Heterobifunctional molecules for binding MRGX2 and methods of treating medical conditions using same

Abstract

The invention provides heterobifunctional cotinine-containing compounds, pharmaceutical compositions, and methods of using same to treat medical conditions, such as a mast cell disease or pain.

Description

HETEROBIFUNCTIONAL MOLECULES FOR BINDING MRGX2 AND METHODS OF TREATING MEDICAL CONDITIONS USING SAME CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 695,583, filed September 17, 2024, the contents of which are hereby incorporated by reference in their entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] This application contains a Sequence Listing which has been submitted electronically via Patent Center in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on September 16, 2025, is named 221527_seqlist.xml and is 15,200 bytes in size. FIELD OF THE INVENTION

[0003] The invention provides heterobifunctional cotinine-containing compounds, pharmaceutical compositions, and methods of using same to treat medical conditions, such as a mast cell disease or pain. BACKGROUND

[0004] Mast cells play an important role in a variety of inflammatory and / or autoimmune diseases, such as urticaria, atopic dermatitis, inflammatory bowel disease, and asthha. Urticaria often features the sensation of itch in the affected skin. Skin mast cells, in particular the MCTC subtype, are a primary effector cell in urticaria. Because histamine released from mast cells contributes to urticaria, one approach for treating urticaria that has been described previously is use of anti-histamines. However, despite significant research into the causes of, and treatments for, urticaria and other mast-cell-related diseases, existing therapies are not effective for all patients and / or can have adverse side effects.

[0005] Pain can function as a protective mechanism that allows healthy human beings and animals to avoid tissue damage and / or prevent further damage to injured tissue. However, there are many instances in which pain persists beyond its usefulness. Such unnecessary suffering from pain can impair a subject’s physical mobility, mental performance, and even contribute to depression. Such unnecessary suffering from pain can be due to acute pain and / or chronic pain.Such pain can also be characterized according to whether the pain is neuropathic pain or nociceptive pain. Substantial resources have been devoted over the years to researching the causes of various types of pain and to the development of medicine to attenuate pain experienced by a patient. Exemplary classes of common pain-relief medications include opioids, non-steroidal anti- inflammatory agents, corticosteroids, and centrally acting agents such as anti-depressants and anti- epileptics. However, existing therapies for treating pain are not effective for all patients and / or can have adverse side effects.

[0006] Mas-related G-protein-coupled receptor X2 (MRGX2) is expressed in cutaneous mast cells, sensory neurons, and keratinocytes. Treatment of conditions involving these cell types, such as inflammatory conditions, autoimmune conditions, and pain, has been reported for molecules that inhibit MRGX2. See, for example, International Patent Application Publications WO 2020 / 223255 and WO 2022 / 073904.

[0007] The use of heterobifuctional compounds that are able to simultaneously bind a target cell-surface protein as well as an exogenous antibody protein are described in, for example, international patent application publication nos. WO 2018 / 134731, WO 2023 / 017484, and WO 2023 / 017483. Such heterobifuctional compounds are used with an anti-cotinine antibody to treat a variety of medical diseases and conditions. Additional heterobifunctional cotinine-containing compounds that bind MRGX2 and an exogenous antibody protein are needed and would provide benefits to patients suffering from MRGX2-associated diseases and conditions, such as mast cell diseases or pain.

[0008] The present invention addresses the foregoing need and provides other related advantages. SUMMARY

[0009] The invention provides heterobifunctional cotinine-containing compounds, pharmaceutical compositions, and methods of using same to treat medical conditions, such as a mast cell disease or pain. In particular, one aspect of the invention provides a collection of heterobifunctional cotinine-containing compounds represented by Formula I:or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heterobifunctional cotinine- containing compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0010] The heterobifunctional compounds bind to Mas-related G-protein-coupled receptor X2(MRGX2). The heterobifunctional compounds also bind to an anti-cotinine antibody or fragment thereof that binds cotinine. In this way, the heterobifunctional compounds may be characterized as an antibody recruiting molecule (ARM).

[0011] Another aspect of the invention provides a method of treating or preventing aMRGX2-associated disease or condition in a patient in nyyy thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a heterobifunctional compound described herein (such as a compound of Formula I) and an anti-cotinine antibody, or antigen-binding fragment thereof.

[0012] Another aspect of the invention provides a method of treating or preventing a mast celldisease in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a heterobifunctional compound described herein (such as a compound of Formula I) and an anti-cotinine antibody, or antigen-binding fragment thereof.

[0013] Another aspect of the invention provides a method of treating or preventing a diseaseselected from the group consisting of urticaria, prurigo nodularis, atopic dermatitis, psoriasis, allergic rhinitis, asthma, systemic mastocytosis, mast cell activation syndrome, inflammatory bowel disease, anaphylaxis, food allergy, and insert sting in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a heterobifunctional compound described herein (such as a compound of Formula I) and an anti- cotinine antibody, or antigen-binding fragment thereof.

[0014] Another aspect of the invention provides a method of treating or preventing pain in apatient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a heterobifunctional compound described herein (such as a compound of Formula I) and an anti-cotinine antibody, or antigen-binding fragment thereof. Another aspect of the invention provides a method of increasing antibody-dependent cell cytotoxicity (ADCC) of MRGX2-expressing cells, comprising contacting the cells with an effective amount of a heterobifunctional compound described herein (such as a compound of Formula I) and an anti-cotinine antibody, or antigen-binding fragment thereof. In certain embodiments, the MRGX2-expressing cells are mast cells. Another aspect of the invention provides a method of depleting MRGX2-expressing cells, comprising contacting the cells with an effective amount of a heterobifunctional compound described herein (such as a compound of Formula I) and an anti-cotinine antibody, or antigen- binding fragment thereof. In certain embodiments, the MRGX2-expressing cells are mast cells.

[0015] Another aspect of the invention provides a combination comprising aheterobifunctional compound described herein (such as a compound of Formula I) and an anti- cotinine antibody, or antigen-binding fragment thereof. DETAILED DESCRIPTION

[0016] The invention provides heterobifunctional cotinine-containing compounds,pharmaceutical compositions, and methods of using same to treat medical conditions, such as a mast cell disease or pain. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D.M. Weir & C.C. Blackwell, eds.); “Current protocols in molecular biology” (F.M. Ausubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (J.E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety.

[0017] Various aspects of the invention are set forth below in sections; however, aspects ofthe invention described in one particular section are not to be limited to any particular section.Further, when a variable is not accompanied by a definition, the previous definition of the variable controls. Definitions

[0018] Compounds of the present invention include those described generally herein, and arefurther illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0019] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e.,unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0020] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclicring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation,having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:

[0021] Exemplary bridged bicyclics include:.

[0022] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplarylower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0023] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that issubstituted with one or more halogen atoms.

[0024] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0025] The term “unsaturated,” as used herein, means that a moiety has one or more units ofunsaturation.

[0026] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight orbranched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0027] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is apolymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0028] The term “-(C0 alkylene)-“ refers to a bond. Accordingly, the term “-(C0-3 alkylene)-”encompasses a bond (i.e., C0) and a -(C1-3alkylene)- group.

[0029] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylenechain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0030] The term “halogen” means F, Cl, Br, or I.

[0031] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or“aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “phenylene” refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it. For example, “phenylene” is a bivalent phenyl group when it has two groups attached t “phenylene” is a trivalent phenyl group when it has three groups attachedThe term “arylene” refers to a bivalent aryl group.

[0032] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g.,“heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or9 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0033] The term “heteroarylene” refers to a multivalent heteroaryl group having the appropriatenumber of open valences to account for groups attached to it. For example, “heteroarylene” is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it.

[0034] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and“heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl).

[0035] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “oxo-heterocyclyl” refers to a heterocyclyl substituted by one or more oxo group. The term “heterocyclylene” refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it. The term “oxo-heterocyclylene” refers to a multivalent oxo-heterocyclyl group having the appropriate number of open valences to account for groups attached to it.

[0036] As used herein, the term “partially unsaturated” refers to a ring moiety that includes atleast one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0037] As described herein, compounds of the invention may contain “optionally substituted”moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasiblecompounds. The term “stable,” as used herein, refers to compounds that are not substantiallyaltered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0038] Each optional substituent on a substitutable carbon is a monovalent substituentindependently selected from halogen; –(CH2)0–4R^; –(CH2)0–4OR^; -O(CH2)0-4Ro, –O–(CH2)0– 4C(O)OR°; –(CH2)0–4CH(OR^)2; –(CH2)0–4SR^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; – N3; -(CH2)0–4N(R^)2; –(CH2)0–4N(R^)C(O)R^; –N(R^)C(S)R^; –(CH2)0–4N(R^)C(O)NR^2; -N(R^)C(S)NR^2; –(CH2)0–4N(R^)C(O)OR^; –N(R^)N(R^)C(O)R^; -N(R^)N(R^)C(O)NR^2; -N(R^)N(R^)C(O)OR^; –(CH2)0–4C(O)R^; –C(S)R^; –(CH2)0–4C(O)OR^; –(CH2)0–4C(O)SR^; -(CH2)0–4C(O)OSiR^3; –(CH2)0–4OC(O)R^; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R^; –(CH2)0–4C(O)NR^2; –C(S)NR^2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR^2;-C(O)N(OR^)R^; –C(O)C(O)R^; –C(O)CH2C(O)R^; –C(NOR^)R^; -(CH2)0–4SSR^; –(CH2)0–4S(O)2R^; –(CH2)0–4S(O)2OR^; –(CH2)0–4OS(O)2R^; –S(O)2NR^2; –S(O)(NR^)R^; – S(O)2N=C(NR^2)2; -(CH2)0–4S(O)R^; -N(R^)S(O)2NR^2; –N(R^)S(O)2R^; –N(OR^)R^; – C(NH)NR^2; –P(O)2R^; -P(O)R^2; -OP(O)R^2; –OP(O)(OR^)2; SiR^3; –(C1–4 straight or branched alkylene)O–N(R^)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R^)2.

[0039] Each R^ is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R^ selected from =O and =S; or each R^ is optionally substituted with a monovalent substituent independently selected from halogen, –(CH2)0–2R●, –(haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, – (CH2)0–2CH(OR●)2; -O(haloR●), –CN, –N3, –(CH2)0–2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, –(CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR●, –(CH2)0–2NR●2, –NO2, –SiR●3, –OSiR●3, -C(O)SR●, –(C1–4 straight or branched alkylene)C(O)OR●, or –SSR●.

[0040] Each R^ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R●is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or – S(C(R*2))2–3S–, or a divalent substituent bound to vicinal substitutable carbons of an “optionallysubstituted” group is –O(CR*2)2–3O–, wherein each independent occurrence of R* is selectedfrom hydrogen, C1–6aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0041] When R* is C1–6R●, -(haloR●aliphatic, R* is optionally substituted with halogen, –), -OH, –OR●, –O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or –NO2, wherein each R●is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R●is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0042] An optional substituent on a substitutable nitrogen is independently –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, – C(NH)NR†2,† †wherein each R†is independently hydrogen, C1–6aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R†is C1–6aliphatic, R†is optionally substituted with halogen, –R●, -(haloR●), -OH, –OR●, – O(haloR●), –CN, –C(O)OH, –C(O)OR●, –NH2, –NHR●, –NR●2, or –NO2, wherein each R●is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, and wherein each R●is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0043] As used herein, the term "pharmaceutically acceptable salt" refers to those salts whichare, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0044] Further, acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference.

[0045] Salts derived from appropriate bases include alkali metal, alkaline earth metal,ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0046] Unless otherwise stated, structures depicted herein are also meant to include all isomeric(e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0047] Diastereomeric mixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.

[0048] Individual stereoisomers of the compounds of the invention may, for example, besubstantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as an atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this invention.

[0049] Chemical names, common names, and chemical structures may be usedinterchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0050] The terms “a” and “an” as used herein mean “one or more” and include the pluralunless the context is inappropriate.

[0051] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as astraight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10alkyl, and C1-C6alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0052] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridgedcyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group.

[0053] The term “haloalkyl” refers to an alkyl group that is substituted with at least onehalogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term “haloalkylene” refers to a bivalent haloalkyl group.

[0054] The term “hydroxyalkyl” refers to an alkyl group that is substituted with at least onehydroxyl. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0055] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturatedaliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0056] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, asdefined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like.

[0057] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, acyclopentane susbstituted with an oxo group is cyclopentanone.

[0058] The symbol “ ” indicates a point of attachment.

[0059] When any substituent or variable occurs more than one time in any constituent or thecompound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0060] One or more compounds of the invention may exist in unsolvated as well as solvatedforms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.

[0061] As used herein, the terms “subject” and “patient” are used interchangeable and refer toorganisms to be treated by the methods of the present invention. Such organisms preferablyinclude, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

[0062] The term “IC50” is art-recognized and refers to the concentration of a compound that isrequired to achieve 50% inhibition of the target.

[0063] As used herein, the term “effective amount” refers to the amount of a compoundsufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0064] As used herein, the term “pharmaceutical composition” refers to the combination of anactive agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0065] As used herein, the term “pharmaceutically acceptable carrier” refers to any of thestandard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0066] For therapeutic use, salts of the compounds of the present invention are contemplatedas being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0067] In addition, when a compound of the invention contains both a basic moiety (such as,but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention may be formed,for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0068] Throughout the description, where compositions are described as having, including, orcomprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0069] As a general matter, compositions specifying a percentage are by weight unlessotherwise specified. I. Heterobifunctional Cotinine-Containing Compounds

[0070] One aspect of the invention provides heterobifunctional cotinine-containingcompounds. The compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds. Part A: Compounds of Formula I

[0071] One aspect of the invention provides a compound represented by Formula I:or a pharmaceutically acceptable salt thereof, wherein: R1is C1-4alkyl or C3-6cycloalkyl; X1is a C1-10 bivalent saturated straight or branched hydrocarbon chain wherein one, two, three, or four methylene units of the chain are independently replaced by -N(H)-, -N(CH3)-,-O-, or -C(O)-; or X1is -N(H)-, -N(CH3)-, or a 5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms which are nitrogen; X2is ɸ-(C1-5 alkylene)-N(H)- or a covalent bond, wherein ɸ is a bond to L; Y1is defined by Formula I-1 that is substituted by one occurrence of R4, wherein Formula I-1 is represented by:wherein: A1is a 9- or 10-membered bicyclic heteroaryl containing 1 or 2 heteroatoms which are nitrogen, wherein the heteroaryl is substituted with 0, 1, or 2 occurrences of R2; A2is phenyl, a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 heteroatoms which are nitrogen, or a 9- or 10-membered bicyclic heteroaryl containing 1 or 2 heteroatoms which are nitrogen; each of which is substituted with 0, 1, or 2 occurrences of R3; R2represents independently for each occurrence C1-4haloalkyl, halo, or C1-4alkyl; R3represents independently for each occurrence C1-4 alkyl, C1-4 alkoxyl, halo, -N(R5)S(O)2-(C1-4 alkyl), -N(R5)S(O)2-(phenyl), -N(R5)C(O)-(C1-4 alkyl), or -N(R5)-(C1-4 alkyl); R4is a bond to X1; R5represents independently for each occurrence H or C1-3 alkyl; and L is a divalent linker selected from: (i) a bivalent, saturated or unsaturated, straight or branched C1-60hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, - S-, -N(H)-, -N(C1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C1-6 alkyl)-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C1-6alkyl)-, -OC(O)N(H)-, -OC(O)N(C1-6alkyl)-, -N(H)C(O)O- , -N(C1-6 alkyl)C(O)O-, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5-6membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein Ring A and Ring B are each independently C4-6cycloalkylene; L1ais C3-5linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3 alkyl; and L2ais -O-, -NHC(O)-, or -CH2-O-; (iii)) wherein Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; L1bis -CH2-NH-C(O)-, -NHC(O)-, or -C(O)NH-; L2bis C6-12linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR1b-, -wherein n is 1, 2, 3, or 4, and represents a covalent bond to L1b; and each R1bis independently hydrogen or C1-3alkyl; (iv)(L-c) wherein L1cis C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; Ring A is C4-6cycloalkylene or C7-9bridged bicyclic cycloalkylene; and L2cis -O- or a saturated C2-10linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-; (v)(L-d) wherein L1dis C12-22 linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-;(vii) (L-f) wherein L1fis a bond; C1-6 linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-, -NH-, or -C(O)-; or -(C3-6cycloalkylene)-NHC(O)-; L2fis a bond, -NHC(O)-, -C(O)NH-, or a C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-; and each of Z1and Z2is independently N or CH; (viii)(L-g) wherein Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; L1gis a bond, -CH2-, -NH-, or -O-; and L2giswherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bond to L1g;1hrepresents a covalent bond to L3h; L3his a bond, -C(O)CH2-, -O-(C3-6 cycloalkylene)-O-, or -C(O)NH(CH2)3OCH2-; L4his a bond, -C(O)-, -CH2C(O)-, or - C(O)CH2-; and m is 1, 2, or 3;bond to L3iandrepresents a covalent bond to NH; L2iis a bond, C1-12 linear alkylene, or, wherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bond to HN; and L3iis a bond or -C(O)-; and Z is independently CH or N, provided that no more than two of Z , Z , Z and Z are N; L1jis -NH-, -C(O)NH-, -NHC(O)-, or -O-; L2jis C1-6 linear alkylene orrepresents a covalent bond to L1j; andrepresents a single bond or a double bond;wherein Ring A is phenylene or a 5- or 6-membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z1and Z2is independently CH or N; L1kis a bond, -C(O)-, -C(O)NH-, or -NHC(O)-; and L2kis a C3-8 *** **straight chain alkylene or, wherein n is 1, 2, or 3, and represents a covalent bond to L1k;- y y , , , covalent bond to L1m;C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)2NH-, or -NHS(O)2-; and L2pis –(4-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-C(O))-; or (xvi)wherein Ring A, Ring B, Ring C, and Ring D are each independently C4-6 cycloalkylene; L1qand L3qare each independently C3-5linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3alkyl; and L2qand L3qare each independently -O-, -NHC(O)-, or -CH2-O-; and wherein eachrepresents a covalent bond to X1, and eachrepresents a covalent bond to X2.

[0072] The definitions of variables in Formula I above encompass multiple chemical groups.The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).

[0073] In certain embodiments, the compound is a compound of Formula I.

[0074] As generally defined above, R1 is C1-4 alkyl or C3-6 cycloalkyl. In certainembodiments, R1is C1-4 alkyl. In certain embodiments, R1is -CH3. In certain embodiments, R1is C3-6cycloalkyl. In certain embodiments, R1is cyclopropyl. In certain embodiments, R1is selected from the groups depicted in the compounds in Tables 1, 2, 3, 4, 5, and 6, below. In certain embodiments, R1is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments, R1is selected from the groups depicted in the compounds in Tables 4, 5, and 6, below.

[0075] As generally defined above, X1 is a C1-10 bivalent saturated straight or branchedhydrocarbon chain wherein one, two, three, or four methylene units of the chain are independently replaced by -N(H)-, -N(CH3)-, -O-, or -C(O)-; or X1is -N(H)-, -N(CH3)-, or a 5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms which are nitrogen. In certain embodiments, X1is -N(H)-, -N(CH3)-, or a 5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms which are nitrogen.

[0076] In certain embodiments, X1 is a C1-10 bivalent saturated straight or branchedhydrocarbon chain wherein one, two, three, or four methylene units of the chain are independently replaced by -N(H)-, -N(CH3)-, -O-, or -C(O)-. In certain embodiments, X1is a C1-10 bivalent saturated straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are independently replaced by –N(H)-, –N(CH3)-, or -O-. In certain embodiments, X1is a C2-8bivalent saturated straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are independently replaced by –N(H)- or -O-. In certain embodiments, X1is a C1-10 bivalent saturated straight hydrocarbon chain wherein one, two, or three methylene units of the chain are independently replaced by –N(H)-, –N(CH3)-, or - O-. In certain embodiments, X1is a C1-10bivalent saturated straight or branched hydrocarbon chain wherein one, two, or three methylene units of the chain are independently replaced by – N(H)- or -O-. In certain embodiments, X1is a C1-10 bivalent saturated straight hydrocarbon chain wherein one, two, or three methylene units of the chain are independently replaced by –N(H)- or -O-.

[0077] In certain embodiments, X1 is -(C0-4 alkylene)-N(H)-, wherein the nitrogen atom of X1is attached to L. In certain embodiments, X1is -(C0-3alkylene)-N(H)-, wherein the nitrogen atom of X1is attached to L. In certain embodiments, X1is a C2-4 bivalent saturated straight hydrocarbon chain wherein one methylene unit of the chain is replaced by -N(H)-. In certain embodiments, X1is -(C1-3alkylene)-N(H)-, wherein the nitrogen atom of X1is attached to L. Incertain embodiments, X1is -(propylene)-N(H)-, wherein the nitrogen atom of X1is attached to L. In certain embodiments, X1is -(CH2)2-N(H)-, wherein the nitrogen atom of X1is attached to L. In certain embodiments, X1is -(CH2)-N(H)-, wherein the nitrogen atom of X1is attached to L. In certain embodiments, X1is -N(H)-.

[0078] In certain embodiments, X1 is -N(H)- or -N(CH3)-. In certain embodiments, X1 is-N(CH3)-.

[0079] In certain embodiments, X1 is -O-(C2-4 alkylene)-N(H)-, wherein the nitrogen atom ofX1is attached to L. In certain embodiments, X1is -O-(CH2CH2CH2)-N(H)-, wherein the nitrogen atom of X1is attached to L.

[0080] In certain embodiments, X1 is -(C2-3 alkylene)-O-(C2-4 alkylene)-N(H)-, wherein thenitrogen atom of X1is attached to L. In certain embodiments, X1is -(C2-3alkylene)-O-(C2-3alkylene)-N(H)-, wherein the nitrogen atom of X1is attached to L. In certain embodiments, X1is -(CH2CH2)-O-(CH2CH2CH2)-N(H)-, wherein the nitrogen atom of X1is attached to L. In certain embodiments, X1is -(CH2CH2)-O-(CH2CH2)-N(H)-, wherein the nitrogen atom of X1is attached to L.

[0081] In certain embodiments, X1 is -O-(C2-3 alkylene)-O-(C2-6 alkylene)-N(H)-, wherein thenitrogen atom of X1is attached to L. In certain embodiments, X1is -O-(C2-3alkylene)-O-(C2-3alkylene)-N(H)-, wherein the nitrogen atom of X1is attached to L. In certain embodiments, X1is -O-(CH2CH2)-O-(CH2CH2)-N(H)-, wherein the nitrogen atom of X1is attached to L. In certain embodiments, X1is -O-(CH2CH2)-O-(CH2CH2CH2)-N(H)-, wherein the nitrogen atom of X1is attached to L.

[0082] In certain embodiments, X1 is -C(O)-N(H)-(C2-3 alkylene)-O-(C2-3 alkylene)-N(H)- or -C(O)-N(H)-(C2-3 alkylene)-N(H)-, wherein the terminal nitrogen atom of X1is attached to L. In certain embodiments, X1is -C(O)-N(H)-(C2-3alkylene)-O-(C2-3alkylene)-N(H)-, wherein the terminal nitrogen atom of X1is attached to L. In certain embodiments, X1is -C(O)-N(H)- (CH2CH2)-O-(CH2CH2)-N(H)-, wherein the terminal nitrogen atom of X1is attached to L. In certain embodiments, X1is -C(O)-N(H)-(C2-3alkylene)-N(H)-, wherein the terminal nitrogen atom of X1is attached to L.

[0083] In certain embodiments, X1 is -N(H)-(C2-4 alkylene)-N(H)- or -N(H)-(C2-4 alkylene)-O-(C2-4 alkylene)-N(H)-. In certain embodiments, X1is -N(H)-(C2-4 alkylene)-N(H)-. In certain embodiments, X1is -N(H)-(C2-4 alkylene)-O-(C2-4 alkylene)-N(H)-.

[0084] In certain embodiments, X1 is a C5-10 bivalent saturated straight hydrocarbon chainwherein one, two, or three methylene units of the chain are independently replaced by –N(H)- or -O-. In certain embodiments, X1is –(C2-3 alkylene)-O-(C2-3 alkylene)-N(H)-, wherein the nitrogen atom of X1is attached to L. In certain embodiments, X1is –(propylene)-O-(propylene)- N(H)-, wherein the nitrogen atom of X1is attached to L. In certain embodiments, X1is –(C1-3 alkylene)-N(H)-(C2-3 alkylene)-O-(C2-3 alkylene)-N(H)-, wherein the terminal nitrogen atom of X1is attached to L. In certain embodiments, X1is –(CH2)-N(H)-(CH2CH2)-O-(CH2CH2)-N(H)-, wherein the terminal nitrogen atom of X1is attached to L.

[0085] In certain embodiments, X1 is a 5- or 6-membered saturated monocyclicheterocyclylene containing 1 or 2 heteroatoms which are nitrogen. In certain embodiments, X1is piperidinylene or piperazinylene. In certain embodiments, X1is piperidinylene. In certain embodiments, X1is, wherein the nitrogen atom of X1is attached to L. In certain embodiments, X1is piperazinylene.

[0086] In certain embodiments, X1 is selected from the groups depicted in the compounds inTables 1, 2, 3, 4, 5, and 6, below. In certain embodiments, X1is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments, X1is selected from the groups depicted in the compounds in Tables 4, 5, and 6, below.

[0087] As generally defined above, X2 is ɸ-(C1-5 alkylene)-N(H)- or a covalent bond, whereinɸ is a bond to L. In certain embodiments, X2is ɸ-(C1-5 alkylene)-N(H)-. In certain embodiments, X2is ɸ-CH2CH2-N(H)-. In certain embodiments, X2is ɸ-C(H)(CH3)-N(H)-. In certain embodiments, X2is a covalent bond. In certain embodiments, X2is selected from the groups depicted in the compounds in Tables 1, 2, 3, 4, 5, and 6, below. In certain embodiments, X2is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments, X2is selected from the groups depicted in the compounds in Tables 4, 5, and 6, below.

[0088] As generally defined above, Y1 is defined by Formula I-1 that is substituted by oneoccurrence of R4, wherein Formula I-1 is represented by:wherein: A1is a 9- or 10-membered bicyclic heteroaryl containing 1 or 2 heteroatoms which are nitrogen, wherein the heteroaryl is substituted with 0, 1, or 2 occurrences of R2; A2is phenyl, a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 heteroatoms which are nitrogen, or a 9- or 10-membered bicyclic heteroaryl containing 1 or 2 heteroatoms which are nitrogen; each of which is substituted with 0, 1, or 2 occurrences of R3; R2represents independently for each occurrence C1-4haloalkyl, halo, or C1-4alkyl; R3represents independently for each occurrence C1-4 alkyl, C1-4 alkoxyl, halo, -N(R5)S(O)2-(C1-4 alkyl), -N(R5)S(O)2-(phenyl), -N(R5)C(O)-(C1-4 alkyl), or -N(R5)-(C1-4 alkyl); R4is a bond to X1; and R5represents independently for each occurrence H or C1-3 alkyl.

[0089] In certain embodiments, Y1substituted by oneoccurrence of R4.

[0090] In certain embodiments,

[0091] In certain embodiments,embodiments,. In certain embodiments,.

[0093] In certain embodiments,

[0094] In certain embodiments, Y1 isIn certain. In certain embodiments, Y1isIn certain embodiments, Y1is[

[0100] In certain embodiments,substituted by oneoccurrence of R4.

[0101] In certain embodiments,.

[0102] In certain embodiments,

[0103] In certain embodiments,. In certainIn certain embodiments,certain embodiments, Y1isIn certain embodiments, Y1is

[0104] In certain embodiments,[. In certain embodiments, Y1isIn certainembodiments,certain embodiments, Y1iscertain embodiments, Y1is

[0112] In certain embodiments, Y1 is selected from the groups depicted in the compounds inTables 1, 2, 3, 4, 5, and 6, below. In certain embodiments, Y1is selected from the groupsdepicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments, Y1is selected from the groups depicted in the compounds in Tables 4, 5, and 6, below.

[0113] As generally defined above, A1 is a 9- or 10-membered bicyclic heteroaryl containing1 or 2 heteroatoms which are nitrogen, wherein the heteroaryl is substituted with 0, 1, or 2 occurrences of R2. In certain embodiments, A1is quinolinyl or imidazo[1,2-a]pyridinyl, each of which is substituted with 0, 1, or 2 occurrences of R2. In certain embodiments, A1is quinolin-4- yl or imidazo[1,2-a]pyridin-5-yl, each of which is substituted with 1 or 2 occurrences of R2.

[0114] In certain embodiments, A1 is quinolinyl substituted with 0, 1, or 2 occurrences of R2.In certain embodiments, A1is quinolin-4-yl substituted with 1 or 2 occurrences of R2. In certain

[0115] In certain embodiments, A1 is imidazo[1,2-a]pyridinyl substituted with 0, 1, or 2occurrences of R2. In certain embodiments, A1is imidazo[1,2-a]pyridin-5-yl substituted with 1 or 2 occurrences of R2. In certain embodiments, A1is

[0116] In certain embodiments, A1 is quinolinyl or imidazo[1,2-a]pyridinyl, each of which issubstituted with one occurrence of R4and 0, 1, or 2 occurrences of R2. In certain embodiments, A1is quinolin-4-yl or imidazo[1,2-a]pyridin-5-yl, each of which is substituted with one occurrence of R4and 1 or 2 occurrences of R2. In certain embodiments, A1is quinolinyl substituted with one occurrence of R4and 0, 1, or 2 occurrences of R2. In certain embodiments, A1is quinolin-4-yl substituted with one occurrence of R4and 1 or 2 occurrences of R2. In certain embodiments, A1is imidazo[1,2-a]pyridinyl substituted with one occurrence of R4and 0, 1, or 2occurrences of R2. In certain embodiments, A1is imidazo[1,2-a]pyridin-5-yl substituted with one occurrence of R4and 1 or 2 occurrences of R2.

[0117] In certain embodiments, A1 is selected from the groups depicted in the compounds inTables 1, 2, 3, 4, 5, and 6, below. In certain embodiments, A1is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments, A1is selected from the groups depicted in the compounds in Tables 4, 5, and 6, below.

[0118] As defined generally above, A2 is phenyl, a 5- or 6-membered monocyclic heteroarylcontaining 1 or 2 heteroatoms which are nitrogen, or a 9- or 10-membered bicyclic heteroaryl containing 1 or 2 heteroatoms which are nitrogen; each of which is substituted with 0, 1, or 2 occurrences of R3.

[0119] In certain embodiments, A2 is phenyl, pyrazolyl, pyridinyl, or pyrrolo[2,3-b]pyridinyl;each of which is substituted with 0, 1, or 2 occurrences of R3. In certain embodiments, A2is phenyl, 1H-pyrazolo-4-yl, pyridin-3-yl, pyridin-4-yl, or pyrrolo[2,3-b]pyridin-4-yl; each of which is substituted with 0 or 1 occurrence of R3. In certain embodiments, A2is phenyl, pyridinyl, or pyrrolo[2,3-b]pyridinyl; each of which is substituted with 0, 1, or 2 occurrences of R3. In certain embodiments, A2is phenyl, pyridin-4-yl, or pyrrolo[2,3-b]pyridin-4-yl; each of which is substituted with 0 or 1 occurrence of R3. In certain embodiments, A2is pyrazolyl, pyridinyl, or phenyl; each of which is substituted with 0, 1, or 2 occurrences of R3. In certain embodiments, A2is 1H-pyrazolo-4-yl, pyridin-3-yl, or phenyl, each of which is substituted with one occurrence of R3. In certain embodiments,.

[0120] In certain embodiments, A2 is phenyl substituted with 0, 1, or 2 occurrences of R3. Incertain embodiments, A2is phenyl substituted with 0 or 1 occurrence of R3. In certain embodiments, A2is phenyl substituted with one occurrence of R3. In certain embodiments, A2is. In certain embodiments, A2is . In certainembodiments,

[0121] In certain embodiments, A2 is a 5- or 6-membered monocyclic heteroaryl containing 1or 2 heteroatoms which are nitrogen, wherein the heteroaryl is substituted with 0, 1, or 2 occurrences of R3. In certain embodiments, A2is pyrazolyl or pyridinyl, each of which is substituted with 0, 1, or 2 occurrences of R3. In certain embodiments, A2is 1H-pyrazolo-4-yl, pyridin-3-yl, or pyridin-4-yl, each of which is substituted with 0 or 1 occurrence of R3. In certain embodiments, A2is 1H-pyrazolo-4-yl or pyridin-3-yl, each of which is substituted with one occurrence of R3. In certain embodiments,

[0122] In certain embodiments, A2 is a 5-membered monocyclic heteroaryl containing 1 or 2heteroatoms which are nitrogen, wherein the heteroaryl is substituted with 0, 1, or 2 occurrences of R3. In certain embodiments, A2is pyrazolyl substituted with 0, 1, or 2 occurrences of R3. In certain embodiments, A2is 1H-pyrazolo-4-yl substituted with 0 or 1 occurrence of R3. In certain embodiments, A2is 1H-pyrazolo-4-yl substituted with one occurrence of R3. In certain embodiments,.

[0123] In certain embodiments, A2 is a 6-membered monocyclic heteroaryl containing 1 or 2heteroatoms which are nitrogen, wherein the heteroaryl is substituted with 0, 1, or 2 occurrences of R3. In certain embodiments, A2is pyridinyl substituted with 0, 1, or 2 occurrences of R3. In certain embodiments, A2is pyridin-3-yl or pyridin-4-yl, each of which is substituted with 0 or 1 occurrence of R3. In certain embodiments, A2is pyridin-3-yl substituted with one occurrence of R3. In certain embodiments, A2is pyridin-4-yl substituted with 0 or 1 occurrence of R3. In certain embodiments,

[0124] In certain embodiments, A2 is a 9- or 10-membered bicyclic heteroaryl containing 1 or2 heteroatoms which are nitrogen, wherein the heteroaryl is substituted with 0, 1, or 2occurrences of R3. In certain embodiments, A2is a 9-membered bicyclic heteroaryl containing 1 or 2 heteroatoms which are nitrogen, wherein the heteroaryl is substituted with 0, 1, or 2 occurrences of R3. In certain embodiments, A2is pyrrolo[2,3-b]pyridinyl substituted with 0, 1, or 2 occurrences of R3. In certain embodiments, A2is pyrrolo[2,3-b]pyridin-4-yl substituted with 0 or 1 occurrence of R3.

[0125] In certain embodiments, A2 is selected from the groups depicted in the compounds inTables 1, 2, 3, 4, 5, and 6, below. In certain embodiments, A2is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments, A2is selected from the groups depicted in the compounds in Tables 4, 5, and 6, below.

[0126] As defined generally above, R2 represents independently for each occurrence C1-4haloalkyl, halo, or C1-4alkyl. In certain embodiments, R2represents independently for each occurrence C1-4 haloalkyl or halo. In certain embodiments, R2represents independently for each occurrence -CF3, chloro, or fluoro. In certain embodiments, R2represents independently for each occurrence C1-4haloalkyl or C1-4alkyl.

[0127] In certain embodiments, R2 represents independently for each occurrence C1-4haloalkyl. In certain embodiments, R2is -CF3. In certain embodiments, R2represents independently for each occurrence halo. In certain embodiments, R2represents independently for each occurrence chloro or fluoro. In certain embodiments, R2is chloro. In certain embodiments, R2is fluoro. In certain embodiments, R2represents independently for each occurrence C1-4alkyl. In certain embodiments, R2is methyl.

[0128] In certain embodiments, R2 is selected from the groups depicted in the compounds inTables 1, 2, 3, 4, 5, and 6, below. In certain embodiments, R2is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments, R2is selected from the groups depicted in the compounds in Tables 4, 5, and 6, below.

[0129] As defined generally above, R3 represents independently for each occurrence C1-4alkyl, C1-4 alkoxyl, halo, -N(R5)S(O)2-(C1-4 alkyl), -N(R5)S(O)2-(phenyl), -N(R5)C(O)-(C1-4 alkyl), or -N(R5)-(C1-4alkyl). In certain embodiments, R3represents independently for each occurrence C1-4 alkyl, C1-4 alkoxyl, halo, -N(H)S(O)2-(C1-4 alkyl), -N(H)S(O)2-(phenyl), - N(H)C(O)-(C1-4 alkyl), or -N(H)-(C1-4 alkyl).

[0130] In certain embodiments, R3 represents independently for each occurrence C1-4 alkyl,C1-4 alkoxyl, or halo. In certain embodiments, R3represents independently for each occurrence C1-4 alkyl or halo. In certain embodiments, R3is -CH3, -OCH3, chloro, or fluoro. In certain embodiments, R3is -CH3, chloro, or fluoro.

[0131] In certain embodiments, R3 represents independently for each occurrence-N(R5)S(O)2-(C1-4 alkyl), -N(R5)S(O)2-(phenyl), -N(R5)C(O)-(C1-4 alkyl), or -N(R5)-(C1-4 alkyl). In certain embodiments, R3represents independently for each occurrence -N(H)S(O)2-(C1-4alkyl), -N(H)S(O)2-(phenyl), -N(H)C(O)-(C1-4 alkyl), or -N(H)-(C1-4 alkyl). In certain embodiments, R3is -N(H)S(O)2CH3, -N(H)S(O)2-(phenyl), -N(H)C(O)CH3, or -N(H)CH3. In certain embodiments, R3is -N(H)S(O)2CH3, -N(H)C(O)CH3, or -N(H)CH3. In certain embodiments, R3is -N(H)S(O)2CH3or -N(H)C(O)CH3.

[0132] In certain embodiments, R3 represents independently for each occurrence C1-4 alkyl.In certain embodiments, R3is -CH3. In certain embodiments, R3represents independently for each occurrence C1-4alkoxyl. In certain embodiments, R3is -OCH3. In certain embodiments, R3represents independently for each occurrence halo. In certain embodiments, R3is chloro or fluoro. In certain embodiments, R3is chloro. In certain embodiments, R3is fluoro.

[0133] In certain embodiments, R3 represents independently for each occurrence-N(R5)S(O)2-(C1-4 alkyl). In certain embodiments, R3represents independently for each occurrence -N(H)S(O)2-(C1-4 alkyl). In certain embodiments, R3is -N(H)S(O)2CH3. In certain embodiments, R3represents independently for each occurrence -N(R5)S(O)2-(phenyl). In certain embodiments, R3is -N(H)S(O)2-(phenyl). In certain embodiments, R3represents independently for each occurrence -N(R5)C(O)-(C1-4 alkyl). In certain embodiments, R3represents independently for each occurrence -N(H)C(O)-(C1-4 alkyl). In certain embodiments, R3is -N(H)C(O)CH3. In certain embodiments, R3represents independently for each occurrence -N(R5)-(C1-4 alkyl). In certain embodiments, R3represents independently for each occurrence -N(H)-(C1-4 alkyl). In certain embodiments, R3is -N(H)CH3.

[0134] In certain embodiments, R3 is selected from the groups depicted in the compounds inTables 1, 2, 3, 4, 5, and 6, below. In certain embodiments, R3is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments, R3is selected from the groups depicted in the compounds in Tables 4, 5, and 6, below.

[0135] As defined generally above, R4 is a bond to X1. In certain embodiments, R4 replacesthe R5on the nitrogen atom attached to A1. In certain embodiments, R4replaces the R5on the nitrogen atom attached to the carbonyl group attached to A2. In certain embodiments, R4occurs on the core cyclohexyl ring of Y1. In certain embodiments, R4occurs on A1. In certain embodiments, R4occurs on A2. In certain embodiments, R4occurs on an R3substituent on A2. In certain embodiments, R4occurs on an R3substituent on A2, wherein the R3substituent is - N(H)S(O)2CH3or -N(H)S(O)2-(phenyl). In certain embodiments, R4replaces the -N(H)- hydrogen atom of an R3substituent on A2, wherein the R3substituent is -N(H)S(O)2CH3 or - N(H)S(O)2-(phenyl). In certain embodiments, R4occurs on the -CH3 or phenyl group of an R3substituent on A2, wherein the R3substituent is -N(H)S(O)2CH3or -N(H)S(O)2-(phenyl). In certain embodiments, the position of R4on Y1is selected from the positions depicted in the compounds in Tables 1, 2, 3, 4, 5, and 6, below. In certain embodiments, the position of R4on Y1is selected from the positions depicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments, the position of R4on Y1is selected from the positions depicted in the compounds in Tables 4, 5, and 6, below.

[0136] As defined generally above, R5 represents independently for each occurrence H or C1-3alkyl. In certain embodiments, R5represents independently for each occurrence H or methyl. In certain embodiments, R5is hydrogen. In certain embodiments, R5represents independently for each occurrence C1-3 alkyl. In certain embodiments, R5is methyl. In certain embodiments, R5is selected from the groups depicted in the compounds in Tables 1, 2, 3, 4, 5, and 6, below. In certain embodiments, R5is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments, R5is selected from the groups depicted in the compounds in Tables 4, 5, and 6, below.

[0137] In certain embodiments, Y1-X1- is one of the following:

[0138] In certain embodiments, Y1-X1- is one of the following:

[0139] In certain embodiments, Y1-X1- is one of the following:[

[0141] In certain embodiments, Y1-X1- is one of the following:

[0142] In certain embodiments, Y1-X1- is one of the following:

[0143] In certain embodiments, Y1-X1- is one of the following:[

[0146] In certain embodiments, Y1-X1- is one of the following:

[0147] In certain embodiments, Y1-X1- is one of the following:

[0148] In certain embodiments, Y1-X1- is one of the following:

[0149] In certain embodiments, Y1-X1- is one of the following:

[0150] In certain embodiments, Y1-X1- is one of the following:

[0151] In certain embodiments, Y1-X1- is one of the following:. In certain embodiments, Y1-X1- is.

[0153] In certain embodiments, Y1-X1- is one of the following:.

[0154] In certain embodiments, Y1-X1- is one of the following:

[0155] In certain embodiments, Y1-X1- is one of the following:

[0156] In certain embodiments, Y1-X1- is one of the following:.

[0157] In certain embodiments, Y1-X1- is one of the following:

[0158] In certain embodiments, Y1-X1- is one of the following:

[0159] In certain embodiments, Y1-X1- is selected from the groups depicted in the compoundsin Tables 1, 2, 3, 4, 5, and 6, below. In certain embodiments, Y1-X1- is selected from the groupsdepicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments, Y1-X1- is selected from the groups depicted in the compounds in Tables 4, 5, and 6, below.

[0160] As defined generally above, L is a divalent linker selected from:(i) a bivalent, saturated or unsaturated, straight or branched C1-60hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, - S-, -N(H)-, -N(C1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C1-6alkyl)-, -N(H)C(O)-, -N(C1-6alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C1-6 alkyl)-, -N(H)C(O)O- , -N(C1-6 alkyl)C(O)O-, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein Ring A and Ring B are each independently C4-6 cycloalkylene; L1ais C3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3alkyl; and L2ais -O-, -NHC(O)-, or -CH2-O-; (iii)) wherein Ring A is C4-6cycloalkylene or C7-9bridged bicyclic cycloalkylene; L1bis -CH2-NH-C(O)-, -NHC(O)-, or -C(O)NH-; L2bis C6-12linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR1b-, -wherein n is 1, 2, 3, or 4, and represents a covalent bond to L1b; and each R1bis independently hydrogen or C1-3 alkyl;(iv)(L-c) wherein L1cis C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; Ring A is C4-6cycloalkylene or C7-9 bridged bicyclic cycloalkylene; and L2cis -O- or a saturated C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-; (v)(L-d) wherein L1dis C12-22linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-;wherein n is an integer of 3 to 50; (vii) (L-f) wherein L1fis a bond; C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-, -NH-, or -C(O)-; or -(C3-6 cycloalkylene)-NHC(O)-; L2fis a bond, -NHC(O)-, -C(O)NH-, or a C1-6 linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-; and each of Z1and Z2is independently N or CH; (viii) (L-g) wherein Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; L1gis a bond, -CH2-, -NH-, or -O-; and L2giswherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L1g; 1wherein each Z is independently N or CH; L1his a bond, -C(O)-, -C(O)-NH-, or -NHC(O)-; L2his C2-10 linear alkylene or, wherein n is 1, 2, 3, or 4, and represents a covalent bond to L1handrepresents a covalent bond to L3h; L3his a bond, -C(O)CH2-, -O-(C3-6 cycloalkylene)-O-, or -C(O)NH(CH2)3OCH2-; L4his a bond, -C(O)-, -CH2C(O)-, or - C(O)CH2-; and m is 1, 2, or 3;bond to L3iandrepresents a covalent bond to NH; L2iis a bond, C1-12linear alkylene, or, wherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bond to HN; and L3iis a bond or -C(O)-; and Z is independently CH or N, provided that no more than two of Z , Z , Z and Z are N; L1jis -NH-, -C(O)NH-, -NHC(O)-, or -O-; L2jis C1-6linear alkylene or, wherein n is 1 or 2, and represents a covalent bond to L1j; and represents a single bond or a double bond;wherein Ring A is phenylene or a 5- or 6-membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z1and Z2isindependently CH or N; L1kis a bond, -C(O)-, -C(O)NH-, or -NHC(O)-; and L2kis a C3-8straight chain alkylene or, wherein n is 1, 2, or 3, andrepresents a covalent bond to L1k;(xiii)) wherein Z1is CH or N; m is 1 or 2; p is 1 or 2; 0, 1, or 2 hydrogen atomsare replaced with F; L1mis a bond, - C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH-, or -NHS(O)2-; and L2mis C3-6 linear alkylene, C3-6 cycloalkylene, or, wherein n is 1 or 2, andrepresents a covalent bond to L1m;C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)2NH-, or -NHS(O)2-; and L2pis –(4-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-C(O))-; or (xvi)wherein Ring A, Ring B, Ring C, and Ring D are each independently C4-6 cycloalkylene; L1qand L3qare each independently C3-5linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3alkyl; and L2qand L3qare each independently -O-, -NHC(O)-, or -CH2-O-; and wherein eachrepresents a covalent bond to X1, and eachrepresents a covalent bond to X2.

[0161] In certain embodiments, L is a divalent linker selected from:(i) a bivalent, saturated or unsaturated, straight or branched C1-60hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, - S-, -N(H)-, -N(C1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C1-6alkyl)-, -N(H)C(O)-, -N(C1-6alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C1-6 alkyl)-, -N(H)C(O)O- , -N(C1-6 alkyl)C(O)O-, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5-6membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein Ring A and Ring B are each independently C4-6cycloalkylene; L1ais C3-5linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3 alkyl; and L2ais -O-, -NHC(O)-, or -CH2-O-; (iii)) wherein Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; L1bis -CH2-NH-C(O)-, -NHC(O)-, or -C(O)NH-; L2bis C6-12linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR1b-, -wherein n is 1, 2, 3, or 4, and represents a covalent bond to L1b; and each R1bis independently hydrogen or C1-3alkyl; (iv)(L-c) wherein L1cis C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; Ring A is C4-6cycloalkylene or C7-9bridged bicyclic cycloalkylene; and L2cis -O- or a saturated C2-10linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-; (v)(L-d) wherein L1dis C12-22 linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-;(vii) (L-f) wherein L1fis a bond; C1-6 linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-, -NH-, or -C(O)-; or -(C3-6cycloalkylene)-NHC(O)-; L2fis a bond, -NHC(O)-, -C(O)NH-, or a C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-; and each of Z1and Z2is independently N or CH; (viii)(L-g) wherein Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; L1gis a bond, -CH2-, -NH-, or -O-; and L2giswherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bond to L1g;1hrepresents a covalent bond to L3h; L3his a bond, -C(O)CH2-, -O-(C3-6 cycloalkylene)-O-, or -C(O)NH(CH2)3OCH2-; L4his a bond, -C(O)-, -CH2C(O)-, or - C(O)CH2-; and m is 1, 2, or 3;sents a covalent bond to NH; L2iis a bond, C1-12 linear aye e, o , wherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bond to HN; and L3iis a bond or -C(O)-; and Z is independently CH or N, provided that no more than two of Z , Z , Z and Z are N; L1jis -NH-, -C(O)NH-, -NHC(O)-, or -O-; L2jis C1-6 linear alkylene or, wherein n is 1 or 2, and represents a covalent bond to L1j; and represents a single bond or a double bond;wherein Ring A is phenylene or a 5- or 6-membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z1and Z2is independently CH or N; L1kis a bond, -C(O)-, -C(O)NH-, or -NHC(O)-; and L2kis a C3-8 *** **straight chain alkylene or, wherein n is 1, 2, or 3, and represents a covalent bond to L1k; ** ) wherein Z1is CH or N; m is 1 or 2; pis 1 or 2; 0, 1, or 2 hydrogen atomsare replaced with F; L1mis a bond, - C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH-, or -NHS(O)2-; and L2mis C3-6linear alkylene, C3-6 cycloalkylene, or, wherein n is 1 or 2, andrepresents a covalent bond to L1m;C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)2NH-, or -NHS(O)2-; and L2pis –(4-6membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-C(O))-; and wherein eachrepresents a covalent bond to X1, and eachrepresents a covalent bond to X2.

[0162] In certain embodiments,wherein RingA and Ring B are each independently C4-6 cycloalkylene; L1ais C3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3 alkyl; and L2ais -O-, -NHC(O)-, or -CH2-O-; wherein represents a covalent bond to X1, and represents a covalent bond to X2.

[0163] In certain embodiments, L is selected from the groups depicted in the compounds inTables 1, 2, 3, 4, 5, and 6, below. In certain embodiments, L is selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments, L is selected from the groups depicted in the compounds in Tables 4, 5, and 6, below.

[0164] Further description and embodiments for variable L are provided below in, forexample, Part B.

[0165] The description above describes multiple embodiments relating to compounds ofFormula I. The patent application specifically contemplates all combinations of the embodiments. Part B: Additional Description of the Linker

[0166] Further description and embodiments for the linker, variable L, are provided below.For example, in certain embodiments, L is a bivalent, saturated or unsaturated, straight or branched C1-60hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, -S-, -N(H)-, -N(C1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C1-6 alkyl)-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)-, -C(O)N(H)-, -C(O)N(C1-6alkyl)-, -OC(O)N(H)-, -OC(O)N(C1-6alkyl)-, -N(H)C(O)O-, -N(C1-6alkyl)C(O)O-, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0167] In certain embodiments, L is a divalent linker of Formula (L-a), (L-b), (L-c), (L-d),(L-e), (L-f), (L-g), (L-h), (L-i), (L-j), (L-k), (L-m), (L-n-i), (L-n-ii), (L-n-iii), (L-n-iv), (L-p), or (LL-q). In certain embodiments, L is a divalent linker of Formula (L-a), (L-b), (L-c), (L-d), (L- e), (L-f), (L-g), (L-h), (L-i), (L-j), (L-k), (L-m), (L-n-i), (L-n-ii), (L-n-iii), (L-n-iv), or (L-p).

[0168] In certain embodiments, L is a divalent linker of Formula (L-a):wherein: Ring A and Ring B are each independently C4-6cycloalkylene; L1ais C3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3 alkyl; and L2ais -O-, -NHC(O)-, or -CH2-O-; wherein represents a covalent bond to X1, and represents a covalent bond to X2.

[0169] In certain embodiments, Ring A and Ring B of Formula (L-a) are each independently

[0170] In certain embodiments, L is a divalent linker of Formula (L-a-i):wherein: Ring A is C4-6cycloalkylene;L1ais C3-5linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3 alkyl; and L2ais -O-, -NHC(O)-, or -CH2-O-; wherein represents a covalent bond to X1, andrepresents a covalent bond to X2.

[0171] In certain embodiments, Ring A of Formula (L-a-i) is,

[0172] In certain embodiments, L is a divalent linker of Formula (L-a-ii):wherein: L1ais C3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3alkyl; L2ais -O-, -NHC(O)-, or -CH2-O-; p is 1 or 2; and m is 1 or 2; wherein represents a covalent bond to X1, andrepresents a covalent bond to X2.

[0173] In certain embodiments, L1a of Formula (L-a), (L-a-i), or (L-a-ii) is selected fromwherein: j is 1, 2, 3, or 4; k is 0, 1, 2, or 3; the sum of j and k is 2, 3, or 4; q is 1 or 2; r is 1 or 2;s is 0 or 1; the sum of q, r, and s is 2 or 3; X1Aand X2Aare independently -O- or NRa; and each Rais independently hydrogen or C1-3alkyl; wherein represents a covalent bond to the C(O) group of Formula (L-a), (L-a-i), or (L-a-ii), and represents a covalent bond to Ring B of Formula (L-a) or to the cyclohexylene group of Formula (L-a-i) or (L-a-ii).

[0174] In certain embodiments, L1a of Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH2)2O-, -(CH2)3O-, -(CH2)4O-, -(CH2)2OCH2-, -(CH2)3OCH2-, -(CH2)2O(CH2)2-, -CH2OCH2-, -CH2O(CH2)2-, -CH2O(CH2)3-, -CH2OCH2O-, or -CH2OCH2OCH2-. In certain embodiments, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH2)2O-, -(CH2)3O-, -(CH2)2OCH2-, or -(CH2)3OCH2-. In certain embodiments, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH2)2NRa-, -(CH2)3NRa-, -(CH2)4NRa-, -(CH2)2NRaCH2-, -(CH2)3NRaCH2-, - (CH2)2NRa(CH2)2-, -CH2NRaCH2-, -CH2NRa(CH2)2-, -CH2NRa(CH2)3-, -CH2NRaCH2NRa-, or - CH2NRaCH2NRaCH2-, wherein each Rais independently hydrogen or C1-3alkyl. In certain embodiments, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH2)2NRa-, - (CH2)3NRa-, -(CH2)2NRaCH2-, or -(CH2)3NRaCH2-, wherein Rais hydrogen or C1-3 alkyl. In certain embodiments, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH2)2NH-, - (CH2)3NH-, -(CH2)4NH-, -(CH2)2NHCH2-, -(CH2)3NHCH2-, -(CH2)2NH(CH2)2-, -CH2NHCH2-, - CH2NH(CH2)2-, -CH2NH(CH2)3-, -CH2NHCH2NH-, or -CH2NHCH2NHCH2-. In certain embodiments, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH2)2NH-, -(CH2)3NH- , -(CH2)2NHCH2-, or -(CH2)3NHCH2-. In certain embodiments, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -CH2OCH2NRa-, -CH2NRaCH2O-, -CH2OCH2NRaCH2-, - CH2NRaCH2OCH2-, wherein Rais independently hydrogen or C1-3 alkyl. In certain embodiments, L1aof Formula (L-a), (L-a-i), or (L-a-ii) is selected from -CH2OCH2NH-, - CH2NHCH2O-, -CH2OCH2NHCH2-, -CH2NHCH2OCH2-.

[0175] In certain embodiments, L is a divalent linker of Formula (L-a-iii):p is 1 or 2; m is 1 or 2; and n is 1, 2, or 3; wherein represents a covalent bond to X1, andrepresents a covalent bond to X2.

[0176] In certain embodiments, L is selected from the group consisting of:point of attachment indicated on the cycloalkyl-bound carbonyl group is the attachment point to X1.

[0177] In certain embodiments, L is selected from the group consisting of:indicated on the cycloalkyl-bound carbonyl group is the attachment point to X1.

[0178] In certain embodiments, L is a divalent linker of Formula (L-b):wherein: Ring A is C4-6cycloalkylene or C7-9bridged bicyclic cycloalkylene; L1bis -CH2-NH-C(O)-, -NHC(O)-, or -C(O)NH-; L2bis C6-12 linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR1b-, - C(O)NR1b-, or -NR1bC(O)-; orL2bis, wherein n is 1, 2, 3, or 4, and represents a covalent bond to L1b; and each R1bis independently hydrogen or C1-3alkyl; wherein represents a covalent bond to X1, andrepresents a covalent bond to X2.

[0180] In certain embodiments, L is a divalent linker of Formula (L-b-i):wherein: L1bis -CH2-NH-C(O)-, -NHC(O)-, or -C(O)NH-; L2bis C6-12linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR1b-, - C(O)NR1b-, or -NR1bC(O)-; or L2bis, wherein n is 1, 2, 3, or 4, and represents a covalent bond to L1b; each R1bis independently hydrogen or C1-3 alkyl; p is 1 or 2; and m is 1 or 2; wherein represents a covalent bond to X1, and represents a covalent bond to X2.

[0181] In certain embodiments, L2b of Formula (L-b) or (L-b-i) is selected fromwherein: j is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; the sum of j and k is 5, 6, 7, 8, 9, 10, or 11; q is 1, 2, 3, 4, 5, 6, 7, 8, or 9; r is 1, 2, 3, 4, 5, 6, 7, 8, or 9; s is 0, 1, 2, 3, 4, 5, 6, 7, or 8; the sum of q, r, and s is 4, 5, 6, 7, 8, 9, or 10; t is 1, 2, 3, 4, 5, 6, or 7; u is 1, 2, 3, 4, 5, 6, or 7; v is 1, 2, 3, 4, 5, 6, or 7; w is 0, 1, 2, 3, 4, 5, or 6; the sum of t, u, v, and w is 3, 4, 5, 6, 7, 8, or 9; a is 1, 2, 3, 4, or 5; b is 1, 2, 3, 4, or 5; c is 1, 2, 3, 4, or 5; d is 1, 2, 3, 4, or 5; e is 0, 1, 2, 3, or 4; the sum of a, b, c, d, and e is 4, 5, 6, 7, or 8; X1A, X2A, X3A, and X4Aare independently -O-, -NR1b-, -C(O)NR1b-, or -NR1bC(O)-; and each R1bis independently hydrogen or C1-3alkyl; wherein represents a covalent bond to L1bof Formula (L-b) or (L-b-i), and represents a covalent bond to X2.

[0182] In certain embodiments, L is selected from the group consisting of:indicated on the cycloalkyl-bound carbonyl group is the attachment point to X1.

[0183] In certain embodiments, L is a divalent linker of Formula (L-c):wherein: L1cis C2-10linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-; Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; and L2cis -O- or a saturated C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; wherein represents a covalent bond to X1, andrepresents a covalent bond to X2.

[0184] In certain embodiments, Ring A of Formula (L-c) is

[0185] In certain embodiments, L is a divalent linker of Formula (L-c-i):wherein:L1cis C2-10linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-; L2cis -O- or a saturated C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; p is 1 or 2; and m is 1 or 2; wherein represents a covalent bond to X1, and represents a covalent bond to X2.

[0186] In certain embodiments, L1c of Formula (L-c) or (L-c-i) is selected fromwherein: j is 1, 2, 3, 4, 5, 6, 7, 8, or 9; k is 0, 1, 2, 3, 4, 5, 6, 7, or 8; the sum of j and k is 1, 2, 3, 4, 5, 6, 7, 8, or 9; q is 1, 2, 3, 4, 5, 6, or 7; r is 1, 2, 3, 4, 5, 6, or 7; s is 0, 1, 2, 3, 4, 5, or 6; the sum of q, r, and s is 2, 3, 4, 5, 6, 7, or 8; t is 1, 2, 3, 4, or 5; u is 1, 2, 3, 4, or 5; v is 1, 2, 3, 4, or 5; w is 0, 1, 2, 3, or 4; the sum of t, u, v, and w is 3, 4, 5, 6, or 7; and X1A, X2Aand X3Aare independently -O-, -NH-, -NHC(O)-, or -C(O)NH-; wherein represents a covalent bond to the C(O) group of Formula (L-c) or (L-c-i), andrepresents a covalent bond to the ring of Formula (L-c) or (L-c-i).

[0187] In certain embodiments, L2c of Formula (L-c) or (L-c-i) is selected fromwherein: j is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; k is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; the sum of j and k is 1, 2, 3, 4, 5, 6, 7, 8, or 9; q is 0, 2, 3, 4, 5, 6, or 7; r is 1, 2, 3, 4, 5, 6, 7, or 8; s is 0, 1, 2, 3, 4, 5, 6, or 7; the sum of q, r, and s is 1, 2, 3, 4, 5, 6, 7, or 8; t is 0, 1, 2, 3, 4, or 5; u is 1, 2, 3, 4, 5, or 6; v is 1, 2, 3, 4, 5, or 6; w is 0, 1, 2, 3, 4, or 5; the sum of t, u, v, and w is 2, 3, 4, 5, 6, or 7; and X1A, X2Aand X3Aare independently -O-, -NH-, -NHC(O)-, or -C(O)NH-; wherein represents a covalent bond to the ring of Formula (L-c) or (L-c-i), andrepresents a covalent bond to X2.

[0188] In certain embodiments, L is selected from the group consisting of:wherein the point of attachment indicated on the carbonyl group is the attachment point to X1. 1I i i L i l f h i i fcarbonyl group is the attachment point to X1.

[0190] In certain embodiments, L is a divalent linker of Formula (L-d):* **wherein: L1dis C12-22linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-; wherein*represents a covalent bond to X1, and **represents a covalent bond to X2.

[0191] In certain embodiments, L1d of Formula (L-d) is selected fromwherein:j is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; the sum of j and k is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; the sum of q, r, and s is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; t is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17; u is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17; v is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17; w is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; the sum of t, u, v, and w is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; c is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; d is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; e is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; the sum of a, b, c, d, and e is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; f is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; g is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; h is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; i is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13; z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; the sum of f, g, h, i, y, and z is 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17; and X1A, X2A, X3A, X4A, and X5Aare independently -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)- NH-; wherein represents a covalent bond to the C(O) group of Formula (L-d), and represents a covalent bond to X2.

[0192] In certain embodiments, L is selected from the group consisting of:wherein the point of attachment indicated on the carbon-bound carbonyl group is the attachment point to X1.

[0193] In certain embodiments, L is a divalent linker of Formula (L-e):wherein: n is an integer of 3 to 50; wherein represents a covalent bond to X1, and represents a covalent bond to X2.

[0194] In certain embodiments, n of Formula (L-e) is 3 to 25, 3 to 10, 3 to 8, 3 to 7, 3 to 5, or3 to 4. In certain embodiments, n of Formula (L-e) is 3, 4, 5, 7, 8, 22, or 50.

[0195] In certain embodiments, L is a divalent linker of Formula (L-f):wherein: L1fis a bond; C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-, -NH- , or -C(O)-; or -(C3-6cycloalkylene)-NHC(O)-;L2fis a bond, -NHC(O)-, -C(O)NH-, or a C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-; and each of Z1and Z2is independently N or CH; wherein represents a covalent bond to X1, andrepresents a covalent bond to X2.

[0196] In certain embodiments, L1f of Formula (L-f) is selected fromwherein: j is 1, 2, 3, 4, or 5; k is 0, 1, 2, 3, or 4; the sum of j and k is 1, 2, 3, 4, or 5; q is 1, 2, or 3; r is 1, 2, or 3; s is 0, 1, 2; the sum of q, r, and s is 2, 3, or 4; and X1Aand X2Aare independently -O-, -NH-, or -C(O)-; or -(C3-6 cycloalkylene)-NHC(O)-; wherein represents a covalent bond to the C(O) group of Formula (L-f), and represents a covalent bond to the ring of Formula (L-f).

[0197] In certain embodiments, L2f of Formula (L-f) is selected fromwherein: j is 1, 2, 3, 4, or 5; k is 0, 1, 2, 3, or 4; the sum of j and k is 1, 2, 3, 4, or 5; q is 1, 2, or 3; r is 1, 2, or 3; s is 0, 1, 2; and the sum of q, r, and s is 2, 3, or 4;whereinrepresents a covalent bond to the ring of Formula (L-f), and represents a covalent bond to the X2.

[0198] In certain embodiments, L is selected from the group consisting of:attachment indicated on the carbonyl group is the attachment point to X1.

[0199] In certain embodiments, L is a divalent linker of Formula (L-g):Owherein: Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; L1gis a bond, -CH2-, -NH-, or -O-; andL2giswherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L1g; wherein represents a covalent bond to Xrepresents a covalent bond to X2.

[0200] In certain embodiments, L is a divalent linker of Formula (L-g-i):wherein: L1gis a bond, -CH2-, -NH-, or -O-; L2giswherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bond to L1g; Z1, Z2, and Z3are each independently selected from N or CH, provided that one or two of Z1, Z2, and Z3is N; wherein represents a covalent bond to Xrepresents a covalent bond to X2.

[0201] In certain embodiments, L is selected from the group consisting of:; wherein the point of attachment indicated on the carbonyl group is the attachment point to X1.

[0202] In certain embodiments, L is a divalent linker of Formula (L-h):wherein: each Z1is independently N or CH; L1his a bond, -C(O)-, -C(O)-NH-, or -NHC(O)-; L2his C2-10 linear alkylene or, wherein n is 1, 2, 3, or 4, andrepresents a covalent bond to L1handrepresents a covalent bond to L3h; L3his a bond, -C(O)CH2-, -O-(C3-6 cycloalkylene)-O-, or -C(O)NH(CH2)3OCH2-; L4his a bond, -C(O)-, -CH2C(O)-, or -C(O)CH2-; and m is 1, 2, or 3; wherein represents a covalent bond to X1, andrepresents a covalent bond to X2.

[0203] In certain embodiments, L is selected from the group consisting of:O

[0204] In certain embodiments, L is a divalent linker of Formula (L-i):wherein: L1iis a bond, C1-12 linear alkylene, or, wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to L3iandrepresents a covalent bond to NH; L2iis a bond, C1-12linear alkylene, or, wherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bond to HN; and L3iis a bond or -C(O)-; wherein represents a covalent bond to X1, and represents a covalent bond to X2.

[0205] In certain embodiments, L is selected from the group consisting of:O ,1represents a covalent bond to X , and represents a covalent bond to X2.

[0206] In certain embodiments, L is a divalent linker of Formula (L-j):wherein: Z1is C, CH, or N; each of Z2, Z3, Z4and Z5is independently CH or N, provided that no more than two of Z2, Z3, Z4and Z5are N; L1jis -NH-, -C(O)NH-, -NHC(O)-, or -O-; L2jis C1-6linear alkylene or, wherein n is 1 or 2, and represents a covalent bond to L1j; and represents a single bond or a double bond; wherein represents a covalent bond to X1, andrepresents a covalent bond to X2.

[0207] In certain embodiments, L is selected from the group consisting of:; wherein the point of attachment indicated on the carbonyl group is the attachment point to X1.

[0208] In certain embodiments, L is a divalent linker of Formula (L-k):wherein: Ring A is phenylene or a 5 or 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z1and Z2is independently CH or N; L1kis a bond, -C(O)-, -C(O)NH- or -NHC(O)-; and L2kis a C3-8 straight chain alkylene or, wherein n is 1, 2, or 3, andrepresents a covalent bond to L1k; wherein represents a covalent bond to X1, andrepresents a covalent bond to X2.

[0209] In certain embodiments, L is selected from the group consisting of:on the carbonyl group is the attachment point to X1.

[0210] In certain embodiments, L is a divalent linker of Formula (L-m):wherein: Z1is CH or N; m is 1 or 2; p is 1 or 2; 0, 1, or 2 hydrogen atomsare replaced with F; L1mis a bond, -C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH-, or -NHS(O)2-; andL2mis C3-6 linear alkylene, C3-6 cycloalkylene, or, wherein n is 1 or 2, and represents a covalent bond to L1m; wherein represents a covalent bond to X1, and represents a covalent bond to X2.

[0211] In certain embodiments, L is selected from the group consisting of:; wherein the point of attachment indicated on the carbonyl group is the attachment point to X1.

[0212] In certain embodiments, L is a divalent linker of Formula (L-n-i), (L-n-ii), (L-n-iii), or(L-n-iv). In certain embodiments, L is a divalent linker of Formula (L-n-i):wherein represents a covalent bond to X1, andrepresents a covalent bond to X2.

[0213] In certain embodiments, L is a divalent linker of Formula (L-n-ii):i) wherein represents a covalent bond to X1, and represents a covalent bond to X2.

[0214] In certain embodiments, L is a divalent linker of Formula (L-n-iii):iii) wherein represents a covalent bond to X1, andrepresents a covalent bond to X2.

[0215] In certain embodiments, L is a divalent linker of Formula (L-n-iv):v) wherein represents a covalent bond to Xrepresents a covalent bond to X2.

[0216] In certain embodiments,wherein Z1is CH or N; m is 1 or 2; p is 1 or 2; 0, 1, or 2 hydrogen atomsare replaced with F; L1pis a bond, -C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)2NH-, or -NHS(O)2-; and L2pis – (4-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-C(O))-; whereinrepresents a covalent bond to X1, and represents a covalent bond to X2.

[0217] In certain embodiments,; whereinrepresents a covalent bond torepresents a covalent bond to X2.

[0218] In certain embodiments,; wherein the point of attachment indicated on the carbonyl group is the attachment point to X1.

[0219] In certain embodiments, L is one of the following:

[0220] In certain embodiments, L is one of the following:

[0221] In certain embodiments, L is one of the following:X1, andrepresents a covalent bond to X2.

[0222] In certain embodiments,whereinrepresents a covalent bond to X1, and represents a covalent bond to X2.

[0223] In certain embodiments, L is a divalent linker of Formula (L-q):wherein Ring A, Ring B, Ring C, and Ring D are each independently C4-6cycloalkylene; L1q, L2q, and L3qare each independently C3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or - NRa-; each Rais independently hydrogen or C1-3alkyl; and L4qis -O-, -NHC(O)-, or -CH2-O-; and wherein represents a covalent bond to X1and represents a covalent bond to X2.

[0224] In certain embodiments, L is a divalent linker of Formula (L-q-i):1q 2qwherein L , L , L3q, L4q,are as defined for Formula (L-q); and each p and m is independently for each occurrence 1 or 2.

[0225] In certain embodiments, L is a divalent linker of Formula (L-q-ii):and are as defined for Formula (L-q); each p and m is independently for each occurrence 1 or 2; and n is independently for each occurrence 1, 2, or 3.

[0226] In certain embodiments, L is

[0227] In certain embodiments, L is one of the following:wherein represents a covalent bond to X1and represents a covalent bond to X2. In certain embodiments, L iswherein represents a covalent bond to X1andrepresents a covalent bond to X2. Part C: Additional Embodiments

[0228] Compounds of Formula I may be further defined according to the following additionalembodiments. For example, in certain embodiments,following:

[0229] In certain embodiments,one of the following:

[0230] In certain embodiments,one of the following:

[0231] In certain embodiments,is:

[0232] In certain embodiments,selected from the groups depicted inthe compounds in Tables 1, 2, 3, 4, 5, and 6, below. In certain embodiments,selected from the groups depicted in the compounds in Tables 1, 2, and 3, below. In certain embodiments,selected from the groups depicted in the compounds in Tables 4, 5, and 6, below. Exemplary Specific Compounds

[0233] In certain embodiments, the compound is a compound in Table 1, 2, 3, 4, 5, or 6, or apharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 2, 3, 4, 5, or 6. In certain embodiments, the compound is a compound in Table 1, 2, or 3, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, 2, or 3. In certain embodiments, the compound is a compound in Table 4, 5, or 6, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 4, 5, or 6.

[0234] In certain embodiments, the compound is a compound in Table 1 or apharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1. In certain embodiments, the compound is a compound in Table 2 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 2. In certain embodiments, the compound is a compound in Table 3 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 3. In certain embodiments, the compound is a compound in Table 4 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 4. In certain embodiments, the compound is a compound in Table 5 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 5. In certain embodiments, the compound is a compound in Table 6 or apharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 6.

[0235] In certain embodiments, the compound is any one of compounds I-1 to I-68 in Table1, any one of compounds II-1 to II-63 in Table 2, a compound in Table 3, a compound in Table 4, any one of compounds V-1 to V-60 in Table 5, or any one of compounds VI-1 to VI-45 in Table 6; or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds I-1 to I-68 in Table 1, any one of compounds II-1 to II-63 in Table 2, a compound in Table 3, a compound in Table 4, any one of compounds V-1 to V-60 in Table 5, or any one of compounds VI-1 to VI-45 in Table 6.

[0236] In certain embodiments, the compound is any one of compounds I-1 to I-68 in Table1, any one of compounds II-1 to II-63 in Table 2, a compound in Table 3; or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds I-1 to I- 68 in Table 1, any one of compounds II-1 to II-63 in Table 2, a compound in Table 3. In certain embodiments, the compound is a compound in Table 4, any one of compounds V-1 to V-60 in Table 5, or any one of compounds VI-1 to VI-45 in Table 6; or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 4, any one of compounds V-1 to V-60 in Table 5, or any one of compounds VI-1 to VI-45 in Table 6.

[0237] In certain embodiments, the compound is any one of compounds I-1 to I-68 in Table 1or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds I-1 to I-68 in Table 1. In certain embodiments, the compound is any one of compounds II-1 to II-63 in Table 2 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds II-1 to II-63 in Table 2. In certain embodiments, the compound is a compound in Table 3 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 3. In certain embodiments, the compound is a compound in Table 4 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 4. In certain embodiments, the compound is any one of compounds V-1 to V-60 in Table 5 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds V-1 to V-60 in Table 5. In certain embodiments, the compound is or any one ofcompounds VI-1 to VI-45 in Table 6 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is or any one of compounds VI-1 to VI-45 in Table 6. TABLE 1. Exemplary CompoundsTABLE 2. Exemplary CompoundsTABLE 3. Exemplary CompoundsTABLE 4. Exemplary CompoundsTABLE 5. Exemplary CompoundsTABLE 6. Exemplary CompoundsSynthetic Methods

[0238] Methods for preparing compounds described herein are illustrated in the followingsynthetic schemes. The schemes are provided for the purpose of illustrating the invention and are not intended to limit the scope or spirit of the invention. Starting materials shown in the schemes can be obtained from commercial sources or can be prepared based on procedures described in the literature.

[0239] In the schemes, it is understood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule should be compatible with the reagentsand reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated (for example, use of protecting groups or alternative reactions). Protecting group chemistry and strategy is well known in the art, for example, as described in detail in Protecting Groups in Organic Synthesis, 3rdEdition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, 1999 and Greene's Protective Groups in Organic Synthesis, 5th Ed., (Peter G. M. Wuts, John Wiley & Sons: 2014).

[0240] The synthetic route illustrated in Scheme 1-1 is a general method for preparingcompound I-55, which may be applied with appropriate adjustments to make additional compounds shown in Table 1. Scheme 1-1

[0241] In step 1 of Scheme 1-1, compound 2 is coupled with compound 1 under basic conditions(e.g., DIPEA, DMSO, 130 ℃) to provide compound 3. Compound 3 is deprotected in step 2(e.g., using HCl, dioxane) resulting in compound 4, which is coupled with compound 5 in step 3(e.g., using HATU, DIPEA, DMF) to give compound 6. Compound 6 is alkylated with compound 7 under basic conditions (e.g., NaH) to give compound 8. In step 5, compound 8 is deprotected under acidic conditions (e.g., HCl, dioxane) to provide compound 9, and then in step 6 compound 9 is coupled with compound 10 (e.g., using HATU, DIPEA, DMF) to provide compound I-55.

[0242] The synthetic route illustrated in Scheme 1-2 is a general method for preparingcompound II-1, which may be applied with appropriate adjustments to make additional compounds shown in Table 2.Scheme 1-2

[0243] In step 1 of Scheme 1-2, compound 11 is transformed into compound 12 using mesylchloride (e.g., 1.25 eq. MsCl, 3.15 eq. pyridine, DCM, 0 ℃ to RT). In step 2, compound 12 is hydrolyzed to compound 13 under basic conditions (e.g., 2 eq. LiOH, MeOH, water, RT).Compound 13 is coupled with compound 4 under standard peptide coupling conditions (e.g., 1.1 eq. HATU, 3.5 eq. DIPEA, DMF, RT) to provide compound 14. In step 4, the Boc group of compound 14 is removed under acidic conditions (e.g., 4.0 eq. HCl (4M in dioxane), dioxane, 0 ℃ to RT) to generate compound 15, which is then coupled with compound 10 under standard peptide coupling conditions (e.g., 1.1 eq. HATU, 3.5 eq. DIPEA, DMF, RT) to yield compound II-1.

[0244] The synthetic route illustrated in Scheme 1-3 is a general method for preparingcompound III-49, which may be applied with appropriate adjustments to make additional compounds shown in Table 3. Scheme 1-3

[0245] In step 1 of Scheme 1-3, compound 16 is reacted with compound 17 to give compound18 (e.g., PPA, 130 ℃). In step 2, compound 18 is converted into compound 19 (e.g., POCl3, 90 ℃). Alkylation of compound 19 with compound 2 (e.g., DIPEA, DMSO) provides compound 20, which can be deprotected using acidic conditions (e.g., HCl, dioxane) to give compound 21. In step 5, compound 21 is coupled with compound 5 using standard peptide coupling conditions (e.g., HATU, DIPEA, DMF) to give compound 22. In step 6, compound 22 is converted into compound 23 using standard demethylation conditions (e.g., BBr3, DCM). Compound 23 is reacted with compound 24 to give compound 25 (e.g., TPP, DIAD, DCM), which is deprotected under acidic conditions (e.g., HCl, dioxane) in step 8 to give compound 26. Compound 26 is coupled with compound 10 under standard peptide coupling conditions (e.g., HATU, DIPEA, DMF) to give compound III-49.

[0246] The synthetic route illustrated in Scheme 1-4 is a general method for preparingcompound IV-28, which may be applied with appropriate adjustments to make additional compounds shown in Table 4. Scheme 1-4

[0247] In step 1 of Scheme 1-4, compound 1 and compound 27 are coupled under basicconditions (e.g., DIPEA, DMSO) to provide compound 28. Compound 28 is deprotected underacidic conditions (e.g., HCl, dioxane) and then coupled with compound 30 to provide compound 31 (e.g., HATU, DIPEA, DMF). In step 4, compound 31 is reacted with compound 32 to provide compound 33 (e.g., NaH), which is then deprotected under acidic conditions (e.g., HCl, dioxane) to provide compound 34. Compound 34 is coupled with compound 10 under standard peptide coupling conditions (e.g., HATU, DIPEA, DMF) to yield compound IV-28.

[0248] The synthetic route illustrated in Scheme 1-5 is a general method for preparingcompound V-12, which may be applied with appropriate adjustments to make additional compounds shown in Table 5. Scheme 1-5

[0249] In step 1 of Scheme 1-5, compound 36 is coupled with compound 35 using basicconditions to give compound 37 (e.g., 1.3 eq. NaH, DMF, 0 ℃ to RT). In step 2, the methyl ester in compound 37 is converted to a carboxylic acid under basic conditions (e.g., 1.5 eq. LiOH, THF, water, RT) to give compound 38. In step 3, compound 38 is coupled with compound 29 under standard peptide coupling conditions (e.g., 1.2 eq. HATU, 3.0 eq. DIPEA, DMF, RT) to give compound 39. In step 4, Boc deprotection of compound 39 (e.g., 20 eq. HCl(4M in dioxane), dioxane, 0 ℃ to RT) gives compound 40, which is subsequently coupled withcompound 10 (e.g., 1.3 eq. HATU, 3.0 eq. DIPEA, DMF, RT) to give compound V-12.

[0250] The synthetic route illustrated in Scheme 1-6 is a general method for preparingcompound VI-39, which may be applied with appropriate adjustments to make additional compounds shown in Table 6. Scheme 1-6

[0251] In step 1 of Scheme 1-6, compound 41 is transformed into compound 42 using NBoc2(e.g., NaH). Compound 42 is deprotected under acidic conditions (e.g., HCl, dioxane) to give compound 43, which is then coupled with compound 10 (e.g., HATU, DIPEA, DMF) to give compound 44. In step 4, compound 44 is coupled with compound 27 under basic conditions (e.g., DIPEA, DMSO) to give compound 45, which is subsequently deprotected under acidic conditions (e.g., HCl, dioxane) to provide compound 46. Compound 46 is coupled with compound 30 to give compound VI-39.

[0252] The modular synthetic route illustrated in the Schemes can be adjusted to provideadditional compounds by conducting functional group transformations on the intermediate and final compounds. Such functional group transformations are well known in the art, as described in, for example, Comprehensive Organic Synthesis (B.M. Trost & I. Fleming, eds., 1991-1992); Organic Synthesis, 3rdEd. (Michael B. Smith, Wavefunction, Inc., Irvine: 2010); Modern Methods of Organic Synthesis, 4thEd. (William Carruthers and Iain Coldham, Cambridge University Press, Cambridge: 2004); March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8thEd., (Michael B. Smith, John Wiley & Sons, New York: 2020); and Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Ed. (Richard C. Larock, ed., John Wiley & Sons, New York: 2018). II. Anti-cotinine Antibody

[0253] Also provided is an antibody, or antigen-binding fragment thereof, that binds to acotinine moiety. As used herein, the term “anti-cotinine antibody or antigen-binding fragment thereof” refers to an antibody, or antigen binding fragment thereof that binds to a cotinine moiety. Cotinine has the following structure:.

[0254] As used herein, the term “cotinine moiety” refers to cotinine or an analog of cotinine.Compounds of Formula (I) described herein comprise a cotinine moiety linked via a linker to a MRGX2-binding moiety. In certain embodiments, the cotinine moiety has the following structure:wherein R1is C1-4alkyl or C3-6cycloalkyl. In certain embodiments, R1is methyl, ethyl, 1-propyl,2-propyl, 1-butyl, 2-butyl, or t-butyl. In certain embodiments, R1is methyl. In certain embodiments, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0255] The term “antibody” is used herein in the broadest sense to refer to molecules with animmunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanised, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g., a domain antibody (DAB)), antigen binding antibody fragments, Fab, F(ab’)2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABS, etc. and modified versions of any of the foregoing (for a summary of alternative “antibody” formats see Holliger and Hudson, Nature Biotechnology, 2005, 23(9): 1126-1136).

[0256] The term, full, whole or intact antibody, used interchangeably herein, refers to aheterotetrameric glycoprotein with an approximate molecular weight of 150,000 daltons. An intact antibody is composed of two identical heavy chains (HCs) and two identical light chains (LCs) linked by covalent disulphide bonds. This H2L2 structure folds to form three functional domains comprising two antigen-binding fragments, known as ‘Fab’ fragments, and a ‘Fc’ crystallisable fragment. The Fab fragment is composed of the variable domain at the amino- terminus, variable heavy (VH) or variable light (VL), and the constant domain at the carboxyl terminus, CH1 (heavy) and CL (light). The Fc fragment is composed of two domains formed by dimerization of paired CH2and CH3 regions. The Fc may elicit effector functions by binding to receptors on immune cells or by binding C1q, the first component of the classical complement pathway. The five classes of antibodies IgM, IgA, IgG, IgE and IgD are defined by distinct heavy chain amino acid sequences, which are called µ, α, γ, ε and δ respectively, each heavy chain can pair with either a Κ or λ light chain. The majority of antibodies in the serum belong to the IgG class, there are four isotypes of human IgG (IgG1, IgG2, IgG3 and IgG4), the sequences of which differ mainly in their hinge region.

[0257] “CDRs” are defined as the complementarity determining region amino acid sequencesof an antibody or antigen binding fragment thereof. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, “CDRs” as used hereinrefers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.

[0258] Throughout this specification, amino acid residues in variable domain sequences andvariable domain regions within full-length antigen binding sequences, e.g. within an antibody heavy chain sequence or antibody light chain sequence, are numbered according to the Kabat numbering convention. Similarly, the terms “CDR”, “CDRL1”, “CDRL2”, “CDRL3”, “CDRH1”, “CDRH2”, “CDRH3” used in the Examples follow the Kabat numbering convention. For further information, see Kabat et al., Sequences of Proteins of Immunological Interest, 4th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1987).

[0259] It will be apparent to those skilled in the art that there are alternative numberingconventions for amino acid residues in variable domain sequences and full-length antibody sequences. There are also alternative numbering conventions for CDR sequences, for example those set out in Chothia et al., Nature, 1989, 342: 877-883. The structure and protein folding of the antigen binding protein may mean that other residues are considered part of the CDR sequence and would be understood to be so by a skilled person.

[0260] Other numbering conventions for CDR sequences available to a skilled person include“AbM” (University of Bath) and “contact” (University College London) methods.

[0261] Table 7 below represents one definition using each numbering convention for eachCDR or binding unit. It should be noted that some of the CDR definitions may vary depending on the individual publication used. Table 7.

[0262] In a further embodiment, the anti-cotinine antibody is humanized. In a furtherembodiment, the Fc region of the anti-cotinine antibody is modified to increase ADCC activity, ADCP activity, and / or CDC activity, suitable modifications of which are provided below. In afurther embodiment, the Fc region of the anti-cotinine antibody is modified to increase ADCC activity.

[0263] Fc engineering methods can be applied to modify the functional or pharmacokineticsproperties of an antibody. Effector function may be altered by making mutations in the Fc region that increase or decrease binding to C1q or Fcγ receptors and modify CDC or ADCC activity respectively. Modifications to the glycosylation pattern of an antibody can also be made to change the effector function. The in vivo half-life of an antibody can be altered by making mutations that affect binding of the Fc to the FcRn (neonatal Fc receptor).

[0264] The term “effector function” as used herein refers to one or more of antibody-mediated effects including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody- mediated complement activation including complement-dependent cytotoxicity (CDC), complement-dependent cell-mediated phagocytosis (CDCP), antibody dependent complement- mediated cell lysis (ADCML), and Fc-mediated phagocytosis or antibody-dependent cellular phagocytosis (ADCP).

[0265] The interaction between the Fc region of an antigen binding protein or antibody andvarious Fc receptors (FcR), including FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16), FcRn, C1q, and type II Fc receptors is believed to mediate the effector functions of the antigen binding protein or antibody. Significant biological effects can be a consequence of effector functionality. Usually, the ability to mediate effector function requires binding of the antigen binding protein or antibody to an antigen and not all antigen binding proteins or antibodies will mediate every effector function.

[0266] Effector function can be assessed in a number of ways including, for example,evaluating ADCC effector function of antibody coated to target cells mediated by Natural Killer (NK) cells via FcγRIII, or monocytes / macrophages via FcγRI, or evaluating CDC effector function of antibody coated to target cells mediated by complement cascade via C1q. For example, an antibody, or antigen binding fragment thereof, of the present invention can be assessed for ADCC effector function in a Natural Killer cell assay. Examples of such assays can be found in Shields et al., The Journal of Biological Chemistry, 2001, 276: 6591-6604; Chappel et al., The Journal of Biological Chemistry, 1993, 268: 25124-25131; Lazar et al., PNAS, 2006, 103: 4005-4010.

[0267] Examples of assays to determine CDC function include those described in J ImmMeth, 1995, 184: 29-38.

[0268] The effects of mutations on effector functions (e.g., FcRn binding, FcγRs and C1qbinding, CDC, ADCML, ADCC, ADCP) can be assessed, e.g., as described in Grevys et al., J Immunol., 2015,194(11): 5497–5508; Tam et al., Antibodies, 2017, 6(3): 12; or Monnet et al., mAbs, 2014, 6(2): 422-436.

[0269] Throughout this specification, amino acid residues in Fc regions, in antibodysequences or full-length antigen binding protein sequences, are numbered according to the EU index numbering convention.

[0270] Human IgG1 constant regions containing specific mutations have been shown toenhance binding to Fc receptors. In some cases these mutations have also been shown to enhance effector functions, such as ADCC and CDC, as described below. Antibodies, or antigen binding fragments thereof, of the present invention may include any of the following mutations.

[0271] Enhanced CDC: Fc engineering can be used to enhance complement-based effectorfunction. For example (with reference to IgG1), K326W / E333S; S267E / H268F / S324T; and IgG1 / IgG3 cross subclass can increase C1q binding; E345R (Diebolder et al., Science, 2014, 343: 1260-1293) and E345R / E430G / S440Y results in preformed IgG hexamers (Wang et al., Protein Cell, 2018, 9(1): 63–73).

[0272] Enhanced ADCC: Fc engineering can be used to enhance ADCC. For example (withreference to IgG1), F243L / R292P / Y300L / V305I / P396L; S239D / I332E; and S298A / E333A / K334A increase FcγRIIIa binding; S239D / I332E / A330L increases FcγRIIIa binding and decreases FcγRIIb binding; G236A / S239D / I332E improves binding to FcγRIIa, improves the FcγRIIa / FcγRIIb binding ratio (activating / inhibitory ratio), and enhances phagocytosis of antibody-coated target cells by macrophages. An asymmetric Fc in which one heavy chain contains L234Y / L235Q / G236W / S239M / H268D / D270E / S298A mutations and D270E / K326D / A330M / K334E in the opposing heavy chain, increases affinity for FcγRIIIa F158 (a lower-affinity allele) and FcγRIIIa V158 (a higher-affinity allele) with no increased binding affinity to inhibitory FcγRIIb (Mimoto et al., mAbs, 2013, 5(2): 229-236).

[0273] Enhanced ADCP: Fc engineering can be used to enhance ADCP. For example (withreference to IgG1), G236A / S239D / I332E increases FcγRIIa binding and increases FcγRIIIa binding (Richards, J. et al., Mol. Cancer Ther., 2008, 7: 2517-2527).

[0274] Increased co-engagement: Fc engineering can be used to increase co-engagement withFcRs. For example (with reference to IgG1), S267E / L328F increases FcγRIIb binding; N325S / L328F increases FcγRIIa binding and decreases FcγRIIIa binding Wang et al., Protein Cell, 2018, 9(1): 63–73).

[0275] In a further embodiment, an antibody, or antigen binding fragment thereof, of thepresent invention may comprise a heavy chain constant region with an altered glycosylation profile, such that the antibody, or antigen binding fragment thereof, has an enhanced effector function, e.g., enhanced ADCC, enhanced CDC, or both enhanced ADCC and CDC. Examples of suitable methodologies to produce an antibody, or antigen binding fragment thereof, with an altered glycosylation profile are described in WO 2003 / 011878, WO 2006 / 014679 and EP1229125.

[0276] The absence of the α1,6 innermost fucose residues on the Fc glycan moiety on N297of IgG1 antibodies enhances affinity for FcγRIIIA. As such, afucosylated or low fucosylated monoclonal antibodies may have increased therapeutic efficacy (Shields et al., J Biol Chem., 2002, 277(30): 26733-40 and Monnet et al., mAbs, 2014, 6(2): 422-436).

[0277] In certain embodiments there is provided an antibody, or antigen binding fragmentthereof, comprising a chimeric heavy chain constant region. In an embodiment, the antibody, or antigen binding fragment thereof, comprises an IgG1 / IgG3 chimeric heavy chain constant region, such that the antibody, or antigen binding fragment thereof, has an enhanced effector function, for example enhanced ADCC or enhanced CDC, or enhanced ADCC and CDC functions. For example, a chimeric antibody, or antigen binding fragment thereof, of the invention may comprise at least one CH2domain from IgG3. In one such embodiment, the antibody, or antigen binding fragment thereof, comprises one CH2domain from IgG3 or both CH2domains may be from IgG3. In a further embodiment, the chimeric antibody, or antigen binding fragment thereof, comprises an IgG1 CH1 domain, an IgG3 CH2domain, and an IgG3 CH3 domain. In a further embodiment, the chimeric antibody, or antigen binding fragmentthereof, comprises an IgG1 CH1 domain, an IgG3 CH2domain, and an IgG3 CH3 domain except for position 435 that is histidine.

[0278] In a further embodiment, the chimeric antibody, or antigen binding fragment thereof,comprises an IgG1 CH1 domain and at least one CH2domain from IgG3. In an embodiment, the chimeric antibody, or antigen binding fragment thereof, comprises an IgG1 CH1 domain and the following residues, which correspond to IgG3 residues, in a CH2domain: 274Q, 276K, 296F, 300F and 339T. In an embodiment, the chimeric antibody, or antigen binding fragment thereof, also comprises 356E, which corresponds to an IgG3 residue, within a CH3 domain. In an embodiment, the antibody, or antigen binding fragment thereof, also comprises one or more of the following residues, which correspond to IgG3 residues within a CH3 domain: 358M, 384S, 392N, 397M, 422I, 435R, and 436F.

[0279] Also provided is a method of producing an antibody, or antigen binding fragmentthereof, according to the invention comprising the steps of: a) culturing a recombinant host cell comprising an expression vector comprising a nucleicacid sequence encoding a chimeric Fc region having both IgG1 and IgG3 Fc region amino acid residues (e.g. as described above); and b) recovering the antibody, or antigen binding fragment thereof.

[0280] Such methods for the production of antibody, or antigen binding fragment thereof,with chimeric heavy chain constant regions can be performed, for example, using the COMPLEGENT technology system available from BioWa, Inc. (Princeton, NJ) and Kyowa Hakko Kirin Co., Ltd. The COMPLEGENT system comprises a recombinant host cell comprising an expression vector in which a nucleic acid sequence encoding a chimeric Fc region having both IgG1 and IgG3 Fc region amino acid residues is expressed to produce an antibody, or antigen binding fragment thereof, having enhanced CDC activity, i.e. CDC activity is increased relative to an otherwise identical antibody, or antigen binding fragment thereof, lacking such a chimeric Fc region, as described in WO 2007 / 011041 and US 2007 / 0148165, each of which are incorporated herein by reference. In an alternative embodiment, CDC activity may be increased by introducing sequence specific mutations into the Fc region of an IgG chain. Those of ordinary skill in the art will also recognize other appropriate systems.

[0281] Also provided is a method of producing an antibody, or antigen binding fragmentthereof, according to the invention comprising the steps of: a) culturing a recombinant host cell comprising an expression vector comprising a nucleicacid encoding the antibody, or antigen binding fragment thereof, optionally wherein the FUT8 gene encoding alpha-1,6-fucosyltransferase has been inactivated in the recombinant host cell; and b) recovering the antibody, or antigen binding fragment thereof.

[0282] Such methods for the production of an antibody, or antigen binding fragment thereof,can be performed, for example, using the POTELLIGENT technology system available from BioWa, Inc. (Princeton, NJ) in which CHOK1SV cells lacking a functional copy of the FUT8 gene produce monoclonal antibodies having enhanced ADCC activity that is increased relative to an identical monoclonal antibody produced in a cell with a functional FUT8 gene as described in US Patent No.7,214,775, US Patent No.6,946,292, WO 00 / 61739 and WO 02 / 31240, all of which are incorporated herein by reference. Those of ordinary skill in the art will also recognize other appropriate systems.

[0283] In certain embodiments, the antibody, or antigen binding fragment thereof, isproduced in a host cell in which the FUT8 gene has been inactivated. In a further embodiment, the antibody, or antigen binding fragment thereof, is produced in a - / - FUT8 host cell. In a further embodiment, the antibody, or antigen binding fragment thereof, is afucosylated at Asn297 (IgG1).

[0284] It will be apparent to those skilled in the art that such modifications may not only beused alone but may be used in combination with each other in order to further enhance effector function.

[0285] In one such embodiment, there is provided an antibody, or antigen binding fragmentthereof, comprising a heavy chain constant region that comprises a both a mutated and chimeric heavy chain constant region, individually described above. For example, an antibody, or antigen binding fragment thereof, comprising at least one CH2domain from IgG3 and one CH2domain from IgG1, and wherein the IgG1 CH2domain has one or more mutations at positions selected from 239, 332 and 330 (for example the mutations may be selected from S239D, I332E andA330L), such that the antibody, or antigen binding fragment thereof, has enhanced effector function, e.g. enhanced ADCC or enhanced CDC, or enhanced ADCC and enhanced CDC in comparison to an equivalent antibody, or antigen binding fragment thereof, with an IgG1 heavy chain constant region lacking said mutations. In certain embodiments, the IgG1 CH2domain has the mutations S239D and I332E. In certain embodiments, the IgG1 CH2domain has the mutations S239D, A330L, and I332E.

[0286] In an alternative embodiment, there is provided an antibody, or antigen bindingfragment thereof, comprising both a chimeric heavy chain constant region and an altered glycosylation profile, as individually described above. In an embodiment, the antibody, or antigen binding fragment thereof, comprises an altered glycosylation profile such that the ratio of fucose to mannose is 0.8:3 or less. In one such embodiment, the heavy chain constant region comprises at least one CH2domain from IgG3 and one CH2domain from IgG1 and has an altered glycosylation profile such that the ratio of fucose to mannose is 0.8:3 or less, for example wherein the antibody, or antigen binding fragment thereof, is defucosylated. Said antibody, or antigen binding fragment thereof, has an enhanced effector function, e.g. enhanced ADCC or enhanced CDC, or enhanced ADCC and enhanced CDC, in comparison to an equivalent antibody, or antigen binding fragment thereof, with an IgG1 heavy chain constant region lacking said glycosylation profile.

[0287] In an alternative embodiment, the antibody, or antigen binding fragment thereof, hasat least one IgG3 heavy chain CH2domain and at least one heavy chain constant domain from IgG1 wherein both IgG CH2domains are mutated in accordance with the limitations described herein.

[0288] In one aspect, there is provided a method of producing an antibody, or antigen bindingfragment thereof, according to the invention described herein comprising the steps of: a) culturing a recombinant host cell containing an expression vector comprising anucleic acid sequence encoding a chimeric Fc domain having both IgG1 and IgG3 Fc domain amino acid residues (e.g. as described above); and wherein the FUT8 gene encoding alpha-1,6-fucosyltransferase has been inactivated in the recombinant host cell; and b) recovering the antibody, or antigen binding fragment thereof.

[0289] Such methods for the production of an antibody, or antigen binding fragment thereof,can be performed, for example, using the ACCRETAMAB technology system available from BioWa, Inc. (Princeton, NJ) that combines the POTELLIGENT and COMPLEGENT technology systems to produce an antibody, or antigen binding fragment thereof, having both enhanced ADCC and CDC activity relative to an otherwise identical monoclonal antibody that lacks a chimeric Fc domain and that is fucosylated.

[0290] In certain embodiments, there is provided an antibody, or antigen binding fragmentthereof, comprising a mutated and chimeric heavy chain constant region wherein said antibody, or antigen binding fragment thereof, has an altered glycosylation profile such that the antibody, or antigen binding fragment thereof, has enhanced effector function, e.g. enhanced ADCC or enhanced CDC, or both enhanced ADCC and CDC. In certain embodiments the mutations are selected from positions 239, 332 and 330, e.g. S239D, I332E and A330L. In a further embodiment the heavy chain constant region comprises at least one CH2domain from IgG3 and one CH1 domain from IgG1. In certain embodiments the heavy chain constant region has an altered glycosylation profile such that the ratio of fucose to mannose is 0.8:3 or less, e.g. the antibody, or antigen binding fragment thereof, is defucosylated, such that said antibody, or antigen binding fragment thereof, has an enhanced effector function in comparison with an equivalent non-chimeric antibody, or antigen binding fragment thereof, lacking said mutations and lacking said altered glycosylation profile.

[0291] In a further embodiment, the anti-cotinine antibody, or antigen binding fragmentthereof, comprises a heavy chain CDR1 having SEQ ID NO: 1, a heavy chain CDR2 having SEQ ID NO: 2, a heavy chain CDR3 having SEQ ID NO: 3, a light chain CDR1 having SEQ ID NO: 4, a light chain CDR2 having SEQ ID NO: 5, and a light chain CDR3 having SEQ ID NO: 6. In a further embodiment, the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6. In a further embodiment, the anti- cotinine antibody is of IgG1 isotype. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity, wherein the substitution is S239D / I332E orS239D / I332E / A330L, wherein residue numbering is according to the EU Index. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity, wherein the substitution is S239D / I332E, wherein residue numbering is according to the EU Index.

[0292] In a further embodiment, the anti-cotinine antibody, or antigen binding fragmentthereof, comprises a heavy chain variable region (VH) having SEQ ID NO: 7, a light chain variable region (VL) having SEQ ID NO: 8. In a further embodiment, the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity, wherein the substitution is S239D / I332E or S239D / I332E / A330L, wherein residue numbering is according to the EU Index. In a further embodiment, the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity, wherein the substitution is S239D / I332E, wherein residue numbering is according to the EU Index.

[0293] In a further embodiment, the anti-cotinine antibody has a heavy chain comprising SEQID NO: 9 and a light chain comprising SEQ ID NO: 10.

[0294] Also provided is a pharmaceutical composition comprising an anti-cotinine antibody,or antigen binding fragment thereof as disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0295] Also provided is a combination comprising a heterobifunctional compound describedherein (e.g., a compound of Formula (I)), and an anti-cotinine antibody, or antigen-binding fragment thereof as disclosed herein. The heterobifunctional compound and anti-cotinine antibody, or antigen binding fragment thereof can be present in the same composition or in separate compositions. In certain embodiments, a combination comprises a pharmaceutical composition comprising a heterobifunctional compound (e.g., a compound of Formula (I)) and an anti-cotinine antibody, or antigen binding fragment thereof as disclosed herein, and apharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, a combination comprises a first pharmaceutical composition comprising a heterobifunctional compound (e.g., a compound of Formula (I)) and a pharmaceutically acceptable carrier, diluent, or excipient; and a second pharmaceutical composition comprising an anti-cotinine antibody or antigen binding fragment thereof as disclosed herein, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0296] The heterobifunctional compounds (e.g., a compound of Formula (I)) andpharmaceutically acceptable salts thereof are capable of simultaneously binding a cell surface- expressed MRGX2 and an anti-cotinine antibody, or antigen binding fragment thereof to form a ternary complex for the treatment and / or prevention of diseases or disorders associated with MRGX2-expressing cells.

[0297] In a further embodiment, the compound and the antibody, or antigen-binding fragmentthereof, are administered simultaneously. In a further embodiment, the compound and the antibody, or antigen-binding fragment thereof, are administered simultaneously from a single composition, including as a fixed-dose composition or by pre-mixing the compound and the antibody, or antigen-binding fragment thereof, prior to administration. For example, the compound and the antibody, or antigen-binding fragment thereof, can be pre-mixed about 2 seconds to about 30 seconds, about 30 seconds to about 2 minutes, about 2 minutes to about 10 minutes, about 10 minutes to about 30 minutes, or about 30 minutes to about 2 hours prior to administration. In a further embodiment, the compound and the antibody, or antigen-binding fragment thereof, are administered simultaneously from two separate compositions.

[0298] In a further embodiment, the compound and the antibody, or antigen-binding fragmentthereof, are administered sequentially.

[0299] In certain embodiments, the compound and the antibody, or antigen-binding fragmentthereof, whether administered simultaneously or sequentially, may be administered by the same route or may be administered by different routes. In certain embodiments, the compound and the antibody, or antigen-binding fragment thereof, are both administered intraveneously or subcutaneously, in the same composition or in separate compositions. In certain embodiments, the compound is administered orally and the antibody or antigen-binding fragment thereof is administered intravenously or subcutaneously.

[0300] In a further embodiment, the compound and the antibody, or antigen-binding fragmentthereof, are administered in a molar ratio of compound to antibody, or antigen-binding fragment thereof, of about 2:1, about 1.8:1, about 1.6:1, about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1:1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.8, about 1:2, about 2:1 to about 1.5:1, about 1.5:1 to about 1.2:1, about 1.2:1 to about 1:1, about 1:1 to about 1:1.2, about 1:1.2 to about 1:1.5, or about 1:1.5 to about 1:2.

[0301] In a further embodiment, the compound and the antibody, or antigen-binding fragmentthereof, are present as a combination in a molar ratio of compound to antibody, or antigen- binding fragment thereof, of about 2:1, about 1.8:1, about 1.6:1, about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1:1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.8, about 1:2, about 2:1 to about 1.5:1, about 1.5:1 to about 1.2:1, about 1.2:1 to about 1:1, about 1:1 to about 1:1.2, about 1:1.2 to about 1:1.5, or about 1:1.5 to about 1:2.

[0302] In a further embodiment, the compound and the antibody, or antigen-binding fragmentthereof, are administered at a dosage of compound of 0.0001 mg / kg to 1 mg / kg and antibody of 0.01 mg / kg to 100 mg / kg. For example, in a further embodiment, the compound is administered at a dosage of about 0.0001 mg / kg to about 0.0002 mg / kg, about 0.0002 mg / kg to about 0.0003 mg / kg, about 0.0003 mg / kg to about 0.0004 mg / kg, about 0.0004 mg / kg to about 0.0005 mg / kg, about 0.0005 mg / kg to about 0.001 mg / kg, about 0.001 mg / kg to about 0.002 mg / kg, about 0.002 mg / kg to about 0.003 mg / kg, about 0.003 mg / kg to about 0.004 mg / kg, about 0.004 mg / kg to about 0.005 mg / kg, about 0.005 mg / kg to about 0.01 mg / kg, about 0.01 mg / kg to about 0.02 mg / kg, about 0.02 mg / kg to about 0.03 mg / kg, about 0.03 mg / kg to about 0.04 mg / kg, about 0.04 mg / kg to about 0.05 mg / kg, about 0.05 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.2 mg / kg, about 0.2 mg / kg to about 0.3 mg / kg, about 0.3 mg / kg to about 0.4 mg / kg, about 0.4 mg / kg to about 0.5 mg / kg, and / or about 0.5 mg / kg to about 1 mg / kg, and the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 0.01 mg / kg to about 0.02 mg / kg, about 0.02 mg / kg to about 0.03 mg / kg, about 0.03 mg / kg to about 0.04 mg / kg, about 0.04 mg / kg to about 0.05 mg / kg, about 0.05 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 0.2 mg / kg, about 0.2 mg / kg to about 0.3 mg / kg, about 0.3 mg / kg to about 0.4 mg / kg, about 0.4 mg / kg to about 0.5 mg / kg, about 0.5 mg / kg to about 1 mg / kg, about 1 mg / kg to about 2 mg / kg, about 2 mg / kg to about 3 mg / kg, about 3 mg / kg to about 4 mg / kg, about 4 mg / kg to about 5 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg toabout 20 mg / kg, about 20 mg / kg to about 25 mg / kg, about 25 mg / kg to about 30 mg / kg, about 30 mg / kg to about 35 mg / kg, about 35 mg / kg to about 40 mg / kg, about 40 mg / kg to about 45 mg / kg, about 45 mg / kg to about 50 mg / kg, about 50 mg / kg to about 60 mg / kg, about 60 mg / kg to about 70 mg / kg, about 70 mg / kg to about 80 mg / kg, about 80 mg / kg to about 90 mg / kg, and / or about 90 mg / kg to about 100 mg / kg.

[0303] In a further embodiment, the compound and the antibody, or antigen-binding fragmentthereof, are administered at a dosage of compound of 0.007 mg to 70 mg and antibody of 0.7 mg to 7000 mg. For example, in a further embodiment, the compound is administered at a dosage of about 0.007 mg to about 0.01 mg, about 0.01 mg to about 0.02 mg, about 0.02 mg to about 0.03 mg, about 0.03 mg to about 0.04 mg, about 0.04 mg to about 0.05 mg, about 0.05 mg to about 0.1 mg, about 0.1 mg to about 0.2 mg, about 0.2 mg to about 0.3 mg, about 0.3 mg to about 0.4 mg, about 0.4 mg to about 0.5 mg, about 0.5 mg to about 1 mg, about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 60 mg, and / or about 60 mg to about 70 mg, and the antibody, or antigen-binding fragment thereof, is administered at a dosage of about 0.7 mg to about 1 mg, about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 500 mg, about 500 mg to about 1000 mg, about 1000 mg to about 1500 mg, about 1500 mg to about 2000 mg, about 2000 mg to about 2500 mg, about 2500 mg to about 3000 mg, about 3000 mg to about 3500 mg, about 3500 mg to about 4000 mg, about 4000 mg to about 4500 mg, about 4500 mg to about 5000 mg, about 5000 mg to about 5500 mg, about 5500 mg to about 6000 mg, about 6000 mg to about 6500 mg, and / or about 6500 mg to about 7000 mg.

[0304] In a further embodiment, the compound and the antibody, or antigen-binding fragmentthereof, are administered in a molar ratio and / or dosage as described herein once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks for a period of one week to one year, such as a period of one week, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, or twelve months.III. Therapeutic Applications

[0305] One aspect of the invention provides a method of treating or preventing a disease orcondition in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a heterobifunctional compound described herein (e.g., a compound of Formula I) and an anti-cotinine antibody, or antigen-binding fragment thereof.

[0306] Another aspect of the invention provides a method of treating or preventing aMRGX2-associated disease or condition in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a heterobifunctional compound described herein (such as a compound of Formula I) and an anti-cotinine antibody, or antigen-binding fragment thereof.

[0307] In certain embodiments, the MRGX2-associated disease or condition is a mast celldisease, pain, cough, acute itch, or chronic itch. In certain embodiments, the MRGX2-associated disease or condition is a mast cell disease. In certain embodiments, the MRGX2-associated disease or condition is pain. In certain embodiments, the MRGX2-associated disease or condition is cough. In certain embodiments, the MRGX2-associated disease or condition is acute itch or chronic itch.

[0308] For each of the foregoing methods, in certain embodiments, the method is to treatingthe disease or condition. In certain embodiments, the method is to preventing the disease or condition.

[0309] Another aspect of the invention provides a method of treating or preventing a mast celldisease in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a heterobifunctional compound described herein (such as a compound of Formula I) and an anti-cotinine antibody, or antigen-binding fragment thereof. In certain embodiments, the mast cell disease is an inflammatory disease associated with mast cell activity.

[0310] Another apect of the invention provides a method of treating or preventing a diseaseselected from the group consisting of urticaria, prurigo nodularis, atopic dermatitis, psoriasis, allergic rhinitis, asthma, systemic mastocytosis, mast cell activation syndrome, inflammatory bowel disease, anaphylaxis, food allergy, and insect sting in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I) and an anti-cotinine antibody, or antigen-binding fragment thereof.

[0311] For the foregoing two methods, in certain embodiments, the method is to treating thedisease. In certain embodiments, the method is to preventing the disease.

[0312] In certain embodiments, the disease is urticaria, prurigo nodularis, atopic dermatitis,psoriasis, allergic rhinitis, asthma, systemic mastocytosis, mast cell activation syndrome, inflammatory bowel disease, or anaphylaxis. In certain embodiments, the disease is urticaria, prurigo nodularis, atopic dermatitis, psoriasis, allergic rhinitis, asthma, systemic mastocytosis, mast cell activation syndrome, or inflammatory bowel disease.

[0313] In certain embodiments, the disease is urticaria. In certain embodiments, the disease ischronic urticaria. In certain embodiments, the disease is spontaneous urticaria. In certain embodiments, the disease is chronic and spontaneous urticaria. In certain embodiments, the disease is inducible urticaria. In certain embodiments, the disease is chronic and inducible urticaria. In certain embodiments, the disease is heat inducible urticaria (also referred to as cholinergic urticaria (ChoIU)). In certain embodiments, the disease is cold inducible urticaria. In certain embodiments, the disease is delayed pressure urticaria (DPU). In certain embodiments, the disease is friction inducible urticaria (also referred to as symptomatic dermographism). In certain embodiments, the disease is vibratory angioedema. In certain embodiments, the disease is solar urticaria. In certain embodiments, the disease is contact urticaria. In certain embodiments, the disease is aquagenic urticaria.

[0314] In certain embodiments, the disease is prurigo nodularis. In certain embodiments, thedisease is atopic dermatitis. In certain embodiments, the disease is psoriasis. In certain embodiments, the disease is allergic rhinitis. In certain embodiments, the disease is asthma. In certain embodiments, the disease is type 2 asthma. In certain embodiments, the disease is systemic mastocytosis. In certain embodiments, the disease is mast cell activation syndrome. In certain embodiments, the disease is inflammatory bowel disease. In certain embodiments, the disease is anaphylaxis. In certain embodiments, the disease is food allergy. In certain embodiments, the disease is insect sting.

[0315] Another aspect of the invention provides a method of treating or preventing pain in apatient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a heterobifunctional compound described herein (such as a compound of Formula I) and an anti-cotinine antibody, or antigen-binding fragment thereof.

[0316] In certain embodiments, the method is to treating pain. In certain embodiments, themethod is to preventing pain.

[0317] In certain embodiments, the pain is chronic pain. In certain embodiments, the pain isacute pain. In certain embodiments, the pain is neuropathic pain. In certain other embodiments, the pain is inflammatory pain. In certain embodiments, the pain is arthritis pain. In certain embodiments, the pain is arthritis pain selected from osteoarthritis pain and rheumatoid arthritis pain.

[0318] In certain other embodiments, the pain is pain due to cancer. In certain embodiments,the pain is due to a cancer selected from the group consisting of a solid tumor, leukemia, and lymphoma. In certain embodiments, the pain is due to a cancer selected from the group consisting of a bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, stomach cancer, testicular cancer, and uterine cancer.

[0319] In certain other embodiments, the pain is complex regional pain syndrome. In certainembodiments, the complex regional pain syndrome is reflex sympathetic dystrophy pain. In certain other embodiments, the pain is trauma pain. In certain embodiments, the pain is due to surgery.

[0320] In certain other embodiments, the pain is located in the patient’s hand, wrist, arm,shoulder, back, leg, knee, ankle, foot, toe, neck, or head. In certain embodiments, the pain is low back pain. In certain embodiments, the pain is chronic low back pain.

[0321] In certain other embodiments, the pain is a neuropathic pain selected from the groupconsisting of low back pain, hip pain, leg pain, non-herpetic neuralgia, post-herpetic neuralgia, diabetic neuropathy pain, lumbosacral radiculopathy pain, nerve injury-induced pain, acquired immune deficiency syndrome (AIDS) related neuropathic pain, head trauma pain, phantom limbpain, multiple sclerosis pain, root avulsion pain, painful traumatic mononeuropathy, painful polyneuropathy, thalamic pain syndrome, post-stroke pain, central nervous system injury pain, post-surgical pain, carpal tunnel syndrome pain, trigeminal neuralgia pain, post mastectomy syndrome pain, post-thoracotomy syndrome pain, stump pain, repetitive motion pain, neuropathic pain associated hyperalgesia and allodynia, drug-induced pain, toxin-caused nerve injury pain, chemotherapy-caused nerve injury pain, and combinations thereof. Amount of Reduction in Pain Intensity

[0322] The method may be further characterized according to the amount of reduction in painintensity relative to pain observed without performing the method. Accordingly, in certain embodiments, the method is characterized by achieving at least a 20% reduction in pain intensity relative to pain observed without performing the method. In certain embodiments, the method is characterized by achieving at least a 40% reduction in pain intensity relative to pain observed without performing the method. In certain embodiments, the method is characterized by achieving at least a 60% reduction in pain intensity relative to pain observed without performing the method. In certain embodiments, the method is characterized by achieving at least an 80% reduction in pain intensity relative to pain observed without performing the method. In certain embodiments, the method is characterized by achieving at least a 90% reduction in pain intensity relative to pain observed without performing the method. Duration of Reduction in Pain Intensity

[0323] The method may be further characterized according to the duration of reduction inpain intensity. Accordingly, in certain embodiments, the reduction in pain intensity lasts for at least 1 week. In certain embodiments, the reduction in pain intensity lasts for at least 2 weeks. In certain embodiments, the reduction in pain intensity lasts for at least 4 weeks. In certain embodiments, the reduction in pain intensity lasts for at least 2 months. In certain embodiments, the reduction in pain intensity lasts for at least 3 months. In certain embodiments, the reduction in pain intensity lasts for at least 6 months.

[0324] In certain embodiments, the reduction in pain intensity lasts for at a duration of 2months to six months. In certain embodiments, the reduction in pain intensity lasts for a duration of 3 months to 9 months. In certain embodiments, the reduction in pain intensity lasts for aduration of 6 months to 9 months. In certain embodiments, the reduction in pain intensity lasts for a duration of 6 months to 12 months. Subjects

[0325] For each of the foregoing therapeutic methods, in certain embodiments, the subject isa human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human. Increasing Antibody-dependent Cell Cytotoxicity

[0326] Another aspect of the invention provides a method of increasing antibody-dependentcell cytotoxicity (ADCC) of MRGX2-expressing cells, wherein the method comprises contacting the cells with an effective amount of a heterobifunctional compound described herein (such as a compound of Formula I) and an anti-cotinine antibody, or antigen-binding fragment thereof. Depleting MRGX2-Expressing Cells

[0327] Another aspect of the invention provides a method of depleting MRGX2-expressingcells, wherein the method comprises contacting the cells with an effective amount of a heterobifunctional compound described herein (such as a compound of Formula I) and an anti- cotinine antibody, or antigen-binding fragment thereof. Additional Features of the Methods

[0328] Each of the foregoing methods may be characterized according to additional features,such as administration aspects and aspects of the anti-cotinine antibody. Administration Aspects

[0329] In certain embodiments, the compound and the antibody, or antigen-binding fragmentthereof, are administered simultaneously.

[0330] In certain embodiments, the compound and the antibody, or antigen-binding fragmentthereof, are administered sequentially. Aspects of the Anti-cotinine Antibody

[0331] In certain embodiments, the anti-cotinine antibody has a heavy chain and a light chain,the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, anda CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6. In certain embodiments, the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8.

[0332] In certain embodiments, the anti-cotinine antibody is of IgG1 isotype comprising asubstitution in an Fc region to increase ADCC activity. In certain embodiments, the substitution in the Fc region is S239D / I332E, wherein residue numbering is according to the EU Index.

[0333] In certain embodiments, the anti-cotinine antibody has a heavy chain comprising SEQID NO: 9 and a light chain comprising SEQ ID NO: 10. Medical Uses

[0334] Another aspect of the invention provides for the use of a heterobifunctional compounddescribed herein (such as a compound of Formula I, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as a mast cell disease or pain.

[0335] Another aspect of the invention provides for a heterobifunctional compound describedherein (such as a compound of Formula I, or other compounds in Section I) for use in treating a medical disorder, such as a medical disorder described herein, such as a mast cell disease or pain. Combination

[0336] Another aspect of the invention provides a combination comprising aheterobifunctional compound described herein (e.g., a compound of Formula I) and an anti- cotinine antibody, or antigen-binding fragment thereof.

[0337] In certain embodiments, the anti-cotinine antibody has a heavy chain and a light chain,the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6. In certain embodiments, the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8.

[0338] In certain embodiments, the anti-cotinine antibody is of IgG1 isotype comprising asubstitution in an Fc region to increase ADCC activity. In certain embodiments, the substitution in the Fc region is S239D / I332E, wherein residue numbering is according to the EU Index.

[0339] In certain embodiments, the anti-cotinine antibody has a heavy chain comprising SEQID NO: 9 and a light chain comprising SEQ ID NO: 10. IV. Biological Assays for Evaluating Compound Activity

[0340] Heterobifunctional compounds may be evaluated for biological activity using one ormore of the assays described below. Assay 1: Antibody Dependent Cellular Cytotoxicity Reporter Assay

[0341] An antibody dependent cellular cytoxocity reporter assay is conducted using thefollowing four assay components: (i) ARM compound of Formula (I) targeting MRGX2 (concentrations ranging from 1 pM to 10 µM) (ii) anti-cotinine antibody having a heavy chain sequence of SEQ ID NO: 11 and a light chain sequence of SEQ ID NO: 12 (rabbit variable region with human IgG1 Fc domain containing a DE mutation (S239D / I332E)) (concentrations ranging from 0.01 µg / mL to 200 µg / mL); (iii) target cells: cells engineered to overexpress either human MRGX2 (typically 1000-20,000 cells per well) and (iv) reporter cells: Reagents are combined in a final volume of 20 µL in a 384 - well tissue culture treated plate. All four assay components are incubated together for about 12-18 hours. Thereafter, BioGlo Detection reagent (Promega) is added to the wells to lyse the cells and provide a substrate for the luciferase reporter protein. Luminescence signal is measured on a microplate reader and signal:background is calculated by dividing the signal of a test well by the signal obtained when no heterobivalent compound of Formula (I) was added. EC50 calculations are done using Graphpad Prism Software, specifically a nonlinear regression curve fit ( Y = Bottom + ( Top - Bottom ) / ( 1 + 10 ^ ( ( Log EC50 - X ) * HillSlope ) ) ). Assay 2: Binding of Anti-Cotinine Antibody to ARM Compounds of Formula I Measured by Surface Plasmon Resonance (SPR)

[0342] Anti-cotinine antibodies having a heavy chain sequence of SEQ ID NO: 11 and a lightchain sequence of SEQ ID NO: 12 (rabbit variable region with human IgG1 Fc domain containing a DE mutation (S239D / I332E)) can be captured on one or more flow cells of a proteinA sensor chip (Cytiva) using a Biacore T200 while reserving flow cell 1 as a reference. Following capture, a 3000 second wait step is included to reduce drift during compound analysis. ARM compounds (e.g., of Formula I) are then injected at 100 µL / min with 200 and 2000 second association and dissociation times. The entire experiment may be run at 37°C with running buffer containing 10 mM HEPES pH 7.4, 150 mM NaCl, 0.005% P20 and 1% DMSO. ARM compounds of Formula (I) are titrated with a top concentration of 200 nM using a 3-fold 5-point dilution series and a corresponding 5-injection buffer cycle is run for blank subtraction. Data are double referenced by subtracting the response of the reference flow cell from that of the antibody-containing flow cell and subsequently subtracting the referenced blank sensorgrams. Following compound analysis, the surface is regenerated using a 30 second injection of pH 1.5 glycine at a flow rate of 30 µL / min after which antibody is re-captured. The experiment may be run using Biacore T200 control software and evaluated using Biacore T200 Evaluation software. Curves are fit with a 1:1 kinetic binding model to obtain kon (1 / Ms), koff (1 / s), Kd (M) determined as koff / kon, and residence time determined as 1 / koff. (s).

[0343] Anti-cotinine antibodies having a heavy chain sequence of SEQ ID NO: 9 and a lightchain sequence of SEQ ID NO: 10 (humanized version) or a heavy chain sequence of SEQ ID NO: 11 and a light chain sequence of SEQ ID NO: 12 (rabbit version) may be captured via the Fc domain to a protein A or A / G surface on flow cell 2 of a CM5 sensor chip using the Biacore 8k. Both antibodies may have a human IgG1 Fc domain containing a DE mutation (S239D / I332E).

[0344] After antibody capture, a 1500 second wait step is included to reduce drift in thebinding step. ARM compounds of Formula (I) are then flowed over the captured antibodies at varying top concentrations ranging from 250 nM to 4 µM. The top concentration is diluted 4- fold over 5 dilutions (with a 0 nM compound cycle included to blank subtract the data). Association and dissociation times of the ARMs compounds of Formula (I) may vary between experiments as follows: reference 1- association for 600 seconds and dissociation for 1200 seconds at 20µl / min; reference 2- association for 240 seconds and dissociation for 300 seconds at 30µl / min; reference 3- association for 360 seconds and dissociation for 600 seconds at 30µl / min. Anti-cotinine antibody bound to the protein A or A / G surface is regenerated using 50mM NaOH. Experiments are run at 25°C at pH 7.4 using HBS-EP+ buffer using Biacore 8K control softwareand evaluated using Biacore Insight Evaluation software. Curves are fit with the 1:1 kinetic fit inherent to the software, utilising a local Rmax and local drift setting. V. Combination Therapy

[0345] Another aspect of the invention provides for combination therapy. Heterobifunctionalcompounds described herein (such as a compound of Formula I, or other compounds in Section I) or their pharmaceutically acceptable salts may be used in combination with additional therapeutic agents to treat medical disorders, such as a mast cell disease or pain.

[0346] In some embodiments, the present invention provides a method of treating a discloseddisease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, an anti-cotinine antibody, or antigen-binding fragment thereof, and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.

[0347] One or more other therapeutic agent may be administered separately from a compoundor composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent and a compound or composition of the invention are administered as a multiple dosage regimen more than 24 hours apart.

[0348] In certain embodiments, the additional therapeutic agent is an anti-inflammatoryagent, analgesic, biological response modifier, disease modifying antirheumatic drug (DMARD), antihistamine, mast cell stabilizer, prokinetic agent, antidiarrheal, prosecretory agent, antibiotic, antidepressant, anxiolytic, antipsychotic, or anticonvulsant.

[0349] In certain embodiments, the additional therapeutic agent is an anti-inflammatoryagent. In certain embodiments, the additional therapeutic agent is a nonsteroidal anti- inflammatory drug (NSAID) or corticosteroid.

[0350] In certain embodiments, the additional therapeutic agent is a nonsteroidal anti-inflammatory drug (NSAID). In certain embodiments, the additional therapeutic agent is apazone, aspirin, celecoxib, diclofenac (with or without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylates, salsalate, or sulindac. In certain embodiments, the additional therapeutic agent is aspirin, ibuprofen, diclofenac, diflunisal, ibuprofen, naproxen, fenoprofen, piroxicam, flurbiprofen, mefenamic acid, sulindac, salts thereof, or mixtures thereof. In certain embodiments, the additional therapeutic agent is acetaminophen.

[0351] In certain embodiments, the additional therapeutic agent is a corticosteroid. In certainembodiments, the additional therapeutic agent is betamethasone, cortisone acetate, dexamethasone, hydrocortisone, methylprednisolone, prednisolone and prednisone.

[0352] In certain embodiments, the additional therapeutic agent is an analgesic. In certainembodiments, the additional therapeutic agent is an opioid analgesic. In certain embodiments, the additional therapeutic agent is alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl; heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacyl morphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, salts thereof, or mixtures thereof.

[0353] In certain embodiments, the additional therapeutic agent is a biological responsemodifier. In certain embodiments, the additional therapeutic agent is a TNF-^ inhibitor, selective B-cell inhibitor, IL-1 inhibitor, or selective costimulation modulator. In certain embodiments, the additional therapeutic agent is a TNF-^ inhibitor. In certain embodiments, the additional therapeutic agent is adalimumab, etanercept, or infliximab. In certain embodiments, the additional therapeutic agent is adalimumab. In certain embodiments, the additional therapeutic agent is etanercept. In certain embodiments, the additional therapeutic agent is infliximab. In certain embodiments, the additional therapeutic agent is a selective B-cell inhibitor. In certain embodiments, the additional therapeutic agent is rituximab. In certain embodiments, the additional therapeutic agent is an IL-1 inhibitor. In certain embodiments, the additional therapeutic agent is anakinra. In certain embodiments, the additional therapeutic agent is a selective costimulation modulator. In certain embodiments, the additional therapeutic agent is abatacept.

[0354] In certain embodiments, the additional therapeutic agent is a disease modifyingantirheumatic drug (DMARD). In certain embodiments, the additional therapeutic agent is auranofin (oral gold), azathioprine, chlorambucil, cyclophosamide, cyclosporine, gold sodium thiomalate (injectable gold), hydroxychloroquine, leflunomide, methotrexate, minocycline, myophenolate mofetil, penicillamine, sulfasalazine, or a JAK inhibitor. In certain embodiments, the additional therapeutic agent is leflunomide or methotrexate. In certain embodiments, the additional therapeutic agent is leflunomide. In certain embodiments, the additional therapeutic agent is methotrexate. In certain embodiments, the additional therapeutic agent is a JAK inhibitor. In certain embodiments, the additional therapeutic agent is a JAK3 inhibitor. In certain embodiments, the additional therapeutic agent is tofacitinib.

[0355] In certain embodiments, the additional therapeutic agent is methotrexate,lefluonomide, adalimumab, etanercept, or infliximab.

[0356] In certain embodiments, the additional therapeutic agent is an antihistamine. In certainembodiments, the additional therapeutic agent is an H1- antihistamine, H1 inverse agonist, H2- antihistamine, H3-antihistamine, or H4-antihistamine. In certain embodiments, the additional therapeutic agent is an H1-antihistamine. In certain embodiments, the additional therapeutic agent is acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine,carbinoxamine, cetirizine, chlorodiphenhydramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, rupatadine, tripelennamine, or triprolidine. In certain embodiments, the additional therapeutic agent is an H1 inverse agonist. In certain embodiments, the additional therapeutic agent is levocetirizine, desloratadine, or pyrilamine. In certain embodiments, the additional therapeutic agent is an H2-antihistamine. In certain embodiments, the additional therapeutic agent is cimetidine, famotidine, lafutidine, nizatidine, ranitidine, or roxatidine. In certain embodiments, the additional therapeutic agent is an H3- antihistamine. In certain embodiments, the additional therapeutic agent is clobenpropit, ciproxifan, conessine, or thioperamide. In certain embodiments, the additional therapeutic agent is an H4-antihistamine. In certain embodiments, the additional therapeutic agent is thioperamide.

[0357] In certain embodiments, the additional therapeutic agent is a mast cell stabilizer. Incertain embodiments, the additional therapeutic agent is azelastine, a ^2 adrenergic receptor agonist, cromoglicic acid, ketotifen, mepolizumab, nedocromil, olopatadine, omalizumab, palmitoylethanolamide, pemirolast, quercetin, rupatadine, tranilast, or vitamin D. In certain embodiments, the additional therapeutic agent is azelastine, cromoglicic acid, ketotifen, mepolizumab, nedocromil, olopatadine, omalizumab, palmitoylethanolamide, pemirolast, quercetin, rupatadine, tranilast, or vitamin D. In certain embodiments, the additional therapeutic agent is a ^2adrenergic receptor agonist. In certain embodiments, the additional therapeutic agent is abediterol, arformoterol, bambuterol, bitolterol, carmoterol, clenbuterol, fenoterol, formoterol, indacaterol, isoprenaline, isoxsuprine, levosalbutamol, mabuterol, olodaterol, orciprenaline, pirbuterol, procaterol, ritodrine, salbutamol, terbutaline, vilanterol, or zilpaterol.

[0358] In certain embodiments, the additional therapeutic agent is a prokinetic agent. Incertain embodiments, the additional therapeutic agent is cinitapride, cisapride, domperidone, itopride, levosulpiride, linaclotide, metoclopramide, mitemcinal, mosapride, prucalopride, renzapride, or tegaserod.

[0359] In certain embodiments, the additional therapeutic agent is an antidiarrheal,prosecretory agent, or antibiotic. In certain embodiments, the additional therapeutic agent is anantidiarrheal. In certain embodiments, the additional therapeutic agent is bismuth subsalicylate, crofelemer, difenoxin HCl / atropine, diphenoxylate HCl / atropine, loperamide, loperamide / simethicone, octreotide, or paregoric. In certain embodiments, the additional therapeutic agent is a prosecretory agent. In certain embodiments, the additional therapeutic agent is lubiprostone, linaclotide, plecanatide, or elobixibat. In certain embodiments, the additional therapeutic agent is an antibiotic. In certain embodiments, the additional therapeutic agent is tetracycline, amoxicillin clavulanate, metronidazole, a fluoroquinolone (e.g., norfloxacin), or rifaximin.

[0360] In certain embodiments, the additional therapeutic agent is an antidepressant,anxiolytic, antipsychotic, or anticonvulsant.

[0361] In certain embodiments, the additional therapeutic agent is an antidepressant. Incertain embodiments, the additional therapeutic agent is a tricyclic antidepressant, selective seretonin reuptake inhibitor (SSRI), or selective serotonin and norepinephrine reuptake inhibitors (SNRI). In certain embodiments, the additional therapeutic agent is amitriptyline, amoxapine, bupropion, citalopram, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, imipramine, isocarboxazid, levomilnacipran, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine, protriptyline, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, vilazodone, or vortioxetine.

[0362] In certain embodiments, the additional therapeutic agent is an anxiolytic. In certainembodiments, the additional therapeutic agent is a benzodiazepine or a non-benzodiazepine anxiolytic. In certain embodiments, the additional therapeutic agent is a benzodiazepine. In certain embodiments, the additional therapeutic agent is alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, or triazolam. In certain embodiments, the additional therapeutic agent is a non-benzodiazepine anxiolytic. In certain embodiments, the additional therapeutic agent is eszopiclone, zaleplon, zolpidem, or zopiclone. In certain embodiments, the additional therapeutic agent is buspirone.

[0363] In certain embodiments, the additional therapeutic agent is antipsychotic, includingatypical antipsychotics. In certain embodiments, the additional therapeutic agent is aripiprazole,asenapine, chlorpromazine, clozapine, desipramine, fluphenazine, haloperidol, iloperidone, lurasidone, olanzapine, paliperidone, perphenazine, quetiapine, risperidone, or ziprasidone.

[0364] In certain embodiments, the additional therapeutic agent is an anticonvulsant. Incertain embodiments, the additional therapeutic agent is acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, or zonisamide.

[0365] In certain embodiments, particularly when treating pain, the additional therapeuticagent is an opioid analgesic, a non-steroidal anti-inflammatory drug, or acetaminophen. Additional Considerations

[0366] The doses and dosage regimen of the active ingredients used in the combinationtherapy may be determined by an attending clinician. In certain embodiments, the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disorder. In other embodiments, the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disorder. In certain embodiments, the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.

[0367] In certain embodiments, the compound described herein (such as a compound ofFormula I, or other compounds in Section I) and the additional therapeutic agent(s) may act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and / or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.

[0368] Another aspect of this invention is a kit comprising a therapeutically effective amountof the compound described herein (such as a compound of Formula I, or other compounds inSection I), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above. In some embodiments, the kit further comprises an anti-cotinine antibody, or antigen-binding fragment thereof. VI. Pharmaceutical Compositions and Dosing Considerations

[0369] As indicated above, the invention provides pharmaceutical compositions, whichcomprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound described herein (such as a compound of Formula I, or other compounds in Section I) and a pharmaceutically acceptable carrier.

[0370] The phrase “therapeutically effective amount” as used herein means that amount of acompound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit / risk ratio applicable to any medical treatment.

[0371] The phrase “pharmaceutically acceptable” is employed herein to refer to thosecompounds, 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.

[0372] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, release agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0373] Examples of pharmaceutically-acceptable antioxidants include: (1) water solubleantioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0374] Formulations of the present invention include those suitable for oral, nasal, topical(including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0375] In certain embodiments, a formulation of the present invention comprises an excipientselected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.

[0376] Methods of preparing these formulations or compositions include the step of bringinginto association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0377] Formulations of the invention suitable for oral administration may be in the form ofcapsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.

[0378] In solid dosage forms of the invention for oral administration (capsules, tablets, pills,dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0379] A tablet may be made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active ordispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0380] The tablets, and other solid dosage forms of the pharmaceutical compositions of thepresent invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0381] Liquid dosage forms for oral administration of the compounds of the invention includepharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0382] Besides inert diluents, the oral compositions can also include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0383] Suspensions, in addition to the active compounds, may contain suspending agents as,for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0384] Formulations of the pharmaceutical compositions of the invention for rectal or vaginaladministration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0385] Formulations of the present invention which are suitable for vaginal administrationalso include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0386] Dosage forms for the topical or transdermal administration of a compound of thisinvention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0387] The ointments, pastes, creams and gels may contain, in addition to an activecompound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0388] Powders and sprays can contain, in addition to a compound of this invention,excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0389] Transdermal patches have the added advantage of providing controlled delivery of acompound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0390] Ophthalmic formulations, eye ointments, powders, solutions and the like, are alsocontemplated as being within the scope of this invention.

[0391] Pharmaceutical compositions of this invention suitable for parenteral administrationcomprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0392] Examples of suitable aqueous and nonaqueous carriers which may be employed in thepharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0393] These compositions may also contain adjuvants such as preservatives, wetting agents,emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

[0394] In some cases, in order to prolong the effect of a drug, it is desirable to slow theabsorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of aparenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0395] Injectable depot forms are made by forming microencapsule matrices of the subjectcompounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.

[0396] When the compounds of the present invention are administered as pharmaceuticals, tohumans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0397] The preparations of the present invention may be given orally, parenterally, topically,or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.

[0398] The phrases “parenteral administration” and “administered parenterally” as usedherein 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.

[0399] The phrases “systemic administration,” “administered systemically,” “peripheraladministration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0400] These compounds may be administered to humans and other animals for therapy byany suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.

[0401] Regardless of the route of administration selected, the compounds of the presentinvention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.

[0402] Actual dosage levels of the active ingredients in the pharmaceutical compositions ofthis invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0403] The selected dosage level will depend upon a variety of factors including the activityof the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0404] A physician or veterinarian having ordinary skill in the art can readily determine andprescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0405] In general, a suitable daily dose of a compound of the invention will be that amount ofthe compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the compounds are administered at about 0.01 mg / kg to about 200 mg / kg, more preferably at about 0.1 mg / kg to about 100 mg / kg, even more preferably at about 0.5 mg / kg to about 50 mg / kg.When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone.

[0406] If desired, the effective daily dose of the active compound may be administered astwo, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.

[0407] The invention further provides a unit dosage form (such as a tablet or capsule)comprising a compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein. VII. SEQUENCE LISTINGS

[0408] Heavy chain CDR1 amino acid sequence (SEQ ID NO: 1): NYWMS

[0409] Heavy chain CDR2 amino acid sequence (SEQ ID NO: 2):DIHGNRGFNYHASWAKG

[0410] Heavy chain CDR3 amino acid sequence (SEQ ID NO: 3): ADDSGSHDI

[0411] Light chain CDR1 amino acid sequence (SEQ ID NO: 4): QSSQSVYSAKLS

[0412] Light chain CDR2 amino acid sequence (SEQ ID NO: 5): YGSTLAS

[0413] Light chain CDR3 amino acid sequence (SEQ ID NO: 6): QGTFYGPDWYFA

[0414] Variable heavy chain amino acid sequence (SEQ ID NO: 7):EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMSWVRQAPGKGLEWVGDIHG NRGFNYHASWAKGRFTVSRSKNTLYLQMNSLRAEDTAVYYCAKADDSGSHDIW GQGTLVTVSS

[0415] Variable light chain amino acid sequence (SEQ ID NO: 8):DIQMTQSPSSLSASVGDRVTITCQSSQSVYSAKLSWYQQKPGKAPKLLIYYGSTLASGVP SRFSGSGSGTQFTLTISSLQPEDFATYYCQGTFYGPDWYFAFGGGTKVEIK

[0416] Heavy chain amino acid sequence (SEQ ID NO: 9):EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMSWVRQAPGKGLEWVGDIHGNRGF NYHASWAKGRFTVSRSKNTLYLQMNSLRAEDTAVYYCAKADDSGSHDIWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPEEKTISKAKGQPREPQVYTL PPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0417] Light chain amino acid sequence (SEQ ID NO: 10):DIQMTQSPSSLSASVGDRVTITCQSSQSVYSAKLSWYQQKPGKAPKLLIYYGST LASGVPSRFSGSGSGTQFTLTISSLQPEDFATYYCQGTFYGPDWYFAFGGGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0418] Heavy chain amino acid sequence (SEQ ID NO: 11): QQQLVESGGRLVTPGGSLTL TCTASGFSLN NYWMSWVRQA PGKGLEWIGD IHGNRGFNYHASWAKGRFTV SRTSTTVDLR MTSLTTEDTA IYFCARADDS GSHDIWGPGTLVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCD KTHTCPPCPA PELLGGPDVF LFPPKPKDTL MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP EEKTISKAKG QPREPQVYTL PPSRDELTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK

[0419] Light chain amino acid sequence (SEQ ID NO: 12):ELDLTQTPSPVSAAVGDTVTINCQSSQSVYSAKLSWYQQKPGQPPKLLIYYGSTLASGV PSRFKGSGSGTQFSLTISDVQCADAATYYCQGTYYGPDWYFAFGGGTEVVVKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0420] Heavy chain amino acid sequence (SEQ ID NO: 13):QQQLVESGGRLVTPGGSLTLTCTASGFSLNNYWMSWVRQAPGKGLEWIGDIHGNRGF NYHASWAKGRFTVSRTSTTVDLRMTSLTTEDTAIYFCARADDSGSHDIWGPGTLVTVS SAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQS DLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPMVTCVVVDVSEDDPDVQISWFVNNVEVLTAQTQTHREDYN STLRVVSALPIQHQDWMSGKEFKCKVNNKALPAPIERTISKPKGSVRAPQVYVLPPPEEE MTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEK KNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK

[0421] Light chain amino acid sequence (SEQ ID NO: 14):ELDLTQTPSPVSAAVGDTVTINCQSSQSVYSAKLSWYQQKPGQPPKLLIYYGSTLASGV PSRFKGSGSGTQFSLTISDVQCADAATYYCQGTYYGPDWYFAFGGGTEVVVKRADAA PTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDST YSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC EXAMPLES

[0422] The invention now being generally described, will be more readily understood byreference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and is not intended to limit the invention. Example 1 - Synthesis of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl) cyclohexane-1,3-diamine (7).

[0423] Step 1. Preparation of 6-chloro-2-(trifluoromethyl)quinolin-4-ol (3). 4-chloroaniline (1) (5g, 39.2 mmol) and polyphosphoric acid (30 ml) were combined in a round bottom flask outfitted with a temperature probe and condenser. Ethyl 4,4,4-trifluoro-3-oxobutanoate (2) (8.66 g, 47.0 mmol) was then added at RT and the reaction was stirred at 140 °C. After 3h, the reaction was cooled, diluted with water (500 mL), and stirred for 30 minutes. The solid was collected, washed with water (150 mL), and driedunder vacuum to yield compound 3 (3 g, 10.3 mmol, 26% yield) as a yellow solid. LC-MS m / z 248.1 (M+H)+.

[0424] Step 2. Preparation of 4,6-dichloro-2-(trifluoromethyl)quinoline (4). Phosphoryltrichloride (21.52 ml, 230 mmol) was added to 6-chloro-2-(trifluoromethyl)quinolin-4-ol (3) (3 g, 12.12 mmol) in a round bottom flask outfitted with a condenser and temperature probe. The reaction was stirred at 90 °C. After 2h, the reaction was cooled and concentrated. The resulting solid was triturated with ice water before purification by column chromatography (0-30% EtOAc / pet. ether) to give compound 4 (1.8 g, 6.6 mmol, 54% yield) as a yellow solid. LC-MS m / z 266.1 (M+H)+.

[0425] Step 3. Preparation of tert-butyl ((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate (6). To a stirred solution of tert-butyl ((1R,3S)-3- aminocyclohexyl)carbamate (5) (3.22 g, 15.04 mmol) and DIPEA (4.86 g, 37.6 mmol) in DMSO (40 ml), 4,6-dichloro-2-(trifluoromethyl)quinoline (4) (4 g, 15.04 mmol) was added and the reaction was stirred at 130 °C. After 12h, the reaction was cooled and diluted with water (100 mL). The resulting solid which formed was filtered, dried under vacuum and purified by column chromatography (30-50% EtOAc / hexanes) to give compound 6 (5 g, 11.26 mmol, 75% yield) as an off-white solid. LC-MS m / z 444.2 (M+H)+.

[0426] Step 4. Preparation of (1S,3R)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (7). To a stirred solution of tert-butyl ((1R,3S)-3-((6-chloro-2- (trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate (6) (5 g, 11.26 mmol) in DCM (50 ml) at 0 °C, HCl (4M in dioxane, 50 ml, 200 mmol) was added and the reaction was slowly warmed to RT. After 16h, the reaction was concentrated, and the crude product was triturated with pet. ether and dried under vacuum to give compound 7 (4 g, 10.52 mmol, 93% yield) as an off-white solid. LC-MS m / z 344.2 (M+H)+.Example 2 - Synthesis of (1s,4s)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane- 1,4-diamine (10).

[0427] Step 1. Preparation of tert-butyl ((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate (9). To a solution of tert-butyl ((1s,4s)-4- aminocyclohexyl)carbamate (8) (1.772 g, 8.27 mmol) in DMSO (20 mL), 4,6-dichloro-2- (trifluoromethyl)quinoline (4) (2 g, 7.52 mmol) and DIPEA (2.62 ml, 15.04 mmol) were added. The resulting mixture was stirred at 130 °C. After 2h, the reaction was cooled and diluted with water (100 mL) and stirred for an additional 1h. The resulting solid was collected before being triturated with 20% methanol in DCM (50 mL) and purified by column chromatography (20% EtOAc / pet. ether) to provide compound 9 (0.5 g, 3.9 mmol, 52% yield). LC-MS m / z 444.2 (M+H)+.

[0428] Step 2. Preparation of (1s,4s)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,4-diamine (10). To a stirred solution of tert-butyl ((1s,4s)-4-((6-chloro-2- (trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamate (9) (1.75 g, 3.94 mmol) in 1,4- dioxane (20 ml) at 10 °C, HCl (4M in dioxane, 6.90 ml, 27.6 mmol) was added. The resulting mixture was stirred at RT for 16 h before being concentrated. The crude product was triturated with acetonitrile and dried under vacuum to yield compound 10 (1.3 g, 3.8 mmol, 96% yield) as an off-white solid. LC-MS m / z 344.1(M+H)+.Example 3 - Synthesis of (1s,4s)-N1-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl) cyclohexane-1,4-diamine (15).

[0429] Step 1. Preparation of 5-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine (13).To a stirred solution of 6-bromopyridin-2-amine (11) (0.5 g, 2.89 mmol) in ethanol (10 mL), 3- bromo-1,1,1-trifluoropropan-2-one (12) (1.104 g, 5.78 mmol) was added at RT. The reaction was stirred at 70 °C for 16 h and then for an additional 1h at 10 °C. The reaction was filtered, and the filtrate was concentrated. The resulting solid was dissolved in DCM (25 mL) before being washed with a saturated sodium bicarbonate solution and then concentrated under reduced pressure. The crude product was triturated with 20% ethyl acetate in petroleum ether to yield compound 13 (760 mg, 2.9 mmol, 99% yield) as a pale brown solid. LC-MS m / z 266.1 (M+H)+.

[0430] Step 2. Preparation of tert-butyl ((1s,4s)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamate (14). To a stirred solution of 5-bromo-2- (trifluoromethyl)imidazo[1,2-a]pyridine (13) (0.02 g, 0.075 mmol) in dioxane (1 mL), tert-butyl ((1s,4s)-4-aminocyclohexyl)carbamate (8) (0.016 g, 0.075 mmol) and cesium carbonate (0.049 g, 0.151 mmol) were added at RT under a nitrogen atmosphere. After 5 minutes, BINAP (0.329 g, 0.528 mmol) and PdOAc2 (0.059 g, 0.264 mmol) were added, and the resulting reaction was stirred at 90 °C. After 6h, the reaction was cooled to RT and filtered through a bed of celite, which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the resulting crude product was purified by column chromatography (10% methanol / DCM) andtriturated with 50% EtOAc / pet. ether (x2). The resulting solid was dissolved in 50% MeOH / DCM and stirred with charcoal for 1h, before being filtered and dried under vacuum to give compound 14 (650 mg, 1.6 mmol, 60% yield) as a pale brown solid. LC-MS m / z 399.2 (M+H)+.

[0431] Step 3. Preparation of (1s,4s)-N1-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (15). To a stirred solution of tert-butyl ((1s,4s)-4-((2- (trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamate (14) (0.55 g, 1.380 mmol) in dioxane (15 ml) and DCM (10 ml) at 10 °C, HCl (4M in dioxane, 10 ml, 1.380 mmol) was added. The reaction was stirred at RT for 3 h before being concentrated under reduced pressure. The crude product was triturated with diethyl ether and dried under vacuum to give compound 15 (0.46 g, 1.3 mmol, 97% yield) as a solid. LC-MS m / z 299.2 (M+H)+. Example 4 - Synthesis of 1-(2-amino-2-methylpropyl)-3-chloro-N-((1R,3S)-3-((6-chloro-2- (trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (24).

[0432] Step 1. Preparation of tert-butyl (1-hydroxy-2-methylpropan-2-yl)carbamate(17). To a stirred solution of 2-amino-2-methylpropan-1-ol (16) (6 g, 67.3 mmol) in DCM (60 ml) under a nitrogen atmosphere, DIPEA (29.3 ml, 168 mmol) and Boc2O (15.46 ml, 67.3 mmol) were added, and the reaction was stirred at RT. After 3h, the reaction was concentrated under reduced pressure to give compound 17 (10.2 g, 50.7 mmol, 75% yield) as a colorless viscous liquid which slowly turned to a white solid.

[0433] Step 2. Preparation of tert-butyl 4,4-dimethyl-1,2,3-oxathiazolidine-3-carboxylate2-oxide (18). To a stirred solution of imidazole (8.63 g, 127 mmol) in DCM (80 ml), TEA (6.42 g, 63.4 mmol) was added and the solution was cooled to -70 °C. Thionyl chloride (4.53 g, 38.0 mmol) was added dropwise followed by a solution of tert-butyl (1-hydroxy-2-methylpropan-2- yl)carbamate (17) (6 g, 31.7 mmol) solution in DCM (80 ml) (dropwise). The reaction was stirred for 2h before slowly warmed to RT. After stirring for an additional 16h, the reaction was poured over ice (100 g) with vigorous stirring and then extracted with DCM (80 mL x 2). The combined organic extracts were washed sequentially with a saturated NH4Cl solution (150 mL) and brine (70 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by column chromatography (2-30% EtOAc / pet. ether) gave compound 18 (2 g, 8.5 mmol, 27% yield) as a colorless liquid.

[0434] Step 3. Preparation of tert-butyl 4,4-dimethyl-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide (19). Tert-butyl 4,4-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (18) (2 g, 8.50 mmol) was dissolved in acetonitrile (50 ml) before water (20 ml) and sodium periodate (NaIO4) (2.000 g, 9.35 mmol) were added. After stirring for 2 min, ruthenium(III) chloride hydrate (8.82 mg, 0.042 mmol) was added, and the reaction was stirred at RT exposed to the air. After 30 minutes, the reaction was diluted with water (70 mL) and extracted with DCM (40 mL x 2). The combined organic extracts were washed with brine (70 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The resulting brown viscous liquid was dissolved in 10% EtOAc / pet. ether (50 mL), filtered, and concentrated under reduced pressure to give compound 19 (2 g, 8.0 mmol, 94% yield) as an off-white solid.

[0435] Step 4. Preparation of ethyl 1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-chloro-1H-pyrazole-4-carboxylate (21). To a stirred solution of ethyl 3-chloro-1H-pyrazole- 4-carboxylate (20) (1.1 g, 6.30 mmol) in DMF (15 ml), K2CO3 (2.61 g, 18.90 mmol) and tert- butyl 4,4-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (19) (1.900 g, 7.56 mmol) were added at RT and the resulting mixture was stirred at 90 °C. After 5h, the reaction was cooled, diluted with a saturated NH4Cl solution (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed sequentially with a 10% citric acid solution (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to give compound 21 (2.0 g, 5.2 mmol, 83% yield) as an off-white solid. LC-MS m / z 346.2 (M+H)+.

[0436] Step 5. Preparation of 1-(2-((tert-butoxycarbonyl)amino)-2-methylpropyl)-3-chloro-1H-pyrazole-4-carboxylic acid (22). To a solution of ethyl 1-(2-((tert- butoxycarbonyl)amino)-2-methylpropyl)-3-chloro-1H-pyrazole-4-carboxylate (21) (2.1 g, 6.07 mmol) in MeOH (6 ml) and THF (6 ml), a solution of LiOH.H2O (0.436 g, 18.22 mmol) in water (6 mL) was added and the reaction was slowly heated to 50 °C. After 5h, the reaction was cooled and concentrated under reduced pressure. The resulting solid was dissolved in water (10 mL) and acidified with citric acid (15 mL). The resulting solid was collected, triturated with diethyl ether (10 mL), and dried under vacuum to give compound 22 (1.6 g, 4.0 mmol, 66% yield) as an off-white solid. LC-MS m / z 318.2 (M+H)+.

[0437] Step 6. Preparation of tert-butyl (1-(3-chloro-4-(((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)-2- methylpropan-2-yl)carbamate (23). To a stirred solution of 1-(2-((tert-butoxycarbonyl)amino)- 2-methylpropyl)-3-chloro-1H-pyrazole-4-carboxylic acid (22) (1.6 g, 5.04 mmol) ) in DMF (10 mL) at 0 °C, HATU (2.87 g, 7.55 mmol) and DIPEA (2.2 mL) were added. The reaction was stirred at RT for 10 min before being cooled to 0 °C. A solution of (1S,3R)-N1-(6-chloro-2- (trifluoromethyl)quinolin-4-yl)cyclohexane-1,3-diamine (7) (2.077 g, 6.04 mmol) and DIPEA (2.2 mL) in DMF (5 mL) was added and the reaction was stirred at RT. After 5h, the reaction was quenched with a saturated NH4Cl solution (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic extracts were washed with cold brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (neutral alumina, 12-30% EtOAc / pet. ether) to give compound 23 (2 g, 3.1 mmol, 61% yield) as a solid. LC-MS m / z 643.2 (M+H)+.

[0438] Step 7. Preparation of 1-(2-amino-2-methylpropyl)-3-chloro-N-((1R,3S)-3-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide (24). To a stirred solution of tert-butyl (1-(3-chloro-4-(((1R,3S)-3-((6-chloro-2- (trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-1H-pyrazol-1-yl)-2-methylpropan- 2-yl)carbamate (23) (2 g, 3.11 mmol) in dioxane (15 ml) at 0 °C, HCl (4M in dioxane, 15 ml, 3.11 mmol) was added dropwise. The reaction was stirred at RT for 2h before it was concentrated under reduced pressure. The crude solid was mixed with EtOAc (50 mL) and sonicated. The solid was collected and dried under vacuum to give compound 24 (1.7 g, 2.9 mmol, 93% yield) as a white solid. LC-MS m / z 543.2 (M+H)+.Example 4 - Synthesis of 3-(aminomethyl)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl) quinolin-4-yl)amino)cyclohexyl)-5-(methylsulfonamido)benzamide (32).

[0439] Step 1. Preparation of methyl 3-((benzylamino)methyl)-5-nitrobenzoate (26). To astirred solution of methyl 3-formyl-5-nitrobenzoate (25) (5 g, 23.91 mmol) in DCM (96 ml), phenylmethanamine (2.82 g, 26.3 mmol) and sodium sulphate (3.4 g, 23.91 mmol) were added at RT. After stirring for 16h, the reaction mixture was filtered through a bed of celite which was then washed with DCM. The filtrate was concentrated under reduced pressure to yield the crude intermediate, which was dissolved in methanol (96 mL) and cooled to 0 °C. Sodium borohydride(0.452 g, 11.95 mmol) was added, and the mixture was stirred at RT. After 4h, the mixture was concentrated and the obtained residue was dissolved in DCM (100 mL), washed with water and brine, and then concentrated under reduced pressure. Purification by column chromatography (0-20% EtOAc / pet. ether) gave compound 26 (5 g, 16.6 mmol, 70% yield) as a yellow liquid. LC-MS m / z 301.2 (M+H)+.

[0440] Step 2. Preparation of methyl 3-amino-5-(aminomethyl)benzoate (27). To asolution of methyl 3-((benzylamino)methyl)-5-nitrobenzoate (26) (4 g, 13.32 mmol) in methanol (40 mL), acetic acid (0.2 ml, 13.32 mmol) was added followed by 10% Pd on carbon (0.5 g, 0.470 mmol). The reaction was stirred under a hydrogen atmosphere for 20h before it was filtered through a bed of celite which was then washed with methanol. The filtrate was evaporated under reduced pressure and re-exposed to the reaction conditions (10% Pd on carbon (400 mg, 0.376 mmol) under a hydrogen atmosphere) for an additional 20h. The reaction was again filtered through a bed of celite which was then washed with methanol. The filtrate was concentrated under reduced pressure and the resulting solid was triturated with acetonitrile to give compound 27 (1.6 g, 8.8 mmol, 66% yield) as an off-white solid.

[0441] Step 3. Preparation of methyl 3-amino-5-(((tert-butoxycarbonyl)amino)methyl)benzoate (28). To a stirred solution of methyl 3-amino-5-(aminomethyl)benzoate (27) (2.1 g, 11.65 mmol) in methanol (60 mL), triethylamine (3.25 ml, 23.31 mmol) and di-tert-butyl dicarbonate (2.54 g, 11.65 mmol) were added. The reaction was stirred at RT for 3 h before it was concentrated under reduced pressure. Purification by column chromatography (neutral alumina, 0-18% EtOAc / petroleum ether) gave compound 28 (1.8 g, 6.2 mmol, 53% yield) as a liquid.

[0442] Step 4. Preparation of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-5-(methylsulfonamido)benzoate (29). To a stirred solution of methyl 3-amino-5-(((tert- butoxycarbonyl)amino)methyl)benzoate (28) (1.8 g, 6.42 mmol) in DCM (30 mL) at 0 °C, pyridine (1.629 ml, 20.23 mmol) was added followed by methanesulfonyl chloride (0.626 ml, 8.09 mmol). The reaction was stirred at RT for 3h before being quenched with water and extracted with DCM. The combined organic extracts were washed sequentially with 1.5 N HCl, water and brine and then concentrated under reduced pressure. The crude product was purifiedby column chromatography (neutral alumina, 0-30% EtOAc / petroleum ether) to give compound 29 (1.2 g, 3.3 mmol, 52% yield) as an off-white solid. LC-MS m / z 357.0 (M-H)-.

[0443] Step 5. Preparation of 3-(((tert-butoxycarbonyl)amino)methyl)-5-(methylsulfonamido)benzoic acid (30). To a stirred solution of methyl 3-(((tert- butoxycarbonyl)amino)methyl)-5-(methylsulfonamido)benzoate (29) (1.2 g, 3.35 mmol) in methanol (15 ml), a solution of lithium hydroxide (0.241 g, 10.04 mmol) in water (5 mL) was added. The reaction was stirred at RT for 6 h before it was concentrated under reduced pressure. The crude product was diluted with water and acidified with citric acid (aq.). The resulting solid was collected, washed with petroleum ether and dried under vacuum to yield compound 30 (0.95 g, 2.7 mmol, 82% yield) as an off-white solid. LC-MS m / z 343.0 (M-H)-.

[0444] Step 6. Preparation of tert-butyl (3-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-5-(methylsulfonamido)benzyl)carbamate (31). To a stirred solution of 3-(((tert-butoxycarbonyl)amino)methyl)-5-(methylsulfonamido)benzoic acid (30) (0.95 g, 2.76 mmol) in DMF (15 mL) at 0 °C under a nitrogen atmosphere, DIPEA (1.682 ml, 9.65 mmol) and HATU (1.154 g, 3.03 mmol) were added, followed by (1s,4s)-N1-(6- chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,4-diamine hydrochloride (10) (1.154 g, 3.03 mmol). The reaction was stirred at RT for 2.5h before it was diluted with ice water. The resulting solid was collected and purified by column chromatography (neutral alumina, 0-30% EtOAc / petroleum ether) to obtain compound 31 (1.2 g, 1.7 mmol, 61% yield) as an off-white solid. LC-MS m / z 670.1 (M+H)+.

[0445] Step 7. Preparation of 3-(aminomethyl)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-5-(methylsulfonamido)benzamide (32). To a stirred solution of tert-butyl (3-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4- yl)amino)cyclohexyl)carbamoyl)-5-(methylsulfonamido)benzyl)carbamate (31) (1.2 g, 1.791 mmol) in 1,4-dioxane (10 ml) at 0 °C, HCl (4M in dioxane, 6.27 ml, 25.07 mmol) was added. The reaction was stirred at RT for 4 h before it was concentrated. The crude product was triturated with diethyl ether (20 mL) and dried under vacuum to yield compound 32 (0.95 g, 1.6 mmol, 90% yield) as an off-white solid. LC-MS m / z 570.1 (M+H)+.Example 5 - Synthesis of 4-(aminomethyl)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl) quinolin-4-yl)amino)cyclohexyl)-3-(methylsulfonamido)benzamide (40).

[0446] Step 1. Preparation of methyl 4-((benzylamino)methyl)-3-nitrobenzoate (34). To astirred solution of methyl 4-formyl-3-nitrobenzoate (33) (5 g, 23.91 mmol) in DCM (20 mL), phenylmethanamine (2.82 g, 26.3 mmol) and sodium sulfate (3.40 g, 23.91 mmol) were added, and the reaction was stirred at RT. After 16h, the mixture was filtered through a bed of celite which was then washed with DCM. The filtrate was concentrated under reduced pressure to yield the crude intermediate which was dissolved in methanol (40 mL). The solution was cooled to 0 °C before sodium borohydride (1.176 g, 31.1 mmol) was added. The reaction was allowed tocome to RT and after stirring for 4h, it was concentrated under reduced pressure. The resulting residue was dissolved in DCM, washed with brine, and concentrated under reduced pressure. Purification by column chromatography (neutral alumina, 10 % EtOAc / petroleum ether) gave compound 34 (5 g, 16.2 mmol, 68% yield) as a yellow liquid. LC-MS m / z 301.2 (M+H)+.

[0447] Step 2. Preparation of methyl 3-amino-4-(aminomethyl)benzoate (35). To a stirredsolution of methyl 4-((benzylamino)methyl)-3-nitrobenzoate (34) (4.5 g, 14.98 mmol) in methanol (20 mL) and THF (20 mL), a catalytic amount of acetic acid was added followed by 10% Pd on carbon (500 mg). The reaction was stirred under a hydrogen atmosphere for 16h before it was filtered and resubjected to the reaction conditions for an additional 16h. The reaction was then filtered through a bed of celite which was washed with methanol. The filtrate was concentrated under reduced pressure and the crude product was triturated with acetonitrile (10 mL). Purification by reverse phase preparative chromatography compound 35 (0.98 g, 5.3 mmol, 35% yield).

[0448] Step 3. Preparation of methyl 3-amino-4-(((tert-butoxycarbonyl)amino)methyl)benzoate (36). To a stirred solution of methyl 3-amino-4-(aminomethyl)benzoate (35) (0.68 g, 3.77 mmol) in methanol (10 mL), triethylamine (1.052 ml, 7.55 mmol) and di-tert-butyl dicarbonate (0.876 ml, 3.77 mmol) were added at RT. The reaction was stirred for 4 h before it was concentrated under reduced pressure. The crude product was purified by column chromatography (10% EtOAc / petroleum ether) to give compound 36 (800 mg, 2.2 mmol, 59% yield) as a yellow liquid. LC-MS m / z 281.2 (M+H)+.

[0449] Step 4. Preparation of methyl 4-(((tert-butoxycarbonyl)amino)methyl)-3-(methylsulfonamido)benzoate (37). To a stirred solution of methyl 3-amino-4-(((tert- butoxycarbonyl)amino)methyl)benzoate (36) (0.8 g, 2.85 mmol) in DCM (10 mL) at 0 °C, pyridine (0.733 ml, 8.99 mmol) and methanesulfonyl chloride (0.278 ml, 3.60 mmol) were added. The reaction was stirred at RT for 2h before it was quenched with 1.5 N HCl and extracted with DCM. The combined organic extracts were washed with brine and then concentrated under reduced pressure. Crude product was triturated with diethyl ether and dried under vacuum to give compound 37 (600 mg, 1.7 mmol, 58% yield) as an off-white solid. LC- MS m / z 356.9 (M-H)-.

[0450] Step 5. Preparation of 4-(((tert-butoxycarbonyl)amino)methyl)-3-(methylsulfonamido)benzoic acid (38). To a stirred solution of methyl 4-(((tert- butoxycarbonyl)amino)methyl)-3-(methylsulfonamido)benzoate (37) (0.7 g, 1.953 mmol) in methanol (4 mL) and THF (4 mL), a solution of lithium hydroxide (0.117 g, 4.88 mmol) in water (2 mL) was added at RT. The reaction was stirred at 55 °C for 3h before it was cooled and concentrated under reduced pressure. The residue was dissolved in water and then acidified with a citric acid solution, which resulted in a precipitate to form. The solid was collected and dried under vacuum to give compound 38 (450 mg, 1.3 mmol, 67% yield) as an off-white solid. LC- MS m / z 342.9 (M-H)-.

[0451] Step 6. Preparation of tert-butyl (4-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-2-(methylsulfonamido)benzyl)carbamate (39). To a stirred solution of 4-(((tert-butoxycarbonyl)amino)methyl)-3-(methylsulfonamido)benzoic acid (38) (0.45 g, 1.307 mmol) in DMF (5 mL) at 0 °C, HATU (0.547 g, 1.437 mmol) and DIPEA (0.685 ml, 3.92 mmol) were added and stirred for 10 minutes. A solution of (1s,4s)-N1- (6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,4-diamine hydrochloride (10) (0.547 g, 1.437 mmol) in DMF (5 mL) was then added and the reaction mixture was allowed to come to RT. After stirring for 6h, the reaction was quenched with water and extracted with DCM. The combined organic extracts were concentrated under reduced pressure and the crude product was purified by column chromatography (neutral alumina, 5% MeOH in DCM) to give compound 39 (560 mg, 0.75 mmol, 57% yield) as an off-white solid. LC-MS m / z 669.8 (M+H)+.

[0452] Step 7. Preparation of 4-(aminomethyl)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-(methylsulfonamido)benzamide (40). To a stirred solution of tert-butyl (4-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4- yl)amino)cyclohexyl)carbamoyl)-2-(methylsulfonamido)benzyl)carbamate (39) (0.11 g, 0.164 mmol) in dioxane (2 ml) at 10 °C, HCl (4M in dioxane, 2 ml, 8.00 mmol) was added and the reaction was allowed to come to RT. After stirring for 3h, the reaction was concentrated under reduced pressure. The crude product was triturated with diethyl ether and dried under vacuum to give compound 40 (90 mg, 0.14 mmol, 86% yield) as an off-white solid. LC-MS m / z 569.8 (M+H)+.Example 6 - Synthesis of 2-(aminomethyl)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl) quinolin-4-yl)amino)cyclohexyl)-5-(methylsulfonamido)benzamide (47).

[0453] Step 1. Preparation of methyl 2-cyano-5-(methylsulfonamido)benzoate (42). To astirred solution of methyl 5-amino-2-cyanobenzoate (41) (1.5 g, 8.51 mmol) in DCM (20 ml) at 0 °C, pyridine (1.029 ml, 12.77 mmol) and methanesulfonyl chloride (0.725 ml, 9.37 mmol) were added sequentially and dropwise. After stirring at RT for 7h, the reaction was quenched with water and upon stirring, a solid was formed. The solid was collected and dried under vacuum to give compound 42 (1.4 g, 5.34 mmol, 63% yield) as a pink colored solid. LC-MS m / z 253.0 (M- H)-.

[0454] Step 2. Preparation of methyl 2-(aminomethyl)-5-(methylsulfonamido)benzoate(43). To a stirred solution of methyl 2-cyano-5-(methylsulfonamido)benzoate (42) (0.700 g, 2.75mmol) in MeOH (7 ml) and THF (7 ml), 10% palladium on carbon (2.051 g, 19.27 mmol) and HCl (4M in dioxane, 0.688 ml, 2.75 mmol) were added. The reaction was stirred under a hydrogen atmosphere (5 ATM) for 3d. The reaction was filtered through a bed of celite, which was then washed with 1:1 THF / MeOH solution. The filtrate was concentrated and the solid was triturated with a mixture of diethyl ether and pet. ether and dried under vacuum to give compound 43 (0.700 g, 2.412 mmol, 88% yield) as an off-white solid. LC-MS m / z 259.2 (M+H)+.

[0455] Step 3. Preparation of methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-(methylsulfonamido)benzoate (44). To a stirred solution of methyl 2-(aminomethyl)-5- (methylsulfonamido)benzoate (43) (0.30 g, 1.157 mmol) in THF (5 ml) at -78 °C, TEA (0.645 ml, 4.63 mmol) and Boc2O (0.403 ml, 1.735 mmol) were added. The reaction was stirred at -78 °C for 10 min before it was warmed to RT. After an additional 1h, the reaction was concentrated under reduced pressure to give compound 44 (0.300 g, 0.703 mmol, 61% yield), which was used as is in the next step. LC-MS m / z 357.2 (M-H)-.

[0456] Step 4. Preparation of 2-(((tert-butoxycarbonyl)amino)methyl)-5-(methylsulfonamido)benzoic acid (45). To a stirred solution of methyl 2-(((tert- butoxycarbonyl)amino)methyl)-5-(methylsulfonamido)benzoate (44) (0.300 g, 0.837 mmol) in THF (5 ml) at 0 °C, water (1 ml) and LiOH (0.060 g, 2.51 mmol) were added. The reaction was stirred at RT for 1h before it was concentrated under reduced pressure. The solid was washed with pet. ether and dried under vacuum to give compound 45 (220 mg, 0.594 mmol, 71% yield), which was used as is in the next step. LC-MS m / z 342.9 (M-H)-.

[0457] Step 5. Preparation of tert-butyl (2-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-4-(methylsulfonamido)benzyl)carbamate (46). To a stirred solution of 2-(((tert-butoxycarbonyl)amino)methyl)-5-(methylsulfonamido)benzoic acid (45) (240 mg, 0.697 mmol) in DMF (2 ml) at 0 °C, DIPEA (0.609 ml, 3.48 mmol) followed by PyBOP (544 mg, 1.045 mmol) were added. The reaction was stirred at RT for 10 min before (1s,4s)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl)cyclohexane-1,4-diamine (10) (264 mg, 0.767 mmol) was added. After stirring for an additional 16h, the reaction was quenched with water and extracted with 10% MeOH in DCM. The combined organic extracts were dried over sodium sulphate, filtered, and concentrated under reduced pressure. Purification using reversephase column chromatography gave compound 46 (160 mg, 0.201 mmol, 28% yield). LC-MS m / z 670.2 (M+H)+.

[0458] Step 6. Preparation of 2-(aminomethyl)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-5-(methylsulfonamido)benzamide (47). To a stirred solution of tert-butyl (2-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4- yl)amino)cyclohexyl)carbamoyl)-4-(methylsulfonamido)benzyl)carbamate (46) (160 mg, 0.239 mmol) in 1,4-dioxane (3 ml) at 0 °C, HCl (4M in dioxane, 0.060 ml, 0.239 mmol) was slowly added. The reaction was stirred at RT for 1h before it was concentrated under reduced pressure. The solid was washed with petroleum ether and dried under vacuum to obtain compound 47 (130 mg, 0.169 mmol, 70% yield). LC-MS m / z 570.1 (M+H)+. Example 7 - Synthesis of 3-(aminomethyl)-5-(methylsulfonamido)-N-((1s,4s)-4-((2- (trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)benzamide (49).

[0459] Step 1. Preparation of tert-butyl (3-(methylsulfonamido)-5-(((1s,4s)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamoyl)benzyl) carbamate (48). To a stirred solution of 3-(((tert-butoxycarbonyl)amino)methyl)-5-(methylsulfonamido)benzoic acid (30) (0.589 g, 1.710 mmol), and PyBOP (1.335 g, 2.56 mmol) in DMF (8 ml), DIPEA (1.493 ml, 8.55 mmol) was added. After stirring for 20 min, (1s,4s)-N1- (2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (15) (0.510 g, 1.710 mmol) was added, and the reaction was stirred at RT. After 2h, additional PyBOP (1.335 g, 2.56 mmol) was added. After an additional 16h, the reaction was quenched with an aqueous ammonium chloride solution and extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. Purification by reverse phase column chromatography gave compound 48 (430 mg, 0.662 mmol, 39% yield) as a white solid. LC-MS m / z 625.2 (M+H)+.

[0460] Step 2. Preparation of 3-(aminomethyl)-5-(methylsulfonamido)-N-((1s,4s)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)benzamide (49). To a stirred solution of tert-butyl (3-(methylsulfonamido)-5-(((1s,4s)-4-((2-(trifluoromethyl)imidazo[1,2- a]pyridin-5-yl)amino)cyclohexyl)carbamoyl)benzyl)carbamate (48) (430 mg, 0.688 mmol) in DCM (5 ml) at 0 °C, HCl (4M in dioxane, 5 ml, 20 mmol) was added. The reaction was stirred at RT for 4h before it was concentrated under reduced pressure. The solid was washed with EtOAc and dried under vacuum to give compound 49 (410 mg, 0.774 mmol, >95% yield) as a solid. LC-MS m / z 525.2 (M+H)+. Example 8 - Synthesis of 3-amino-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4- yl)amino)cyclohexyl)benzamide (52).

[0461] Step 1. Preparation of tert-butyl (3-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl)carbamate (51). To a stirred solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (50) (0.1 g, 0.421 mmol) in DMF (2 ml), DIPEA (0.221 ml, 1.264 mmol) and HATU (0.192 g, 0.506 mmol) were added. The reaction was cooled to 0 °C before (1s,4s)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4- yl)cyclohexane-1,4-diamine (10) (0.159 g, 0.464 mmol) was added. After stirring at RT for 1h, the reaction was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered, and concentrated under reduced pressure to provide compound 51 (200 mg, 0.32 mmol, 76% yield). LC-MS m / z 563.2 (M+H)+.

[0462] Step 2. Preparation of 3-amino-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide (52). To a solution of tert-butyl (3-(((1s,4s)-4-((6- chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl)carbamate (51) (0.2 g, 0.355 mmol) in dioxane (2 ml) at 0 °C, HCl (4M in dioxane, 2 ml, 8.00 mmol) was added dropwise. After stirring at RT for 4h, the reaction was diluted with ethyl acetate and concentrated under reduced pressure to give compound 52 (150 mg, 0.30 mmol, 84% yield) as an off-white solid. LC-MS m / z 463.2 (M+H)+.Example 9 - Synthesis of 3-amino-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4- yl)amino)cyclohexyl)-5-(methylsulfonamido)benzamide (57).

[0463] Step 1. Preparation of methyl 3-(methylsulfonamido)-5-nitrobenzoate (54). To asolution of methyl 3-amino-5-nitrobenzoate (53) (1 g, 5.10 mmol) in DCM (50 ml), pyridine (1.237 ml, 15.29 mmol) was added and the reaction mixture was cooled to 0 °C. Methanesulfonyl chloride (0.588 ml, 7.65 mmol) was added dropwise and the reaction was then allowed to come to room temperature. After stirring for 16h, the reaction was quenched with 1.5N HCl and extracted with EtOAc (2x). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. Purification by column chromatography (10-50% EtOAc / petroleum ether) gave compound 54 (1 g, 3.39 mmol, 66% yield) as an off-white solid. LC-MS m / z 273.2 (M-H)-.

[0464] Step 2. Preparation of 3-(methylsulfonamido)-5-nitrobenzoic acid (55). Methyl 3-(methylsulfonamido)-5-nitrobenzoate (54) (1 g, 3.65 mmol) was dissolved in THF (5 ml) and methanol (5 ml) and cooled to 0 °C before a solution of lithium hydroxide (0.131 g, 5.47 mmol) in water (0.1 ml, 5.55 mmol) was added. The reaction was allowed to come to RT and stirred for 16h before the solvent was removed by concentration under reduced pressure. The residue was diluted with water, acidified with a citric acid solution, and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered, and concentrated underreduced pressure. The solid was co-evaporated with petroleum ether and dried under vacuum to give compound 55 (0.65 g, 2.404 mmol, 65% yield) as a yellow solid. LC-MS m / z 258.9 (M-H)-.

[0465] Step 3. Preparation of N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3-(methylsulfonamido)-5-nitrobenzamide (56). To a solution of 3- (methylsulfonamido)-5-nitrobenzoic acid (55) (0.65 g, 2.498 mmol) and (1s,4s)-N1-(6-chloro-2- (trifluoromethyl)quinolin-4-yl)cyclohexane-1,4-diamine (10) (0.859 g, 2.498 mmol) in DMF (2 ml), TEA (1.025 ml, 7.49 mmol) and PyBOP (1.560 g, 3.00 mmol) were added and the reaction was stirred at RT. After 16h, the reaction was quenched with ice cold water and then extracted with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered, and concentrated under reduced pressure. Purification by column chromatography (10-50% EtOAc / petroleum ether) gave compound 56 (0.6 g, 0.851 mmol, 34% yield) as an off-white solid. LC-MS m / z 585.7 (M+H)+.

[0466] Step 4. Preparation of 3-amino-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-5-(methylsulfonamido)benzamide (57). To a solution of N- ((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-3- (methylsulfonamido)-5-nitrobenzamide (56) (200 mg, 0.341 mmol) in ethanol (4 ml), aq. ammonium chloride solution (2 ml, 0.341 mmol) and iron powder (95 mg, 1.707 mmol) were sequentially added. The reaction mixture was warmed to 70 °C and stirred for 3h, before being cooled, diluted with ethyl acetate, and filtered through a bed of celite. The organic layer was separated, washed with water and brine, dried over sodium sulphate, filtered, and concentrated to give compound 57 (90 mg, 0.146 mmol, 43% yield) as an off-white solid. LC-MS m / z 556.2 (M+H)+. Example 10 - Synthesis of 3-((2-aminoethyl)sulfonamido)-N-((1s,4s)-4-((6-chloro-2- (trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide (64).

[0467] Step 1. Preparation of tetrabutylammonium 2-((tert-butoxycarbonyl)amino)ethane-1-sulfonate (59).2-Aminoethane-1-sulfonic acid (58) (2 g, 15.98 mmol) was dissolved in THF (60 ml) and water (20 ml) before tetrabutylammonium hydroxide (4.15 g, 15.99 mmol) was added. The reaction was cooled to 0 °C before Boc-anhydride (4.64 ml, 19.99 mmol) was added. The reaction was allowed to come to RT and after stirring overnight, it was quenched with water and extracted using ethyl acetate. The combined organic extracts were dried over sodium sulphate and concentrated under reduced pressure to give compound 59 (1.5 g, 3.2 mmol, 20% yield) which was used as is in the next step.

[0468] Step 2. Preparation of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonamido)benzoate (61). To a solution of tetrabutylammonium 2-((tert- butoxycarbonyl)amino)ethane-1-sulfonate salt (59) (1 g, 2.143 mmol) in DCM (5 ml), dimethylformamide (0.2 ml, 2.58 mmol) followed by triphosgene (0.254 g, 0.857 mmol) were added. The reaction mixture was stirred for 2h before pyridine (1.2 ml, 14.90 mmol) was added followed by methyl 3-aminobenzoate (60) (0.324 g, 2.143 mmol). After stirring at RT for 16h,the reaction was concentrated under reduced pressure and purified by column chromatography (50-60% EtOAc / petroleum ether) to give compound 61 (270 mg, 0.704 mmol, 33% yield) as a pale-yellow solid. LC-MS m / z 357.2 (M-H)-.

[0469] Step 3. Preparation of 3-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonamido)benzoic acid (62). To a solution of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl) sulfonamido)benzoate (61) (0.26 g, 0.725 mmol) in THF (5 ml) and Methanol (5 ml) at 0 °C, a solution of lithium hydroxide (0.052 g, 2.176 mmol) in water was added. The reaction was warmed to 50°C and stirred for 16h. The reaction was then cooled and concentrated under reduced pressure. The crude material was diluted with water and neutralized with 10% citric acid before it was concentrated under reduced pressure. The resulting solid was washed with diethyl ether and dried under vacuum to give compound 62 (0.23 g, 0.667 mmol, 92% yield) as an off-white solid. LC-MS m / z 343.2 (M-H)-.

[0470] Step 4. Preparation of tert-butyl (2-(N-(3-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl)sulfamoyl) ethyl) carbamate (63). To a solution of 3-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonamido) benzoic acid (62) (220 mg, 0.639 mmol) and (1s,4s)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl) cyclohexane-1,4-diamine (10) (220 mg, 0.639 mmol) in DMF (2 ml) at 0 °C, DIPEA (0.334 ml, 1.916 mmol) and HATU (291 mg, 0.767 mmol) were added. The reaction mixture was allowed to come to room temperature and stirred for 16h before being quenched with a saturated ammonium chloride solution. The solution was stirred for an additional 15 min and the resulting solid was collected, washed with water, and dried under vacuum to give compound 63 (0.3 g, 0.362 mmol, 57% yield) as an off-white solid. LC-MS m / z 670.3 (M+H)+.

[0471] Step 5. Preparation of 3-((2-aminoethyl)sulfonamido)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide (64). To a solution of tert-butyl (2-(N-(3-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl) phenyl)sulfamoyl)ethyl)carbamate (63) (0.3 g, 0.448 mmol) in 1,4-dioxane (3 ml), HCl (4M in 1,4-dioxane, 2 ml, 8.00 mmol) was added and the reaction was stirred at room temperature. After 3h, the reaction was concentrated under reduced pressure and the solid obtained was washed with diethyl ether and dried under vacuum to provide compound 64 (0.21 g, 0.328 mmol, 73% yield) as a white solid. LC-MS m / z 570.2 (M+H)+.Example 11 - Synthesis of (1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-cyclopropyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane- 1-carboxylic acid (22).

[0472] Step 1. Preparation of (E)-N-cyclopropyl-1-(pyridin-3-yl)methanimine (67). To astirred solution of nicotinaldehyde (65) (10 g, 93 mmol) in toluene (100 ml) at 0 °C, cyclopropanamine (66) (5.86 g, 103 mmol) was added and the reaction was stirred at RT. After 16h, Na2SO4was added and the reaction mixture was filtered and concentrated under reducedpressure to afford compound 67 (13 g, 84 mmol, 90% yield) as a yellow oil. LC-MS m / z 147.1 (M+H)+.

[0473] Step 2. Preparation of 1-cyclopropyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxylic acid (69). To a stirred solution of (E)-N-cyclopropyl-1-(pyridin-3-yl)methanimine (67) (13 g, 84 mmol) in m-xylene (120 ml), dihydrofuran-2,5-dione (68) (10.68 g, 107 mmol) was added and the reaction mixture was stirred at 145 °C. After 16 hours, the xylene layer was decanted, and the remaining brown gum was concentrated and azeotroped with toluene. Ethyl acetate was added, and the mixture was scratched until a solid precipitated. The precipitated solid was filtered and dried to obtain the crude product, which was further stirred with EtOH. The resulting precipitated solid was filtered and dried to afford compound 69 (3.3 g, 13.2 mmol, 15%yield) as a mixture of isomers. LC-MS m / z 247.1 (M+H)+.

[0474] Step 3. Preparation of (2S,3S)-1-cyclopropyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxylic acid (70).1-Cyclopropyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxylic acid (69) (3.3 g, 13.2 mmol) was purified by SFC purification (Chiralpak IG, 3 mL / min, 30% EtOH) to afford compound 70 (1.4 g, 5.6 mmol) as a single stereoisomer as assessed by SFC analysis. LC- MS m / z 247.1 (M+H)+.

[0475] Step 4. Preparation of tert-butyl (1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-cyclopropyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy) butanamido)cyclohexane-1-carboxylate (72). To a stirred solution of (2S,3S)-1-cyclopropyl-5- oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxylic acid (70) (0.6 g, 2.436 mmol) in DCM (20 ml) at 0 °C, PyBOP (1.902 g, 3.65 mmol) and DIPEA (2.128 ml, 12.18 mmol) were added. The resulting mixture was stirred for 15 mins before a solution of tert-butyl (1R,4r)-4-(4-(((1r,4R)-4-(2- aminoethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1-carboxylate (71) (1.143 g, 2.68 mmol) in DCM was added. The reaction was stirred at RT for 2h before being quenched with water. The mixture was extracted with DCM (30 ml x 2) and the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified with reverse phase column chromatography to provide compound 72 (1.3 g, 1.886 mmol, 77% yield) as a pale-yellow gum. LC-MS m / z 655.4 (M+H)+.

[0476] Step 5. Preparation of (1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-cyclopropyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1-carboxylic acid (73). To a stirred solution of tert-butyl (1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)- 1-cyclopropyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy) butanamido)cyclohexane-1-carboxylate (72) (1.4 g, 2.138 mmol)) in DCM (10 ml) at 0 °C, HCl (4M in dioxane, 5.34 ml, 21.38 mmol) was added and the reaction was allowed to come to RT. After 2h of stirring at RT, the mixture was concentrated under reduced pressure. The resulting crude product was triturated with petroleum ether to afford compound 73 (1.2 g, 1.944 mmol, 91% yield). LC-MS m / z 599.4 (M+H)+. Example 12 - Synthesis of (1R,4r)-4-(4-(((1R,4R)-4-(2-((1R,4R)-4-(4-(((1S,4R)-4-(2-((2S,3S)- 1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy) butanamido)cyclohexane-1-carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane- 1-carboxylic acid (76).

[0477] Step 1. Preparation of tert-butyl (1R,4r)-4-(4-(((1R,4R)-4-(2-((1R,4R)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy) cyclohexyl)oxy)butanamido)cyclohexane-1-carboxamido)ethoxy)cyclohexyl)oxy) butanamido)cyclohexane-1-carboxylate (75). (1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido) cyclohexane-1-carboxylic acid (74) (2.5 g, 4.37 mmol) was dissolved in DMF (25 ml) before DIPEA (2.287 ml, 13.10 mmol) and HATU (1.992 g, 5.24 mmol) were added. The reaction was cooled to 0 °C and tert-butyl (1R,4r)-4-(4-(((1r,4R)-4-(2-aminoethoxy)cyclohexyl)oxy) butanamido)cyclohexane-1-carboxylate (71) (1.862 g, 4.37 mmol) was added. The reaction was warmed to room temperature, stirred for 5h, and then concentrated. Water was added and stirred for 15 min. The resulting solid was collected, dried under vacuum, and purified by column chromatography (10-20% DCM in methanol) to afford compound 75 (1.9 g, 1.590 mmol, 36% yield) as an off-white solid. LC-MS m / z 981.6 (M+H)+.

[0478] Step 2. Preparation of (1R,4r)-4-(4-(((1R,4R)-4-(2-((1R,4R)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy) butanamido)cyclohexane-1-carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane- 1-carboxylic acid (76). To a stirred solution of tert-butyl (1R,4r)-4-(4-(((1R,4R)-4-(2-((1R,4R)- 4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy) cyclohexyl)oxy)butanamido)cyclohexane-1-carboxamido)ethoxy)cyclohexyl)oxy)butanamido) cyclohexane-1-carboxylate (75) (1.7 g, 1.732 mmol) in DCM (15 ml) and dioxane (15 ml) at 0 °C, HCl (4M solution in dioxane, 17 ml, 68.0 mmol) was added. The reaction was stirred at RT for 5 h and then concentrated to provide the crude product. Purification by reverse phase column chromatography afforded compound 76 (1.3 g, 1.370 mmol, 79% yield) as a white solid. LC-MS m / z 925.5 (M+H)+. Example 13 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((2-(((1s,4S)-4-((6-chloro- 2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-4-(methylsulfonamido) benzyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (I-2)

[0479] Step 1. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((2-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-4- (methylsulfonamido)benzyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy) ethyl)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-2). To a stirred solution of (1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy)cyclohexyl) oxy)butanamido)cyclohexane-1-carboxylic acid (77) (90 mg, 0.157 mmol) in DMF (3 ml) at 0 °C, DIPEA (0.137 ml, 0.786 mmol) and PyBOP (123 mg, 0.236 mmol) were added. The reaction was stirred for 10 min at RT before 2-(aminomethyl)-N- ((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-5-(methylsulfonamido) benzamide (47) (99 mg, 0.173 mmol) was added. After stirring for an additional 16h, the reaction was quenched with water and extracted with 10% MeOH in DCM. The combined organic extracts were dried over sodium sulphate, filtered, and concentrated under reduced pressure. Purification by reverse phase preparative chromatography gave compound I-2 (80 mg,0.070 mmol, 45% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.10-1.13 (m, 7H), 1.38-1.41 (m,2H), 1.40 (t, J = 10.40 Hz, 2H), 1.76-1.79 (m, 17H), 2.06 (t, J = 8.00 Hz, 3H), 2.45-2.47 (m, 1H), 2.50-2.50 (m, 1H), 2.68-2.71 (m, 1H), 2.95-2.97 (m, 4H), 3.15-3.16 (m, 5H), 3.32-3.34 (m, 5H), 4.29 (d, J = 5.60 Hz, 3H), 4.76 (d, J = 6.00 Hz, 2H), 6.83 (s, 1H), 7.17-7.17 (m, 3H), 7.38 (d, J = 6.40 Hz, 1H), 7.61 (d, J = 8.00 Hz, 1H), 7.72-7.74 (m, 2H),8.01-8.02 (m, 2H), 8.20 (t, J = 6.00 Hz, 1H), 8.52 (d, J = 6.80 Hz, 1H), 8.67 (d, J = 2.00 Hz, 1H), 8.73 (d, J = 4.80 Hz, 1H), 9.78 (s, 1H). LC-MS m / z 1124.4 (M+H)+.Example 14 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1r,4R)-4-((2-(N-(3-(((1s,4s)-4-((6- chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl)sulfamoyl) ethyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (I-42)

[0480] Step 1. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1r,4R)-4-((2-(N-(3-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl) sulfamoyl)ethyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1- methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-42). To a stirred solution of 3-((2- aminoethyl)sulfonamido)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino) cyclohexyl)benzamide (64) (80 mg, 0.140 mmol) and (1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1- methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido) cyclohexane-1-carboxylic acid (77) (80 mg, 0.140 mmol) in DMF (3 ml), TEA (0.1 ml, 0.719 mmol) and PyBOP (88 mg, 0.168 mmol) were added and the reaction was stirred at RT. After 16h, the reaction was concentrated under reduced pressure and purified by reverse phase preparative chromatography to give compound I-42 (65 mg, 0.057 mmol, 41% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.06-1.17 (m, 5H), 1.24-1.33 (m, 2H), 1.61-1.83(m, 17H), 1.91-1.96 (m, 5H), 2.03-2.06 (m, 2H), 2.42-2.47 (m, 1H), 2.67-2.75 (m, 1H), 2.95-3.05 (m, 4H), 3.12-3.30 (m, 5H), 3.32-3.43 (m, 6H), 3.86 (m, 1H), 3.97 (m, 1H), 4.75 (d, J = 6.20 Hz,1H), 6.83 (s, 1H), 7.36-7.45 (m, 3H), 7.59-7.64 (m, 2H), 7.68-7.73 (m, 1H), 7.74-7.78 (m, 2H), 7.86 (t, J = 5.60 Hz, 1H), 7.91-7.93 (m, 1H), 7.99-8.04 (m, 2H), 8.19 (d, J = 6.48 Hz, 1H), 8.67- 8.73 (m, 3H), 9.94 (m, 1H). LC-MS m / z 1124.4 (M+H)+. Example 15 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro- 2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl)carbamoyl) cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2-(pyridin-3- yl)pyrrolidine-3-carboxamide (I-43)

[0481] Step 1. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl)carbamoyl) cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2-(pyridin-3- yl)pyrrolidine-3-carboxamide (I-43). To a stirred solution of (1R,4r)-4-(4-(((1S,4R)-4-(2- ((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy) butanamido)cyclohexane-1-carboxylic acid (77) (0.204 g, 0.356 mmol) in DMF (1 ml), HATU (0.148 g, 0.389 mmol) and DIPEA (0.170 ml, 0.972 mmol) were added and the reaction was cooled to 0 °C.3-Amino-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino) cyclohexyl)benzamide (52) (0.15 g, 0.324 mmol) was then added and the reaction was allowedto come to RT. After stirring for 16h, the reaction was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by reverse phase preparative chromatographygave compound I-43 (45 mg, 0.044 mmol, 14% yield) as an off-white solid. 1H NMR (400 MHz,DMSO-d6) δ 1.15-1.24 (m, 6H), 1.44-1.53 (m, 2H), 1.64-1.75 (m, 4H), 1.79-1.86 (m, 9H), 1.93- 1.95 (m, 4H), 2.08 (t, J = 7.60 Hz, 2H), 2.26-2.34 (m, 1H), 2.43-2.45 (m, 1H), 2.49-2.53 (m, 4H), 2.67-2.70 (m, 1H), 2.93-2.99 (m, 1H), 3.08-3.14 (m, 1H), 3.19-3.24 (m, 3H), 3.25-3.34 (m, 4H), 3.50-3.52 (m, 1H), 3.85 (m, 1H), 3.97 (m, 1H), 4.66 (d, J = 6.40 Hz, 1H), 6.83 (s, 1H), 7.35-7.39 (m, 2H), 7.43-7.46 (m, 1H), 7.53-7.55 (m, 1H), 7.67-7.70 (m, 2H), 7.75-7.81 (m, 2H), 7.91-7.93 (m, 1H), 8.01-8.05 (m, 2H), 8.15 (d, J = 6.40 Hz, 1H), 8.47-8.48 (m, 1H), 8.56-8.57 (m, 1H), 8.67-8.68 (m, 1H), 9.97 (s, 1H). LC-MS m / z 1017.4 (M+H)+. Example 16 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1r,4R)-4-((3-(N-(3-(((1s,4s)-4-((6- chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl) methylsulfonamido)propyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy) ethyl)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-55)

[0482] Step 1. Preparation of tert-butyl (3-(N-(3-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl)methylsulfonamido) propyl)carbamate (79). To a stirred solution of N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl) quinolin-4-yl)amino)cyclohexyl)-3-(methylsulfonamido)benzamide (78) (0.2 g, 0.370 mmol) in DMF (2 ml), tert-butyl (3-bromopropyl)carbamate (0.132 g, 0.555 mmol) and K2CO3 (0.102 g, 0.739 mmol) were added and the reaction mixture was stirred at 90 °C. After 2 hours, thereaction was cooled, quenched with water under continued stirring and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 79 (150 mg, 0.215 mmol, 58% yield). LC-MS m / z 698.2 (M+H)+.

[0483] Step 2. Preparation of 3-(N-(3-aminopropyl)methylsulfonamido)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide (80). To a stirred solution of tert-butyl (3-(N-(3-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino) cyclohexyl) carbamoyl)phenyl)methylsulfonamido)propyl)carbamate (79) (110 mg, 0.158 mmol) in DCM (1 ml) at 0 °C, HCl (2N in diethyl ether, 1 ml, 2.000 mmol) was added. The reaction was allowed to come to RT. After stirring for 1h, the solvent was decanted and the solid was dried under reduced pressure. The crude product was triturated with pet. ether to give compound 80 (100 mg, 0.167 mmol, >95% yield) as a pale-yellow solid. LC-MS m / z 598.3 (M+H)+.

[0484] Step 3. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1r,4R)-4-((3-(N-(3-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl) methylsulfonamido)propyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl) oxy)ethyl)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-55). To a stirred solution of (1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1-carboxylic acid (77) (80 mg, 0.140 mmol) in DCM (3 ml), HATU (58.4 mg, 0.154 mmol) and DIPEA (0.226 ml, 0.698 mmol) were added. After the mixture was stirred at RT for 15 mins, 3-(N-(3-aminopropyl) methylsulfonamido)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl) benzamide (80) (100 mg, 0.168 mmol) was added and the reaction was continued to be stirred at RT. After 2 hours, the reaction was quenched with water and extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by reverse phase preparative chromatography gavecompound I-55 (40 mg, 0.032 mmol, 23% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.07-1.20 (m, 7H), 1.27-1.33 (m, 2H), 1.47-1.51 (m, 2H), 1.63-1.68 (m, 4H), 1.74-1.82 (m, 10H), 1.92-1.96 (m, 5H), 2.05 (t, J = 7.60 Hz, 2H), 2.40-2.46 (m, 2H), 2.67-2.73 (m, 1H), 2.94- 2.98 (m, 1H), 3.03-3.07 (m, 5H), 3.08-3.23 (m, 5H), 3.31-3.46 (m, 5H), 3.66 (t, J = 7.20 Hz, 2H), 3.86 (s, 1H), 3.98 (s, 1H), 4.69 (d, J = 6.00 Hz, 1H), 6.83 (s, 1H), 7.39 (d, J = 5.60 Hz, 1H), 7.51-7.57 (m, 3H), 7.61-7.68 (m, 2H), 7.75-7.80 (m, 2H), 7.85-7.93 (m, 3H), 8.02 (t, J = 5.60Hz, 1H), 8.28 (d, J = 6.80 Hz, 1H), 8.28 (d, J = 6.80 Hz, 1H), 8.53 (d, J = 1.60 Hz, 1H), 8.61 (dd, J = 1.20, 4.80 Hz, 1H), 8.69 (d, J = 2.40 Hz, 1H). LC-MS m / z 1153.4 (M+H)+. Example 17 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((2-(((1R,4R)-4-(4- (((1R,4R)-4-((2-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl) carbamoyl)-4-(methylsulfonamido)benzyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy) cyclohexyl)oxy)ethyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1- methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-69)

[0485] Step 1. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((2-(((1R,4R)-4-(4-(((1R,4R)-4-((2-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl) carbamoyl)-4-(methylsulfonamido)benzyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy) cyclohexyl)oxy) ethyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1- methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-69). To a stirred solution of (1R,4r)-4-(4-(((1R,4R)-4-(2-((1R,4R)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin- 3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1- carboxamido)ethoxy) cyclohexyl)oxy)butanamido)cyclohexane-1-carboxylic acid (76) (100 mg, 0.108 mmol) in DMF (2 ml) at 0 °C, DIPEA (0.094 ml, 0.540 mmol) and PyBOP (84 mg, 0.162 mmol) were added. The reaction mixture was stirred for 10 min at RT before 2-(aminomethyl)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-5- (methylsulfonamido)benzamide (47) (67.8 mg, 0.119 mmol) was added. After stirring for an additional 16h at RT, the reaction was quenched with water and extracted with 10% MeOH in DCM. The combined organic extracts were dried over sodium sulphate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phasepreparative chromatography to provide compound I-69 (88 mg, 0.060 mmol, 55% yield). 1HNMR (400 MHz, DMSO-d6) δ 1.07-1.21 (m, 14H), 1.35-1.41 (m, 5H), 1.64-1.73 (m, 7H), 1.83- 1.87 (m, 19H), 2.01-2.11 (m, 7H), 2.39-2.45 (m, 1H), 2.66-2.73 (m, 2H), 2.95-2.98 (m, 1H), 3.06-3.25 (m, 9H), 3.41-3.49 (m, 12H), 3.49 (s, 1H), 3.99 (s, 1H), 4.29 (d, J = 6.00 Hz, 2H), 4.66 (d, J = 6.00 Hz, 1H), 6.82 (s, 1H), 7.17 (s, 1H), 7.21-7.26 (m, 2H), 7.35 (d, J = 6.00 Hz, 1H), 7.42-7.46 (m, 1H), 7.61 (t, J = 8.40 Hz, 2H), 7.66-7.71 (m, 2H), 7.74 (dd, J = 2.00, 9.00 Hz, 1H), 7.91 (d, J = 8.80 Hz, 1H), 8.02 (t, J = 5.60 Hz, 1H), 8.16 (s, 1H), 8.21 (t, J = 5.60 Hz, 1H), 8.47 (d, J = 2.00 Hz, 1H), 8.52 (d, J = 6.80 Hz, 1H), 8.56 (dd, J = 1.60, 4.80 Hz, 1H), 8.66 (d, J = 2.00 Hz, 1H). LC-MS m / z 1477.6 (M+H)+. Example 18 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((2-(((1R,4R)-4-(4- (((1r,4R)-4-((2-(N-(3-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino) cyclohexyl)carbamoyl)phenyl)sulfamoyl)ethyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy) cyclohexyl)oxy)ethyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl) oxy)ethyl)-1- methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-70)

[0486] Step 1. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((2-(((1R,4R)-4-(4-(((1r,4R)-4-((2-(N-(3-(((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl)sulfamoyl)ethyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy) cyclohexyl) oxy)ethyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl) oxy)ethyl)-1- methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-70). To a solution of 3-((2- aminoethyl)sulfonamido)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino) cyclohexyl)benzamide (64) (70 mg, 0.123 mmol) and (1R,4r)-4-(4-(((1R,4R)-4-(2-((1R,4R)-4- (4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy) cyclohexyl)oxy)butanamido)cyclohexane-1-carboxamido)ethoxy)cyclohexyl)oxy)butanamido) cyclohexane-1-carboxylic acid (76) (114 mg, 0.123 mmol) in DMF (2 ml), TEA (0.086 ml, 0.614 mmol) and PyBOP (77 mg, 0.147 mmol) were sequentially added. The reaction mixture was stirred at room temperature for 16h before it was concentrated under reduced pressure. Purification by reverse phase preparative chromatography gave compound I-70 (65 mg, 0.043 mmol, 35% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 1.06-1.38 (m, 16H), 1.62-1.72 (m, 6H), 1.73-1.80 (m, 11H), 1.84-1.86 (m, 5H), 1.88-1.94 (m, 4H), 2.01-2.08 (m, 4H), 2.33-2.41 (m, 1H), 2.53-2.56 (m, 1H), 3.02-3.04 (m, 9H), 3.12-3.23 (m, 9H), 3.30-3.45 (m, 10H), 3.85 (m, 2H), 3.96 (m, 2H), 4.73 (t, J = 5.60 Hz, 1H), 6.83 (s, 1H), 7.36-7.45 (m, 3H), 7.61-7.78 (m, 7H), 7.91-7.93 (m, 3H), 8.02-8.05 (m, 1H), 8.20-8.22 (m, 1H), 8.60-8.68 (m, 3H), 9.95 (s, 1H). LC-MS m / z 1476.6 (M+H)+. Example 19 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((2-(((1R,4R)-4-(4- (((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl) carbamoyl)phenyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (I-71)

[0487] Step 1. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((2-(((1R,4R)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl) carbamoyl) phenyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl) carbamoyl) cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (I-71). To a stirred solution of (1R,4r)-4-(4- (((1R,4R)-4-(2-((1R,4R)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl) pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1-carboxamido) ethoxy) cyclohexyl)oxy)butanamido)cyclohexane-1-carboxylic acid (76) (0.220 g, 0.238 mmol) in DMF (5 ml), PyBOP (0.169 g, 0.324 mmol) and DIPEA (0.084 g, 0.648 mmol) were added. After the mixture was stirred at RT for 10 min, 3-amino-N-((1s,4s)-4-((6-chloro-2- (trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)benzamide (52) (0.1 g, 0.216 mmol) was added. After stirring for an additional 3h at RT, the reaction was quenched with water and extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were washed with brine, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography to give compound I-71 (12 mg, 8.41μmol, 4% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.09-1.24 (m, 12H),1.35-1.50 (m, 4H), 1.64-1.94 (m, 28H), 2.00-2.10 (m, 5H), 2.28 (s, 1H), 2.39-2.45 (m, 1H), 2.66- 2.73 (m, 1H), 2.28 (s, 1H), 2.39-2.45 (m, 1H), 2.93-2.97 (m, 2H), 3.09-3.24 (m, 8H), 3.28-3.39 (m, 3H), 3.43-3.53 (m, 8H), 3.85 (s, 1H), 3.96-3.97 (m, 2H), 4.65-4.66 (m, 1H), 6.830 (s, 1H), 7.35-7.39 (m, 2H), 7.44-7.47 (m, 1H), 7.54 (d, J = 7.60 Hz, 1H), 7.63-7.80 (m, 6H), 7.92 (d, J = 9.20 Hz, 1H), 8.00-8.04 (m, 2H), 8.48 (d, J = 1.60 Hz, 1H), 8.56-8.57 (m, 1H), 8.67 ( = 2.00 Hz, H , . 6 s 1 ) L - S / +1 ) 99 ( , H . C M mz 1369.7986 (M+H) .Example 20 - Synthesis of (2S,3S)-1-methyl-5-oxo-N-(2-(((1R,4S)-4-(4-oxo-4-(((1R,4R)-4-((3- (((1s,4S)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl) carbamoyl) phenyl)carbamoyl)cyclohexyl)amino)butoxy)cyclohexyl)oxy)ethyl)-2-(pyridin-3-yl) pyrrolidine-3-carboxamide (I-72)

[0488] Step 1. Preparation of 3-((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane- 1-carboxamido)benzoic acid (82). To a stirred solution of (1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)- 1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido) cyclohexane-1-carboxylic acid (77) (100 mg, 0.175 mmol) in DMF (1 ml) at 0 °C, HATU (100 mg, 0.262 mmol) and DIPEA (0.094 ml, 0.524 mmol) were added sequentially. After the mixture was stirred for 15 min, 3-aminobenzoic acid (81) (23.95 mg, 0.175 mmol) was added and the resulting reaction was allowed to come to RT. After stirring for 16h, the reaction was concentrated under reduced pressure. The solid was triturated with ethyl acetate and petroleum ether and dried under vacuum to give compound 82 (50 mg, 0.051 mmol, 29% yield) as an off- white solid. LC-MS m / z 692.4 (M+H)+.

[0489] Step 2. Preparation of (2S,3S)-1-methyl-5-oxo-N-(2-(((1R,4S)-4-(4-oxo-4-(((1R,4R)-4-((3-(((1s,4S)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino) cyclohexyl)carbamoyl) phenyl)carbamoyl)cyclohexyl)amino)butoxy)cyclohexyl)oxy)ethyl)- 2-(pyridin-3-yl) pyrrolidine-3-carboxamide (I-72). To a solution of 3-((1R,4r)-4-(4-(((1S,4R)- 4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl) oxy)butanamido) cyclohexane-1-carboxamido)benzoic acid (82) (60 mg, 0.061 mmol) in DMF(4 ml) at 0 °C, HATU (34.6 mg, 0.091 mmol) and DIPEA (0.025 ml, 0.182 mmol) were added. After stirring for 15 min, (1s,4s)-N1-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl) cyclohexane-1,4-diamine (15) (27.2 mg, 0.091 mmol) was added and the reaction mixture was allowed to come up to room temperature. After stirring for 16h, the reaction was concentrated and purified by reverse phase preparative chromatography to give compound I-72 (26 mg, 0.026mmol, 44% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.04-1.24 (m, 6H),1.41-1.60 (m, 5H), 1.66-1.71 (m, 3H), 1.79-1.86 (m, 10H), 1.94-2.02 (m, 2H), 2.07-2.19 (m, 3H), 2.23-2.36 (m, 1H), 2.39-2.47 (m, 1H), 2.61-2.73 (m, 3H), 2.87-3.10 (m, 1H), 3.12-3.26 (m, 3H), 3.33-3.43 (m, 4H), 3.43-3.61 (m, 2H), 3.72-3.93 (m, 2H), 4.66 (d, J = 6.40 Hz, 1H), 6.11-6.13 (m, 1H), 6.46-6.47 (m, 1H), 6.92-6.97 (m, 1H), 7.67-7.68 (m, 2H), 7.69-7.70 (m, 2H), 7.77-7.79 (m, 2H), 7.79-1.24 (m, 1H), 7.99-8.05 (m, 2H), 8.15-8.43 (m, 1H), 8.47-8.48 (m, 1H), 8.48-8.56 (m, 1H), 8.56-8.72 (m, 1H), 9.96-9.97 (m, 1H). LC-MS m / z 972.4 (M+H)+. Example 21 - Synthesis of (2S,3S)-1-cyclopropyl-5-oxo-N-(2-(((1R,4S)-4-(4-oxo-4-(((1R,4R)- 4-((3-(((1s,4S)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl) carbamoyl)phenyl)carbamoyl)cyclohexyl)amino)butoxy)cyclohexyl)oxy)ethyl)-2-(pyridin-3- yl)pyrrolidine-3-carboxamide (I-73) NHStep 2

[0490] Step 1. Preparation of 3-amino-N-((1s,4s)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)benzamide (83).3-Aminobenzoic acid (81) (46.0 mg, 0.335 mmol) in DMF (2 ml) was cooled to 0 °C before HATU (213 mg, 0.670 mmol) and DIPEA (0.155 ml, 1.341 mmol) were added. The mixture was stirred for 15 min before (1s,4s)-N1-(2- (trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (15) (100 mg, 0.335 mmol) was added and the reaction was allowed to come to RT. After stirring for 16h, the reaction was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was washed with 20% ethyl acetate / petroleum ether and dried under vacuum to give compound 83 (60 mg, 0.121 mmol, 36% yield). LC-MS m / z 418.2 (M+H)+.

[0491] Step 2. Preparation of (2S,3S)-1-cyclopropyl-5-oxo-N-(2-(((1R,4S)-4-(4-oxo-4-(((1R,4R)-4-((3-(((1s,4S)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino) cyclohexyl) carbamoyl)phenyl)carbamoyl)cyclohexyl)amino)butoxy)cyclohexyl)oxy)ethyl)- 2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-73). To a stirred solution (1R,4r)-4-(4- (((1S,4R)-4-(2-((2S,3S)-1-cyclopropyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy) cyclohexyl)oxy) butanamido)cyclohexane-1-carboxylic acid (73) (50 mg, 0.084 mmol) in DCM (2 ml), DIPEA (0.075 ml, 0.418 mmol) and T3P (0.234 ml, 0.334 mmol) were added and the mixture was stirred for 15 min.3-Amino-N-((1s,4s)-4-((2-(trifluoromethyl)imidazo[1,2-a] pyridin-5-yl)amino)cyclohexyl)benzamide (83) (34.9 mg, 0.084 mmol) was then added and the reaction was stirred for 16h before it was concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography to give compound I-73 (25mg, 0.025 mmol, 30% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.32-0.38(m, 1H), 0.50-0.70 (m, 3H), 1.15-1.23 (m, 6H), 1.45-1.57 (m, 4H), 1.66-1.71 (m, 3H), 1.77-1.94 (m, 12H), 2.07-2.19 (m, 4H), 2.26-2.33 (m, 1H), 2.33-2.34 (m, 1H), 2.53-2.65 (m, 1H), 2.91-2.96 (m, 1H), 3.09-3.28 (m, 4H), 3.33-3.38 (m, 4H), 3.50 (s, 2H), 3.72-3.93 (m, 2H), 4.65 (d, J = 5.36 Hz, 1H), 6.11-6.17 (m, 1H), 6.45-6.62 (m, 1H), 6.92-6.97 (m, 1H), 7.35 (t, J = 1.76 Hz, 2H),7.38-7.43 (m, 1H), 7.49-7.52 (m, 1H), 7.67-8.00 (m, 3H), 8.00-8.15 (m, 2H), 8.15-8.29 (m, 1H), 8.52-8.56 (m, 2H), 8.66-8.72 (m, 1H). LC-MS m / z 998.4 (M+H)+. Example 22 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro- 2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl)carbamoyl) cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-cyclopropyl-5-oxo-2-(pyridin-3-yl) pyrrolidine-3-carboxamide (I-74)

[0492] Step 1. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)phenyl)carbamoyl) cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-cyclopropyl-5-oxo-2-(pyridin-3- yl)pyrrolidine-3-carboxamide (I-74). To a stirred solution of (1R,4r)-4-(4-(((1S,4R)-4-(2- ((2S,3S)-1-cyclopropyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl) oxy)butanamido)cyclohexane-1-carboxylic acid (73) (90 mg, 0.150 mmol) in DCM (5 ml), T3P (0.370 ml, 0.601 mmol) and DIPEA (0.131 ml, 0.752 mmol) were added and the reaction was cooled to 0°C. After 15min, 3-amino-N-(4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino) cyclohexyl)benzamide (52) (70 mg, 0.151 mmol) was added and the reaction was allowed to come to RT. After stirring for 16h, the reaction was concentrated under reduced pressure andpurified by reverse phase preparative chromatography to give compound I-74 (25 mg, 0.023mmol, 15% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.30-0.40 (m, 1H),0.54-0.58 (m, 1H), 0.59-0.67 (m, 1H), 0.68-0.70 (m, 1H), 0.80-1.00 (m, 1H), 1.15-1.47 (m, 6H), 1.50-1.65 (m, 3H), 1.69-1.75 (m, 5H), 1.79-1.93 (m, 9H), 1.94-2.06 (m, 4H), 2.08 (t, J = 7.20 Hz, 2H), 2.15-2.28 (m, 1H), 2.33-2.50 (m, 1H), 2.60-2.69 (m, 1H), 2.94-2.96 (m, 1H), 3.09-3.29 (m, 5H), 3.44-3.51 (m, 2H), 3.85 (m, 1H), 3.96 (m, 1H), 4.65 (d, J = 5.20 Hz, 1H), 6.83 (s, 1H), 7.35-7.42 (m, 2H), 7.43-7.53 (m, 1H), 7.55-7.69 (m, 1H), 7.71-7.80 (m, 4H), 7.91-7.93 (m, 1H), 8.00-8.03 (m, 2H), 8.15-8.16 (m, 1H), 8.52-8.56 (m, 2H), 8.67 (s, 1H), 9.97 (s, 1H). LC-MS m / z 1043.3 (M+H)+. Example 23 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((5-(((1s,4S)-4-((6-chloro- 2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-2,4-difluorophenyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (I-75)

[0493] Step 1. Preparation of methyl 2,4-difluoro-5-((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy) butanamido) cyclohexane-1-carboxamido)benzoate (85). To a stirred solution of (1R,4r)-4-(4- (((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy) cyclohexyl)oxy) butanamido)cyclohexane-1-carboxylic acid (77) (150 mg, 0.262 mmol) in DCM (0.5 ml), HATU (149 mg, 0.393 mmol) and DIPEA (0.229 ml, 1.310 mmol) were added. After 15 mins, methyl 5-amino-2,4-difluorobenzoate (84) (58.8 mg, 0.314 mmol) was added and the reaction was stirred at RT. After 16 hours, the reaction was diluted with water (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography to give compound 85 (80 mg, 0.099 mmol, 38% yield). LC-MS m / z 742.4 (M+H)+.

[0494] Step 2. Preparation of 2,4-difluoro-5-((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy) butanamido)cyclohexane-1-carboxamido)benzoic acid (86). To a stirred solution of methyl 2,4-difluoro-5-((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl) pyrrolidine-3-carboxamido)ethoxy) cyclohexyl)oxy)butanamido)cyclohexane-1-carboxamido) benzoate (85) (75 mg, 0.101 mmol) in THF (0.1 ml), methanol (0.1 ml) and water (10 μl),lithium hydroxide (3.63 mg, 0.152 mmol) was added. After stirring for 1h at RT, the reaction was quenched with 1.5N HCl (pH 2-3) and concentrated under reduced pressure. Purification by reverse phase column chromatography gave compound 86 (40 mg, 0.053 mmol, 52% yield) as an off-white solid.. LC-MS m / z 728.3 (M+H)+.

[0495] Step 3. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((5-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-2,4-difluorophenyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (I-75). To a stirred solution of 2,4-difluoro-5- ((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1-carboxamido)benzoic acid (86) (40 mg, 0.055 mmol) in DCM (2 ml), HATU (31.3 mg, 0.082 mmol) was added and stirred at 0 °C. After 15 mins, a solution of (1s,4s)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl) cyclohexane-1,4-diamine (10) (22.67 mg, 0.066 mmol) in DCM (2 ml) and DIPEA (0.048 ml, 0.275 mmol) were sequentially added and the reaction was allowed to warm to RT. After 2 hours, the reaction was concentrated under reduced pressure and purified by reverse phase preparative chromatography to give compound I-75 (30 mg, 0.028 mmol, 52% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.15-1.23 (m, 7H), 1.43-1.52 (m, 2H), 1.64-1.71(m, H), 1.75-1.86 (m, 17H), 2.08 (t, J = 7.60 Hz, 2H), 2.23-2.28 (m, 1H), 2.42-2.56 (m, 1H), 2.70-2.82 (m, 1H), 2.97-3.01 (m, 1H), 3.09-3.21 (m, 5H), 3.33-3.38 (m, 4H), 3.50-3.51 (m, 1H), 3.82 (s, 1H), 4.73 (d, J = 6.00 Hz, 1H), 6.84 (s, 1H), 7.22 (t, J = 9.20 Hz, 1H), 7.40 (d, J = 6.40 Hz, 1H), 7.65-7.77 (m, 4H), 7.83 (dd, J = 2.80, 6.40 Hz, 1H), 7.90-7.97 (m, 2H), 8.02 (t, J = 5.60 Hz, 1H), 8.12-8.14 (m, 1H), 8.62-8.70 (m, 3H), 9.97 (s, 1H). LC-MS m / z 1053.5 (M+H)+.Example 24 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((2,4-difluoro-5-(((1s,4S)- 4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamoyl) phenyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (I-76)

[0496] Step 1. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((2,4-difluoro-5-(((1s,4S)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamoyl) phenyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo- 2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-76). To a stirred solution of 2,4-difluoro-5- ((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1-carboxamido)benzoic acid (86) (65 mg, 0.089 mmol) in DCM (20 ml) at 0 °C, HATU (50.9 mg, 0.134 mmol) was added. After 15 mins, a solution of (1s,4s)-N1-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)cyclohexane- 1,4-diamine (15) (32.0 mg, 0.107 mmol) and DIPEA (46.2 mg, 0.357 mmol) in DCM was added and the reaction was allowed to warm to RT. After stirring for 16 hours, the reaction was concentrated under reduced pressure. Purification by reverse phase preparative chromatographygave compound I-76 (92 mg, 0.082 mmol, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.15-1.23 (m, 6H), 1.42-1.52 (m, 4H), 1.64-1.72 (m, 3H), 1.78-1.83 (m, 12H), 1.97 (s, 1H), 2.06-2.12 (m, 3H), 2.38-2.47 (m, 2H), 2.67-2.75 (m, 1H), 2.95-3.01 (m, 1H), 3.13-3.21 (m, 4H), 3.33-3.38(m, 4H), 3.50-3.66 (m, 2H), 3.78-3.96 (m, 1H), 4.75 (d, J = 8.00 Hz, 1H), 6.12-6.18 (m, 1H), 6.50-6.63 (m, 2H), 6.94 (t, J = 8.96 Hz, 1H), 7.22-0.43 (m, 2H), 7.67-7.75 (m, 2H), 7.97-8.04 (m, 3H), 8.20-8.32 (m, 1H), 8.66-8.73 (m, 2H), 9.70 (d, J = 3.12 Hz, 1H). LC-MS m / z 1008.4 (M+H)+. Example 25 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro- 2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-4-fluorophenyl)carbamoyl) cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2-(pyridin-3-yl) pyrrolidine-3-carboxamide (I-77)

[0497] Step 1. Preparation of methyl 2-fluoro-5-((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy) butanamido) cyclohexane-1-carboxamido)benzoate (88). To a stirred solution of (1R,4r)-4-(4- (((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy) cyclohexyl)oxy) butanamido)cyclohexane-1-carboxylic acid (77) (150 mg, 0.262 mmol) in DCM (0.5 ml), HATU (149 mg, 0.393 mmol) and DIPEA (0.229 ml, 1.310 mmol) were added. After stirring for 15 mins, methyl 5-amino-2-fluorobenzoate (87) (53.2 mg, 0.314 mmol) was added and the reaction was stirred for an additional 16 hours. The reaction was diluted with water (5 mL) and extracted with EtOAc (5 mL x 2). The combined organic extracts were washed with brine (5 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography to give compound 88 (100 mg, 0.127 mmol, 49% yield). LC-MS m / z 724.4 (M+H)+.

[0498] Step 2. Preparation of 2-fluoro-5-((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido) cyclohexane-1-carboxamido)benzoic acid (89). To a stirred solution of methyl 2-fluoro-5- ((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy) cyclohexyl)oxy)butanamido)cyclohexane-1-carboxamido)benzoate (88) (100 mg, 0.138 mmol) in THF (1 ml), methanol (1 ml) and water (0.1 ml), lithium hydroxide (4.96 mg, 0.207 mmol) was added and the reaction was stirred at RT. After 1 hour, the reaction was quenched with 1.5N HCl (pH 2-3) and concentrated under reduced pressure. Purification by reverse phase column chromatography gave compound 89 (60 mg, 0.083 mmol, 60% yield) as an off-white solid. LC-MS m / z 710.4 (M+H)+.

[0499] Step 3. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-4-fluorophenyl) carbamoyl) cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-77). To a stirred solution of 2-fluoro-5-((1R,4r)-4- (4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy) cyclohexyl) oxy)butanamido)cyclohexane-1-carboxamido)benzoic acid (89) (55 mg, 0.077 mmol) in DCM (2 ml) at 0 °C, HATU (44.2 mg, 0.116 mmol) was added. After the mixture was stirred for 15 mins, a solution of (1s,4s)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl) cyclohexane-1,4-diamine (10) (32.0 mg, 0.093 mmol) in DCM (2 ml) and DIPEA (0.068 ml, 0.387 mmol) were added and the reaction was allowed to warm to RT. After 2 hours, the reaction was concentrated under reduced pressure and purified by reverse phase preparative chromatography to give compound I-77 (50 mg, 0.048 mmol, 62% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 1.15-1.23 (m, 7H), 1.43-1.52 (m, 2H), 1.64-1.71 (m, 2H), 1.75-1.86 (m, 16H), 2.08 (t, J = 7.60 Hz, 2H), 2.25 (t, J = 11.60 Hz, 1H), 2.42-2.48 (m, 1H), 2.97-3.01 (m, 1H), 3.09-3.21 (m, 5H), 3.33-3.37 (m, 4H), 3.50-3.51 (m, 1H), 3.82 (s, 1H), 4.73 (d, J = 6.00 Hz, 1H), 6.84 (s, 1H), 7.22 (t, J = 9.20 Hz, 1H), 7.40 (d, J = 6.40 Hz, 1H), 7.65-7.77 (m, 4H), 7.83 (dd, J = 2.80, 6.40 Hz, 1H), 7.90-7.97 (m, 2H), 8.02 (t, J = 5.60 Hz, 1H), 8.12-8.14 (m, 1H), 8.62-8.70 (m, 3H), 9.97 (s, 1H). LC-MS m / z 1035.4 (M+H)+. Example 26 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((4-fluoro-3-(((1s,4S)-4- ((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamoyl)phenyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (I-78)

[0500] Step 1. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((4-fluoro-3-(((1s,4S)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamoyl) phenyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo- 2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-78). To a stirred solution of 2-fluoro-5-((1R,4r)- 4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy) cyclohexyl)oxy)butanamido)cyclohexane-1-carboxamido)benzoic acid (89) (70 mg, 0.099 mmol) in DCM (3 ml) at 0 °C, HATU (37.5 mg, 0.099 mmol) was added and the mixture stirred for 15 mins. A solution of (1s,4s)-N1-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl) cyclohexane-1,4-diamine (15) (29.4 mg, 0.099 mmol) and DIPEA (0.017 ml, 0.099 mmol) in DCM was then added and the reaction was warmed to RT. After 2 hours, the reaction was concentrated under reduced pressure. Purification by reverse phase preparative chromatographygave compound I-78 (65 mg, 0.066 mmol, 67% yield) as an off-white solid. 1H NMR (400 MHz,DMSO-d6) δ 1.20-1.27 (m, 6H), 1.47-1.57 (m, 4H), 1.68-1.79 (m, 3H), 1.85-1.89 (m, 11H), 1.95- 2.28 (m, 6H), 2.50-2.53 (m, 3H), 2.67-2.72 (m, 1H), 2.96-3.02 (m, 1H), 3.15-3.26 (m, 4H), 3.37- 3.42 (m, 4H), 3.53-3.68 (m, 2H), 3.83-4.03 (m, 1H), 4.71 (d, J = 6.00 Hz, 1H), 6.11-6.13 (m, 1H), 6.28-6.41 (m, 1H), 6.94 (t, J = 8.80 Hz, 1H), 7.14-7.15 (m, 1H), 7.33-7.33 (m, 2H), 7.50 (q, J = 4.80 Hz, 1H), 7.76-7.93 (m, 5H), 8.53-8.53 (m, 3H), 9.71 (s, 1H). LC-MS m / z 991.4 (M+H)+.Example 27 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro- 2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-2,4-difluorophenyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (I-79)

[0501] Step 1. Preparation of 3-amino-2,6-difluorobenzoic acid (91). Methyl 3-amino-2,6-difluorobenzoate (90) (0.5 g, 2.67 mmol) was dissolved in THF (2 ml) and MeOH (2 ml) before lithium hydroxide (0.192 g, 8.02 mmol) and water (5 drops) were added. The resulting mixture was stirred for 16 h at RT before it was acidified with HCl (1.5 N solution, 4 mL) and concentrated under reduced pressure. The obtained solid was washed with water and dried under vacuum to give compound 91 (420 mg, 2.4 mmol, 90% yield) as a light brown solid. LC-MS m / z 173.8 (M+H)+.

[0502] Step 2. Preparation of 2,6-difluoro-3-((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy) butanamido)cyclohexane-1-carboxamido)benzoic acid (92). To a stirred solution of (1R,4r)-4- (4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy) cyclohexyl)oxy)butanamido) cyclohexane-1-carboxylic acid (77) (0.662 g, 1.155 mmol) in DMF (5 ml), DIPEA (5.03 ml, 28.9 mmol) and HATU (0.439 g, 1.155 mmol) were added sequentially. After the reaction was stirred for 10 min, 3-amino-2,6-difluorobenzoic acid (91) (0.2 g, 1.155 mmol) was added to the pale-yellow solution and the reaction was stirred at RT. After 16h, the reaction was concentrated under reduced pressure and purified by reverse phase column chromatography to give compound 92 (440 mg, 0.55 mmol, 48% yield) as a yellow solid. LC- MS m / z 728.4 (M+H)+.

[0503] Step 3. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-2,4-difluorophenyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (I-79). To a stirred solution of 2,6-difluoro-3- ((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1-carboxamido)benzoic acid (92) (200 mg, 0.275 mmol) in DMF (6 ml), HATU (209 mg, 0.550 mmol) and DIPEA (1.200 ml, 6.87 mmol) were added. After 15 min, (1s,4s)-N1-(6-chloro-2-(trifluoromethyl)quinolin-4-yl) cyclohexane-1,4-diamine hydrochloride (10) (125 mg, 0.330 mmol) was added and the reaction was stirred at RT. After 4h, the reaction was concentrated under reduced pressure and purified by reverse phase preparative chromatography to give compound I-79 (80 mg, 0.076 mmol, 28%yield) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ 1.15-1.24 (m, 7H), 1.46 (q, J =10.40 Hz, 2H), 1.67 (t, J = 7.20 Hz, 2H), 1.76-1.92 (m, 18H), 2.08 (t, J = 7.60 Hz, 2H), 2.47- 2.41 (m, 2H), 3.12-3.23 (m, 5H), 3.33-3.38 (m, 4H), 3.49-3.51 (m, 1H), 3.78 (s, 1H), 3.99 (s, 1H), 4.72 (d, J = 6.40 Hz, 1H), 6.83 (s, 1H), 7.11 (t, J = 6.80 Hz, 1H), 7.43 (d, J = 6.00 Hz, 1H), 7.63 (t, J = 5.20 Hz, 1H), 7.68 (d, J = 8.00 Hz, 1H), 7.79-7.84 (m, 1H), 7.90-7.93 (m, 2H), 8.02 (t, J = 5.20 Hz, 1H), 8.61 (s, 1H), 8.66-8.68 (m, 2H), 8.74 (d, J = 6.40 Hz, 1H), 9.65 (s, 1H). LC- MS m / z 1053.4 (M+H)+.Example 28 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((2,4-difluoro-3-(((1s,4S)- 4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamoyl)phenyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (I-80)

[0504] Step 1. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((2,4-difluoro-3-(((1s,4S)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)carbamoyl) phenyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo- 2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-80). To a stirred solution of 2,6-difluoro-3- ((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1-carboxamido)benzoic acid (92) (150 mg, 0.206 mmol) in DMF (4 ml), HATU (157 mg, 0.412 mmol) and DIPEA (0.900 ml, 5.15 mmol) were added. After 15 min, (1s,4s)-N1-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-5- yl)cyclohexane-1,4-diamine hydrochloride (15) (69.0 mg, 0.206 mmol) was added and the reaction was stirred at RT. After 4h, the reaction was concentrated under reduced pressure and purified by reverse phase preparative chromatography to give compound I-80 (60 mg, 0.059mmol, 29% yield) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ 1.15-1.24 (m, 8H),1.66-1.71 (m, 4H), 1.79-1.91 (m, 73H), 1.99-1.99 (m, 1H), 2.06-2.14 (m, 4H), 2.70-2.74 (m, 1H), 2.94-3.00 (m, 1H), 3.10-3.23 (m, 4H), 3.33-3.39 (m, 5H), 3.51 (s, 1H), 3.62 (s, 1H), 3.79 (s, 1H),3.96 (s, 1H), 4.72 (d, J = 6.40 Hz, 1H), 6.15 (dd, J = 7.60, 22.80 Hz, 1H), 6.61 (d, J = 7.60 Hz, 1H), 6.94 (t, J = 8.80 Hz, 1H), 7.09-7.13 (m, 1H), 7.36 (t, J = 6.40 Hz, 1H), 7.62 (t, J = 7.60 Hz, 1H), 7.68 (d, J = 5.60 Hz, 1H), 7.81 (t, J = 6.80 Hz, 1H), 7.90 (d, J = 8.00 Hz, 1H), 8.03 (t, J = 5.60 Hz, 1H), 8.59 (s, 1H), 8.65-8.65 (m, 3H), 9.65 (d, J = 9.20 Hz, 1H). LC-MS m / z 1008.4 (M+H)+. Example 29 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro- 2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-5-(trifluoromethyl)phenyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (I-81)

[0505] Step 1. Preparation of methyl 3-((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido) cyclohexane-1-carboxamido)-5-(trifluoromethyl)benzoate (94). (1R,4r)-4-(4-(((1S,4R)-4-(2- ((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy) butanamido) cyclohexane-1-carboxylic acid (77) (0.523 g, 0.913 mmol) and methyl 3-amino-5- (trifluoromethyl)benzoate (53) (0.2 g, 0.913 mmol) were dissolved in DCM (5 ml) before DCC (0.377 g, 1.825 mmol) and DMAP (1.115 mg, 9.13 μmol) were added. The reaction was stirred at RT for 16h, diluted with a saturated ammonium chloride solution (50 ml), and then extracted with DCM. The combined organic extracts were washed with water and concentrated under reduced pressure. The crude product was purified by reverse phase preparative chromatography to give compound 94 (120 mg, 0.152 mmol, 17% yield) as a colorless solid. LC-MS m / z 774.4 (M+H)+.

[0506] Step 2. Preparation of 3-((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane- 1-carboxamido)-5-(trifluoromethyl)benzoic acid (95). To a stirred solution of methyl 3- ((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy) cyclohexyl)oxy)butanamido)cyclohexane-1-carboxamido)-5- (trifluoromethyl)benzoate (94) (120 mg, 0.155 mmol) in THF (2 ml), a solution of lithium hydroxide (5.57 mg, 0.233 mmol) in water (0.5 ml) was added and the reaction was stirred at RT. After 2h, the reaction was acidified with an HCl solution (1.5 N, 5 mL, pH 3) and then concentrated under reduced pressure. Purification by reverse phase column chromatography provided compound 95 (100 mg, 0.13 mmol, 84% yield) as a yellow solid. LC-MS m / z 760.3 (M+H)+.

[0507] Step 3. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-5-(trifluoromethyl)phenyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo- 2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-81).3-((1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1- methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido) cyclohexane-1-carboxamido)-5-(trifluoromethyl)benzoic acid (95) (80 mg, 0.105 mmol) and HATU (52.0 mg, 0.137 mmol) were dissolved in DMF (3 ml) before DIPEA (0.184 ml, 1.053 mmol) was added. The reaction was stirred for 10 min before (1s,4s)-N1-(6-chloro-2- (trifluoromethyl)quinolin-4-yl)cyclohexane-1,4-diamine hydrochloride (10) (44.0 mg, 0.116 mmol) was added to the pale brown solution. The reaction was stirred at RT for 4h before it was concentrated under reduced pressure. Purification by reverse phase preparative chromatography provided compound I-81 (25 mg, 0.023 mmol, 22% yield) as a white fluffy solid.1H NMR (400 MHz, DMSO-d6) δ 1.15-1.24 (m, 8H), 1.45-1.54 (m, 2H), 1.64-1.96 (m, 20H), 2.09 (t, J = 7.60 Hz, 2H), 2.27-2.30 (m, 2H), 2.39-2.45 (m, 1H), 2.71-2.73 (m, 1H), 2.93-2.99 (m, 1H), 3.08-3.15 (m, 1H), 3.19-0.26 (m, 1H), 3.36-3.40 (m, 3H), 3.48-3.53 (m, 1H), 3.86 (s, 1H), 3.98 (s, 1H), 4.66 (d, J = 6.40 Hz, 1H), 6.83 (s, 1H), 7.38 (d, J = 5.60 Hz, 1H), 7.44 (t, J = 4.80 Hz, 1H), 7.67- 7.70 (m, 2H), 7.76 (d, J = 6.80 Hz, 1H), 7.91 (s, 1H), 7.93 (s, 1H), 8.03 (d, J = 5.60 Hz, H), 8.23 (s, 1H), 8.30 (s, 1H), 8.47-8.49 (m, 2H), 8.57 (d, J = 3.20 Hz, 1H), 8.69 (d, J = Hz, 1H), 10.32 (s, 1H). LC-MS m / z 1087.4 (M+H)+. Example 30 - Synthesis of (2S,3S)-1-methyl-5-oxo-N-(2-(((1R,4S)-4-(4-oxo-4-(((1R,4R)-4-((3- (trifluoromethyl)-5-(((1s,4S)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino) cyclohexyl)carbamoyl)phenyl)carbamoyl)cyclohexyl)amino)butoxy)cyclohexyl)oxy)ethyl)- 2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-82)

[0508] Step 1. Preparation of (2S,3S)-1-methyl-5-oxo-N-(2-(((1R,4S)-4-(4-oxo-4-(((1R,4R)-4-((3-(trifluoromethyl)-5-(((1s,4S)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin- 5-yl)amino)cyclohexyl)carbamoyl)phenyl)carbamoyl)cyclohexyl)amino)butoxy) cyclohexyl) oxy)ethyl)-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (I-82).3-((1R,4r)-4-(4-(((1S,4R)-4-(2- ((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy) cyclohexyl)oxy) butanamido) cyclohexane-1-carboxamido)-5-(trifluoromethyl)benzoic acid (95) (75 mg, 0.099 mmol) and HATU (56.3 mg, 0.148 mmol) were dissolved in DMF (8 ml) before DIPEA (0.345 ml, 1.974 mmol) was added. After stirring at RT for 10 min, (1s,4s)-N1-(2-(trifluoromethyl) imidazo[1,2-a]pyridin-5-yl)cyclohexane-1,4-diamine (15) (32.4 mg, 0.109 mmol) was added and the reaction was continued to be stirred at RT. After 4h, the reaction was concentrated under reduced pressure and purified by reverse phase preparative chromatography to give compound I-82 (40 mg, 0.038 mmol, 39% yield) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ1.15-1.21 (m, 7H), 1.48-1.56 (m, 5H), 1.66-1.71 (m, 3H), 1.84-1.99 (m, 13H), 2.09 (t, J = 7.60 Hz, 2H), 2.11-2.19 (m, 1H), 2.30-2.34 (m, 1H), 2.41-2.45 (m, 1H), 2.67-2.73 (m, 1H), 2.95-2.97 (m, 1H), 3.12-3.13 (m, 1H), 3.21-3.23 (m, 3H), 3.35-3.37 (m, 3H), 3.42-3.59 (m, 1H), 3.67-3.78 (m, 1H), 4.08-3.81 (m, 1H), 4.66 (d, J = 6.40 Hz, 1H), 6.08-6.19 (m, 1H), 6.49-6.63 (m, 1H), 6.95 (t, J = 8.80 Hz, 1H), 7.38 (t, J = 7.60 Hz, 1H), 7.43-7.46 (m, 1H), 7.67-7.70 (m, 2H), 7.89 (d, J = 9.60 Hz, 1H), 8.03 (t, J = 5.60 Hz, 1H), 8.23 (s, 1H), 8.30 (s, 1H), 8.47 (s, 1H), 8.56 (s, 1H), 8.61 (d, J = 7.60 Hz, 1H), 8.66 (s, 1H), 8.74 (s, 1H), 10.36 (s, 1H). LC-MS m / z 1040.4 (M+H)+.Example 31 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro- 2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-5-(methylsulfonamido) benzyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (II-1)

[0509] Step 1. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-5- (methylsulfonamido)benzyl) carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy) ethyl)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (II-1). To a stirred solution of (1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy)cyclohexyl) oxy)butanamido)cyclohexane-1-carboxylic acid (77) (0.5 g, 0.873 mmol) in DMF (5 mL) at 0 °C under a nitrogen atmosphere, HATU (0.365 g, 0.960 mmol) and DIPEA (0.532 ml, 3.06 mmol) were added. The reaction was stirred for 15 minutes before a solution of 3-(aminomethyl)-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino) cyclohexyl)-5-(methylsulfonamido) benzamide (32) (0.547 g, 0.960 mmol) in DMF (5 mL) was added. The reaction was then warmed to RT and stirred for 5h before being quenched with cold water and extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were washed with brine and concentrated under reduced pressure. Purification of the crude product by reversephase preparative chromatography provided compound II-1 (170 mg, 0.15 mmol, 17% yield). 1HNMR (400 MHz, DMSO-d6) δ 1.10-1.24 (m, 6H), 1.39-1.42 (m, 2H), 1.64-2.12 (m, 22H), 2.39- 2.45 (m, 2H), 2.68-2.73 (m, 1H), 2.70-3.00 (m, 1H), 3.05 (s, 3H), 3.08-3.24 (m, 5H), 3.24-3.48 (m, 5H), 3.82-3.88 (m, 1H), 3.92-3.99 (m, 1H), 4.28 (d, J = 5.20 Hz, 2H), 4.66 (d, J = 6.00 Hz, 1H), 6.82 (s, 1H), 7.21 (m, 1H), 7.35-7.37 (m, 1H), 7.44-7.52 (m, 4H), 7.63-7.78 (m, 3H), 7.91- 7.93 (m, 1H), 8.02 (t, J = 5.60 Hz, 1H), 8.19 (d, J = 6.40 Hz, 1H), 8.31 (t, J = 6.00 Hz, 1H), 8.49- 8.57 (m, 2H), 8.68-8.69 (m, 1H). LC-MS m / z 1124.3 (M+H)+. Example 32 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro- 2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-5-(methylsulfonamido) phenyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3-carboxamide (II-4)

[0510] Step 1. Preparation of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1R,4R)-4-((3-(((1s,4S)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-5- (methylsulfonamido)phenyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy)cyclohexyl)oxy) ethyl)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (II-4). To a stirred solution of 3-amino-N-((1s,4s)-4-((6-chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)-5-(methylsulfonamido) benzamide (57) (80 mg, 0.144 mmol) and (1R,4r)-4-(4-(((1S,4R)-4-(2- ((2S,3S)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy) butanamido)cyclohexane-1-carboxylic acid (77) (82 mg, 0.144 mmol) in DMF (2 ml), TEA (0.101 ml, 0.719 mmol) and propylphosphonic anhydride (0.127 ml, 0.216 mmol) were added sequentially. The reaction mixture was stirred at 70 °C for 16h before being cooled and concentrated under reduced pressure. Purification by reverse phase preparative chromatographygave compound II-4 (35 mg, 0.030 mmol, 21% yield) as an off-white solid. 1H NMR (400 MHz,DMSO-d6) δ 1.17-1.24 (m, 5H), 1.46-1.49 (m, 2H), 1.66-1.79 (m, 9H), 1.83-1.90 (m, 9H), 1.93- 1.95 (m, 2H), 2.08 (t, J = 7.28 Hz, 1H), 2.29-2.34 (m, 1H), 2.42-2.47 (m, 1H), 2.67-2.74 (m, 1H), 2.94-3.04 (m, 8H), 3.13-3.23 (m, 4H), 3.33-3.36 (m, 3H), 3.68 (m, 1H), 3.85 (m, 1H), 3.93 (m, 1H), 4.69-4.70 (m, 1H), 6.82 (m, 1H), 7.26 (m, 1H), 7.34-7.35 (m, 1H), 7.56-7.56 (m, 1H), 7.67-7.69 (m, 2H), 7.75-7.77 (m, 2H), 7.78-7.81 (m, 1H), 7.91-7.93 (m, 1H), 8.03 (m, 1H), 8.16- 8.18 (m, 1H), 8.56 (m, 1H), 8.63 (d, J = 4.84 Hz, 1H), 8.69-8.69 (m, 1H), 9.84 (s, 1H), 10.02 (s, 1H). LC-MS m / z 1110.3 (M+H)+. Example 32 - Synthesis of (2S,3S)-N-(2-(((1R,4S)-4-(4-(((1r,4R)-4-((2-(3-(((1s,4s)-4-((6- chloro-2-(trifluoromethyl)quinolin-4-yl)amino)cyclohexyl)carbamoyl)-5- (methylsulfonamido)phenoxy)ethyl)carbamoyl)cyclohexyl)amino)-4-oxobutoxy) cyclohexyl)oxy)ethyl)-1-methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3-carboxamide (II-9)

[0511] Step 1. Preparation of methyl 3-((tert-butoxycarbonyl)amino)-5-hydroxybenzoate(97). To a solution of methyl 3-amino-5-hydroxybenzoate (96) (1.5 g, 8.97 mmol) in THF (10 ml) and water (20 ml), sodium bicarbonate (1.508 g, 17.95 mmol) and di-tertbutyl dicarbonate (2.5 ml, 10.88 mmol) were added and the reaction was stirred at room temperature. After 16h, the reaction was diluted with water and extracted with ethyl acetate (2x). The combined organic extracts were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered, and concentrated to give compound 97 (2.1 g, 7.86 mmol, 88% yield) as a gummy solid, which was used as is for the next step. LC-MS m / z 168.1 (M-Boc+H)+.

[0512] Step 2. Preparation of meth...

Claims

Claims:

1. A compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is C1-4alkyl or C3-6cycloalkyl; X1is a C1-10 bivalent saturated straight or branched hydrocarbon chain wherein one, two, three, or four methylene units of the chain are independently replaced by -N(H)-, -N(CH3)-, -O-, or -C(O)-; or X1is -N(H)-, -N(CH3)-, or a 5- or 6-membered saturated monocyclic heterocyclylene containing 1 or 2 heteroatoms which are nitrogen; X2is ɸ-(C1-5 alkylene)-N(H)- or a covalent bond, wherein ɸ is a bond to L; Y1is defined by Formula I-1 that is substituted by one occurrence of R4, wherein Formula I-1 is represented by:wherein: A1is a 9- or 10-membered bicyclic heteroaryl containing 1 or 2 heteroatoms which are nitrogen, wherein the heteroaryl is substituted with 0, 1, or 2 occurrences of R2; A2is phenyl, a 5- or 6-membered monocyclic heteroaryl containing 1 or 2 heteroatoms which are nitrogen, or a 9- or 10-membered bicyclic heteroaryl containing 1 or 2 heteroatoms which are nitrogen; each of which is substituted with 0, 1, or 2 occurrences of R3; R2represents independently for each occurrence C1-4haloalkyl, halo, or C1-4alkyl;R3represents independently for each occurrence C1-4alkyl, C1-4alkoxyl, halo, -N(R5)S(O)2-(C1-4 alkyl), -N(R5)S(O)2-(phenyl), -N(R5)C(O)-(C1-4 alkyl), or -N(R5)-(C1-4 alkyl); R4is a bond to X1; R5represents independently for each occurrence H or C1-3alkyl; and L is a divalent linker selected from: (i) a bivalent, saturated or unsaturated, straight or branched C1-60 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, - S-, -N(H)-, -N(C1-6 alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C1-6 alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C1-6 alkyl)-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C1-6alkyl)-, -OC(O)N(H)-, -OC(O)N(C1-6alkyl)-, -N(H)C(O)O- , -N(C1-6alkyl)C(O)O-, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein Ring A and Ring B are each independently C4-6cycloalkylene; L1ais C3-5linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3 alkyl; and L2ais -O-, -NHC(O)-, or -CH2-O-; (iii)) wherein Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; L1bis -CH2-NH-C(O)-, -NHC(O)-, or -C(O)NH-; L2bis C6-12linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR1b-, -wherein n is 1, 2, 3, or 4, andrepresents a covalent bond to L1b; and each R1bis independently hydrogen or C1-3 alkyl; (iv)(L-c) wherein L1cis C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; Ring A is C4-6cycloalkylene or C7-9 bridged bicyclic cycloalkylene; and L2cis -O- or a saturated C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-; (v)(L-d) wherein L1dis C12-22linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-; (vii) (L-f) wherein L is a bond; C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-, -NH-, or -C(O)-; or -(C3-6 cycloalkylene)-NHC(O)-; L2fis a bond, -NHC(O)-, -C(O)NH-, or a C1-6 linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-; and each of Z1and Z2is independently N or CH; (viii)(L-g) wherein Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; L1gis a bond, -CH2-, -NH-, or -O-; and L2giswherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bond to L1g;, , , , ,1hrepresents a covalent bond to L3h; L3his a bond, -C(O)CH2-, -O-(C3-6 cycloalkylene)-O-, or -C(O)NH(CH2)3OCH2-; L4his a bond, -C(O)-, -CH2C(O)-, or - C(O)CH2-; and m is 1, 2, or 3;bond to L3iandrepresents a covalent bond to NH; L2iis a bond, C1-12linear alkylene, or, wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to HN; and L3iis a bond or -C(O)-; 12 3 4wherein Z is C, CH, or N; each of Z , Z , Z and Z5is independently CH or N, provided that no more than two of Z2, Z3, Z4and Z5are N; L1jis -NH-, -C(O)NH-, -NHC(O)-, or -O-; L2jis C1-6 linear alkylene orrepresents a covalent bond to L1j; and represents a single bond or a double bond;wherein Ring A is phenylene or a 5- or 6-membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z1and Z2is independently CH or N; L1kis a bond, -C(O)-, -C(O)NH-, or -NHC(O)-; and L2kis a C3-8 straight chain alkylene or, wherein n is 1, 2, or 3, andrepresents a covalent bond to L1k; **(xiii)) wherein Z1is CH or N; m is 1 or 2; p is 1 or 2; 0, 1, or 2 hydrogen atomsare replaced with F; L1mis a bond, - C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH-, or -NHS(O)2-; and L2mis C3-6linear alkylene, C3-6cycloalkylene, or, wherein n is 1 or 2, andrepresents a covalent bond to L1m;C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)2NH-, or -NHS(O)2-; and L2pis –(4-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-C(O))-; or (xvi)wherein Ring A, Ring B, Ring C, and Ring D are each independently C4-6 cycloalkylene; L1qand L3qare each independently C3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3alkyl; and L2qand L3qare each independently -O-, -NHC(O)-, or -CH2-O-; and wherein eachrepresents a covalent bond to X1, and eachrepresents a covalent bond to X2.

2. The compound of claim 1, wherein the compound is a compound of Formula I.

3. The compound of claim 1 or 2, wherein A2 is phenyl, pyrazolyl, pyridinyl, or pyrrolo[2,3-b]pyridinyl; each of which is substituted with 0, 1, or 2 occurrences of R3.

4. The compound of any one of claims 1-3, wherein R5 is hydrogen.

5. The compound of any one of claims 1-3, wherein Y1 issubstituted by one occurrence of R4.

6. The compound of any one of claims 1-3, wherein7. The compound of any one of claims 1-6, wherein A2 is phenyl, pyridin-4-yl, orpyrrolo[2,3-b]pyridin-4-yl; each of which is substituted with 0 or 1 occurrence of R3.

8. The compound of any one of claims 1-6, wherein A2 is phenyl substituted with 0 or 1occurrence of R3.

9. The compound of any one of claims 1-3, wherein10 The compound of any one of claims 1-3, wherein.

11. The compound of any one of claims 1-3, wherein.1 The compound of any one of claims 1-3, wherein Y1 is.

13. The compound of any one of claims 1-12, wherein R3 represents independently for eachoccurrence -N(H)S(O)2-(C1-4alkyl), -N(H)S(O)2-(phenyl), -N(H)C(O)-(C1-4alkyl), or - N(H)-(C1-4 alkyl).

14. The compound of any one of claims 1-12, wherein R3 is -N(H)S(O)2CH3,-N(H)C(O)CH3, or -N(H)CH3.

15. The compound of any one of claims 1-3, wherein Y1 is.

16. The compound of any one of claims 1-15, wherein A1 is quinolinyl or imidazo[1,2-a]pyridinyl, each of which is substituted with 0, 1, or 2 occurrences of R2.

17. The compound of any one of claims 1-15, wherein A1 is quinolin-4-yl or imidazo[1,2-a]pyridin-5-yl, each of which is substituted with 1 or 2 occurrences of R2.

18. The compound of any one of claims 1-17, wherein R2 represents independently for eachoccurrence -CF3, chloro, or fluoro.1 The compound of any one of claims 1-15, wherein20. The compound of any one of claims 1-15, wherein A1 is21. The compound of any one of claims 1-3, wherein Y1 is22. The compound of claim 21, wherein A1 is quinolinyl or imidazo[1,2-a]pyridinyl, each ofwhich is substituted with one occurrence of R4and 0, 1, or 2 occurrences of R2.

23. The compound of any one of claims 1-3, wherein24. The compound of any one of claims 21-23, wherein R2 represents independently for eachoccurrence -CF3, chloro, or fluoro.

25. The compound of any one of claims 21-24, wherein A2 is phenyl, pyridinyl, orpyrrolo[2,3-b]pyridinyl; each of which is substituted with 0, 1, or 2 occurrences of R3.

26. The compound of any one of claims 1-6 or 21-24, wherein A2 isor.

27. The compound of any one of claims 21-26, wherein R3 is -N(H)S(O)2CH3,-N(H)C(O)CH3, or -N(H)CH3.

28. The compound of any one of claims 1-3, wherein Y1 is29. The compound of any one of claims 1-3, wherein Y1 is31. The compound of any one of claims 1-3, wherein Y1 is32 The compound of any one of claims 1-3, wherein Y1 is. The compound of any one of claims 1-3, whereinsubstituted by one occurrence of R4.

34. The compound of any one of claims 1-3, wherein35. The compound of any one of claims 1-3, wherein36. The compound of any one of claims 33-35, wherein A2 is pyrazolyl, pyridinyl, or phenyl;each of which is substituted with 0, 1, or 2 occurrences of R3.

37. The compound of any one of claims 33-35, wherein,38. The compound of any one of claims 1-3, wherein.

40. The compound of any one of claims 1-3, wherein Y1 is.

41. The compound of any one of claims 33-39, wherein R3 represents independently for eachoccurrence C1-4 alkyl, C1-4 alkoxyl, or halo.

42. The compound of any one of claims 33-39, wherein R3 is -CH3, -OCH3, chloro, or fluoro.

43. The compound of any one of claims 33-42, wherein A1 is quinolinyl or imidazo[1,2-a]pyridinyl, each of which is substituted with 0, 1, or 2 occurrences of R2.

44. The compound of any one of claims 33-42, wherein A1 is quinolin-4-yl substituted with 1or 2 occurrences of R2.

45. The compound of any one of claims 33-44, wherein R2 represents independently for eachoccurrence -CF3, chloro, or fluoro.

46. The compound of any one of claims 33-42, wherein47 The compound of any one of claims 1-3, wherein48. The compound of claim 47, wherein A1 is quinolinyl or imidazo[1,2-a]pyridinyl, each ofwhich is substituted with one occurrence of R4and 0, 1, or 2 occurrences of R2.The compound of any one of claims 1-3, wherein50. The compound of any one of claims 47-49, wherein R2 represents independently for eachoccurrence -CF3, chloro, or fluoro.

51. The compound of any one of claims 47-50, wherein A2 is pyrazolyl, pyridinyl, or phenyl;each of which is substituted with 0, 1, or 2 occurrences of R3.

52. The compound of any one of claims 47-50, wherein53. The compound of any one of claims 47-52, wherein R3 is -CH3, -OCH3, chloro, or fluoro.

54. The compound of any one of claims 1-3, wherein Y1 is55. The compound of any one of claims 1-3, wherein Y1 is56. The compound of any one of claims 1-3, wherein Y1 is57.1.58.Th f f l i 1 h i Y1 i59. The compound of any one of claims 1-58, wherein X1 is -(C0-4 alkylene)-N(H)-, whereinthe nitrogen atom of X1is attached to L.

60. The compound of any one of claims 1-58, wherein X1 is -(CH2)2-N(H)-, wherein thenitrogen atom of X1is attached to L.

61. The compound of any one of claims 1-58, wherein X1 is -(CH2)-N(H)-, wherein thenitrogen atom of X1is attached to L.

62. The compound of any one of claims 1-58, wherein X1 is -N(H)-.

63. The compound of any one of claims 1-58, wherein X1 is -O-(C2-4 alkylene)-N(H)-,wherein the nitrogen atom of X1is attached to L.

64. The compound of any one of claims 1-58, wherein X1 is -(C2-3 alkylene)-O-(C2-3alkylene)-N(H)-, wherein the nitrogen atom of X1is attached to L.

65. The compound of any one of claims 1-58, wherein X1 is, wherein thenitrogen atom of X1is attached to L.

66. The compound of any one of claims 1-3, wherein Y1-X1- is one of the following:

67. The compound of any one of claims 1-3, wherein Y1-X1- is one of the following:

68. The compound of any one of claims 1-3, wherein Y1-X1- is one of the following:

69. The compound of any one of claims 1-3, wherein Y1-X1- is one of the following:

70. The compound of any one of claims 1-3, wherein Y1-X1- is one of the following:

71. The compound of any one of claims 1-3, wherein Y1-X1- is one of the following:

72. The compound of any one of claims 1-3, wherein Y1-X1- is one of the following:

73. The compound of any one of claims 1-3, wherein Y1-X1- is one of the following:.

74. The compound of any one of claims 1-3, wherein Y1-X1- is one of the following:.

75. The compound of any one of claims 1-3, wherein Y1-X1- is one of the following:.

76. The compound of any one of claims 1-75, wherein R1 is -CH3.

77. The compound of any one of claims 1-76, wherein X2 is ɸ-(C1-5 alkylene)-N(H)-.

78. The compound of any one of claims 1-76, wherein X2 is ɸ-CH2CH2-N(H)-.

79. The compound of any one of claims 1-76, wherein X2 is ɸ-C(H)(CH3)-N(H)-.

80. The compound of any one of claims 1-76, wherein X2 is a covalent bond.

81. The compound of any one of claims 1-80, wherein L is a divalent linker of Formula (L-a-i):are as defined for Formula (L-a).

82. The compound of any one of claims 1-80, wherein L is a divalent linker of Formula (L-a-ii):are as defined for Formula (L-a); p is 1 or 2; and m is 1 or 2.

83. The compound of any one of claims 1-80, wherein L is a divalent linker of Formula (L-a-iii):

84. The compound of any one of claims 1-80, wherein L is selected from the groupconsisting of:indicated on the cycloalkyl-bound carbonyl group is the attachment point to X1.

85. The compound of any one of claims 1-80, wherein L is a divalent linker of Formula (L-b-are as defined for Formula (L-b); p is 1 or 2; and m is 1 or 2.

86. The compound of any one of claims 1-80, wherein L is selected from the groupconsisting of:,; wherein the point of attachment indicated on the cycloalkyl-bound carbonyl group is the attachment point to X1.

87. The compound of any one of claims 1-80, wherein L is a divalent linker of Formula (L-are as defined for Formula (L-c); p is 1 or 2; and m is 1 or 2.

88. The compound of any one of claims 1-80, wherein L is selected from the groupconsisting of:indicated on the carbonyl group is the attachment point to X1.

89. The compound of any one of claims 1-80, wherein L is selected from the groupconsisting of:wherein the point of attachment indicated on the carbon-bound carbonyl group is the attachment point to X1.

90. The compound of any one of claims 1-80, wherein L is selected from the groupconsisting of:1 point of attachment indicated on the carbonyl group is the attachment point to X.

91. The compound of any one of claims 1-80, wherein L is a divalent linker of Formula (L-g-i):wherein are as defined for Formula (L-g);1 2 3Z, Z, and Z are each independently selected from N or CH, 12 3provided that one or two of Z, Z, and Z is N.

92. The compound of any one of claims 1-80, wherein L is selected from the groupconsisting of:; wherein the point of attachment indicated on the carbonyl group is the attachment point to X1.

93. The compound of any one of claims 1-80, wherein L is selected from the groupconsisting of:bond to X1, andrepresents a covalent bond to X2.

94. The compound of any one of claims 1-80, wherein L is selected from the groupconsisting of:indicated on the carbonyl group is the attachment point to X1.

95. The compound of any one of claims 1-80, wherein L is selected from the groupconsisting of:; wherein the point of attachment indicated on the carbonyl group is the attachment point to X1.

96. The compound of any one of claims 1-80, wherein L is selected from the groupconsisting of:; wherein the point of attachment indicated on the carbonyl group is the attachment point to X1.

97. The compound of any one of claims 1-80, wherein L is-C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)2NH-, or -NHS(O)2-; and L2pis –(4-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-C(O))-; wherein represents a covalent bond to X1, and represents a covalent bond to X2.

98. The compound of any one of claims 1-80, wherein L is99. The compound of any one of claims 1-80, wherein L is one of the following:

100. The compound of any one of claims 1-80, wherein L isrepresents a covalent bond torepresents a covalent bond to X2.

101. The compound of any one of claims 1-80, wherein L is:(i) a bivalent, saturated or unsaturated, straight or branched C1-60 hydrocarbon chain, wherein 0-20 methylene units of the hydrocarbon are independently replaced with -O-, - S-, -N(H)-, -N(C1-6alkyl)-, -OC(O)-, -C(O)O-, -S(O)-, -S(O)2-, -N(H)S(O)2-, -N(C1-6alkyl)S(O)2-, -S(O)2N(H)-, -S(O)2N(C1-6 alkyl)-, -N(H)C(O)-, -N(C1-6 alkyl)C(O)-, - C(O)N(H)-, -C(O)N(C1-6 alkyl)-, -OC(O)N(H)-, -OC(O)N(C1-6 alkyl)-, -N(H)C(O)O- , -N(C1-6alkyl)C(O)O-, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;wherein Ring A and Ring B are each independently C4-6cycloalkylene; L1ais C3-5linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NRa-; each Rais independently hydrogen or C1-3alkyl; and L2ais -O-, -NHC(O)-, or -CH2-O-; (iii)) wherein Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene; L1bis -CH2-NH-C(O)-, -NHC(O)-, or -C(O)NH-; L2bis C6-12 linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with -O-, -NR1b-, -wherein n is 1, 2, 3, or 4, andrepresents a covalent bond to L1b; and each R1bis independently hydrogen or C1-3 alkyl; (iv)(L-c) wherein L1cis C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; Ring A is C4-6cycloalkylene or C7-9 bridged bicyclic cycloalkylene; and L2cis -O- or a saturated C2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-; (v)(L-d) wherein L1dis C12-22linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-; (vii) (L-f) wherein L is a bond; C1-6linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-, -NH-, or -C(O)-; or -(C3-6 cycloalkylene)-NHC(O)-; L2fis a bond, -NHC(O)-, -C(O)NH-, or a C1-6 linear alkylene, wherein 0, 1, or 2 methylene units are replaced with -O-; and each of Z1and Z2is independently N or CH; (viii)(L-g) wherein Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; L1gis a bond, -CH2-, -NH-, or -O-; and L2giswherein n is 1, 2, 3, 4, or 5, andrepresents a covalent bond to L1g;, , , , ,1hrepresents a covalent bond to L3h; L3his a bond, -C(O)CH2-, -O-(C3-6 cycloalkylene)-O-, or -C(O)NH(CH2)3OCH2-; L4his a bond, -C(O)-, -CH2C(O)-, or - C(O)CH2-; and m is 1, 2, or 3;bond to L3iandrepresents a covalent bond to NH; L2iis a bond, C1-12linear alkylene, or, wherein n is 1, 2, 3, 4, or 5, and represents a covalent bond to HN; and L3iis a bond or -C(O)-; 12 3 4wherein Z is C, CH, or N; each of Z , Z , Z and Z5is independently CH or N, provided that no more than two of Z2, Z3, Z4and Z5are N; L1jis -NH-, -C(O)NH-, -NHC(O)-, or -O-; L2jis C1-6 linear alkylene orrepresents a covalent bond to L1j; and represents a single bond or a double bond;wherein Ring A is phenylene or a 5- or 6-membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z1and Z2is independently CH or N; L1kis a bond, -C(O)-, -C(O)NH-, or -NHC(O)-; and L2kis a C3-8 straight chain alkylene or, wherein n is 1, 2, or 3, andrepresents a covalent bond to L1k; **(xiii)) wherein Z1is CH or N; m is 1 or 2; p is 1 or 2; 0, 1, or 2 hydrogen atomsare replaced with F; L1mis a bond, - C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2NH-, or -NHS(O)2-; and L2mis C3-6linear alkylene, C3-6cycloalkylene, or, wherein n is 1 or 2, andrepresents a covalent bond to L1m;C(O)-, -C(O)NH-, -NHC(O)-, -S(O)2-, -S(O)2NH-, or -NHS(O)2-; and L2pis –(4-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-C(O))-; and wherein eachrepresents a covalent bond to X1, and eachrepresents a covalent bond to X2.

102. The compound of any one of claims 1-80, wherein L iswherein Ring A, Ring B, Ring C, and Ring D are each independently C4-6 cycloalkylene; L1qand L3qare each independently C3-5linear alkylene, wherein 1 or 2 methylene units are replaced with-O- or -NRa-; each Rais independently hydrogen or C1-3alkyl; and L2qand L3qare each independently -O-, -NHC(O)-, or -CH2-O-.

103. The compound of any one of claims 1-80, wherein L is one of the following:wherein represents a covalent bond to X1andrepresents a covalent bond to X2.

104. The compound of any one of claims 1-75, whereinfollowing:

105. A compound in Table 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt.

106. A pharmaceutical composition, comprising a compound of any one of claims 1-105 and apharmaceutically acceptable carrier.

107. A method of treating or preventing a MRGX2-associated disease or condition in a patientin need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-105 and an anti-cotinine antibody, or antigen-binding fragment thereof.

108. The method of claim 107, wherein the MRGX2-associated disease or condition is a mastcell disease, pain, cough, acute itch, or chronic itch.

109. A method of treating or preventing a mast cell disease in a patient in need thereof,comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-105 and an anti-cotinine antibody, or antigen-binding fragment thereof.

110. The method of claim 109, wherein the mast cell disease is an inflammatory diseaseassociated with mast cell activity.

111. A method of treating or preventing a disease selected from the group consisting ofurticaria, prurigo nodularis, atopic dermatitis, psoriasis, allergic rhinitis, asthma, systemic mastocytosis, mast cell activation syndrome, inflammatory bowel disease, anaphylaxis, food allergy, and insect sting in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-105 and an anti-cotinine antibody, or antigen-binding fragment thereof.

112. The method of claim 111, wherein the method is to treating the disease.

113. The method of claim 111 or 112, wherein the disease is urticaria, prurigo nodularis,atopic dermatitis, psoriasis, allergic rhinitis, asthma, systemic mastocytosis, mast cell activation syndrome, inflammatory bowel disease, or anaphylaxis.

114. The method of claim 111 or 112, wherein the disease is urticaria, prurigo nodularis,atopic dermatitis, psoriasis, allergic rhinitis, asthma, systemic mastocytosis, mast cell activation syndrome, or inflammatory bowel disease.

115. The method of claim 111 or 112, wherein the disease is urticaria.

116. The method of claim 111 or 112, wherein the disease is chronic urticaria.

117. The method of claim 111 or 112, wherein the disease is prurigo nodularis.

118. The method of claim 111 or 112, wherein the disease is atopic dermatitis.

119. The method of claim 111 or 112, wherein the disease is type 2 asthma.

120. A method of treating or preventing pain in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of a compound of any one of claims 1-105 and an anti-cotinine antibody, or antigen-binding fragment thereof.

121. The method of claim 120, wherein the method is to treating pain.

122. The method of claim 120 or 121, wherein the pain is chronic pain.

123. The method of claim 120 or 121, wherein the pain is acute pain.

124. The method of any one of claims 120-123, wherein the pain is neuropathic pain.

125. The method of any one of claims 120-123, wherein the pain is inflammatory pain.

126. The method of any one of claims 107-125, wherein the compound and the antibody, orantigen-binding fragment thereof, are administered simultaneously.

127. The method of any one of claims 107-125, wherein the compound and the antibody, orantigen-binding fragment thereof, are administered sequentially.

128. A method of increasing antibody-dependent cell cytotoxicity (ADCC) of MRGX2-expressing cells, comprising contacting the cells with an effective amount of the compound of any one of claims 1-105 and an anti-cotinine antibody, or antigen-binding fragment thereof.

129. A method of depleting MRGX2-expressing cells, comprising contacting the cells with aneffective amount of the compound of any one of claims 1-105 and an anti-cotinine antibody, or antigen-binding fragment thereof.

130. The method of claim 128 or 129, wherein the MRGX2-expressing cells are mast cells.

131. The method of any one of claims 107-130, wherein the anti-cotinine antibody has a heavychain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, aCDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6.

132. The method of any one of claims 107-130, wherein the anti-cotinine antibody has a heavychain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8.

133. The method of any one of claims 107-132, wherein the anti-cotinine antibody is of IgG1isotype comprising a substitution in an Fc region to increase ADCC activity.

134. The method of claim 130, wherein the substitution in the Fc region is S239D / I332E,wherein residue numbering is according to the EU Index.

135. The method of any one of claims 107-130, wherein the anti-cotinine antibody has a heavychain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.

136. A combination comprising the compound of any one of claims 1-105 and an anti-cotinineantibody, or antigen-binding fragment thereof.

137. The combination of claim 136, wherein the anti-cotinine antibody has a heavy chain anda light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6.

138. The combination of claim 136, wherein the anti-cotinine antibody has a heavy chain anda light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8.

139. The combination of any one of claims 136-138, wherein the anti-cotinine antibody is ofIgG1 isotype comprising a substitution in an Fc region to increase ADCC activity.

140. The combination of claim 139, wherein the substitution in the Fc region is S239D / I332E,wherein residue numbering is according to the EU Index.

141. The combination of claim 136, wherein the anti-cotinine antibody has a heavy chaincomprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.

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