WO2021072330A1

WO2021072330A1 - Galnac-tgfbr1 inhibitor conjugates for the treatment of liver diseases

Info

Publication number: WO2021072330A1
Application number: PCT/US2020/055159
Authority: WO
Inventors: Sean W. Smith
Original assignee: Silverback Therapeutics, Inc.
Priority date: 2019-10-09
Filing date: 2020-10-09
Publication date: 2021-04-15

Abstract

Conjugates comprising GalNAc moiety and a TGFβR1 inhibitor are provided. In some embodiments, the conjugates are useful for the treatment of viral infections, cancer, and fibrosis.

Description

GALNAC-TGFΒR1 INHIBITOR CONJUGATES FOR THE TREATMENT OF LIVER DISEASES BACKGROUND Fibrosis is the formation of excess fibrous connective tissue or scar tissue in an organ or tissue in a reparative or reactive process. Fibrosis can occur in many tissues within the body, typically as a result of inflammation or damage, which include the lungs, liver, heart, and brain. Scar tissue blocks arteries, immobilizes joints and damages internal organs, wreaking havoc on the body's ability to maintain vital functions. Every year, millions of people are hospitalized due to the damaging effects of fibrosis. However, current therapeutics for treating fibrotic diseases are lacking or have drawbacks. Thus, there remains a considerable need for alternative or improved treatments for fibrotic diseases. SUMMARY In one aspect, the present disclosure provides a conjugate of Formula (I): wherein

Region G comprises at least one GalNAc moiety; Region L³ is a connector that connects Region G to Region Inh; Region Inh comprises a TGFβR1 inhibitor; z is 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure relates to a pharmaceutical composition comprising a conjugate of Formula (I) as described herein and a pharmaceutically acceptable carrier. In another aspect, the present disclosure relates to a method for treating a disease mediated by TGFβR1 activity in subject in need thereof, such as liver cancer or liver fibrosis, comprising administering to the subject an effective amount of a conjugate of Formula (I) or a pharmaceutical composition comprising a conjugate of Formula (I) as described herein. In another aspect, the present disclosure provides a method for enhancing an immune response (e.g., an anti-cancer immune response) in a subject comprising administering to the subject an effective amount of a conjugate of Formula (I) or a pharmaceutical composition comprising a conjugate of Formula (I) as described herein. Disclosed herein is a compound of Formula (XX): [Inh]−Z (XX) wherein Region Inh comprises a TGFβR1 inhibitor; and Z is the residual portion of a released, cleavable linker or comprises a non-cleavable linker and a residual portion of a degraded Region G; or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative aspects, in which the principles of the disclosure are utilized. FIGS. 1A-1C illustrate the activity of GalNAc−TGFβR1 inhibitor conjugates in a HEK293 cell reporter assay (ASGR-positive and ASGR-negative cells: Fig. 1A, Conjugate 3.1; Fig. 1B, Conjugate 3.2; Fig. 1C, Conjugate 3.3). DETAILED DESCRIPTION Additional aspects and advantages of the present disclosure will become apparent to those skilled in this art from the following detailed description, wherein illustrative aspects of the present disclosure are shown and described. As will be appreciated, the present disclosure is capable of other and different aspects, and its several details are capable of modifications in various respects, all without departing from the disclosure. Accordingly, the descriptions are to be regarded as illustrative in nature, and not as restrictive. Where values are described as ranges, it will be understood that such disclosure includes the disclosure of all possible sub-ranges within such ranges, as well as specific numerical values that fall within such ranges irrespective of whether a specific numerical value or specific sub- range is expressly stated. Activin receptor-like kinase 5 (ALK5), which is also commonly known as transforming growth factor beta receptor 1 (TGFβR1), is a serine/threonine kinase transmembrane receptor. It is a part of the TGFβ signaling pathway and is involved in signal transduction from the cell surface to the cytoplasm. The TGFβ signaling pathway regulates gene expression of genes involved in cellular processes such as differentiation, apoptosis, wound healing, and cell growth. In the absence of TGFβ ligands, ALK5 remains a homodimeric cell surface receptor. However, ligand binding to type II TGFβ receptor (TGFβR2) induces the formation of the TGFβR1/TGFβR2 complex, which leads to phosphorylation of Mothers Against Decapentaplegic homolog 2 (Smad2) and Mothers Against Decapentaplegic homolog 3 (Smad3) and subsequent modulation of a number of downstream signaling targets involved in the regulation of gene expression. ALK5 inhibitors and conjugates thereof may be useful for treatment and/or prevention, e.g., vaccination, of cancer, autoimmune diseases, inflammation, fibrosis, sepsis, allergy, asthma, graft rejection, graft-versus-host disease, immunodeficiencies, and infectious diseases. In some aspects, an ALK5 inhibitor has an IC₅₀ value of between 0.1 nM and 1000 nM, between 0.1 nm and 100 nM, or between 0.1 nM and 80 nM in an ALK5 enzyme inhibition assay and/or in a TGFβR1 reporter assay. Exemplary ALK5 enzyme inhibition and TGFβR1 reporter assays are as set forth in the example section. Definitions 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 disclosure belongs. As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise. The term “about” as used herein in the context of a number refers to a range centered on that number and spanning 10% less than that number and 10% more than that number. The term “about” used in the context of a range refers to an extended range spanning 10% less than that the lowest number listed in the range and 10% more than the greatest number listed in the range. In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. It should be understood that the terms "a" and "an" as used herein refer to "one or more" of the enumerated components. The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the terms "include" and "comprise" are used synonymously. The phrase “at least one of” when followed by a list of items or elements refers to an open ended set of one or more of the elements in the list, which may, but does not necessarily, include more than one of the elements. As used herein, a “TGFβR1 inhibitor” refers to a compound that reduces, minimizes, or inactivates activin receptor-linke kinase 5 (ALK5) activity (e.g., directly inhibiting serine/threonine kinase activity or indirectly inhibiting downstream TGFβ-dependent signaling activity, such as SBE-mediated responsiveness to TGFβ and SMAD proteins) by about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% as compared to untreated ALK5. The terms ALK5 and TGFβR1 can be used interchangeably. As used herein, a “conjugate” refers to a GalNAc moiety covalently attached to at least one TGFβR1 inhibitor via a linker. As used herein, a “liver cell” refers to any cell type associated with normal liver tissue. For example, a liver cell can be a canalicular cell, a Kupffer cell, a hepatocyte, sinusoidal endothelial cell, or a stellate cell. As used herein, an “immune cell” refers to a T cell, B cell, NK cell, NKT cell, or an antigen presenting cell. In some embodiments, an immune cell is a T cell, B cell, NK cell, or NKT cell. In some embodiments, an immune cell is an antigen presenting cell. In some embodiments, an immune cell is not an antigen presenting cell. The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. The term “C_x-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 “C_1-6alkyl” 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 −C_x-yalkylene− refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example −C_1-6alkylene− may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted. The terms “C_x-yalkenyl” and “C_x-yalkynyl” refer to substituted or unsubstituted 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 −C_x-yalkenylene− refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, −C_2-6alkenylene− 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 −C_x-yalkynylene− refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, −C_2-6alkenylene− 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. “Alkyl” refers to a monovalent hydrocarbon consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, and the like. In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C₁-C₅ alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C₁-C₄ alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C₁-C₃ alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C₁-C₂ alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C₁ alkyl or methyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C₅- C₈ alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C₂-C₅ alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C₃-C₅ alkyl). Unless stated otherwise specifically in the specification, an alkyl chain is optionally substituted by one or more substituents such as those substituents described herein. “Alkylene” refers to a 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 points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C₁-C₅ alkylene). 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-C₂ alkylene). 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-C₅ alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C₃-C₅ alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more substituents such as those substituents described herein. “Alkenyl” refers to a monovalent hydrocarbon chain consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenyl chain is attached to the rest of the molecule through a single bond. In other embodiments, an alkenyl comprises two to five carbon atoms (i.e., C₂-C₅ alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C₂-C₄ alkenyl). In other embodiments, an alkenyl comprises two to three carbon atoms (i.e., C₂-C₃ alkenyl). In other embodiments, an alkenyl comprises two carbon atom (i.e., C₂ alkenyl). In other embodiments, an alkenyl comprises five to eight carbon atoms (i.e., C₅-C₈ alkenyl). In other embodiments, an alkenyl comprises three to five carbon atoms (i.e., C₃-C₅ alkenyl). Unless stated otherwise specifically in the specification, an alkenyl chain is optionally substituted by one or more substituents such as those substituents described herein. “Alkenylene” refers to a 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 points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. 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-C₄ alkenylene). 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-C₈ alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C₃-C₅ alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more substituents such as those substituents described herein. “Alkynyl” refers to a monovalent hydrocarbon chain consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynyl chain is attached to the rest of the molecule through a single bond. In other embodiments, an alkynyl comprises two to five carbon atoms (i.e., C₂-C₅ alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C₂-C₄ alkynyl). In other embodiments, an alkynyl comprises two to three carbon atoms (i.e., C₂-C₃ alkynyl). In other embodiments, an alkynyl comprises two carbon atom (i.e., C₂ alkynyl). In other embodiments, an alkynyl comprises five to eight carbon atoms (i.e., C₅-C₈ alkynyl). In other embodiments, an alkynyl comprises three to five carbon atoms (i.e., C₃-C₅ alkynyl). Unless stated otherwise specifically in the specification, an alkynyl chain is optionally substituted by one or more substituents such as those substituents described herein. “Alkynylene” refers to a 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 radical group through a single bond. 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. 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-C₄ alkynylene). 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-C₈ alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C₃-C₅ alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more substituents such as those substituents described herein. “Heteroalkyl” refers to a monovalent hydrocarbon chain including at least one heteroatom in the chain, containing no unsaturation, and preferably having from one to twelve carbon atoms and from one to 6 heteroatoms, e.g., −O−, −NH−, −S−. The heteroalkyl is attached to the rest of the molecule through a single bond. In other embodiments, a heteroalkyl comprises one to five carbon atoms and from one to three heteroatoms. In other embodiments, a heteroalkyl comprises one to four carbon atoms and from one to three heteroatoms. In other embodiments, a heteroalkyl comprises one to three carbon atoms and from one to two heteroatoms. In other embodiments, a heteroalkyl comprises one to two carbon atoms and from one to two heteroatoms. In other embodiments, a heteroalkyl comprises one carbon atom and from one to two heteroatoms. In other embodiments, a heteroalkyl comprises five to eight carbon atoms and from one to four heteroatoms. In other embodiments, a heteroalkyl comprises two to five carbon atoms and from one to three heteroatoms. In other embodiments, a heteroalkyl comprises three to five carbon atoms and from one to three heteroatoms. Unless stated otherwise specifically in the specification, a heteroalkyl chain is optionally substituted by one or more substituents such as those substituents described herein. “Heteroalkylene” refers to a divalent hydrocarbon chain including at least one heteroatom in the chain, containing no unsaturation, and preferably having from one to twelve carbon atoms and from one to 6 heteroatoms, e.g., −O−, −NH−, −S−. The heteroalkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the heteroalkylene chain to the rest of the molecule and to the radical group are through the terminal atoms of the chain. In other embodiments, a heteroalkylene comprises one to five carbon atoms and from one to three heteroatoms. In other embodiments, a heteroalkylene comprises one to four carbon atoms and from one to three heteroatoms. In other embodiments, a heteroalkylene comprises one to three carbon atoms and from one to two heteroatoms. In other embodiments, a heteroalkylene comprises one to two carbon atoms and from one to two heteroatoms. In other embodiments, a heteroalkylene comprises one carbon atom and from one to two heteroatoms. In other embodiments, a heteroalkylene comprises five to eight carbon atoms and from one to four heteroatoms. In other embodiments, a heteroalkylene comprises two to five carbon atoms and from one to three heteroatoms. In other embodiments, a heteroalkylene comprises three to five carbon atoms and from one to three heteroatoms. Unless stated otherwise specifically in the specification, a heteroalkylene chain is optionally substituted by one or more substituents such as those substituents described herein. The term “carbocycle” or “carbocyclyl” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle includes 3- to 10- membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. 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. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. A bicyclic carbocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. The term “unsaturated carbocycle” refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene. The term “aryl” refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system. 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) π-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. The term “cycloalkyl” refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. 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), decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, and the like. The term “halo” or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo. The term “haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, and the like. The term “heterocycle” or “heterocyclyl” as used herein refers to a saturated, unsaturated 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, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. The term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. The term “heteroaryl” includes aromatic single ring structures, preferably 5- to 7- membered rings, more 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. The term “heteroaryl” also includes polycyclic ring systems having two or more rings in which two or more carbons 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. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The term “heterocycloalkyl” refers to a saturated ring with carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. 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. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., −NH−, of the structure. 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. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. 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), −R^b−OR^a, −R^b−OC(O)−R^a, −R^b−OC(O)−OR^a, −R^b−OC(O)−N(R^a)₂, −R^b−N(R^a)₂, −R^b−C(O)R^a, −R^b−C(O)OR^a, −R^b−C(O)N(R^a)₂, −R^b−O−R^c−C(O)N(R^a)₂, −R^b−N(R^a)C(O)OR^a, −R^b−N(R^a)C(O)R^a, −R^b−N(R^a)S(O)_tR^a (where t is 1 or 2), −R^b−S(O)_tR^a (where t is 1 or 2), −R^b−S(O)_tOR^a (where t is 1 or 2), and −R^b−S(O)_tN(R^a)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), −R^b−OR^a, −R^b−OC(O)−R^a, −R^b−OC(O)−OR^a, −R^b−OC(O)−N(R^a)₂, −R^b−N(R^a)₂, −R^b−C(O)R^a, −R^b−C(O)OR^a, −R^b−C(O)N(R^a)₂, −R^b−O−R^c−C(O)N(R^a)₂, −R^b−N(R^a)C(O)OR^a, −R^b−N(R^a)C(O)R^a, −R^b−N(R^a)S(O)_tR^a (where t is 1 or 2), −R^b−S(O)_tR^a (where t is 1 or 2), −R^b−S(O)_tOR^a (where t is 1 or 2) and −R^b−S(O)_tN(R^a)₂ (where t is 1 or 2); wherein each R^a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R^a, 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), −R^b−OR^a, −R^b−OC(O)−R^a, −R^b−OC(O)−OR^a, −R^b−OC(O)−N(R^a)₂, −R^b−N(R^a)₂, −R^b−C(O)R^a, −R^b−C(O)OR^a, −R^b−C(O)N(R^a)₂, −R^b−O−R^c−C(O)N(R^a)₂, −R^b−N(R^a)C(O)OR^a, −R^b−N(R^a)C(O)R^a, −R^b−N(R^a)S(O)_tR^a (where t is 1 or 2), −R^b−S(O)_tR^a (where t is 1 or 2), −R^b−S(O)_tOR^a (where t is 1 or 2) and −R^b−S(O)_tN(R^a)₂ (where t is 1 or 2); and wherein each R^b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R^c is a straight or branched alkylene, alkenylene or alkynylene chain. “Protecting group” refers to a moiety, except alkyl groups, that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3.sup.rd edition, John Wiley & Sons, New York, 1999, and Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996), which are incorporated herein by reference in their entirety. Representative amino or amine protecting groups include, formyl, acyl groups (such as acetyl, trifluoroacetyl, and benzoyl), benzyl, alkoxycarbonyl (such as benzyloxycarbonyl (CBZ), and tert-butoxycarbonyl (Boc)), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), sulfonyl, and the like. Compounds described herein can include protecting groups (e.g., a hydrogen on a reactive nitrogen atom of a compound described herein can be replaced by an amino protecting group). It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants. 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, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well. 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. T he compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

. The compounds described 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 appropriate mixtures thereof. 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. The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of ²H, ³H, ¹⁴

and/or C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of the present disclosure. 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 with ²H, ¹¹C, ¹³C, ¹⁴C, ¹⁵C, ¹²N, ¹³N, ¹⁵N, ¹⁶N, ¹⁶O, ¹⁷O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S, ³⁶S, ³⁵Cl, ³⁷Cl, ⁷⁹Br, ⁸¹Br, ¹²⁵I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. In certain embodiments, the compounds disclosed herein have some or all of the ¹H atoms replaced with ²H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. 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. 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. The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The 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. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. Conjugates A conjugate as described herein comprises a GalNAc moiety linked to a TGFβR1 inhibitor via a linker. In one aspect, the present disclosure provides a conjugate of Formula (I):

(I) wherein Region G comprises at least one GalNAc moiety; Region L³ is a connector that connects Region G to Region Inh; Region Inh comprises a TGFβR1 inhibitor; z is 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof. In some embodiments, Region G is as described herein. In some embodiments, Region L³ is as described herein. In some embodiments, the TGFβR1 inhibitor is as described herein. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. Synthetic chemistry transformations and methodologies useful in synthesizing the compounds and conjugates described herein are known in the art and 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). Region G/GalNAc Moiety A conjugate as described herein comprises Region G, which comprises at least one GalNAc moiety. In some embodiments, Region G comprises a Display Element for display of the one or more GalNAc moieties. In some embodiments, Region G comprises 1, 2, or 3 GalNAc moieties. In some embodiments, Region G comprises two or three GalNAc moieties. In some embodiments, Region G comprises a structure of Formula (V):

wherein n is 1, 2, or 3; SP is a spacer, wherein each SP is independently a heteroalkylene, heteroalkenylene, or heteroalkynylene comprising 5 to 30 components in the longest linear chain, wherein the components are selected from −CH₂−, −CH(C_1-4alkyl), −C(C_1-4alkyl)₂, −CH=CH−, −C≡C−, −C(O)−, −O−, −NH−, −N(C_1-4alkyl), −S−, −S(O)−, −S(O)₂−, and −P(O)(O-)−; and DE is a branched Display Element, wherein the asterisk (*) is the position of connection to the rest of the conjugate. In some embodiments, n is 2 or 3. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, when n is 1, the branched Display Element is absent. In some embodiments, one or more SP units comprise an ethylene glycol or poly(ethylene glycol) region. In some embodiments, one or more SP units comprise an amide bond. In some embodiments, one or more SP units comprise an unsubstituted ethylene or propylene unit. In some embodiments, each SP comprises 5 to 20 components in the longest linear chain. In some embodiments, each SP is −(CH₂)₂−C(O)−NH−(CH₂)_x−CH₂− (where x is 1, 2, 3, 4, 5, or 6, or x is 1, 2, or 3, or x is 1, or x is 3, or x is 4, or x is 5); −CH₂−(CH₂)_a−CH₂−NH−C(O)−(CH₂)_b−, where a is 0, 1, 2, or 3 (or a is 1 or 2, or a is 1); and b is 1, 2, 3, 4, 5, or 6 (or b is 3, 4, or 5, or b is 5); −C(O)−NH−(CH₂)_(a+2)−NH−C(O)−(CH₂)_b−, where a is 0, 1, 2, or 3 (or a is 1) and b is 1, 2, 3, 4, 5, or 6 (or b is 3, 4, or 5, or b is 5); or −C(O)−NH−(CH₂)_p− where p is 2, 3, 4, 5, or 6 (or p is 2, or p is 4, or p is 6). The Display Element (DE) comprises a central atom unit and two or three Arm Elements (AE) attached to the central atom unit that connect DE to each SP. In some embodiments, the central atom unit is methine (CH). In some embodiments, the central atom unit is carbon (C). In some embodiments, the central atom unit is nitrogen (N). In some embodiments, the central atom unit i

, where the two nitrogen substituents and one carbon substituent are each an SP, and the other carbon substituent connects the central atom unit to the linker. In some embodiments, each AE is independently −(CH₂)_1-3O−, −(CH₂)_1-3NR−, −NR−, −(CH₂)_1-3−, or a bond, wherein each CH₂ is optionally substituted with one or more C_1-4alkyl or fluoro substituents, and R is H or C_1-4alkyl. In some embodiments, DE is one of the following structures:

. Representative structures of Formula (V) and representative Display Elements are described in U.S. Patent Nos. 8,450,467, 9,399,775, and 10,077,433, which are incorporated herein by reference. In some embodiments, the Region G has the structure:

, where x is 1, 2, 3, 4, 5, or 6. In some embodiments, x is 1, 2, or 3. In some embodiments, x is 1. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, Region G has the structure:

where a is 0, 1, 2, or 3; and b is 1, 2, 3, 4, 5, or 6. In some embodiments, a is 1 or 2. In some embodiments, a is 1. In some embodiments, b is 3, 4, or 5. In some embodiments, b is 5. In some embodiments, Region G has the structure:

wherein each p is independently 2, 3, 4, 5, or 6. In some embodiments, each p is 2. In some embodiments, each p is 4. In some embodiments, each p is 6. TGFβR1 Inhibitors The conjugates described herein comprise a TGFβR1 inhibitor. The TGFβR1 inhibitor can provide a direct or indirect effect. In some preferred embodiments, the TGFβR1 inhibitor is not an siRNA, an antisense RNA, or other oligonucleotide. In some embodiments, the TGFβR1 inhibitor is a non-naturally occurring small molecule. A “small molecule” is an organic compound with a molecular weight of less than 1500, or 1000, or 900, or 750, or 600, or 500 Daltons. In some embodiments, a small molecule TGFβR1 inhibitor has an octanol-water partition coefficient (logP) in the range of 3 to 6, or from 4 to 5, or from 2 to 4. In some embodiments, a small molecule TGFβR1 inhibitor has a polar surface area of less than 200, or less than 150 Å². In some embodiments, a small molecule TGFβR1 inhibitor has not more than five, or not more than three, hydrogen bond donors, and not more than 10, or not more than three hydrogen bond acceptors. A small molecule TGFβR1 inhibitor is not a protein, a polysaccharide, or a nucleic acid. TGFβR1 Inhibitors of Formula (A-I) In some aspects, the TGFβR1 inhibitor is a compound of Formula (A-I): wherein

one of M¹ and M² is and the other of M¹ and M² is selected from:

R¹ and R² are, at each occurrence, independently selected from hydrogen, halogen, −OR¹¹, −SR¹¹, −N(R¹¹)₂, −NO₂, −CN, phenyl, and −C₁-C₆ alkyl, wherein said −C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from halogen, −OR¹¹, −SR¹¹, −S(O)R¹⁰, −S(O)₂R¹¹, −S(O)₂N(R¹¹)₂, −N(R¹¹)₂, −C(O)R¹⁰, −C(O)N(R¹¹)₂, −N(R¹¹)C(O)R¹⁰, −C(O)OR¹¹, −OC(O)R¹⁰, −NO₂, and −CN; R³ is, at each occurrence, independently selected from halogen, −C1-C3 alkyl, −C1-C3 haloalkyl, −OH, -NO₂, -CN, -OC₁-C₃ alkyl, and -OC₁-C₃ haloalkyl; each R⁴ is, at each occurrence, independently selected from hydrogen and C₁-C₃ alkyl or two R⁴ join together with atoms to which they are attached to form a 5- or 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C₁-C₃ alkyl, -OH, OC₁-C₃ alkyl, and -OC₁-C₃ haloalkyl; R⁵ is hydrogen, halogen, -OR⁶¹, -SR⁶¹, -N(R⁶¹)₂, -NO₂, -CN, and -C₁-C₆ alkyl, wherein said -C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR⁶¹, -SR⁶¹, -N(R⁶¹)2, -NO2, and -CN; R⁶ is, at each occurrence, independently selected from: halogen, -OR²¹, -SR²¹, -N(R²¹)₂, -C(O)R²⁰, -C(O)N(R²¹)₂, -N(R²¹)C(O)R²⁰ , - C(O)OR²¹, -OC(O)R²¹, -S(O)R²⁰, -S(O)₂R²¹, -S(O)₂N(R²¹)₂, -OC(O)OR²¹, -OC(O)N(R²¹)₂, −NR²¹C(=O)OR²¹, -N(R²¹)C(O)N(R²¹)_2, -NO₂, and -CN; C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR²¹, -SR²¹, −N(R²¹)₂, -C(O)R²⁰, -C(O)N(R²¹)₂, -N(R²¹)C(O)R²⁰ , -C(O)OR²¹, -OC(O)R²¹, -S(O)R²⁰, - S(O)₂R²¹, -S(O)₂N(R²¹)₂, -OC(O)OR²¹, -OC(O)N(R²¹)₂, -NR²¹C(=O)OR²¹, -N(R²¹)C(O)N(R²¹)_2, -NO₂, =O, =S, =N(R²¹), -CN, a C₃-C₁₀ carbocycle, and a 3- to 10-membered heterocycle wherein said C₃-C₁₀ carbocycle and said 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from R^X; and a C₃-C₁₀ carbocycle and a 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR²⁰, -OH, -SR²⁰, -SH, -N(R²¹)₂, -C(O)R²⁰, -C(O)N(R²¹)₂, -N(R²¹)C(O)R²⁰ , -C(O)OR²¹, −OC(O)R²¹, -S(O)R²⁰, -S(O)₂R²¹, -S(O)₂N(R²¹)₂, -OC(O)OR²¹, -OC(O)N(R²¹)₂, −NR²¹C(=O)OR²¹, -N(R²¹)C(O)N(R²¹)_2, -NO₂, =O, =S, =N(R²¹), -CN, -C₂-C₆ alkenyl, −C₂-C₆ alkynyl and C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from R^Y; R⁷ and R⁸ are independently selected from hydrogen, halogen, C₁-C₃ alkyl, -OH, OC₁-C₃ alkyl, and -OC₁-C₃ haloalkyl, or R⁷ and R⁸ join together with the atoms to which they are attached to form a C₅-C₆ carbocycle or 5- or 6- membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR³¹, -SR³¹, -N(R³¹)₂, -NO₂, -CN and -C₁-C₆ alkyl wherein said C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR³¹, -SR³¹, -N(R³¹)₂, - NO₂, and −CN; Y is selected from −O- and -N(R⁹)- and R⁹ is, at each occurrence, independently selected from: hydrogen; and -C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen, -OR⁴¹, -SR⁴¹, -S(O)R⁴⁰, -S(O)₂R⁴¹, -S(O)₂N(R⁴¹)₂, −N(R⁴¹)₂, -C(O)R⁴⁰, -C(O)N(R⁴¹)₂, -N(R⁴¹)C(O)R⁴⁰ , -C(O)OR⁴¹, -OC(O)R⁴⁰, -NO₂, and -CN; each R¹⁰, R²⁰, and R⁴⁰ is independently selected at each occurrence from: -C₁-C₁₀ alkyl, -C₂-C₁₀ alkenyl, and -C₂-C₁₀ alkynyl, each of which is optionally substituted with one or more substituents independently selected from R^Y; and a C₃-C₁₂ carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from R^X; each R¹¹, R²¹, R³¹, R⁴¹, and R⁶¹ is independently selected at each occurrence from: hydrogen; -C₁-C₁₀ alkyl, -C₂-C₁₀ alkenyl, and -C₂-C₁₀ alkynyl, each of which is optionally substituted with one or more substituents independently selected from R^Y; and a C₃-C₁₂ carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from R^X, or two R¹¹, R²¹, R³¹, R⁴¹, or R⁶¹ on the same N atom are taken together with the N atom to which they are attached to form a N-containing heterocycle optionally substituted with R^X; each R^X is independently selected at each occurrence from: halogen, -OR⁵¹, -SR⁵¹, −N(R⁵¹)₂, -C(O)R⁵⁰, -C(O)N(R⁵¹)₂, -N(R⁵¹)C(O)R⁵⁰ , -C(O)OR⁵¹, -OC(O)R⁵¹, -S(O)R⁵⁰, −S(O)₂R⁵¹, -S(O)₂N(R⁵¹)₂, -OC(O)OR⁵¹, -OC(O)N(R⁵¹)₂, -NR⁵¹C(=O)OR⁵¹, −N(R⁵¹)C(O)N(R⁵¹)_2, -NO₂, =O, =S, =N(R⁵¹), -CN, -C₂-C₆ alkenyl, -C₂-C₆ alkynyl, and C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from -OR⁵¹, -SR⁵¹, -N(R⁵¹)₂, -C(O)R⁵⁰, -C(O)N(R⁵¹)₂, -N(R⁵¹)C(O)R⁵⁰ , −C(O)OR⁵¹, -OC(O)R⁵¹, -S(O)R⁵⁰, -S(O)₂R⁵¹, -S(O)₂N(R⁵¹)₂, -OC(O)OR⁵¹, -OC(O)N(R⁵¹)₂, −NR⁵¹C(=O)OR⁵¹, -N(R⁵¹)C(O)N(R⁵¹)₂, and =O; each R^Y is independently selected at each occurrence from: halogen, -OR⁵¹, -SR⁵¹, −N(R⁵¹)₂, -C(O)R⁵⁰, -C(O)N(R⁵¹)₂, -N(R⁵¹)C(O)R⁵⁰, -C(O)OR⁵¹, -OC(O)R⁵¹, -S(O)R⁵⁰, −S(O)₂R⁵¹, -S(O)₂N(R⁵¹)₂, -OC(O)OR⁵¹, -OC(O)N(R⁵¹)₂, -NR⁵¹C(=O)OR⁵¹, −N(R⁵¹)C(O)N(R⁵¹)_2, -NO₂, =O, =S, =N(R⁵¹), and -CN; each R⁵⁰ is independently selected at each occurrence from: -C₁-C₁₀ alkyl, -C₂-C₁₀ alkenyl, and -C₂-C₁₀ alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO₂, −NH₂, =O, =S, -O-C₁-C₁₀ alkyl, C₃-C₁₂ carbocycle, and a 3- to 12-membered heterocycle; and a C₃-C₁₂ carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO₂, -NH₂, =O, =S, -C₁-C₁₀ alkyl, -O-C₁-C₁₀ alkyl, and -C₁-C₁₀ haloalkyl; each R⁵¹ is independently selected at each occurrence from: hydrogen; -C₁-C₁₀ alkyl, -C₂-C₁₀ alkenyl, and -C₂-C₁₀ alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO₂, −NH₂, =O, =S, -O-C₁-C₁₀ alkyl, C₃-C₁₂ carbocycle, and a 3- to 12-membered heterocycle; and a C₃-C₁₂ carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, −CN, -NO₂, -NH₂, =O, =S, -C₁-C₁₀ alkyl, -O-C₁-C₁₀ alkyl, and -C₁-C₁₀ haloalkyl; Z¹, Z², Z³, and Z⁴ are each independently selected from N or C(H); n is selected from 1, 2, and 3; m is 0, 1, or 2; s is selected from 0 and 1; and w is selected from 0, 1, 2, 3, 4, and 5. or a pharmaceutically acceptable salt thereof. In a second aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein one of M¹ and M² is

and the other of M¹ and M² is

the remaining variables (e.g., R¹-R⁸, R¹⁰, R²⁰, R⁴⁰, R¹¹, R²¹, R³¹, R⁴¹, R⁵⁰, R⁵¹, R⁶¹, Y, R^X, R^Y, Z¹, Z², Z³, Z⁴, n, m, s, and w) are as set forth in the first aspect. In a third aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein one of M¹

and the other of M¹ and M² is

the remaining variables are as set forth in the first aspect. In a fourth aspect, disclosed herein is a compound represented by Formula (A-I) wherein one of one of M¹ and M² is and the other of M¹ and M² is ; and the remaining variables are as set forth in the first aspect. In a fifth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein one of one of M¹ and M² is and the other of M¹ and M² is ; and the remaining variables are as set forth in the first aspect. In a sixth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹ and M² is as set forth in the fifth aspect and R⁷ and R⁸ are independently selected from hydrogen, halogen, C₁-C₃ alkyl, -OH, OC₁-C₃ alkyl, and -OC₁-C₃ haloalkyl, or R⁷ and R⁸ join together with the atoms to which they are attached to form a C₅-C₆ carbocycle or 5- or 6- membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR³¹, -SR³¹, -N(R³¹)₂, and -C₁-C₆ alkyl wherein said C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR³¹, -SR³¹, and -N(R³¹)₂; and the remaining variables are as set forth in the first aspect. In a seventh aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹ and M² is as set forth in the fifth aspect and R⁷ and R⁸ are independently selected from hydrogen, halogen, C₁-C₃ alkyl, -OH, OC₁-C₃ alkyl, and -OC₁-C₃ haloalkyl, or R⁷ and R⁸ join together with the atoms to which they are attached to form an unsubstituted C₅-C₆ carbocycle or an unsubstituted 5- or 6- membered heterocycle; and the remaining variables are as set forth in the first aspect. In an eighth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹ and M² is as set forth in any one of aspects 5-7 wherein the 5- or 6- membered heterocycle of R⁷ and R⁸ is a 5- or 6- membered heterocycle contains one ring heteroatom selected from nitrogen contains one ring heteroatom selected from nitrogen; and the remaining variables are as set forth in the first aspect. In a ninth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹ and M² is as set forth in any one of aspects 5-7 wherein R⁷ and R⁸ join together with the atoms to which they are attached to form a phenyl ring optionally substituted with one or more substituents independently selected from halogen, -OR³¹, -SR³¹, -N(R³¹)₂, and - C₁-C₆ alkyl wherein said C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR³¹, -SR³¹, and -N(R³¹)_2; and the remaining variables are as set forth in the first aspect. In a tenth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹ and M² is as set forth in any one of aspects 5-7 wherein R⁷ and R⁸ join together with the atoms to which they are attached to form an unsubstituted phenyl ring; and the remaining variables are as set forth in the first aspect. In an eleventh aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹ and M² is as set forth in any one of aspects 5-7 wherein R⁷ and R⁸ are each hydrogen; and the remaining variables are as set forth in the first aspect. In a twelfth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷ and R⁸ are as set forth in any one of aspects 1-11 and wherein m is 1 or 2 and R³ is, at each occurrence, independently selected from halogen, -C₁-C₃ alkyl, -C₁-C₃ haloalkyl, -OH, OC₁-C₃ alkyl, and -OC₁-C₃ haloalkyl; and the remaining variables are as set forth in the first aspect. In a thirteenth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷ and R⁸ are as set forth in any one of aspects 1-11 and wherein m is 1 and R³ is, at each occurrence, independently selected from halogen, -C₁-C₃ alkyl, -C₁-C₃ haloalkyl, -OH, and -OC₁-C₃ alkyl; and the remaining variables are as set forth in the first aspect. In a fourteenth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷ and R⁸ are as set forth in any one of aspects 1-11 and wherein m is zero; and the remaining variables are as set forth in the first aspect. In a fifteenth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein one of one of M¹ and M² is and the other of M¹ and M² is ; and the remaining variables are as set forth in the first aspect. In a sixteenth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹ and M² is as set forth in aspect 15 wherein Z¹, Z², Z³, and Z⁴ are -C(H); and the remaining variables are as set forth in the first aspect. In a seventeenth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹ and M² is as set forth in aspect 15 wherein Z² is N and Z¹, Z³, and Z⁴ are -C(H); and the remaining variables are as set forth in the first aspect. In a eighteenth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹ and M² are as set forth in aspect 15 wherein Z¹ is N and Z², Z³, and Z⁴ are -C(H); and the remaining variables are as set forth in the first aspect. In a nineteenth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M², R⁷, R⁸, m, R³, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1- 18 wherein M¹ is ; and the remaining variables are as set forth in the first aspect. In a twentieth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, R⁷, R⁸, m, R³, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1- 18 wherein M² is ; and the remaining variables are as set forth in the first aspect. In a twenty-first aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R³, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-20 wherein R⁵ is hydrogen, halogen, or C₁-C₃ alkyl optionally substituted with halogen; and the remaining variables are as set forth in the first aspect. In a twenty-second aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R³, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-20 wherein R⁵ is hydrogen or C₁-C₃ alkyl; and the remaining variables are as set forth in the first aspect. In a twenty-third aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R³, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-20 and wherein R⁵ is methyl; and the remaining variables are as set forth in the first aspect. In a twenty-fourth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein one of M¹ and M

and the other of M¹ and M² is selected from:

and the remaining variables are as set forth in the first aspect. In a twenty-fifth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹ is as set forth in aspect 24 and wherein M² is

; and the remaining variables are as set forth in the first aspect. In a twenty-sixth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-25 and wherein R¹ and R² are, at each occurrence, independently selected from hydrogen, halogen, -OR¹¹, -SR¹¹, -N(R¹¹)₂, phenyl, and -C₁-C₆ alkyl wherein said C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from halogen, −OR¹¹, -SR¹¹, -S(O)R¹⁰, -S(O)₂R¹¹, -S(O)₂N(R¹¹)₂, -N(R¹¹)₂, -C(O)R¹⁰, -C(O)N(R¹¹)₂, −N(R¹¹)C(O)R¹⁰, -C(O)OR¹¹, and -OC(O)R¹⁰; and the remaining variables are as set forth in the first aspect. In a twenty-seventh aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-25 and wherein R¹ and R² are independently selected at each occurrence from hydrogen, phenyl, and -C₁-C₃ alkyl wherein said -C₁-C₃ alkyl is optionally substituted with one or more substituents independently selected from halogen, -OR¹¹, and -C(O)OR¹¹; and the remaining variables are as set forth in the first aspect. In a twenty-eighth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-25 and wherein R¹ and R² are independently selected at each occurrence from hydrogen, -CH₃, -CH₂OH, CH₂CO₂CH₃, and phenyl; and the remaining variables are as set forth in the first aspect. In a twenty-ninth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-25 and wherein R¹ and R² are each hydrogen; and the remaining variables are as set forth in the first aspect. In a thirtieth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R¹, R², R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-29 and wherein s is zero; and the remaining variables are as set forth in the first aspect. In a thirty-first aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R¹, R², R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-29 and wherein s is one; and the remaining variables are as set forth in the first aspect. In a thirty-second aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R¹, R², R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-29 and wherein s is one and n is two or three; and the remaining variables are as set forth in the first aspect. In a thirty-third aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R¹, R², R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-29 and wherein s is zero or one and n is one; and the remaining variables are as set forth in the first aspect. In a thirty-fourth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R¹, R², R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-29 and wherein s is zero or one and n is two; and the remaining variables are as set forth in the first aspect. In a thirty-fifth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R¹, R², R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-29 and wherein s is zero or one and n is three; and the remaining variables are as set forth in the first aspect. In a thirty-sixth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n R¹, R², R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-35 and wherein Y is selected from −O- and -N(R⁹)- and R⁹ is, at each occurrence, independently selected from: hydrogen; and -C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen, -OR⁴¹, -SR⁴¹, -S(O)R⁴⁰, −S(O)₂R⁴¹, -S(O)₂N(R⁴¹)₂, -N(R⁴¹)₂, -C(O)R⁴⁰, -C(O)N(R⁴¹)₂, -N(R⁴¹)C(O)R⁴⁰, -C(O)OR⁴¹, and −OC(O)R⁴⁰; and the remaining variables are as set forth in the first aspect. In a thirty-seventh aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n R¹, R², R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-35 and wherein Y is selected from −O- and -N(R⁹)- and R⁹ is, at each occurrence, independently selected from: hydrogen; and unsubstituted-C₁-C₆ alkyl; and the remaining variables are as set forth in the first aspect. In a thirty-eight aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n R¹, R², R³, R⁵, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-35 and wherein Y is selected from O, N(H), and N(Me); and unsubstituted −C₁-C₆ alkyl; and the remaining variables are as set forth in the first aspect. In a thirty-ninth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-38 and wherein w is zero; and the remaining variables are as set forth in the first aspect. In a fortieth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-38 and wherein w is 1, 2, 3, 4, or 5; and the remaining variables are as set forth in the first aspect. In a forty-first aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-38 and wherein w is 1, 2, or 3; and the remaining variables are as set forth in the first aspect. In a forty-second aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-38 and wherein w is 1 or 2; and the remaining variables are as set forth in the first aspect. In a forty-third aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-38 having formula (A-IA), (A-IB), (A-IC), (A-ID) or (A-IE):

or a pharmaceutically acceptable salt of any one of formula (A-IA), (A-IB), (A-IC), (A-ID) or (A-IE); and the remaining variables are as set forth in the first aspect. In a forty-fourth aspect, disclosed herein is a compound represented by Formula (A-I) wherein M¹, M², R⁷, R⁸, m, s, n R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-38 having formula (A-IC) or (A-ID)

or a pharmaceutically acceptable salt of any one of formula (A-IC), or (A-ID); and the remaining variables are as set forth in the first aspect. In a forty-fifth aspect, disclosed herein is a compound represented by Formula (A-I) wherein M¹, M², R⁷, R⁸, m, s, n R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-38 having formula (A-IF):

wherein w is 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof); and the remaining variables are as set forth in the first aspect. In a forty-sixth aspect, disclosed herein is a compound represented by Formula (A-IF) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n, R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-38 and w is 2 or 3; and the remaining variables are as set forth in the first aspect. In a forty-seventh aspect, disclosed herein is a compound represented by Formula (A-IF) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n, R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-38 and w is 2; and the remaining variables are as set forth in the first aspect. In a forty-eighth aspect, disclosed herein is a compound represented by Formula (A-I), (A-IA), (A-IB), (A-IC), (A-ID), (A-IE), or (A-IF) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n, w, R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-47 and R⁶ is independently selected at each occurrence from: halogen, -OR²¹, -N(R²¹)₂ and -CN; and C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen, -OR²¹, -SR²¹, -N(R²¹)₂, -C(O)R²⁰, -C(O)N(R²¹)₂, -N(R²¹)C(O)R²⁰ , - C(O)OR²¹, −OC(O)R²¹, -S(O)R²⁰, -S(O)₂R²¹, -S(O)₂N(R²¹)₂, -OC(O)OR²¹, -OC(O)N(R²¹)₂, −NR²¹C(=O)OR²¹, -N(R²¹)C(O)N(R²¹)_2, -NO₂, =O, =S, =N(R²¹), -CN, a C₃-C₁₀ carbocycle, and a 3- to 10-membered heterocycle wherein said C₃-C₁₀ carbocycle and said 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from R^X; and a C₃-C₁₀ carbocycle and a 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR²⁰, −OH, - SR²⁰, -SH, -N(R²¹)₂, -C(O)R²⁰, -C(O)N(R²¹)₂, -N(R²¹)C(O)R²⁰ , -C(O)OR²¹, −OC(O)R²¹, - S(O)R²⁰, -S(O)₂R²¹, -S(O)₂N(R²¹)₂, -OC(O)OR²¹, -OC(O)N(R²¹)₂, −NR²¹C(=O)OR²¹, - N(R²¹)C(O)N(R²¹)_2, -NO₂, =O, =S, =N(R²¹), -CN, -C₂-C₆ alkenyl, −C₂-C₆ alkynyl and C₁-C₆ alkyl wherein said C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from R^Y; and the remaining variables are as set forth in the first aspect. In a forty-ninth aspect, disclosed herein is a compound represented by Formula (A-I), (A- IA), (A-IB), (A-IC), (A-ID), (A-IE) or (A-IF) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n, w, R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-47 and R⁶ is independently selected at each occurrence from: halogen, -OR²¹, and -N(R²¹)₂; C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen, -OR²¹, -SR²¹, -N(R²¹)₂, -C(O)R²⁰, -C(O)N(R²¹)₂, -N(R²¹)C(O)R²⁰ , −C(O)OR²¹, -OC(O)R²¹, -S(O)R²⁰, -S(O)₂R²¹, -S(O)₂N(R²¹)₂, -OC(O)OR²¹, -OC(O)N(R²¹)₂, −NR²¹C(=O)OR²¹, -N(R²¹)C(O)N(R²¹)_2, -NO₂, =O, =S, =N(R²¹), -CN, a C₃-C₁₀ carbocycle, and a 3- to 10-membered heterocycle, wherein said C₃-C₁₀ carbocycle and said 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from R^X; and phenyl and a 6-membered heterocycle comprising 1, 2, or 3 ring heteroatoms selected from nitrogen, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR²⁰, -OH, -SR²⁰, -SH, -N(R²¹)₂, -C(O)R²⁰, −C(O)N(R²¹)₂, -N(R²¹)C(O)R²⁰ , -C(O)OR²¹, -OC(O)R²¹, -S(O)R²⁰, -S(O)₂R²¹, -S(O)₂N(R²¹)₂, −OC(O)OR²¹, -OC(O)N(R²¹)₂, -NR²¹C(=O)OR²¹, -N(R²¹)C(O)N(R²¹)_2, -NO₂, =O, =S, =N(R²¹), - CN, -C₂-C₆ alkenyl, -C₂-C₆ alkynyl and C₁-C₆ alkyl wherein said C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from R^Y; and the remaining variables are as set forth in the first aspect. In some such aspects, at least one R⁶ is phenyl optionally substituted with one or more substituents independently selected from halogen, -OR²⁰, -OH, -SR²⁰, -SH, -N(R²¹)₂, -C(O)R²⁰, −C(O)N(R²¹)₂, -N(R²¹)C(O)R²⁰ , -C(O)OR²¹, -OC(O)R²¹, -S(O)R²⁰, -S(O)₂R²¹, -S(O)₂N(R²¹)₂, −OC(O)OR²¹, -OC(O)N(R²¹)₂, -NR²¹C(=O)OR²¹, -N(R²¹)C(O)N(R²¹)_2, -NO₂, =O, =S, =N(R²¹), −CN, -C₂-C₆ alkenyl, -C₂-C₆ alkynyl and C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from R^Y. In a fiftieth aspect, disclosed herein is a compound represented by Formula (A-I), (A-IA), (A-IB), (A-IC), (A-ID), (A-IE) or (A-IF) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n, w, R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-47 and R⁶ is independently selected at each occurrence from: halogen, -OR²¹, and -N(R²¹)₂; C₁-C₆ alkyl optionally substituted with halogen; and a C₃-C₁₀ carbocycle and a 3- to 10-membered heterocycle, each of which is optionally substituted with C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is optionally substituted with halogen; and the remaining variables are as set forth in the first aspect. In a fifty-first aspect, disclosed herein is a compound represented by Formula (A-I), (A- IA), (A-IB), (A-IC), (A-ID), (A-IE) or (A-IF) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n, w, R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-47 and R⁶ is independently selected at each occurrence from: halogen, and -OR²¹; C₁-C₆ alkyl optionally substituted with halogen; and phenyl and a 6-membered heterocycle comprising 1, 2, or 3 ring heteroatoms selected from nitrogen, each of which is optionally substituted with C₁-C₆ alkyl wherein said C₁- C₆ alkyl is optionally substituted with one or more substituents independently selected from R^Y; and the remaining variables are as set forth in the first aspect. In a fifty-second aspect, disclosed herein is a compound represented by Formula (A-I), (A-IA), (A-IB), (A-IC), (A-ID), (A-IE) or (A-IF) or a salt thereof, wherein M¹, M², R⁶, R⁷, R⁸, m, s, n, w, R¹, R², R³, R⁵, R⁹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-51 and R²¹ is C₁-C₃alkyl, phenyl, or a 6-membered heterocycle comprising 1, 2, or 3 ring heteroatoms selected from nitrogen; and the remaining variables are as set forth in the first aspect. In a fifty-third aspect, disclosed herein is a compound represented by Formula (A-I), (A- IA), (A-IB), (A-IC), (A-ID), (A-IE) or (A-IF) or a salt thereof, wherein M¹, M², R⁶, R⁷, R⁸, m, s, n, w, R¹, R², R³, R⁵, R⁹, R²¹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-52 and R^Y on the phenyl or heterocycle of R⁶ is selected from halogen; and the remaining variables are as set forth in the first aspect. In a fifty-fourth aspect, disclosed herein is a compound represented by Formula (A-I), (A-IA), (A-IB), (A-IC), (A-ID), (A-IE) or (A-IF) or a salt thereof, wherein M¹, M², R⁶, R⁷, R⁸, m, s, n, w, R¹, R², R³, R⁵, R⁹, R²¹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-52 and R^Y on the phenyl or heterocycle of R⁶ is selected from fluorine or chlorine; and the remaining variables are as set forth in the first aspect. In a fifty-fifth aspect, disclosed herein is a compound represented by Formula (A-I), (A- IA), (A-IB), (A-IC), (A-ID), (A-IE) or (A-IF) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n, w, R¹, R², R³, R⁵, R⁹, R²¹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-54 and R⁶ is independently selected at each occurrence from: F, Cl, -OCH₃, -CF₃, -CN, -CH₃, -CH₂CH₃, −CH(CH₃)₂, -OCF₃, -CH₂CF₃, -CH(OH)(CF₃), N(CH₃)₂, pyridyl, cyclohexyl, cyclopentyl, -O- phenyl, -O-pyridyl, and phenyl optionally substituted with one or more substituents independently selected from F, and -CH₂NH₂; and the remaining variables are as set forth in the first aspect. In some such aspects, R⁶ does not comprise cyano. In a fifty-sixth aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, s, n, R¹, R², R³, R⁵, R⁹, R²¹, Y, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-55 and

is:

, wherein represents the point of attachment to

and the remaining variables are as set forth in the first aspect. In a fifty-seventh aspect, disclosed herein is a compound represented by Formula (A-I) or a salt thereof, wherein M¹, M², R⁷, R⁸, m, R³, R⁵, R⁹, R²¹, Z¹, Z², Z³, and Z⁴ are as set forth in any one of aspects 1-55 and wherein

is:

, wherein represents the point of attachment to and the remaining variables are as set forth in the first aspect.

In another aspect, the TGFβR1 inhibitor is a compound from Table 14. TGFβR1 Inhibitors of Formula (B-I) In some aspects, the TGFβR1 inhibitor is a compound of Formula (B-I): wherein:

M¹ and M² are independently selected from

R¹ and R² are independently selected at each occurrence from: a halogen, -OR¹⁰, -SR¹⁰, -N(R¹⁰)₂, -C(O)R¹⁰, -C(O)N(R¹⁰)₂, -N(R¹⁰)C(O)R¹⁰ , -C(O)OR¹⁰, −OC(O)R¹⁰, -S(O)R¹⁰, -S(O)₂R¹⁰, -S(O)₂N(R¹⁰)₂, -P(O)(OR¹⁰)₂, -OP(O)(OR¹⁰)₂, -NO₂, and -CN; -C₁-C₁₀ alkyl, -C₂-C₁₀ alkenyl, and -C₂-C₁₀ alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, −OR¹⁰, -SR¹⁰, -N(R¹⁰)₂, -C(O)R¹⁰, -C(O)N(R¹⁰)₂, -N(R¹⁰)C(O)R¹⁰ , -C(O)OR¹⁰, −OC(O)R¹⁰, -S(O)R¹⁰, -S(O)₂R¹⁰, -S(O)₂N(R¹⁰)₂, -P(O)(OR¹⁰)₂, -OP(O)(OR¹⁰)₂, -NO₂, =O, =S, =N(R¹⁰), -CN, a C₃-C₁₀ carbocycle, and a 3- to 10-membered heterocycle; and a C₃-C₁₀ carbocycle and a 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from a halogen, - OR¹⁰, -SR¹⁰, -N(R¹⁰)₂, -C(O)R¹⁰, -C(O)N(R¹⁰)₂, -N(R¹⁰)C(O)R¹⁰ , -C(O)OR¹⁰, -OC(O)R¹⁰, −S(O)R¹⁰, -S(O)₂R¹⁰, -S(O)₂N(R¹⁰)₂, -P(O)(OR¹⁰)₂, -OP(O)(OR¹⁰)₂, -NO₂, =O, =S, =N(R¹⁰), -CN, -C₁-C₆ alkyl, -C₂-C₆ alkenyl, and -C₂-C₆ alkynyl; R³ is selected from hydrogen and -C₁-C₁₀ alkyl optionally substituted with one or more substituents independently selected from a halogen, -NO₂, =O, =S, =N(R¹⁰), -CN, -OR¹⁰, −SR¹⁰, -N(R¹⁰)₂, -C(O)R¹⁰, -C(O)N(R¹⁰)₂, -N(R¹⁰)C(O)R¹⁰ , -C(O)OR¹⁰, and -OC(O)R¹⁰; n and m are independently selected from 0, 1, 2, 3, and 4; Q is selected from a bond, -(CR¹⁰ 2)_p-, -(CR¹⁰ 2)_qC(=O)(CR¹⁰ 2)_q-, -(CR¹⁰ 2)_qC(=S)(CR¹⁰ 2)_q-, −(CR¹⁰ 2)_qC(=NR¹⁰)(CR¹⁰ 2)_q-, -(CR¹⁰ 2)_qO(CR¹⁰ 2)_q-, -(CR¹⁰ 2)_qS(CR¹⁰ 2)_q-, −(CR¹⁰ 2)_qN(R¹⁰)(CR¹⁰ 2)_q-, -(CR¹⁰ 2)_qOC(=O)O(CR¹⁰ 2)_q-, -(CR¹⁰ 2)_qC(=O)N(R¹⁰)(CR¹⁰ 2)_q-, −(CR¹⁰ 2)_qN(R¹⁰)C(=O)(CR¹⁰ 2)_q-, and -(CR¹⁰ 2)_qN(R¹⁰)SO₂(CR¹⁰ 2)_q-; p is selected from 1, 2, 3, 4, and 5; q is independently selected at each occurrence from 0, 1, 2, 3, 4, and 5; T is selected from an optionally substituted saturated C₃-C₇ carbocycle, an optionally substituted C_5-12 bicyclic carbocycle, and an optionally substituted 4- to 12-membered heterocycle, wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³; R¹³ is independently selected at each occurrence from: a halogen, -OR¹⁰, -SR¹⁰, -N(R¹⁰)₂, -C(O)R¹⁰, -C(O)N(R¹⁰)₂, -N(R¹⁰)C(O)R¹⁰ , −C(O)OR¹⁰, -OC(O)R¹⁰, -S(O)R¹⁰, -S(O)₂R¹⁰, -S(O)₂N(R¹⁰)₂, -P(O)(OR¹⁰)₂, -OP(O)(OR¹⁰)₂, −NO₂, =O, =S, =N(R¹⁰), and -CN; -C₁-C₁₀ alkyl, -C₂-C₁₀ alkenyl, and -C₂-C₁₀ alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, -OR¹⁰, -SR¹⁰, -N(R¹⁰)₂, -C(O)R¹⁰, -C(O)N(R¹⁰)₂, -N(R¹⁰)C(O)R¹⁰ , -C(O)OR¹⁰, −OC(O)R¹⁰, -S(O)R¹⁰, -S(O)₂R¹⁰, -S(O)₂N(R¹⁰)₂, -P(O)(OR¹⁰)₂, -OP(O)(OR¹⁰)₂, -NO₂, =O, =S, =N(R¹⁰), -CN, a C₃-C₁₀ carbocycle, and a 3- to 10-membered heterocycle; and a C₃-C₁₀ carbocycle and a 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from a halogen, −OR¹⁰, -SR¹⁰, -N(R¹⁰)₂, -C(O)R¹⁰, -C(O)N(R¹⁰)₂, -N(R¹⁰)C(O)R¹⁰ , -C(O)OR¹⁰, -OC(O)R¹⁰, −S(O)R¹⁰, -S(O)₂R¹⁰, -S(O)₂N(R¹⁰)₂, -P(O)(OR¹⁰)₂, -OP(O)(OR¹⁰)₂, -NO₂, =O, =S, =N(R¹⁰), -CN, -C₁-C₆ alkyl, -C₂-C₆ alkenyl, and -C₂-C₆ alkynyl; and R¹⁰ is independently selected at each occurrence from: hydrogen; -C₁-C₁₀ alkyl, -C₂-C₁₀ alkenyl, and -C₂-C₁₀ alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, -OH, -CN, -NO₂, -NH₂, =O, =S, -O-C₁-C₁₀ alkyl, C₃-C₁₂ carbocycle, and a 3- to 12- membered heterocycle; and a C₃-C₁₂ carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, -OH, -CN, -NO₂, -NH₂, =O, =S, -C₁-C₁₀ alkyl, -O-C₁-C₁₀ alkyl, and -C₁-C₁₀ haloalkyl; or a pharmaceutically acceptable salt thereof. In some embodiments, one of M¹ and M² is and the other of M¹ and M² is . For example, M¹ may be . In some embodiments, the compound or salt is represented by Formula (B-Ia): (B-Ia); or a pharmaceutically acceptable salt thereof. In some embodiments, M² is . In some embodiments, the compound or salt is represented by Formula (B-Ib): (B-Ib); or a pharmaceutically acceptable salt thereof. In some embodiments, M¹ is and M² is . In other embodiments, M¹ is and M² is . In some embodiments, the compound or salt is represented by Formula (B-Ic) or Formula (B-Id): (B-Ic) (B-Id) or a salt thereof. In some embodiments, R³ for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id) is selected from hydrogen and -C₁-C₁₀ alkyl optionally substituted with one or more substituents independently selected from a halogen, -NO₂, -CN, -OR¹⁰, -SR¹⁰, −N(R¹⁰)₂, - C(O)R¹⁰, -C(O)N(R¹⁰)₂, -N(R¹⁰)C(O)R¹⁰ , -C(O)OR¹⁰, and -OC(O)R¹⁰. For example, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), R³ may be selected from hydrogen and -C₁-C₁₀ alkyl optionally substituted with one or more substituents independently selected from a halogen, -NO₂, -CN, -OR¹⁰, -SR¹⁰, and -N(R¹⁰)₂. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), R³ is hydrogen. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), n is 0. In other embodiments, for a compound or salt of any of Formulas (B- I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), n is selected from 1, 2, 3, and 4. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), each R¹ is independently selected from a halogen, -OR¹⁰, -SR¹⁰, -N(R¹⁰)₂, -C(O)R¹⁰, -C(O)N(R¹⁰)₂, ⁻N(R¹⁰)C(O)R¹⁰ , -C(O)OR¹⁰, -OC(O)R¹⁰, -S(O)R¹⁰, -S(O)₂R¹⁰, -S(O)₂N(R¹⁰)₂, -P(O)(OR¹⁰)₂, −OP(O)(OR¹⁰)₂, -NO₂, and -CN; and -C₁-C₁₀ alkyl, -C₂-C₁₀ alkenyl, and -C₂-C₁₀ alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, -OR¹⁰, -SR¹⁰, -N(R¹⁰)₂, -C(O)R¹⁰, -C(O)N(R¹⁰)₂, -N(R¹⁰)C(O)R¹⁰ , ₋C(O)OR¹⁰, -OC(O)R¹⁰, -S(O)R¹⁰, -S(O)₂R¹⁰, -S(O)₂N(R¹⁰)₂, -P(O)(OR¹⁰)₂, -OP(O)(OR¹⁰)₂, −NO₂, =O, =S, =N(R¹⁰), -CN, a C₃-C₁₀ carbocycle, and a 3- to 10-membered heterocycle. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), each R¹ is selected from a halogen, -OR¹⁰, -SR¹⁰, -N(R¹⁰)₂, -NO₂, and -CN; and -C₁-C₁₀ alkyl optionally substituted at each occurrence with one or more substituents independently selected from a halogen, -OR¹⁰, -SR¹⁰, -N(R¹⁰)₂, -C(O)R¹⁰, -NO₂, and -CN. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), each R¹ is independently selected from a -C₁-C₁₀ alkyl optionally substituted at each occurrence with one or more substituents independently selected from a halogen, -OR¹⁰, -SR¹⁰, - N(R¹⁰)₂, -C(O)R¹⁰, -NO₂, and −CN. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), m is 0. In other embodiments, for a compound or salt of any of Formulas (B- I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), m is selected from 1, 2, 3, and 4. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), each R² is independently selected from a halogen, -OR¹⁰, -SR¹⁰, -N(R¹⁰)₂, -C(O)R¹⁰, -C(O)N(R¹⁰)₂, −N(R¹⁰)C(O)R¹⁰ , −C(O)OR¹⁰, −OC(O)R¹⁰, −S(O)R¹⁰, −S(O)₂R¹⁰, −S(O)₂N(R¹⁰)₂, −P(O)(OR¹⁰)₂, −OP(O)(OR¹⁰)₂, −NO₂, and −CN; and −C₁-C₁₀ alkyl, −C₂-C₁₀ alkenyl, and −C₂-C₁₀ alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −C(O)N(R¹⁰)₂, −N(R¹⁰)C(O)R¹⁰ ,₋C(O)OR¹⁰, −OC(O)R¹⁰, −S(O)R¹⁰, −S(O)₂R¹⁰, −S(O)₂N(R¹⁰)₂, −P(O)(OR¹⁰)₂, −OP(O)(OR¹⁰)₂, −NO₂, =O, =S, =N(R¹⁰), −CN, a C₃-C₁₀ carbocycle, and a 3- to 10-membered heterocycle. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), each R² is independently selected from a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −NO₂, and −CN; and −C₁-C₁₀ alkyl optionally substituted at each occurrence with one or more substituents independently selected from a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −NO₂, and −CN. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), each R² is independently selected from −OR¹⁰ and −C₁-C₁₀ alkyl optionally substituted with one or more substituents independently selected from a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −NO₂, and −CN. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), m is 1 and R² is −CH₃. For example, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), and (B-Id), M² may be . In a particular example, for a compound or salt of any of Formulas (B-I), (B- Ia), (B-Ib), (B-Ic), and (B-Id), M² is . In some embodiments, the compound of Formula (B-I) is represented by Formula (B-Ie): (B-Ie); or a salt thereof. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), Q is selected from −(CR¹⁰ 2)_p−, −(CR¹⁰ 2)_qO(CR¹⁰ 2)_q−, −(CR¹⁰ 2)_qS(CR¹⁰ 2)_q−, and −(CR¹⁰ 2)_qNR¹⁰(CR¹⁰ 2)_q−, where p is selected from 1, 2, 3, 4, and 5 and q is independently selected at each occurrence from 0, 1, 2, 3, 4, and 5. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), Q is selected from −(CR¹⁰ 2)_p−. For example, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), p may be 1 such that Q is −C(R¹⁰)₂−. Alternatively, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), Q may be selected from −(CR¹⁰ 2)_qO(CR¹⁰ 2)_q−, −(CR¹⁰ 2)_qS(CR¹⁰ 2)_q−, and −(CR¹⁰ 2)_qNR¹⁰(CR¹⁰ 2)_q−. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B- Id), and (B-Ie), Q is −CH₂NH−. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), Q is selected from −(CR¹⁰ 2)_qNR¹⁰(CR¹⁰ 2)_q−. In some embodiments, for a compound or salt of any of Formulas (B- I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), Q is selected from −(CR¹⁰ 2)_qNR¹⁰−. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), Q is selected from −(CR¹⁰ 2)_qNR¹⁰−. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), Q is −CR¹⁰ 2NR¹⁰(CR¹⁰ 2)_1-2−. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B- Id), and (B-Ie), Q is −CH₂NHCH₂− or −CH₂NHCH₂CH₂−. In another example, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), Q is −CH₂NHCH₂−. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), each R¹⁰ is independently selected from hydrogen; and −C₁-C₁₀ alkyl, −C₂-C₁₀ alkenyl, and −C₂-C₁₀ alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, −OH, −CN, −NO₂, and −NH₂. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), R¹⁰ is hydrogen at each occurrence. In some embodiments, for a compound or salt of any one of Formulas (B-I), (B-Ia), (B- Ib), (B-Ic), (B-Id), and (B-Ie), each R¹⁰ of Q is hydrogen at each occurence. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from a saturated C₃-C₇ carbocycle optionally substituted with one or more substituents independently selected at each occurrence from R¹³. For example, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be a saturated C₃ carbocycle optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from: , , , , and , each of which is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B- I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from , , , , , , and . For example, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be: . In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from a C_5-12 bicyclic carbocycle optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from a saturated C_5-12 bridged carbocycle optionally substituted with one or more substituents independently selected at each occurrence from R¹³, such as an optionally substituted C₅ bridged carbocycle. For example, for a compound or salt of any of Formulas (B- I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from: , and , each of which is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In other embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from C_8-11 bicyclic carbocycle optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is a fused bicyclic ring. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from a C_8-11 fused bicyclic carbocycle. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B- Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from:

, , , , , , , , , , , , , , and , and wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. For example, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from: , , and , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B- Id), and (B-Ie), T may be selected from: and . In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from: and . In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from: , , , , , , , , , , and . In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from naphthalene, 1,2,3,4-tetrahydronaphthalene, decahydronaphthalene, octahydro-1H-indene, 2,3-dihydro-1H-indene, 1H-indene, octahydropentalene, decahydro-1H-benzo[7]annulene, 7H-benzo[7]annulene, 4aH- benzo[7]annulene, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3,4,5-tetrahydro-1H- benzo[7]annulene, 2,3,4,7-tetrahydro-1H-benzo[7]annulene, azulene, and decahydroazulene, and wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from a 4- to 12-membered heterocycle optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B- Id), and (B-Ie), T is selected from:

, , , , , , , , , , , , , , , , , , , and , any one of which is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from: , , , , , , , , , , , , , , , ,

In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from a 7- to 12-membered bicyclic heterocycle optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B- Id), and (B-Ie), T is selected from an 8- to 11-membered bicyclic heterocycle optionally substituted with one or more substituents independently selected at each occurrence from R¹³, such as an 8- to 11-membered bicyclic heteroaryl group. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from:

wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any one of Formulas (B-I), (B-Ia), (B- Ib), (B-Ic), (B-Id), and (B-Ie), −Q−T is selected from:

wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, −Q−T is selected from

In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T has one to four ring heteroatoms independently selected from N, O, S, and B. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B- Ib), (B-Ic), (B-Id), and (B-Ie), T has at least one ring heteroatom that is boron. For example, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from:

wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from , , , , and , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is represented by: , wherein dashed lines represent single or double bonds, valence permitting; k is selected from 0, 1, 2, and 3; and W, X, Y, and Z are independently selected from N(R¹⁰)_g and C(R¹⁰)_h, wherein g is selected from 0 and 1 and h is selected from 1 and 2, and wherein a straight line linked to a wavy line indicates connectivity to Q from any position, valence permitting, of the bicyclic heterocycle. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is represented by: . In other embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is represented by: . In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from: , , , , , , , , , , , , , , , , , , , , and , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. For example, for a compound or salt of any of Formulas (B-I), (B-Ia), (B- Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from: , , , , , , , , , , , , and , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from: , , , , , , , , , , , , , , , , , , , and , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from: , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. For example, for a compound or salt of any of Formulas (B-I), (B-Ia), (B- Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from: , , , and , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from: , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. For example, for a compound or salt of any of Formulas (B-I), (B-Ia), (B- Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from: , , , and , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from: and . In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from: . For example, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T may be selected from: , , , , , , , and . In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from: , , , , , , , , and , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from: , , , , , , , , , , , , , , , , , , , and ,wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from: , , , , , , , , , , , and , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), T is selected from 1,2,3,4-tetrahydroquinoline, 1,2,3,4- tetrahydroisoquinoline, 1,2-dihydroquinoline, 1,2-dihydroisoquinoline, 1,2,3,4- tetrahydroquinazoline, decahydroquinoline, decahydroisoquinoline, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, and cinnoline, wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³. In some embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), each R¹³ may be independently selected from: a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −C(O)N(R¹⁰)₂, −N(R¹⁰)C(O)R¹⁰ , −C(O)OR¹⁰, −OC(O)R¹⁰, −S(O)R¹⁰, −S(O)₂R¹⁰, −S(O)₂N(R¹⁰)₂, −P(O)(OR¹⁰)₂, −OP(O)(OR¹⁰)₂, −NO₂, =O, =S, =N(R¹⁰), and −CN; and −C₁-C₁₀ alkyl, −C₂-C₁₀ alkenyl, and −C₂-C₁₀ alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −C(O)N(R¹⁰)₂, −N(R¹⁰)C(O)R¹⁰ , −C(O)OR¹⁰, −OC(O)R¹⁰, −S(O)R¹⁰, −S(O)₂R¹⁰, −S(O)₂N(R¹⁰)₂, −P(O)(OR¹⁰)₂, −OP(O)(OR¹⁰)₂, −NO₂, =O, =S, =N(R¹⁰), −CN, a C₃-C₁₀ carbocycle, and a 3- to 10-membered heterocycle. In certain embodiments, for a compound or salt of any of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie), each R¹³ may be independently selected from a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −NO₂, and −CN; and −C₁-C₁₀ alkyl optionally substituted at each occurrence with one or more substituents independently selected from a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −NO₂, and −CN. In certain embodiments, for a compound or salt of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie): Q is selected from a bond, −(CR¹⁰ 2)_p−, and −(CR¹⁰ 2)_qNR¹⁰(CR¹⁰ 2)_q−; T is selected from an optionally substituted saturated C₃-C₇ carbocycle, an optionally substituted C_5-12 bicyclic carbocycle, and an optionally substituted 4- to 12-membered heterocycle, wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³, wherein R¹³ is independently selected at each occurrence from halogen, −OR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −C(O)OR¹⁰, −N(R¹⁰)C(O)R¹⁰, and −C₁-C₃ alkyl optionally substituted with one or more substituents independently selected from a halogen, −OR¹⁰ and −N(R¹⁰)₂; and R¹⁰ is as set forth herein (and in some aspects, R¹⁰ is H or C₁-C₃ alkyl). In certain embodiments, for a compound or salt of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie): Q is selected from a bond, −(CR¹⁰ 2)_p−, and −(CR¹⁰ 2)_qNR¹⁰(CR¹⁰ 2)_q−; T is selected from an optionally substituted saturated C₃-C₇ carbocycle, an optionally substituted C_5-12 bicyclic carbocycle, and an optionally substituted 4- to 12-membered heterocycle, wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³, wherein R¹³ is independently selected at each occurrence from halogen, −OR¹⁰, −N(R¹⁰)₂, and −C₁-C₃ alkyl optionally substituted with one or more substituents independently selected from a halogen, −OR¹⁰ and −N(R¹⁰)₂; and R¹⁰ is as set forth herein (and in some aspects, R¹⁰ is H or C₁-C₃ alkyl). In certain embodiments, for a compound or salt of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie): Q is selected from a bond, −CH₂−, −CH₂NH−, −CH₂NHCH₂−, and −CH₂NHCH₂CH₂−; and T is selected from: , , , , , , , , , , , , , , , , , , , and , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³ wherein R¹³ is independently selected at each occurrence from halogen, −OR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −C(O)OR¹⁰, −N(R¹⁰)C(O)R¹⁰, and −C₁-C₃ alkyl optionally substituted with one or more substituents independently selected from a halogen, −OR¹⁰ and −N(R¹⁰)₂; and R¹⁰ is as set forth herein (and in some aspects, R¹⁰ is H or C₁-C₃ alkyl). In certain embodiments, for a compound or salt of Formulas (B-I), (B-Ia), (B-Ib), (B-Ic), (B-Id), and (B-Ie): Q is selected from −CH₂−, −CH₂NH−, −CH₂NHCH₂−, and −CH₂NHCH₂CH₂−; and T is selected from: , , , , , , , , , and , wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³, wherein R¹³ is independently selected at each occurrence from halogen, −OH, −NH₂, and −C₁-C₃ alkyl. In some embodiments, the compound of Formula (B-I) is selected from:

a salt of any one thereof. In some embodiments, the compound of Formula (B-I) is selected from:

, and a salt of any one thereof. In some embodiments, the compound of Formula (B-I) is selected from the compounds in Table 15. TGFβR1 Inhibitors of Formula (C-I) In some aspects, the TGFβR1 inhibitor is a compound of Formula (C-I):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein: L is −[CR′₂]p−L’−[CH₂]q− L’ is absent, −S−, −O−, or −NH−; A is absent, carbocycle, or heterocycle; Q³ is N or CR³; Q⁴ is N or CR⁴; Q⁵ is N or CR⁵; Q⁶ is N or CR⁶; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R³ is H, halo, C_1–3alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁴ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁵ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁶ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; n is 0–5; p is 1-3; and q is 0-3. In certain embodiments, compounds are provided having the structure of Formula (C-I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein L’ is absent. In other embodiments, L’ is −S−. In other embodiments, L’ is −O−. In still other embodiments, L’ is −NH−. In certain embodiments, compounds are provided having the structure of Formula (C-I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein p is 1. In some embodiments, p is 2. In other embodiments, p is 3. In certain embodiments, compounds are provided having the structure of Formula (C-I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein q is 0. In other embodiments, q is 1. In still other embodiments, q is 2. In further embodiments, q is 3. In certain embodiments, compounds are provided having the structure of Formula (C-II):

(C-II) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; Q³ is N or CR³; Q⁴ is N or CR⁴; Q⁵ is N or CR⁵; Q⁶ is N or CR⁶; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R³ is H, halo, C_1–3alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁴ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁵ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-II-A):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-II-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (II-C):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-III):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; Q³ is N or CR³; Q⁴ is N or CR⁴; Q⁵ is N or CR⁵; Q⁶ is N or CR⁶; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R³ is H, halo, C_1–3alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁴ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁵ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-III-A):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-III-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)2, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-III-C):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-IV):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; Q³ is N or CR³; Q⁴ is N or CR⁴; Q⁵ is N or CR⁵; Q⁶ is N or CR⁶; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R³ is H, halo, C_1–3alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁴ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁵ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-IV-A):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-IV-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)2, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-IV-C):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-V):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; Q³ is N or CR³; Q⁴ is N or CR⁴; Q⁵ is N or CR⁵; Q⁶ is N or CR⁶; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R³ is H, halo, C_1–3alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁴ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁵ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-V-A):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-V-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)2, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-V-C):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: A is carbocycle or heterocycle; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-VI):

(C-VI) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q³ is N or CR³; Q⁴ is N or CR⁴; Q⁵ is N or CR⁵; Q⁶ is N or CR⁶; R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R³ is H, halo, C_1–3alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁴ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁵ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-VI-A):

(C-VI-A) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-VI-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C1-4 haloalkyl, C2–5 haloalkenyl, C2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (C-VI-C):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R¹ is hydrogen, C_1–3 alkyl, or C_1–3 haloalkyl, wherein R¹ is substituted with 0–3 R¹⁰; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1–3 alkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R¹ is hydrogen. In other embodiments, R¹ is unsubstituted C_1–3 alkyl. In certain embodiments, R¹ is methyl. In other embodiments, R¹ is C_1–3 alkyl substituted with 1–3 R¹⁰. In certain embodiments, R¹ is −CH₂OCH₃. In another embodiment, R¹ is unsubstituted C_1–3 haloalkyl. In certain embodiments, R¹ is −CF₃. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein m is 0. In other embodiments, m is 1–3. In certain embodiments, m is 1. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R² is halo. In some embodiments, at least one R² is F. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein A is heterocycle. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein A is carbocycle. In certain embodiments, A is phenyl. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein n is 0. In some embodiments, n is 1–5. In other embodiments, n is 1 or 2. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is halo. In some embodiments, at least one R⁹ is F or Cl. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is −OR′. In some embodiments, R′ of the at least one −OR′ is C_1–6 alkyl. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is C_1–4 alkyl. In some embodiments, at least one R⁹ is methyl. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is −CN. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is −C(O)N(R′)₂. In some embodiments, at least one R⁹ is −C(O)N(CH₃)₂. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is −N(R′)₂. In some embodiments, at least one R⁹ is −N(CH₃)₂. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is −NO₂. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R⁶ is H. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R⁶ is halo. In some embodiments, R⁶ is F or Cl. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R⁶ is C_1–3 alkyl. In some embodiments, R⁶ is methyl. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R⁶ is C_1–3 alkoxy. In some embodiments, R⁶ is −OCH₃. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein the reactive moiety capable of attachment to a linker or the reactive moiety capable of attachment to an antibody is −Y−(CR¹¹R¹²)_p−NHR¹³, −Y−(CR¹¹R¹²)_p−C(O)OH, or −Y−(CR¹¹R¹²)_p−C(O)NHR¹³, wherein: Y is −O−, −CH₂−, −OCH₂CH₂−, or −OCH₂CH₂NR¹⁴−; R¹¹ is at each occurrence, independently, H, halogen, C_1–3 alkyl, or C_1–3 haloalkyl; R¹² is at each occurrence, independently, H, halogen, C_1–3 alkyl, or C_1–3 haloalkyl; R¹³ is H; or R¹¹ at one occurrence and R¹² at one occurrence, together with the atom to which they are attached, form a ring; or R¹¹ at one occurrence and R¹³ form a ring; R¹⁴ is H, halogen, C_1–3 alkyl, or C_1–3 haloalkyl; and p is 0–5. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R⁷ is −Y−(CR¹¹R¹²)_p−NHR¹³. In some embodiments, Y is

. In other embodiments, Y is −CH₂−. In still other embodiments, Y is −OCH₂CH₂−. In further embodiments, Y is−OCH₂CH₂NR¹⁴−. In certain embodiments, compounds are provided having the structure of any one of Formula (C-I), (C-II), (C-III), (C-IV), (C-V), or (C-VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R⁷ is:

Representative compounds of Formula (C-I), and Formulas (C-II) through (C-VI) as applicable, include the compounds listed in Tables 16–20 below, as well as pharmaceutically acceptable salts thereof. To this end, representative compounds are identified herein by their respective “Compound Number”, which is sometimes abbreviated as “Compound No.”, “Cmpd No.” or “No.” TGFβR1 Inhibitors of Formula (D-I) In some aspects, the TGFβR1 inhibitor is a compound of Formula (D-I):

(D-I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q^A is CR^A or N; Q^B is CR^B; Q³ is N or CR³; Q⁴ is N or CR⁴; Q⁵ is N or CR⁵; R^A is H, halo, C_1-3 alkyl, or C_1-3 haloalkyl and R^B is ^B

R , together with the atoms to which they are attached, form a heterocyclic ring; R^a and R^b are each H, or R^a and R^b, together with the atoms to which they are attached, form a heterocyclic ring; ring B is carbocycle or heterocycle; R¹ is H, C_1-3 alkyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R³ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R⁴ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R⁵ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹, R², R³, R⁴, and R⁵ are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy or C_1-3 haloalkoxy; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided having the structure of Formula (D-II):

(D-II) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q³ is N or CR³; Q⁴ is N or CR⁴; Q⁵ is N or CR⁵; Q⁶ is N or CR⁶; R^a and R^b are each H, or R^a and R^b, together with the atoms to which they are attached, form a heterocyclic ring; R¹ is H, C_1-3 alkyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R³ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R⁴ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R⁵ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹, R², R³, R⁴, R⁵, and R⁶ are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy or C_1-3 haloalkoxy; and m is 0–3. In certain embodiment of Formula (II), Q⁶ is CR⁶ when R¹ is methyl and R^a and R^b, together with the atoms to which they are attached, form a heterocyclic ring. In certain embodiments, compounds are provided having the structure of Formula (D-III):

(D-III) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q⁶ is N or CR⁶; R¹ is H, C_1-3 alkyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹, R², and R⁶ are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy or C_1-3 haloalkoxy; and m is 0–3. wherein Q⁶ is CR⁶ when R¹ is methyl. In certain embodiments, compounds are provided having the structure of Formula (D-IV):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q⁶ is N or CR⁶; R¹ is H, C1-3 alkyl, or C1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R⁶ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹, R², and R⁶ are each substituted with 0–3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy or C_1-3 haloalkoxy; and m is 0–3. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is H. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is C_1-3 alkyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is methyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, R¹ is ethyl or propyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, R¹ is C_1-3 haloalkyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is −CFH₂, −CF₂H, or −CF₃. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 0. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 1–3. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q⁶ is N. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q⁶ is CR⁶. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R⁶ is H. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R⁶ is halo, C_1-3 alkyl, or C_1-3 haloalkyl. In certain embodiments, compounds are provided wherein the TGFβR1 inhibitor is a compound having the structure of Formula (D-V):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R^a and R^b are each H, or R^a and R^b, together with the atoms to which they are attached, form a heterocyclic ring; Q^A is CR^A or N; Q³ is N or CR³; Q⁴ is N or CR⁴; Q⁵ is N or CR⁵; R^A is H, halo, C_1-3 alkyl, or C_1-3 haloalkyl; R^a and R^b are each H, or R^a and R^b, together with the atoms to which they are attached, form a heterocyclic ring; ring B is carbocycle or heterocycle; R¹ is H, C_1-3 alkyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R³ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R⁴ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R⁵ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹, R², R³, R⁴, and R⁵ are, at each occurrence, independently substituted with 0– 3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy or C_1-3 haloalkoxy; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided wherein the TGFβR1 inhibitor is a compound having the structure of Formula (D-VI):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q^A is CR^A or N; R^A is H, halo, C_1-3 alkyl, or C_1-3 haloalkyl; ring B is carbocycle or heterocycle; R¹ is H, C_1-3 alkyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹ and R² are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy or C_1-3 haloalkoxy; m is 0–3; and n is 0–5. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is heterocycle. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is heteroaryl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, compounds are provided having the structure of Formula (D-VI-A):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q^A is CR^A or N; R^A is H, halo, C_1-3 alkyl, or C_1-3 haloalkyl; R¹ is H, C_1-3 alkyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; wherein R¹ and R² are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy or C_1-3 haloalkoxy; m is 0–3; and n is 0–2. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is carbocycle. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is aryl. In certain embodiments, compounds are provided having the structure of Formula (D-VI-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q^A is CR^A or N; R^A is H, halo, C_1-3 alkyl, or C_1-3 haloalkyl; R¹ is H, C_1-3 alkyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹ and R² are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy or C_1-3 haloalkoxy; m is 0–3; and n is 0–4. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q^A is N. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q^A is CR^A. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^A is H. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^A is halo. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^A is F. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^A is C_1-3 alkyl, or C_1-3 haloalkyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is H. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is C_1-3 alkyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is methyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is ethyl or propyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is C_1-3 haloalkyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is −CFH₂, −CF₂H, or −CF₃. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 0. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 1–3. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 0. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 1–2. In certain embodiments, compounds are provided, wherin the TGFβR1 inhibitor is a compound having the structure of Formula (D-VII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q^A is CR^A or N; R^A is H, halo, C_1-3 alkyl, or C_1-3 haloalkyl; ring B is carbocycle or heterocycle; R¹ is H, C_1-3 alkyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹ and R² are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy; m is 0–3; and n is 0–5. In certain embodiments of Formula (D-VII), compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R¹ is not H or methyl when ring B is carbocycle; ring B is a five membered heteroaryl when R¹ is H and Q^A is N; and R⁷ is substituted with an acidic amino acid sidechain when R¹ is methyl and Q^A is CR^A. In certain embodiments, compounds are provided having the structure of Formula (D-VIII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R^A is H, halo, C_1-3 alkyl, or C_1-3 haloalkyl; ring B is carbocycle or heterocycle; R¹ is H, ethyl, propyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹ and R² are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy; m is 0–3; and n is 0–5; wherein R¹ is ethyl, propyl, or C_1-3 haloalkyl when ring B is carbocycle. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is heterocycle. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is heteroaryl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, compounds are provided having the structure of Formula (D-VIII-A):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R^A is H, halo, C_1-3 alkyl, or C_1-3 haloalkyl; R¹ is H, ethyl, propyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹ and R² are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy; m is 0–3; and n is 0–2. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is carbocycle. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is aryl. In certain embodiments, compounds are provided having the structure of Formula (D-VIII-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R^A is H, halo, C_1-3 alkyl, or C_1-3 haloalkyl; R¹ is ethyl, propyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹ and R² are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy or C_1-3 haloalkoxy; m is 0–3; and n is 0–4. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^A is H. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^A is halo. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^A is F. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R^A is C_1-3 alkyl, or C_1-3 haloalkyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is H. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is ethyl or propyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is C_1-3 haloalkyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is −CFH₂, −CF₂H, or −CF₃. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 0. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 1–3. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 0. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 1–2. In certain embodiments, compounds are provided having the structure of Formula (D-IX):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: ring B is carbocycle or heterocycle; R¹ is H, C_1-3 alkyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹ and R² are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy; m is 0–3; and n is 0–5; wherein: R¹ is ethyl, propyl, or C_1-3 haloalkyl when ring B is carbocycle; and ring B is a 5-membered heteroaryl when R¹ is H In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is heterocycle. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is heteroaryl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is a 5-membered heteroaryl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, compounds are provided having the structure of Formula (D-IX-A):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: R¹ is H, C_1-3 alkyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹ and R² are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C1-3 alkoxy or C1-3 haloalkoxy; m is 0–3; and n is 0–2. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is carbocycle. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is aryl. In certain embodiments, compounds are provided having the structure of Formula (D-IX-B):

R¹ is ethyl, propyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹ and R² are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy or C_1-3 haloalkoxy; m is 0–3; and n is 0–4. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is H. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is C1-3 alkyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is methyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is ethyl or propyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is C_1-3 haloalkyl. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹ is −CFH₂, −CF₂H, or −CF₃. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 0. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein m is 1–3. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 0. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n is 1–2. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R⁷, the reactive moiety capable of attachment to a linker or the reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety, is −Y−(CR¹¹R¹²)_p−NHR¹³, −Y−(CR¹¹R¹²)_p−C(O)OR¹³, or −Y−(CR¹¹R¹²)_p−C(O)NHR¹³, wherein: Y is −O−, −CH₂−, −OCH₂CH₂−, −OCH₂CH₂NR¹⁴−, −C(O)NR¹⁴−; −CH₂C(O)NR¹⁴−, −CH₂CH₂C(O)NR¹⁴−, −C(O)O−; −CH₂C(O)O−, −CH₂CH₂C(O)O−,, or −CH₂CH₂NR¹⁴C(O)C(O)−, R¹¹ is at each occurrence, independently, H, halo, C_1–3 alkyl, C_1–3 haloalkyl, or R¹⁵; R¹² is at each occurrence, independently, H, halo, C_1–3 alkyl, C_1–3 haloalkyl, or R¹⁵; R¹³ is H, C_1-3 alkyl, or C_1-3 haloalkyl; or R¹¹ at one occurrence and R¹² at one occurrence, together with the atom to which they are attached, form a ring; or R¹¹ at one occurrence and R¹³ form a ring; R¹⁴ is H, halo, C_1-3 alkyl, or C_1-3 haloalkyl; and R¹⁵ is an amino acid side chain;−C_1-3 alkyl−C(O)OR¹³; p is 0–5. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R¹⁵ is −C_1-3 alkyl−C(O)OR¹³; In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R⁷ is −Y−(CR¹¹R¹²)_p−NHR¹³. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is −O−. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is −CH₂−. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is −OCH₂CH₂−. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Y is−OCH₂CH₂NR¹⁴−. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R⁷ is:

. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R⁷, the reactive moiety capable of attachment to a linker or the reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety, comprises a substitutable nitrogen atom. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R⁷, the reactive moiety capable of attachment to a linker or the reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety, comprises a moiety that enhances cell permeability. In certain embodiments, compounds are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the compound has a pKa of about 3.5 to about 5.5. Representative compounds of Formula (D-I), and Formulas (D-II) through (D-IX) as applicable, include the compounds listed in Tables 21–24 below, as well as pharmaceutically acceptable salts thereof. To this end, representative compounds are identified herein by their respective “Compound Number”, which is sometimes abbreviated as “Compound No.”, “Cmpd No.” or “No.” Linker Region L³ The conjugates of the present disclosure include a linker region, L³. As shown in Formula (I), Region L³ covalently links Region G, which comprises the GalNAc moiety, to Region Inh, which comprises the TGFβR1 inhibitor. The covalent linkages can be formed by reaction between functional groups in synthetic precursors for each region. Linkers of the disclosure (L³) may have from about 10 to about 500 atoms in a linker, such as from about 10 to about 400 atoms, such as about 10 to about 300 atoms in a linker. In certain embodiments, linkers of the disclosure have from about 30 to about 400 atoms, such as from about 30 to about 300 atoms in the linker. In the conjugates, an inhibitor as described herein is covalently bound to a GalNAc moiety by way of a linker, also referred to herein as L³. L³, as used herein, may be selected from any of the linker moieties discussed herein. As will be appreciated by skilled artisans, a conjugate may be prepared by contacting an GalNAc moiety with a linker-compound described herein under conditions in which the linker- compound covalently links to the GalNAc moiety. One embodiment pertains to a method of making a conjugate by contacting a linker-compound with a unit comprising Region G under conditions in which the linker-compound covalently links to the GalNAc moiety. In certain embodiments, any one of the inhibitors described herein is covalently bound to a linker (L³). The linker may be covalently bound to any position on the inhibitor, valence permitting. The linker may comprise a reactive moiety, e.g., a nucleophile or an an electrophile that can react to form a covalent bond. Linkers can be short, long, flexible, rigid, cleavable, non-cleavable, hydrophilic, hydrophobic, unbranched (e.g., where z is 1), or branched (e.g., where z is greater than 1). A linker can contain connector segments that have different characteristics, such as segments of flexibility and segments of rigidity, or segments that are cleavable and segments that are cleavable. A linker can contain multiple segments, such as one or more non-cleavable segments and one or more cleavable segments. The linkers may be polyvalent such that they covalently link more than one inhibitor to a single site on the GalNAc moiety, or monovalent such that covalently they link a single inhibitor to a single site on the GalNAc moiety. A linker can comprise alkylene, alkenylene, alkynylene, polyether, polyester, polyamide, polyamino acid, polypeptide, cleavable peptide, and/or para-aminobenzylcarbamate groups. In some embodiments, the linker comprises a “non-cleavable” segment, such as a “non-cleavable linker,” that is chemically stable to extracellular environments, for example, chemically stable in the blood stream and in intracellular environments. In some embodiments, the linker comprises a “cleavable” segment, such as a “cleavable linker,” that includes one or more linkages that are not stable, such as linkages that are designed to cleave and/or immolate or otherwise breakdown specifically or non-specifically in the blood stream and/or inside cells (i.e., in an intracellular environment). Linkers comprise one or more cleavable segments, one or more non-cleavable segments, or a combination thereof. In some embodiments, a moiety, construct, or conjugate described herein includes the symbol , which indicates the point of attachment, e.g., the point of attachment of a chemical or functional moiety to the compound, the point of attachment of a linker to a compound of the disclosure, or the point of attachment of a linker to a GalNAc moiety. Sulfamide linkers may be used to link many compounds of the present invention to a GalNAc moiety. Sulfamide linkers are as described herein and e.g., U.S. Patent Publication Number 2019/0038765, the linkers of which are incorporated by reference herein. Cleavable linkers can be cleavable in vitro and in vivo. Cleavable linkers can include chemically or enzymatically unstable or degradable linkages. Cleavable linkers can rely on processes inside the cell to liberate a TGFβR1 inhibitor, such as reduction in the cytoplasm, exposure to acidic conditions in the lysosome, or cleavage by specific proteases or other enzymes within the cell. A cleavable linker can be sensitive to (i.e., cleavable by) enzymes at a specific site. A cleavable linker can be cleaved by enzymes such as proteases. Cleavable linkers can incorporate one or more chemical bonds that are either chemically or enzymatically cleavable while the remainder of the linker can be non-cleavable. In some embodiments, L is a linker comprising a reactive moiety. In some embodiments, for a linker-payload comprising a compound of the present disclosure, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, −L is represented by the formula:

. In some embodiments, −L is represented by the formula:

, wherein each R³⁰ is independently selected from optionally substituted C₁-C₆ alkyl and optionally substituted phenyl, and RX is the reactive moiety. RX may comprise a leaving group. RX may be a maleimide. L may be further covalently bound to a GalNAc moiety. In some embodiments, −L− is represented by the formula:

, wherein RX^* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a GalNAc moiety, wherein

on RX* represents the point of attachment; and each R³⁰ is independently selected from optionally substituted C₁-C₆ alkyl and optionally substituted phenyl. In some embodiments, for a linker-payload comprising a compound of the present disclosure, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof, and linker L; L comprises a methylene carbamate unit. A linker can contain a chemically labile group such as hydrazone and/or disulfide groups. Linkers comprising chemically labile groups can exploit differential properties between the plasma and some cytoplasmic compartments. The intracellular conditions that can facilitate TGFβR1 inhibitor release for hydrazone containing linkers can be the acidic environment of endosomes and lysosomes, while the disulfide containing linkers can be reduced in the cytosol, which can contain high thiol concentrations, e.g., glutathione. The plasma stability of a linker containing a chemically labile group can be increased by introducing steric hindrance using substituents near the chemically labile group. Acid-labile groups, such as hydrazone, can remain intact during systemic circulation in the blood’s neutral pH environment (pH 7.3-7.5) and can undergo hydrolysis once the conjugate is internalized into mildly acidic endosomal (pH 5.0-6.5) and lysosomal (pH 4.5-5.0) compartments of the cell. This pH dependent release mechanism can be associated with nonspecific release of the drug. To increase the stability of the hydrazone group of the linker, the linker can be varied by chemical modification, e.g., substitution, allowing tuning to achieve more efficient release in the lysosome with a minimized loss in circulation. In some embodiments, for a linker-payload comprising a compound of the present disclosure, or pharmaceutically acceptable isomer, tautomer, racemate, hydrate, solvate, isotope, or salt thereof; and a linker L, −L comprises a hydrazone moiety. For example, L may be selected from:

wherein M is selected from C₁-C₆ alkyl, aryl, and −O−C₁-C₆ alkyl. Hydrazone-containing linkers can contain additional cleavage sites, such as additional acid-labile cleavage sites and/or enzymatically labile cleavage sites. Conjugates including exemplary hydrazone-containing linkers can include, for example, the following structures:

In certain linkers, such as linker (Ia), the linker can comprise two cleavable groups– a disulfide and a hydrazone moiety. For such linkers, effective cleavage can require acidic pH or disulfide reduction and acidic pH. Linkers such as (Ib) and (Ic) can be effective with a single hydrazone cleavage site. Other acid-labile groups that can be included in linkers include cis-aconityl-containing linkers. cis-Aconityl chemistry can use a carboxylic acid juxtaposed to an amide bond to accelerate amide hydrolysis under acidic conditions. Cleavable linkers can also include a disulfide group. Disulfides can be thermodynamically stable at physiological pH and can be designed to release upon internalization inside cells, wherein the cytosol can provide a significantly more reducing environment compared to the extracellular environment. Scission of disulfide bonds can require the presence of a cytoplasmic thiol cofactor, such as (reduced) glutathione (GSH), such that disulfide-containing linkers can be reasonably stable in circulation, selectively releasing the TGFβR1 inhibitor in the cytosol. The intracellular enzyme protein disulfide isomerase, or similar enzymes capable of cleaving disulfide bonds, can also contribute to the preferential cleavage of disulfide bonds inside cells. GSH can be present in cells in the concentration range of 0.5-10 mM compared with a significantly lower concentration of GSH or cysteine, the most abundant low-molecular weight thiol, in circulation at approximately 5 μM. Tumor cells, where irregular blood flow can lead to a hypoxic state, can result in enhanced activity of reductive enzymes and therefore even higher glutathione concentrations. The in vivo stability of a disulfide-containing linker can be enhanced by chemical modification of the linker, e.g., use of steric hindrance adjacent to the disulfide bond. For example, L may be selected from:

, wherein M is selected from C₁-C₆ alkyl, aryl, and −O-C₁-C₆ alkyl. Exemplary cleavable linkers including disulfide moieties can include the following

wherein R is independently selected at each occurrence from hydrogen or alkyl, for example. Increasing steric hindrance adjacent to the disulfide bond can increase the stability of the linker. Structures such as (Id) and (If) can show increased in vivo stability when one or more R groups is selected from a lower alkyl such as methyl. Another type of cleavable linker is specifically cleaved by an enzyme. For example, the linker can be cleaved by a lysosomal enzyme. Such linkers can be peptide-based or can include peptidic regions that can act as substrates for enzymes. Peptide-based linkers can be more stable in plasma and extracellular milieu than chemically labile linkers. Peptide bonds can have good serum stability, as lysosomal proteolytic enzymes can have very low activity in blood due to endogenous inhibitors and the unfavorably high pH value of blood compared to lysosomes. Release of a TGFβR1 inhibitor from a conjugate can occur due to the action of lysosomal proteases, e.g., cathepsin and/or plasmin. These proteases can be present at elevated levels in certain tumor tissues. The linker can be cleavable by a lysosomal enzyme. The lysosomal enzyme can be, for example, cathepsin B, β-glucuronidase, or β-galactosidase. The cleavable peptide can be selected from tetrapeptides such as Gly-Phe-Leu-Gly, Ala- Leu-Ala-Leu or dipeptides such as Val-Cit, Val-Ala, and Phe-Lys. Dipeptides can have lower hydrophobicity compared to longer peptides. In some embodiments, the cleavable linker comprises a cleavable peptide. In some embodiments, the cleavable peptide is a dipeptide, tripeptide, or tetrapeptide. In some embodiments, the cleavable peptide is Val−Cit; Cit−Val; Ala−Ala; Ala−Cit; Cit−Ala; Asn−Cit; Cit−Asn; Cit−Cit; Val−Glu; Glu−Val; Ser−Cit; Cit−Ser; Lys−Cit; Cit−Lys; Asp−Cit; Cit−Asp; Ala−Val; Val−Ala; Phe−Lys; Lys−Phe; Val−Lys; Lys−Val; Ala−Lys; Lys−Ala; Phe−Cit; Cit−Phe; Leu− Cit; Cit−Leu; Ile−Cit; Cit−Ile; Phe−Arg; Arg−Phe; Cit−Trp; Trp−Cit; Ala−Ala−Asn; Gly−Phe−Leu−Gly; Gly−Gly−Phe−Gly; or Ala−Leu−Ala−Leu. In some embodiments, the cleavable linker comprises a structure of formula:

wherein −AA₁−AA₂− is the cleavable dipeptide and AA₁ and AA₂ are each an amino acid. In some embodiments, the cleavable dipeptide is Val−Cit. Enzymatically cleavable linkers can include a self-immolative spacer to spatially separate the TGFβR1 inhibitor from the site of enzymatic cleavage. The direct attachment of a TGFβR1 inhibitor to a peptide linker can result in proteolytic release of an amino acid adduct of the TGFβR1 inhibitor, thereby impairing its activity. The use of a self-immolative spacer can allow for the elimination of the fully active, chemically unmodified TGFβR1 inhibitor upon amide bond hydrolysis. One self-immolative spacer can be a bifunctional para-aminobenzyl alcohol (PABA) group, which can link to the peptide through the amino group, forming an amide bond, while amine containing TGFβR1 inhibitors can be attached through carbamate functionalities to the benzylic hydroxyl group of the linker to form a para-aminobenzyl carbamate (PMBC) group. The resulting pro-TGFβR1 inhibitor can be activated upon protease-mediated cleavage, leading to a 1,6-elimination reaction releasing the unmodified TGFβR1 inhibitor, carbon dioxide, and remnants of the linker group. The following scheme depicts the fragmentation of a substituted p- aminobenzyl carbamate and release of the compound:

wherein HX−D represents the unmodified inhibitor. In some embodiments, a cleavable linker comprises a valine-citrulline peptide or a valine-alanine peptide. A valine-citrulline or valine-alanine-containing linker can contain a succimide group. A valine-citrulline- or valine-alanine-containing linker can contain a para- aminobenzyl (PAB) group. In some embodiments, the PAB group is a para-aminobenzyl alcohol (PABA) group or a para-aminobenzyl carbamate (PABC) group. In some embodiments, a valine-citrulline- or valine-alanine-containing linker also includes a PAB group, such as a PABC group. In some embodiments, a cleavable linker comprises a −(valine−citrulline)−(para−aminobenzyloxycarbonyl) group. In some embodiments, a cleavable linker comprises a lysine with an N-terminal amine acetylated, and a valine-citrulline cleavage site. In some embodiments, the cleavable linker comprises a succinimide group. The enzymatically cleavable linker can be a ß-glucuronic acid-based linker. Facile release of the TGFβR1 inhibitor can be realized through cleavage of the ß-glucuronide glycosidic bond by the lysosomal enzyme ß-glucuronidase. This enzyme can be abundantly present within lysosomes and can be overexpressed in some tumor types, while the enzyme activity outside cells can be low. ß-Glucuronic acid-based linkers can be used to circumvent the tendency of a conjugate to undergo aggregation due to the hydrophilic nature of ß-glucuronides. In certain embodiments, ß-glucuronic acid-based linkers can link the GalNAc moiety to a hydrophobic TGFβR1 inhibitor. A variety of cleavable β-glucuronic acid-based linkers useful for linking drugs such as auristatins, camptothecin and doxorubicin analogues, CBI minor-groove binders, and psymberin to antibodies have been described, and such linkers are useful for the present conjugates as well. All of these β-glucuronic acid-based linkers may be used in the conjugates comprising a TGFβR1 inhibitor described herein. In certain embodiments, the enzymatically cleavable linker is a β-galactoside-based linker. β-Galactoside is present abundantly within lysosomes, while the enzyme activity outside cells is low.Additionally, cleavable linkers may comprise a phenol and connection through the phenolic oxygen. One such linker employs diamino-ethane unit (e.g., “Space Link”) in conjunction with traditional “PABO”-based self-immolative groups to deliver a phenol. Inhibitors containing an aromatic or aliphatic hydroxyl group can be covalently bonded to a linker through the hydroxyl group using a methodology that relies on a methylene carbamate linkage, as described in WO 2015/095755. Cleavable linkers can include non-cleavable portions or segments, and/or cleavable segments or portions can be included in an otherwise non-cleavable linker to render it cleavable. By way of example only, polyethylene glycol (PEG) and related polymers can include cleavable groups in the polymer backbone. For example, a polyethylene glycol or polymer linker can include one or more cleavable groups such as a disulfide, a hydrazone or a dipeptide. Other degradable linkages that can be included in cleavable linkers include ester linkages formed by the reaction of PEG carboxylic acids or activated PEG carboxylic acids with alcohol groups on a TGFβR1 inhibitor, wherein such ester groups can hydrolyze under physiological conditions to release the TGFβR1 inhibitor. Hydrolytically degradable linkages can include, but are not limited to, carbonate linkages; imine linkages resulting from reaction of an amine and an aldehyde; phosphate ester linkages formed by reacting an alcohol with a phosphate group; acetal linkages that are the reaction product of an aldehyde and an alcohol; orthoester linkages that are the reaction product of a formate and an alcohol; and oligonucleotide linkages formed by a phosphoramidite group, including but not limited to, at the end of a polymer, and a 5’ hydroxyl group of an oligonucleotide. A linker can be a link created by a microbial transglutaminase, wherein the link can be created between an amine-containing moiety and a moiety engineered to contain glutamine as a result of the enzyme catalyzing a bond formation between the acyl group of a glutamine side chain and the primary amine of a lysine chain. A linker can contain a reactive primary amine. A linker can be a Sortase A linker. A Sortase A linker can be created by a Sortase A enzyme fusing an LPXTG (SEQ ID NO:1) recognition motif to an N-terminal GGG motif to regenerate a native amide bond. The linker created can therefore link a moiety attached to the LPXTG (SEQ ID NO:1) recognition motif with a moiety attached to the N-terminal GGG motif. A linker can be a link created between an unnatural amino acid on one moiety reacting with oxime bond that was formed by modifying a ketone group with an alkoxyamine on another moiety. A moiety can be a TGFβR1 inhibitor. Although cleavable linkers can provide certain advantages, the linkers in the conjugates described herein need not include cleavable linkers. For non-cleavable linkers, the TGFβR1 inhibitor release may not depend on the differential properties between the plasma and some cytoplasmic compartments. A non-cleavable linker can be protease insensitive. A non-cleavable linker can contain a succinimide group. A non-cleavable linker can contain a caproyl group or a succinimidocaproyl group. A succinimidocaproyl linker can comprise N-succinimidomethylcyclohexane-1- carboxylate. A non-cleavable linker can be a combination of a succinimidocaproyl group and one or more ethylene glycol units. A non-cleavable linker can be a PEG4 linker or a succinimido-PEG4 linker. A non-cleavable linker can be a combination of a succinimidocaproyl linker containing a succinimide group and one or more ethylene glycol units. A non-cleavable linker can contain one or more succinimido groups linked to polyethylene glycol units in which the polyethylene glycol can allow for more linker flexibility or can be used lengthen the linker. In some embodiments, a non-cleavable linker independently comprises a heteroalkylene, heteroalkenylene, or heteroalkynylene comprising 3 to 30 components in the longest linear chain, wherein the components are selected from −CH₂−, −CH(C_1-4alkyl), −C(C_1-4alkyl)₂, −CH=CH−, −C≡C−, −C(O)−, −O−, −NH−, −N(C_1-4alkyl), −S−, −S(O)−, −S(O)₂−, and −P(O)(O-)−. In some embodiments, a non-cleavable linker independently comprises a heteroalkylene comprising 3 to 15 components in the longest linear chain, wherein the components are selected from −CH₂−, −CH(C_1-4alkyl), −C(O)−, −O−, −NH−, and −N(C_1-4alkyl). In some embodiments, the non-cleavable linker comprises a polyethylene glycol region comprising two to six ethylene glycol units. In some embodiments, a non-cleavable linker is −NH−C(O)−(CH₂)_2-5−C(O)−, −NH−C(O)−(CH₂)_2-5−C(O)NH−(CH₂)_2-7−C(O)−, or −NH−C(O)−(CH₂)_2-5−C(O)NH−(CH₂)_2-7−NH−C(O)−(CH₂)_2-4−C(O)−. In some embodiments, a non-cleavable linker is −NH−C(O)−(CH₂)₃−C(O)−. Attachment groups that are used to attach the linkers in a conjugate can be electrophilic in nature and include, for example, active esters such as NHS esters and HOBt esters, haloformates, acid halides, carboxylic acids, amines, alkyl halides, benzyl halides such as haloacetamides, maleimide groups, or activated disulfides. In some embodiments, Region L³ comprises or is the following structure:

, wherein: L⁴ represents the C-terminus of the peptide; L⁵ is selected from a bond, alkylene, and heteroalkylene, wherein L⁵ is optionally substituted with one or more groups independently selected from R³²; R³² is independently selected at each occurrence from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −NH₂, −NO₂; and C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −NH₂, −NO₂; and RX* is a bond. In some embodiments, the peptide comprises Val—Cit or Val—Ala. In any of the aforementioned embodiments, −L³ is:

A linker can comprise a cleavable peptide, for example, a linker comprising structural formula (IVa), (IVb), (IVc), or (IVd):

or a salt thereof, wherein: peptide represents a cleavable peptide (illustrated N→C, wherein peptide includes the amino and carboxy “termini”) as described herein; T represents a polymer comprising one or more ethylene glycol units or an alkylene chain, or combinations thereof; R^a is selected from hydrogen, alkyl, sulfonate and methyl sulfonate; R^y is hydrogen or C_1-4 alkyl−(O)_r−(C_1-4 alkylene)_s−G¹ or C_1-4 alkyl−(N)−[(C_1-4 alkylene)−G¹]₂; R^z is C_1-4 alkyl−(O)_r−(C_1-4 alkylene)_s−G²; G¹ is SO₃H, CO₂H, PEG 4-32, or sugar moiety; G² is SO₃H, CO₂H, or PEG 4-32 moiety; r is 0 or 1; s is 0 or 1; p is an integer ranging from 0 to 5; q is 0 or 1; x is 0 or 1; y is 0 or 1; represents one point of attachment of the linker to the inhibitor; and * represents the point of attachment to the GalNAc moiety. Exemplary polyvalent linkers that may be used to link inhibitors include Fleximer® linker technology that has the potential to enable high loading of conjugates with good physicochemical properties. The Fleximer® linker technology is based on incorporating drug molecules into a solubilizing poly-acetal backbone via a sequence of ester bonds.

The methodology renders highly-loaded conjugates (drug loading up to 20) while maintaining good physicochemical properties. In certain embodiments, to utilize the Fleximer® linker technology depicted above, an aliphatic alcohol can be present or introduced into an inhibitor or salt thereof (e.g., an ALK5 inhibitor, as described herein). The alcohol moiety is then conjugated to an alanine moiety, which is then synthetically incorporated into the Fleximer® linker. Liposomal processing of the conjugate in vitro releases the parent alcohol-containing drug. Sulfamide linkers may also be used in the disclosed conjugates. Sulfamide linkers are as described herein and e.g., U.S. Patent Publication No. 2019/0038765, the linkers of which are incorporated by reference herein. Exemplary embodiments of linkers according to structural formula (IVa) that can be included in the conjugates described herein can include the structures illustrated below:

. wherein one of represents the point of attachment of the linker (L³) to the inhibitor. Exemplary embodiments of linkers according to structural formula (IVb), (IVc), and (IVd) that can be included in the conjugates described herein can include the structures illustrated below:

.

wherein one of represents the point of attachment of the linker (L³) to the inhibitor. Exemplary embodiments of linkers according to structural formula (IVa) that can be included in the conjugates described herein can include the structures illustrated below:

wherein one of represents the point of attachment of the linker (L³) to the inhibitor. The cleavable linker can contain an enzymatically cleavable sugar moiety, for example, a linker comprising structural formula (Va), (Vb), (Vc), (Vd), or (Ve):

or a salt thereof, wherein: q is 0 or 1; r is 0 or 1; X¹ is CH₂, O or NH;

represents the point of attachment of the linker to the TGFβR1 inhibitor; and * represents the point of attachment to the remainder of the conjugate. Exemplary embodiments of linkers according to structural formula (IVa) that may be included in the conjugates described herein can include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the TGFβR1 inhibitor:

, Exemplary embodiments of linkers according to structural formula (IVb) that may be included in the conjugates described herein can include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the TGFβR1 inhibitor:

. Exemplary embodiments of linkers according to structural formula (IVc) that may be included in the conjugates described herein can include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the TGFβR1 inhibitor:

. Exemplary embodiments of linkers according to structural formula (IVd) that may be included in the conjugates described herein can include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the TGFβR1 inhibitor:

. Exemplary embodiments of linkers according to structural formula (IVe) that may be included in the conjugates described herein can include the linkers illustrated below (as illustrated, the linkers include a group suitable for covalently linking the TGFβR1 inhibitor:

. The linker can be non-cleavable in vivo, for example, a linker according to the formulations below:

or salts thereof, wherein: R^a is selected from hydrogen, alkyl, sulfonate and methyl sulfonate; R^x is a moiety that covalently links the linker to the rest of the conjugate, such as a bond; and represents the point of attachment of the linker to the rest of the conjugate. Exemplary embodiments of linkers according to structural formula (Va)-(Vf) that may be included in the conjugates described herein include the linkers illustrated:

. Attachment groups that are used to attach the linkers to a TGFβR1 inhibitor can be electrophilic in nature and include, for example, maleimide groups, alkynes, alkynoates, allenes and allenoates, activated disulfides, active esters such as NHS esters and HOBt esters, haloformates, acid halides, alkyl, and benzyl halides such as haloacetamides. There are also emerging technologies related to "self-stabilizing" maleimides and "bridging disulfides" that can be used in accordance with the disclosure. A linker described herein with a maleimide group may include an electron withdrawing group such as, but not limited to, -C(O)R, =O, -CN, -NO₂, -CX₃, -X, -COOR, -CONR₂, -COR, - COX, -SO₂R, -SO₂OR, -SO₂NHR, -SO₂NR₂, PO₃R₂, -P(O)(CH₃)NHR, -NO, -NR₃ ⁺, -CR=CR₂, and -C≡CR, where each R is independently selected from H and C_1-6 alkyl and each X is independently selected from F, Br, Cl, and I. Self-stabilizing linkers may also include aryl, e.g., phenyl, or heteroaryl, e.g., pyridine, groups optionally substituted with electron withdrawing groups such as those described herein. Examples of self-stabilizing linkers are provided in, e.g., U.S. Patent Publication No. US 2013/0309256, the linkers of which are incorporated by reference herein. It will be understood that a self-stabilizing linker useful in conjunction with immune-stimulatory compounds may be equivalently described as unsubstituted maleimide-including linkers, thio- substituted succinimide-including linkers, or hydrolyzed, ring-opened thio-substituted succinimide-including linkers. In certain embodiments, a linker comprises a stabilizing linker moiety selected from:

. In the scheme provided above, the bottom structure may be referred to as (maleimido)- DPR-Val-Cit-PAB, where DPR refers to diaminopropinoic acid, Val refers to valine, Cit refers to citrulline, and PAB refers to para-aminobenzylcarbonyl, wherein represents the point of attachment of the linker to a nitrogen of the inhibitor. A method for bridging a pair of sulfhydryl groups derived from reduction of a native hinge disulfide bond has been disclosed and is depicted in the schematic below. An advantage of this methodology is the ability to synthesize homogenous DAR4 conjugates by full reduction of IgGs (to give 4 pairs of sulfhydryls from interchain disulfides) followed by reaction with 4 equivalents of the alkylating agent. Conjugates containing "bridged disulfides" are also claimed to have increased stability.

Similarly, as depicted below, a maleimide derivative that is capable of bridging a pair of sulfhydryl groups has been developed.

A linker can contain the following structural formulas (VIa), (VIb), or (VIc):

or salts thereof, wherein: R^q is H or–O-(CH₂CH₂O)₁₁-CH₃; x is 0 or 1; y is 0 or 1; G² is -CH₂CH₂CH₂SO₃H or–CH₂CH₂O-(CH₂CH₂O)₁₁-CH₃; R^w is–O-CH₂CH₂SO₃H or -NH(CO)-CH₂CH₂O-(CH₂CH₂O)₁₂-CH₃; and * represents the point of attachment to the remainder of the linker. Exemplary embodiments of linkers according to structural formula (VIa) and (VIb) that can be included in the conjugates described herein can include the linkers illustrated:

, wherein represents the point of attachment of the linker to a nitrogen of the inhibitor. Exemplary embodiments of linkers according to structural formula (Vic) that can be included in the immune-stimulatory conjugates described herein can include the linkers illustrated below:

 wherein represents the point of attachment of the linker to a nitrogen of the inhibitor. Some exemplary linkers (L³) are described in the following paragraphs. In some embodiments for an inhibitor wherein attachment of the linker is to a nitrogen of the inhibitor, −L³ is represented by the formulas set forth in Table 1 below: TABLE 1

wherein

represents attachment to a nitrogen of a TGFβR1 inhibitor; L⁴ represents the C-terminus of the peptide and L⁵ is selected from a bond, alkylene and heteroalkylene, wherein L⁵ is optionally substituted with one or more groups independently selected from R³⁰, and R³⁰ is independently selected at each occurrence from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −S(O)₂OH, −NH₂, −NO₂; and C₁−C₁₀alkyl, C₂-C₁₀alkenyl, and C₂-C₁₀alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −S(O)₂OH, −NH₂, and −NO₂; and RX represents a reactive moiety. The reactive moiety may be selected, for example, from an electrophile, e.g., an αǡ ^-unsaturated carbonyl, such as a maleimide, and a leaving group. For example, –L can be represented by the formulas set forth in Table 2 below: TABLE 2

wherein

represents attachment to a nitrogen of a TGFβR1 inhibitor and L⁴ represents the C-terminus of the peptide and L⁵ is selected from a bond, alkylene and heteroalkylene, wherein L⁵ is optionally substituted with one or more groups independently selected from R³⁰, and R³⁰ is independently selected at each occurrence from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −NH₂, −NO₂; and C₁-C₁₀alkyl, C₂-C₁₀alkenyl, and C₂-C₁₀alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −NH₂, and −NO_2. When conjugated to the GalNAc moiety, such linkers can be, for example, represented by the Formulas set forth in Table 3 below: TABLE 3

where represents attachment to a nitrogen of a TGFβR1 inhibitor and −RX* represents the point of attachment to the GalNAc moiety; L⁴ represents the C-terminus of the peptide and L⁵ is selected from a bond, alkylene and heteroalkylene, wherein L⁵ is optionally substituted with one or more groups independently selected from R³⁰, and R³⁰ when present is independently selected at each occurrence from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −S(O)₂OH, −NH₂, −NO₂; and C₁-C₁₀alkyl, C₂-C₁₀alkenyl, and C₂-C₁₀alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −S(O)₂OH, −NH₂, and −NO₂; and RX represents the point of attachment to the GalNAc moiety. In some embodiments, –L³ is represented by the formulas set forth in Table 4 below: TABLE 4

wherein

represents attachment to a nitrogen of a TGFβR1 inhibitor and RX represents a reactive moiety. The reactive moiety may be selected from, for example, a leaving group. For example, –L can be represented by the formulas set forth in Table 5 below:

TABLE 5

The linkers, can, for example, be represented by the Formulas set forth in Table 6 below wherein RX^* is a bond to the GalNAc moiety, wherein

on RX* represents the point of attachment to such residue: TABLE 6

represents the point of attachment to the GalNAc moiety. As is known by skilled artisans, the linker selected for a particular conjugate may be influenced by a variety of factors, including the site of attachment to GalNAc moiety structural constraints of the drug pharmacophore, and the lipophilicity of the drug. The specific linker selected for a conjugate should seek to balance these different factors. For example, cytotoxic conjugates have been observed to effect killing of bystander antigen-negative cells present in the vicinity of the antigen-positive tumor cells. The mechanism of the bystander effect by cytotoxic conjugates has indicated that metabolic products formed during intracellular processing of the conjugates may play a role. Neutral cytotoxic metabolites generated by metabolism of the conjugates in antigen-positive cells appear to play a role in bystander cell killing while charged metabolites may be prevented from diffusing across the membrane into the medium, or from the medium across the membrane and, therefore, cannot effect cell killing via the bystander effect. In some embodiments, a linker is selected to attenuate the bystander effect caused by cellular metabolites of the conjugate. In further embodiments, a linker is selected to increase the bystander effect. The properties of the linker, or linker-payload, may also impact aggregation of a conjugate under conditions of use and/or storage. Conjugates reported in the literature contain about 3-4 drug molecules per antibody molecule. Attempts to obtain higher drug-to-antibody ratios (“DAR”) often failed, particularly if both the drug and the linker were hydrophobic, due to aggregation of the conjugate. In many instances, DARs higher than 3-4 could be beneficial as a means of increasing potency. In instances where the payload compound is more hydrophobic in nature, it may be desirable to select linkers that are relatively hydrophilic as a means of reducing conjugate aggregation, especially in instances where DARs greater than 3-4 are desired. Thus, in some embodiments, a linker incorporates chemical moieties that reduce aggregation of the conjugates during storage and/or use. A linker may incorporate polar or hydrophilic groups such as charged groups or groups that become charged under physiological pH to reduce the aggregation of the conjugates. For example, a linker may incorporate charged groups such as salts or groups that deprotonate, e.g., carboxylates, or protonate, e.g., amines, at physiological pH. In preferred embodiments, aggregation of conjugates during storage or use is less than about 40% as determined by size-exclusion chromatography (SEC). In particular embodiments, the aggregation of the conjugates during storage or use is less than about 35%, such as less than about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 4%, or even less, as determined by size-exclusion chromatography (SEC). Some exemplary linkers (L) are described in the following paragraphs. In some embodiments for a compound wherein attachment of the linker is to a nitrogen of the of a TGFβR1 inhibitor and −RX represents a reactive group for attachment to the GalNAc moiety. –L is represented by the formulas set forth in Table 7 below:

wherein

represents attachment to a nitrogen of a TGFβR1 inhibitor. L⁴ represents the C-terminus of the peptide and L⁵ is selected from a bond, alkylene and heteroalkylene, wherein L⁵ is optionally substituted with one or more groups independently selected from R³⁰, and R³⁰ is independently selected at each occurrence from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −S(O)₂OH, −NH₂, −NO₂; and C₁-C₁₀alkyl, C₂-C₁₀alkenyl, and C₂-C₁₀alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −S(O)₂OH, −NH₂, and −NO₂; and RX represents a reactive moiety. The reactive moiety may be selected, for example, from an electrophile, e.g., an α,β-unsaturated carbonyl, such as a maleimide, and a leaving group. For example, –L³ can be represented by the formulas set forth in Table 8 below: TABLE 8

wherein

represents attachment to a nitrogen of a TGFβR1 inhibitor and L⁴ represents the C-terminus of the peptide and L⁵ is selected from a bond, alkylene and heteroalkylene, wherein L⁵ is optionally substituted with one or more groups independently selected from R³⁰, and R³⁰ is independently selected at each occurrence from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −S(O)₂OH, −NH₂, −NO₂; and C₁-C₁₀alkyl, C₂-C₁₀alkenyl, and C₂-C₁₀alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −S(O)₂OH, −NH₂, and −NO_2. Additional linkers can be, for example, represented by the Formulas set forth in Table 9 below: TABLE 9

wherein RX^* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety, wherein on RX* represents the point of attachment to such residue; L⁴ when present represents the C-terminus of the peptide and L⁵ is selected from a bond, alkylene and heteroalkylene, wherein L⁵ is optionally substituted with one or more groups independently selected from R³⁰; and R³⁰ when present is independently selected at each occurrence from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −S(O)₂OH, −NH₂, −NO₂; and C₁-C₁₀alkyl, C₂-C₁₀alkenyl, and C₂-C₁₀alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, −OH, −CN, −O−alkyl, −SH, =O, =S, −S(O)₂OH, −NH₂, and −NO₂. A particularly preferred pepide is val-ala or val-cit. In some embodiments wherein attachment of the linker is to a nitrogen of a TGFβR1 inhibitor and −RX represents the reactive moiety for the point of attachment to the GalNAc moiety, –L³ is represented by the formulas set forth in Table 10 below: TABLE 10

The reactive moiety may be selected from, for example, a leaving group. For example, – L³ can be represented by the formulas set forth in Table 11 below: TABLE 11

L3 can be represented by the Formulas set forth in Table 12 below wherein RX^* is a bond to the GalNAc moiety, wherein on RX* represents the point of attachment to such residue: TABLE 12

As noted,

represents attachment to a nitrogen of a TGFβR1 inhibitor and −RX* represents the point of attachment to the GalNAc moiety. In exemplary embodiments, the linkers described herein, including those in the preceding paragraphs, are attached to a compound of the present invention through the nitrogen of a secondary acyclic amine depicted in the structure of any one the compounds of the present invention. In exemplary embodiments, the linkers described herein, including those in the preceding paragraphs, are attached to a compound of the present invention at a nitrogen atom. As is known by skilled artisans, the linker selected for a particular conjugate may be influenced by a variety of factors, including but not limited to, the site of attachment to the antibody construct (e.g., lys, cys or other amino acid residues), structural constraints of the drug pharmacophore and the lipophilicity of the drug. The specific linker selected for a conjugate should seek to balance these different factors for the specific GalNAc construct/drug combination. In some aspects, the conjugate comprises one of the following structures: ,

or a salt thereof. In some aspects, the conjugate comprises a structure as shown in Table 13: TABLE 13

In some aspects, the conjugate comprises one of the following structures, where the wavy bond is the point of attachment to the rest of the conjugate:

,

,

. In some embodiments, Region L³ comprises a dipeptide. In some embodiments, the dipeptide is Val−Cit. In some embodiments, Region L³ comprises a para-aminobenzyl moiety. In some embodiments, Region L³ comprises a PABC moiety. In some embodiments, Region L³ comprises −NHC(O)−(CH₂)_p−C(O)− where p is 2, 3, 4, 5, or 6. In some embodiments, Region L³ is −NHC(O)−(CH₂)_p−C(O)−Val−Cit−PAB−O−C(O)−. A TGFβR1 inhibitor-linker compound can be synthesized by various methods known in the art. See, for example, WO2018170179. As is known by skilled artisans, the linker selected for a particular conjugate may be influenced by a variety of factors, including but not limited to, the site of attachment to the GalNAc moiety, structural constraints of the drug pharmacophore, and the lipophilicity of the drug. The specific linker selected for a conjugate should seek to balance these different factors for the specific conjugate. Additional Inhibitors In some aspects, the disclosure includes a TGFβR1 inhibitor of Formula (XX): [Inh]−Z (XX) wherein Region Inh comprises a TGFβR1 inhibitor (e.g., a compound of Formula (A-I), (B-I), or (C-1); and Z is the residual portion of a released, cleavable linker or comprises a non-cleavable linker and a residual portion of a degraded Region G; or a salt thereof. In such aspects, Z is a moiety that remains covalently attached to the rest of the inhibitor structure following cleavage (e.g., in vivo) of a cleavable linker of a conjugate as described herein. In some embodiments, Z comprises an amino acid. In some embodiments, Z comprises valine or citrulline. In some embodiments, Z is −NH₂. In some embodiments, Z is a moiety that remains covalently attached to the inhibitor following degradation (e.g., in vivo) of Region G of a conjugate as described herein. In some embodiments, Z comprises a degraded Region G and a non-cleavable linker as described herein. In some embodiments, the degradation is by enzyme- or acid-mediated degradation, such as hydrolysis. In some embodiments, a degraded Region G comprises one or more degraded GalNAc groups. Pharmaceutical Formulations The conjugates described herein are useful as pharmaceutical compositions for administration to a subject in need thereof. Pharmaceutical compositions can comprise the conjugates described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and/or thickening agents. A pharmaceutical composition can comprise any conjugate described herein. A pharmaceutical composition can further comprise buffers, antibiotics, steroids, carbohydrates, drugs (e.g., chemotherapy drugs), radiation, polypeptides, chelators, adjuvants and/or preservatives. In a pharmaceutical composition, conjugates for which a is 1 comprise a Region Fc. These conjugates can have an average drug loading. The average drug loading is the average number of TGFβR1 inhibitor molecules per Region Fc. The average number of TGFβR1 inhibitors per Region Fc in a preparation may be characterized by conventional means such as mass spectroscopy, HIC, ELISA assay, and HPLC. In some embodiments, the average drug loading is 1 to 8, or 1 to 6, or 1 to 4, or 1 to 3, or 1 to 2, or 2 to 4, or 2 to 3, TGFβR1 inhibitor molecules per Region Fc. 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 conjugate as described herein can be manufactured, for example, by lyophilizing the conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions can also include the conjugates described herein in a free-base form or pharmaceutically-acceptable salt form. Methods for formulation of the pharmaceutical compositions can include formulating any of the conjugates described herein 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 compositions described herein can be lyophilized or in powder form for re- constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use Pharmaceutical compositions of the conjugates described herein can comprise at least a conjugate as an active ingredient, respectively. 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. Pharmaceutical compositions as described herein often further can comprise more than one active compound 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 pharmaceutical composition can also comprise a 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. The pharmaceutical compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration. The pharmaceutical compositions described herein 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 pharmaceutical compositions described herein can be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. For parenteral administration, the conjugates can be formulated in a unit dosage injectable form (e.g., use letter solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently nontoxic, and non-therapeutic. A vehicle can be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Nonaqueous 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). Sustained-release preparations can also be prepared. Examples of sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), 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 DEPO^TM (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-( – )-3-hydroxybutyric acid. Pharmaceutical formulations of the compositions described herein can be prepared for storage by mixing a 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.

The conjugates, pharmaceutical compositions, and methods of the present disclosure can be useful for treating a subject such as, but not limited to, a mammal, a human, a non-human mammal, a domesticated animal (e.g., laboratory animals, household pets, or livestock), a non- domesticated animal (e.g., wildlife), a dog, a cat, a rodent, a mouse, a hamster, a cow, a bird, a chicken, a fish, a pig, a horse, a goat, a sheep, or a rabbit. In preferred embodiments, conjugates, pharmaceutical compositions, and methods of the present disclosure are used for treating a human. The conjugates, pharmaceutical compositions, and methods described herein can be useful as a therapeutic, for example a treatment that can be administered to a subject in need thereof. A therapeutic effect can be obtained in a subject by reduction, suppression, remission, or eradication of a disease state, including, but not limited to, a symptom thereof. A therapeutic effect in a subject having a disease or condition, or pre-disposed to have or is beginning to have the disease or condition, can be obtained by a reduction, a suppression, a prevention, a remission, or an eradication of the condition or disease, or pre-condition or pre-disease state. In practicing the methods described herein, therapeutically-effective amounts of the conjugates, or pharmaceutical compositions described herein can be administered to a subject in need thereof, often for treating and/or preventing a condition or progression thereof. A pharmaceutical composition can affect the physiology of the subject, such as the immune system, inflammatory response, or other physiologic affect. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. Treat and/or treating can refer to any indicia of success in the treatment or amelioration of the disease or condition. 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. Treat 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. Prevent, preventing and the like can refer to the prevention of the disease or condition, e.g., viral infection, in the patient. For example, if an individual at risk of contracting a viral infection is treated with the methods of the present disclosure and does not later become infected with the virus, then the disease has been prevented, at least over a period of time, in that individual. A therapeutically effective amount can be the amount of conjugates or pharmaceutical compositions or an active component thereof sufficient to provide a beneficial effect or to otherwise reduce a detrimental non-beneficial event to the individual to whom the composition is administered. A therapeutically effective dose can be a dose that produces one or more desired or desirable (e.g., beneficial) effects for which it is administered, such administration occurring one or more times over a given period of time. An exact dose can depend on the purpose of the treatment, and can be ascertainable by one skilled in the art using known techniques. The conjugates or pharmaceutical compositions described herein that can be used in therapy can be formulated and dosages established in a fashion consistent with good medical practice taking into account the disorder to be treated, the condition of the individual patient, the site of delivery of the conjugate, or pharmaceutical composition, the method of administration and other factors known to practitioners. The conjugates or pharmaceutical compositions can be prepared according to the description of preparation described herein. One of ordinary skill in the art would understand that the amount, duration and frequency of administration of a pharmaceutical composition or conjugate described herein to a subject in need thereof depends on several factors including, for example but not limited to, the health of the subject, the specific disease or condition of the patient, the grade or level of a specific disease or condition of the patient, the additional therapeutics the subject is being or has been administered, and the like. The methods, conjugates and pharmaceutical compositions described herein can be for administration to a subject in need thereof. Often, administration of the conjugates, or pharmaceutical compositions can include routes of administration, non-limiting examples of administration routes include intravenous, intraarterial, subcutaneous, subdural, intramuscular, intracranial, intrasternal, intratumoral, or intraperitoneally. Additionally, a pharmaceutical composition, or conjugate can be administered to a subject by additional routes of administration, for example, by inhalation, oral, dermal, intranasal, or intrathecal administration. Pharmaceutical compositions or conjugates of the present disclosure can be administered to a subject in need thereof in a first administration, and in one or more additional administrations. The one or more additional administrations can be administered to the subject in need thereof minutes, hours, days, weeks or months following the first administration. Any one of the additional administrations can be administered to the subject in need thereof less than 21 days, or less than 14 days, less than 10 days, less than 7 days, less than 4 days or less than 1 day after the first administration. The one or more administrations can occur more than once per day, more than once per week or more than once per month. The conjugates or pharmaceutical compositions can be administered to the subject in need thereof in cycles of 21 days, 14 days, 10 days, 7 days, 4 days or daily over a period of one to seven days. In one aspect, the disclosure relates to a method for treating a disease mediated by TGFβR1 activity, comprising administering an effective amount of a conjugate or a pharmaceutical composition as described herein to a subject in need thereof. In some aspects, the disease is cancer. In certain embodiments, the cancer is hepatocellular carcinoma (HCC). In further embodiments, the cancer is metastatic liver cancer from colon, lung, breast, neuroendocrine, stomach or pancreatic cancer. In some aspects the disease is liver fibrosis. In some aspects, the fibrosis is liver fibrosis. In some aspects, the fibrosis is cancer-associated. In some aspects, the fibrosis is not cancer- associated. In some aspects, the fibrosis is associated with scleroderma, systemic fibrosis, steatohepatitis, or non-alcoholic steatohepatitis (NASH) , chronic liver viral disease (such as HBV and HCV infection), autoimmune hepatitis, or primary biliary cholangitis. In certain embodiments, the disease is a liver metabolic disease, such as steatosis. In further embodiments, treatment with conjugates or pharmaceutical compositions of the present disclosure reduces hepatocyte apoptosis or reduces altered lipid metabolism in subject consuming a fatty-diet. In one aspect is a method of treating a subject having liver cancer, such as hepatocellular carcinoma (HCC), comprising administering to the subject an effective amount of a conjugate as described herein or a pharmaceutical composition comprising the conjugate. In certain embodiments, the presently described conjugates or pharmaceutical compositions can be used to decrease HCC tumor cell growth and invasiveness. In further embodiments, the presently described conjugates or pharmaceutical compositions can be utilized to enhance liver-localized immune responses against liver cancer, such as HCC. In some embodiments, the administering is in a regimen that comprises administering the conjugates or pharmaceutical compositions intravenously or subcutaneouly. In certain embodiments, the dose level and schedule are chosen to maintain a high ratio of liver exposure to systemic exposure. In further embodiments, the dose and schedule are chosen to attain about an IC₉₀, IC₈₀, IC₅₀ or IC₃₀ of phospho-SMAD2/3 levels in hepatocytes as compared to non- conjugated treatment for at least 24 hours. In still furthre embodiments, the dose and schedule are chosen to attain about an IC₉₀, IC₈₀, IC₅₀ or IC₃₀ of non-hepatocyte liver cells compared to non-conjugate treatment for 24 hours. Increased dosages and reduced side-effects In certain embodiments, using a conjugate of this disclosure can allow administration of the conjugate at greater levels of the inhibitor in the form of the conjugate than the level of inhibitor alone. For example, the conjugate can be administered at a level higher than the maximum tolerated dose for that inhibitor administered in the absence of the being conjugated to the antibody construct in the conjugate. In certain embodiments, administration of the conjugate can be associated with fewer side effects than when administered as the inhibitor alone. Diseases, Conditions and the Like The conjugates, pharmaceutical compositions, and methods provided herein can be useful for the treatment of a plurality of diseases, conditions, preventing a disease or a condition in a subject or other therapeutic applications for subjects in need thereof. The conjugates, pharmaceutical compositions, and methods provided herein can be useful for treatment of liver diseases, such as liver fibrosis or liver cancer. In some aspects, the fibrosis is cancer-associated. In some aspects, the fibrosis is not cancer-associated. In some aspects, the fibrosis is associated with scleroderma, systemic fibrosis, steatohepatitis, or non-alcoholic steatohepatitis (NASH), chronic viral HBV and HCV infection, autoimmune hepatitis, or primary biliary cholangitis. The disclosure further provides any conjugates disclosed herein for use in a method of treatment of the human or animal body by therapy. Therapy may be by any mechanism disclosed herein, such as inhbiting, reducing, or reducing progression of fibrosis or other liver damage. The disclosure further provides any conjugate disclosed herein for prevention or treatment of any condition disclosed herein, for example, fibrosis or cancer. The disclosure also provides any conjugate or pharmaceutical composition thereof disclosed herein for obtaining any clinical outcome disclosed herein for any condition disclosed herein, such as treating fibrosis or cancer. The disclosure also provides use of any conjugate disclosed herein in the manufacture of a medicament for preventing or treating any condition disclosed herein. EXAMPLES The following examples illustrate the various methods of making compounds described herein. The examples are included to further describe some embodiments of the present disclosure, and should not be used to limit the scope of the disclosure. The following synthetic schemes are provided for purposes of illustration, not limitation. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. 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 synthesized according to sources known to those skilled in the art or prepared as described herein. General Scheme 1 for the Preparation of Exemplary Inhibitors of

Formula (A-I) or (B-I)

In one method, compounds of Formula (A-I), or compounds of Formula (B-I) wherein Q is CH₂N, are prepared according to Scheme 1. Specifically, R²-substituted pyridine-2- carbaldehydes are reacted with aniline and diphenyl phosphite to give N,P-acetal (iv), which can be further coupled with R¹ substituted [1,2,4]triazolo[1,5-a]pyridine-6-carbaldehydes (iii) followed by hydrolysis in acidic condition to produce a monoketone (v). The monoketone (v) may be oxidized to a diketone (vi) with HBr in DMSO. Certain diketone analogs (vi) were commercially available (e.g. R¹ = H and R² = CH³: CAS No. 356560-84-4) and were used as a starting point when appropriate. Diketones (vi) can be condensed with 2,2- dimethoxyacetaldehyde in the presence of ammonium acetate to yield an acetal-protected imidazole (vii), which can be hydrolyzed in acidic condition to produce an imidazole-2- carbaldehyde (viii). The imidazole-2-carbaldehyde (viii) can be reductively aminated in the presence of an amine and a reducing agent such as sodium borohydride or sodium cyanoborohydride to yield a compound of Formula (A-I) or Formula (B-I), where substituents are selected as appropriate. General Scheme 2 for the Preparation of Exemplary ALK5 Inhibitors of Formula (C-I)

In one method, compounds of Formula (C-I) wherein Q³, Q⁴, Q⁵ and Q⁶ are CH are prepared according to Scheme 1. Specifically, R¹-substituted pyridine-2-carbaldehydes are reacted with aniline and diphenyl phosphite to give N,P-acetal (ii), which can be further coupled with R⁷, R⁸ substituted quinoline-6-carbaldehydes (i) followed by hydrolysis in acidic condition to produce a monoketone (iii). The monoketone (iii) may be oxidized to a diketone (iv) with HBr in DMSO. Diketones (iv) can be condensed with aldehydes (v) in the presence of ammonium acetate to yield an imidazole (vi). The protecting group (PG) substituted nitrogen can then be depretoected under appropriate conditions to yield a compound of Formula (C-I). General Scheme 3 for the Preparation of Exemplary ALK5 Inhibitors of Formula (D-I)

In one method, compounds of Formula (I) are prepared according to Scheme 1. Specifically, bromo-substituted pyrazoles (i) are reacted with an aryl- or heteroaryl-boronic acid (or ester) (iii) in the presence of an appropriate transition metal catalyst (e.g. palladium-based) to generate compounds of Formula (I). Alternatively, bromo-substituted pyrazoles can be converted to a boronic ester, or ester, (ii) via a borylation reaction. The resultant compound (ii) can then be coupled with an appropriate aryl- or heteroaryl-halide (or pseudohalide) (iv) to generate compounds of Formula (I). EXAMPLE 1: Synthesis of 1-(5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2- yl)-N-benzylmethanamine (Compound 1)

Step A. Preparation of Int 1a

(Int 1a) To a stirred solution of 1-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(6-methylpyridin-2- yl)ethane-1,2-dione (CAS 356560-84-4; 2.7 g, 10.1 mmol) in a 2:1 mixture of tert-butyl methyl ether and methanol (25 mL) were added 60% 2,2-dimethoxyacetaldehyde in H₂O (3.5 mL, 20 mmol) and NH₄OAc (1.95 g, 25.2 mmol). The mixture was stirred at room temperature for 5 h before the solvent was removed. The pH of the reaction mixture was adjusted to 8 with saturated aqueous NaHCO₃ solution and extracted with CH₂Cl₂ (2 × 10 mL). The combined organic extracts were washed with brine (10 mL) and dried over anhydrous Na₂SO₄, filtered, and evaporated. The residue was purified on silica gel (ISCO gold, 40 g; 0% to 20% CH₂Cl₂/MeOH over 15 min) to give the desired imidazole product, which was dissolved in 1 N HCl (20 mL) and heated at 70°C for 4 h. The reaction mixture was allowed to cool to 0°C and then it was neutralized with saturated aqueous NaHCO₃ solution. The precipitate was collected and washed with water (20 mL) and ether (40 mL) to give Int 1a as a yellow-brown solid. ¹H NMR (DMSO- d⁶) δ 10.0 (dd, J=1.6, 0.8 Hz, 1H), 9.56 (s, 1H), 8.42 (s, 1H), 8.27 (dd, J=9.2, 1.6Hz, 1H), 7.82 (br d, J = 0.8 Hz, 1H), 7.72 (dd, J = 9.2, 0.8Hz, 1H), 7.65 (t, J=7.8Hz, 1H), 7.05 (d, J=7.6Hz, 1H), 2.46 (s, 3H). LCMS (M+H) = 305.1. Step B. Preparation of Compound 1

To a solution of 4-(6-methyl-2-pyridyl)-5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H- imidazole-2-carbaldehyde (200 mg, 0.66 mmol) in dichloroethane (30 mL) was added acetic acid (79 mg, 1.3 mmol, 75 μL) and phenylmethanamine (106 mg, 0.99 mmol). The mixture was stirred at 60°C for 2 h then cooled to 0°C. Methanol (20 mL) and THF (10 mL) were added followed by NaBH₃CN (165 mg, 2.63 mmol, 4.0 eq) and then the reaction mixture was allowed to warm to 15°C and stirred for an additional 3 h, at which time LCMS showed the reaction to be complete. The reaction mixture was quenched by addition of water (0.10 mL) at 0°C and was then concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (0 Æ 10% MeOH in DCM) to afford 240 mg of 1-(5-([1,2,4]triazolo[1,5- a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)-N-benzylmethanamine as an off- white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 9.54 (s, 1H), 8.55 (s, 1H), 7.99-7.96 (m, 1H), 7.92-7.88 (m, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.58-7.53 (m, 3H), 7.49-7.41 (m, 3H), 7.26 (d, J = 7.7 Hz, 1H), 4.37 (d, J = 12.8 Hz, 4H), 2.52 (s, 3H). LCMS M/z 396.1 [M+H]⁺. EXAMPLE 2: Synthesis of 6-(4-(6-methylpyridin-2-yl)-2-(piperidin-4-yl)-1H-imidazol-5-yl)- [ ound 1.47)

Step A. Preparation of Int. 1.47a

To a solution of 1-(6-methyl-2-pyridyl)-2-([1,2,4]triazolo[1,5-a]pyridin-6-yl) ethane-1,2- dione (0.2 g, 751.16 umol, 1 eq) and tert-butyl 4-formylpiperidine-1-carboxylate (160.20 mg, 751.16 umol, 1 eq) in MTBE (5 mL) and MeOH (10 mL) was added NH₄OAc (289.51 mg, 3.76 mmol, 5 eq). The mixture was stirred at 25°C for 4 h. The reaction mixture was quenched by addition of H₂O (20 mL), and was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give tert-butyl 4-(5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin- 2-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (0.3 g, crude) was obtained as a yellow solid. Step B. Preparation of Compound 1.47

To a solution of tert-butyl 4-[4-(6-methyl-2-pyridyl)-5-([1,2,4]triazolo[1,5-a]pyridin-6- yl) -1H-imidazol-2-yl]piperidine-1-carboxylate (Int.1.47a) (0.3 g, 652.82 umol, 1 eq) in DCM (10 mL) was added HCl/EtOAc (4 M, 326.41 uL, 2 eq). The mixture was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Nano-micro Kromasil C18100*30mm 5um; mobile phase: [water (0.1%TFA) -ACN]; B%: 1%-20%, 10 min) and freeze-drying. Compound 6-[4-(6- methyl-2-pyridyl)-2-(4-piperidyl)-1H-imidazol-5-yl]-[1,2,4]triazolo[1,5-a]pyridine (Compound 1.47) (0.17 g, 359.07 umol, 55.00% yield, TFA) was obtained as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 9.44 (s, 1H), 8.94 (s, 1H), 8.65 (d, J = 6.0 Hz, 1H), 8.60 (s, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.87-7.80 (m, 3H), 7.52-7.47 (m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 3.86 (s, 1H), 3.46 (d, J = 12.4 Hz, 2H), 3.41-3.33 (m, 1H), 3.17-3.04 (m, 2H), 2.56-2.53 (m, 3H), 2.27 ( d, J = 12.4 Hz, 2H), 2.11-2.00 (m, 2H); HPLC: 96.356% (220 nm), 98.486% (254 nm); MS (ESI): mass calcd. for C₂₀H₂₁N₇359.19, m/z found 360.0[M+H]⁺. The compounds in Tables 14 and 15 were prepared in a manner similar to that described for Compounds 1 or 1.47 using the appropriately substituted amine. TABLE 14

TABLE 15

EXAMPLE 3 Preparation of ALK5 Inhibitors of Formula (C-I) Synthesis of tert-butyl (2-((6-(2-(6-methylpyridin-2-yl)-2-oxoacetyl)quinolin-3-yl)oxy)ethyl) carbamate (Compound A1)

Step 1: Preparation of 6-bromo-3-hydroxy-quinoline-4-carboxylic acid (Compound A1-b)

To a solution of KOH (40.3 g, 718 mmol, 8.0 equiv) in H₂O (400 mL) was added 5- bromoindoline-2,3-dione (A1-a) (20.3 g, 89.8 mmol, 1.0 equiv) at 20°C under N₂. The mixture was stirred at 50°C for 1.5 hours, then 3-bromo-2-oxo-propanoic acid (15.0 g, 89.8 mmol, 1.0 equiv) was added and it was stirred at 25°C for 90 hours. The reaction mixture was quenched with aq HCl (4 M) at 0°C until pH = 4, desired solid was precipitated and filtered to afford 6- bromo-3-hydroxy-quinoline-4-carboxylic acid (A1-b) (21.0 g, 78.3 mmol, 87.2% yield) as a brown solid. 1H NMR (DMSO-d₆, 400 MHz) δ8.69 (s, 1H), 8.54 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H) Step 2: Preparation of 6-bromoquinolin-3-ol (Compound A1-c)

A solution of 6-bromo-3-hydroxy-quinoline-4-carboxylic acid (A1-b) (15.0 g, 56.0 mmol, 1.0 equiv) in nitrobenzene (150 mL) was heated to 180°C and then stirred for 6 hours at this temperature. The reaction mixture was cooled to 0 °C and methyl tert-butyl ether (300 mL) was added, desired solid was precipitated and then filtered to afford 6-bromoquinolin-3-ol (A1-c) (7.0 g, 31.2 mmol, 55.8% yield) as brown solid. 1H NMR (DMSO-d₆, 400 MHz) δ8.57 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 1.2 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.53 (dd, J = 2.0, 9.2 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H) Step 3: Preparation 2-[(6-bromo-3-quinolyl)oxy]ethyl]carbamate

(Compound A1-d)

To a mixture of 6-bromoquinolin-3-ol (A1-c) (1.00 g, 4.46 mmol, 1.0 equiv) and tert- butyl N-(2-bromoethyl)carbamate (5.00 g, 22.3 mmol, 5.0 equiv) in DMF (30 mL) was added KI (741 mg, 4.46 mmol, 1.0 equiv) and K₂CO₃ (1.85 g, 13.4 mmol, 3.0 equiv) at 25°C under N₂. The mixture was stirred at 45 °C for 10 hours. Water (70 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (40 mL x 2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=10/1, 1/1) to afford tert-butyl N-[2-[(6-bromo-3-quinolyl)oxy]ethyl]carbamate (A1-d) (700 mg, 1.91 mmol, 42.7% yield) as brown solid. 1H NMR (400 MHz, DMSO-d₆) δ8.60 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 2.4, 8.8 Hz, 1H), 7.05 (br t, J = 5.6 Hz, 1H), 4.08 (t, J = 5.6 Hz, 2H), 3.34 (q, J = 5.6 Hz, 2H), 1.33 (s, 9H) Step 4: Preparation o butyl N-[2-[(6-formyl-3-quinolyl)oxy]ethyl]carbamate

(Compound A1-e)

To a solution of tert-butyl N-[2-[(6-bromo-3-quinolyl)oxy]ethyl]carbamate (A1-d) (1.80 g, 4.90 mmol, 1.0 equiv) in DMF (30 mL) was added Pd(dppf)Cl₂ (357 mg, 490 umol, 0.1 equiv), Et₃N (1.49 g, 14.7 mmol, 2.05 mL, 3.0 equiv) and Et₃SiH (11.4 g, 98.0 mmol, 15.7 mL, 20.0 equiv) under N₂. The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50 psi) at 80°C for 15 hours. Water (70 mL) was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate = 10/1, 1/1) to afford tert-butyl N-[2-[(6-formyl-3-quinolyl) oxy]ethyl]carbamate (A1-e) (800 mg, 2.53 mmol, 51.6% yield) as yellow solid. 1H NMR (CDCl₃, 400 MHz) δ10.13 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 4.18-4.13 (m, 2H), 3.62-3.58 (m, 2H), 1.41 (s, 9H) Step 5: Preparation of tert-butyl N-[2-[[6-[2-(6-methyl-2-pyridyl)-2-oxo-ethyl]-3- quinolyl]oxy]ethyl]carbamate (Compound A1-f)

To a mixture of tert-butyl N-[2-[(6-formyl-3-quinolyl)oxy]ethyl]carbamate (A1-e) (760 mg, 2.40 mmol, 1.0 equiv) and N-[diphenoxyphosphoryl-(6-methyl-2-pyridyl)methyl]aniline (1.03 g, 2.40 mmol, 1.0 equiv) in THF (15 mL) and i-PrOH (5 mL) was added Cs₂CO₃ (783 mg, 2.40 mmol, 1.0 equiv) at 25°C under N₂ and then stirred at 25°C for 2 hours. The reaction mixture was quenched with aq HCl (4 M) at 0°C until pH = 4 and then stirred for another 2 hours. Water (20 mL) was added and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate = 10/1, 1/1) to afford tert-butyl N-[2-[[6-[2-(6-methyl-2-pyridyl)- 2-oxo-ethyl]-3-quinolyl]oxy]ethyl] carbamate (A1-f) (0.45 g, 1.07 mmol, 44.4% yield) as yellow oil. Step 6: Preparation of tert-butyl N-[2-[[6-[2-(6-methyl-2-pyridyl)-2-oxo-acetyl]-3- quinolyl]oxy]ethyl]carbamate (Compound A1)

To a solution of tert-butyl N-[2-[[6-[2-(6-methyl-2-pyridyl)-2-oxo-ethyl]-3-quinolyl]oxy] ethyl]carbamate (A1-f) (450 mg, 1.07 mmol, 1.0 equiv) in MeCN (15 mL) was added Pd/C (518 mg, 5% purity, 0.2 equiv) under N₂. The suspension was degassed under vacuum and purged with O2 several times. The mixture was stirred under O2 (15 psi) at 80°C for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuum to afford tert-butyl N-[2-[[6-[2- (6-methyl-2-pyridyl)-2-oxo-acetyl]-3-quinolyl]oxy]ethyl]carbamate (Compound A1) (390 mg, 896 umol, 83.9% yield) as yellow oil. 1H NMR (CDCl₃, 400 MHz) δ8.75 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 8.15-8.07 (m, 2H), 8.02 (d, J = 7.6 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 5.01 (s, 1H), 4.12 (t, J = 5.2 Hz, 2H), 3.59 (q, J = 5.2 Hz, 2H), 2.44 (s, 3H), 1.42 (s, 9H)

Synthesis of tert-butyl (2-((7-(2-(6-methylpyridin-2-yl)-2-oxoacetyl)quinoxalin-2-yl) ethyl)

carbamate (Compound A2)

Step 1: Preparation 2-(7-bromoquinoxalin-2-yl)oxyethyl]carbamate

(Compound A2-b)

To a mixture of 7-bromo-2-chloro-quinoxaline (A2-a) (2 g, 8.21 mmol, 1.0 equiv) and tert-butyl N-(2-hydroxyethyl)carbamate (1.99 g, 12 mmol, 1.9 mL, 1.5 equiv) in DMF (20 mL) was added K₂CO₃ (1.70 g, 12 mmol, 1.5 equiv), and then stirred at 80°C for 12 h. The reaction mixture was quenched by addition H2O (20 mL) at 20°C, and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 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 compound tert-butyl N- [2-(7-bromoquinoxalin-2-yl)oxyethyl]carbamate (A2-b) (2.5 g, 7 mmol, 82.66% yield) as a yellow solid. 1H NMR (CDCl₃, 400MHz) δ8.45 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.64 (dd, J = 2.4, 8.8 Hz, 1H), 4.53 (t, J = 5.2 Hz, 2H), 3.65-3.60 (m, 2H), 1.44 (s, 9H) Step 2: Preparation of tert-butyl N-[2-(7-formylquinoxalin-2-yl)oxyethyl]carbamate (Compound A2-c)

To a solution of tert-butyl N-[2-(7-bromoquinoxalin-2-yl)oxyethyl]carbamate (A2-b) (2.5 g, 6.79 mmol, 1.0 equiv) in DMF (30 mL) was added Et₃N (2.06 g, 20.4 mmol, 2.83 mL, 3.0 equiv), Et₃SiH (15.8 g, 136 mmol, 21.7 mL, 20.0 equiv), and Pd(dppf)Cl₂ (496 mg, 678 umol, 0.1 equiv), the suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50 psi) at 80°C for 20 hours. The reaction mixture was quenched by addition H₂O (50 mL) at 20°C, and then extracted with EtOAc (30 mL x 3). The combined organic layers were 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=10/1 to 3/1) to give compound tert-butyl N-[2-(7- formylquinoxalin-2-yl)oxyethyl]carbamate (A2-c) (1 g, 3 mmol, 46.41% yield) as a yellow solid. 1H NMR (CDCl₃, 400MHz) δ10.22 (s, 1H), 8.59 (s, 1H), 8.32 (d, J = 1.6 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 5.00 (s, 1H), 4.60 (t, J = 5.2 Hz, 2H), 3.68-3.62 (m, 2H), 1.46 (s, 9H) Step 3: Preparation of tert-butyl N-[2-[7-[2-(6-methyl-2-pyridyl)-2-oxo-ethyl]quinoxalin- 2-yl]oxyethyl]carbamate (Compound A2-d) To a mixture of tert-butyl N-[2-(7-formylquinoxalin-2-yl)oxyethyl]carbamate (A2-c) (1 g, 3.15 mmol, 1.0 equiv) and N-[diphenoxyphosphoryl-(6-methyl-2-pyridyl)methyl]aniline (2.03 g, 4.73 mmol, 1.5 equiv) in THF (10 mL) and i-PrOH (4 mL) was added Cs₂CO₃ (1.54 g, 4.73 mmol, 1.5 equiv) at 20°C, and then stirred at 35°C for 6 h, the pH of the mixture was adjusted to pH~3 with 2N HCl at 0°C, and it was stirred at 20°C for another 2 h. The reaction mixture was poured into H₂O (20 mL), and then the pH of the mixture was adjusted to ~8 by adding aq. NaHCO₃, extracted with EtOAc (20 mL) for twice. The organic lawyers were washed with brine (20 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=10/1 to 3/1) to give compound tert-butyl N-[2-[7-[2-(6-methyl-2-pyridyl)-2-oxo-ethyl]quinoxalin-2- yl]oxyethyl]carbamate (A2-d) (1.5 g, crude) as a yellow solid. 1H NMR (MeOD, 400MHz) δ8.39 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.85-7.82 (m, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 1.2 Hz, 1H), 7.56 (dd, J = 1.6, 8.4 Hz, 1H), 7.45 (dd, J = 1.2, 7.2 Hz, 1H), 4.73 (s, 2H), 4.52 (t, J = 5.2 Hz, 2H), 3.53 (t, J = 5.2 Hz, 2H), 2.66 (s, 3H), 1.42 (s, 9H)

Step 3: Preparation of tert-butyl N-[2-[7-[2-(6-methyl-2-pyridyl)-2-oxo-acetyl] quinoxalin-2-yl]oxyethyl]carbamate (Compound A2)

To a solution of tert-butyl N-[2-[7-[2-(6-methyl-2-pyridyl)-2-oxo-ethyl]quinoxalin-2-yl] oxyethyl]carbamate (A2-d) (1.5 g, 3.55 mmol, 1.0 equiv) in MeCN (20 mL) was added Pd/C (0.5 g, 10% purity) at 20°C, the suspension was degassed under vacuum and purged with O₂ several times. The mixture was stirred under O₂ (15psi) at 80°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 2/1) to give compound tert-butyl N-[2-[7-[2-(6-methyl-2-pyridyl)-2-oxo-acetyl]quinoxalin-2- yl]oxyethyl]carbamate (Compound A2) (0.94 g, 2.15 mmol, 60.66% yield) as a yellow solid. 1H NMR (CDCl₃, 400MHz) δ8.57 (s, 1H), 8.27 (d, J = 1.2 Hz, 1H), 8.21-8.18 (m, 1H), 8.17-8.13 (m, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 4.54 (t, J = 5.2 Hz, 2H), 3.61 (d, J = 5.2 Hz, 2H), 2.48 (s, 3H), 1.44 (s, 9H) ALK5 INHIBITORS OF FORMULA (C-I)—SYNTHETIC METHOD A Synthesis of N-[[5-[3-(2-aminoethoxy)-6-quinolyl]-4-(6-methyl-2-pyridyl)-1H-imidazol-2- yl] methyl]-2-fluoro-aniline (Compound C1.1)

Synthetic Scheme

Step 1: Preparation of tert-butyl N-(2-fluorophenyl)carbamate (Compound C1.1-b)

To a solution of 2-fluoroaniline (C1.1-a) (25 g, 225 mmol, 1.0 equiv) in THF (300 mL) was added Boc₂O (73.6 g, 337 mmol, 77.5 mL, 1.5 equiv) at 25°C, and then stirred at 80°C for 12h. The reaction mixture was concentrated under reduced pressure to give tert-butyl N-(2- fluorophenyl) carbamate (C1.1-b) (47 g, 223 mmol, 98.90% yield) as colorless oil. 1H NMR (DMSO-d₆, 400MHz) δ8.98 (s, 1H), 7.68-7.60 (m, 1H), 7.27-7.10 (m, 3H), 1.50 (s, 9H) Step 2: Preparation of tert-butyl N-allyl-N-(2-fluorophenyl)carbamate (Compound C1.1-c)

To a mixture of tert-butyl N-(2-fluorophenyl)carbamate (C1.1-b) (10 g, 47 mmol, 1.0 equiv) in DMF (100 mL) was added NaH (2.84 g, 71 mmol, 60% purity, 1.5 equiv) slowly at 0°C, the mixture was stirred 10 min at 0°C, then 3-bromoprop-1-ene (8.59 g, 71 mmol, 1.5 equiv) was added, and it was stirred at 20°C for 2 h. The reaction mixture was poured into H₂O (100 mL), extracted with EtOAc (100 mL) for twice. The organic lawyers 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 1/0) to give compound tert-butyl N-allyl-N-(2-fluorophenyl)carbamate (C1.1-c) (10.3 g, 41 mmol, 86.58% yield) as a colorless liquid. 1H NMR (DMSO-d₆,400 MHz) δ7.35-7.10 (m, 4H), 5.86-5.72 (m, 1H), 5.14-5.02 (m, 2H), 4.14 (d, J = 5.6 Hz, 2H), 1.38-1.31 (m, 9H) Step 3: Preparation of tert-butyl N-(2-fluorophenyl)-N-(2-oxoethyl)carbamate (Compound C1.1-d)

To a mixture of tert-butyl N-allyl-N-(2-fluorophenyl)carbamate (1.1-c) (10.3 g, 41.0 mmol, 1.0 equiv) in THF (100 mL) and H₂O (100 mL) was added K₂OsO₄ ^.2H₂O (453 mg, 1 mmol, 0.03 equiv) and NaIO₄ (43.8 g, 205 mmol, 5.0 equiv) at 20°C, and then stirred at 35°C for 5h. The reaction mixture was filtered and the filtrate was poured into H₂O (100 mL), extracted with EtOAc(100 mL) for twice. The organic lawyers were washed with brine (50 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 9/1) to give compound tert-butyl N-(2-fluorophenyl)-N -(2-oxoethyl)carbamate (1.1-d) (4.26 g, 17 mmol, 41.04% yield) as a brown oil. 1H NMR (CDCl₃, 400 MHz) δ9.71 (s, 1H), 7.34-7.17 (m, 2H), 7.12 (d, J = 8.8 Hz, 2H), 4.28-4.16 (m, 2H), 1.40 (d, J = 6.4 Hz, 9H) Step 4: Preparation of tert-butyl N-[[5-[3-[2-(tert-butoxycarbonylamino)ethoxy]-6- quinolyl]-4-(6-methyl-2-pyridyl)-1H-imidazol-2-yl] methyl]-N-(2-fluorophenyl) carbamate (Compound C1.1-e)

To a mixture of tert-butyl N-[2-[[6-[2-(6-methyl-2-pyridyl)-2-oxo-acetyl]-3- quinolyl]oxy] ethyl]carbamate (A1) (100 mg, 223 umol, 1.0 equiv) and tert-butyl N-(2- fluorophenyl)-N-(2-oxoethyl)carbamate (1.1-d) (87.0 mg, 344 umol, 1.5 equiv) in THF (5 mL) was added NH₄OAc (89 mg, 1.15 mmol, 5 equiv), and then stirred at 35°C for 12 hr. The reaction mixture was quenched by addition of H₂O ^10 mL ^at 20°C, and then extracted with EtOAc (10 mL). The combined organic layers were 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=10/1 to 1/1) to give compound tert-butyl N-[[5-[3-[2-(tert-butoxycarbonylamino)ethoxy]-6-quinolyl]-4-(6-methyl-2- pyridyl)-1H-imidazol-2-yl]methyl]-N-(2-fluorophenyl)carbamate (1.1-e) (127 mg, 190 umol, 82.7% yield) as a white solid. 1H NMR (MeOD, 400MHz) δ8.59 (d, J = 2.8 Hz, 1H), 7.97 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 2.8 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J = 6.4 Hz, 1H), 7.20-7.11 (m, 4H), 6.95 (s, 1H), 4.94 (s, 2H), 4.19 (t, J = 5.2 Hz, 2H), 3.52 (q, J = 5.2 Hz, 2H), 2.50 (s, 3H), 1.44 (s, 18H) Step 5: Preparation of N-[[5-[3-(2-aminoethoxy)-6-quinolyl]-4-(6-methyl-2-pyridyl)-1H- imidazol-2-yl] methyl]-2-fluoro-aniline (Compound C1.1)

To a mixture of tert-butyl N-[[5-[3-[2-(tert-butoxycarbonylamino)ethoxy]-6-quinolyl]-4- (6- methyl-2-pyridyl)-1H-imidazol-2-yl]methyl]-N-(2-fluorophenyl)carbamate (0.127 g, 189.91 umol, 1 equiv) in EtOAc (2 mL) was added HCl/EtOAc (4M, 5 mL) and then stirred at 20°C for 30 min. The reaction mixture was concentrated under reduced pressure to give N-[[5-[3-(2- aminoethoxy)-6-quinolyl]-4-(6-methyl-2-pyridyl)-1H-imidazol-2-yl]methyl]-2-fluoro-aniline (Compound C1.1) (80.0 mg, 146 umol, 77.0% yield, 92.3% purity, HCl) as a yellow solid. 1H NMR (MeOD, 400 MHz) δ9.22 (d, J = 2.4 Hz, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 9.2 Hz, 1H), 8.16-8.02 (m, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.10-7.00 (m, 2H), 6.91-6.83 (m, 1H), 6.80-6.71 (m, 1H), 4.89 (s, 2H), 4.65 (t, J = 4.8 Hz, 2H), 3.54 (t, J = 4.4 Hz, 2H), 2.76 (s, 3H) HPLC: 92.30% (220 nm), 95.72% (254 nm) MS (ESI): mass calcd. For C₂₇H₂₅FN₆O 468.21, m/z found 469.2[M+H]⁺

Synthesis of N-[[5-[3-(2-aminoethoxy)-6-quinolyl]-4-(6-methyl-2-pyridyl)-1H-imidazol-2- yl] methyl]-2-fluoro-aniline (Compound C1.2)

Step 1: Preparation of tert-butyl N-[[5-[3-[2-(tert-butoxycarbonylamino)ethoxy] quinoxalin-6-yl]-4-(6-methyl-2-pyridyl)-1H-imidazol-2-yl]methyl]-N-(2-fluorophenyl) carbamate (Compound C1.2-a)

To a mixture of tert-butyl N-[2-[7-[2-(6-methyl-2-pyridyl)-2-oxo-acetyl]quinoxalin-2-yl] oxyethyl]carbamate (A2) (300 mg, 687 umol, 1.0 equiv) and tert-butyl N-(2-fluorophenyl)-N-(2- oxoethyl)carbamate (C1.1-d) (261 mg, 1.03 mmol, 1.5 equiv) in THF (5 mL) was added NH₄OAc (265 mg, 3.44 mmol, 5.0 equiv), and then stirred at 35°C for 12 h. The reaction mixture was quenched by addition H₂O (10 mL) at 20 °C, and then extracted with EtOAc (10 mL x 3). The combined organic layers were 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=10/1 to 1/1) to give compound tert-butyl N-[[5-[3-[2-(tert-butoxycarbonylamino) ethoxy]quinoxalin-6-yl]-4-(6-methyl-2- pyridyl)-1H-imidazol-2-yl]methyl]-N-(2-fluorophenyl)carbamate (C1.2-a) (300 mg, 448 umol, 65.17% yield) as a yellow solid. 1H NMR (MeOD, 400MHz) δ8.44 (s, 1H), 7.97 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.34-7.28 (m, 3H), 7.21-7.13 (m, 3H), 4.95 (s, 2H), 4.51 (t, J = 5.2 Hz, 2H), 3.51 (t, J = 5.6 Hz, 2H), 2.51 (s, 3H), 1.41 (s, 18H) Step 2: Preparation of tert-butyl N-[[5-[3-[2-(tert-butoxycarbonylamino)ethoxy] quinoxalin-6-yl]-4-(6-methyl-2-pyridyl)-1H-imidazol-2-yl]methyl]-N-(2-fluorophenyl) carbamate (Compound C1.2)

To a mixture of tert-butyl N-[[5-[3-[2- (tert-butoxycarbonylamino)ethoxy]quinoxalin-6- yl]-4-(6-methyl-2-pyridyl)-1H-imidazol-2-yl]methyl]-N-(2-fluorophenyl)carbamate (C1.2-a) (300 mg, 448 umol, 1.0 equiv) in EtOAc (5 mL) was added HCl/EtOAc (4 M 10 mL), and then stirred at 20°C for 1h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC(column: YMC-Actus Triart C18100 x 30mm x 5um;mobile phase: [water(0.04%HCl)-ACN];B%: 10%-40%,7min) to give compound N-[[5-[3-(2-aminoethoxy)quinoxalin-6-yl]-4-(6-methyl-2-pyridyl)-1H-imidazol-2- yl]methyl]-2-fluoro-aniline (Compound C1.2) (101 mg, 164 umol, 36.64% yield, 4HCl) as a yellow solid. 1H NMR (MeOD, 400MHz) δ8.66 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.75 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.09-7.01 (m, 2H), 6.84 (t, J = 8.4 Hz, 1H), 6.79-6.73 (m, 1H), 4.86 (s, 2H), 4.78-4.74 (m, 2H), 3.48 (t, J = 4.8 Hz, 2H), 2.74 (s, 3H) HPLC: 96.99% (220 nm), 96.53% (254 nm) MS (ESI): mass calcd. For C₂₆H₂₄FN₇O 469.20, m/z found 470.1 [M+H]⁺. Compounds C1.3-C1.66, as illustrated in Table 16, could be prepared in a manner similar to that described for Compound 1.1 and Compound 1.2 using appropriate intermediates according to Method A as described herein. TABLE 16 COMPOUND C1.3–C1.66

ALK5 INHIBITORS OF FORMULA (C-I)—SYNTHETIC METHOD B Synthesis of 2-[7-[2- [2-(2- fluorophenyl) ethyl]-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl] quinoxalin-2-yl]oxyethanamine (Compound C2.1) METHOD B

Step 1: Preparation of tert- 2-[7-[2-[2-(2-fluorophenyl)ethyl]-4-(6-methyl-2-

imidazol-5-yl]quinoxalin-2-yl]oxyethyl]carbamate (Compound C2.1-a)

To a mixture of tert-butyl N-[2-[7-[2-(6-methyl-2-pyridyl)-2-oxo-acetyl]quinoxalin-2-yl] oxyethyl]carbamate (A2) (0.15 g, 343 umol, 1.0 equiv) and 3-(2-fluorophenyl)propanal (104 mg, 687 umol, 2.0 equiv) in THF (20 mL) was added NH₄OAc (132 mg, 1.72 mmol, 5.0 equiv) at 25°C and then stirred at 35°C for 12 hours. The mixture was added water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=30/1 to 0:1). Compound tert- butyl N-[2-[7- [2-[2-(2-fluorophenyl)ethyl]-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl] quinoxalin-2-yl]oxyethyl]carbamate (C2.1-a) (0.14 g, 246 umol, 71.64% yield) was obtained as a yellow solid. Step 2: Preparation of tert-butyl N-[2-[7-[2-[2-(2-fluorophenyl)ethyl]-4-(6-methyl-2- pyridyl)-1H-imidazol-5-yl]quinoxalin-2-yl]oxyethyl]carbamate (Compound C2.1)

A solution of tert-butyl N-[2- [7-[2- [2-(2- fluorophenyl) ethyl]-4- (6-methyl-2-pyridyl)- 1H-imidazol-5-yl] quinoxalin-2-yl] oxyethyl] carbamate (C2.1-a) (0.14 g, 246 umol, 1 equiv) in HCl/EtOAc (4 M, 20 mL) was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure at 45°C. Compound 2-[7-[2-[2-(2-fluorophenyl) ethyl]-4-(6-methyl-2-pyridyl)- 1H-imidazol-5-yl]quinoxalin-2-yl]oxyethanamine (Compound C2.1) (90 mg, 182 umol, 73.78% yield, 94.56% purity) was obtained as a yellow solid. 1H NMR (MeOD, 400 MHz) δ8.68 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.10 (d, J = 1.8 Hz, 1H), 7.82-7.70 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.36-7.25 (m, 3H), 7.21-7.07 (m, 2H), 4.78 (t, J = 5.2 Hz, 2H), 3.49-3.51 (m, 2H), 3.39-3.41 (m, 2H), 3.34-3.32 (m, 2H), 2.65 (s, 3H) HPLC: 94.56% (220 nm), 96.23% (254 nm) LCMS (ESI): mass calcd. for C₂₇H₂₅N₆OF 468.21, m/z found 469.1 [M+H]+. Compound C2.2, as illustrated in Table 17, could be prepared in a manner similar to that described for Compound C2.1 using appropriate intermediates according to Method B as described herein. TABLE 17 COMPOUND C2.2

ALK5 INHIBITORS OF FORMULA (C-1)—SYNTHETIC METHOD C Synthesis of 2-[7-[2- fluorophenoxy)methyl]-4-(6-methyl-2-pyridyl)- midazol -5-yl]

quinoxalin-2-yl]oxyethanamine (Compound C3.1) METHOD C

Synthetic Scheme

Step 1: Preparation of 1-(2,2-diethoxyethoxy)-2-fluoro-benzene (Compound

To a mixture of 2-fluorophenol (C3.1-a) (3 g, 26.7 mmol, 2.48 mL, 1.0 equiv) and 2- bromo-1,1-diethoxy-ethane (6.33 g, 32.1 mmol, 4.8 mL, 1.2 equiv) in DMF (20 mL) was added K₂CO₃ (5.55 g, 40.1 mmol, 1.5 equiv) at 25°C, and then stirred at 100°C for 12h. The reaction mixture was quenched by addition H₂O (40 mL) at 20°C, and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 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=10/1 to 3/1) to give compound 1-(2,2- diethoxyethoxy)-2-fluoro-benzene (C3.1-b) (3.2 g, 14.0 mmol, 52.39% yield) as a yellow oil. 1H NMR (CDCl₃, 400MHz) δ7.10-6.97 (m, 3H), 6.94-6.87 (m, 1H), 4.85 (t, J = 5.2 Hz, 1H), 4.07 (d, J = 5.2 Hz, 2H), 3.83-3.73 (m, 2H), 3.70-3.62 (m, 2H), 1.27-1.24 (m, 6H) Step 2: Preparation of 2-(2-fluorophenoxy) acetaldehyde (Compound 3.1-c)

To a mixture of 1-(2, 2-diethoxyethoxy)-2-fluoro-benzene (C3.1-b) (1.40 g, 6.13 mmol, 1.0 equiv) in THF (20 mL) and H₂O (15 mL) was added HCl (12 M, 14.9 mL, 29.2 equiv), and then stirred at 20°C for 12 hr. The reaction mixture was quenched by addition of H₂O (20 mL), diluted with aqueous of NaHCO₃ (1 M) until pH to between 8 and 9. The reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 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=10/1 to 3/1) to give compound 2-(2-fluorophenoxy) acetaldehyde (C3.1-c) (700 mg, 4.54 mmol, 74.0% yield) as yellow oil. 1H NMR (CDCl₃, 400 MHz) δ9.95-9.86 (m, 1H), 7.18-6.89 (m, 4H), 4.65 (d, J = 0.8 Hz, 2H)

Step 3: Preparation of tert-butyl N-[2-[7-[2-[(2-fluorophenoxy)methyl]-4-(6-methyl-2- pyridyl)-1H-imidazol-5-yl]quinoxalin-2-yl]oxyethyl]carbamate (Compound 3.1-d)

To a mixture of tert-butyl N-[2-[7-[2-(6-methyl-2-pyridyl)-2-oxo-acetyl]quinoxalin-2- yl]oxyethyl]carbamate (A2) (150 mg, 343 umol, 1.0 equiv) and 2-(2- fluorophenoxy)acetaldehyde (3.1-c) (79 mg, 515 umol, 1.5 equiv) in THF (3 mL) was added NH₄OAc (132 mg, 1.72 mmol, 5.0 equiv), and then stirred at 35°C for 12h. The reaction mixture was quenched by addition H₂O (10 mL) at 20°C, and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC(column: Phenomenex Luna C18200 x 40mm x 10um;mobile phase: [water(0.1%TFA)-ACN];B%: 18%-48%,8min) to give compound tert-butyl N-[2-[7-[2-[(2- fluorophenoxy)methyl]-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl]quinoxalin-2-yl]oxyethyl] carbamate (C3.1-d) (150 mg, 146 umol, 42.51% yield, TFA salt) as a yellow solid. 1H NMR (MeOD, 400MHz) δ8.57 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 8.03 (t, J = 8.0 Hz, 1H), 7.75 (dd, J = 2.0, 8.4 Hz, 1H), 7.56 (dd, J = 8.0, 12.4 Hz, 2H), 7.31 (t, J = 8.4 Hz, 1H), 7.21-7.13 (m, 2H), 7.07-7.00 (m, 1H), 5.41 (s, 2H), 4.53 (t, J = 5.2 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 2.78 (s, 3H), 1.42 (s, 9H)

Step 4: Preparation of 2-[7-[2-[(2-fluorophenoxy)methyl]-4-(6-methyl-2-pyridyl)-1H- imidazol -5-yl]quinoxalin-2-yl]oxyethanamine (Compound C3.1)

A mixture of tert-butyl N-[2-[7-[2-[(2-fluorophenoxy)methyl]-4-(6-methyl-2-pyridyl)- 1H-imidazol-5-yl]quinoxalin-2-yl]oxyethyl]carbamate (C3.1-d) (150 mg, 263 umol, 1.0 equiv) in HCl/EtOAc (4 M, 10 mL) was stirred at 20°C for 1h. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 2-[7-[2-[(2- fluorophenoxy) methyl]-4-(6- methyl-2-pyridyl)-1H-imidazol -5-yl]quinoxalin-2-yl] oxyethanamine (Compound C3.1) (74 mg, 120 umol, 45.67% yield, HCl salt) was obtained as a yellow solid. 1H NMR (MeOD, 400MHz) δ8.67 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 8.10 (t, J = 8.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.36-7.31 (m, 1H), 7.21-7.14 (m, 2H), 7.09-7.02 (m, 1H), 5.45 (s, 2H), 4.80-4.75 (m, 2H), 3.52- 3.46(m, 2H), 2.80 (s, 3H) HPLC: 94.71% (220 nm), 96.21% (254 nm) MS (ESI): mass calcd. For C₂₆H₂₃FN₆O₂470.19, m/z found 471.1 [M+H]⁺. Compounds C3.2 and C3.3, as illustrated in Table 18, could be prepared in a manner similar to that described for Compound C3.1 using appropriate intermediates according to Method C as described herein.

TABLE 18 COMPOUNDS C3.2–C3.3

ALK5 INHIBITORS OF FORMULA (C-1)—SYNTHETIC METHOD D Synthesis of N-[[5-[3-(2-aminoethoxy)quinoxalin-6-yl]-4-(6-methyl-2-pyridyl)-1H-imidazol -2- yl]methyl]-5-fluoro-pyridin-2-amine (Compound C4.1)

Step 1: Preparation of tert-butyl N-[2-[7- [2-(dimethoxymethyl)- 4-(6-methyl-2-pyridyl)- 1H-imidazol-5-yl]quinoxalin-2-yl]oxyethyl]carbamate (Compound C4.1-a)

To a mixture of tert-butyl N-[2-[7-[2-(6-methyl-2-pyridyl)-2-oxo-acetyl]quinoxalin-2-yl] oxyethyl]carbamate (A2) (2 g, 4.58 mmol, 1.0 eq) and 2,2-dimethoxyacetaldehyde (954 mg, 9.16 mmol, 830 uL, 2.0 eq) in THF (20 mL) was added NH₄OAc (1.77 g, 22.9 mmol, 5.0 eq), and then stirred at 35 °C for 12h. The reaction mixture was poured into ice-water (20 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=2/1 to 1/1) to give compound tert-butyl N-[2-[7- [2- (dimethoxymethyl)-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl]quinoxalin-2- yl]oxyethyl]carbamate (C4.1-a) (1.8 g, 3.46 mmol, 75.46% yield) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ8.47 (s, 1H), 8.16 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.46-7.42 (m, 1H), 7.38-7.31 (m, 1H), 7.02 (d, J = 7.6 Hz, 1H), 5.61 (s, 1H), 5.01 (s, 1H), 4.54 (t, J = 5.2 Hz, 2H), 3.65-3.60 (m, 2H), 3.50 (s, 6H), 2.60 (s, 3H), 1.46 (s, 9H) Step 2: Preparation of 5-[3- (2-aminoethoxy)quinoxalin-6-yl]-4-(6-methyl-2-pyridyl)- 1H-imidazole-2-carbaldehyde (Compound C4.1-b)

To a solution of tert-butyl N-[2-[7- [2-(dimethoxymethyl)-4-(6-methyl-2-pyridyl)-1H- imidazol-5-yl]quinoxalin-2-yl]oxyethyl]carbamate (C4.1-a) (1.8 g, 3.46 mmol, 1.0 eq) in DCM (20 mL) was added TFA (5.12 mL, 20 eq) dropwise at 25°C and then stirred for 12 hours at this temperature. The mixture was concentrated in vacuum to give 5-(3-(2-aminoethoxy)quinoxalin- 6-yl)-4-(6-methylpyridin-2-yl)-1H-imidazole-2-carbaldehyde (C4.1-b) (1.5 g crude) as yellow oil. Step 3: Preparation of tert-butyl N-[2-[7-[2-formyl-4-(6-methyl-2-pyridyl)-1H-imidazol- 5-yl]quinoxalin-2-yl]oxyethyl]carbamate (Compound C4.1-c)

To a solution of 5-[3-(2-aminoethoxy)quinoxalin-6-yl]-4-(6-methyl-2-pyridyl) -1H- imidazole-2-carbaldehyde (C4.1-b) (1.3 g, 3.47 mmol, 1 eq) in THF (20 mL) was added NaHCO₃ (584 mg, 6.94 mmol, 2 eq) in H₂O (2 mL) and Boc₂O (909 mg, 4.17 mmol, 957 uL, 1.2 eq) at 25°C, and then stirred at 25°C for 1 hour. The mixture was added water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The crude product was triturated with MTBE (20 mL) at 25^oC for 30 min. Compound tert-butyl N-[2-[7- [2- formyl-4- (6-methyl-2-pyridyl)- 1H-imidazol-5-yl]quinoxalin-2-yl]oxyethyl]carbamate (C4.1-c) (1.4 g, 2.95 mmol, 84.97% yield) was obtained as a yellow solid. 1H NMR (CDCl₃,400 MHz) δ9.86 (s, 1H), 8.52 (s, 1H), 8.17 (d, J = 1.2 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.91-7.84 (m, 1H), 7.51-7.45 (m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 4.56 (t, J = 5.2 Hz, 2H), 3.64-3.61 (m, 2H), 2.63 (s, 3H), 1.54 (s, 9H) Step 4: Preparation of tert-butyl N-[2-[7-[2-[[(5-fluoro-2-pyridyl)amino]methyl]-4-(6- methyl-2-pyridyl)-1H-imidazol-5-yl]quinoxalin-2-yl]oxyethyl]carbamate (Compound C4.1-d)

To a solution of tert-butyl N-[2- [7-[2-formyl- 4-(6-methyl- 2-pyridyl)- 1H-imidazol- 5- yl]quinoxalin-2-yl]oxyethyl]carbamate (C4.1-c) (0.13 g, 273 umol, 1.0 eq) and 5-fluoropyridin- 2-amine (92.1 mg, 821 umol, 3.0 eq) in DCE (20 mL) was added AcOH (16.4 mg, 273 umol, 15.6 uL, 1.0 eq) at 25°C and then stirred at 70°C for 12 hours. The mixture was cooled to 0°C, MeOH (2 mL) and NaBH₃CN (25.8 mg, 410 umol, 1.5 eq) were added, and it was stirred at 0°C for 1 hour. The pH of the reaction mixture was adjusted to ~7 with aq NaHCO_3, and then extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18100 x 40mm x 5 um; mobile phase: [water (0.1%TFA)-ACN]; B%: 25%-38%, 8 min). Compound tert-butyl N-[2-[7-[2-[[(5-fluoro-2- pyridyl)amino]methyl]-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl]quinoxalin-2- yl]oxyethyl]carbamate (C4.1-d) (0.1 g, 175 umol, 63.97% yield) was obtained as a yellow solid. 1H NMR (MeOH, 400 MHz) δ8.56 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.92- 7.94 (m, 1H), 7.74-7.67 (m, 2H), 7.42-7.34 (m, 2H), 7.27 (d, J = 7.6 Hz, 1H), 6.75 (dd, J = 3.2, 9.4 Hz, 1H), 4.87 (s, 2H), 4.53 (t, J = 5.4 Hz, 2H), 3.52 (t, J = 5.4 Hz, 2H), 2.64 (s, 3H), 1.41 (s, 9H)

Step 5: Preparation of N-[[5-[3-(2-aminoethoxy)quinoxalin-6-yl]-4-(6-methyl-2-pyridyl)- 1H-imidazol-2-yl]methyl]-5-fluoro-pyridin-2-amine (Compound C4.1)

To a solution of tert-butyl N-[2 [7-[2- [[(5-fluoro- 2-pyridyl) amino]methyl]- 4-(6- methyl-2-pyridyl)-1H-imidazol-5-yl]quinoxalin-2-yl]oxyethyl]carbamate (C4.1-d) (0.1 g, 175 umol, 1.0 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 10 mL) at 25°C and then stirred for 1 hour. The mixture was concentrated under reduced pressure at 45°C. Compound N-[[5-[3- (2-aminoethoxy)quinoxalin-6-yl]-4-(6-methyl-2-pyridyl)-1H-imidazol -2-yl]methyl]-5-fluoro- pyridin-2-amine (Compound C4.1) (56 mg, 116 umol, 66.67% yield, 98.16% purity, 4HCl) was obtained as a yellow solid. 1H NMR (MeOD, 400 MHz) δ8.65 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 8.01-8.03 (m, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.75-7.79 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 4.0, 9.8 Hz, 1H), 4.93 (s, 2H), 4.76 (t, J = 4.8 Hz, 1H), 3.48-3.50 (m, 2H), 2.75 (s, 3H) HPLC: 98.16% (220 nm), 99.39% (254 nm) MS (ESI): mass calcd. For C₂₅H₂₃FN₈O 470.20, m/z found 471.1 [M+H]⁺. Compounds C4.2–C4.9, as illustrated in Table 19, could be prepared in a manner similar to that described for Compound C4.1 using appropriate intermediates according to Method D as described herein.

TABLE 19 COMPOUNDS C4.2–C4.9

ALK5 INHIBITOROF FORMULA (C-1)—SYNTHETIC METHOD E Synthesis of 2-[7-[2-tert-butyl-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl]quinoxalin-2- yl] oxyethanamine (Compound C5.1)

Synthetic Scheme

imidazol-5-yl] quinoxalin-2-yl] oxyethyl] carbamate (Compound C5.1-a)

To a solution of tert-butyl N-[2-[7-[2-(6-methyl-2-pyridyl)-2-oxo-acetyl] quinoxalin-2- yl] oxyethyl]carbamate (A2) (150 mg, 344 umol, 1.0 eq) in THF (9 mL) was added 2,2- dimethylpropanal (59.2 mg, 687 umol, 76.0 uL, 2.0 eq) and NH₄OAc (132 mg, 1.72 mmol, 5.0 eq), and then stirred at 35°C for 12 hr. The mixture was poured into ice-water (w/w = 1/1) (20 mL). The aqueous phase was extracted with ethyl acetate (25 mL*3). The combined organic phase was washed with brine (25 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 1/1). Compound tert-butyl N-[2-[7-[2-tert-butyl-4-(6-methyl-2-pyridyl)-1H- imidazol-5-yl] quinoxalin-2-yl] oxyethyl] carbamate (C5.1-a) (115 mg, 229 umol, 66.6% yield) was obtained as yellow oil. ¹H NMR (MeOD, 400 MHz) δ8.44 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.71-7.57 (m, 2H), 7.29-7.17 (m, 2H), 4.52 (t, J = 5.6 Hz, 2H), 3.51 (t, J = 5.6 Hz, 2H), 2.54 (s, 3H), 1.49 (s, 9H), 1.42 (s, 9H) Step 2: Preparation of 2-[7-[2-tert-butyl-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl] quinoxalin-2-yl] oxyethanamine (Compound C5.1)

To a solution of tert-butyl N-[2-[7-[2-tert-butyl-4-(6-methyl-2-pyridyl)-1H-imidazol-5- yl] quinoxalin-2-yl]oxyethyl]carbamate (C5.1-a) (115 mg, 229 umol, 1.0 eq) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 20 mL), and then stirred at 25°C for 30 min. The mixture was concentrated in vacuum. The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18150*25*10um; mobile phase: [water (0.1%TFA)-ACN]; B%: 1%-30%, 8min). Compound 2-[7-[2-tert-butyl-4-(6-methyl-2-pyridyl)-1H-imidazol-5-yl] quinoxalin-2-yl] oxyethanamine (Compound C5.1) (37.1 mg, 42.0 umol, 18.4% yield, 97.2% purity, 4TFA) was obtained as yellow oil. 1H NMR (MeOD, 400MHz) δ8.65 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.78-7.70 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.75 (t, J = 5.6 Hz, 2H), 3.48 (t, J = 5.6 Hz, 2H), 2.65 (s, 3H), 1.61 (s, 9H) HPLC: 97.18% (220 nm), 98.37% (254 nm) Compound C5.2, as illustrated in Table 20, could be prepared in a manner similar to that described for Compound C5.1 using appropriate intermediates according to Method E as described herein. TABLE 20 COMPOUND C5.2

EXAMPLE 4 Preparation of ALK5 Inhibitors of Formula (D-I) SYNTHESIS OF COMPOUNDS OF FORMULA (D-I) ACCORDING TO METHOD A Example 4-1A Synthesis of a TFA salt of 4-((6-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)quinolin-3-yl)oxy)butan-1-amine (Compound D-3.1)

Step 1: Preparation of benzyl (4-((6-bromoquinolin-3-yl)oxy)butyl)carbamate

To a solution of 6-bromoquinolin-3-ol (500.0 mg, 2.2 mmol, 1.0 equiv.) in tetrahydrofuran (10.0 mL) with an inert atmosphere of nitrogen, was added benzyl N-(4- hydroxybutyl)carbamate (491.2 mg, 2.2 mmol, 1.0 equiv.), triphenylphosphine (864.6 mg, 3.3 mmol, 1.5 equiv.), diisopropyl azodicarboxylate (666.6 mg, 3.3 mmol, 1.5 equiv.) with stirring at 0^°C. The resulting solution was stirred for 5 h at 50^°C. The reaction mixture was cooled to 25^°C with a water/ice bath, diluted with 100 mL of water and extracted with 3x100 mL of dichloromethane and the organic layers were combined, washed with 3x100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 400 mg (42%) of benzyl (4-((6-bromoquinolin- 3-yl)oxy)butyl)carbamate was obtained as a white solid. MS m/z [M+H]⁺ (ESI): 429. Step 2: Preparation of (4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3- yl)oxy)butyl)carbamate

To a solution of benzyl benzyl (4-((6-bromoquinolin-3-yl)oxy)butyl)carbamate (100.0 mg, 0.23 mmol, 1.0 equiv.) in 1,4-dioxane (4.0 mL) with an inert atmosphere of nitrogen, was added bis(pinacolato)diboron (71.1 mg, 0.28 mmol, 1.2 equiv.), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (33.6 mg, 0.046 mmol, 0.2 equiv.) and potassium acetate (67.6 mg, 0.69 mmol, 3.0 equiv.). The resulting solution was stirred for 2 h at 110^°C. The reaction mixture was cooled to 25^°C with a water/ice bath and diluted with 20 mL of water. The resulting mixture was extracted with ethyl acetate 3x 20 mL and the organic layers were combined, washed with 3x20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product without further purification was used at next step directly. 85 mg (77%) of (4-((6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinolin-3-yl)oxy)butyl)carbamate was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 477. Step 3: Preparation of ethyl 3-(6-methylpyridin-2-yl)-3-oxopropanoate

To a solution of methyl 6-methylpyridine-2-carboxylate (3.0 g, 19.8 mmol, 1.0 equiv.) in ethyl acetate (45.0 mL) with an inert atmosphere of nitrogen, was added sodium hydride (1.6 g, 39.6 mmol, 2.0 equiv.). The resulting solution was stirred for 12 h at 55^°C and then quenched by the addition of ice/water. The resulting solution was extracted with 2x50 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 2.4 g (58%) of ethyl 3-(6-methylpyridin-2-yl)-3-oxopropanoate was obtained as a colorless oil.MS m/z [M+H]⁺ (ESI): 208. Step 4: Preparation of ethyl (E)-3-(6-methylpyridin-2-yl)-3-((2-oxopyrrolidin-1- yl)imino)propanoate

To a solution of ethyl 3-(6-methylpyridin-2-yl)-3-oxopropanoate (1.5 g, 7.2 mmol, 1.0 equiv.) in pyridine (30.00 mL) with an inert atmosphere of nitrogen, was added 1- aminopyrrolidin-2-one hydrochloride (1.2 g, 8.6 mmol, 1.2 equiv.). The resulting solution was stirred for 20 h at 25^°C. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 25 min); Detector, UV 254 nm. 1.4 g (67%) of ethyl (E)-3-(6- methylpyridin-2-yl)-3-((2-oxopyrrolidin-1-yl)imino)propanoate was obtained as a white oil. MS m/z [M+H]⁺ (ESI): 290. Step 5: Preparation of 2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3- carboxylic acid

To a solution of ethyl (E)-3-(6-methylpyridin-2-yl)-3-((2-oxopyrrolidin-1-yl)imino) propanoate (1.0 g, 3.5 mmol, 1.0 equiv.) in toluene (20.0 mL) with an inert atmosphere of nitrogen, was added sodium ethoxide (476.0 mg, 7.0 mmol, 2.0 equiv.). The resulting solution was stirred for 24 h at 80^°C. LCMS showed the reaction was completed. It was followed by the addition of 1mol/L hydrochloric acid dropwise with stirring adjust pH to 4. The resulting solution was stirred for 3 h at 25^oC. The pH of the reaction was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. The resulting solution was diluted with 100 mL of water and extracted with 3x200 mL of dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 520 mg (62%) of 2-(6-methylpyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole-3-carboxylic acid was obtained as a yellow oil. MS m/z [M+H]⁺ (ESI): 244. Step 6: Preparation of 3-bromo-2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

To a solution of 2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3- carboxylic acid (200.0 mg, 0.82 mmol, 1.0 equiv.) in N,N-dimethylformamide (5.0 mL) with an inert atmosphere of nitrogen, was added N-bromosuccinimide (445.0 mg, 2.5 mmol, 3.0 equiv.). The resulting solution was stirred for 16 h at 25^°C. The resulting solution was diluted with 20 mL of water and extracted with 3x20 mL of dichloromethane and the organic layers were combined, washed with 3x20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 170 mg (75%) of 3-bromo-2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 278. Step 7: Preparation of benzyl (4-((6-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)quinolin-3-yl)oxy)butyl)carbamate

To a solution of 3-bromo-2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b] pyrazole (100.0 mg, 0.36 mmol, 1.0 equiv.) in 1,4-dioxane/water (5.0 mL/0.5 mL) with an inert atmosphere of nitrogen, was added (4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin- 3-yl)oxy)butyl)carbamate (205.0 mg, 0.43 mmol, 1.2 equiv.), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (52.6 mg, 0.072 mmol, 0.2 equiv.) and sodium carbonate (116.6 mg, 1.1 mmol, 3.0 equiv.). The resulting solution was stirred for 4 h at 80^oC. The reaction mixture was cooled to 25 ^°C with a water/ice bath and diluted with 10 mL of water and extracted with 3x10 mL of dichloromethane and the organic layers were combined, washed with 3x10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 110 mg (56%) of benzyl (4-((6-(2- (6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-3-yl)oxy)butyl) carbamate was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 548. Step 8: Preparation of a TFA salt of 4-((6-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)quinolin-3-yl)oxy)butan-1-amine (Compound D-3.1

To a solution of benzyl (4-((6-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- yl)quinolin-3-yl)oxy)butyl)carbamate (60.0 mg, 0.11 mmol, 1.0 equiv.) trifluoroacetic acid (2.0 mL) with inert atmosphere of nitrogen, the resulting solution was stirred for 4 h at 50^°C. The reaction mixture was cooled to 25^°C with a water/ice bath, diluted with 10 mL of dichloromethane and concentrated under vacuum. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 19 mg (43%) of 4-((6-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)quinolin-3-yl)oxy)butan-1-amine TFA salt (Compound D-3.1) was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 414. ¹H NMR (300 MHz, Methanol-d₄) δ: 1.87-1.96 (m, 4H), 2.46 (s, 3H), 2.67-2.83 (m, 2H), 2.95-3.00 (m, 2H), 3.10-3.20 (m, 2H), 4.18- 4.22 (m, 2H), 4.27-4.35 (m, 2H), 7.25-7.39 (m, 2H), 7.40-7.54 (m, 1H), 7.62-7.68 (m, 1H), 7.69- 7.82 (m, 2H), 7.83-7.85 (m, 1H), 8.50 (s, 1H). Example 4-1B Synthesis of a TFA salt of N-(2-aminoethyl)-6-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-3-carboxamide (Compound D-3.15)

Compound D-3.15 was prepared according to synthetic Method A for compounds of Formula (D-1) with the appropriate starting materials, as shown below. Step 1: Preparation of benzyl (2-(6-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)quinoline-3-carboxamido)ethyl)carbamate

To solution of 3-bromo-2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole (160.0 mg, 0.5 mmol, 1.0 equiv.) in 1,4-dioxane/water (5.0 mL/0.5 mL) with an inert atmosphere of nitrogen, was added benzyl (2-(6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinoline-3-carboxamido)ethyl)carbamate (285.2 mg, 0.6 mmol, 1.2 equiv.), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73.1 mg, 0.1 mmol, 0.2 equiv.) and sodium carbonate (159.0 mg, 1.5 mmol, 3.0 equiv.). The resulting solution was stirred for 10 h at 80^oC. The reaction mixture was cooled to 25^oC with a water/ice bath and diluted with 50 mL of water and extracted with 3x50 mL of dichloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 140 mg (47%) of benzyl (2-(6-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)quinoline-3-carboxamido)ethyl)carbamate was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 583. Step 2: Preparation of N-(2-aminoethyl)-6-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)quinoline-3-carboxamide TFA salt (Compound D-3.15)

To a solution of benzyl (2-(6-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)quinoline-3-carboxamido)ethyl)carbamate (116.0 mg, 0.2 mmol, 1.0 equiv.) trifluoroacetic acid (2.0 mL) with inert atmosphere of nitrogen, the resulting solution was stirred for 4 h at 50^oC. The reaction mixture was cooled to 25^oC with a water/ice bath, diluted with 10 mL of dichloromethane and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 55 mg (62%) of N-(2-aminoethyl)-6-(2-(6-(difluoromethyl)pyridin- 2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-3-carboxamide TFA salt (Compound D-3.15) was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 449; ¹H NMR (300 MHz, Methanol-d₄) δ: 2.71-2.81 (m, 2H), 3.12-3.16 (m, 2H), 3.21-3.25 (m, 2H), 3.74-3.78 (m, 2H), 4.31 (t, J = 7.5 Hz, 2H), 6.19-6.57 (m, 1H), 7.59 (d, J = 6.9 Hz, 1H), 7.89-8.00 (m, 3H), 8.04-8.16 (m, 2H), 8.94 (d, J = 2.1 Hz, 1H), 9.30 (d, J = 2.1 Hz, 1H). Example 4-1C Synthesis of a TFA salt of 2-(7-(2-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro-4H-pyrrolo [1,2-b]pyrazol-3-yl)quinoxalin-2-yl)ethan-1-amine (Compound D-3.22)

Compound 3.22 was prepared according to synthetic Method A for compounds of Formula (D-1) with the appropriate starting materials, as shown below. Step 1: Preparation of benzyl (2-(7-(2-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)quinoxalin-2-yl)ethyl)carbamate To a solution of 3-bromo-2-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole (208 mg, 0.48 mmol, 1.2 equiv.) in 1,4-dioxane/water (5.0 mL/0.5 mL) with an inert atmosphere of nitrogen, was added benzyl (2-(7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)quinoxalin-2-yl)ethyl)carbamate (130.0 mg, 0.4 mmol, 1.0 equiv.), [1,1'-Bis (diphenylphosphino)ferrocene]dichloropalladium(II) (58.0 mg, 0.08 mmol, 0.2 equiv.), sodium carbonate (127.2 mg, 1.2 mmol, 3 equiv.). The resulting solution was stirred for 6 h at 80^oC. The reaction mixture was cooled to 25^oC with a water/ice bath and diluted with 50 mL of water and extracted with 3x50 mL of dichloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 102 mg (47%) of benzyl (2-(7-(2-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3- yl)quinoxalin-2-yl)ethyl)carbamate was obtained a yellow solid. MS m/z [M+H]⁺ (ESI): 559. Step 2: Preparation of 2-(7-(2-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)quinoxalin-2-yl)ethan-1-amine TFA salt (Compound D-3.22)

To a solution of benzyl (2-(7-(2-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)quinoxalin-2-yl)ethyl)carbamate (102.0 mg, 0.18 mmol, 1.0 equiv.) in trifluoroacetic acid (3.0 mL) with inert atmosphere of nitrogen, the resulting solution was stirred for 4 h at 50^oC. The reaction mixture was cooled to 25^oC with a water/ice bath, diluted with 20 mL of dichloromethane and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 55 mg (71%) of 2-(7-(2-(6-(trifluoromethyl)pyridin-2-yl)-5,6- dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoxalin-2-yl)ethan-1-amine TFA salt (Compound D-3.22) was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 425; ¹H NMR (300 MHz, Methanol-d₄) δ: 2.72-2.82 (m, 2H), 3.13-3.17 (m, 2H), 3.43-3.47 (m, 2H), 3.56-3.60 (m, 2H), 4.30-4.35 (m, 2H), 7.63-7.69 (m, 1H), 7.71-7.83 (m, 1H), 7.98-8.09 (m, 3H), 8.10-8.13 (m, 1H), 8.82 (s, 1H). Examples (4-1D)–(4-1V) The compounds in Table 21 were prepared according to synthetic Method A in a manner similar to that described within for Examples (4-1A)–(4-1C). TABLE 21

SYNTHESIS OF COMPOUNDS OF FORMULA (D-I) ACCORDING TO METHOD B Example 4-2A Synthesis of a TFA salt of 4-((6-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)quinolin-3-yl)oxy) butan-1-amine (Compound D-4.1)

Compound D-4.1 was prepared according to synthetic Method B with the appropriate starting materials, as shown below. Step 1: Preparation of (E)-3-(dimethylamino)-1-(6-methylpyridin-2-yl)prop-2-en-1-one

To a solution of 1-(6-methylpyridin-2-yl)ethanone (270.0 mg, 2.0 mmol, 1.0 equiv.) in (dimethoxy- methyl)dimethylamine (262.2 mg, 2.2 mmol, 1.1 equiv.) with an inert atmosphere of nitrogen, The resulting solution was stirred for 7 h at 105^oC. The reaction mixture was cooled to 25^oC with a water/ice bath, diluted with 100 mL of water and extracted with 3x100 mL of dichloromethane and the organic layers were combined, washed with 3x100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 305 mg (80%) of (E)-3-(dimethylamino)-1-(6- methylpyridin-2-yl)prop-2-en-1-one was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 191. Step 2: Preparation of 2-methyl-6-(1H-pyrazol-3-yl)pyridine

To a solution of (E)-3-(dimethylamino)-1-(6-methylpyridin-2-yl)prop-2-en-1-one (190.0 mg, 1.0 mmol, 1.0 equiv.) in ethanol (5.0 mL) with an inert atmosphere of nitrogen, was added hydrazine hydrate (2.0 mL). The resulting solution was stirred for 20 h at 25^oC and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 150 mg (90%) of 2-methyl-6-(1H- pyrazol-3-yl)pyridine was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI):160. Step 3: Preparation of 2-(4-bromo- pyrazol-3-yl)-6-methylpyridine

To a solution of 2-methyl-6-(1H-pyrazol-3-yl)pyridine (318 mg, 2.0 mmol, 1.0 equiv.) in dichloromethane (6.0 mL) with an inert atmosphere of nitrogen, was added N-bromosuccinimide (391.6 mg, 2.2 mmol, 1.1 equiv.). The resulting solution was stirred for 4 h at 25^oC. The resulting solution was diluted with 20 mL of water and extracted with 3x20 mL of dichloromethane and the organic layers were combined, washed with 3x20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 430 mg (90%) 2-(4-bromo-1H-pyrazol-3-yl)-6- methylpyridine was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 238. Step 4: Preparation of tert-butyl 4-bromo-3-(6-methylpyridin-2-yl)-1H-pyrazole-1-carboxylate

To a solution of 2-(4-bromo-1H-pyrazol-3-yl)-6-methylpyridine (474.0 mg, 2.0 mmol, 1.0 equiv.) in tetrahydrofuran (8.0 mL) with an inert atmosphere of nitrogen, was added di-tert- butyl pyrocarbonate (523.7 mg, 2.4 mmol, 1.2 equiv.), triethylamine (303.0 mg, 3.0 mmol, 1.5 equiv.). The resulting solution was stirred for 4 h at 25^oC. The resulting solution was diluted with 50 mL of water and extracted with 3x50 mL of dichloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 600 mg (89%) of tert-butyl 4-bromo-3-(6-methylpyridin-2-yl)-1H-pyrazole-1-carboxylate was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 338. Step 5: Preparation of tert-butyl 4-(3-(4-(((benzyloxy)carbonyl)amino)butoxy)quinolin-6-yl)-3- (6-methylpyridin-2-yl)-1H-pyrazole-1-carboxylate

To a solution of tert-butyl 4-bromo-3-(6-methylpyridin-2-yl)-1H-pyrazole-1-carboxylate (202.0 mg, 0.6 mmol, 1.0 equiv.) in 1,4-dioxane/water (5.0 mL/0.5 mL) with an inert atmosphere of nitrogen, was added (4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3- yl)oxy)butyl)carbamate (343.0 mg, 0.72 mmol, 1.2 equiv.), [1,1'-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) (87.7 mg, 0.12 mmol, 0.2 equiv.), sodium carbonate (190.8 mg, 1.8 mmol, 3.0 equiv.). The resulting solution was stirred for 2 h at 80^oC. The reaction mixture was cooled to 25^oC with a water/ice bath and diluted with 20 mL of water and extracted with 3x20 mL of dichloromethane and the organic layers were combined, washed with 3x20 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 230 mg (63%) of tert-butyl 4-(3-(4- (((benzyloxy)carbonyl)amino)butoxy)quinolin-6-yl)-3-(6-methylpyridin-2-yl)-1H-pyrazole-1- carboxylate was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 608. Step 6: Preparation of 4-((6-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)quinolin-3-yl)oxy)butan-

To a solution of (4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3- yl)oxy)butyl)carbamate (200.0 mg, 0.33 mmol, 1.0 equiv.) in trifluoroacetic acid (5.0 mL) with an inert atmosphere of nitrogen, the resulting solution was stirred for 3 h at 50^oC. The resulting solution was diluted with 10 mL of dichloromethane and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 80 mg (65%) of 4-((6-(3-(6-methylpyridin-2- yl)-1H-pyrazol-4-yl)quinolin-3-yl)oxy)butan-1-amine TFA salt was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 374.¹H NMR (300 MHz, Methanol-d₄) δ: 1.91-1.99 (m, 4H), 2.82 (s, 3H), 3.04-3.09 (m, 2H), 4.23-4.27 (m, 2H), 7.56 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.88-7.91 (m, 1H), 8.01-8.04 (m, 2H), 8.17-8.22 (m, 2H), 8.69 (s, 1H).SYNTHESIS OF COMPOUNDS OF FORMULA (D-I) ACCORDING TO METHOD C Example 4-3A Synthesis of a TFA salt of 2-(4-(5-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)-2-fluorophenyl)-1H-pyrazol-1-yl)ethan-1-amine (Compound D-6.3)

Compound D-6.3 was prepared according to synthetic Method C with the appropriate starting materials, as shown below. Step 1: Preparation of (2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b] pyrazol-3-yl)boronic acid

To a solution of 3-bromo-2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole (100.0 mg, 0.3 mmol, 1.0 equiv.) in tetrahydrofuran (10.0 mL) with an inert atmosphere of nitrogen, was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (296.2 mg, 1.6 mmol, 5.0 equiv.). The reaction mixture was cooled to -78^oC by the addition of n- butyllithium (51.0 mg, 0.8 mmol, 2.5 equiv.) to the reaction at -78^oC. The resulting solution was stirred for 3 h at -78^oC. The reaction was then quenched by the addition of water/ice. The resulting solution was diluted with 50 mL of water and extracted with 3x50 mL of dichloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 60 mg (68%) of (2-(6-(difluoromethyl)pyridin- 2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)boronic acid was obtained as a white solid. MS m/z [M+H]⁺ (ESI): 280. Step 2: Preparation of benzyl (2-(4-(5-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)-2-fluorophenyl)-1H-pyrazol-1-yl)ethyl)carbamate

To a solution of benzyl (2-(4-(5-bromo-2-fluorophenyl)-1H-pyrazol-1-yl)ethyl)carbamate (220.0 mg, 0.5 mmol, 1.0 equiv.) in 1,2-dimethoxyethane (5.0 mL) with an inert atmosphere of nitrogen, was added (2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol- 3-yl)boronic acid (220.2 mg, 0.8 mmol, 1.5 equiv.), Tetrakis(triphenylphosphine)palladium (60.8 mg, 0.05 mmol, 0.1 equiv.), Cesium fluoride (159.8 mg, 1.1 mmol, 2.0 equiv.). The resulting solution was stirred for 2 h at 80℃. The reaction mixture was cooled to 25^oC with a water/ice bath, diluted with 50 mL of water and extracted with 3x50 mL of dichloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 174 mg (58%) of benzyl (2-(4-(5-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6- dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2-fluorophenyl)-1H-pyrazol-1-yl)ethyl)carbamate was obtained as a white solid. MS m/z [M+H]⁺ (ESI): 573. Step 3: Preparation of a TFA salt of 2-(4-(5-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)-2-fluorophenyl)-1H-pyrazol-1-yl)ethan-1-amine (Compound D-6.3)

To a solution of benzyl (2-(4-(5-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)-2-fluorophenyl)-1H-pyrazol-1-yl)ethyl)carbamate (174.0 mg, 0.304 mmol, 1.0 equiv.) in trifluoroacetic acid (3 mL), the resulting solution was stirred for 4 h at 50℃. The reaction mixture was cooled to 25^oC with a water/ice bath, diluted with 10 mL of dichloromethane and concentrated under vacuum. The crude product was purified by Flash-Prep- HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 87 mg (65%) of 2-(4-(5-(2-(6-(difluoromethyl)pyridin-2-yl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazol-3-yl)-2-fluorophenyl)-1H-pyrazol-1-yl)ethan-1-amine TFA salt (Compound D-6.3) was obtained as a white solid. MS m/z [M+H]⁺ (ESI): 439; ¹H NMR (400 MHz, Methanol-d₄) δ: 2.69-2.77 (m, 2H), 3.05-3.09 (m, 2H), 3.47 (t, J = 5.6 Hz, 2H), 4.27 (t, J = 7.2 Hz, 2H), 4.49 (t, J = 6.0 Hz, 2H), 6.35-6.62 (m, 1H), 7.09-7.20 (m, 2H), 7.57-7.61 (m, 2H), 7.75-7.77 (m, 1H), 7.86 (s, 1H), 7.93-7.97 (m, 1H), 8.06 (s, 1H). Examples (4-3B)–(4-3D) The compounds in Table 22 were prepared according to synthetic Method C in a manner similar to that described within for Examples 4-3A.

TABLE 22

SYNTHESIS OF COMPOUNDS OF FORMULA (D-I) ACCORDING TO METHOD D Example 4-4A Synthesis of 2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-1- yl)ethan-1-amine (Compound D-7.2)

Compound D-7.2 was prepared according to synthetic Method D with the appropriate starting materials, as shown below. Step 1: Preparation of 2-(2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl pyrazol-4-yl)phenyl)-

1H-pyrazol-1-yl)ethyl)isoindoline-1,3-dione

To a solution of 2-(4-[2-fluoro-5-[3-(6-methylpyridin-2-yl)-1H-pyrazol-4- yl]phenyl]pyrazol-1-yl)ethanol (600.0 mg, 1.65 mmol, 1.0 equiv.) in tetrahydrofuran (10.0 mL) with an inert atmosphere of nitrogen, was added phthalimide (485.1 mg, 3.3 mmol, 2.0 equiv.), triphenyl phosphine (657.5 mg, 2.5 mmol, 1.5 equiv.), diisopropyl azodiformate (505.0 mg, 2.5 mmol, 1.5 equiv.) with stirring at 0^oC. The resulting solution was stirred for 4 h at 25^oC. The resulting solution was diluted with 50 mL of water and extracted with 3x50 mL of dichloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 80.0% in 20 min); Detector, UV 254 nm. 450 mg (55%) 2-(2-(4-(2-fluoro-5-(3-(6- methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-1-yl)ethyl)isoindoline-1,3-dione was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 493. Step 2: Preparation of 2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-1H- pyrazol-1-yl)ethan-1-amine

To a solution of 2-(2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)- 1H-pyrazol-1-yl)ethyl)isoindoline-1,3-dione (450.0 mg, 0.9 mmol, 1.0 equiv.) in ethanol (4.0 mL) with an inert atmosphere of nitrogen, was added hydrazine hydrate (2.0 mL). The resulting solution was stirred for 1 h at 70^oC in an oil bath, cooled to 25^oC with a water/ice bath and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 100.0% in 20 min); Detector, UV 254 nm. 240 mg (73%) of 2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-1-yl)ethan-1- amine (Compound D-7.2) was obtained as a white solid. MS m/z [M+H]⁺ (ESI): 363; ¹H NMR (300 MHz, Methanol-d₄) δ: 2.52 (s, 3H), 3.07-3.11 (m, 2H), 4.23 (t, J = 6.0 Hz, 2H), 7.05-7.17 (m, 2H), 7.21-7.27 (m, 2H), 7.59-7.67 (m, 2H), 7.74-7.82 (m, 2H), 8.01 (s, 1H). Examples (4-4B)–(4-4J) The compounds in Table 23 were prepared according to synthetic Method D in a manner similar to that described within for Example (4-4A.) TABLE 23

SYNTHESIS OF COMPOUNDS OF FORMULA (D-I) ACCORDING TO METHOD E Example 4-5A Synthesis of a TFA salt of (S)-4-amino-5-((2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl

pyrazol-4-yl)phenyl)-1H-pyrazol-1-yl)ethyl) -5-oxopentanoic acid (Compound D-7.14)

Compound D-7.14 was prepared according to synthetic Method E with the appropriate starting materials, as shown below. Step 1: Preparation of methyl (S)-4-((tert-butoxycarbonyl)amino)-5-((2-(4-(2-fluoro-5-(3-(6- methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-1-yl)ethyl)amino)-5-oxopentanoate

To a solution of 2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-1H- pyrazol-1-yl)ethan-1-amine (150.0 mg, 0.41 mmol, 1.0 equiv.) in tetrahydrofuran (3.0 mL) with an inert atmosphere of nitrogen, was added N,N-carbonyldiimidazole (79.4 mg, 0.49 mmol, 1.2 equiv.), methyl (4S)-4-(benzylcarbamoyl)-4-[(tert-butoxycarbonyl)amino]butanoate (107.0 mg, 0.41 mmol, 1.0 equiv.). The resulting solution was stirred for 6 h at 25^oC. The resulting solution was diluted with 50 mL of water and extracted with 3x50 mL of dichloromethane and the organic layers were combined, washed with 3x50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, water and acetonitrile (10.0% acetonitrile up to 80.0% in 20 min); Detector, UV 254 nm. 120 mg (48%) of methyl (S)-4-((tert-butoxycarbonyl)amino)-5-((2-(4-(2- fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-1-yl)ethyl)amino)-5- oxopentanoate was obtained as a yellow solid. MS m/z [M+H]⁺ (ESI): 606.

Step 2: Preparation of a TFA salt of methyl (S)-4-amino-5-((2-(4-(2-fluoro-5-(3-(6- methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-1-yl)ethyl)amino)-5-oxopentanoate T

To a solution of methyl (S)-4-((tert-butoxycarbonyl)amino)-5-((2-(4-(2-fluoro-5-(3-(6- methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-1H-pyrazol-1-yl)ethyl)amino)-5-oxopentanoate (138.0 mg, 0.23 mmol, 1.0 equiv.) in dichloromethane (4.0 mL) with an inert atmosphere of nitrogen, was added trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at 25^oC. The reaction mixture was diluted with 10 mL of dichloromethane and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 100.0% in 15 min); Detector, UV 254 nm. 102 mg (89%) of methyl (S)-4-amino-5-((2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)- 1H-pyrazol-1-yl)ethyl)amino)-5-oxopentanoate TFA salt (Compound D-7.13) was obtained as a yellow semi-solid. MS m/z [M+H]⁺ (ESI): 506; ¹H NMR (400 MHz, Methanol-d₄) δ: 2.02-2.09 (m, 2H), 2.35-2.39 (m, 2H), 2.78 (s, 3H), 3.59-3.64 (m, 4H), 3.82-3.87 (m, 2H), 4.33-4.41 (m, 2H), 7.20-7.22 (m, 2H), 7.53-7.66 (m, 1H), 7.70-7.72 (m, 2H), 7.88 (s, 1H), 8.02 (s, 1H), 8.10- 8.15 (m, 2H). Step 3: Preparation of (S)-4-amino-5-((2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4- yl)phenyl)-1H-pyrazol-1-yl)ethyl)amino)-5-oxopentanoic acid TFA salt (Compound D-7.14)

To a solution of Compound D-7.13 (190.0 mg, 0.38 mmol, 1.0 equiv.) in tetrahydrofuran/water (2.0 mL/2.0 mL) with an inert atmosphere of nitrogen, was added lithium hydroxide monohydrate (31.9 mg, 0.76 mmol, 2.0 equiv.). The resulting solution was stirred for 6 h at 25^oC. The pH of the reaction was adjusted to 7 with trifluoroacetic acid. The resulting mixture was concentrated under vacuum and purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): C18 Column; mobile phase, water (with 0.5% trifluoroacetic acid) and acetonitrile (10.0% acetonitrile up to 50.0% in 15 min); Detector, UV 254 nm. 70 mg (38%) of (S)-4-amino-5-((2-(4-(2-fluoro-5-(3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl)phenyl)-1H- pyrazol-1-yl)ethyl)amino)-5-oxopentanoic acid TFA salt (Compound D-7.14) was obtained as a yellow semi-solid. MS m/z [M+H]⁺ (ESI): 492; ¹H NMR (400 MHz, Methanol-d₄) δ: 2.02-2.09 (m, 2H), 2.36-2.39 (m, 2H), 2.79 (s, 3H), 3.61-3.65 (m, 1H), 3.79-3.87 (m, 2H), 4.39-4.43 (m, 2H), 7.19-7.22 (m, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.66-7.72 (m, 2H), 7.89 (s, 1H), 8.03 (s, 1H), 8.11-8.18 (m, 2H). Examples (4-5C)–(4-5D) The compounds in Table 24 were prepared according to synthetic Method E in a manner similar to that described within for Examples (4-5A) and (4-5B). TABLE 24

EXAMPLE 5 Preparation of 4-((2S,5S)-23-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-13,13-bis((3-((4-(((2R,3R,4R,5R,6R)-3- acetamido-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butyl)amino)-3- oxopropoxy)methyl)-5-isopropyl-4,7,11,18-tetraoxo-2-(3-ureidopropyl)-15-oxa-3,6,12,19- tetraazatricosanamido)benzyl ((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)- 1H-imidazol-2-yl)methyl)(2,6-difluorophenethyl)carbamate (Compound 3.1).

The title compound was prepared according to Scheme 2. Scheme 5-1

Step 1: Synthesis of 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5- ureidopentanamido)benzyl ((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2- yl)-1H-imidazol-2-yl)methyl)(2,6-difluorophenethyl)carbamate (Intermediate 3).

To a stirred solution of 1 N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2- yl)-1H-imidazol-2-yl)methyl)-2-(2,6-difluorophenyl)ethan-1-amine (Compound 60, 199.5 mg, 0.448 mmol) in DMF (4 mL) were added Fmoc-vc-PAB-PNP (327 mg, 0.448 mmol) and DIEA (165 mg, 1.28 mmol). The mixture was stirred at 40°C for 12 h. Once the reaction was deemed complete by LCMS, the reaction mixture was cooled to RT and 10 equiv. DBU was added to the reaction mixture. After 1 h the deprotection of the Fmoc protecting group was deemed complete by LCMS and the crude reaction mixture was purified via direct injection on a RP-HPLC (Teledyne ISCO, C18Aq, 0Æ45% acetonitrile in water (0.1% TFA)). Pure fractions were pooled, frozen and lyophilized. The product was obtained as an off-white solid (63 mg, 14% yield). LCMS (M+H) = 851.9. Step 2: Preparation of tert-butyl 3-[2-amino-3-(3-tert-butoxy-3-oxo-propoxy) -2-[(3-tert- butoxy-3-oxo-propoxy)methyl]propoxy]propanoate. To a mixture of 2-amino-2-(hydroxymethyl)propane-1,3-diol (30 g, 247.66 mmol, 35.71 mL, 1 eq) in DMSO (83 mL) was added dropwise NaOH (5 M, 4.96 mL, 0.1 eq) at 0-15°C over 5 min. After the addition was complete, the mixture was stirred at 0-15°C for 5 min, and then tert-butyl prop-2-enoate (126.97 g, 990.63 mmol, 143.79 mL, 4 eq) was added dropwise at 20°C. The resulting mixture was stirred at 15°C for 12 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc (200 mL), quenched by addition H₂O (200 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give tert-butyl 3-[2-amino-3- (3-tert-butoxy-3-oxo-propoxy)-2 -[(3-tert-butoxy-3-oxo-propoxy)methyl]propoxy]propanoate (100 g, 197.77 mmol, 79.86% yield) as a colorless oil. ¹H NMR (DMSO-d₆, 400MHz) δ 3.55(t, J = 6.0 Hz, 6H), 3.21-3.17 (m, 5H), 2.40 (t, J = 6.0 Hz, 6H), 1.99 (s, 27H). Step 3: Preparation of benzyl 5-[[2-(3-tert-butoxy-3-oxo-propoxy)-1,1-bis[(3-tert- butoxy- 3-oxo-propoxy)methyl]ethyl]amino]-5-oxo-pentanoate. To a solution of 5-benzyloxy-5-oxo-pentanoic acid (4.40 g, 19.78 mmol, 1 eq) in DMF (20 mL) was added dropwise HATU (9.02 g, 23.73 mmol, 1.2 eq) at 15°C. After the addition was complete, the mixture was stirred at 15°C for 5 min and then tert-butyl 3-[2-amino-3-(3-tert- butoxy-3-oxo-propoxy)-2-[(3-tert-butoxy-3-oxo-propoxy)methyl]propoxy]propanoate (10 g, 19.78 mmol, 1 eq) and Et₃N (3.00 g, 29.67 mmol, 4.13 mL, 1.5 eq) were added at 15°C. The resulting mixture was stirred at 15°C for 12 h. LCMS showed the reaction was complete. The reaction mixture was quenched by the addition or H₂O (200 mL) at 0°C, and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL x 2), 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=10/1 to 4/1) to give benzyl 5-[[2-(3-tert-butoxy-3-oxo-propoxy)-1,1-bis[(3-tert-butoxy-3-oxo- propoxy)methyl]ethyl]amino]-5-oxo-pentanoate (10 g, crude) as a colorless oil. ¹H NMR (DMSO-d₆, 400MHz) δ 7.39-7.30 (m, 5H), 6.97 (s, 1H), 5.08 (s, 2H), 3.57-3.48 (m, 12H), 2.38 (t, J = 6.0 Hz, 6H), 2.36-2.31 (m, 2H), 2.10 (t, J= 7.2 Hz, 2H), 1.72 (q, J = 7.6 Hz, 2H), 1.39 (s, 27H). Step 4: Preparation of 3-[2-[(5-benzyloxy-5-oxo-pentanoyl)amino]-3-(2-carboxyethoxy)- 2-(2-carboxyethoxymethyl)propoxy]propanoic acid. To a solution of benzyl 5-[[2-(3-tert-butoxy-3-oxo-propoxy)-1,1-bis [(3-tert-butoxy-3- oxo-propoxy)methyl]ethyl]amino]-5-oxo-pentanoate (10 g, 14.09 mmol, 1 eq) in DCM (100 mL) was added TFA (15.40 g, 135.06 mmol, 10 mL, 9.59 eq). The mixture was stirred at 15°C for 12 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was washed with petroleum ether (100 mL) to give 3-[2-[(5-benzyloxy-5-oxo-pentanoyl)amino] -3-(2-carboxyethoxy)-2-(2- carboxyethoxymethyl)propoxy]propanoic acid (7 g, 12.93 mmol, 91.76% yield) as a white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 12.14 (br s, 3H), 7.56-7.25 (m, 5H), 6.98 (s, 1H), 5.08 (s, 2H), 3.61-3.47 (m, 12H), 2.41 (t, J = 6.4 Hz, 6H), 2.37-2.31 (m, 2H), 2.09 (t, J = 7.2 Hz, 2H), 1.77- 1.67 (m, 2H). Step 5: Preparation of benzyl 5-oxo-5-[[2-[3-oxo-3-(2,3,4,5,6-pentafluorophenoxy) propoxy]-1,1-bis[[3-oxo-3-(2,3,4,5,6-pentafluorophenoxy)propoxy]methyl]ethyl]amino] pentanoate. To a solution of 3-[2-[(5-benzyloxy-5-oxo-pentanoyl)amino]-3-(2-carboxyethoxy) -2-(2- carboxyethoxymethyl)propoxy]propanoic acid (2.5 g, 4.62 mmol, 1 eq) in DMF (40 mL) was added DIEA (4.77 g, 36.93 mmol, 6.43 mL, 8 eq) and (2,3,4,5,6-pentafluorophenyl)-2,2,2- trifluoroacetate (5.17 g, 18.47 mmol, 4 eq). The mixture was stirred at 15°C for 12 h. The reaction mixture was quenched by addition of satd. aq. NaHCO₃ (50 mL) at 0°C, and was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with satd. aq. NH₄Cl (50 mL) and brine (100 m), 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=5/1 to 3/1) to give benzyl 5-oxo-5-[[2-[3-oxo-3-(2,3,4,5,6- pentafluorophenoxy)propoxy]-1,1-bis[[3-oxo-3-(2,3,4,5,6- pentafluorophenoxy)propoxy]methyl]ethyl]amino]pentanoate (3.3 g, 3.17 mmol, 68.75% yield) was obtained as a yellow solid. ¹H NMR (DMSO-d₆, 400MHz) δ 7.45-7.26 (m, 5H), 7.07 (s, 1H), 5.05 (s, 2H), 3.69 (t, J = 5.6 Hz, 6H), 3.63 (s, 5H), 3.02-2.92 (m, 6H), 2.33 (t, J = 7.6 Hz, 2H), 2.10 (t, J = 7.2 Hz, 2H), 1.71 (q, J = 7.2 Hz, 2H). Step 6: Preparation of 5-[[2-[3-[4-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxybutylamino]-3-oxo-propoxy]-1,1-bis[[3-[4- [(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxybutylamino]-3-oxo-propoxy]methyl]ethyl]amino]-5-oxo-pentanoic acid. To a solution of [5-acetamido-3,4-diacetoxy-6-[4-(benzyloxycarbonylamino) butoxy]tetrahydropyran-2-yl]methyl acetate (850.36 mg, 1.54 mmol, 3.2 eq) and benzyl 5-oxo-5- [[2-[3-oxo-3-(2,3,4,5,6-pentafluorophenoxy)propoxy]-1,1-bis[[3-oxo-3-(2,3,4,5,6- pentafluorophenoxy)propoxy]methyl]ethyl]amino]pentanoate (0.5 g, 480.91 umol, 1 eq) in THF (20 mL) was added Pd(OH)₂/C (10%, 0.1g) under N₂ atmosphere. The suspension was degassed and purged with H₂ three times. The mixture was stirred under H₂ (15 psi) at 15°C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, DCM/MeOH = 10/1 to 0/1) to give 5- [[2-[3-[4-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxybutylamino]-3-oxo-propoxy]-1,1-bis[[3-[4-[(2R,3R,4R,5R,6R)-3-acetamido-4,5- diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]oxybutylamino]-3-oxo- propoxy]methyl]ethyl]amino]-5-oxo-pentanoic acid (0.56 g, crude) as a white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 7.98-7.68 (m, 6H), 7.03 (s, 1H), 5.75 (s, 1H), 5.21 (d, J = 3.2 Hz, 3H), 4.96 (dd, J = 3.6, 11.2 Hz, 3H), 4.48 (d, J = 8.4 Hz, 3H), 4.02 (s, 9H), 3.94-3.83 (m, 3H), 3.78- 3.65 (m, 4H), 3.59-3.49 (m, 13H), 3.46-3.36 (m, 4H), 3.03 (d, J = 6.0 Hz, 8H), 2.28 (t, J = 6.4 Hz, 6H), 2.22-2.14 (m, 3H), 2.10 (s, 11H), 1.99 (s, 9H), 1.89 (s, 9H), 1.77 (s, 9H), 1.71-1.61 (m, 3H), 1.53-1.33 (m, 14H). Step 7: Preparation of (2,3,4,5,6-pentafluorophenyl) 5-[[2-[3-[4-[(2R,3R,4R,5R,6R)-3- acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]oxybutylamino]-3-oxo- propoxy]-1,1-bis[[3-[4-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxybutylamino]-3-oxo-propoxy]methyl]ethyl] amino]-5-oxo-pentanoate. To a solution of 5-[[2-[3-[4-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxybutylamino]-3-oxo-propoxy]-1,1-bis[[3-[4- [(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxybutylamino]-3-oxo-propoxy]methyl]ethyl]amino]-5-oxo-pentanoic acid (1.5 g, 907.61 umol, 1 eq) in DCM (30 mL) was added Et₃N (275.52 mg, 2.72 mmol, 378.99 uL, 3 eq) and (2,3,4,5,6-pentafluorophenyl)-2,2,2-trifluoroacetate (762.59 mg, 2.72 mmol, 3 eq). The mixture was stirred at 20°C for 2 h. The reaction mixture was quenched by addition of H₂O (20 mL), and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Ethyl acetate/ EtOH=1/1) to give (2,3,4,5,6-pentafluorophenyl) 5-[[2-[3-[4-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl) tetrahydropyran-2-yl]oxybutylamino]-3-oxo-propoxy]-1,1-bis[[3-[4- [(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxybutylamino]-3-oxo-propoxy]methyl]ethyl]amino]-5-oxo-pentanoate (1.5 g, 824.75 umol, 90.87% yield) was obtained as a white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 7.82 (d, J = 8.4 Hz, 6H), 7.16 (s, 1H), 5.22 (d, J = 2.8 Hz, 3H), 4.97 (dd, J = 2.8, 11.4 Hz, 3H), 4.49 (d, J = 8.4 Hz, 3H), 4.03 (s, 10H), 3.93-3.83 (m, 3H), 3.76-3.67 (m, 3H), 3.61-3.50 (m, 14H), 3.48-3.39 (m, 4H), 3.12-2.98 (m, 7H), 2.79 (t, J = 7.2 Hz, 2H), 2.30 (t, J = 6.0 Hz, 7H), 2.22 (t, J = 7.0 Hz, 2H), 2.11 (s, 9H), 2.00 (s, 10H), 1.90 (s, 9H), 1.78 (s, 9H), 1.52-1.35 (m, 14H); MS (ESI): mass calcd. for C₇₈H₁₁₂F₅N₇O_36.1818.71, m/z found 910.0[M/2+H]⁺. Step 8: Preparation of Intermediate 4. To a solution of (2,3,4,5,6-pentafluorophenyl) 5-[[2-[3-[4-[(2R,3R,4R,5R,6R)-3- acetamido-4,5-diacetoxy-6- (acetoxymethyl) tetrahydropyran-2-yl]oxybutylamino]-3-oxo- propoxy]-1,1-bis[[3-[4-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxybutylamino]-3-oxo-propoxy]methyl]ethyl]amino]-5- oxo-pentanoate (81 mg, 44.5 umol, 1.0 equiv) and 4-((S)-2-((S)-2-amino-3-methylbutanamido)- 5-ureidopentanamido)benzyl ((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)- 1H-imidazol-2-yl)methyl)(2,6-difluorophenethyl)carbamate (Intermediate 3) (37.5 mg, 42.2 μmol, 1.0 equiv) in DMF (4 mL) was added DIEA (4.0 equiv) via syringe. The resultant solution was allowed to stir at ambient temperature for 60 min. Upon confirmation the reaction had proceeded to completion (by LCMS), the reaction mixture was purified directly via prep- HPLC (column: Teledyne RediSep Prep C18, 100 Å, 5 μM (length: 150 mm; ID: 20 mm); mobile phase: [water (0.1% TFA)-AcN (0.1% TFA)]; B%: 10%-80%, 30 min). Fractions containing the desired product were dried via lyophilization. Intermediate 4 (16.2 mg, 6.5 μmol, 15% yield) was obtained as an off white solid. MS (ESI): mass calcd. for C₁₁₅H₁₅₉F₂N₁₉O₄₀ 2485.6, m/z found 1243.8 [M/2+H]⁺. Step 9: Preparation of Compound 3.1. To a solution of Intermediate 4 (16.2 mg, 6.5 umol, 1.0 equiv) in MeOH (5 mL) was added NaOMe (6.9 mg, 0.13 mmol, 20 equiv), the mixture was stirred at 20°C for 1 h. LCMS showed the reaction was complete. The reaction mixture was adjusted to pH~5-6 using acetic acid, and then was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Teledyne RediSep Prep C18, 100 Å, 5 μM (length: 150 mm; ID: 20 mm); mobile phase: [water (0.1% TFA)-AcN (0.1% TFA)]; B%: 10%-60%, 30 min). Compound 4-((2S,5S)-21-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-13,13-bis((3-((2-(((3R,4R,5R,6R)-3-acetamido- 4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethyl)amino)-3- oxopropoxy)methyl)-5-isopropyl-4,7,11,18-tetraoxo-2-(3-ureidopropyl)-15-oxa-3,6,12,19- tetraazahenicosanamido)benzyl ((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)- 1H-imidazol-2-yl)methyl)(2,6-difluorophenethyl)carbamate (6.3 mg, 2.9 μmol, 45% yield) was obtained as a white solid. MS (ESI): mass calcd. for C₉₇H₁₄₁F₂N₁₉O₃₁2107.3, m/z found 1054.6 [M/2+H]⁺. The compounds in Table 25 were prepared in a manner similar to that described for Compound 3.1. TABLE 25

BIOLOGICAL EXAMPLE 1: In vitro ALK5 Inhibitor-GalNAc Conjugate Screening The resultant conjugates were tested via a cell reporter assay. HEK293 SBE-LUC reporter cells (i.e., containing luciferase under the control of the SMAD-binding element (SBE), a TGFβ responsive transcriptional element) transfected to stably express full length human ASGR1 were seeded in 96 well plates at about 4 x 10⁵ cells/well in an assay media of MEM containing 0.5% FBS, 1% NEAA, 1% NaPyr, and 1% Pen/Strep. ALK5 Inhibitor-GalNAc conjugates and vehicle controls were added to wells containing either HEK293 SBE-LUC or ASGR1-HEK293 SBE-LUC cells in a dose titration ranging from about 5 μM to about 0.06 nM. After 24 hours of culture at 37°C in a 5% CO₂ environment, human TGFβ1 was added (PeproTech Inc.) to a final concentration of 1.6 ng/ml followed by an additional 18 hour incubation. Luciferase Steady Glo reagent (Promega Corporation) was added to each well, incubated for 10 minutes with shaking, and then luciferase activity was determined by measuring luminescence with an Envision Plate Reader (Perkin-Elmer Inc.). Using Prism Software v7.04 (GraphPad Inc.), data were fit with a four-parameter non-linear regression to calculate IC₅₀ values. By way of background, the mammalian asialoglycoprotein receptor (ASGR) is located on the sinusoidal membrane of hepatocytes where it binds and endocytoses galactose-terminated glycoproteins, such as N-acetylgalactosamine (GalNAc) (Braun et al., J. Biol. Chem. 271:21160, 1996). GalNAc is a well-defined liver-targeted moiety having high affinity to ASGR1. HEK293 transfected with ASGR1 is known model for detecting uptake of GalNAc conjugates (see, e.g., Tanowitz et al., Nucleic Acid Res. 45:12388, 2017). The results for exposure of the ASGR1- positive cells (Conjugate X + ASGR1) and ASGR1-negative cells (Conjugate X) as compared to DMSO control are shown in Figures 1A (Conjugate 3.1), 1B (Conjugate 3.2), and 1C (Conjugate 3.3). These data indicate that GalNAc-ALK5 inhibitor conjugates are unable to be taken up by HEK cells that do not express ASGR1. In contrast, HEK cells expressing ASGR1 show increased uptake of the GalNAc-ALK5 inhibitor conjugates, with release of the ALK5 inhibitor and ALK5 activity inhibition, which is reflected by the reduced expression of the luciferase reporter that is under the control of the SMAD-binding element (SBE). BIOLOGICAL EXAMPLE 2: TGFE Reporter Assay TGFE/SMAD Signaling Pathway SBE reporter cell line are obtained from BPS Bioscience. Cells are passed, expanded, and stored in liquid nitrogen as per the supplier's instructions with the exception that growth media is changed to DMEM-C with Geneticin (DMEM supplemented with 10% fetal bovine serum, 1X NEAA, 1 mM Pyruvate, 2 mM glutamine, 50 μg/mL penicillin, 50 U/mL streptomycin and 400 μg/mL of Geneticin). The assay media is MEM supplemented with 0.5% fetal bovine serum, 1X NEAA, 1mM Pyruvate, 50 μg/mL penicillin and 50 U/mL streptomycin. Compounds are assayed to measure their activity as ALK5 inhibitors. Enzyme Inhibition Assay ALK5 enzyme inhibition assays were performed by Reaction Biology Corp (Malvern, PA). 1 mg/mL of peptide subtrate (casein) and 10 uM ATP were prepared in a mixture of fresh reaction buffer. The kinase was delivered into the substrate solution which was gently mixed. Compounds in 100% DMSO were added to the kinase reaction mixture by Acoustic technology (Echo550; nanoliter range) and the mixture was incubated for 20 min at room temperature. ³³P- ATP (Specific activity 10 uCi/uL) was added into the reaction mixture to initiate the reaction and the reaction mixture was incubated for 2 hours at room temperature. Radioactivity was detected by filter-binding method and kinase activity data were expressed as the percent remaining kinase activity in test samples compared to vehicle (dimethyl sulfoxide) reactions. IC₅₀ values and curve fits were obtained using Prism (GraphPad Software). Results are reported in Table 26. TABLE 26

Table 26 Key: Compounds having an IC₅₀ value between 0.1 nM and 50 nM are denoted 50 nM and 100 nM as +++, 100 nM and 1000 nM as ++, and 1000 nM to 10,000 nM as +. The data in Table 26 shows that the ALK5 inhibitors of this disclosure are capable of diffusing into the cells and inhibiting ALK5 serine/threonine kinase activity at nanomolar and sub-nanomolar concentrations. TGFβ Reporter Assay The HEK293 SBE-LUC reporter cells from Example 1 were grown in DMEM-C with Geneticin (DMEM supplemented with 10% fetal bovine serum, 1X NEAA, 1mM Pyruvate, 2mM glutamine, 50 μg/mL penicillin, 50 U/mL streptomycin and 400 ug/mL of Geneticin). The assay media was MEM supplemented with 0.5% fetal bovine serum, 1X NEAA, 1 mM Pyruvate, 50 μg/mL penicillin and 50 U/mL streptomycin. The HEK293 SBE-LUC reporter cells were harvested from the tissue culture flasks by incubation in small quantity of Versene at room temperature for three to five minutes after the media in the flask is removed and cells rinsed with PBS. Cells were counted and diluted in the assay media at ~0.8 x 10⁶ cells/mL then 50 uL/well were added to 96-well assay plate. Test samples (at desired concentrations diluted in assay media) were added to assay plate containing the 50 uL/well of cells (or media only), 50 uL per well, and incubated for 5-6 hours at 37°C in a 5% CO₂ humidified incubator. After that time, 15 uL of TGFβ diluted to 12.5ng/mL in the assay media was added to the plate. Controls included TGFβ titration (from 25 to 0 ng/mL) without inhibitors, and media only (without cells, inhibitor or TGFβ). Plates were incubated at 37°C in a 5% CO₂ humidified incubator for 18h. Luciferase substrate solution was subsequently added at 75uL per well, incubated in dark with shaking at room temperature for 10 min, and luminescence

Table 27 Key: Compounds having an IC₅₀ value between 0.1 nM and 10 nM are denoted as ++++, 10 nM and 100 nM as +++, 100 nM and 1000 nM as ++, and 1000 nM to 10,000 nM as +. These data from the TGFbβ reporter assay demonstrate that ALK5 inhibitors are capable of diffusing into the cells and indirectly reducing expression of the luciferase reporter that is under the control of the SMAD-binding element (SBE) by inhibiting ALK5 activity. While aspects of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such aspects 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 disclosure. It should be understood that various alternatives to the aspects of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby. The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, including U.S. patent application Serial No. 62/912,783, filed October 9, 2019, and U.S. patent application Serial No. 63/047,252, filed July 2, 2020, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.

Claims

CLAIMS: 1. A conjugate of Formula (I):

wherein Region G comprises at least one GalNAc moiety; Region L³ is a connector that connects Region G to Region Inh; Region Inh comprises a TGFβR1 inhibitor; z is 1, 2, 3, 4, or 5; or a salt thereof. 2. The conjugate of claim 1, wherein the TGFβR1 inhibitor is a compound of Formula (A-I): wherein

one of M¹ and M² is

and the other of M¹ and M² is selected from:

R¹ and R² are, at each occurrence, independently selected from hydrogen, halogen, −OR¹¹, −SR¹¹, −N(R¹¹)₂, −NO₂, −CN, phenyl, and −C₁-C₆ alkyl, wherein said −C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from halogen, −OR¹¹, −SR¹¹, −S(O)R¹⁰, −S(O)2R¹¹, −S(O)2N(R¹¹)2 −N(R¹¹)2, −C(O)R¹⁰, −C(O)N(R¹¹)₂, −N(R¹¹)C(O)R¹⁰, −C(O)OR¹¹, −OC(O)R¹⁰, −NO₂, and −CN; R³ is, at each occurrence, independently selected from halogen, −C₁-C₃ alkyl, −C₁-C₃ haloalkyl, −OH, −NO₂, −CN, −OC₁-C₃ alkyl, and −OC₁-C₃ haloalkyl; each R⁴ is, at each occurrence, independently selected from hydrogen and C₁-C₃ alkyl or two R⁴ join together with atoms to which they are attached to form a 5- or 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, C₁-C₃ alkyl, −OH, OC₁-C₃ alkyl, and −OC₁-C₃ haloalkyl; R⁵ is hydrogen, halogen, −OR⁶¹, −SR⁶¹, −N(R⁶¹)₂, −NO₂, −CN, and −C₁-C₆ alkyl, wherein said −C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from halogen, −OR⁶¹, −SR⁶¹, −N(R⁶¹)₂, −NO₂, and −CN; R⁶ is, at each occurrence, independently selected from: halogen, −OR²¹, −SR²¹, −N(R²¹)₂, −C(O)R²⁰, −C(O)N(R²¹)₂, −N(R²¹)C(O)R²⁰ , −C(O)OR²¹, −OC(O)R²¹, −S(O)R²⁰, −S(O)₂R²¹, −S(O)₂N(R²¹)₂, −OC(O)OR²¹, −OC(O)N(R²¹)₂, −NR²¹C(=O)OR²¹, −N(R²¹)C(O)N(R²¹)_2, −NO₂, and −CN; C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, −OR²¹, −SR²¹, −N(R²¹)₂, −C(O)R²⁰, −C(O)N(R²¹)₂, −N(R²¹)C(O)R²⁰ , −C(O)OR²¹, −OC(O)R²¹, −S(O)R²⁰, −S(O)₂R²¹, −S(O)₂N(R²¹)₂, −OC(O)OR²¹, −OC(O)N(R²¹)₂, −NR²¹C(=O)OR²¹, −N(R²¹)C(O)N(R²¹)_2, −NO₂, =O, =S, =N(R²¹), −CN, a C₃-C₁₀ carbocycle, and a 3- to 10- membered heterocycle wherein said C₃-C₁₀ carbocycle and said 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from R^X; and a C₃-C₁₀ carbocycle and a 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, −OR²⁰, −OH, −SR²⁰, −SH, −N(R²¹)₂, −C(O)R²⁰, −C(O)N(R²¹)₂, −N(R²¹)C(O)R²⁰ , −C(O)OR²¹, −OC(O)R²¹, −S(O)R²⁰, −S(O)₂R²¹, −S(O)₂N(R²¹)₂, −OC(O)OR²¹, −OC(O)N(R²¹)₂, −NR²¹C(=O)OR²¹, −N(R²¹)C(O)N(R²¹)_2, −NO₂, =O, =S, =N(R²¹), −CN, −C₂-C₆ alkenyl, −C₂-C₆ alkynyl and C₁-C₆ alkyl wherein said C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from R^Y; R⁷ and R⁸ are independently selected from hydrogen, halogen, C₁-C₃ alkyl, −OH, OC₁-C₃ alkyl, and −OC₁-C₃ haloalkyl, or R⁷ and R⁸ join together with the atoms to which they are attached to form a C₅-C₆ carbocycle or 5- or 6- membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, −OR³¹, −SR³¹, −N(R³¹)₂, −NO₂, −CN and −C₁-C₆ alkyl wherein said C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from halogen, −OR³¹, −SR³¹, −N(R³¹)2, −NO2, and −CN; Y is selected from −O− and −N(R⁹)− and R⁹ is, at each occurrence, independently selected from: hydrogen; and −C₁-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen, −OR⁴¹, −SR⁴¹, −S(O)R⁴⁰, −S(O)₂R⁴¹, −S(O)₂N(R⁴¹)₂, −N(R⁴¹)₂, −C(O)R⁴⁰, −C(O)N(R⁴¹)₂, −N(R⁴¹)C(O)R⁴⁰ , −C(O)OR⁴¹, −OC(O)R⁴⁰, −NO₂, and −CN; each R¹⁰, R²⁰, and R⁴⁰ is independently selected at each occurrence from: −C₁-C₁₀ alkyl, −C₂-C₁₀ alkenyl, and −C₂-C₁₀ alkynyl, each of which is optionally substituted with one or more substituents independently selected from R^Y; and a C₃-C₁₂ carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from R^X; each R¹¹, R²¹, R³¹, R⁴¹, and R⁶¹ is independently selected at each occurrence from: hydrogen; −C₁-C₁₀ alkyl, −C₂-C₁₀ alkenyl, and −C₂-C₁₀ alkynyl, each of which is optionally substituted with one or more substituents independently selected from R^Y; and a C₃-C₁₂ carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from R^X, or two R¹¹, R²¹, R³¹, R⁴¹, or R⁶¹ on the same N atom are taken together with the N atom to which they are attached to form a N-containing heterocycle optionally substituted with R^X; each R^X is independently selected at each occurrence from: halogen, −OR⁵¹, −SR⁵¹, −N(R⁵¹)₂, −C(O)R⁵⁰, −C(O)N(R⁵¹)₂, −N(R⁵¹)C(O)R⁵⁰ , −C(O)OR⁵¹, −OC(O)R⁵¹, −S(O)R⁵⁰, −S(O)₂R⁵¹, −S(O)₂N(R⁵¹)₂, −OC(O)OR⁵¹, −OC(O)N(R⁵¹)₂, −NR⁵¹C(=O)OR⁵¹, −N(R⁵¹)C(O)N(R⁵¹)_2, −NO₂, =O, =S, =N(R⁵¹), −CN, −C₂-C₆ alkenyl, −C₂-C₆ alkynyl, and C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is optionally substituted with one or more substituents independently selected from −OR⁵¹, −SR⁵¹, −N(R⁵¹)₂, −C(O)R⁵⁰, −C(O)N(R⁵¹)₂, −N(R⁵¹)C(O)R⁵⁰ , −C(O)OR⁵¹, −OC(O)R⁵¹, −S(O)R⁵⁰, −S(O)₂R⁵¹, −S(O)₂N(R⁵¹)₂, −OC(O)OR⁵¹, −OC(O)N(R⁵¹)₂, −NR⁵¹C(=O)OR⁵¹, −N(R⁵¹)C(O)N(R⁵¹)₂, and =O; each R^Y is independently selected at each occurrence from: halogen, −OR⁵¹, −SR⁵¹, −N(R⁵¹)2, −C(O)R⁵⁰, −C(O)N(R⁵¹)2, −N(R⁵¹)C(O)R⁵⁰, −C(O)OR⁵¹, −OC(O)R⁵¹, −S(O)R⁵⁰, −S(O)₂R⁵¹, −S(O)₂N(R⁵¹)₂, −OC(O)OR⁵¹, −OC(O)N(R⁵¹)₂, −NR⁵¹C(=O)OR⁵¹, −N(R⁵¹)C(O)N(R⁵¹)_2, −NO₂, =O, =S, =N(R⁵¹), and −CN; each R⁵⁰ is independently selected at each occurrence from: −C₁-C₁₀ alkyl, −C₂-C₁₀ alkenyl, and −C₂-C₁₀ alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, −OH, −CN, −NO₂, −NH₂, =O, =S, −O−C₁-C₁₀ alkyl, C₃-C₁₂ carbocycle, and a 3- to 12-membered heterocycle; and a C₃-C₁₂ carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, −OH, −CN, −NO₂, −NH₂, =O, =S, −C₁-C₁₀ alkyl, −O−C₁-C₁₀ alkyl, and −C₁-C₁₀ haloalkyl; each R⁵¹ is independently selected at each occurrence from: hydrogen; −C₁-C₁₀ alkyl, −C₂-C₁₀ alkenyl, and −C₂-C₁₀ alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, −OH, −CN, −NO₂, −NH₂, =O, =S, −O−C₁-C₁₀ alkyl, C₃-C₁₂ carbocycle, and a 3- to 12-membered heterocycle; and a C₃-C₁₂ carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, −OH, −CN, −NO₂, −NH₂, =O, =S, −C₁-C₁₀ alkyl, −O−C₁-C₁₀ alkyl, and −C₁-C₁₀ haloalkyl; Z¹, Z², Z³, and Z⁴ are each independently selected from N or C(H); n is selected from 1, 2, and 3; m is 0, 1, or 2; s is selected from 0 and 1; and w is selected from 0, 1,

2, 3, 4, and 5; or a salt thereof.

3. The conjugate of claim 2, wherein the compound of Formula (A-I) is a compound of Formula (A-IA), (A-IB), (A-IC), (A-ID) or (A-IE):

wherein the remaining variables are as defined in claim 2.

4. The conjugate of claim 2, wherein

, wherein represents the point of attachment to

5. The conjugate of claim 1, wherein the the TGFβR1 inhibitor is a compound selected from: Cmpd. Cmpd. Structure Structure No. No. 1 46 2 47 3 48 4 49

and pharmaceutically acceptable salts thereof.

6. The conjugate of claim 1, wherein the TGFβR1 inhibitor is a compound of Formula (B-I):

wherein: M¹ and M² are independently selected from

and

; R¹ and R² are independently selected at each occurrence from: a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −C(O)N(R¹⁰)₂, −N(R¹⁰)C(O)R¹⁰ , −C(O)OR¹⁰, −OC(O)R¹⁰, −S(O)R¹⁰, −S(O)₂R¹⁰, −S(O)₂N(R¹⁰)₂, −P(O)(OR¹⁰)₂, −OP(O)(OR¹⁰)₂, −NO₂, and −CN; −C₁-C₁₀ alkyl, −C₂-C₁₀ alkenyl, and −C₂-C₁₀ alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −C(O)N(R¹⁰)₂, −N(R¹⁰)C(O)R¹⁰ , −C(O)OR¹⁰, −OC(O)R¹⁰, −S(O)R¹⁰, −S(O)₂R¹⁰, −S(O)₂N(R¹⁰)₂, −P(O)(OR¹⁰)₂, −OP(O)(OR¹⁰)₂, −NO₂, =O, =S, =N(R¹⁰), −CN, a C₃-C₁₀ carbocycle, and a 3- to 10-membered heterocycle; and a C₃-C₁₀ carbocycle and a 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −C(O)N(R¹⁰)₂, −N(R¹⁰)C(O)R¹⁰ , −C(O)OR¹⁰, −OC(O)R¹⁰, −S(O)R¹⁰, −S(O)₂R¹⁰, −S(O)₂N(R¹⁰)₂, −P(O)(OR¹⁰)₂, −OP(O)(OR¹⁰)₂, −NO₂, =O, =S, =N(R¹⁰), −CN, −C₁-C₆ alkyl, −C₂-C₆ alkenyl, and −C₂-C₆ alkynyl; R³ is selected from hydrogen and −C1-C10 alkyl optionally substituted with one or more substituents independently selected from a halogen, −NO₂, =O, =S, =N(R¹⁰), −CN, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −C(O)N(R¹⁰)₂, −N(R¹⁰)C(O)R¹⁰ , −C(O)OR¹⁰, and −OC(O)R¹⁰; n and m are independently selected from 0, 1, 2, 3, and 4; Q is selected from a bond, −(CR¹⁰ 2)_p−, −(CR¹⁰ 2)_qC(=O)(CR¹⁰ 2)_q−, −(CR¹⁰ 2)_qC(=S)(CR¹⁰ 2)_q−, −(CR¹⁰ 2)_qC(=NR¹⁰)(CR¹⁰ 2)_q−, −(CR¹⁰ 2)_qO(CR¹⁰ 2)_q−, −(CR¹⁰ 2)_qS(CR¹⁰ 2)_q−, −(CR¹⁰ 2)_qN(R¹⁰)(CR¹⁰ 2)_q−, −(CR¹⁰ 2)_qOC(=O)O(CR¹⁰ 2)_q−, −(CR¹⁰ 2)qC(=O)N(R¹⁰)(CR¹⁰ 2)q−, −(CR¹⁰ 2)qN(R¹⁰)C(=O)(CR¹⁰ 2)q−, and −(CR¹⁰ 2)_qN(R¹⁰)SO₂(CR¹⁰ 2)_q−; p is selected from 1, 2, 3, 4, and 5; q is independently selected at each occurrence from 0, 1, 2, 3, 4, and 5; T is selected from an optionally substituted saturated C₃-C₇ carbocycle, an optionally substituted C_5-12 bicyclic carbocycle, and an optionally substituted 4- to 12-membered heterocycle, wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³; R¹³ is independently selected at each occurrence from: a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −C(O)N(R¹⁰)₂, −N(R¹⁰)C(O)R¹⁰ , −C(O)OR¹⁰, −OC(O)R¹⁰, −S(O)R¹⁰, −S(O)₂R¹⁰, −S(O)₂N(R¹⁰)₂, −P(O)(OR¹⁰)₂, −OP(O)(OR¹⁰)₂, −NO₂, =O, =S, =N(R¹⁰), and −CN; −C₁-C₁₀ alkyl, −C₂-C₁₀ alkenyl, and −C₂-C₁₀ alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −C(O)N(R¹⁰)₂, −N(R¹⁰)C(O)R¹⁰ , −C(O)OR¹⁰, −OC(O)R¹⁰, −S(O)R¹⁰, −S(O)₂R¹⁰, −S(O)₂N(R¹⁰)₂, −P(O)(OR¹⁰)₂, −OP(O)(OR¹⁰)₂, −NO₂, =O, =S, =N(R¹⁰), −CN, a C₃-C₁₀ carbocycle, and a 3- to 10-membered heterocycle; and a C₃-C₁₀ carbocycle and a 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from a halogen, −OR¹⁰, −SR¹⁰, −N(R¹⁰)₂, −C(O)R¹⁰, −C(O)N(R¹⁰)₂, −N(R¹⁰)C(O)R¹⁰ , −C(O)OR¹⁰, −OC(O)R¹⁰, −S(O)R¹⁰, −S(O)₂R¹⁰, −S(O)₂N(R¹⁰)₂, −P(O)(OR¹⁰)₂, −OP(O)(OR¹⁰)₂, −NO₂, =O, =S, =N(R¹⁰), −CN, −C₁-C₆ alkyl, −C₂-C₆ alkenyl, and −C₂-C₆ alkynyl; and R¹⁰ is independently selected at each occurrence from: hydrogen; −C₁-C₁₀ alkyl, −C₂-C₁₀ alkenyl, and −C₂-C₁₀ alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, −OH, −CN, −NO₂, −NH₂, =O, =S, −O−C₁-C₁₀ alkyl, C₃-C₁₂ carbocycle, and a 3- to 12-membered heterocycle; and a C₃-C₁₂ carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, −OH, −CN, −NO₂, −NH₂, =O, =S, −C₁-C₁₀ alkyl, −O−C₁-C₁₀ alkyl, and −C₁-C₁₀ haloalkyl; or a salt thereof.

7. The conjugate of claim 6, wherein the compound of Formula (B-I) is a compound of Formula (B-Ia), (B-Ib), (B-Ic), (B-Id), or (B-Ie):

wherein the variables are defined as in claim 6; or a salt thereof.

8. The conjugate of claim 6 or claim 7, wherein: Q is selected from −CH₂−, −CH₂NH−, −CH₂NHCH₂−, and −CH₂NHCH₂CH₂−; T is selected from: ,

wherein T is optionally substituted with one or more substituents independently selected at each occurrence from R¹³, wherein R¹³ is independently selected at each occurrence from halogen, −OH, −NH₂, and −C₁-C₃ alkyl.

9. The conjugate of claim 1, wherein the TGFβR1 inhibitor is selected from:

and pharmaceutically acceptable salts thereof.

10. The conjugate of claim 1, wherein the TGFβR1 inhibitor is a compound of Formula (C-I):

(C-I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein: L is −[CR′₂]p−L’−[CH₂]q− L’ is absent, −S−, −O−, or −NH−; A is absent, carbocycle, or heterocycle; Q³ is N or CR³; Q⁴ is N or CR⁴; Q⁵ is N or CR⁵; Q⁶ is N or CR⁶; R¹ is hydrogen, C1–3 alkyl, or C1–3 haloalkyl; R² is, at each occurrence, independently halo, C_1–3 alkyl, C_1-3 alkoxy, C_1–3 haloalkyl, or C_1-3 haloalkoxy; R³ is H, halo, C_1–3alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁴ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁵ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁶ is H, halo, C_1–3 alkyl, C_1–3haloalkyl, or C_1–3 alkoxy; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to a GalNAc moiety; R⁹ is, at each occurrence, independently halo, −OR′, −SR′, −N(R′)₂, −C(O)R′, −C(O)N(R′)₂, −N(R′)C(O)R′_, −C(O)OR′, −OC(O)R′, −S(O)R′, −S(O)₂R′, −S(O)₂OR′, −P(O)(OR′)₂, −OP(O)(OR′)₂, −NO₂, =O, −CN, C_1–4 alkyl, C_2–5 alkenyl, C_2–5 alkynyl, C_1-4 haloalkyl, C_2–5 haloalkenyl, C_2–5 haloalkynyl, carbocycle, or heterocycle; wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ are each substituted with 0–3 R¹⁰; R¹⁰ is, at each occurrence, independently C_1–3 alkoxy or C_1–3 haloalkoxy; R′ is, at each occurrence, independently hydrogen, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, or C_1–6 haloalkyl; m is 0–3; n is 0–5; p is 1-3; and q is 0-3.

11. The conjugate of claim 10, wherein the compound of Formula (C-I) is a compound of Formula (C-II), (C-II-A), (C-II-B), (C-II-C), (C-III-A), (C-III-C), (C-III-C), (C-IV-A), (C-IV-B), (C-IV-C), (C-V-A), (C-V-B), (C-V-C), (C-IV-A), (C-VI-B), OR (C-VI-C):

wherein the variables are defined as in claim 10; or a salt thereof.

12. The conjugate of claim 1, wherein the TGFβR1 inhibitor is selected from:

Structure

or a salt thereof.

13. The conjugate of claim 1, wherein the TGFβR1 inhibitor is a compound of Formula (D-I):

(D-I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein: Q^A is CR^A or N; Q^B is CR^B; Q³ is N or CR³; Q⁴ is N or CR⁴; Q⁵ is N or CR⁵; R^A is H, halo, C_1-3 alkyl, or C_1-3 haloalkyl and R^B is ^{A B}

, or R and R , together with the atoms to which they are attached, form a heterocyclic ring; R^a and R^b are each H, or R^a and R^b, together with the atoms to which they are attached, form a heterocyclic ring; ring B is carbocycle or heterocycle; R¹ is H, C_1-3 alkyl, or C_1-3 haloalkyl; R² is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R³ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R⁴ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; R⁵ is H, halo, C_1-3 alkyl, C_1-3 alkoxy, C_1-3 haloalkyl, or C_1-3 haloalkoxy; wherein R¹, R², R³, R⁴, and R⁵ are, at each occurrence, independently substituted with 0-3 R¹⁰; R⁷ is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R⁹ is, at each occurrence, independently halo, C_1-3 alkyl, C_1-3 haloalkyl, C_1-3 alkoxy, or C_1-3 haloalkoxy; R¹⁰ is, at each occurrence, independently C_1-3 alkoxy or C_1-3 haloalkoxy; m is 0–3; and n is 0–5.

14. The conjugate of claim 13, wherein the compound of Formula (D-I) is a compound of Formula (D-II), (D-III), (D-IV), (D-V), (D-VI), (D-IV-A), (D-VI-B), (D-VII), (D-VIII), (D-VIII-A), (D-VIII-B), (D-IX), (D-IX-A), OR (D-IX-B), or a salt thereof:

wherein the variables are defined as in claim 13; or a salt thereof.

15. The conjugate of claim 1, wherein the TGFβR1 inhibitor is selected from:

or a salt thereof.

16. The conjugate of any one of claims 1 to 15, wherein Region G comprises a structure of Formula (V):

wherein n is 1, 2, or 3; SP is a spacer, wherein each SP is independently a heteroalkylene, heteroalkenylene, or heteroalkynylene comprising 5 to 30 components in the longest linear chain, wherein the components are selected from −CH₂−, −CH(C_1-4alkyl), −C(C_1-4alkyl)₂, −CH=CH−, −C≡C−, −C(O)−, −O−, −NH−, −N(C1-4alkyl), −S−, −S(O)−, −S(O)2−, and −P(O)(O⁻)−; and DE is a branched Display Element, wherein the asterisk (*) is the position of connection to the rest of the conjugate.

17. The conjugate of claim 16, wherein n is 2 or 3.

18. The conjugate of claim 16, wherein n is 3.

19. The conjugate of any one of claims 16 to 18, wherein one or more SP units comprise an ethylene glycol or poly(ethylene glycol) region, an amide bond, or an unsubstituted ethylene or propylene unit.

20. The conjugate of any one of claims 16 to 19, each SP is −(CH₂)₂−C(O)−NH−(CH₂)_x−CH₂− (where x is 1, 2, 3, 4, 5, or 6, or x is 1, 2, or 3, or x is 1, or x is 3, or x is 4, or x is 5); −CH₂−(CH₂)_a−CH₂−NH−C(O)−(CH₂)_b−, where a is 0, 1, 2, or 3 (or a is 1 or 2, or a is 1); and b is 1, 2, 3, 4, 5, or 6 (or b is 3, 4, or 5, or b is 5); −C(O)−NH−(CH₂)_(a+2)−NH−C(O)−(CH₂)_b−, where a is 0, 1, 2, or 3 (or a is 1) and b is 1, 2, 3, 4, 5, or 6 (or b is 3, 4, or 5, or b is 5); or −C(O)−NH−(CH₂)_p− where p is 2, 3, 4, 5, or 6 (or p is 2, or p is 4, or p is 6)..

21. The conjugate of any one of claims 16 to 20, wherein the Display Element (DE) comprises a central atom unit and two or three Arm Elements (AE) attached to the central atom unit that connect DE to each SP.

22. The conjugate of claim 21, wherein the central atom unit is methine (CH), carbon (C), nitrogen (

23. The conjugate of claim 21 or 22, wherein each AE is independently −(CH₂)_1-3O−, −(CH₂)_1-3NR−, −NR−, −(CH₂)_1-3−, or a bond, wherein each CH₂ is optionally substituted with one or more C_1-4alkyl or fluoro substituents, and R is H or C_1-4alkyl.

24. The conjugate of claim 16, wherein DE is one of the following structures:

.

25. The conjugate of claim 16, wherein Region G has the structure:

where x is 1, 2, 3, 4, 5, or 6.

26. The conjugate of claim 16, wherein Region G has the structure:

wherein a is 0, 1, 2, or 3; and b is 1, 2, 3, 4, 5, or 6.

27. The conjugate of claim 16, wherein Region G has the structure:

wherein each p is independently 2, 3, 4, 5, or 6.

28. The conjugate of any one of claims 1 to 27, wherein Region L³ comprises a dipeptide.

29. The conjugate of claim 28, wherein the dipeptide is Val−Cit.

30. The conjugate of any one of claims 1 to 29, wherein Region L³ comprises a para-aminobenzyl moiety.

31. The conjugate of any one of claims 1 to 30, wherein Region L³ comprises −NHC(O)−(CH₂)_p−C(O)− where p is 2, 3, 4, 5, or 6.

32. The conjugate of claim 31, wherein Region L³ is −NHC(O)−(CH₂)_p−C(O)−Val−Cit−PAB−O−C(O)−.

33. A conjugate selected from:

and pharmaceutically acceptable salts thereof.

34. A pharmaceutical composition comprising the conjugate of any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof.

35. A method of treating a disease mediated by TGFβR1 activity in a subject in need thereof comprising administering to the subject an effective amount of a conjugate of any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof.

36. The method of claim 35, wherein the disease is a viral infection, Hepatitis B, Hepatatis C, cancer, liver cancer, hepatocellular carcinoma, fibrosis, liver fibrosis, scleroderma, systemic fibrosis, steatohepatitis, or non-alcoholic steatohepatitis.

37. A compound of Formula (XX): [Inh]−Z (XX) wherein Region Inh comprises a TGFβR1 inhibitor; and Z is the residual portion of a released, cleavable linker or comprises a non- cleavable linker and a residual portion of a degraded Region G; or a pharmaceutically acceptable salt thereof.