – 3.41 (m, 5H), 2.79 – 2.68 (m, 2H), 2.34 (t, J = 7.1 Hz, 2H), 1.79 – 1.58 (m, 4H); MS (ES+, m / z): [M+H]+ = 296.0 / 297.9.

[0359] Step 3. Methyl 5-(5-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)- 4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2- methyl-2H-indazol-4-yl)pentanoate. To a solution of methyl 5-(5-amino-6-chloro-2-methyl- 2H-indazol-4-yl)pentanoate (198.0 mg, 0.670 mmol) and tert-butyl ((4-(4-(methylthio)-2,6- dioxo-3-(3,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5- yl)methyl)carbamate (150.0 mg, 0.268 mmol) in THF (3.35 mL), cooled to -78 °C, was added dropwise a 1M THF solution of LiHMDS (0.61 mL, 0.61 mmol) and the resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched by adding drops of sat. aq. NH4Cl solution then the mixture was purified by C18 column chromatography (0-100% MeCN in 10 mM aq. NH4HCO3) to provide methyl 5-(5-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4- yl)-4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2- methyl-2H-indazol-4-yl)pentanoate (126.0 mg, 55 %): MS (ES+, m / z): [M+H]+ = 807.5 / 809.5.

[0360] Step 4. Lithium 5-(5-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)- 4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2- methyl-2H-indazol-4-yl)pentanoate. To a solution of methyl 5-(5-((5-(5-(((tert-butoxycar-bonyl)amino)methyl)isoquinolin-4-yl)-4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro- 1,3,5-triazin-2-yl)amino)-6-chloro-2-methyl-2H-indazol-4-yl)pentanoate (126.0 mg, 0.156 mmol) in a (1:1) mixture of THF (0.8 mL) and H2O (0.8 mL) was added, at rt, LiOH (11.4 mg, 0.468 mmol) then the resulting mixture was stirred at rt overnight. Solvents were removed under reduced pressure to give lithium 5-(5-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4- yl)-4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2- methyl-2H-indazol-4-yl)pentanoate (125.0 mg, quantitative yield assumed): MS (ES+, m / z): [M+H]+ = 793.5 / 795.4 (acid).

[0361] Step 5.5-(5-((5-(5-(Aminomethyl)isoquinolin-4-yl)-4,6-dioxo-1-(3,4,5- trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2-methyl-2H-indazol- 4-yl)pentanoic acid. Lithium 5-(5-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4- yl)-4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2- methyl-2H-indazol-4-yl)pentanoate (123.0 mg, 0.151 mmol) in HCl (0.95 mL, 3.77 mmol) (4M solution in dioxane) was stirred at rt, under N2. After 30 min, the mixture was concentrated under reduced pressure to give 5-(5-((5-(5-(aminomethyl)isoquinolin-4-yl)-4,6-dioxo-1-(3,4,5- trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2-methyl-2H-indazol-4- yl)pentanoic acid (107.0 mg, quantitative yield assumed) : MS (ES+, m / z): [M+H]+ = 693.1 / 695.0.

[0362] Step 6.46-Chloro-42-methyl-21-(3,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-42H- 3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacycloundecaphane-22,24,9- trione, atropisomer 1 and atropisomer 2. To a solution of 5-(5-((5-(5- (aminomethyl)isoquinolin-4-yl)-4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5- triazin-2-yl)amino)-6-chloro-2-methyl-2H-indazol-4-yl)pentanoic acid (107.0 mg, 0.156 mmol) in DMF (5.00 mL), cooled to 0 °C, were successively added DIPEA (0.16 mL, 0.935 mmol) and HATU (121.0 mg, 0.312 mmol) then the resulting mixture was warmed to and stirred at rt for 15 min. The mixture was purified by C18 column chromatography (0-100% MeCN in 10 mM aq. NH4HCO3) to provide 46-chloro-42-methyl-21-(3,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-42H- 3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacycloundecaphane-22,24,9-trione (33.0 mg, 31 %):1H NMR (400 MHz, CD3OD): δ = 9.31 (s, 1H), 8.51 (s, 1H), 8.33 (br, s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 7.1 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.56 (s, 1H), 7.49 – 7.40 (m, 2H), 5.54 – 5.22 (m, 2H), 4.75 (d, J = 15.8 Hz, 1H), 4.30 (d, J = 13.6 Hz, 1H), 4.16 (s, 3H), 3.18-3.09 (m, 1H), 2.88 – 2.78 (m, 1H), 2.28 (dd, J = 14.8, 3.4 Hz, 1H), 2.20 – 2.09 (m, 1H), 1.95 – 1.47 (m, 3H); MS (ES+, m / z): [M+H]+ = 675.4 / 677.3.

[0363] 46-Chloro-42-methyl-21-(3,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro-42H-3,10-diaza- 1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)-triazinacycloundecaphane-22,24,9-trione atropisomer 1 (Compound 17) and atropisomer 2 (Compound 18) were separated using following conditions. System Name: Waters SFC, System Description: Autopurification SFC-MS (Fluid Delivery Module, Pump Control Module II, 2767 Injector / Collector, Stack injector Thar, Analytical Prep 2 Oven, Heat Exchanger, 515 ACD, 515 MUP, ABPR-20, 2998 PDA, QDa Performance). Control / Processing SW: MassLynx 4.2, SCN 993 / FractionLynx / OpenLynx, UV detection: Waters PDA 2998 (198-360nm), MS detection:Waters QDa Performance, ESI (ES (+ / -), 100- 1200 amu), Column: Lux i-Amylose-1, 10mm ID x 250mm L, 5 μm, Pre-Column: Security Guard SemiPrep Cartidge Lux i-Amylose-1, 10mm ID x 10mm L, 5 μm, Manufacturer: Phenomenex, Stationary Phase:Amylose tris(3,5-dimethylphenylcarbamate), Mode: isocratic, Eluent B: Supercritical CO2, Eluent A: IPA + 0.1% NH4OH, Mobile Phase: 50% IPA + 0.1% NH4OH / 50% supercritical CO2, Flow:10 mL / min, Back Pressure:150 bar, Column Temp.:40 C, Run Time:12 min, Trigger: MS (Mass = 675.9).

[0364] The purified compounds in IPA concentrated by vacuum and lyophilized to give Compound 17 (10.0 mg, 30 %):1H NMR (400 MHz, CD3OD): δ = 9.34 (s, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 6.9 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.59 (s, 1H), 7.57 – 7.43 (m, 2H), 5.60 – 5.28 (m, 2H), 4.86 – 4.70 (m, 1H), 4.39 – 4.22 (m, 1H), 4.19 (s, 3H), 3.29 – 3.17 (m, 1H), 3.01 – 2.71 (m, 1H), 2.31 (d, J = 14.6 Hz, 1H), 2.17 (t, J = 13.1 Hz, 1H), 1.95 – 1.64 (m, 4H), 2H exchanged with CD3OD; MS (ES+, m / z): [M+H]+ = 675.08 / 676.13. And Compound 18 (8.8 mg, 27 %):1H NMR (400 MHz, CD3OD): δ = 9.31 (s, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.27 – 8.18 (m, 1H), 7.84 (d, J = 6.7 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.56 (s, 1H), 7.56 – 7.39 (m, 2H), 5.66 – 5.13 (m, 2H), 4.82 – 4.66 (m, 1H), 4.41 – 4.22 (m, 1H), 4.16 (s, 3H), 3.27 – 3.13 (m, 1H), 2.98 – 2.72 (m, 1H), 2.28 (d, J = 16.1 Hz, 1H), 2.23 – 2.10 (m, 1H), 1.95 – 1.60 (m, 4H).2H exchanged with CD3OD; MS (ES+, m / z): 675.18 / 676.88.

[0365] Example 19: Synthesis of (Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-3,11-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)- benzenacyclododecaphane-22,24,10-trione (Compound 19)

[0366] Step 1. Methyl 6-(2-amino-3-chloro-5-methoxyphenyl)hex-5-ynoate. To a mixture of 2-bromo-6-chloro-4-methoxyaniline (300.0 mg, 1.230 mmol), CuI (12.0 mg, 0.062 mmol), PdCl2(PPh3)2(44.1 mg, 0.062 mmol) and PPh3(32.6 mg, 0.123 mmol) were added THF (2.5 mL) and TEA (2.5 mL). The reaction mixture was purged with N2 for 5 min then methyl hex-5- ynoate (0.23 mL, 1.720 mmol) was added. The reaction mixture was stirred at 65 °C for 3 h. The reaction was cooled down to rt and concentrated under reduced pressure. Residue was purified by silica gel chromatography (0-100% EtOAc) to provide methyl 6-(2-amino-3-chloro-5- methoxyphenyl)hex-5-ynoate (345.0 mg, 87 %): MS (ES+, m / z): [M+H]+ = 282.0 / 284.0.

[0367] Step 2. Methyl 6-(2-amino-3-chloro-5-methoxyphenyl)hexanoate. A solution of methyl 6-(2-amino-3-chloro-5-methoxyphenyl)hex-5-ynoate (345.0 mg, 1.070 mmol), in dry MeOH (11 mL) was purged with N2for 3 min. PtO2(25.5 mg, 0.107 mmol) was added and the reaction was stirred at rt overnight under H2 balloon pressure. The reaction mixture was degassed with N2, filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to afford crude methyl 6-(2-amino-3-chloro-5-methoxyphenyl)hexanoate (150.0 mg, 47 %). Product was used in the next step without purification: MS (ES+, m / z): [M+H]+ = 286.0. / 288.0

[0368] Step 3. Methyl 6-(2-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)- 4,6-dioxo-1-(2,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro-5- methoxyphenyl)hexanoate. A solution of tert-butyl ((4-(4-(methylthio)-2,6-dioxo-3-(2,4,5- trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)methyl)carbamate (60.0 mg, 0.107 mmol) and crude methyl 6-(2-amino-3-chloro-5-methoxyphenyl)hexanoate (39.8 mg, 0.139 mmol) in dry THF (1.35 mL) was cooled to -78 °C. LiHMDS (1 M in THF) (0.38 mL, 0.380 mmol) was added dropwise, the mixture was stirred at -78 °C for 1 h then at 0 °C for 15 min. The reaction was quenched with few drops of saturated aq. solution of NH4Cl and purified by C18 column chromatography (0-100% MeCN in 10mM aq. NH4HCO3) to provide methyl 6- (2-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)-4,6-dioxo-1-(2,4,5- trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro-5- methoxyphenyl)hexanoate (32.0 mg, 36 %): MS (ES+, m / z): [M+H]+ = 797.0 / 799.0.

[0369] Step 4.6-(2-((5-(5-(Aminomethyl)isoquinolin-4-yl)-4,6-dioxo-1-(2,4,5- trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro-5- methoxyphenyl)hexanoic acid. To a solution of methyl 6-(2-((5-(5-(((tert- butoxycarbonyl)amino)methyl)isoquinolin-4-yl)-4,6-dioxo-1-(2,4,5-trifluorobenzyl)-1,4,5,6- tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro-5-methoxyphenyl)hexanoate (32.0 mg, 0.040 mmol) in a (1:1) mixture of THF (0.2 mL) and H2O (0.2 mL) was added LiOH (2.94 mg, 0.120 mmol). The reaction mixture was stirred at rt overnight, then concentrated under reduced pressure. HCl (4 M in dioxane) (0.01 mL, 0.04 mmol) was added to the residue and stirred at rt for 30 min. The reaction mixture was concentrated under reduced pressure to afford crude 6-(2- ((5-(5-(aminomethyl)isoquinolin-4-yl)-4,6-dioxo-1-(2,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro- 1,3,5-triazin-2-yl)amino)-3-chloro-5-methoxyphenyl)hexanoic acid (27 mg, quantitative yield assumed). The product was used in the next step without purification: MS (ES+, m / z): [M+H]+ = 683.4 / 685.4.

[0370] Step 5. (Z)-46-Chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro- 3,11-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclododecaphane-22,24,10- trione. To crude 6-(2-((5-(5-(aminomethyl)isoquinolin-4-yl)-4,6-dioxo-1-(2,4,5-trifluorobenzyl)- 1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-3-chloro-5-methoxyphenyl)hexanoic acid (27.0 mg, 0.040 mmol) in DMF (4.00 mL), cooled to 0 °C, were successively added DIPEA (0.04 mL, 0.237 mmol) and HATU (30.7 mg, 0.079 mmol). The resulting mixture was stirred at rt for 15 min. The reaction mixture was purified C18 column chromatography (0-100%MeCN in 10mM aq. NH4HCO2) to provide (Z)-46-chloro-44-methoxy-21-(2,4,5-trifluorobenzyl)-21,22,23,24- tetrahydro-3,11-diaza-1(4,5)-isoquinolina-2(3,6)-triazina-4(1,2)-benzenacyclododecaphane- 22,24,10-trione (6.50 mg, 24 %):1H NMR (400 MHz, CD3CN): δ = 9.35 (s, 1H), 8.53 (s, 1H), 8.24 – 8.12 (m, 1H), 7.78 (d, J = 6.3 Hz, 1H), 7.74 – 7.65 (m, 1H), 7.30 (dd, J = 8.6, 6.8 Hz, 2H), 6.93 (d, J = 2.5 Hz, 1H), 6.80 (s, 1H), 6.17 (s, 1H), 5.39 – 5.19 (m, 2H), 4.82 (s, 1H), 4.36 (d, J = 13.4 Hz, 1H), 3.77 (s, 3H), 2.59 – 2.47 (m, 1H), 2.43 – 2.30 (m, 2H), 1.88 – 1.80 (m, 2H), 1.71 – 1.48 (m, 1H), 1.47 – 1.36 (m, 2H), 1.31 – 1.19 (m, 2H), 1H is missing; MS (ES+, m / z): [M+H]+ = 665.0 / 667.0.

[0371] Example 20: Synthesis of (Z)-46-Chloro-42-methyl-21-(3,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-42H-8-oxa-3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacycloundecaphane-22,24,9-trione (Compound 20)

[0372] Step 1. Ethyl (E)-3-(5-Amino-6-chloro-2-methyl-2H-indazol-4-yl)acrylate. To a degassed mixture of 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine (500.0 mg, 1.900 mmol), tri-o-tolylphosphine (118.0 mg, 0.380 mmol), Pd(OAc)2(42.7 mg, 0.190 mmol) and DMF (9.5 mL). DIPEA (1.0 mL, 5.70 mmol) and ethyl acrylate (0.42 mL, 3.800 mmol) were added, the solution was purged with N2for 2 minutes, and the mixture was heated at 100 °C for 2 h. The reaction mixture was cooled to rt and was then partitioned between EtOAc and sat. aq. NH4Cl and aq. layer was re-extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (5-100% EtOAc in heptanes) to provide ethyl (E)-3-(5-amino- 6-chloro-2-methyl-2H-indazol-4-yl)acrylate (500.0 mg, 93 %) : MS (ES+, m / z): [M+H]+ = 280.2 / 282.3.

[0373] Step 2. (E)-4-(3-((tert-Butyldimethylsilyl)oxy)prop-1-en-1-yl)-6-chloro-2-methyl-2H- indazol-5-amine. A solution of ethyl (E)-3-(5-amino-6-chloro-2-methyl-2H-indazol-4- yl)acrylate (200.0 mg, 0.708 mmol) in CH2Cl2(2.00 mL) was cooled to -78 °C, then diisobutylaluminum hydride (1.0 M in CH2Cl2, 1.60 mL, 1.600 mmol) was added dropwise. Continued to stir at -78 °C for 2 h. The cold bath was removed and the reaction mixture was quenched with excess EtOAc (10 mL), then aq. saturated Rochelle's salt was added (10 mL). Stirred the mixture for 10 min, then extracted with EtOAc (10 mL) and washed with brine. The aq. layer was re-extracted with EtOAc (3 x 10 mL), then the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product from the first step was dissolved in CH2Cl2 (2 mL), then imidazole (58.4 mg, 0.849 mmol) and tert- butyldimethylsilyl chloride (119.0 mg, 0.779 mmol) were added and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was extracted with CH2Cl2(20 mL) and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptanes) to provide (E)-4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-6-chloro- 2-methyl-2H-indazol-5-amine (172.0 mg, 69 %): MS (ES+, m / z): [M+H]+ = 352.5 / 354.4.

[0374] Step 3.4-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-chloro-2-methyl-2H-indazol-5- amine. To (E)-4-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-6-chloro-2-methyl-2H- indazol-5-amine (157.0 mg, 0.446 mmol) was added PtO2(5.3 mg, 0.022 mmol) and MeOH (4.5 mL). The solution was purged with N2, then the mixture was stirred at rt under H2 for 30 min. The reaction mixture was flushed with N2 before filtering through Celite. The filtrate was concentrated under reduced pressure and the crude material was purified by silica gel chromatography (0-100% EtOAc in heptanes) to afford 4-(3-((tert-butyldimethyl- silyl)oxy)propyl)-6-chloro-2-methyl-2H-indazol-5-amine (118.0 mg, 75 %): MS (ES+, m / z): [M+H]+ = 354.5 / 356.5.

[0375] Step 4. tert-Butyl ((4-(4-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-2- methyl-2H-indazol-5-yl)amino)-2,6-dioxo-5-(3,4,5-trifluorobenzyl)-5,6-dihydro-1,3,5- triazin-1(2H)-yl)isoquinolin-5-yl)methyl)carbamate. To 4-(3-((tert- butyldimethylsilyl)oxy)propyl)-6-chloro-2-methyl-2H-indazol-5-amine (57.0 mg, 0.161 mmol) was added tert-butyl ((4-(4-(methylthio)-2,6-dioxo-3-(3,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5- triazin-1(2H)-yl)isoquinolin-5-yl)methyl)carbamate (94.9 mg, 0.161 mmol) and THF (1.60 mL). The solution was cooled to -78 °C, then LiHMDS (1.0 M in THF, 0.40 mL, 0.400 mmol) (1M in THF) was added dropwise to the mixture. Continued to stir under N2 at -78 °C for 1 h. The cold bath was removed and the reaction mixture was quenched with excess sat. aq. NH4Cl (5 mL).The mixture was extracted with EtOAc (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-100% EtOAc in heptanes). A second purification was performed by C18 column chromatography (0-100% MeCN in 10 mM aq. NH4HCO3) to provide tert-butyl ((4-(4-((4-(3- ((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6-dioxo-5- (3,4,5-trifluorobenzyl)-5,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)methyl)carbamate (30.0 mg, 21 %): MS (ES+, m / z): [M+H]+ = 865.8.

[0376] Step 5.3-(5-(aminomethyl)isoquinolin-4-yl)-6-((6-chloro-4-(3-hydroxypropyl)-2- methyl-2H-indazol-5-yl)amino)-1-(3,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione dihydrochloride. To tert-butyl ((4-(4-((4-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloro-2- methyl-2H-indazol-5-yl)amino)-2,6-dioxo-5-(3,4,5-trifluorobenzyl)-5,6-dihydro-1,3,5-triazin- 1(2H)-yl)isoquinolin-5-yl)methyl)carbamate (30.0 mg, 0.034 mmol) was added HCl (4 M in dioxane, 0.43 mL, 1.700 mmol) and the mixture was stirred at rt for 16 h. The mixture was concentrated under reduced pressure to afford 3-(5-(aminomethyl)isoquinolin-4-yl)-6-((6-chloro- 4-(3-hydroxypropyl)-2-methyl-2H-indazol-5-yl)amino)-1-(3,4,5-trifluorobenzyl)-1,3,5-triazine- 2,4(1H,3H)-dione dihydrochloride (24.6 mg, 100 %). Yield assumed to be quantitative as a dihydrochloride salt: MS (ES+, m / z): [M+H]+ = 651.6 / 653.6 (free base).

[0377] Step 6. (Z)-46-Chloro-42-methyl-21-(3,4,5-trifluorobenzyl)-21,22,23,24-tetrahydro- 42H-8-oxa-3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacycloundecaphane- 22,24,9-trione. To 3-(5-(aminomethyl)isoquinolin-4-yl)-6-((6-chloro-4-(3-hydroxypropyl)-2- methyl-2H-indazol-5-yl)amino)-1-(3,4,5-trifluorobenzyl)-1,3,5-triazine-2,4(1H,3H)-dione dihydrochloride (15.0 mg, 0.021 mmol) were added CH3CN (2.1 mL) and DIPEA (0.02 mL, 0.120 mmol). Then, CDI (1.0 M in CH3CN, 0.21 mL, 0.021 mmol) was dropwise added at rt. The resulting mixture was stirred at 50 °C for 1 h. Additional DIPEA (0.02 mL, 0.114 mmol) was added. Stirred at 50 °C for 1 h, then at 70 °C for 65 h. The reaction mixture was concentrated under reduced pressure, then was subjected to C18 column purification (5-100% MeCN in 10 mM aq. NH4HCO2) to provide (Z)-46-chloro-42-methyl-21-(3,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-42H-8-oxa-3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazinacycloundecaphane-22,24,9-trione (1.80 mg, 12 %):1H NMR (400 MHz, CD3OD) δ = 9.33 (s, 1H), 8.54 (s, 1H), 8.49 – 8.32 (m, 1H), 8.27 – 8.12 (m, 1H), 7.93 – 7.81 (m, 1H), 7.80 – 7.67 (m, 1H), 7.61 (s, 1H), 7.55 – 7.22 (m, 2H), 5.57 – 5.25 (m, 2H), 4.64 – 4.50 (m, 1H), 4.49 – 4.28 (m, 1H), 4.18 (s, 3H), 4.12 – 3.80 (m, 1H), 3.11 – 2.66 (m, 3H), 2.59 – 2.28 (m, 1H), 2.03 – 1.71 (m, 1H).2H are exchange with CD3OD; MS (ES+, m / z): [M+H]+ = 677.4 / 679.2.

[0378] Example 21: Synthesis of (25Z,54Z)-46-chloro-42-methyl-21-(3,4,5-trifluorobenzyl)- 21,22,23,24-tetrahydro-42H,51H-3,10-diaza-1(4,5)-isoquinolina-4(5,4)-indazola-2(3,6)- triazina-5(4,1)-pyrazolacycloundecaphane-22,24,9-trione (Compound 21)Compound 21

[0379] Step 1. tert-Butyl ((4-(4-((4-bromo-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6- dioxo-3-(3,4,5-trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5- yl)methyl)carbamate. To a mixture of tert-butyl ((4-(4-(methylthio)-2,6-dioxo-3-(3,4,5- trifluorobenzyl)-3,6-dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)methyl)carbamate (200.0 mg, 0.340 mmol) and 4-bromo-6-chloro-2-methyl-2H-indazol-5-amine (4-bromo-6-chloro-2- methyl-2H-indazol-5-amine (107.0 mg, 0.407 mmol) in dry THF (3.4 mL) under N2at -78 °C was added dropwise LiHMDS (1.0 mL, 1.0 mmol) (1M in THF) and the mixture was stirred for 30 min at -78 °C and warmed to rt and stirred for an additional 30 min. The mixture was quenched by adding sat. NH4Cl (0.5 mL), diluted with H2O (5 mL), and was extracted with EtOAc (5 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and was purified by C18 column chromatography (0-100% MeCN in 10 mM aq. NH4HCO2). Further purification was performed by silica gel column chromatography (0-100% EtOAc in heptane) to provide tert-butyl ((4-(4- ((4-bromo-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3-(3,4,5-trifluorobenzyl)-3,6- dihydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)methyl)carbamate (122.0 mg, 42 %): MS (ES+, m / z): [M+H]+ = 771.6 / 773.6.

[0380] Step 2. Methyl 4-(4-(5-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)- 4,6-dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2- methyl-2H-indazol-4-yl)-1H-pyrazol-1-yl)butanoate. To a mixture of tert-butyl ((4-(4-((4- bromo-6-chloro-2-methyl-2H-indazol-5-yl)amino)-2,6-dioxo-3-(3,4,5-trifluorobenzyl)-3,6-di- hydro-1,3,5-triazin-1(2H)-yl)isoquinolin-5-yl)methyl)carbamate (239.0 mg, 0.310 mmol) and methyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butanoate (137.0 mg, 0.464 mmol) in 1,4-dioxane (2.8 mL) and H2O (0.28 mL) was added Pd(dppf)Cl2·CH2Cl2(13.0 mg, 0.016 mmol) and K2CO3 (128.0 mg, 0.929 mmol) and the reaction mixture was purged with N2 for 5 min. Then, the reaction was stirred at 80ºC for 18 h. The reaction mixture was cooled to rt and was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and purified by C18 column chromatography (0-100% MeCN in 10 mM aq. NH4HCO2). Further purification was performed by silica gel column chromatography (40 g, 0-10% MeOH in EtOAc) to provide methyl 4-(4-(5-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)-4,6- dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2-methyl- 2H-indazol-4-yl)-1H-pyrazol-1-yl)butanoate (90.0 mg, 23%) : MS (ES+, m / z): [M+H]+ = 859.8.

[0381] Step 3.4-(4-(5-((5-(5-(((tert-Butoxycarbonyl)amino)methyl)isoquinolin-4-yl)-4,6- dioxo-1-(3,4,5-trifluorobenzyl)-1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2- methyl-2H-indazol-4-yl)-1H-pyrazol-1-yl)butanoic acid. To a solution of methyl 4-(4-(5-((5-(5-(((tert-butoxycarbonyl)amino)methyl)isoquinolin-4-yl)-4,6-dioxo-1-(3,4,5-trifluorobenzyl)- 1,4,5,6-tetrahydro-1,3,5-triazin-2-yl)amino)-6-chloro-2-methyl-2H-indazol-4-yl)-1H-pyrazol-1- yl)butanoate (31.0 mg, 0.042 mmol) in THF (0.37 mL) and H2O (0.37 mL) was added LiOH monohydrate (10.0 mg, 0.220...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound represented by the structure of Formula (I):, or a pharmaceutically acceptable salt thereof, wherein: R1aand R1bare each independently selected from: hydrogen; and C1-4alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -and -CN; R2is selected from: hydrogen; and C1-4alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; R3is absent; or selected from C6-10 carbocyclene and 5- to 10-membered heterocyclene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, - OC(O)R13, -N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, - S(O)R13, -S(O)2R13, -NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, -N(R13)C(O)R13, -N(R13)C(O)OR13, - N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; or R2and R3come together with the nitrogen to which they are each bound to form a 4- to 6- membered heterocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR13A, -SR13A, -N(R13A)2, -C(O)R13A, -C(O)N(R13A)2, -C(O)OR13A, - OC(O)R13A, -N(R13A)C(O)R13A, -N(R13A)C(O)OR13A, -N(R13A)S(O)2R13A, - S(O)2N(R13A)2, -S(O)R13A, -S(O)2R13A, -NO2, =O, =S, =N(R13A), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13A, -SR13A, -N(R13A)2, -C(O)R13A, - C(O)N(R13A)2, -C(O)OR13A, -OC(O)R13A, -N(R13A)C(O)R13A, -N(R13A)C(O)OR13A, - N(R13A)S(O)2R13A, -S(O)2N(R13A)2, -S(O)R13A, -S(O)2R13A, -NO2, =O, =S, =N(R13A), and -CN; Ring A is C6 carbocycle; L1is absent or C1-2alkylene; Ring B is 5- to 10-membered heterocyclene; R4and R5are each independently selected at each occurrence from: halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, - S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, - OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, - S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; L2is selected from: -(C1-10alkylene)-, -O-(C1-10alkylene)-, -O-(C2-10alkenylene)-, -C(=O)N(R6)- (C1-10alkylene)-, -C(=O)N(R6)-(C2-10alkenylene)-, -(C1-10alkylene)-O-C(=O)N(R6)-(C1-10alkylene)-, -(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-, -(5- to 6-membered heterocyclene)- (C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-, -(C1-10alkylene)-N(R6)C(=O)-(C1-10carbocyclene)-, and -(C1-10alkylene)-N(R6)C(=O)-(C6-10 carbocyclene)-(C1-10alkylene)-, wherein each alkylene, alkenylene, carbocyclene, and heterocyclene is optionally substituted with one or more substituents independently selected from:halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, - S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, - OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, - S(O)R15, -S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; R6is selected from: hydrogen; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR16, -SR16, -N(R16)2, -C(O)R16, -C(O)N(R16)2, -C(O)OR16, - OC(O)R16, -N(R16)C(O)R16, -N(R16)C(O)OR16, -N(R16)S(O)2R16, -S(O)2N(R16)2, - S(O)R16, -S(O)2R16, -NO2, =O, =S, =N(R16), and -CN; R11, R12, R13, R13A, R14, R15, and R16are each independently selected at each occurrence from: hydrogen; C1-6alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein each C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-6alkyl, -O-C1-6haloalkyl, -NH2, -NO2, =O, and -CN; n is selected from 0, 1, 2, 3, and 4; and m is selected from 0, 1, 2, 3, and 4.

2. The compound or salt of claim 1, wherein R1aand R1bare each hydrogen.

3. The compound or salt of claim 1 or claim 2, wherein R2is hydrogen.

4. The compound or salt of any one of claims 1-3, wherein R3is absent.

5. The compound or salt of any one of claims 1-3, wherein R3is selected from C6-C10 arylene and 5- to 10-membered heteroarylene, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, - N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, - NO2, and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, - N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, - NO2, =O, =S, =N(R13), and -CN.

6. The compound or salt of claim 5, wherein R3is selected from C6 arylene and 9-membered heteroarylene, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, and C1-6alkyl optionally substituted with one or two substituents independently selected from halogen and -OR13.

7. The compound or salt of claim 6, wherein R3is selected from:,denotes the point of connection between R3and L2.

8. The compound or salt of claim 1 or claim 2, wherein R2and R3come together with the nitrogen to which they are each bound to form a 4- to 6-membered heterocycloalkylene optionally substituted with one or more substituents independently selected from: halogen, -OR13A, -SR13A, -N(R13A)2, -C(O)R13A, -C(O)N(R13A)2, -C(O)OR13A, - OC(O)R13A, -N(R13A)C(O)R13A, -N(R13A)C(O)OR13A, -N(R13A)S(O)2R13A, -S(O)2N(R13A)2, - S(O)R13A, -S(O)2R13A, -NO2, =O, =S, =N(R13A), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13A, -SR13A, -N(R13A)2, -C(O)R13A, -C(O)N(R13A)2, -C(O)OR13A, -OC(O)R13A, -N(R13A)C(O)R13A, -N(R13A)C(O)OR13A, -N(R13A)S(O)2R13A, -S(O)2N(R13A)2, - S(O)R13A, -S(O)2R13A, -NO2, =O, =S, =N(R13A), and -CN.

9. The compound or salt of claim 8, wherein R2and R3come together with the nitrogen to which they are each bound to form a 6-membered heterocycloalkylene optionally substituted with one or two or three substituents independently selected from: C1-6alkyl.

10. The compound or salt of claim 9, wherein R2and R3come together with the nitrogen to which they are each bound to form, wherein x denotes the point of connection to L2.

11. The compound or salt of any one of claims 1-10, wherein Ring A is phenyl.

12. The compound or salt of any one of claims 1-11, wherein R4is independently selected at each occurrence from halogen and -CN.

13. The compound or salt of any one of claims 1-12, wherein n is 1, 2, or 3.

14. The compound or salt of any one of claims 1-13, whereinselected from15. The compound or salt of any one of claims 1-14, wherein L1is absent or -CH2-.

16. The compound or salt of any one of claims 1-15, wherein Ring B is 5- to 10-membered heteroarylene.

17. The compound or salt of any one of claims 1-16, wherein R5is independently selected at each occurrence from halogen.

18. The compound or salt of any one of claims 1-17, wherein m is 0 or 1.wherein y denotes the point of connection to L2.

20. The compound or salt of any one of claims 1-19, wherein: L2is selected from: -(C1-10alkylene)-, -O-(C1-10alkylene)-, -O-(C2-10alkenylene)-, -C(=O)N(R6)-(C1-10alkylene)-, - C(=O)N(R6)-(C2-10alkenylene)-, -(C1-10alkylene)-O-C(=O)N(R6)-(C1-10alkylene)-, -(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-, -(5- to 6-membered heteroarylene)-(C1-10alkylene)- C(=O)N(R6)-(C1-10alkylene)-, -(C1-10alkylene)-N(R6)C(=O)-(C6-10 arylene)-, and -(C1-10alkylene)-N(R6)C(=O)-(C6-10arylene)-(C1-10alkylene)-, wherein each alkylene, alkenylene, arylene, and heteroarylene are optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, - N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, -S(O)2R15, - NO2, =O, =S, =N(R15), and -CN; and C1-6alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, - N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, -S(O)2R15, - NO2, =O, =S, =N(R15), and -CN.

21. The compound or salt of claim 20, wherein L2is selected from: -(C1-10alkylene)-t, -O-(C1-10alkylene)-t, -(C1-10alkylene)-O-t, -O-(C2-10alkenylene)-t, -C(=O)N(R6)-(C1-10alkylene)-t, - C(=O)N(R6)-(C2-10alkenylene)-t, -(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-t, -(5- to 6- membered heteroarylene)-(C1-10alkylene)-C(=O)N(R6)-(C1-10alkylene)-t, -(C1-10alkylene)- O-C(=O)N(R6)-(C1-10alkylene)-t, -(C1-10alkylene)-N(R6)C(=O)-t, -(C1-10alkylene)- N(R6)C(=O)-(C1-10alkylene)-t, -(C1-10alkylene)-N(R6)C(=O)-(C6-10 arylene)-t, and -(C1-10alkylene)-N(R6)C(=O)-(C6-10 arylene)-(C1-10alkylene)-t; wherein t denotes the point of connection to Ring B.

22. The compound or salt of any one of claims 1-21, wherein R6is selected from hydrogen and methyl.

23. The compound or salt of any one of claims 1-22, wherein L2is selected from:

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

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

26. A method of treating a disease or disorder associated with a coronavirus 3CL protease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or salt of any one of claims 1-24 or a pharmaceutical composition of claim 25.

27. The method of claim 26, wherein the disease or disorder associated with a coronavirus 3CL protease is a SARS-CoV-2 infection.

28. A method of inhibiting the replication of a coronavirus, the method comprising contacting the coronavirus or a cell infected thereby with an effective amount of a compound or salt of any one of claims 1-24 or a pharmaceutical composition of claim 25.

29. The method of claim 28, wherein the coronavirus is SARS-CoV-2.

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