Conjugates targeting fibroblast activation protein and uses thereof

Abstract

Compounds and conjugates which modulate the Fibroblast Activation Protein (FAP) for the active delivery of various payloads (e.g., cytotoxic drugs, proteins, immunomodulators, radioactive components, metal chelating groups / chelating agents, fluorescent dyes, or contrast agents) are described. Such compositions may find use in therapy for treatment of diseases or disorders, such as cancer, inflammation or another disease characterized by overexpression of FAP.

Description

CONJUGATES TARGETING FIBROBLAST ACTIVATION PROTEIN AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority benefit of U.S. Provisional Patent Application No. 63 / 599,982, filed November 16, 2023, which is incorporated by reference herein in its entirety.FIELD OF THE INVENTION

[0002] The present invention generally relates to compounds which modulate the Fibroblast Activation Protein (FAP) for the active delivery of various payloads (e.g., cytotoxic drugs, proteins, immunomodulators, radioactive components, metal chelating groups / chelating agents, fluorescent dyes or contrast agents) at the site of action. The present invention relates to the development of FAP ligands for targeting applications, in particular diagnostic methods and / or methods for therapy or surgery in relation to a disease or disorder, such as cancer, inflammation or another disease characterized by overexpression of FAP.BACKGROUND OF THE INVENTION

[0003] Fibroblast activation protein (FAP) is highly overexpressed in stromal tissue of various cancers. Fibro-proliferative response in tumors such as breast, colon, and pancreatic cancer, the tumor stroma (TS) forms > 90% of the tumor mass. The TS consists of a large number of fibroblasts, particularly cancer-associated fibroblasts (CAFs). The CAFs contributes to tumor growth, migration, and progression, thus, its valuable for tumor diagnosis and also as a therapeutic target. The expression of fibroblast-activating protein alpha (FAP) is a unique feature of CAFs. FAP is a 97-kDa type II membrane-bound glycoprotein from the dipeptidyl peptidase IV (DPPIV4) family and shows dipeptidyl peptidase and endopeptidase activity. The endopeptidase activity of FAP distinguishes it from other members of the DPPIV family. Substrates of FAP endopeptidase activity are type I collagen, al -antitrypsin, and several neuropeptides. FAP is reported to play an essential role in embryonic development, and tissue remodeling. FAP expression is low in normal adult tissues but its high expression is reported in wound healing, arthritis, atherosclerotic plaques, fibrosis, and > 90% of epithelial cancers. In the CAFs of many epithelial tumors, FAP is highly expressed and is associated with poorer cancer prognosis. Overall, FAP activity is associated with cancer development and progression.

[0004] While FAP has been recognized as a potential diagnostic or therapeutic cancer target, FAP targeted delivery of a payload including one or more drugs and / or agents after systemic administration is desired. A therapeutic / diagnostic payload like proteins, immunomodulators, radioactive components, metal chelating groups or chelating agents, fluorescent dyes or contrast agents, can be conjugated to a FAP ligand. FAP-targeting antibodies have been utilized as ligands for developing antibody-drug conjugates (ADCs). OMTX705 is a novel antibody-drug conjugate (ADC) molecule targeting fibroblast-activating protein a (FAPa). It has reached clinical stages and demonstrates activities in chemotherapy and Pembrolizumab-Resistant solid tumor models (Clin Cancer Res (2020) 26 (13): 3420-3430).

[0005] However, small molecule ligands have several advantages compared to bigger molecules, peptides and antibodies, as it offers rapid and efficient tumor penetration, lower immunogenicity, and lower manufacturing costs. Small molecule-drug conjugates (SMDCs) have been reported as effective approaches for targeted anticancer therapy. Therefore, there remains a need for conjugates comprising improved small-molecule binders (ligands) of fibroblast activation protein (FAP).SUMMARY OF THE INVENTION

[0006] The present invention provides a chemical conjugate comprising a fibroblast activation protein (FAP) moiety and a payload for therapeutic and / or diagnostic applications.

[0007] In one aspect, the present invention provides a compound of formula (I):formula (I), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X, Q, A, L, D, m, n, R1and R2are as defined for formula (I).

[0008] In one aspect, the compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, is any of compounds of formula (II) to formula (VI), and theirsub-formulas, a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, as detailed herein.

[0009] In some another aspect, the present invention provides method of treating a disease or disorder associated with FAP (e.g., FAP-alpha), in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention. In some embodiments, the disease is a cancer.

[0010] In some another aspect, the present invention provides method of imaging, diagnosis or detecting a proliferative disease associated with this FAP (e.g., FAP-alpha) in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention. In some embodiments, the disease is a cancer.

[0011] In some another aspect, the present invention provides method of inhibiting FAP (e.g., FAP-alpha) in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of a compound of the present invention.

[0012] In some another aspect, the present invention provides a pharmaceutical composition, for use in a method for targeted delivery of a therapeutic and / or diagnostic agent in an individual suffering from or having risk for a disease or disorder; as well as a method for targeted delivery of a therapeutically and / or diagnostically effective amount of a compound of the present invention by administering the pharmaceutically acceptable composition in an individual suffering from or having risk for a disease or disorder.

[0013] In some embodiments, the methods described herein further comprise co-administering to an individual in need thereof another therapeutic and / or diagnostic agent.

[0014] In some another aspect, the present invention provides compounds, their method of use in imaging, diagnosis or detecting and treating cancer associated with FAP, it also provides processes for preparing compounds and intermediates thereof disclosed in the present invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1A shows fluorescence over time for PRXS-AMC in the presence of rhFAPa.

[0016] FIG. IB shows fluorescence over time for Z-gly-pro-AMC in the presence of rhFAPa.

[0017] FIG. 2 A shows fluorescence over time for PRXS-AMC in the presence of rhPREP.

[0018] FIG. 2B shows fluorescence over time for Z-gly-pro-AMC in the presence of rhPREP.

[0019] FIG. 3A shows fluorescence over time for PRXS-AMC in the presence of rhDPPIV.

[0020] FIG. 3B shows fluorescence over time for Z-gly-pro-AMC in the presence of rhDPPIV.

[0021] FIG. 4A shows percentages of hFAP+cells in WT HEK293 cells.

[0022] FIG. 4B shows percentages of hFAP+cells in selected HEK293-hFAP cells

[0023] FIG. 4C shows percentages of hFAP+cells in WT HT-1080 cells.

[0024] FIG. 4D shows percentages of hFAP+cells in selected HT-1080-hFAP cells.

[0025] FIG. 5 shows the total expressions of FAPά in WT HEK293, HEK293-hFAP, WT HT- 1080 and HT-1080-hFAP cells, determined by Western Blot.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0026] “Alkyl” refers to and includes saturated linear and branched univalent hydrocarbon structures and combination thereof, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a “Ci- C20 alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “C1-C8alkyl”), 3 to 8 carbon atoms (a “C3-C8alkyl”), 1 to 6 carbon atoms (a “C1-C6alkyl”), 1 to 5 carbon atoms (a “C1-C5 alkyl”), or 1 to 4 carbon atoms (a “C1-C4 alkyl”). Examples of alkyl include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0027] “Alkenyl” as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). The alkenyl group may be in “cis” or “trans” configurations, or alternatively in “E” or “Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenyl”), having 2 to 8 carbon atoms (a “C2-C8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkenyl”). Examples of alkenyl include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl,prop-2-enyl (or allyl), 2-methylprop- 1 -enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta- 1,3 -dienyl, 2- methylbuta- 1,3 -dienyl, homologs and isomers thereof, and the like.

[0028] “Alkylene” as used herein refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 6 carbon atoms (a “C1-C6alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C1-C3alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), and the like.

[0029] “Alkynyl” as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynyl”), having 2 to 8 carbon atoms (a “C2-C8 alkynyl”), having 2 to 6 carbon atoms (a “C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkynyl”). Examples of alkynyl include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.

[0030] “Aryl” refers to and includes polyunsaturated aromatic hydrocarbon groups. Aryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and / or heterocyclyl rings. In one variation, the aryl group contains from 6 to 14 annular carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, and the like.

[0031] “Carbonyl” refers to the group C=O.

[0032] “Cycloalkyl” refers to and includes cyclic univalent hydrocarbon structures, which may be fully saturated, mono- or polyunsaturated, but which are non-aromatic, having the number of carbon atoms designated (e.g., C1-C10 means one to ten carbons). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantly, but excludes aryl groups. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 13 annular carbon atoms. A more preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.

[0033] “Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include fluoro, chloro, bromo and iodo. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halo; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoroalkyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0034] “Heteroaryl” refers to and includes unsaturated aromatic cyclic groups having from 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule at an annular carbon or at an annular heteroatom. Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and / or heterocyclyl rings. Examples of heteroaryl groups include, but are not limited to imidazolyl, pyrrolyl, pyrazolyl, 1,2,4-triazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl or pyrazinyl, and the like.

[0035] “Heterocycle” or “heterocyclyl” refers to a saturated or an unsaturated non-aromatic group having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heterocyclyl group may have a single ring or multiple condensed rings, but excludes heteroaryl groups. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be aryl or heteroaryl. Examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl,azepanyl tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydro thiophenyl, and the like.

[0036] “Oxo” refers to the moiety =0.

[0037] The compounds of the present disclosure may include one or more asymmetric centers depending upon the location and nature of the various desired substituents. An asymmetric carbon atom may be present in the (R) or (S) configuration, a racemic mixture is obtained with an asymmetric center, and a diastereomer mixture is obtained with a plurality of asymmetric centers. In some cases, there may also be asymmetry due to rotation around a particular bond, such as two substituted aromatic rings connecting a particular compound with the center key.

[0038] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5 substituents.

[0039] A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0040] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For example, beneficial or desired results include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and / or prolonging survival of individuals. In reference to cancers or other unwanted cell proliferation, beneficial or desired results include shrinking a tumor (reducing tumor size); decreasing the growth rate of the tumor (such as to suppress tumor growth); reducing the number of cancer cells; inhibiting, retarding or slowing to some extent and preferably stopping cancer cell infiltration into peripheral organs; inhibiting (slowing to some extent and preferably stopping) tumor metastasis; inhibitingtumor growth; preventing or delaying occurrence and / or recurrence of tumor; and / or relieving to some extent one or more of the symptoms associated with the cancer.

[0041] As used herein, “delaying development of a disease” means to defer, hinder, slow, retard, stabilize, and / or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.

[0042] As used herein, an “effective dosage” or “effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to effect beneficial or desired results. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity of, or delaying the onset of the disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include ameliorating, palliating, lessening, delaying or decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and / or prolonging survival. In reference to cancers or other unwanted cell proliferation, an effective amount comprises an amount sufficient to cause a tumor to shrink and / or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation. In some embodiments, an effective amount is an amount sufficient to delay development. In some embodiments, an effective amount is an amount sufficient to prevent or delay occurrence and / or recurrence. An effective amount can be administered in one or more administrations, in the case of cancer, the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and / or recurrence of tumor; and / or (vii) relieve to some extent one or more of the symptoms associated with the cancer. An effective dosage can be administered in one or more administrations. For purposes of this disclosure, an effective dosage of compound or a salt thereof,or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. It is intended and understood that an effective dosage of a compound or salt thereof, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

[0043] As used herein, the term “individual” is a mammal, including humans. An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the individual is human. The individual (such as a human) may have advanced disease or lesser extent of disease, such as low tumor burden. In some embodiments, the individual is at an early stage of a proliferative disease (such as cancer). In some embodiments, the individual is at an advanced stage of a proliferative disease (such as an advanced cancer).

[0044] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0045] “FAP” refers to fibroblast-activated protein.

[0046] As used herein, “linker” refers to a divalent, trivalent, or multivalent moiety that covalently links one or more FAP ligands described herein to one or more payload, for instance, payload or antiviral compounds and enhancement agents. Generally, suitable linkers for the conjugates described herein are those that are sufficiently stable to exploit the circulating half-life of a conjugate and, at the same time, capable of releasing its payload after delivering the conjugate to a targeted site. Linkers can be cleavable or non-cleavable. Cleavable linkers are linkers that are cleaved by intracellular metabolism following internalization, e.g., cleavage via hydrolysis, reduction, or enzymatic reaction. Non-cleavable linkers are linkers that release an attached payload via lysosomal degradation of the antibody following internalization. Suitable linkers include, but are not limited to, acid-labile linkers, hydrolytically-labile linkers, enzymatically cleavable linkers, reduction labile linkers, self-immolative linkers, and non-cleavable linkers. In some embodiments, linkers are or comprise peptides, glucuronides, succinimide-thioethers, polyethylene glycol (PEG)units, hydrazones, mal-caproyl units, dipeptide units, valine-citruline units, and para- aminobenzyloxycarbonyl (PABC), para-aminobenzyl (PAB) units.

[0047] A “payload” can be generally any molecule or particle. Various payloads (e.g. cytotoxic drugs, proteins, immunomodulators, radioactive components, metal chelating groups / chelating agents, fluorescent dyes or contrast agents) can be delivered at the site of disease in particular diagnostic methods and / or methods for therapy or surgery in relation to a disease or disorder, such as cancer, inflammation or another disease.

[0048] The “radionuclide” is the radioactive forms of elements which have the ability to chelate with the chelator unit of the chelating agents (eg.68Ga chelates with a chelator unit derived from DOTA). The different radionuclides are18F,51Cr,67Ga,68Ga,1 HIn, "mTc,186Re,188Re,139La,140La,175Yb,153Sm,166Ho,86Y,88Y,90Y,149Pm,165Dy,169Er,177Lu,47Sc,142Pr,159Gd,212Bi,213Bi,72As,72Se,97RU,109Pd,105Rh,101mRh,119Sb,128Ba,123I,124I,131I,197Hg,211At,151Eu,153Eu,169Eu,2O1T1,203Pb ,212Pb,64Cu,67Cu,188Re,186Re,198Au,225Ac,227Th,161Tb and199Ag. For example, the radionuclide is68Ga.

[0049] The “metal chelating groups (chelator units)” mentioned with respect to a compound of general formula (I) refers to a molecular fragment derived from a chelating agent. For example, the chelating agent unit is a molecular segment derived from 1,4,7,10-tetraazacyclododecane- 1,4,7, 10-tetraacetic acid (DOTA), which may be formed amide bond through one of the carboxyl groups of DOTA. Amide formationintroduced into the compound of general formula (I) with a help of linker (L). Other chelating agents are but not limited to ethylenediaminetetraacetic acid (EDTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), triethylenetetramine (TETA), iminodiacetic acid, diethylenetriamine-N,N,N',N',N"-pentaacetic acid (DTPA), bis-(carboxymethylimidazole)glycine or 6-hydrazinopyridine-3-carboxylic acid (HYNIC).

[0050] It is understood that aspects and variations described herein also include “consisting” and / or “consisting essentially of’ aspects and variations.Compounds

[0051] The present invention discloses small molecule binders of fibroblast activation protein (FAP) which are suitable for targeting applications. The binders can provide high inhibition of FAP, high affinity for FAP and / or are suitable for targeted delivery of a payload, such as a therapeutic or diagnostic agent, to a site afflicted by or at risk of disease or disorder characterized by overexpression of FAP. The binders form a stable complex with FAP, display an increased affinity, increased inhibitory activity, a slower rate of dissociation from the complex, and / or prolonged residence at a disease site. The binders further can have an increased tumor-to- liver, tumor-to-kidney and / or tumor-to-intestine uptake ratio; a more potent anti-tumor effect (e.g., can be measured by mean tumor volume increase), and / or lower toxicity (e.g., can be assessed by the evaluation of changes (%) in body weight).

[0052] In some embodiments, binders can exhibit a very high, specific uptake in FAP- expressing tumors in combination with low uptake in normal organs. That is, the binders can provide advantageous therapeutic index in terms of tumor to non -tumor ratio when it is administered in vivo.

[0053] The binders further can have a high or improved affinity for human and murine fibroblast activation protein and / or cross-reactivity to the murine antigen. The binders according to the invention preferably attain FAP-specific cellular binding; FAP-selective accumulation on the cell membrane; FAP-selective accumulation inside the cytosol. In some embodiments, the binders can further rapidly and homogeneously localize at the tumor site in vivo with a high tumor- to- organs selectivity, in particular for melanoma and / or renal cell carcinoma.

[0054] The present invention provides a compound comprising a FAP binder described herein and a payload. In some embodiments, provided is a compound of formula (I):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein,Q is a bondX is N or CR2;A is -0-;D is, independently at each occurrence, a payload;L is, independently at each occurrence, a linker;R1and R2are independently hydrogen, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6alkoxy, C1-C6haloalkoxy, Ci- C6haloalkyl, -OR3, -SR3, -S(O)2R3, -S(O)2NR4R5, -NR3S(O)2R4, -NR4R5,-C(O)R3, -NR3C(O)R4, -NR3C(O)NR4R5, -C(O)OR3, -C(O)ONR4R5or-C(O)NR4R5, wherein each of R1and R2is independently optionally substituted by R10; each R3, R4and R5is independently hydrogen, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6alkoxy, Ci- C6haloalkoxy, C1-C6haloalkyl, -OR7, -SR7, -S(O)2R7, -S(O)2NR8R9, -NR7S(O)2R8, -NR8R9, -C(O)R7, -NR7C(O)R8, -NR7C(O)NR8R9, -C(O)OR7, -C(O)ONR8R9or -C(O)NR8R9; or R4andR5are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl which is optionally substituted by R10; each R7, R8and R9is independently hydrogen or C1-C6alkyl optionally substituted by oxo, -OH or -NH2; or R8and R9are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl which is optionally substituted by oxo, -OH or -NH2;R10is oxo, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6- membered heterocyclyl, -CN, halogen, C1-C6alkoxy, C1-C6haloalkoxy, Ci- C6haloalkyl, -OR14, -SR14, -S(O)2R14, -S(O)2NR15R16, -NR14S(O)2R15, -NR15R16, -C(O)R14, -NR14C(O)R15, -NR14C(O)NR15R16, -C(O)OR14, -C(O)ONR15R16or-C(O)NR15R16; each R14, R15and R16is independently hydrogen or C1-C6alkyl optionally substituted by oxo, -OH or -NH2;or R15and R16are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl which is optionally substituted by oxo, -OH or -NH2; m is 0 or 1 ; and n is 0 or 1 ; provided that m + n is an integer greater than 0.

[0055] In some embodiments, D is a payload comprising one or more drugs or agents. As would be appreciated by a person skilled in the art, many known drugs / agents can be used alone or together as a payload in accordance with the present invention.

[0056] In some embodiments, D comprises or is one or more therapeutic drugs / agents, such as cytotoxic drugs. In some embodiments, D is selected from the group consisting of but not limited to vinblastine, tubulysin, paclitaxel, mitomycin C and any combination thereof (Small molecule drug conjugates (SMDCs): an emerging strategy for anticancer drug design and discovery, New J. Chem., 2021, 45, 5291-5321). In some embodiments, D is selected from the group consisting of but not limited to tubulin inhibitors (e.g., auristatins, maytansinoids, and tubulysins), DNA damaging agents (e.g., Calicheamicins, Duocarmycins, Exatecans, and Pyrrolobenzodiazepines), immunomodulators (e.g., TLR agonists, STING agonists and inflammasome agonist), and any combination thereof (Antibody drug conjugate: the “biological missile” for targeted cancer therapy, Sig Transduct Target Ther 7, 93 (2022)). In some embodiments, D comprise or is anti- fibrotic agent. In some embodiments, D comprises or is Val-boroPro. In some embodiments, D comprises or is a cytolysin, e.g., TAM470.

[0057] In some embodiments, D comprises or is one or more chemotherapy agents. Examples of chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others), and hypomethylating agents (e.g., decitabine (5-aza- deoxycytidine), zebularine, isothiocyanates, azacitidine (5-azacytidine), 5-flouro-2'- deoxycytidine, 5,6-dihydro-5-azacytidine and others). Exemplary agents include Aclarubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene,bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide, Floxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine, Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine, Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinfhmine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein.

[0058] In some embodiments, the one or more drugs or agents of D are selected from the group consisting of, but not limited to, tyrosine kinase inhibitors, PI3K / mT0R inhibitors, PARP inhibitors such as Olaparib, Rucaparib, Niraparib, Talazoparib, Weel inhibitors, CDK4 / 6 inhibitors such as Palbociclib, Ribociclib, Abemaciclib, DNA-PK inhibitors, ATM inhibitors, ATR inhibitors, and any combination thereof.

[0059] In some embodiments, D comprises or is a radioactive component, a metal chelating group, a chelating agent, a fluorescent dye, a contrast agent or any combination thereof. In some embodiment, D comprises or is a radionuclide. In some embodiments, D is a silicon-fluoride acceptor (SIFA), alone or in combination with a chelating agent. An example can be found in WO2023283627, the disclosure of which is incorporated herein by reference.

[0060] In some embodiments, D comprises or islines denote attachment points to L; or a salt thereof.

[0061] In some embodiments of a compound of formula (I), Q is a bond. In some embodiments of a compound of formula (I), Q is -CH=CH-. In some embodiments of a compound of formula

[0062] In some embodiments of a compound of formula (I), X is N. In some embodiments of a compound of formula (I), X is CR2. In some embodiments of a compound of formula (I), X is CH. In some embodiments of a compound of formula (I), X is C-OCH3.

[0063] In some embodiments of a compound of formula (I), R1is hydrogen, C1-C6alkyl, C2- C6alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, Ci- C6alkoxy, C1-C6haloalkoxy, C3-C6haloalkyl, -OR3, -SR3, -S(O)2R3, -S(O)2NR4R5, -NR3S(O)2R4, -NR4R5, -C(O)R3, -NR3C(O)R4, -NR3C(O)NR4R5, -C(O)OR3, -C(O)ONR4R5or -C(O)NR4R5, wherein each of R1is optionally substituted by R10. In some embodiments of a compound of formula (I), R1is hydrogen.

[0064] In some embodiments of a compound of formula (I), R2is hydrogen, C1-C6alkyl, C2- C6alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, Ci- C6alkoxy, C1-C6haloalkoxy, C1-C6haloalkyl, -OR3, -SR3, -S(O)2R3, -S(O)2NR4R5, -NR3S(O)2R4, -NR4R5, -C(O)R3, -NR3C(O)R4, -NR3C(O)NR4R5, -C(O)OR3, -C(O)ONR4R5or -C(O)NR4R5, wherein each of R2is optionally substituted by R10. In some embodiments of a compound of formula (I), R2is hydrogen.

[0065] In some embodiments of a compound of formula (I), p is 0. In some embodiments of a compound of formula (I), p is 1. In some embodiments of a compound of formula (I), p is 2.

[0066] In some embodiments of a compound of formula (I), m is 1 and n is 0. In some embodiments of a compound of formula (I), m is 0 and n is 1. In some embodiments of a compound of formula (I), m is 1 and n is 1.

[0067] A linker can be cleavable or non-cleavable. Without being bound to any particular theory, a linker between a payload and a FAP ligand in a conjugate can ensure the payload attached to the FAP ligand while the conjugate circulates in plasma. Many linkers that have been used in antibody-drug conjugates can be used in accordance with the present invention. Exemplary linkers can be found in An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy, Molecules. 2021 Sep 27; 26( 19): 5847), the disclosure of which is incorporated herein by reference. In certain embodiments, the linkers are stable in physiological conditions. In some embodiments, a linker is cleavable, for instance, able to release at least the payload portion in the presence of an enzyme or at a particular pH range or value. In some embodiments, a linker comprises an enzyme-cleavable moiety. Illustrative enzyme-cleavable moieties include, but are not limited to, peptide bonds, ester linkages, hydrazones, and disulfide linkages.

[0068] In some embodiments, a linker L of the conjugates described herein is a moiety, for instance a divalent moiety, that covalently links a FAP ligand described herein to a payload. In other embodiments, a linker L is a trivalent or multivalent moiety that covalently links one or more FAP ligands described herein to a payload.

[0069] In some embodiments of a compound of formula (I), L is, independently at each occurrence, is a linker. In some embodiments, the linker comprises or has a structure:, wherein L1and L2are optionally substituted by Z; wherein t is an integer from 1 to 10; denotes attachment to D and - denotes attachment to A;L1is, independently at each occurrence, absent or C3-C6cycloalkyl, C6- aryl, 5- to 6- membered heterocyclyl or 5- to 6-membered heteroaryl, each of which is optionally substituted by R12;L2is, independently at each occurrence, absent or O, S, NR6, C1-C10 alkylene, 2- to 14- membered heteroalkylene, -C(=O)O-, -O(C=O)-, -CONR6-, -NR6CO-, SO2, -SO2NR6-, -NR6SO2-, -S-S-, -(OCH2CH2)V-, -(CH2CH2O)V-, or -C(Rm)=N-, wherein the C1-C10 alkylene and 2- to 14- membered heteroalkylene of each L2, when present, are optionally and independently substituted with Rmand Rn, wherein v is independently an integer from 1 to 3;R6is hydrogen or C1-C6alkyl;Rmand Rnare independently hydrogen, carboxyl, C1-C6alkyl, C3-C6cycloalkyl, C6-C10aryl, 5- to 6-membered heterocyclyl or 5- to 10-membered heteroaryl, -C1-C3-alkylene(C3- C6cycloalkyl), -C1-C3-alkylene(C6-C10aryl), -C1-C3-alkylene(5- to 6-membered heterocyclyl), - C1-C3-alkylene(5- to 10-membered heteroaryl), or -C1-C3-alkylene(NHC(O)NH2) , each of which is optionally substituted by R17; andR12and R17are independently oxo, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6alkoxy, C1-C6haloalkoxy, Ci- C6haloalkyl, -OR14, -SR14, -S(O)2R14, -S(O)2NR15R16, -NR14S(O)2R15, -NR15R16, -C(O)R14, -NR14C(O)R15, -NR14C(O)NR15R16, -C(O)OR14, -C(O)ONR15R16or-C(O)NR15R16; and

[0070] In some embodiments, at least one of L1and L2is substituted by Z, wherein Z comprises

[0071] In some embodiments, L comprises or is 5- to 6-membered heterocyclyl,ring B is C3-C6cycloalkyl, C6-C10aryl, 5- to 6-membered heterocyclyl or 5- to 6- membered heteroaryl, each of which is optionally substituted by Rb; ring C is C3-C6cycloalkyl, C6-C10aryl, 5- to 6-membered heterocyclyl or 5- to 6- membered heteroaryl, each of which is optionally substituted by Rc; andRband Rcare independently oxo, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6alkoxy, C1-C6haloalkoxy, Ci- C6haloalkyl, -OR14, -SR14, -S(O)2R14, -S(O)2NR15R16, -NR14S(O)2R15, -NR15R16, -C(O)R14, -NR14C(O)R15, -NR14C(O)NR15R16, -C(O)OR14, -C(O)ONR15R16or-C(O)NR15R16, and each q is independently an integer from 1 to 3.

[0072] In some embodiments, ring B is ,

[0073] In some embodiments of a compound of formula (I), L comprises or is 5- to 6- membered heterocyclyl. In some embodiments of a compound of formula (I), L comprises or is. In some embodiments of a compound of formula (I), L comprises or isIn some embodiments of a compound of formula (I),HL comprises or isIn some embodiments of a compound of formula (I), L comprises or isIn some embodiments of a compound of formula(I), L comprises or is. In some embodiments of a compound of formula(I), L comprises or is. In some embodiments of a compound of formula (I), L comprises or is. In some embodiments of a compound of formula (I), L comprises or is. In some embodiments of a compound of formula (I), L comprises or isembodiments of a compound of formula (I), L comprises or is some embodiments of a compound of formula (I), L comprises oIn some embodiments of a compound of formula (I), L comprises or is(I), L comprises or is. In some embodiments of a compound of formula (I), L(I), L comprisessome embodiments of a compound of formula (I), L comprisessome embodiments of a compound of formula (I), L comprisessome embodiments of a compound of formula (I), L comprises or is. In some embodiments of a compound of formula (I), L comprises or is. TIn some embodiments of a compound of formula (I), L comprises or issome embodiments of a compound ofcompound of formula (I), L comprises or isIn some embodiments of a compound of formula (I), L comprises or is

[0074] In some embodiments of a compound of formula (I), L comprises or is. p ,L comprises or isIn some embodiments of a compound of formula (I), L comprises or isIn some embodiments of a compound of formula(I), L comprisessome embodiments of a compound of formula (I), L comprisescompound of formula (I), L comprisesof a compound of formula (I), L comprisesembodiments of a compound of formula (I), L comprisessome embodiments of a compound of formula (I), L comprises or is(I), L comprises or isIn some embodiments of a compound of formula (I), LZ 0 comprises orIn some embodiments of a compound of formula (I), Lcomprises or is . In some embodiments of a compound of formula(I), L comprises or is. In some embodiments of a compound of formula (I), L comprises or is.In some embodiments of a compound of formula (I), L comprises or is. In some embodiments of a compound of formula (I), L comprises or is

[0075] In some embodiments, Z is present and represented by. In some embodiments, Z is present and represented. In some embodiments, Z is present and represented by

[0076] In some embodiments of a compound of formula (I), L’ is a linker. In some embodiments, L’ is different from L. In some embodiments, L’s is the same as L.

[0077] In some embodiments of a compound of formula (I), B is C3-C6cycloalkyl optionally substituted by Rb. In some embodiments of a compound of formula (I), B is 5- to 6-membered heterocyclyl optionally substituted by Rb. In some embodiments of a compound of formula (I), B is 5- to 6-membered heteroaryl optionally substituted by Rb.

[0078] In some embodiments of a compound of formula (I), B is piperazinyl optionally substituted by Rb.

[0079] In some embodiments of a compound of formula (I), C is C3-C6cycloalkyl optionally substituted by Rc. In some embodiments of a compound of formula (I), C is 5- to 6-membered heterocyclyl optionally substituted by Rc. In some embodiments of a compound of formula (I), C is 5- to 6-membered heteroaryl optionally substituted by Rc.

[0080] In some embodiments of a compound of formula (I), C is phenyl and piperazinyl, each of C is optionally substituted by Rc.

[0081] In some embodiments of a compound of formula (I), q is 0. In some embodiments of a compound of formula (I), q is 1. In some embodiments of a compound of formula (I), q is 2. In some embodiments of a compound of formula (I), q is 3.

[0082] In some embodiments of a compound of formula (I), Rmand Rnare independently hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C6-C10aryl, 5- to 6-membered heterocyclyl, 5- to 10- membered heteroaryl, -C1-C3-alkylene(C3-C6cycloalkyl), -C1-C3-alkylene( C6-C10aryl), -C1-C3- alkylene(5- to 6-membered heterocyclyl) or -C1-C3-alkylene(5- to 10-membered heteroaryl), each of which is optionally substituted by R17.

[0083] In some embodiments of a compound of formula (I), Rmis hydrogen. In some embodiments of a compound of formula (I), Rmis C1-C6alkyl optionally substituted by R17. In some embodiments of a compound of formula (I), Rmis C3-C6cycloalkyl optionally substituted by R17. In some embodiments of a compound of formula (I), Rmis C6-C10aryl optionally substituted by R17. In some embodiments of a compound of formula (I), Rmis 5- to 6-membered heterocyclyl optionally substituted by R17. In some embodiments of a compound of formula (I), Rmis 5- to 10-membered heteroaryl optionally substituted by R17. In some embodiments of acompound of formula (I), Rmis -C1-C3-alkylene(C3-C6cycloalkyl) optionally substituted by R17. In some embodiments of a compound of formula (I), Rmis -C1-C3-alkylene(C6-C10aryl) optionally substituted by R17. In some embodiments of a compound of formula (I), Rmis -C1-C3-alkylene(5- to 6-membered heterocyclyl) optionally substituted by R17. In some embodiments of a compound of formula (I), Rmis -C1-C3-alkylene(5- to 10-membered heteroaryl) optionally substituted by R17.

[0084] In some embodiments of a compound of formula (I), Rnis hydrogen. In some embodiments of a compound of formula (I), Rnis C1-C6alkyl optionally substituted by R17. In some embodiments of a compound of formula (I), Rnis C3-C6cycloalkyl optionally substituted by R17. In some embodiments of a compound of formula (I), Rnis C6-C10aryl optionally substituted by R17. In some embodiments of a compound of formula (I), Rnis 5- to 6-membered heterocyclyl optionally substituted by R17. In some embodiments of a compound of formula (I), Rnis 5- to 10- membered heteroaryl optionally substituted by R17. In some embodiments of a compound of formula (I), Rnis -C1-C3-alkylene(C3-C6cycloalkyl) optionally substituted by R17. In some embodiments of a compound of formula (I), Rnis -C1-C3-alkylene(C6-C10aryl) optionally substituted by R17. In some embodiments of a compound of formula (I), Rnis -C1-C3-alkylene(5- to 6-membered heterocyclyl) optionally substituted by R17. In some embodiments of a compound of formula (I), Rnis -C1-C3-alkylene(5- to 10-membered heteroaryl) optionally substituted by R17.

[0085] In some embodiments of a compound of formula (I), L comprises or isD and - lines denote attachment points to A.

[0086] In some embodiments of a compound of formula (I), L’ comprises or isL and - lines denote attachment points to A.

[0087] In some embodiments of a compound of formula (I), D is a payload. In some embodiments of a compound of formula (I), payload of D is radioactive components. In some embodiments of a compound of formula (I), payload of D is fluorescent dyes. In some embodiments of a compound of formula (I), payload of D is contrast agents. In some embodiments of a compound of formula (I), payload of D is metal chelating groups / chelating agents.

[0088] In some embodiments, payload of D further comprises one or more motifs. In some embodiments, payload of D further comprises an albumin-binding motif, an amino acid motif, or any combination thereof. For example, ibuprofen can be used an albumin-binding motif. The incorporation of albumin-binding motifs into the structure of radioligands is a validated strategy in literature to enhance blood circulation and ultimately increase tumor accumulation and activity (Preclinical Development of Novel PSMA-Targeting Radioligands: Modulation of Albumin- Binding Properties To Improve Prostate Cancer Therapy, by Christoph A. Umbricht, Martina Benesova, Roger Schibli, and Cristina Muller Molecular Pharmaceutics 2018 15 (6), 2297-2306; Development of a new class of PSMA radioligands comprising ibuprofen as an albumin-binding entity by eberle, L.M.; Benesova, M.; Umbricht, C.A.; Borgna, F.; Buehler, M.; Zhernosekov, K.; Schibli, R.; Muller, C., Theranostics 2020, 10 (4), 1678-1693).

[0090] In some embodiments of a compound of formula (I), pay load of D is a radionuclide. Representative radionuclides, which may be used in connection with the present invention are well known to the person skilled in the art and include, but are not limited, to the following

[0091] In some embodiments, the radionuclide is selected from the group including, but not

[0092] In some embodiments, the radionuclide is18F, whereby18F forms a covalent bond to aluminium and aluminium forms a complex with the chelator. Methods and compositions for18F labeling of proteins, peptides and other molecules are, for example, disclosed in WO 2012 / 082618.

[0093] In some embodiments of a compound of formula (I), payload of D is a chelating agent. Representative chelating agents and their derivatives include, but are not limited to

[0094] In some embodiments, a chelating agent is selected from the group consisting of 1,4,7,10-tetrazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10- tetraazacyclodocecane, 1 -(glutaric acid)-4,7,10-triacetic acid (DOTAGA), NOPO, PCTA, 1,4,7- triazacyclononanetriacetic acid (NOTA), 1,4,7-triazacyclononane-N-glutaric acid-N',N"-diacetic acid (NODAGA), 1,4,7-triazacyclononane-1,4-diacetate-methyl phenylacetic acid (NODA- MPAA), bis(2-hydroxybenzyl) ethylenediaminediacetic acid (HBED), 1,4,8,11- tetraazacyclododecane-1,4,8,l l-tetraacetic acid (TETA), 4,1 l-bis-(carboxymethyl)-l, 4,8,11- tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A), diethylenetriaminepentaacetic acid (DTPA), [(2- {[2-(bis-carboxymethyl-amino)-cyclohexyl]-carboxymethyl- amino } -ethyl)-carboxymethyl- amino]-acetic acid (CHX-A”-DTPA), desferal or desferrioxamine type group of chelators (DFO) (e.g., N-[5-({3-[5-(acetyl-hydroxy-amino)-pentylcarbamoyl]- propionyl }-hydroxy-amino)- pentyl]-N'-(5-amino-pentyl)-N'-hydroxy-succinamide), N,N’-bis[(6-carboxy-2-pyridyl)methyl]- 4,13-diaza-18-crown (Macropa), 1,4,7,10-tetrakis[carbamoylmethyl]-1,4,7,10- tetracyclodecane (DOTAM), octadentate hydroxypyridinone-type group of chelators (HOPO), 3-({4,7-bis-[(2- carboxy-ethyl)-hydroxy-phosphinoylmethyl] - [ 1 ,4,7] triazonan- 1 -ylmethyl } -hydroxy- phosphinoyl)-propionic acid (TRAP), hexadentate tris(3,4-hydroxypyridinone) (THP), [4- carboxymethyl-6-(carboxymethyl-methyl-amino)-6-methyl- [ 1 ,4]diazepan- 1 -yl]-acetic acid (DATA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid) (DOTP), 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane (sarcophagine), 3,15,27-triamino-7,19,31- trihydroxy-10,22,34-trimethyl-l,13,25-trioxa- 7,19,31-triaza-cyclohexatriaconta-9,21,33-triene- 2,8, 14,20,26,32-hexaone (FSC), {4-[2-(bis-carboxymethyl-amino)-ethyl]-7-carboxymethyl- [1,4,7]triazonan- l-yl]-acetic acid (NETA), {4-carboxymethyl-7-[2-(carboxymethyl-amino)- ethyl]-[1,4,7]triazonan-1- yl]-acetic acid (NE3TA), N,N'-(6-carboxy-2-pyridylmethyl)-N,N'- diacetic acid-1,2-diaminoethane (H4octapa), l,8-(2,6-Pyridinedimethylene)-1,4,8,l 1- tetraazacyclo-tetradecane (Pycup), NxS4-x (also known as tetradentate chelators with N-atoms (basic amine or non-basic amide) and thiols as donors stabilizing Tc-complexes, especially Tc(V)- oxo complexes, e.g., N,N'-bis-(2-amino-ethyl)-propane-1,3-diamine (N4), N2S2, N3S), 6- hydrazino-nicotinic acid (Hynic), mTc(C0)3- Chelators (also known as bi- or tridendate chelators capable of forming stable complexes with technetium tricarbonyl fragments), AAZTA5 (6- [Bis(carboxymethyl)amino]-1,4-bis (carboyxmethyl)-6-methyl-1,4-diazepane) and MATS (Mercapto- Acetyl-Tri-Serine).

[0095] In some embodiments, a chelating agent is selected from the group consisting ofand any combination thereof.

[0096] In some embodiments, a chelating agent is selected from the group consisting of DOTA, DOTAGA, 1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid] (NOPO), 1 ,4,7-triazacyclononane-N,N'N"- tris(methylene phosphonic) acid) (NOTP), 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-l(15),l l,13- triene-3, 6, 9, -triacetic acid (PCTA), DOTAM, Macropa, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP, and N4. In some embodiments, a chelating agent is selected from the group consisting of DOTA, DOTAGA, NOPO, PCTA, DOTAM, Macropa, NOTA, and NODAGA. In some embodiments, a chelating agent is selected from the group consisting of 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), triethylenetetramine (TETA), iminodiacetic acid, diethylenetriamine-N,N,N',N',N"-pentaacetic acid (DTPA), bis- (carboxymethylimidazole)glycine or 6-hydrazinopyridine-3-carboxylic acid (HYNIC).

[0097] In some embodiments of a compound of formula (I), payload of D is a fluorescence dye. In some embodiments, D is fluorophore derivative of coumarin, quinoline, styrene, naphthalimide, xanthone fluorescein, bodipy or rhodamine fluorescent dye (Jun JV, Chenoweth DM, Petersson EJ. Rational design of small molecule fluorescent probes for biological applications. Org Biomol Chem., 2020, Aug 5;18(30):5747-5763). In some embodiments, D is near-infrared (NIR) dye. In some embodiments, D is NIR dye to guide intra-operative surgical decision-making or NIR fluorescence-guided surgery. In some embodiments, the NIR dye is S0456 NIR dye with excitation / emission bands at 789 / 807 nm. In some embodiments, the NIR dye is indocyanine green (ICG) NIR dye with excitation / emission bands at 780 / 802 nm. In some embodiments, the NIR dye is IRDye800CW NIR dye with excitation / emission bands at 774 / 789 nm. In some embodiments, the NIR dye is ZW800-1 NIR dye with excitation / emission bands at 768 / 786 nm. In some embodiments, the NIR dye is Sulfo-Cy5 NIR dye with excitation / emission bands at 646 / 662 nm. In some embodiments, the NIR dye is Sulfo-Cy5.5 NIR dye with excitation / emission bands at 673 / 691 nm. In some embodiments, the NIR dye is Sulfo-Cy7 NIR dye with excitation / emission bands at 750 / 773 nm. In some embodiments, the NIR dye is Sulfo- Cy7.5 NIR dye with excitation / emission bands at 778 / 797 nm. In some embodiments, the NIR dye is BM104 NIR dye with excitation / emission bands at 685 / 705 nm. In some embodiments, the NIR dye is CH1055 NIR dye with excitation / emission bands at 750 / 1055 nm (Debie P. and Hernot S., Emerging Fluorescent Molecular Tracers to Guide Intra-Operative Surgical Decision-Making. Front. Pharmacol., 2019, 10:510).

[0098] In some embodiments of a compound of formula. In some embodiments of a compound of formulasome embodiments of a compound of formulasome embodiments of a compound of formula (I),In some embodiments of a compound of formulasome embodiments of a compound of formula (I), D isof formula (I), DIn some embodiments of a compound of formula (I),embodiments of a compound of formula (I),embodiments of a compound of formula (I),embodiments of a compound of formulasome embodiments of a compound of formulasome embodiments of a compoundof formulasome embodiments of a compound of formulaof a compound of formulasome embodiments of a compound of formula (I), D is,of a compound of formula (I), D is. In some embodiments of a compound of formulasome embodiments of a compound of formula (I), In some embodiments of a compound of. In some embodiments of a compound of formula (I), D issome embodiments of a compound of formula (I), D is. In some embodiments of a compound of formula (I), D is someembodiments of a compound of formula (I), D isIn some embodiments of a compound of formula (I), D is. In some embodiments of a compound of formula (I), D isIn some embodiments of a compoundlines denote attachment points to L.

[0099] It is understood that each description of Q, X, A, L, D, m, n, R1and R2may be independently combined with each description of Q, X, A, L, D, m, n, R1and R2the same as if each and every combination were specifically and individually listed.

[0100] In some embodiments, a compound of formula (I) is a compound of formula (I- 1):

[0101] In some embodiments, a compound of formula (I) is a compound of formula (1-2):

[0102] In some embodiments, a compound of formula (I) is a compound of formula (1-3):

[0103] In some embodiments, a compound of formula (I) is a compound of formula (II- 1),or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X, A, L, D, R1and R2are as defined for formula (I). In some embodiments, a compound of formula (II- 1) is of formula:

[0104] In some embodiments, a compound of formula (I) is a compound of formula (Il-a),In some embodiments, a compound of formula (Il-a) is formula:compound of formula (I) is a compound of formula (H-b),some embodiments, a compound of formula (Il-b) is of formula:In some embodiments, a compound of formula (I) is a compound of formulaIn some embodiments, a compound of formula (II-c) is of formula,

[0105] In some embodiments, a compound of formula (I) is a compound of formula (II-2),formula (II-2), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X, A, L, D, R1and R2are as defined for formula (I). In some embodiments, a compound of formula (II-2) is of formula:

[0106] In some embodiments, a compound of formula (I) is a compound of formula (Il-d),In some embodiments, a compound of formula (Il-d) is of formula:In some embodiments, a compound of formula (I) is a compound of formula (Il-e),some embodiments, a compound of formula (Il-e) is of formula. In some embodiments, a compound of formula (I) is a compound of formula (Il-f),

[0107] In some embodiments, a compound of formula (I) is a compound of formula (III),formula (III), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X, A, L, D, R1and R2are as defined for formula (I).

[0108] In some embodiments, a compound of formula (I) is a compound of formula (Ill-a),

[0109] In some embodiments, a compound of formula (I) is a compound of formula (IV- 1),formula (IV- 1), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X, A, L, D, R1and R2are as defined for formula (I).

[0110] In some embodiments, a compound of formula (I) is a compound of formula (IV-a),formula (I) is a compound of formula (IV-b),formula (I) is a compound of formula (IV-c),

[0111] In some embodiments, a compound of formula (I) is a compound of formula (IV-2),formula (IV-2), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X, A, L, D, R1and R2are as defined for formula (I).

[0112] In some embodiments, a compound of formula (I) is a compound of formula (IV-d),formula (I) is a compound of formulaIn some embodiments, a compound of formula (I) is a compound of formula (IV-f),

[0113] In some embodiments, a compound of formula (I) is a compound of formula (V),or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X, A, L, D, R1and R2are as defined for formula (I).

[0114] In some embodiments, a compound of formula (I) is a compound of formula (V-a),

[0115] In some embodiments, a compound of formula (I) is a compound of formula (VI),formula (VI), or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X, Q, A, L, L’ , D, R1and R2are as defined for formula (I).

[0116] In some embodiments, a compound of formula (I) is a compound of formula (VI- 1),formula (VI- 1),or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X, Q, A, L, L’ , D, R1and R2are as defined for formula (I). In some embodiments, a compound of formula (VI-1) is a compound of formula (VI- la):

[0117] In some embodiments, a compound of formula (I) is a compound of formula (VI-2),formula (VI-2),or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X, Q, A, L, L’ , D, R1and R2are as defined for formula (I). In some embodiments, a compound of formula (VI-2) is a compound of formula (

[0118] In some embodiments, a compound of formula (I) is a compound of any of the compounds of formula (Vl-a to Vl-h),or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X, A, L, L’, D, R1, and R2are as defined for formula (I). In some embodiments, a compound of formula (Vl-a to Vl-h) is of one of the following formulae,

[0119] In some embodiments, a compound of formula (I) is a compound of formula (VI) or any one of its sub-formulas, wherein the moietysymmetric with respect to the payload. In some embodiments, the moiety is selected from the group consisting of

[0120] Also provided are salts of compounds referred to herein, such as pharmaceutically acceptable salts. The invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described.

[0121] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. Unless otherwise stated, “substantially pure” intends a composition that contains no more than 35 % impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25 %, 20%, 15%, 10%, or 5% impurity. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3 %, 2%, 1% or 0.5% impurity.

[0122] Representative compounds of the present invention are listed in table 1. It is understood that individual stereoisomers (e.g., enantiomers and diastereomers) and tautomers are included in the generic compound structures shown in table 1. Specific synthetic methods for preparing exemplary compounds are provided example herein.Table-1: Compoundsʼnll

[0123] The compounds illustrated in table 1 can be prepared in a manner analogous to the techniques used in connection with the preparation of the compounds given herein and in accordance, using appropriate, analogous starting materials and by utilizing the general synthetic schemes illustrated below.

[0124] In some embodiments, provided herein are compounds described in table 1, or a salt, isomer or solvate, and uses thereof.

[0125] The embodiments and variations described herein are suitable for compounds of any formulae detailed herein, where applicable.

[0126] Representative examples of compounds detailed herein, including intermediates and final compounds according to the present disclosure are depicted herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual.

[0127] The compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the present disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.

[0128] Where tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted. The tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.

[0129] The present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds described. The structure or name is intended to embrace all possible stereoisomers of a compound depicted, and each unique stereoisomer has a compound number bearing a suffix “a”, “b”, etc. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture.

[0130] The invention also intends isotopically-labeled and / or isotopically-enriched forms of compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine,such as2H,3H,nC,13C,14C13N,150,170,32P,35S,18F,36C1. Certain isotope labeled compounds (e.g.3H and14C) are useful in compound or substrate tissue distribution studies. Incorporation of heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances.

[0131] Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent.

[0132] The invention also includes any or all metabolites of any of the compounds described. The metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human.

[0133] Articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like.

[0134] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds may also be formulated for parenteral (e.g., intravenous) administration.

[0135] One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier may be in various forms. In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of cancer.General synthetic schemes

[0136] The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.

[0137] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.

[0138] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

[0139] Solvates and / or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and / or solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

[0140] In some embodiments, representative compounds of the present invention may be synthesized according to Scheme- 1 to Scheme-4.Scheme- 1:wherein X, Z, A, L, D, R1and R2are as defined for formula (I).Scheme-2:wherein X, Z, A, L, D, R1and R2are as defined for formula (I).Scheme-3wherein X, Z, A, L, D, R1and R2are as defined for formula (I).Scheme-4:wherein X, Z, A, L, D, R1and R2are as defined for formula (I).Pharmaceutical Compositions and Formulations

[0141] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein or a salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.

[0142] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.

[0143] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.

[0144] A compound detailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0145] One or several compounds described herein or a salt thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20thed. (2000), which is incorporated herein by reference.

[0146] Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0147] Any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a salt thereof can be incorporated in tablet in an amount ranging from about 1 mg to about 1000 mg.

[0148] Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound or salt thereof and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided.Methods of Use

[0149] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceuticallyacceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. In some embodiments, the compounds and compositions detailed herein is used in chemotherapy, immunotherapy, radionuclide therapy or diagnosis. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and / or for conducting quality control assays.

[0150] Provided herein is a method of treating a disease in an individual in need thereof comprising administering an effective amount of a compound of the present invention or any embodiment, variation or aspect thereof or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, to the individual (e.g., a human individual or an animal). Further provided herein is a method of treating a proliferative disease in an individual in need thereof, comprising administering an effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, to the individual. Also provided herein is a method of treating cancer in an individual in need thereof comprising administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the compound is administered to the individual according to a dosage and / or method of administration described herein.

[0151] Another aspect of the invention relates to a method of treating a disease or disorder associated with fibroblast-activated protein (FAP). The method involves administering to an individual in need thereof of a treatment for diseases or disorders associated with FAP an effective amount of the compositions and compounds of the present invention.

[0152] Another aspect of the invention is directed to a method inhibiting FAP. The method involves administering to an individual in need thereof an effective amount of the compositions or compounds of the present invention.

[0153] Provided is a method of treating cancer, comprising administering to an individual in need thereof an effective amount of the compositions and compounds of the present invention. The use of a compound of the present invention for the manufacture of a medicament for the treatment of a proliferative disease such as cancer. In some embodiments, the cancer is selected from the group consisting of carcinomas, for example carcinomas of the bladder, breast, colon, kidney, epidermis, liver, lung, oesophagus, gall bladder, ovary, pancreas, stomach, cervix, head and neck,thyroid, prostate, gastrointestinal system, or skin, hematopoieitic tumors such as leukaemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; hematopoieitic tumors of myeloid lineage, for example acute and chronic myelogenous leukaemias, myelodysplastic syndrome, or promyelocytic leukaemia; thyroid follicular cancer; tumors of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; tumors of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; Ewing's sarcoma or Kaposi's sarcoma; Anaplastic large cell lymphoma, Tongue squamous cell carcinoma, Nasopharyngeal carcinoma, Endometrioid adenocarcinoma, Salivary gland adenoid cystic carcinoma, Testis seminoma, and Multiple myeloma. The use of a compound of the present invention for the manufacture of a medicament for the treatment of cancer, wherein the cancer is one which is characterized by a defective DNA repair mechanism or defective cell cycle.

[0154] Provided is a method of treating idiopathic pulmonary fibrosis (IPF), comprising administering to an individual in need thereof an effective amount of the compositions and compounds of the present invention. The use of a compound of the present invention for the manufacture of a medicament for the treatment of idiopathic pulmonary fibrosis (IPF).

[0155] In some embodiments, the method described herein involves FAP targeted radionuclide therapy (TRT), when the compositions and compounds of the present invention comprise radionuclides. (Fibroblast activation protein-targeted radionuclide therapy: background, opportunities, and challenges of first (pre)clinical studies, European Journal of Nuclear Medicine and Molecular Imaging (2023) 50: 1906-1918). In some embodiments, the radionuclide is used for diagnosis. It will, however, also be acknowledged by a person skilled in the art that the use of said radionuclide is not limited to diagnostic purposes, but encompasses their use in therapy and theragnostics when conjugated to the compound of the invention. In some embodiments, the radionuclide is used for therapy. In some embodiments, a radionuclide is provided with a chelate. In such a chelate, the chelator unit chelates directly with the radionuclide (eg.68Ga chelates with a chelator unit derived from DOTA), or the radionuclide is introduced indirectly by chelation with other metals (eg. Al3+is chelated with a chelator unit derived from DOTA, and the radionuclide8F is introduced into the chelate in the form of a counter ion).

[0156] The present invention further provides a method for diagnosis of a disease or disorder, comprising administering to an individual in need thereof a diagnostically effective amount of the compositions and compounds of the present invention. In some embodiments, the method involves nuclear medicine imaging technique, such as Positron Emission Tomography (PET).

[0157] The present invention also provides a method of imaging a disease or disorder, comprising administering to an individual in need thereof a diagnostically effective amount of the compositions and compounds of the present invention. Activated fibroblasts are found in scar formation (e.g., in ischemic tissues after myocardial infarction), chronic inflammatory and / or destructive processes (rheumatoid arthritis, Crohn disease, atherosclerotic plaque, immunoglobulin G4-related diseases), fibrosis (liver, kidney, lung), and benign tumors. (FAPI PET: Fibroblast Activation Protein Inhibitor Use in Oncologic and Nononcologic Disease, Radiology, 2023; 306(2):e220749). In some embodiments, the disease or disorder are the aforementioned diseases.

[0158] The disclosed compounds of the present invention can be administered in effective amounts to treat or prevent a disorder and / or prevent the development thereof in subjects. In some embodiments, the disclosed compounds have low half-maximal inhibitory concentrations, for example, IC50 rhFAP (nM) and great potencies. In some embodiments, the disclosed compounds have high percentages of the compound remaining after incubation with human (Hu) or mouse (Mo) plasma, for example, Hu / Mo plasma (%) and great stability in plasma.Combination Therapy

[0159] The compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agents. The compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.

[0160] In some embodiments, the methods described herein comprise the additional step of co-administering to an individual in need thereof a second therapy e.g., an additional cancer therapeutic agent or an additional cancer treatment. Exemplary additional cancer therapeutic agents include for example, In one embodiment, the other active agent is selected from the group consisting of but not limited to antimetabolites, tubulin targeting agents, DNA binder and topoisomerase II inhibitors, alkylating agents, monoclonal antibodies, hormonal therapy, signaltransduction inhibitors, proteasome inhibitors, DNA methyl transferases, cytokines and retinoids, hypoxia triggered DNA damaging agents, immunomodulaters (e.g. CTLA-4, LAG-3, PD-1 antagonists etc.) and monoclonal antibodies.

[0161] In some embodiments, the additional cancer therapeutic agent is a chemotherapy agent. Examples of chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives), alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others), and hypomethylating agents (e.g. , decitabine (5-aza- deoxycytidine), zebularine, isothiocyanates, azacitidine (5-azacytidine), 5-flouro-2'- deoxycytidine, 5,6-dihydro-5-azacytidine and others). Exemplary agents include Aclarubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide, Floxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine, Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine, Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein

[0162] In some embodiments, the additional cancer therapeutic agents are tyrosine kinase inhibitors, PI3K / mT0R inhibitors, PARP inhibitors such as Olaparib, Rucaparib, Niraparib, Talazoparib, Weel inhibitors, CDK4 / 6 inhibitors such as Palbociclib, Ribociclib, Abemaciclib, DNA-PK inhibitors, ATM inhibitors and ATR inhibitors. Any compound of the present invention can be combined with these targeted inhibitors.

[0163] The compounds of the invention and combinations with chemotherapeutic agents or radiation therapies as described above may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively, they may be administered in a pulsatile or continuous manner.

[0164] Other possible additional therapeutic modalities include gene therapy, peptide and dendritic cell vaccines, synthetic chlorotoxins, and radiolabeled drugs and antibodies.Dosing and Method of Administration

[0165] The dose of a compound administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular disease, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound or salt thereof is a therapeutically effective amount.

[0166] The effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg / kg. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the individual’s health status, condition, and weight. An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.

[0167] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.

[0168] A compound or composition of the invention may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as atleast about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.

[0169] The compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral and transdermal. A compound provided herein can be administered frequently at low doses, known as 'metronomic therapy,' or as part of a maintenance therapy using compound alone or in combination with one or more additional drugs. Metronomic therapy or maintenance therapy can comprise administration of a compound provided herein in cycles. Metronomic therapy or maintenance therapy can comprise intra-tumoral administration of a compound provided herein.

[0170] In one aspect, the invention provides a method of treating cancer in an individual by parenterally administering to the individual (e.g., a human) an effective amount of a compound or salt thereof. In some embodiments, the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous. In some embodiments, the route of administration is oral. In still other embodiments, the route of administration is transdermal.

[0171] The invention also provides compositions (including pharmaceutical compositions) as described herein for the use in treating, preventing, and / or delaying the onset and / or development of cancer and other methods described herein. In certain embodiments, the composition comprises a pharmaceutical formulation which is present in a unit dosage form.

[0172] Also provided are articles of manufacture comprising a compound of the disclosure or a salt thereof, composition, and unit dosages described herein in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials,vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and / or sealed.Kits

[0173] The present disclosure further provides kits for carrying out the methods of the invention, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of cancer.

[0174] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.

[0175] The kits may be in unit dosage forms, bulk packages (e.g. , multi-dose packages) or subunit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and / or a second pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0176] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention. The instructions included with the kit generally include information as to the components and their administration to an individual.

[0177] The invention can be further understood by reference to the following examples, which are provided by way of illustration and are not meant to be limiting.

[0178] All references throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties.EXAMPLESSynthetic Examples

[0179] The chemical reactions in the Synthetic Examples described can be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.Compound 1

[0180] (S)-2,2',2"-(10-(2-(4-(3-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl) quinolin-6-yl)phenoxy)propyl)piperazin-1-yl)-2-oxoethyl)-1,4,7,10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0181] Step-1: Synthesis of 2-(4-(3-chloropropoxy)phenyl)-4, 4,5, 5 -tetramethyl- 1 ,3,2- dioxaborolane

[0182] To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (2.5 g, 11.36 mmol, 1.0 equiv) in ACN (25 mL) was added K2CO3 (3.9 g, 28.26 mmol, 2.5 equiv), followed by the addition of l-bromo-3-chloropropane (17.9 g, 113.30 mmol, 10.0 equiv). The Reaction mixture was allowed to stir at room temperature for 48h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (5 to 20 % ethyl acetate in hexane as an eluent) to obtain 2-(4-(3-chloropropoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.0 g, 89 % Yield) as an off white solid.

[0183] LCMS: 297 [M+l]+

[0184] Step-2: Synthesis of methyl 6-(4-(3-chloropropoxy)phenyl)quinoline-4-carboxylate:

[0185] To a stirred solution of methyl 6-bromoquinoline-4-carboxylate (2.40 g, 9.05 mmol, 1.0 equiv) in Dioxane: Water (30: 4 mL) was added K2CO3 (2.49 g, 18.03 mmol, 2.0 equiv), followed by the addition of 2-(4-(3-chloropropoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (4.0 g, 13.51 mmol,1.5equiv). The reaction mixture was purged with N2 for 5-10minutes, followed by the addition of Bis(triphenylphosphine)palladium chloride (0.317 g, 0.451 mmol, 0.05 equiv). The resulting reaction mixture was heated at 90 °C for 16h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (30 mL) and extracted with ethyl acetate (30 ml x 2). Combined organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (0- 30 % ethyl acetate in hexanes) to obtain methyl 6-(4-(3-chloropropoxy)phenyl)quinoline-4-carboxylate (3.0 g, 93 % Yield) as an off white solid.

[0186] LCMS: 356 [M+l]+

[0187] 'H NMR: (400 MHz, DMSO-d6) δ 9.03 (d, J = 4.29 Hz, 1H), 8.73-8.92 (m, 1H), 8.06- 8.28 (m, 2H), 7.96 (d, J = 4.29 Hz, 1H), 7.76 (m, J = 8.58 Hz, 2H), 7.13 (m, J = 8.58 Hz, 2H), 4.17 (t, J= 5.96 Hz, 2H) 4.01 (s, 3H) 3.83 (t, J = 6.44 Hz, 2H) 2.21 (quin, J = 6.20 Hz, 2H)

[0188] Step-3: Synthesis of methyl 6-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)phenyl)quinoline-4-carboxylate

[0189] To a stirred solution of methyl 6-(4-(3-chloropropoxy)phenyl)quinoline-4-carboxylate (4.6 g, 12.95 mmol, 1.0 equiv) in DMF (40 mL) was added KI (1.0 g, 6.00 mmol, 0.5 equiv), followed by the addition of tert-butyl piperazine- 1 -carboxylate (12.00 g, 64.00 mmol, 5.0 equiv). The resulting reaction mixture was allowed to stir at 70 °C for 16 h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with DCM (100 mL x 3). The organic layer was washed with cold water (100 mL x 3). The combined organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (0- 5 % MeOH in DCM as an eluent) to obtain methyl 6-(4-(3- (4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)phenyl)quinoline-4-carboxylate (3.7 g, 56 % Yield) as an off white solid.

[0190] LCMS: 506 [M+l]+

[0191] ^ NMR: (400 MHz, DMSO-d6) 89.03 (d, J = 4.77 Hz, 1H), 8.80-8.88 (m, 1H), 8.11- 8.23 (m, 2H), 7.97 (d, J = 4.29 Hz, 1H), 7.70-7.82 (m, 2H), 7.06-7.17 (m, 2H), 4.04-4.16 (m, 2H),4.02 (s, 3H), 3.26-3.38 (m, 6H), 2.49-2.61 (m, 9H), 2.46 (t, J = 7.15 Hz, 3H), 2.36 (br. s., 1H), 2.34 (t, J = 4.77 Hz, 4H), 1.92 (t, J = 6.68 Hz, 2H), 1.40 (s, 10H)

[0192] Step-4: Synthesis of lithium 6-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)phenyl)quinoline-4-carboxylate

[0193] To a stirred solution of methyl 6-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)phenyl)quinoline-4-carboxylate (3.8 g, 7.52 mmol, 1.0 equiv) in THF (30 mL) was added LiOH.H2O (0.347 g, 8.26 mmol, 1.1 equiv) in water (6 ml). The Reaction mixture was allowed to stir at RT for Ih. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the solvent was removed under reduced pressure and freeze dried on lyophilizer to obtain lithium 6-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)phenyl)quinoline-4-carboxylate (3.8 g, 90 % Yield) as an off white solid.

[0194] LCMS: 498 [M+l]+

[0195] 'H NMR: (400 MHz, DMSO-d6) δ 8.90 (s, IH), 8.72 (d, J = 4.29 Hz, IH), 7.83-8.03 (m, 2H), 7.67 (m, J = 8.58 Hz, 2H), 7.42 (d, J = 4.29 Hz, IH), 7.07 (m, J = 8.58 Hz, 2H), 4.07 (t, J = 6.20 Hz, 2H) 2.40-2.48 (m, 3 H), 2.24-2.40 (m, 5H), 1.91 (t, J = 6.68 Hz, 2H), 1.39 (s, 10H)

[0196] Step-5: Synthesis of (S)-tert-butyl 4-(3-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)- 2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)propyl)piperazine-1-carboxylate

[0197] To a stirred solution of lithium 6-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)phenyl)quinoline-4-carboxylate (1.7 g, 3.42 mmol, 1.0 equiv) in DMF (20 mL) was added EDC.HC1 (0.849 g, 4.44 mmol, 1.3 equiv) HOBT(0.600 g, 4.44 mmol, 1.3 equiv) and (S)-1- (2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (1.16 g, 5.13 mmol, 1.5 equiv) followed by the addition of DIPEA(1.89 mL, 10.87 mmol, 5.0 equiv). The resulting reaction mixture was allowed to stir at RT for 16h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers was washed with water (20 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure The crude product was purified by Flash chromatography (0-5 % MeOH in DCM as an eluent) to obtain (S)- tert-butyl 4-(3-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6- yl)phenoxy)propyl)piperazine- 1 -carboxylate (1.2 g 57 % Yield) as an off white solid.

[0198] LCMS: 663 [M+l]

[0199] 'H NMR: (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.94 (d, J= 4.29 Hz, 1H), 8.72 (s, 1H) 8.03-8.26 (m, 2H), 7.87 (d, J= 8.58 Hz, 2H), 7.56 (d, J= 4.29 Hz, 1H), 7.08 (d, J = 8.58 Hz, 2H),5.19 (d, J = 7.15 Hz, 1H), 4.28 (t, J = 5.01 Hz, 3H), 4.07 (t, J = 5.96 Hz, 3H), 3.32 (s, 13H), 2.40- 2.60 (m, 22 H), 2.34 (br. s., 4H), 1.91 (t, J = 6.68 Hz, 2H), 1.39 (s, 9H), 1.33 (s, 1H), 1.23 (s, 6H), 0.85 (s, 1H)

[0200] Step-6: Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4- (3-(piperazin-1-yl)propoxy)phenyl)quinoline-4-carboxamide:- To a stirred solution of (S)-tert- butyl 4-(3-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6- yl)phenoxy)propyl)piperazine- 1 -carboxylate (0.550 g, 0.830 mmol, 1.0 equiv) in DCM (7 mL) was added TFA (1.2 mL) drop wise at 0°C. The Reaction mixture was allowed to stir at RT for 2h. The product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (30 mL), washed with ethyl acetate (20 mL). The aqueous layer was separated and basified with sodium bicarbonate (saturated solution in water) and extracted with DCM (2 x 20 ml). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.430 g, 92 % Yield) as an off white solid.

[0201] LCMS: 563 [M+l]+

[0202] 'H NMR: (400 MHz, DMSO-d6) δ 9.17 (t, J = 5.96 Hz, 1H), 8.8- 9.03 (m, 1H), 8.66- 8.81 (m, 1H) 8.02-8.23 (m, 2H), 7.82-7.95 (m, 2H), 7.46-7.66 (m, 1H), 7.08 (d, J = 9.06 Hz, 2H),5.20 (dd, J = 9.30, 2.62 Hz, 1H), 4.16-4.45 (m, 3H), 3.95-4.13 (m, 3H), 2.5- 2.79 (m, 5H), 2.40 (t, J= 7.15 Hz, 3H), 2.32 (d, J = 1.91 Hz, 4H), 1.89 (quin, J = 6.79 Hz, 2H), 1.28-1.38 (m, 1H), LIS128 (m, 2H)

[0203] Step7: Synthesis of tri-tert-butyl 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10- tetraazacyclododecane- 1 ,4,7-triyl)triacetate

[0204] To a stirred solution of 2-(4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10- tetraazacyclododecan-1-yl)acetic acid (0.600 g, 1.137mmol,1.0 equiv) in DMF (5 mL) was added HATU (0.597 g,1.57 mmol, 1.5 equiv) followed by the addition of DIPEA(0.550 mL,3.16 mmol, 3.0 equiv). The resulting reaction mixture was stirred for 10 min. at RT. 4-nitrophenol (0.291 g,2.09 mmol, 2.0 equiv) was added and the resulting reaction mixture was allowed to stir at RT for 16h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (5 mL). The resulting solid was filtered off and purified by flash chromatography (0- 5 % MeOH in DCM as an eluent) to obtain tri-tert-butyl 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (0.250 g, 34 % Yield) as an off white solid.

[0205] LCMS: 694 [M+l]+

[0206] 'H NMR: (400 MHz, DMSO-d6) 8 8.32 (m, J = 9.06 Hz, 2H), 7.50 (m, J = 8.58 Hz, 2 H), 3.07 (br. s., 5 H), 1.35-1.53 (m, 30H), 1.32 (br. s., 12H), 0.99 (d, J = 6.20 Hz, 6H)

[0207] Step-8: Synthesis of 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0208] To a stirred solution of tri-tert-butyl 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)- 1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (0.400 g, 0.577 mmol, 1.0 equiv) in DCM (4 mL) was added TFA (3 mL) drop wise at 0°C. The Reaction mixture was allowed to stir at room temperature for 20 h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was crystallized in diethyl ether and was purified by reversed phase HPLC to obtain 2,2',2"-(10-(2-(4- nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (0.150 g, 49 % Yield) as a white solid.

[0209] LCMS: 526 [M+l]+

[0210] 'H NMR: (400 MHz, DMSO-d6) 8 8.25-8.42 (m, 2H), 7.37-7.55 (m, 2H), 3.96 (br. s., 6H), 3.45 (br. s., 31H), 3.05 (br. s., 10H)

[0211] Step-9: Synthesis of (S)-2,2',2"-(10-(2-(4-(3-(4-(4-((2-(2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)piperazin- 1 -yl)-2- oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7-triyl)triacetic acid

[0212] To a stirred solution of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6- (4-(3 -(piperazin- l-yl)propoxy)phenyl)quinoline-4-carboxamide (0.140 g, 0.249 mmol, 1.0 equiv) in DMF (0.2 mL) was added 2, 2', 2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-l, 4, 7, 10- tetraazacyclododecane- 1,4, 7-triyl)triacetic acid (0.261 g, 0.498 mmol, 2.0 equiv) and TEA (0.21ml, 0.001 mmol, 6.0 equiv). The Reaction mixture was allowed to stir at room temperature for 16 h. The product formation was confirmed by LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure, crystallized in diethyl ether and further purified by reversed phase HPLC to obtain (S)-2,2',2"-(10-(2-(4-(3-(4-(4-((2-(2-cyano-4,4-difluoropyrrohdin- l-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)piperazin-1-yl)-2-oxoethyl)- 1,4, 7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid (0.04 g, 25 % Yield) as an off-white solid.

[0213] LCMS: 949 [M+l]+

[0214] 'H NMR: (400 MHz, DEUTERIUM OXIDE) δ 8..88 (d, J = 4.29 Hz, 1H), 8.43 (d, J = 6.20 Hz, 1H) 8.05-8.25 (m, 2H), 7.81 (m, J = 8.58 Hz, 2H), 7.67 (d, J = 4.29 Hz, 1H), 7.13 (m, J = 9.06 Hz, 2H), 5.17 (dd, J = 8.34, 4.53 Hz, 1H), 4.35 (s, 3H), 4.13-4.31 (m, 4H), 3.64-3.91 (m, 8H), 3.54 (br. s., 6H), 3.47 (br. s., 3H), 3.42 (br. s., 6H), 3.34 (br. s., 3H), 3.13 (br. s., 7H), 2.85- 3.08 (m, 5H), 2.30 (br. s., 3H)Compound 2

[0215] Synthesis of (S)-4-(2-(4-(3-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl) quinolin-6-yl)phenoxy)propyl)piperazin- 1 -yl)-2-oxoethylcarbamoyl)-2-(6- hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0216] Stepl: Synthesis of (S)-tert-butyl 2-(4-(3-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)propyl)piperazin-1-yl)-2-oxoethylcarbamate

[0217] To a stirred solution of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6- (4-(3 -(piperazin- l-yl)propoxy)phenyl)quinoline-4-carboxamide (0.300 g, 0.533 mmol, 1.0 equiv) in DMF(3 mL) was added HATU (0.263 g, 1.44 mmol, 1.3 equiv), 2-(tert-butoxycarbonylamino)acetic acid (0.093 g, 0.533 mmol, 1.0 equiv) followed by the addition of DIPEA(0.295 mL, 0.001 mmol, 3.0 mL). The resulting reaction mixture was allowed to stir at RT for 16 h. The product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (15 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with cold water (10 mL) followed by brine wash (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-5 % MeOH in DCM as an eluent) to obtain (S)- tert-butyl 2-(4-(3-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin- 6-yl)phenoxy)propyl)piperazin-1-yl)-2-oxoethylcarbamate (0.13 g, 34 % Yield) as an off white solid.

[0218] LCMS: 720 [M+l]+

[0219] 'H NMR: (400 MHz, DMSO-76) δ 9.16 (t, J = 5.48 Hz, 1H), 8.72 (s, 1H), 8.04-8.31 (m, 2H), 7.80-7.94 (m, 2H), 7.56 (d, J= 4.29 Hz, 1H), 7.09 (d, J = 8.58 Hz, 2H), 6.72 (br. s., 1H), 5.19 (d, J = 6.20 Hz, 1H), 4.18-4.45 (m, 3H), 3.97-4.18 (m, 3H), 3.77 (d, J = 5.72 Hz, 2H), 3.35- 3.58 (m, 5H), 2.71-2.96 (m, 1H), 2.20-2.45 (m, 8H), 1.93 (d, 7= 5.72 Hz, 2H), 1.29-1.49 (m, 11H), 1.09 (t, 7= 7.15 Hz, 2H)

[0220] Step-2: Synthesis of (S)-6-(4-(3-(4-(2-aminoacetyl)piperazin-1-yl)propoxy)phenyl)-N- (2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide

[0221] To a stirred solution of (S)-tert-butyl 2-(4-(3-(4-(4-(2-(2-cyano-4,4-difhroropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy )propyl)piperazin- 1 -yl)-2-oxoethylcarbamate (0.130 g, 0.180 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (0.3 mL) drop wise at 0°C. The Reaction mixture was allowed to stir at RT for Ih. The product formation was confirmed by LCMS. After completion of the reaction the reaction mixture was basified with saturated solution of sodium bicarbonate and extracted with DCM (2 x 10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain (S)-6-(4-(3-(4-(2-aminoacetyl)piperazin-1- yl)propoxy)phenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide (0.100 g, 90 % Yield) as an off white solid.

[0222] LCMS: 620 [M+l]

[0223] 'H NMR: (400 MHz, DMSO-d6) δ 9.16 (t, J= 5.48 Hz, 1H), 8.94 (d, J = 4.29 Hz, 1H), 8.72 (s, 1H), 8.04-8.26 (m, 2 H), 7.76-7.95 (m, 2H), 7.56 (d, J = 4.29 Hz, 1H), 7.09 (d, J = 8.58 Hz, 2H), 6.72 (br. s., 1H), 5.19 (d, J = 6.20 Hz, 1H), 4.19-4.40 (m, 3H), 3.97-4.19 (m, 3H), 3.77 (d, J = 5.72 Hz, 2H), 3.35-3.54 (m, 5H), 2.79-2.99 (m, 1H), 2.20-2.43 (m, 7H), 1.93 (d, J = 5.72 Hz, 2H), 1.09 (t, J = 7.15 Hz, 2H)

[0224] Step-3: Synthesis of (S)-4-(2-(4-(3-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)phenoxy)propyl)piperazin-1-yl)-2-oxoethylcarbamoyl)-2-(6- hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid:- To a stirred solution of (S)-6-(4-(3-(4-(2- aminoacetyl)piperazin-1-yl)propoxy)phenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)quinoline-4-carboxamide (0.100 g, 0.161 mmol, 1.0 equiv) in DMF (1 mL) was added HATU (0.092 g, 0.242 mmol, 1.5 equiv), 3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-l,9'- xanthene]-6-carboxylic acid (0.060 g, 0.160 mmol, 1.0 equiv) followed by the addition of DIPEA (0.063 mg, 0.484 mmol, 3.0 equiv). The resulting reaction mixture was allowed to stir at room temperature for 16h. The product formation was confirmed by LCMS. After completion of the reaction, the reaction mixture was acidified with 1 M HC1. The resulting solid was filtered off, dried under vacuum and was purified by reversed phase HPLC to obtain (S)-4-(2-(4-(3-(4-(4-(2- (2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6- yl)phenoxy)propyl)piperazin-1-yl)-2-oxoethylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9- yl)benzoic acid (0.014 g, 9 % Yield).

[0225] LCMS: 978 [M+l]+

[0226] 'H NMR: (400 MHz, DMSO-d6) 810.16 (s, 1H), 9.17 (s, 1H), 8.94 (br. s., 1H), 8.16 (br. s., 2H), 7.87 (s, 1 H), 7.09 (s, 1H), 6.69 (d, 7=2.38 Hz, 1H), 6.38-6.64 (m, 2H), 4.28 (br. s., 2H), 4.07 (br. s., 2H), 1.23 (s, 2H)Compound 3

[0227] Synthesis of (S)-2,2',2"-(10-(2-(4-(3-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl carbamoyl)quinolin-6-yl)-5-methoxyphenoxy)propyl)piperazin-1-yl)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7-triyl)triacetic acid

[0228] Step-1: Synthesis of l-bromo-2-(3-chloropropoxy)-4-methoxybenzene

[0229] To a stirred solution of 2-bromo-5-methoxyphenol (0.500 g, 2.463 mmol, 1.0 equiv) in ACN (8 mL) was added K2CO3 (0.849 g, 6.157 mmol, 2.5 equiv), followed by the addition of 1- bromo-3-chloropropane (0.778 g, 4.926 mmol, 2.0 equiv). The Reaction mixture was allowed to stir at 70 °C for 16h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 mL) and passed through celite®. The filtrate was concentrated under reduced pressure and purified by flash chromatography (0 to 20 % ethyl acetate in hexane as an eluent) to obtain l-bromo-2-(3- chloropropoxy)-4-methoxybenzene (0.680 g, 98 % Yield) as an off white solid.

[0230] LCMS: 279 [M+l]+

[0231] 'H NMR: (400 MHz, DMSO-d6) δ 7 44 (d, J = 8.58 Hz, 1H), 6.70 (d, J = 2.38 Hz, 1H), 6.51 (dd, J = 8.82, 2.62 Hz, 1H), 4.02-4.22 (m, 2H), 3.79-3.90 (m, 5H), 2.06-2.26 (m, 2H)

[0232] Step-2: Synthesis of 2-(2-(3-chloropropoxy)-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3, 2-dioxaborolane

[0233] To a stirred solution of l-bromo-2-(3-chloropropoxy)-4-methoxybenzene (1.2 g, 4.316 mmol, 1.0 equiv) in Dioxane (10 mL) was added Bis(pinacolato)diboron (1.63 g, 6.474 mmol, 1.5 equiv), followed by the addition of KOAc (1.27 g, 12.94 mmol, 3.0 equiv). The reaction mixture was purged with N2 for 5 minutes, followed by the addition of Pd(dppf)Ch.DCM (0.352 g, 0.431 mmol, 0.1 equiv). The resulting reaction mixture was heated at 90 °C for 16h. Product formationwas confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (20 ml x 2). Combined organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (0- 10 % ethyl acetate in hexane as an eluent) to obtain 2-(2-(3-chloropropoxy)-4-methoxyphenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (0.608 g, 43 % Yield) as an off white solid. LCMS: 326 [M+l]+

[0234] 'H NMR: (400 MHz, DMSO-d6) δ 7.45 (d, J = 8.58 Hz, 1H), 6.36 - 6.57 (m, 2H), 4.04 (t, J = 5.48 Hz, 2H), 3.88 - 4.02 (m, 2H), 3.68 - 3.85 (s , 3H), 2.01 - 2.27 (m, 2H), 1.25 (s, 12H)

[0235] Step-3: Synthesis of methyl 6-(2-(3-chloropropoxy)-4-methoxyphenyl)quinoline-4- carboxylate

[0236] To a stirred solution of methyl 6-bromoquinoline-4-carboxylate (0.300 g, 1.132 mmol, 1.0 equiv) in Dioxane: Water (3: 0.3 mL) was added K2CO3 (0.312 g, 2.264 mmol, 2.0 equiv), followed by the addition of 2-(2-(3-chloropropoxy)-4-methoxyphenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (0.553 g, 1.698 mmol, 1.5 equiv). The reaction mixture was purged with N2 for 5 minutes, followed by the addition of Pd(dppf)C12.DCM (0.046 g, 0.056 mmol, 0.05 equiv). The resulting reaction mixture was heated at 90 °C for 16h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (10 ml x 2). Combined organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (0- 20 % ethyl acetate in hexane as an eluent) to obtain methyl 6-(2-(3-chloropropoxy)-4-methoxyphenyl)quinoline-4-carboxylate (0.3 g, 68 % Yield) as an off white solid.

[0237] LCMS: 386 [M+l]+

[0238] 'H NMR: (400 MHz, DMSO-d6) δ 9.03 (d, J = 4.29 Hz, 1H), 8.70 (d, J = 1.91 Hz, 1H), 8.12 (d, J = 8.58 Hz, 1H), 7.88-8.01 (m, 2H), 7.40 (d, J = 8.58 Hz, 1H), 6.62-6.79 (m, 2H), 4.15 (t, J = 5.96 Hz, 2H), 3.95-4.04 (m, 3H), 3.84 (s, 3H), 3.67 (t, J = 6.44 Hz, 2H), 2.04-2.16 (m, 2H)

[0239] Step-4: Synthesis of methyl 6-(2-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)- 4-methoxyphenyl)quinoline-4-carboxylate

[0240] To a stirred solution of methyl 6-(2-(3-chloropropoxy)-4-methoxyphenyl)quinoline-4- carboxylate (0.250 g, 0.649 mmol, 1.0 equiv) in DMF (2.5 mL) was added KI (0.053 g, 0.324 mmol, 0.5 equiv), followed by the addition of tert-butyl piperazine- 1 -carboxylate (0.603 g, 3.246 mmol, 5.0 equiv). The Reaction mixture was allowed to stir at 70 °C for 16h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with DCM (10 ml x 2). Combined organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced. The crude product was purified by flash chromatography (0 to 5 % MeOH in DCM as an eluent) to obtain methyl 6-(2-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)-4- methoxyphenyl)quinoline-4-carboxylate (0.250 g, 72 % Yield) as an off white solid.

[0241] LCMS: 536 [M+l]+

[0242] 'H NMR: (400 MHz, DMSO-d6) δ 9.03 (d, J = 4.29 Hz, 1H), 8.71 (d, J = 1.43 Hz, 1H), 8.11 (d, J = 8.58 Hz, 1H), 7.89-8.00 (m, 2H), 7.38 (d, J = 8.58 Hz, 1H), 6.62-6.79 (m, 2H), 4.05 (t, J = 5.96 Hz, 2 H), 3.98 (s, 3 H), 3.83 (s, 3H), 3.17-3.24 (m, 4H), 2.28-2.37 (m, 2H), 2.18 (br. s., 4H), 1.81 (t, J = 6.68 Hz, 2H), 1.39 (s, 9H)

[0243] Step-5: Synthesis of 6-(2-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)-4- methoxyphenyl)quinoline-4-carboxylic acid

[0244] To a stirred solution of methyl 6-(2-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)-4-methoxyphenyl)quinoline-4-carboxylate (0.3 g, 0.561 mmol, 1.0 equiv) in THF (3 mL) was added LiOH.H2O (0.025 g, 0.617 mmol, 1.1 equiv) in water (0.3 ml). The Reaction mixture was allowed to stir at RT for 2h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the solvent was removed under reduced pressure and diluted with water, acidify with IN HC1. The resulting solid was filtered off and dried under vacuum to obtain 6-(2-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)-4-methoxyphenyl)quinoline-4- carboxylic acid (0.17 g, 58.2 % Yield) as an off white solid.

[0245] LCMS: 522 [M+l]+

[0246] 'H NMR: (400 MHz, DMSO-d6) δ 9.03 (d, J = 4.29 Hz, 1H), 8.71 (d, J = 1.43 Hz, 1H), 8.11 (d, J = 8.58 Hz, 1H), 7.89-8.00 (m, 2H), 7.38 (d, J = 8.58 Hz, 1H), 6.62-6.79 (m, 2H),4.05 (t, J = 5.96 Hz, 2H), 3.83 (s, 3H), 3.17-3.24 (m, 4H), 2.28-2.37 (m, 2H), 2.18 (br. s., 4H), 1.81 (t, J = 6.68 Hz, 2H), 1.39 (s, 9H)

[0247] Step-6: Synthesis of (S)-tert-butyl 4-(3-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)- 2-oxoethylcarbamoyl)quinolin-6-yl)-5 -methoxyphenoxy )propyl)piperazine-l -carboxylate

[0248] To a stirred solution of 6-(2-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propoxy)-4- methoxyphenyl)quinoline-4-carboxylic acid (0.150 g, 0.288 mmol, 1.0 equiv) in DMF (1.5 mL) was added EDC.HC1 (0.071 g , 0.374 mmol, 1.3 equiv), HOBT(0.050 g, 0.374 mmol, 1.3 equiv) followed by the addition of DIPEA(0.15 mL, 0.865 mmol, 3.0 equiv) and (S)-1-(2-aminoacetyl)- 4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (0.078 g, 0.346 mmol, 1.2 equiv. The resulting reaction mixture was allowed to stir at RT for 16h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with water (5 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure The crude product was purified by Flash chromatography (0-5 % MeOH in DCM as an eluent) to obtain (S)-tert-butyl 4-(3-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy) propyl)piperazine- 1 -carboxylate (0.150 g 75 % Yield) as off white solid.

[0249] LCMS: 693 [M+l]+

[0250] 'H NMR: (400 MHz, DMSO-d6) δ 9. 15 (t, J= 5.96 Hz, 1H), 8.98 (d, J= 4.29 Hz, 1H), 8.43 (d, J = 1.43 Hz, 1H), 8.12 (d, J = 8.58 Hz, 1H), 7.88-8.01 (m, 1H), 7.59 (d, 7 = 4.29 Hz, 1H), 7.32-7.45 (m, 1H), 6.57-6.77 (m, 2H), 5.07-5.17 (m, 1H), 4.20-4.27 (m, 4H), 4.11 (d, J = 6.20 Hz, 4H), 3.78-3.88 (m, 3H), 3.39 (d, J = 9.54 Hz, 2H), 3.18 (br. s., 2H), 2.84-3.00 (m, 6H), 2.09 (br. s., 2H), 1.39 (s, 9H)

[0251] Step-7: Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4- methoxy-2-(3-(piperazin- 1 -yl)propoxy)phenyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate

[0252] To a stirred solution of (S)-tert-butyl 4-(3-(2-(4-(2-(2-cyano-4,4-difhroropyrrolidin-1- yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5- methoxyphenoxy)propyl)piperazine- 1 -carboxylate (0.150 g, 0.217 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (0.3 mL) drop wise at 0 °C. The Reaction mixture was allowed to stir at RT for 2h. The product formation was confirmed byTLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and crystallized in diethyl ether to obtain (S)-N-(2-(2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)-6-(4-methoxy-2-(3 -(piperazin- 1- yl)propoxy)phenyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.080 g, 53.6 % Yield) as an off white solid.

[0253] LCMS: 593 [M+l]+

[0254] 'H NMR: (400 MHz, DMSO-76) 89.15 (t, J= 5.96 Hz, 1H), 8.98 (d, J= 4.29 Hz, 1H), 8.43 (d, J = 1.43 Hz, 1H), 8.12 (d, J = 8.58 Hz, 1H), 7.88-8.01 (m, 1H), 7.59 (d, 7 = 4.29 Hz, 1H), 7.32-7.45 (m, 1H), 6.57-6.77 (m, 2H), 5.76 (s, 1 H), 5.07-5.17 (m, 1H), 4.20-4.27 (m, 4H), 4.11 (d, J = 6.20 Hz, 4H), 3.78-3.88 (m, 3H), 3.39 (d, J = 9.54 Hz, 2H), 3.18 (br. s., 2H), 2.84-3.00 (m, 6 H), 2.09 (br. s., 2H)

[0255] Step-8: Synthesis of (S)-2,2',2"-(10-(2-(4-(3-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin- l-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)propyl)piperazin-1-yl)-2- oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7-triyl)triacetic acid

[0256] To a stirred solution of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6- (4-methoxy-2-(3 -(piperazin- l-yl)propoxy)phenyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.040 g, 0.058 mmol, 1.0 equiv) in DMF (0.2 mL) was added TEA (0.05 ml, 0.348 mmol, 6.0 equiv) and 2, 2', 2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)- 1,4, 7, 10-tetraazacyclododecane- 1,4, 7- triyl)triacetic acid (0.045 g, 0.087 mmol, 1.5 equiv). The Reaction mixture was allowed to stir at RT for 16 h. The product formation was confirmed by LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure, crystallized in diethyl ether and further purified by reversed phase HPLC to obtain (S)-2,2',2"-(10-(2-(4-(3-(2-(4-(2-(2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl) quinolin-6-yl)-5- methoxyphenoxy)propyl)piperazin- 1 -yl)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7- triyl)triacetic acid (0.027 g, 47 % Yield) as an off-white solid.

[0257] LCMS: 979 [M+l]+

[0258] 'H NMR: (400 MHz, DEUTERIUM OXIDE) δ 8.98 (d, J = .Tl Hz, 1H), 8.35-8.47 (m, 2H), 8.17 (d, 7= 8.58 Hz, 1H), 8.06 (d, 7 = 8.58 Hz, 1H), 7.76 (d, 7 = 4.29 Hz, 1H), 7.44 (d, 7 = 8.58 Hz, 1H), 6.71-6.83 (m, 2H), 5.12 (dd, 7= 8.11, 4.29 Hz, 1H), 4.32-4.49 (m, 2H), 4.18-4.32(m, 5H), 3.95-4.18 (m, 3H), 3.89 (s, 4H) 3.64-3.84 (m, 5H), 3.55 (s, 3H), 3.49 (br. s., 4H), 3.40(br. s., 6H), 3.34 (br. s., 2H), 3.15 (br. s., 5H), 3.10 (br. s., 6H), 2.85-3.02 (m, 6H), 2.22 (br. s., 2H)Compound 4

[0259] Synthesis of (S)-2,2',2"-(10-(2-(2-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethylamino)-2-oxoethyl)- 1 ,4,7, 10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0260] Step- 1 : Synthesis of tert-butyl (2-bromoethyl)carbamate

[0261] To a stirred solution of 2-bromoethanamine hydrobromide (0.500 g, 2.440 mmol, 1.0 equiv) in DCM (5 mL) was added TEA (1.40 ml, 9.760 mmol, 4.0 equiv), followed by the addition of Di-tert-butyl dicarbonate (0.585 g, 2.684 mmol, 1.1 equiv). The Reaction mixture was allowed to stir at room temperature for 16h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 3). The organic layer was separated, washed with cold water followed by brine wash, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (0 to 30 % ethyl acetate in hexane as an eluent) to obtain tert-butyl (2-bromoethyl)carbamate (0.450 g, 82 % Yield) as an off white solid.

[0262] 'H NMR: (400 MHz, DMSO-d6) 87.10 (br. s., 1H), 3.35-3.49 (m, 2H), 3.19-3.34 (m, 2H), 1.42-1.50 (m, 9H).

[0263] Step-2: Synthesis of tert-butyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)ethylcarbamate

[0264] To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (1.1 g, 5.0 mmol, 1.0 equiv) in ACN (10 mL) was added tert-butyl (2-bromoethyl)carbamate (1.67 g, 7.5 mmol, 1.5 equiv), followed by the addition of CS2CO3 (4.0 g, 12.5 mmol, 2.5equiv). The Reaction mixture was allowed to stir at 70 °C for 5h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20 mL) and passed through celite®. The filtrate was concentrated under reduced pressure and purified by flash chromatography (0 to 20 % ethyl acetate in hexane as an eluent) to obtain tertbutyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)ethylcarbamate (0.750 g, 41 % Yield) as an off white solid.

[0265] LCMS: 364 [M+l]+

[0266] 'H NMR: (400 MHz, DMSO-d6) δ 7 59 (m, J = 8.58 Hz, 2H), 7.01 (t, J = 5.25 Hz, 1H), 6.84-6.95 (m, 2H), 3.89-4.05 (m, 2H), 3.20-3.31 (m, 2H), 1.32-1.42 (m, 9H), 1.21-1.32 (m, 12H)

[0267] Step-3: Synthesis of methyl 6-(4-(2-(tert-butoxycarbonylamino)ethoxy)phenyl) quinoline-4-carboxylate

[0268] To a stirred solution of methyl 6-bromoquinoline-4-carboxylate (0.250 g, 0.943 mmol, 1.0 equiv) in Dioxane:Water (3: 0.3 mL) was added K2CO3 (0.260 g, 1.886 mmol, 2.0 equiv), followed by the addition of tert-butyl 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)ethylcarbamate (0.513 g, 1.415 mmol, 1.5 equiv). The reaction mixture was purged with N2 for 5 minutes, followed by the addition of Pd(dppf)C12.DCM (0.038 g, 0.047 mmol, 0.05 equiv). The resulting reaction mixture was heated at 90 °C for 16h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with ethyl acetate (30 ml x 2). Combined organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (0- 30 % ethyl acetate in hexane as aneluent) to obtain methyl 6-(4-(2-(tert-butoxycarbonylamino)ethoxy)phenyl)quinoline-4- carboxylate (0.2 g, 50 % Yield) as an off white solid. LCMS: 423 [M+l]+

[0269] 'H NMR: (400 MHz, DMSO-d6) 89.03 (d, J = 4.29 Hz, 1 H), 8.83 (s, 1 H), 8.09-8.21 (m, 2 H), 7.96 (d, J = 4.29 Hz, 1H), 7.76 (m, J = 8.58 Hz, 2H), 7.11 (m, J = 8.58 Hz, 2H), 7.05 (br. s., 1H), 3.99-4.11 (m, 5H), 3.34 (br. s., 2H), 1.40 (s, 9H)

[0270] Step-4: Synthesis of 6-(4-(2-(tert-butoxycarbonylamino)ethoxy)phenyl)quinoline-4- carboxylic acid

[0271] To a stirred solution of methyl 6-(4-(2-(tert- butoxycarbonylamino)ethoxy)phenyl)quinoline-4-carboxylate (0.4 g, 0.947 mmol, 1.0 equiv) in THF (4 mL) was added LiOH.H2O (0.043 g, 1.042 mmol, 1.1 equiv) in water (0.3 ml). The Reaction mixture was allowed to stir at RT for Ih. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the solvent was removed under reduced pressure and diluted with water, acidify with IN HC1. The resulting solid was filtered off and dried under vacuum to obtain 6-(4-(2-(tert-butoxycarbonylamino)ethoxy)phenyl)quinoline-4-carboxylic acid (0.3 g, 77.7 % Yield) as an off white solid.

[0272] LCMS: 409 [M+l]+

[0273] 'H NMR: (400 MHz, DMSO-d6) 8 9.00 (d, J = 4.29 Hz, IH), 8.92 (d, J = 1.43 Hz, IH), 8.06-8.18 (m, 2H), 7.94 (d, J = 4.29 Hz, IH), 7.73 (m, J = 8.58 Hz, 2H), 7.11 (m, J = 9.06 Hz, 2H), 7.05 (br. s., IH), 4.04 (t, J = 5.96 Hz, 2H), 3.34 (br. s., 2H), 1.39 (s, 9H)

[0274] Step-5: Synthesis of (S)-tert-butyl 2-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethylcarbamate

[0275] To a stirred solution of 6-(4-(2-(tert-butoxycarbonylamino)ethoxy)phenyl)quinoline-4- carboxylic acid (0.2 g, 0.490 mmol, 1.0 equiv) in DMF (2 mL) was added EDC.HC1 (0.121 g, 0.637 mmol, 1.3 equiv), HOBT(0.086 g, 0.637 mmol, 1.3 equiv) followed by the addition of DIPEA(0.27 mL, 1.470 mmol, 3.0 equiv) and (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (0.132 g, 0.588 mmol, 1.2 equiv. The resulting reaction mixture was allowed to stir at RT for 16h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers was washed with water (5 mL x 3), dried overanhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Flash chromatography (0-5 % MeOH in DCM as an eluent) to obtain (S)-tert-butyl 2- (4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6- yl)phenoxy)ethylcarbamate (0.16 g 56 % Yield) as an off white solid.

[0276] LCMS: 580 [M+l]+

[0277] 'H NMR: (400 MHz, DMSO-d6) δ 9..17 (t, J = 5.96 Hz, 1H), 8.94 (d, J = 4.29 Hz, 1H), 8.72 (d, J = 1.43 Hz, 1H), 8.05-8.23 (m, 2H), 7.79-7.93 (m, 2H), 7.56 (d, J = 4.29 Hz, 1H), 6.97-7.16 (m, 3H), 5.19 (dd, J = 9.30, 2.62 Hz, 1H), 4.24-4.37 (m, 3H), 4.10-4.24 (m, 1H), 4.01 (t, J = 5.48 Hz, 2H), 2.76-3.03 (m, 2H), 2.67 (d, J = 1.91 Hz, 1H), 1.39 (s, 9H)

[0278] Step-6: Synthesis of (S)-6-(4-(2-aminoethoxy)phenyl)-N-(2-(2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide

[0279] To a stirred solution of (S)-tert-butyl 2-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)- 2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethylcarbamate (0.100 g, 0.172 mmol, 1.0 equiv) in DCM ( 1 mL) was added TFA (0.2 mL) drop wise at 0 °C. The Reaction mixture was allowed to stir at RT for 2h. The product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (10 mL), washed with ethyl acetate (5 mL). The aqueous layer was separated and basified with sodium bicarbonate (saturated solution in water) and extracted with DCM (10 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the (S)-6-(4-(2-aminoethoxy)phenyl)-N-(2-(2- cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (0.060 g, 73 % Yield) as an off white solid.

[0280] LCMS: 480 [M+l]+

[0281] 'H NMR: (400 MHz, DMSO-tfe) δ 9..17 (s, 1H), 8.94 (d, J = 3.81 Hz, 1H), 8.73 (s, 1H), 8.03-8.22 (m, 2H), 7.88 (d, J = 8.58 Hz, 2H), 7.56 (d, J = 4.29 Hz, 1H), 7.10 (d, J = 8.58 Hz, 2H), 5.19 (d, J = 6.68 Hz, 1H), 4.35 (br. s., 1H), 4.29 (d, J = 3.34 Hz, 2H), 3.87-4.07 (m, 3H), 2.95 (t, J = 5.72 Hz, 2H), 2.89 (s, 2H), 2.83 (br. s., 1H), 2.73 (s, 1H), 2.08 (s, 1H)

[0282] Step7: Synthesis of (S)-2,2',2"-(10-(2-(2-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethyl carbamoyl)quinolin-6-yl)phenoxy)ethylamino)-2-oxoethyl)- 1 ,4,7, 10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0283] To a stirred solution of (S)-6-(4-(2-aminoethoxy)phenyl)-N-(2-(2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide (0.020 g, 0.042 mmol, 1.0 equiv) in DMF (0.2 mL) was added 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid (0.033 g, 0.063 mmol, 1.5 equiv) followed by the addition of TEA (0.03 ml, 0.252 mmol, 6.0 equiv). The reaction mixture was allowed to stir at room temperature for 16 h. The product formation was confirmed by LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure, crystallized in diethyl ether and further purified by reversed phase HPLC to obtain (S)-2,2',2"-(10-(2-(2-(4-(4-(2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethylamino)-2-oxoethyl)- 1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (0.012 g, 35 % Yield) as an off-white solid.

[0284] LCMS: 866 [M+l]+

[0285] 'H NMR : 400 MHz, DEUTERIUM OXIDE) δ 8.92 (d, J = 4.29 Hz, 1H), 8.38 (s, 1H), 8.28-8.36 (m, 1H), 8.15 (d, J= 8.58 Hz, 1H), 8.07 (d, 7= 9.06 Hz, 1H), 7.77 (d, 7 = 4.77 Hz, 1H), 7.56-7.73 (m, 2H), 7.03 (d, 7 = 8.11 Hz, 2H), 5.07 - 5.29 (m, 2H), 4.52 (br. s., 6H), 4.34 (s, 3H), 4.06-4.30 (m, 4H), 3.75-3.95 (m, 2H), 3.68-3.75 (m, 2H), 3.58 (br. s., 3H), 3.51 (br. s., 3H), 3.40 (br. s., 5H), 3.34 (br. s., 4H), 2.96-3.20 (m, 9H), 2.93 (d, 7 = 8.11 Hz, 2H)Compound 5

[0286] Synthesis of 2,2',2"-(10-(2-(3-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)phenoxy)piperidin-1-yl)-2-oxoethyl)- 1,4, 7,10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0287] Step-1: Synthesis of tert-butyl 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy) piperidine- 1 -carboxylate

[0288] To a stirred solution of Triphenylphosphine (2.0 g, 7.46 mmol, 1.5 equiv) in THF (2 mL) was added Diisopropyl azodicarboxylate (1.5 mL, 7. 46mmol, 1.5 equiv) drop wise at 0°C , followed by the addition of tert-butyl 3-hydroxypiperidine-l -carboxylate (1.0 g, 4.975 mmol, 1.0 equiv) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (1.1 g, 4.975 mmol, 1.0 equiv) dissolved in THF (4 mL) respectively. The Reaction mixture was allowed to stir at RT for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and residue was stirred in hexane (50 mL). The resulting solid was filtered off and filtrate was diluted with ethyl acetate (50 mL) and washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (5 to 20 % ethyl acetate in hexane as an eluent) to obtain tert-butyl 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)piperidine- 1 -carboxylate (0.27 g, 14 % Yield) as an off white solid.

[0289] 'H NMR: (400MHz ,DMSO-d6) δ 7.65-7.54 (m, J = 8.6 Hz, 2H), 7.00-6.89 (m, J = 8.6 Hz, 2H), 4.42 (br. s., 1H), 3.53 (br. s., 2H), 3.41 (br. s., 2H), 3.24 (br. s., 1H), 1.91 (br. s., 1 H), 1.71 (d, J = 4.3 Hz, 2H), 1.32-1.16 (m, 21H)

[0290] Step-2: Synthesis of methyl 6-(4-(l-(tert-butoxycarbonyl)piperidin-3- yloxy)phenyl)quinoline-4-carboxylate

[0291] To a stirred solution of tert-butyl 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)piperidine- 1 -carboxylate (0.220 g, 0.545 mmol, 1.0 equiv) in Dioxane:Water (10:1 mL) was added K2CO3 (0.150 g, 1.0 mmol, 2.0 equiv), followed by the addition of methyl 6- bromoquinoline-4-carboxylate (0.145 g, 0.545 mmol, 1.0 equiv). The reaction mixture was purged with N2 for 5 minutes, followed by the addition of Bis(triphenylphosphine)palladium chloride (0.022 g, 0.027 mmol, 0.05 equiv). The resulting reaction mixture was heated at 90 °C for overnight. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through celite® and washed with ethyl acetate. The organic layer was washed with water (10 mL) & brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (0- 50 % ethyl acetate in hexanes) to obtain methyl 6-(4-(l-(tert-butoxycarbonyl)piperidin-3- yloxy)phenyl)quinoline-4-carboxylate (0.16 g, 63 % Yield) as an off white solid.

[0292] LCMS: 463.3 [M+l]+

[0293] 'H NMR (400MHz ,DMSO-d6) δ 9.13 - 8.95 (m, 1H), 8.84-8.75 (m, 1H), 8.27-8.10 (m, 2H), 8.00-7.92 (m, 1H), 7.81-7.71 (m, J = 8.6 Hz, 2H), 7.16-7.02 (m, J = 9.1 Hz, 2H), 4.49 (br. s., 1H), 3.93 (s, 3H), 3.59-3.46 (m, 2H), 1.99 (s, 2H), 1.82 (br. s., 1H), 1.76 (br. s., 1H), 1.47 (br. s., 2H), 1.39 (d, J = 5.2 Hz, 9H)

[0294] Step-3: Synthesis of 6-(4-(l-(tert-butoxycarbonyl)piperidin-3-yloxy)phenyl)quinoline- 4-carboxylic acid

[0295] To a stirred solution of methyl 6-(4-(l -(tert-butoxycarbonyl )piperidin-3- yloxy)phenyl)quinoline-4-carboxylate (0.22 g, 0.43 mmol, 1.0 equiv) in THF (4 mL) was added LiOH.H2O (0.036 g, 0.87 mmol, 2.0 equiv) in water (4 ml). The Reaction mixture was allowed to stir at RT for overnight. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the THF was removed under reduced pressure and aqueous layer acidified with 1 N HC1 (pH~5). The resulting solid was filtered off and dried under vacuum to obtain 6-(4-(l-(tert- butoxycarbonyl)piperidin-3-yloxy)phenyl)quinoline-4-carboxylic acid (0.13 g, 67 % Yield) as yellow solid.

[0296] LCMS: 449.3 [M+l]

[0297] 'H NMR: (400MHz ,DMSO-d6) δ 13.87 (br. s., 1H), 9.10-8.97 (m, 1H), 8.97-8.86 (m, 1H), 8.19-8.03 (m, 2H), 7.98-7.86 (m, 1H), 7.81-7.67 (m, J = 8.6 Hz, 2H), 7.24-7.02 (m, J = 8.6 Hz, 2H), 4.49 (br. s., 1H), 3.50 (br. s., 2H), 1.77 (d, J = 8.1 Hz, 2H), 1.46 (br. s., 2H), 1.40 (br. s., 2H), 1.33 (br. s., 9H)

[0298] Step-4: Synthesis of tert-butyl 3-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)phenoxy)piperidine-l -carboxylate

[0299] To a stirred solution of 6-(4-(l -(tert-butoxycarbonyl )piperidin-3- yloxy)phenyl)quinoline-4-carboxylic acid (0.13 g, 0.29 mmol, 1.0 equiv) in DMF (2 mL) was added EDC.HC1 (0.084 g, 0.44 mmol, 1.5 equiv) HOBT(0.06 g, 0.44 mmol, 1.5 equiv) and (S)-1- (2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (0.065 g, 0.29 mmol, 1.0 equiv) followed by the addition of DIPEA(0.12 mL,0.87 mmol, 3.0 equiv). The resulting reaction mixture was allowed to stir at RT for 16h. Product formation was confirmed LCMS. After completion of the reaction, the reaction mixture was poured into cold water (10 mL). The resulting solid filtered off and the residue was purified by Flash chromatography (0-7 % MeOH in DCM as an eluent) to obtain tert-butyl 3-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)phenoxy)piperidine-l -carboxylate (0.15 g, 84 % Yield) as an off white solid.

[0300] LCMS: 620.4 [M+l]+

[0301] 1H NMR (400MHz ,DMSO-d6) δ 9.22-9.12 (m, 1H), 8.95 (d, J = 4.3 Hz, 1H), 8.72 (s,1H), 8.26-8.06 (m, 2H), 7.87 (d, J = 6.7 Hz, 2H), 7.56 (d, J = 4.3 Hz, 1H), 7.10 (d, J = 8.6 Hz, 2H), 5.18 (d, J = 8.6 Hz, 1H), 4.46 (br. s., 1H), 4.32-4.06 (m, 2H), 3.48 (br. s., 3H), 3.17 (d, J = 5.2 Hz, 2H), 2.92-2.70 (m, 2H), 1.96 (br. s., 1H), 1.74 (br. s., 2H), 1.40 (br. s., 2H), 1.33 (s, 9H).

[0302] Step-5: N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-(piperidin-3- yloxy) phenyl)quinoline-4-carboxamide

[0303] To a stirred solution of tert-butyl 3-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)- 2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)piperidine-l -carboxylate (0.150 g, 0.242 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (0.5 mL) and allowed to stir at RT for 2h. The product formation was confirmed by LCMS. After completion of the reaction, the reaction mixture was diluted with DCM (20 mL). Organic layer washed with saturated NaHCOa solution (10 mL) andextracted with DCM (2 x 10 ml). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-(piperidin-3-yloxy)phenyl)quinoline-4-carboxamide (0.120, 96 % Yield) as an off white solid.

[0304] LCMS: 520.3 [M+l]+

[0305] 'H NMR: (400MHz ,DMSO-d6) δ 9. 18 (t, J = 6.0 Hz, 1H), 8.96 (d, J = 4.3 Hz, 1H), 8.72 (s, 1 H), 8.61 (br. s., 1H), 8.21-8.03 (m, 2H), 7.94-7.81 (m, 2H), 7.65-7.51 (m, 1H), 7.19 (d, J = 8.6 Hz, 2H), 5.26-5.11 (m, 1H), 4.78 (br. s., 1H), 4.37-4.22 (m, 4H), 3.45-3.29 (m, 3H), 3.10 (br. s., 2H), 2.95-2.78 (m, 2H), 1.91 (br. s., 2H), 1.69 (br. s., 1H)

[0306] Step6: Synthesis of 2,2',2"-(10-(2-(3-(4-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)piperidin-1-yl)-2-oxoethyl)- 1,4, 7,10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0307] To a stirred solution of N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6- (4-(piperidin-3-yloxy)phenyl)quinoline-4-carboxamide (0.020 g, 0.038 mmol, 1.0 equiv) and 2,2',2"-( 10-(2-(4-nitrophenoxy)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid (0.06 g, 0.115 mmol, 3.0 equiv.) in DMF (0.2 mL) was added TEA (0.03 ml, 0.023 mmol, 6.0 equiv). The Reaction mixture was allowed to stir at room temperature for 16 h. The product formation was confirmed by LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure, crystallized in diethyl ether and further purified by reversed phase HPLC to obtain 2,2',2"-(10-(2-(3-(4-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)piperidin-1-yl)-2-oxoethyl)- 1,4, 7, 10- tetraazacyclododecane- 1,4, 7-triyl)triacetic acid as formic acid salt (0.007 g, 20 % Yield) as an off-white solid.

[0308] LCMS: 906.2 [M+l]+

[0309] 'H NMR: (400MHz , DEUTERIUM OXIDE) 8 8.85 (br. s., 1H), 8.42-8.33 (m, 1H), 8.31-8.20 (m, 1H), 8.12-7.88 (m, 2H), 7.66 (d, J = 7.6 Hz, 2H), 7.58 (br. s., 1H), 7.02-6.84 (m, 2H), 5.14 (br. s., 1H), 4.62 (br. s., 1H), 4.47 (br. s., 1H), 4.28 (br. s., 3H), 4.11 (dd, J = 10.0, 19.6 Hz, 2H), 3.97-3.77 (m, 3H), 3.70 (br. s., 2H), 3.58 (d, J= 13.4 Hz, 4H), 3.45 (d, J= 14.8 Hz, 3H),3.34 (br. s., 4H), 3.25 (br. s., 4H), 3.13 (br. s., 4H), 2.93 (br. s., 4H), 1.97 (d, J = 15.7 Hz, 1H),1.86 (br. s., 2H), 1.60 (br. s., 1H)Compound 6

[0310] Synthesis of 4-(2-(3-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl) quinolin-6-yl)phenoxy)piperidin- 1 -yl)-2-oxoethylcarbamoyl)-2-(6-hydroxy- 3-oxo-3H-xanthen-9-yl)benzoic acid

[0311] Stepl: Synthesis of tert-butyl 2-(3-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)piperidin-1-yl)-2-oxoethylcarbamate

[0312] To a stirred solution of N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6- (4-(piperidin-3-yloxy)phenyl)quinoline-4-carboxamide (0.05 g, 0.096 mmol, 1.0 equiv) in DMF(2 mL) was added HATU (0.055 g, 0.144 mmol, 1.5 equiv), 2-(tert-butoxycarbonylamino)acetic acid (0.02 g, 0.115 mmol, 1.2 equiv) followed by the addition of DIPEA(0.05 mL, 0.289 mmol, 3.0 mL). The resulting reaction mixture was allowed to stir at RT for 16 h. The product formation was confirmed by LCMS. After completion of the reaction, the reaction mixture was poured in ice cold water (10 mL). The resulting solid was filtered off and dried under vacuum to obtain tert-butyl 2- (3-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6- yl)phenoxy)piperidin- 1 -yl)-2-oxoethylcarbamate (0.050 g,77 % Yield) as an off white solid.

[0313] LCMS: 677.3 [M+l]+

[0314] 'H NMR (400MHz ,DMSO-d6) δ 9.24 - 9.05 (m, 1H), 8.95 (d, J= 4.3 Hz, 1H), 8.74 (d, J = 10.5 Hz, 1H), 8.28-8.01 (m, 2H), 7.88 (d, J = 5.2 Hz, 2H), 7.56 (d, J = 4.3 Hz, 1H), 7.13 (t, J = 9.1 Hz, 2H), 6.75 (br. s., 1H), 5.20 (br. s., 1H), 4.34 (br. s., 1H), 4.28 (br. s., 2H), 4.17-3.98(m, 1H), 3.83 (br. s., 2H), 3.62 (br. s., 2H), 2.96 (br. s., 1H), 2.92-2.80 (m, 1H), 2.07 (s, 1H), 1.96 (br. s., 1H), 1.80 (br. s., 2H), 1.53 (br. s., 1H), 1.38 (d, J = 6.2 Hz, 9H), 1.31 (s, 2H)

[0315] Step-2: Synthesis of 6-(4-(l-(2-aminoacetyl)piperidin-3-yloxy)phenyl)-N-(2-((S)-2- cyano-4,4-difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate

[0316] To a stirred solution of tert-butyl 2-(3-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)piperidin-1-yl)-2-oxoethylcarbamate (0.05 g, 0.073 mmol, 1.0 equiv) in DCM (2 mL) was added TFA (0.2 mL) and allowed to stir at RT for overnight. The product formation was confirmed by LCMS. After completion reaction mixture concentrated under reduced pressure and residue was crystallized in ether to obtain 6-(4-(l-(2- aminoacetyl)piperidin-3-yloxy)phenyl)-N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.05 g, 99 % Yield) as an off white solid.

[0317] LCMS: 577.4 [M+l]+

[0318] Step-3: Synthesis of 4-(2-(3-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)phenoxy)piperidin-1-yl)-2-oxoethylcarbamoyl)-2-(6-hydroxy- 3-oxo-3H-xanthen-9-yl)benzoic acid

[0319] To a stirred solution of 6-(4-(l-(2-aminoacetyl)piperidin-3-yloxy)phenyl)-N-(2-((S)-2- cyano-4,4-difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.050 g, 0.072 mmol, 1.0 equiv) in DMF (2 mL) was added HATU (0.041 g, 0.108 mmol, 1.5 equiv), 3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-l,9'-xanthene]-6-carboxylic acid (0.033 g, 0.086 mmol, 1.2 equiv) followed by the addition of DIPEA (0.052 mL, 0.288 mmol, 4.0 equiv). The resulting reaction mixture was allowed to stir at room temperature for 16h. The product formation was confirmed by LCMS. After completion of the reaction, the reaction mixture was acidified with 1 M HC1. The resulting solid was filtered off, dried under vacuum. The crude product was purified by reversed phase HPLC to obtain 4-(2-(3-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl) quinolin-6-yl)phenoxy)piperidin- 1 -yl)-2- oxoethylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid (0.01 g, 15 % Yield) as a brown solid.

[0320] LCMS: 935.0 [M+l]

[0321] 'H NMR 'H NMR (400MHz ,DMSO-d6) δ 10 15 (s, 2H), 9.16 (br. s., 1H), 8.95 (d, J = 4.3 Hz, 1H), 8.87 (d, J = 12.9 Hz, 1H), 8.72 (br. s., 1H), 8.26-8.02 (m, 4H), 7.85 (br. s., 2H), 7.72 (br. s., 1H), 7.56 (d, J= 4.3 Hz, 1H), 7.20-7.00 (m, 2H), 6.69 (s, 2H), 6.62-6.40 (m, 4H), 5.17 (br. s., 1H), 4.34 (br. s., 1H), 4.27 (br. s., 2H), 4.16 (d, J = 11.4 Hz, 3H), 4.00 (br. s., 1H), 3.71 (br. s., 2H), 2.83 (d, J = 11.9 Hz, 2H), 2.07 (s, 2H), 1.90 (br. s., 2H), 1.64 (br. s., 2H)Compound 7

[0322] Synthesis of (S)-2,2',2"-(10-(2-(2-(2-(2-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethoxy)ethoxy)ethylamino)-2-oxoethyl)-1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7-triyl)triacetic acid

[0323] Step-1: Synthesis of methyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline- 4-carboxylate

[0324] To a stirred solution of methyl 6-bromoquinoline-4-carboxylate (0.500 g, 1.886 mmol, 1.0 equiv) in dioxane (5 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane (0.713 g, 2.830 mmol, 1.5 equiv), followed by the addition of KOAc (0.5512 g, 5.658 mmol, 3.0 equiv). The reaction mixture was purged with N2 for 5 minutes, followed by the addition of Pd(dppf)C12.DCM (0.532 g, 0.188 mmol, 0.1 equiv). The resulting reaction mixture was heated at 90 °C for 16 h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (20 ml x 2). Combined organic layer was separated, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified by flash chromatography OSO % ethyl acetate in hexane as an eluent) to obtain methyl 6-(4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)quinoline-4-carboxylate (0.590 g, Quant. Yield) as an off white solid.

[0325] LCMS: 314 [M+l]+

[0326] 'H NMR: (400 MHz, DMSO-d6) δ 9.11 (d, J = 4.29 Hz, 1H), 9.03 (s, 1H), 8.12 (d, J= 8.11 Hz, 1H), 8.03 (dd, J = 8.34, 1.19 Hz, 1H), 7.91-7.99 (m, 1H), 3.96 (s, 3H), 1.35 (s, 12H)

[0327] Step-2: Synthesis of methyl 6-(4-((2,2-dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan-13- yl)oxy)phenyl)quinoline-4-carboxylate

[0328] To a stirred solution of tert-butyl (2-(2-(2-(4- bromophenoxy)ethoxy)ethoxy)ethyl)carbamate (0.660 g, 1.575 mmol, 1.0 equiv) in Dioxane:Water (6:0.8 mL) was added K2CO3 (0.435 g, 31.150 mmol, 2.0 equiv), followed by the addition of methyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline-4-carboxylate (0.591 g, 1.890 mmol, 1.0 equiv). The reaction mixture was purged with N2 for 5 minutes, followed by the addition of Pd(dppf)Ch.DCM (0.065 g, 0.078 mmol, 0.05 equiv). The resulting reaction mixture was heated at 90 °C for 16 h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with ethyl acetate (20 ml x 2). Combined organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (0- 40 % ethyl acetate in hexane as an eluent) to obtain methyl 6-(4-((2,2- dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan-13-yl)oxy)phenyl)quinoline-4-carboxylate (0.270 g, 32 % Yield) as an off white solid.

[0329] LCMS: 511 [M+l]+

[0330] Step-3: Synthesis of 6-(4-((2,2-dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan-13-yl)oxy) phenyl)quinoline-4-carboxylic acid

[0331] To a stirred solution of methyl 6-(4-((2,2-dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan- 13-yl)oxy)phenyl)quinoline-4-carboxylate (0.300 g, 0.588 mmol, 1.0 equiv) in THF (2.5 mL) was added LiOH.H2O (0.035 g, 0.823 mmol, 1.1 equiv) in water (0.8 ml). The Reaction mixture was allowed to stir at RT for 2 h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the THF was removed under reduced pressure and diluted with water,acidify with IN HC1. The resulting solid was filtered to and dried under vacuum obtain 6-(4-((2,2- dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan-13-yl)oxy)phenyl)quinoline-4-carboxylic acid (0.200 g, 68 % Yield) as an off white solid.

[0332] LCMS: 497 [M+l]+

[0333] 'H NMR: (400 MHz, DMSO-d6) 8 13.88 (br. s., 1H), 9.01 (d, J = 4.29 Hz, 1H), 8.93 (s, 1H), 8.09-8.23 (m, 2H), 7.96 (d, J = 4.29 Hz, 1H), 7.74 (m, J = 8.58 Hz, 2H), 7.13 (m, J = 8.11 Hz, 2H), 6.77 (br. s., 1H), 4.17 (br. s., 2H), 3.78 (br. s., 2H), 3.61 (br. s., 2H), 3.54 (br. s., 2H), 3.40 (t, J = 5.72 Hz, 2H), 3.07 (d, J = 5.72 Hz, 2H), 1.31 (s, 9H)

[0334] Step-4: Synthesis of (S)-tert-butyl (2-(2-(2-(4-(4-((2-(2-cyano-4,4-difluoropyrrolidin- l-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)ethoxy)ethoxy)ethyl)carbamate

[0335] To a stirred solution of 6-(4-((2,2-dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan-13- yl)oxy)phenyl)quinoline-4-carboxylic acid (0.180 g, 0.362 mmol, 1.0 equiv) in DMF (3 mL) was added EDC.HC1 (0.090 g , 0.470 mmol, 1.3 equiv), HOBt (0.064 g, 0.470 mmol, 1.3 equiv) followed by the addition of DIPEA(0.2 mL, 1.088 mmol, 3.0 equiv) and (S)-1-(2-aminoacetyl)- 4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (0.098 g, 0.435 mmol, 1.2 equiv). The resulting reaction mixture was allowed to stir at RT for 16h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers was washed with water (10 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Flash chromatography (0-5 % MeOH in DCM as an eluent) to obtain (S)-tert-butyl (2-(2-(2-(4-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)ethoxy)ethoxy)ethyl)carbamate (0.103 g, 42 % Yield) as an off white solid. LCMS: 668 [M+l]+

[0336] 'H NMR: (400 MHz, DMSO-d6) δ 9.16 (t, J= 5.96 Hz, 1H), 8.95 (d, J= 4.29 Hz, 1H), 8.73 (d, J = 1.43 Hz, 1H), 8.07-8.23 (m, 2H), 7.87 (d, J = 9.06 Hz, 2H), 7.56 (d, J = 4.29 Hz, 1H), 7.10 (d, J = 9.06 Hz, 2H), 6.77 (br. s., 1H), 5.19 (dd, 7=9.30, 2.62 Hz, 1H), 4.10-4.39 (m, 7H), 3.71-3.85 (m, 2H), 3.49-3.66 (m, 5H), 3.39 (t, J = 6.20 Hz, 2H), 3.07 (q, J = 5.88 Hz, 2H), 1.32- 1.43 (m, 9H)

[0337] Step-5: Synthesis of (S)-6-(4-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)phenyl)-N-(2-(2- cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide

[0338] To a stirred solution of (S)-tert-butyl (2-(2-(2-(4-(4-((2-(2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)phenoxy)ethoxy)ethoxy)ethyl)carbamate (0.100 g, 0.149 mmol, 1.0 equiv) in DCM (4 mL) was added TFA (0.2 mL) drop wise at 0 °C. The Reaction mixture was allowed to stir at RT for 2 h. The product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in saturated NaHCO3 (10 mL) and extracted with DCM (25 mL x 2). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain (S)-6-(4-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)phenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)quinoline-4-carboxamide (0.030 g, 35 % Yield) as an off white solid.

[0339] LCMS: 568 [M+l]+

[0340] 'H NMR: (400 MHz, DMSO-d6) 89.17 (br. s., 1H), 8.95 (d, J = 4.77 Hz, 1H), 8.73 (s, 1H), 8.08-8.27 (m, 2H), 7.88 (d, J= 8.58 Hz, 2H), 7.57 (d, J = 4.29 Hz, 1H), 7.10 (d, J= 8.58 Hz, 2H), 5.19 (d, J = 8.58 Hz, 1H), 4.35 (br. s., 2H), 4.27 (br. s., 2H), 4.16 (br. s., 4H), 3.79 (br. s., 2H), 3.61 (m, 2H), 3.63 (s, 2H), 3.53 (t, J = 5.01 Hz, 2H), 2.77-3.03 (m, 2H)

[0341] Step-6:- Synthesis of (S)-2,2',2"-(10-(2-((2-(2-(2-(4-(4-((2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy) ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid

[0342] To a stirred solution of (S)-6-(4-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)phenyl)-N-(2- (2-cyano-4,4-difhioropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (0.030 g, 0.053 mmol, 1.0 equiv) in DMF (0.2 mL) was added 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid (0.042 g, 0.079 mmol, 1.5 equiv) and TEA (0.05 ml, 0.317 mmol, 6.0 equiv). The Reaction mixture was allowed to stir at room temperature for 16 h. The product formation was confirmed by LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure, crystallized in diethyl ether and further purified by reversed phase HPLC to obtain (S)-2,2',2"-(10-(2-((2-(2-(2-(4-(4-((2-(2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7- triyl)triacetic acid (0.011 g, 22 % Yield) as an off-white solid.

[0343] LCMS: 854 [M+l]+

[0344] 'H NMR: (400 MHz, DEUTERIUM OXIDE) δ 8.86 (d, J = 4.29 Hz, 1H), 8.39 (s, 1H), 7.98-8.16 (m, 2H), 7.76 (m, J = 8.58 Hz, 2H), 7.68 (d, J = .Tl Hz, 1H), 7.09 (m, J = 8.58 Hz, 2H), 5.18 (dd, J= 8.11, 4.29 Hz, 1H), 4.09-4.39 (m, 6H), 3.92 (br. s., 2H), 3.55-3.83 (m, 10H), 3.42 (s, 3H), 3.30-3.39 (m, 6H), 3.27 (br. s., 4H), 3.21 (br. s., 2H), 2.96-3.06 (m, 2H), 2.93 (br. s., 6H)Compound 8

[0345] Synthesis of (S)-2,2',2"-(10-(2-(2-(2-(2-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethoxy)ethoxy)ethylamino)-2- oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7-triyl)triacetic acid

[0346] Step-1: Preparation of 2,2-dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan-13-yl 4-methyl benzenesulfonate

[0347] To a stirred solution of tert-butyl 2-(2-(2-hydroxy ethoxy )ethoxy)ethylcarbamate (1.0 g, 4.0 mmol, 1.0 eq) in DCM (20 mL) was added triethylamine (1.6 mL, 28.26 mmol, 3.0 eq) at RT followed by the addition of p-toluenesulfonyl chloride (1.14 g, 6.02 mmol, 1.5 eq) and the mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was quenched with water (50 mL) and extracted with DCM (50 mLx 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by CombiFlash Chromatography to afford the title compound (1.3 g, 80.34 %).

[0348] LCMS: 404 [M+H]+

[0349] Step-2: Preparation of tert-butyl 2-(2-(2-(2-bromo-5-methoxyphenoxy)ethoxy)ethoxy) ethylcarbamate

[0350] To a stirred solution of 2-bromo- 5 -methoxyphenol (0.43 g, 2.2 mmol, 1.2 eq) in DMF (5 mL) was added CS2CO3 (0.86 mL, 2.65 mmol, 1.5 eq) followed by the addition of 2,2-dimethyl- 4-oxo-3,8,l l-trioxa-5-azatridecan- 13-yl 4-methyl benzenesulfonate (0.5 g, 1.76 mmol, 1.0 eq) and the mixture was heated at 80 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was quenched with water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers weere dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.500 g, 93.10 %).

[0351] LCMS: 434 [M+H]+

[0352] Step-3: Preparation of tert-butyl 2-(2-(2-(5-methoxy-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenoxy)ethoxy)ethoxy)ethylcarbamate

[0353] To a stirred solution of tert-butyl 2-(2-(2-(2-bromo-5- methoxyphenoxy)ethoxy)ethoxy) ethylcarbamate (0.5 g, 1.15 mmol, leq) in 1,4-Dioxane (20 mL) were successively added bis(pinacolato)diboron (0.44 g, 1.72 mmol, 1.5 eq) and KO Ac (0.338 g, 3.44 mmol, 3.0 eq) and the mixture was degassed using nitrogenlO min. Pd(dppf)C12 (0.084 g, 0.115 mmol, 0.1 eq) was then added to the mixture and the mixture was further degassed for 5 min. The resultant mixture was then heated at 90 °C for 4 h. After completion, the mixture was quenched with water (20 mL) and extracted using ethyl acetate (40 mL x 2). The combined organic layers were washed with water (25 mLO, brine (25 mL), dried over anhydrous sodium sulfate and concentrated to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.320 g, 57.65 %).

[0354] LCMS: 482 [M+H]+

[0355] Step-4: Preparation of methyl 6-(2-(2,2-dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan- 13-yloxy)-4-methoxyphenyl)quinoline-4-carboxylate

[0356] To a solution of tert-butyl 2-(2-(2-(5-methoxy-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenoxy)ethoxy)ethoxy)ethylcarbamate (0.32 g, 0.66 mmol, leq) and methyl 6-bromoquinoline-4-carboxylate (0.17 g, 0.66 mmol, 1.5 eq) in 1,4-Dioxane (8 mL) were added K2CO3 (0.27 g, 2.0 mmol, 3.0 eq) and water (2 ml) and the mixture was degassed under using nitrogen for 10 min. Pd(dppf)C12 (0.05 g, 0.066 mmol, 0.1 eq) was then added to the mixture and the mixture was further degassed for 5 min. The resultant reaction mixture was heated at 120 °C for 5 h. The progress of the reaction was monitored by TLC and LC-MS. After completion, the mixture was quenched with water (20 mL) and extracted using ethyl acetate (40 mL x 2). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.2 g, 55.67 %).

[0357] LCMS: 541 [M+H]+

[0358] Step-5: Preparation of 6-(2-(2,2-dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan-13- yloxy)-4-methoxyphenyl)quinoline-4-carboxylic acid

[0359] To a stirred solution of methyl 6-(2-(2,2-dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan- 13-yloxy)-4-methoxyphenyl)quinoline-4-carboxylate (0.150 g, 0.27 mmol, 1.0 eq) in THF (12 mL)-MeOH (8 mL) was added LiOH.H2O (0.58 g, 1.38 mmol, 5.0 eq) in water (4 mL) and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was acidified using 2N-HC1 (pH ~ 2-3) to obtain a precipitate which was filtered under vacuum and dried to afford the title compound (150 mg, 82.19 %)

[0360] LCMS: 527 [M+H]+

[0361] Step-6: Preparation of (S)-tert-butyl 2-(2-(2-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin- l-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethoxy)ethoxy) ethylcarbamate

[0362] To a stirred solution of 6-(2-(2,2-dimethyl-4-oxo-3,8,l l-trioxa-5-azatridecan-13- yloxy)-4-methoxyphenyl)quinoline-4-carboxylic acid (0.12 g, 0.23 mmol, 1.0 eq) in DMF (5 mL) were successively added EDC.HC1 (0.048 g, 0.25 mmol, 1.1 eq) and HOBt (0.0.34 g, 0.25 mmol, 1.1 eq) at 0 °C and the mixture was stirred at same temperature for 15 min. Triethylamine (0.05mL,0.34 mmol, 1.5 eq) and (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (0.057 g, 0.25 mmol, 1.1 eq) were the added to the mixture and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC and LC-MS. After completion, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined combined organic layers were washed with water (20 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.120 g ,57 % )

[0363] LCMS: 698 [M+H]+

[0364] Step-7: Preparation of (S)-6-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-4- methoxyphenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide trifluoroacetate salt:

[0365] To a stirred solution of (S)-tert-butyl 2-(2-(2-(2-(4-(2-(2-cyano-4,4-difhroropyrrolidin- l-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethoxy)ethoxy)ethylcarbamate(0.06 g, 0.08 mmol, 1.0 eq) in DCM (2 mL) was added TFA (0.1 mL) drop wise at 0 °C and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue which was triturated with diethyl ether (10 mL x 2) to afford the title compound as a trifluoroacetate salt (0.040 g, 65.45 %)

[0366] LCMS: 598 [M+H]+

[0367] Step-8: Preparation of (S)-2,2',2"-(10-(2-(2-(2-(2-(2-(4-(2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethoxy) ethoxy)ethylamino)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0368] To a stirred solution of (S)-6-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-4- methoxyphenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide trifluoroacetate salt (0.040 g, 0.066 mmol, 1.0 eq) in DMF (0.2 mL) were added 2, 2', 2"-(10-(2-(4-ni trophenoxy)-2-oxoethyl)- 1,4, 7, 10-tetraazacyclododecane- 1, 4, 7-triyl)triacetic acid (0.042 g, 0.080 mmol,1.2eq) and TEA (0.03 mL, 0.198 mmol, 6.0 eq) and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC and LC-MS. Aftercompletion, the mixture was concentrated under reduced pressure, triturated in diethyl ether and further purified by reversed phase HPLC to afford the title compound (0.011 g, 16.9 % )

[0369] LCMS: 984 [M+H]+

[0370] 'H NMR: (400 MHz, D2O) δ 9.15 (d, J = 5.2 Hz, 1H), 8.60 (s, 1H), 8.43 (d, J = 8.6 Hz, 1H), 8.31 (d, J = 9.1 Hz, 1H), 8.09 (d, J = 5.2 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 6.87-6.76 (m, 2H), 5.14 (dd, J= 3.8, 9.1 Hz, 2H), 4.40 (d, J = 8.1 Hz, 1H), 4.33-4.22 (m, 3H), 3.91 (s, 3H), 3.90- 3.80 (m, 4H), 3.80 -3.69 (m, 3H), 3.65-3.53 (m, 4H), 3.52-3.39 (m, 5H), 3.34 (td, J= 5.2, 10.1 Hz, 10H), 3.17-3.03 (m, 8H), 3.03-2.88 (m, 5H)Compound 9

[0371] Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(2-(l- (3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-l,9'-xanthene]-6-yl)-1,4-dioxo-8,l l-dioxa-2,5- diazatridecan-13-yloxy)-4-methoxyphenyl)quinoline-4-carboxamide

[0372] Stepl:- Preparation of (S)-tert-butyl 2-(2-(2-(2-(2-(4-(2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethoxy) ethoxy )ethylamino)-2-oxoethylcarbamate

[0373] To a stirred solution of 2-(tert-butoxycarbonylamino)acetic acid (0.023 g, 0.133 mmol, 1.0 eq) in DMF (2 mL) was added HATU (0.076 g, 0.199mmol, 5 eq) at 0 °C and the mixture was stirred at same temperature for 10 min. DIPEA (0.07 mL, 0.4 mmol, 3.0 mL) and (S)-6-(2-(2- (2-(2-aminoethoxy)ethoxy)ethoxy)-4-methoxyphenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (0.080 g, 0.133 mmol, 1.0 eq) were then added to the mixture and the mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (15 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with ice-cold water (10 mL) followed by brine wash (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.090 g, 89.10 %)

[0374] LCMS: 755 [M+H]+

[0375] Step-2: Preparation of (S)-6-(2-(2-(2-(2-(2-aminoacetamido)ethoxy)ethoxy)ethoxy)-4- methoxyphenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide

[0376] To a stirred solution of (S)-tert-butyl 2-(2-(2-(2-(2-(4-(2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethoxy) ethoxy)ethylamino)-2-oxoethylcarbamate (0.090 g, 0.119 mmol, 1.0 eq) in DCM (2 mL) was added TFA (0.1 mL) drop wise at 0 °C and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue which was triturated with diethyl ether (10 mL x 2) to afford the title compound as a trifluoroacetate salt (0.060 g, 65.54 % )

[0377] LCMS: 655 [M+H]+

[0378] Step-3: Preparation of (S)-4-(2-(2-(2-(2-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethoxy)ethoxy)ethylamino)-2- oxoethylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0379] To a stirred solution of 3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-l,9'-xanthene]- 6-carboxylic acid (0.035 g, 0.09 mmol, 1.0 eq) in DMF (1 mL) was added HATU (0.05 g, 0.14 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 5 min. DIPEA (0.063 mL, 0.366 mmol, 4.0 eq) and (S)-6-(2-(2-(2-(2-(2-aminoacetamido)ethoxy)ethoxy) ethoxy)-4- methoxyphenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide, 2,2,2-trifluoroacetate salt (0.06 g, 0.09 mmol, 1.0 eq) were then added to the mixture and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLCand LCMS. After completion, the mixture was acidified with 1 N-HC1 to obtain a precipitate which was filtered under vacuum, dried and purified by Reversed Phase HPLC to afford the title compound (0.002 g, 25.26 %).

[0380] LCMS: 1013 [M+H]+

[0381] 'H NMR: (400 MHz, DMSO-d6) δ 9.10 (t, J = 6.2 Hz, 1H), 8.96-8.89 (m, 2H), 8.47- 8.34 (m, 2H), 8.28-8.11 (m, 1H), 8.11-7.89 (m, 2H), 7.70 (s, 1H), 7.55 (d, J = 4.3 Hz, 1H), 7.51- 7.30 (m, 2H), 7.18 (br. s., 1H), 7.13-6.99 (m, 1H), 6.75-6.64 (m, 2H), 6.60 (d, J = 9.1 Hz, 2H), 6.56-6.49 (m, 2H), 5.13 (dd, J = 2.9, 9.1 Hz, 1H), 4.36-4.19 (m, 2H), 4.19-4.10 (m, 3H), 3.85-3.67 (m, 2H), 1.62 (br. s., 1H), 1.58-1.41 (m, 4H), 1.24 (s, 6H), 1.21-1.12 (m, 4H), 1.08 (d, J = 7.2 Hz, 2H).Compound 10

[0382] Synthesis of (S)-2,2',2"-(10-(2-(2-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethylamino)-2-oxoethyl)- 1,4, 7,10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0383] Step-1: Synthesis of tert-butyl 2-(2-bromo-5-methoxyphenoxy)ethylcarbamate:

[0384] To a stirred solution of 2-bromo- 5 -methoxyphenol (2.0 g, 9.852mmol, 1.0 equiv) inACN (20 mL) was added K2CO3 (3.39 g, 24.63mmol, 2.5 equiv), followed by the addition of tert-butyl 2-bromoethylcarbamate (4.39 g, 19.70 mmol, 2.0 equiv). The Reaction mixture was allowed to stir at 70 °C for 16h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL) and passed through celite®. The filtrate was concentrated under reduced pressure and purified by flash chromatography (0 to 20 % ethyl acetate in hexane as an eluent) to obtain tert-butyl 2-(2-bromo- 5 -methoxyphenoxy )ethylcarbamate (1.9 g, 55 % Yield) as an off white solid.

[0385] 'H NMR: (400 MHz, DMSO-d6) δ 7.43 (d, J = 9.06 Hz, 1H), 6.89-6.99 (m, 1H), 6.69 (d, J = 2.38 Hz, 1H), 6.50 (dd, J = 8.82, 2.62 Hz, 1H), 4.02 (t, J = 5.96 Hz, 2H), 3.28-3.37 (m, 5H), 1.36-1.44 (m, 9 H)

[0386] Step-2: Synthesis of tert-butyl 2-(5-methoxy-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenoxy)ethylcarbamate

[0387] To a stirred solution of tert-butyl 2-(2-bromo-5-methoxyphenoxy)ethylcarbamate (0.600 g, 1.739 mmol, 1.0 equiv) in dioxane (6 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (0.659 g, 2.608 mmol, 1.5 equiv), followed by the addition of KO Ac (0.512 g, 5.217 mmol, 3.0 equiv). The reaction mixture was purged with N2 for 5 minutes, followed by the addition of Pd(dppf)C12.DCM (0.142 g, 0.173 mmol, 0.1 equiv). The resulting reaction mixture was heated at 90 °C for 16h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (20 ml x 2). Combined organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (0- 30 % ethyl acetate in hexane as an eluent) to obtain tert-butyl 2-(5- methoxy-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)ethylcarbamate (0.210 g, 30 % Yield) as an off white solid.

[0388] LCMS: 346 [M+l]+

[0389] 'H NMR: (400 MHz, DMSO-d6) 87.43 (d, J = 9.06 Hz, 1H), 6.89-6.99 (m, 1H), 6.69 (d, J = 2.38 Hz, 1H), 6.50 (dd, J = 8.82, 2.62 Hz, 1H), 4.02 (t, J = 5.96 Hz, 2H), 3.28-3.37 (m, 5H), 1.36-1.44 (m, 9H), 1.25 (s, 12H).

[0390] Step-3: Synthesis of methyl 6-(2-(2-(tert-butoxycarbonylamino)ethoxy)-4- methoxyphenyl)quinoline-4-carboxylate

[0391] To a stirred solution of methyl 6-bromoquinoline-4-carboxylate (0.150 g, 0.566 mmol, 1.0 equiv) in Dioxane:Water (3:0.3 mL) was added K2CO3 (0.156 g, 1.132 mmol, 2.0 equiv), followed by the addition of tert-butyl 2-(5-methoxy-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)ethylcarbamate (0.333 g, 0.849 mmol, 1.5equiv). The reaction mixture was purged with N2 for 5 minutes, followed by the addition of Pd(dppf)C12.DCM (0.023 g, 0.028 mmol, 0.05 equiv). The resulting reaction mixture was heated at 90 °C for 16h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with ethyl acetate (20 ml x 2). Combined organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (0- 40 % ethyl acetate in hexane as an eluent) to obtain methyl 6-(2-(2-(tert-butoxycarbonylamino)ethoxy)-4-methoxyphenyl)quinoline- 4-carboxylate (0.120 g, 47 % Yield) as an off white solid.

[0392] LCMS: 453 [M+l]+

[0393] 'H NMR: (400 MHz, DMSO-d6) 8 9.02 (d, J = 4.29 Hz, 1 H), 8.71 (s, 1H) 8.01-8.13 (m, 2H), 7.94 (d, J = 4.29 Hz, 1H), 7.40 (d, J = 8.11 Hz, 1H), 6.85 (t, J = 5.25 Hz, 1H), 6.57-6.79 (m, 2H), 4.02-4.09 (m, 2H), 3.99 (s, 3 H), 3.83 (s, 3H), 3.20-3.31 (m, 2H), 1.25-1.33 (m, 9H)

[0394] Step-4: Synthesis of 6-(2-(2-(tert-butoxycarbonylamino)ethoxy)-4-methoxyphenyl) quinoline-4-carboxylic acid

[0395] To a stirred solution of methyl 6-(2-(2-(tert-butoxycarbonylamino)ethoxy)-4- methoxyphenyl)quinoline-4-carboxylate (0.120 g, 0.264 mmol, 1.0 equiv) in THF (1 mL) was added LiOH.H2O (0.012 g, 0.291 mmol, 1.1 equiv) in water (0.3 ml). The Reaction mixture was allowed to stir at RT for 2h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the THF was removed under reduced pressure and diluted with water, acidify with IN HC1. The resulting solid was filtered to and dried under vacuum obtain 6-(2-(2- (tert-butoxycarbonylamino)ethoxy)-4-methoxyphenyl)quinoline-4-carboxylic acid (0.070 g, 60 % Yield) as an off white solid.

[0396] LCMS: 439 [M+l]

[0397] 'H NMR: (400 MHz, DMSO-d6) δ 13.83 (br. s., 1H) 8.99 (d, J = 4.29 Hz, 1H) 8.78 (s, 1H) 8.00-8.11 (m, 2H) 7.92 (d, J = 4.29 Hz, 1H) 7.38 (d, J = 8.58 Hz, 1H) 6.86 (br. s., 1H) 6.60- 6.77 (m, 2H) 4.03 (t, J = 5.96 Hz, 2H) 3.83 (s, 3H) 3.13-3.30 (m, 2H) 1.31 (s, 9H)

[0398] Step-5: Synthesis of (S)-tert-butyl 2-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethylcarbamate:-

[0399] To a stirred solution of 6-(2-(2-(tert-butoxycarbonylamino)ethoxy)-4- methoxyphenyl)quinoline-4-carboxylic acid. (0.050 g, 0.114 mmol, 1.0 equiv) in DMF (0.5 mL) was added EDC.HC1 (0.028 g , 0.148 mmol, 1.3 equiv), HOBT(0.020 g, 0.148 mmol, 1.3 equiv) followed by the addition of DIPEA(0.06 mL, 0.342 mmol, 3.0 equiv) and (S)-1-(2-aminoacetyl)- 4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (0.030 g, 0.136 mmol, 1.2 equiv. The resulting reaction mixture was allowed to stir at RT for 16h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers was washed with water (5 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by Flash chromatography (0-5 % MeOH in DCM as an eluent) to obtain (S)-tert-butyl 2-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethylcarbamate (0.035 g, 50 % Yield) as an off white solid.

[0400] LCMS: 610 [M+l]+

[0401] 'H NMR: (400 MHz, DMSO-d6) δ 9.12 (br. s., 1H) 8.86 - 8.99 (m, 1H), 8.31-8.50 (m, 1H), 8.03 (s, 2H), 7.55 (d, J = 4.29 Hz, 1H), 7.43 (d, J = 8.58 Hz, 1H), 6.89 (br. s., 1H), 6.59-6.76 (m, 2H), 5.03-5.24 (m, 1H), 4.09-4.37 (m, 4H), 3.97-4.09 (m, 2H), 3.82 (s, 3H), 3.28 (d, J = 5.72 Hz, 2H), 2.74-2.98 (m, 2H), 1.27-1.38 (m, 9H)

[0402] Step-6: Synthesis of (S)-6-(2-(2-aminoethoxy)-4-methoxyphenyl)-N-(2-(2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide

[0403] To a stirred solution of (S)-tert-butyl 2-(2-(4-(2-(2-cyano-4,4-difhroropyrrolidin-1-yl)- 2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethylcarbamate (0.045 g, 0.073 mmol, 1.0 equiv) in DCM (0.5 mL) was added TFA (0.1 mL) drop wise at 0°C. The Reaction mixture was allowed to stir at RT for 2h. The product formation was confirmed by TLC andLCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and crystallized in diethyl ether to obtain (S)-6-(2-(2-aminoethoxy)-4-methoxyphenyl)- N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (0.035 g, 79 % Yield) as an off white solid as a TFA salt.

[0404] LCMS: 510 [M+l]+

[0405] 'H NMR: (400 MHz, DMSO-d6) δ 9..19 (s, 1H), 8.97 (d, J = 4.29 Hz, 1H), 8.48 (s, 1H), 8.02-8.12 (m, 2H), 7.79 (br. s., 3H), 7.59 (d, J = 4.29 Hz, 1H), 7.47 (d, J= 8.58 Hz, 1H), 6.77 (s, 2H), 5.14 (d, J = 9.06 Hz, 1H), 4.24 (br. s., 4H), 3.83 (s, 3H), 3.32-3.46 (m, 2H), 3.22 (br. s., 2H), 2.78-2.93 (m, 2H)

[0406] Step-7: Synthesis of (S)-2,2',2"-(10-(2-(2-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethylamino)-2-oxoethyl)- 1 ,4,7, 10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0407] To a stirred solution of (S)-6-(2-(2-aminoethoxy)-4-methoxyphenyl)-N-(2-(2-cyano- 4,4-difhioropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.035 g, 0.057 mmol, 1.0 equiv) in DMF (0.2 mL) was added 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)- 1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (0.045 g, 0.086 mmol, 1.5 equiv) and TEA (0.05 ml, 0.342 mmol, 6.0 equiv). The Reaction mixture was allowed to stir at room temperature for 16 h. The product formation was confirmed by LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure, crystallized in diethyl ether and further purified by reversed phase HPLC to obtain (S)-2,2',2"-(10-(2-(2-(2-(4-(2-(2-cyano-4,4- difhioropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethylamino)-2- oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (0.017 g, 33 % Yield) as an off-white solid.

[0408] LCMS: 896 [M+l]+

[0409] 'H NMR: (400 MHz, DEUTERIUM OXIDE) 8 8.97 (d, J = .Tl Hz, 1H) 8.40 (s, 1H) 8.00-8.24 (m, 2H) 7.76 (d, J = 4.29 Hz, 1H) 7.48 (d, J = 8.11 Hz, 1H) 6.68-6.89 (m, 2H) 5.14 (dd, J = 8.58, 4.29 Hz, 2H) 4.55 (br. s., 6H) 4.39 (s, 3H) 4.28 (br. s., 1H) 4.25 (d, J = 6.68 Hz, 1H) 4.12-4.21 (m, 3H) 4.11 (br. s., 1H), 3.89 (s, 4H) 3.63-3.73 (m, 2H), 3.44-3.63 (m, 5 H), 3.31-3.39(m, 3 H), 3.29 (br. s., 4H), 3.05-3.23 (m, 7H), 3.00 (br. s., 4H), 2.93 (d, J = 11.92 Hz, 3H), 2.71 (s, 1H), 2.47 (br. s., 4H)Compound 11

[0410] Synthesis of (S)-2,2',2"-(10-(2-(4-(5-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)-2-methoxyphenoxy)piperidin-1-yl)-2-oxoethyl)- 1,4,7, 10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0411] Step-1: Preparation of tert-butyl 4-(methylsulfonyloxy)piperidine-l -carboxylate

[0412] To a stirred solution of tert-butyl 4-hydroxypiperidine- 1 -carboxylate (0.20 g, 1.0 mmol, 1.0 eq) in DCM (5 mL) was added triethylamine (0.3 mL, 1.9 mmol, 3.0 eq) at 0 °C followed bythe addition of methylsulfonyl chloride (0.09 mL, 1.19 mmol, 1.5 eq) and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with ice-cold water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.29 g, 80.34 %)

[0413] LCMS: 280 [M+H]+

[0414] Step-2: Preparation of tert-butyl 4-(5-bromo-2-methoxyphenoxy)piperidine-1- carboxylate

[0415] To a stirred solution of 5-bromo-2-methoxyphenol (0.10 g, 0.49 mmol, 1.0 eq) in DMF (5 mL) was added CS2CO3 (0.32 mL g, 0.984 mmol, 2.0 eq) at RT followed by the addition of tertbutyl 4-(methylsulfonyloxy)piperidine-l -carboxylate (0.20 g, 0.74 mmol, 1.5 eq) and the mixture was heated at 80 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.09 g, 65.7 % )

[0416] LCMS: 386 [M+H]+

[0417] Step-3a: Preparation of (S)-4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl carbamoyl)quinolin-6-ylboronic acid

[0418] To a solution of (S)-6-bromo-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)quinoline-4-carboxamide (0.50 g, 1.15 mmol, leq) and bis(pinacolato)diboron (0.438 g, 1.72 mmol, 1.5eq.) in 1,4-dioxane (20 mL) was added KOAc (0.34 g, 3.44 mmol, 3.0 eq) and the mixture was degassed under nitrogen for 10 min. Pd(dppf)C12 (0.084 g, 0.115 mmol, 0.1 eq) was then added to the mixture and the mixture was further degassed for 5 min. The resultant reaction mixture was then heated at 90 °C for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (20 mL) and extracted using ethyl acetate (40 mL x 2). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain acrude residue which was purified using CombiFlash Chromatography to afford the title compound (0.32 g, 57.65 %).

[0419] LCMS: 389 [M+H]+

[0420] Step-3: Preparation of (S)-tert-butyl 4-(5-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-2-methoxyphenoxy)piperidine-l -carboxylate

[0421] To a solution of tert-butyl 4-(5-bromo-2-methoxyphenoxy)piperidine-l -carboxylate

[0422] (0.09 g, 0.23 mmol, 1.0 eq) and (S)-4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-ylboronic acid (0.11 g, 0.28 mmol, 1.2eq) in 1,4-dioxane (5.4 mL) were added K2CO3 (0.096 g, 0.67 mmol, 3.0 eq) and water (0.6 mL) and the mixture was degassed under nitrogen for 10 min. Pd(dppf)Ch (0.016 g, 0.066 mmol, 0.1 eq) was then added to the mixture and the mixture was further degassed for 5 min.The resultant mixture was then heated at 120 °C for 5 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (20 mL) and extracted using ethyl acetate (40 mL x 2). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated to obtain a crude residue which was purified using CombiFlash Chromatography to afford the title compound (0.10 g, 66.25 %).

[0423] LCMS: 650 [M+H]+

[0424] Step-4: Preparation of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-methoxy-3-(piperidin-4-yloxy)phenyl)quinoline-4-carboxamide

[0425] To a stirred solution of (S)-tert-butyl 4-(5-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)- 2-oxoethylcarbamoyl)quinolin-6-yl)-2-methoxyphenoxy)piperidine-1-carboxylate (0.10 g, 0.15 mmol, 1.0 eq) in DCM (4 mL) was added TFA (0.5 mL) drop wise at 0 °C and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure. The resultant residue was washed with diethyl ether (10 mL x3) and concentrated under reduced pressure to afford the title compound as a trifluoroacetate salt (0.09 g, 89.1 %)

[0426] LCMS: 550 [M+H]+

[0427] Step-5: Preparation of (S)-2,2',2"-(10-(2-(4-(5-(4-(2-(2-cyano-4,4-difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-2-methoxyphenoxy)piperidin- 1 -yl)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7-triyl)triacetic acid

[0428] To a stirred solution of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6- (4-methoxy-3-(piperidin-4-yloxy)phenyl)quinoline-4-carboxamide (0.09 g, 0.06 mmol, 1.0 eq) in DMF (0.3 mL) were added 2, 2', 2", 2"'-(l, 4, 7, 10-tetraazacyclododecane- 1,4, 7, 10-tetrayl)tetraacetic acid (0.103 g, 0.19 mmol, 1.2 eq) and TEA (0.07 ml, 0.489 mmol, 3.0 eq) and the mixture was stirrred at RT for 16 h. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure, triturated in diethyl ether and further purified by Reversed Phase HPLC to afford the title compound (0.04 g, 31.49 %)

[0429] LCMS: 936 [M+H]+

[0430] 'H NMR: (400 MHz, DMSO-d6) 8 9.21 (t, J = 6.0 Hz, 1H), 8.95 (d, J = 4.3 Hz, 1H), 8.64 (s, 1H), 8.20-8.10 (m, 2H), 7.57 (d, J = 4.3 Hz, 1H), 7.53-7.47 (m, 2H), 7.16 (d, J = 9.1 Hz, 1H), 5.16 (dd, J= 1.4, 9.5 Hz, 1H), 4.69 (d, J= 3.3 Hz, 1H), 4.39-4.23 (m, 3H), 4.23-4.13 (m, 1H), 3.88-3.77 (m, 6H), 3.65 (d, J = 14.3 Hz, 2H), 3.41-3.24 (m, 11H), 3.04-2.89 (m, 12H), 1.91 (br. s., 3H), 1.81-1.57 (m, 2H)Compound 12

[0431] Synthesis of (S)-4-(2-(2-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethylamino)-2-oxoethylcarbamoyl)-2-(6-hydroxy-3- oxo-3H-xanthen-9-yl)benzoic acid

[0432] Stepl: Synthesis of (S)-tert-butyl 2-(2-(4-(4-(2-(2-cyano-4,4-difhioropyrrolidin-1-yl)- 2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethylamino)-2-oxoethylcarbamate

[0433] To a stirred solution of (S)-6-(4-(2-aminoethoxy)phenyl)-N-(2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (0.060 g, 0.125 mmol, 1.0 equiv) in DMF(0.6 mL) was added HATU (0.061 g, 0.162 mmol, 1.3 equiv), 2-((tert- butoxycarbonyl)amino)acetic acid (0.026 g, 0.150 mmol, 1.2 equiv) followed by the addition of DIPEA(0.069 mL, 0.375 mmol, 3.0 equiv). The resulting reaction mixture was allowed to stir at RT for 16 h. The product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with cold water (2 mL) followed by brine wash (2 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-5 % MeOH in DCM as an eluent) to obtain (S)- tert-butyl 2-(2-(4-(4-(2-(2-cy ano-4,4-difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-6- yl)phenoxy)ethylamino)-2-oxoethylcarbamate (0.060 g, 75 % Yield) as an off white solid.

[0434] LCMS: 637 [M+l]+

[0435] 'H NMR (400 MHz, DMSO-d6) 89.12-9.22 (m, 1H), 8.94 (d, J = 4.29 Hz, 1H), 8.73 (s, 1H), 8.08-8.20 (m, 2H), 8.05 (br. s., 1H), 7.88 (d, J = 9.06 Hz, 2H), 7.56 (d, J = 4.29 Hz, 1H), 7.10 (d, J= 9.06 Hz, 2H), 6.95 (br. s., 1H), 5.19 (d, J= 7.15 Hz, 1H), 4.23-4.39 (m, 2H), 4.12-4.23 (m, 2H), 4.06 (d, J = 6.20 Hz, 2H), 3.56 (s, 2H), 3.48 (d, J = 5.25 Hz, 2H), 2.95 (s, 2H), 1.33-1.40 (m, 9H)

[0436] Step-2: Synthesis of (S)-6-(4-(2-(2-aminoacetamido)ethoxy)phenyl)-N-(2-(2-cyano- 4,4-difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate

[0437] To a stirred solution of (S)-tert-butyl 2-(2-(4-(4-(2-(2-cyano-4,4-difhioropyrrolidin-1- yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethylamino)-2-oxoethylcarbamate (0.100 g, 0.157 mmol, 1.0 equiv) in DCM (1 mL) was added TFA (0.2 mL) drop wise at 0 °C. The Reaction mixture was allowed to stir at RT for 2h. The product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and crystallized in diethyl ether to obtain (S)-6-(4-(2-(2-aminoacetamido)ethoxy)phenyl)- N-(2-(2-cyano-4,4-difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide 2,2,2- trifluoroacetate (0.090 g, 90 % Yield) as a yellow solid.

[0438] LCMS: 537 [M+l]

[0439] 'H NMR: (400 MHz, DMSO-d6) δ 9.18 (br. s., 1H), 8.96 (d, J = 4.29 Hz, 1H), 8.73 (s, 1H), 8.65 (br. s., 1H), 8.05-8.22 (m, 2H), 7.98 (br. s., 2H), 7.79-7.93 (m, 2H), 7.58 (d, J = 4.29 Hz, 1H), 7.11 (d, J = 8.11 Hz, 2H), 5.19 (d, J = 7.63 Hz, 1H), 4.32-4.39 (m, 2H), 4.28 (d, J = 5.72 Hz, 2H), 4.16 (br. s., 1H), 4.10 (br. s.,lH), 3.52-3.61 (m, 2H), 3.38 (q, J = 7.15 Hz, 2H), 2.76-2.95 (m, 2H)

[0440] Step-3: Synthesis of (S)-4-(2-(2-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl) quinolin-6-yl)phenoxy)ethylamino)-2-oxoethylcarbamoyl)-2-(6-hydroxy-3- oxo-3H-xanthen-9-yl)benzoic acid

[0441] To a stirred solution of 3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-l,9'-xanthene]- 6-carboxylic acid (0.053 g, 0.142 mmol, 1.0 equiv) in DMF (0.9 mL) was added HATU (0.080 g, 0.213 mmol, 1.5 equiv), DIPEA (0.05 mL, 0.284 mmol, 2.0 equiv) followed by the addition of (S)-6-(4-(2-(2-aminoacetamido)ethoxy)phenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.090 g, 0.142 mmol, 1.0 equiv). The resulting reaction mixture was allowed to stir at room temperature for 16h. The product formation was confirmed by LCMS. After completion of the reaction, the reaction mixture was acidified with 2N HC1. The resulting solid was filtered off, dried under vacuum and was purified by reversed phase HPLC to obtain (S)-4-(2-(2-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethylamino)-2-oxoethylcarbamoyl)-2-(6-hydroxy-3- oxo-3H-xanthen-9-yl)benzoic acid (0.003 g, 2.3 % Yield) as an off white solid.

[0442] LCMS: 895 [M+l]+

[0443] 'H NMR: (400 MHz, DMSO-d6) δ 10.17 (br. s., 3H), 9.17 (t, J = 5.96 Hz, 2H), 8.89- 9.03 (m, 3H), 8.72 (s, 1H), 8.03-8.31 (m, 8H), 7.79-7.91 (m, 3H), 7.72 (s, 2H), 7.56 (d, J = 4.77 Hz, 2H), 7.28-7.38 (m, 2H), 7.07 (d, J = 8.58 Hz, 3H), 6.69 (d, J = 2.38 Hz, 3H), 6.47 - 6.66 (m, 7H), 5.08-5.22 (m, 1H), 4.51-4.61 (m, 1H), 4.24-4.42 (m, 5H), 4.08-4.20 (m, 2H), 4.02 (t, J= 5.72 Hz, 4H), 3.93 (br. s., 1H), 3.83 (d, J = 5.72 Hz, 4 H), 3.45 (d, J = 5.72 Hz, 14H), 3.16 (d, J = 4.77 Hz, 5H), 3.00 (br. s., 1H), 2.74-2.97 (m, 4H), 2.62-2.74 (m, 4H), 2.33 (d, J = 1.91 Hz, 4H), 2.25 (br. s., 1H), 2.02-2.15 (m, 1H)Compound 13

[0444] Synthesis of 2,2',2"-(10-(2-(4-(3-(5-(4-(2-((2R)-2-cyano-4,4-difluorocyclopentyl)-2- oxoethylcarbamoyl)quinolin-6-yl)-2-methoxyphenoxy)propyl)piperazin-1-yl)-2-oxoethyl)-1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7-triyl)triacetic acid

[0445] Step-1: Preparation of methyl 6-(3-hydroxy-4-methoxyphenyl)quinoline-4- carboxylate

[0446] To a stirred solution of methyl 6-bromoquinoline-4-carboxylate (0.5 g, 1.87 mmol, 1.0 eq) and (2-(3-hydroxy-4-methoxyphenyl)-4,5,5-trimethyl- 1 ,3,2-dioxaborolan-4-yl)methylium (0.56 g, 2.24 mmol, 1.2 eq) in 1 ,4-Dioxane-H2O (4.5 mL : 0.5 mL) was added K2CO3 (0.77 g, 5.61 mmol, 3 eq) and the mixture was degassed under nitrogen for 10 min. Pd(dppf)C12 (0.068 g, 0.09 mmol, 0.05 eq) was then added to the mixture and the mixture was further degassed for 5 min. The resultant mixture was irradiated under MW radiation at 100 °C for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (20 mL) and extracted using ethyl acetate (40 mL x 2). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated to obtain a crude residue which was purified using CombiFlash Chromatography to afford the title compound (0.4 g, 69 %).

[0447] LCMS: 310 [M+H]+

[0448] Step-2: Preparation of 6-(3-hydroxy-4-methoxyphenyl)quinoline-4-carboxylic acid

[0449] To a stirred solution of methyl 6-(3-hydroxy-4-methoxyphenyl)quinoline-4- carboxylate (0.3 g, 0.97 mmol, 1.0 eq) in THF (6 mL) was added LiOH.H2O (0.20 g, 4.84 mmol, 5 eq) dissolved in water (1 mL) and methanol (3 mL) and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was acidified using 2N-HC1 (pH~l-2) to obtain a precipitate which was filtered over vacuum to afford the title compound (0.27 g, 96.5 %).

[0450] LCMS: 296 [M+H]+

[0451] Step-3: Preparation of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(3-hydroxy-4-methoxyphenyl)quinoline-4-carboxamide

[0452] To a stirred solution of 6-(3-hydroxy-4-methoxyphenyl)quinoline-4-carboxylic acid (0.3 g, 1.02 mmol, 1.0 eq) in DMF (12 mL) was added HATU (0.58 g, 1.52 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. DIPEA (0.7 mL, 4.06 mmol, 4 eq) and (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (0.27 g, 1.22 mmol, 1.5 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with ice-cold water (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.1 g, 21 %).

[0453] LCMS: 467 [M+H]+

[0454] Step-4: Preparation of (S)-tert-butyl 4-(3-(5-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-2-methoxyphenoxy)propyl)piperazine-l -carboxylate

[0455] To a stirred solution of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6- (3-hydroxy-4-methoxyphenyl)quinoline-4-carboxamide (0.1 g, 0.21 mmol, 1.0 eq) in DMF (4 mL) was added CS2CO3 (0.14 g, 0.42 mmol, 2 eq) at RT and the mixture was stirred at same temperature for 30 min. tert-butyl 4-(3-bromopropyl) piperazine- 1 -carboxylate (0.13 g, 0.42 mmol, 2 eq) was then added to the mixture and the mixture was heated at 70 °C for 2 h. After completion, themixture was diluted with water (20 mL) to obtain a precipitate which was filtered under vacuum to obtain a crude residue. The crude product was triturated with acetone / n-pentane (1 : 5) to afford the title compound (0.1g, 67 %).

[0456] LCMS: 693 [M+H]+

[0457] Step-5: Preparation of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-methoxy-3-(3-(piperazin-1-yl)propoxy)phenyl)quinoline-4-carboxamide, 2,2,2- trifluoroacetate salt

[0458] To a stirred solution of (S)-tert-butyl 4-(3-(5-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-2-methoxyphenoxy)propyl)piperazine-1-carboxylate (0.1 g, 0.14 mmol, 1.0 eq) in DCM (10 mL) was added TFA (1 mL) dropwise at 0 °C and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was evaporated under reduced pressure to obtain a crude residue which was triturated with diethyl ether (10 mL x 3) to afford the title compound as a trifluoroacetate salt (0.1g, 98 % Yield).

[0459] LCMS: 593 [M+H]+

[0460] Step-6: Preparation of (S)-2,2',2"-(10-(2-(4-(3-(5-(4-((2-(2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-2- methoxyphenoxy)propyl)piperazin- 1 -yl)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7- triyl)triacetic acid

[0461] To a stirred solution of S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6- (4-methoxy-3-(3-(piperazin-1-yl)propoxy)phenyl)quinoline-4-carboxamide, 2,2,2-trifluoro acetate salt (0.1 g, 0.14 mmol, 1.0 eq) in DMF (2 mL) were added TEA (0.12 mL, 0.84 mmol, 5 eq) and 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7- triyl)triacetic acid (0.089 g, 0.17 mmol, 1.2 eq) and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure, triturated with diethyl ether and further purified by Reversed Phase HPLC to afford the title compound (0.02 g, 14 %).

[0462] LCMS: 979 [M+H]+

[0463] 'H NMR: (400 MHz, DMSO-d6) δ 9.22-9.15 (m, 1H), 8.96 (d, J = 4.3 Hz, 1H), 8.66 (s, 1 H), 8.20-8.12 (m, 2H), 7.58 (d, J = 4.3 Hz, 1 H), 7.51-7.41 (m, 2H), 7.15 (d, J = 8.6 Hz, 1H), 5.17 (dd, J = 3.1, 9.3 Hz, 1H), 4.39-4.14 (m, 6H), 3.87-3.80 (m, 4H), 3.63 (br. s., 8H), 3.33-3.10 (m, 8H), 3.12 (br. s., 8H), 3.09-2.97 (m, 13H)Compound 14

[0464] Synthesis of 2,2',2"-(10-(2-((lS,4r)-4-((S)-1-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)-3-(naphthalen-2- yl)propan-2-ylcarbamoyl)cyclohexylamino)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1,4,7- triyl)triacetic acid

[0465] Step-1: Preparation of methyl 6-(4-((S)-2-((lr,4S)-4-(tert-butoxycarbonylamino) cyclohexanecarboxamido)-3-(naphthalen-2-yl)propoxy)phenyl)quinoline-4-carboxylate

[0466] To a stirred solution of (lr,4r)-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (0.09 g, 0.370 mmol, 1.0 eq) in DMF (10 mL) was added HATU (0.21 g, 0.56 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. DIPEA (0.3 mL, 1.48 mmol, 4.0 eq) and (S)-methyl 6-(4-(2-amino-3-(naphthalen-2-yl)propoxy)phenyl)quinoline-4- carboxylate (0.25 mg, 0.44 mmol, 1.2 eq) were then added to the mixture and the mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion, ice-cold water (30 mL) was added to the mixture to obtain a precipitate which wasfiltered under vacuum and dried to obtain a crude residue. The crude compound was purified byCombiFlash Chromatography to afford the title compound (0.19, 74.8 %)

[0467] LCMS: 688 [M+H]+

[0468] Step-2: Preparation of 6-(4-((S)-2-((1r,4S)-4-(tert-butoxycarbonylamino) cyclohexanecarboxamido)-3-(naphthalen-2-yl)propoxy)phenyl)quinoline-4-carboxylic acid

[0469] To a stirred solution of methyl 6-(4-((S)-2-((lr,4S)-4-(tert-butoxycarbonylamino) cyclohexanecarboxamido)-3-(naphthalen-2-yl)propoxy)phenyl)quinoline-4-carboxylate (0.19 g, 0.27 mmol, 1.0 eq) in THF (12 mL) was added LiOH.H2O (0.056 mg, 1.38 mmol, 5 eq) dissolved in MeOH :Water (6 mL: 2mL) and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was acidified with 2N- HC1 (pH ~ 1 -2) to obtain a precipitate which was filtered under vacuum and washed with n-hexane to afford the title compound (0.15 g, 80.6 % )

[0470] LCMS: 674 [M+H]+

[0471] Step-3: Preparation of tert-butyl (lS,4r)-4-((S)-1-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)-3-(naphthalen-2- yl)propan-2-ylcarbamoyl)cyclohexylcarbamate

[0472] To a stirred solution of 6-(4-((S)-2-((lr,4S)-4-(tert-butoxycarbonylamino) cyclohexane carboxamido)-3-(naphthalen-2-yl)propoxy)phenyl)quinoline-4-carboxylic acid (0.15 g, 0.22 mmol, 1.0 eq) in DMF (15 mL) was added HATU (0.13 g, 0.33 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. DIPEA (0.015 mL, 0.89 mmol, 4 eq) and (S)- l-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (0.060 g, 0.27 mmol, 1.2 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with ice- cold water (30 mL) to obtain a precipitate which was filtered under vacuum, dried to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.147 g, 78.2 %)

[0473] LCMS: 845 [M+H]+

[0474] Step-4: Preparation of 6-(4-((S)-2-((lr,4S)-4-aminocyclohexanecarboxamido)-3-(naphthalen-2-yl)propoxy)phenyl)-N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)quinoline-4-carboxamide

[0475] To a stirred solution tert-butyl (lS,4r)-4-((S)-1-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)-3-(naphthalen-2- yl)propan-2-ylcarbamoyl)cyclohexylcarbamate (0.14 g, 0.24 mmol, 1.0 eq) in DCM (5 mL) was added TFA (0.8 mL) drop wise at 0 °C and the mixture was stirred at RT for Ih. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue which was triturated with diethyl ether (10 mL x 3) and concentrated to afford the title compound as a trifluoroacetate salt (0.13 g, 87.24 % )

[0476] LCMS: 745 [M+H]+

[0477] Step-5: Preparation of 2,2',2"-(10-(2-((lS,4r)-4-((S)-1-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)-3-(naphthalen-2- yl)propan-2-ylcarbamoyl)cyclohexylamino)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7- triyl)triacetic acid

[0478] To a stirred solution of 6-(4-((S)-2-((lr,4S)-4-aminocyclohexanecarboxamido)-3- (naphthalen-2-yl)propoxy)phenyl)-N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)quinoline-4-carboxamide trifluoroacetate salt (0.12 g, 0.14 mmol, 1.0 eq) in DMF (0.3 mL) was added 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triyl)triacetic acid (0.088 g, 0.167 mmol, 1.2 eq) and TEA (0.09 mL, 0.7 mmol, 4.0 eq) and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure, triturated with diethyl ether and further purified by Reversed Phase HPLC to afford the title compound (0.04 g, 25.3 %)

[0479] LCMS: 1131 [M+H]+

[0480] 'H NMR: (400 MHz, DMSO-d6) 8 9.17 (t, J = 6.0 Hz, IH), 8.95 (d, J = 4.3 Hz, IH), 8.76-8.69 (m, IH), 8.20-8.10 (m, 2H), 8.05-7.95 (m, 2H), 7.91-7.79 (m, 5H), 7.73 (s, IH), 7.57 (d, J = 4.3 Hz, IH), 7.49-7.39 (m, 3H), 7.13 (d, J = 8.6 Hz, 2H), 5.19 (dd, J = 3.1, 9.3 Hz, IH), 4.43- 4.23 (m, 4H), 4.2- 4.06 (m, IH), 4.06-3.96 (m, 2H), 3.40 (br. s., 6H), 3.03 (br. s., 3H), 3.01-2.86(m, 14H), 2.60 (br. s., 4H), 2.17-2.00 (m, 2H), 1.78-1.61 (m, 3H), 1.56 (d, J = 13.8 Hz, 1H), 1.39- 1.29 (m, 3H), 1.29-1.19 (m, 2H).Compound 15

[0481] Synthesis of (S)-4-(2-(2-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl) quinolin-6-yl)-5-methoxyphenoxy)ethylamino)-2-oxoethylcarbamoyl)-2-(6- hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0482] Stepl: Synthesis of (S)-tert-butyl 2-(2-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethylamino)-2-oxoethylcarbamate

[0483] To a stirred solution of (S)-6-(2-(2-aminoethoxy)-4-methoxyphenyl)-N-(2-(2-cyano- 4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (0.080 g, 0.157 mmol, 1.0 equiv) in DMF (0.8 mL) was added HATU (0.077 g, 0.204 mmol, 1.3 equiv), 2-(tert- butoxycarbonylamino)acetic acid (0.033 g, 0.188 mmol, 1.2 equiv) followed by the addition of DIPEA(0.08 mL, 0.471 mmol, 3.0 equiv). The resulting reaction mixture was allowed to stir at RT for 16 h. The product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (2 mL). The resulting solid was filtered off and dried under vacuum. The crude product was purified by flash chromatography (0-5 % MeOH in DCM as an eluent) to obtain (S)-tert-butyl 2-(2-(2-(4-(2-(2-cyano-4,4- difhioropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethylamino)-2- oxoethylcarbamate (0.065 g, 62 % Yield) as an off white solid.

[0484] LCMS: 667.3 [M+l]+

[0485] 'H NMR: (400 MHz, DMSO-d6) δ 9..14 (s, 1H), 8.96 (d, J = 4.29 Hz, 1H), 8.42 (s, 1H), 7.95-8.12 (m, 1H), 7.89 (s, 2H), 7.57 (d, J = 4.29 Hz, 1H), 7.42 (d, J = 8.58 Hz, 1H), 6.93 (s, 1H), 6.62-6.77 (m, 2H), 5.14 (d, J = 7.63 Hz, 1H), 4.30 (d, J = 18.12 Hz, 2H), 4.23 (s, 2H), 3.94- 4.09 (m, 5H), 3.54 (s, 2H), 3.55 (s, 2H), 3.42 (d, J = 5.72 Hz, 2H), 1.36 (s, 9H)

[0486] Step-2: Synthesis of (S)-6-(2-(2-(2-aminoacetamido)ethoxy)-4-methoxyphenyl)-N-(2- (2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate

[0487] To a stirred solution of (S)-tert-butyl 2-(2-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethylamino)-2-oxoethylcarbamate (0.065 g, 0.097 mmol, 1.0 equiv) in DCM (0.8 mL) was added TFA (0.18 mL) drop wise at 0 °C. The Reaction mixture was allowed to stir at RT for 2h. The product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and crystallized in diethyl ether to obtain (S)-6-(2-(2-(2- aminoacetamido)ethoxy)-4-methoxyphenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.060 g, 93 % Yield) as a yellow solid.

[0488] LCMS: 567.3 [M+l]+

[0489] 'H NMR: (400 MHz, DMSO-d6) δ 9. 15 (s, 1H), 8.97 (d, J = 4.29 Hz, 1H), 8.32 - 8.50 (m, 2H), 8.01-8.15 (m, 2H), 7.95 (br. s., 3H), 7.58 (d, J = 4.29 Hz, 1H), 7.43 (d, J = 8.58 Hz, 1H), 6.64-6.81 (m, 2H), 5.13 (d, J = 6.20 Hz, 1H), 4.30 (d, J = 18.12 Hz, 2H), 4.23 (s, 2H), 3.94-4.09 (m, 5H), 3.54 (s, 2H), 3.55 (s, 2H), 3.42 (d, J = 5.72 Hz, 2H)

[0490] Step-3: Synthesis of (S)-4-(2-(2-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethylamino)-2-oxoethylcarbamoyl)-2-(6- hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0491] To a stirred solution of 3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-l,9'-xanthene]- 6-carboxylic acid (0.034 g, 0.090 mmol, 1.0 equiv) in DMF (0.6 mL) was added HATU (0.051 g, 0.135 mmol, 1.5 equiv), DIPEA (0.03 mL, 0.180 mmol, 2.0 equiv) followed by the addition of (S)-6-(2-(2-(2-aminoacetamido)ethoxy)-4-methoxyphenyl)-N-(2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.060 mg, 0.088 mmol, 1.0 equiv). The resulting reaction mixture was allowed to stir at room temperature for 16 h. The product formation was confirmed by LCMS. After completion of the reaction, thereaction mixture was acidified with 2N HC1. The resulting solid was filtered off, dried under vacuum and was purified by reversed phase HPLC to obtain (S)-4-(2-(2-(2-(4-(2-(2-cyano-4,4- difhioropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)ethylamino)-2- oxoethylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid (0.002 g, 2.3 % Yield) as an off white solid.

[0492] LCMS: 925 [M+l]+

[0493] 'H NMR: (400 MHz, DMSO-d6) δ 10.15 (s, 5H), 9.03-9.20 (m, 2H), 8.84-9.03 (m, 4H), 8.40 (s, 2H), 8.17 (d, J = 8.11 Hz, 2H), 8.08 (d, J = 8.11 Hz, 5H), 8.01 (s, 4 H), 7.71 (s, 2H), 7.55 (d, J = 4.29 Hz, 2H), 7.41 (d, J = 8.58 Hz, 2H), 6.67-6.76 (m, 8H), 6.67 (s, 1H), 6.45-6.64 (m, 9H), 5.13 (d, J = 9.06 Hz, 1H), 4.16-4.42 (m, 6H), 4.11 (d, J = 11.92 Hz, 2H), 3.92-4.07 (m, 5H), 3.70-3.90 (m, 12H), 2.90 (br. s., 3H), 2.79 (d, J = 17.17 Hz, 4H), 2.67 (s, 9H), 2.01-2.14 (m, 3H), 1.23 (s, 5H)Compound 16

[0494] Synthesis of 2,2',2"-(10-(2-(((lS,4r)-4-((S)-1-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)-3-(naphthalen-2- yl)propan-2-ylcarbamoyl)cyclohexyl)methylamino)-2-oxoethyl)- 1 ,4,7, 10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0495] Step-lc: Preparation of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(naphthalen-2- yl)propanoate

[0496] To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(naphthalen-2- yl)propanoic acid (5.0 g, 0.016 mmol, 1.0 eq) in acetone (80 mL) was added KHCO3 (2.5g, 0.025 mmol, 1.6 eq) followed by the addition of Mel (2.4mL, 0.04 mmol, 2.5 eq) at RT and the mixture was refluxed at 70 °C for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (200 mL) and extract by ethyl acetate (200 mL x 2). The combined organic layers were washed with saturated NaHC03solution (200 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (5.0 g, 96 %).

[0497] LCMS: 330 [M+H]+

[0498] Step- lb: Preparation of (S)-tert-butyl (l-hydroxy-3-(naphthalen-2-yl)propan-2- yl)carbamate

[0499] To a stirred solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(naphthalen-2- yl)propanoate (6.2 g, 0.018 mmol, 1.0 eq) in THF (100 mL) was added Li AI1L (2.14 g, 0.06 mmol, 3.0 eq) at -10 °C and the mixture was stirred at same temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was quenched using saturated Na2SO4 solution at 0 °C slowly. The reaction mixture was then filtered over a pad of celite and washed with EtOAc (200 mL x 2). The filtrate obtained was washed with H2O (100 mL x 2), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (4.2 g, 74 % Yield) .

[0500] LCMS: 302 [M+H]+

[0501] Step-la: Preparation of (S)-tert-butyl (l-bromo-3-(naphthalen-2-yl)propan-2- yl)carbamate

[0502] To a stirred solution of triphenylphosphine (7.3 g, 0.027 mmol, 2.0 eq) in CCI4 (80mL) was added CBr4 (18.0 g, 0.056 mmol, 4 eq) and the mixture was stirred at RT for 30 min followed by the addition of (S)-tert-butyl (l-hydroxy-3-(naphthalen-2-yl)propan-2-yl)carbamate (4.2 g, 0.013 mmol, 1 eq). The resultant mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (2.0 g, 39.5 %).

[0503] LCMS: 364 [M+H]+

[0504] Step-1: Preparation of (S)-methyl 6-(4-(2-((tert-butoxycarbonyl)amino)-3-(naphthalen-2-yl)propoxy)phenyl)quinoline-4-carboxylate

[0505] To a stirred solution of methyl 6-(4-hydroxyphenyl)quinoline-4-carboxylate (0.5 g, 1.8 mmol, 1.0 eq) in DMF (10 mL) was added CsCCh (1.3 g, 5.37 mmol, 3 eq) at RT and the mixture was stirred at same temperature for 20 min. (S)-tert-butyl (l-bromo-3-(naphthalen-2-yl)propan-2- yl)carbamate (1.3 g, 3.5 mmol, 2 eq) was then added to the mixture and the resultant mixture was heated at 90 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (20 mL) to obtain a precipitate which was filteredunder vacuum to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.60 g, 59 %)

[0506] LCMS: 563 [M+H]+

[0507] Step-2: Preparation of (S)-methyl 6-(4-(2-amino-3-(naphthalen-2-yl)propoxy)phenyl) quinoline-4-carboxylate, 2,2,2-trifluoroacetate salt

[0508] To a stirred solution of (S)-methyl 6-(4-(2-((tert-butoxycarbonyl)amino)-3- (naphthalen-2-yl)propoxy)phenyl)quinoline-4-carboxylate (0.60 g, 1.06 mmol, 1.0 eq) in DCM (15 mL) was added TFA (1.5 mL dropwise at 0 °C and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was evaporated under reduced pressure to obtain a crude residue which was triturated with diethyl ether (10 mL x 3) to afford the title compound as a trifluoroacetate salt (0.60 g, 98 %).

[0509] LCMS: 463 [M+H]+

[0510] Step-3: Preparation of methyl 6-(4-((S)-2-((lr,4S)-4-(((tert-butoxycarbonyl)amino) methyl)cyclohexanecarboxamido)-3-(naphthalen-2-yl)propoxy)phenyl)quinoline-4-carboxylate

[0511] To a stirred solution of (lr,4r)-4-(((tert- butoxycarbonyl)amino)methyl)cyclohexanecarboxylic acid (0.150 g, 0.583 mmol, 1.0 eq) in DMF (10 mL) was added HATU (0.33 g, 0.87 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. DIPEA (0.4 mL, 2.33 mmol, 4 eq) and (S)-methyl 6-(4-(2-amino-3- (naphthalen-2-yl)propoxy) phenyl)quinoline-4-carboxylate, 2,2,2-trifluoroacetate salt (0.40 g, 0.70 mmol, 1.2 eq were then added to the mixture and the mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion, water (30 mL) was added to the mixture to obtain a precipitate which was filtered over vacuum and dried to obtain a crude residue. The crude product was purified by CombiFlash Chromatography to afford the title compound (0.36 g, 88 %) .

[0512] LCMS: 702 [M+H]+

[0513] Step-4: Preparation of 6-(4-((S)-2-((lr,4S)-4-(((tert-butoxycarbonyl)amino)methyl) cyclohexanecarboxamido)-3-(naphthalen-2-yl)propoxy)phenyl)quinoline-4-carboxylic acid

[0514] To a stirred solution of methyl 6-(4-((S)-2-((lr,4S)-4-(tert-butoxycarbonyl)amino) methyl) cyclohexanecarboxamido)-3-(naphthalen-2-yl)propoxy)phenyl)quinoline-4-carboxylate(0.36 g, 0.51 mmol, 1.0 eq) in THF (12 mL) was added LiOH.H2O (0.107 g, 2.56 mmol, 5 eq) in water (2 mL) and methanol (6 mL) and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was acidified using 2N-HC1 (pH~l-2) to obtain a precipitate which was filtered over vacuum to afford the title compound (0.25 g, 71 %) .

[0515] LCMS: 688 [M+H]+

[0516] Step-5: Preparation of tert-butyl (((lS,4r)-4-(((S)-1-(4-(4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)-3-(naphthalen-2- yl)propan-2-yl)carbamoyl)cyclohexyl)methyl)carbamate

[0517] To a stirred solution of 6-(4-((S)-2-((lr,4S)-4-(((tert-butoxycarbonyl)amino)methyl) cyclohexanecarboxamido)-3-(naphthalen-2-yl)propoxy)phenyl)quinoline-4-carboxylic acid (0.215 g, 0.31 mmol, 1.0 eq) in DMF (12 mL) was added HATU (0.18 g, 0.46 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. DIPEA (0.22 mL, 1.25 mmo1,4.0 eq) and (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (0.082 g, 0.37 mmol, 1.2 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, H2O (30 mL) was added to the mixture to obtain the precipitate which was filtered over vacuum to obtain a crude residue. The crude product was purified by CombiFlash Chromatography to afford the title compound (0.185 g 69 % Yield) .

[0518] LCMS: 859 [M+H]+

[0519] Step-6: Preparation of 6-(4-((S)-2-((lr,4S)-4-(aminomethyl)cyclohexanecarboxamido)-3-(naphthalen-2-yl)propoxy)phenyl)-N-(2-((S)-2- cyano-4,4-difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide, 2,2,2-trifluoroacetate salt

[0520] To a stirred solution of tert-butyl ((lS,4r)-4-(((S)-1-(4-(4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)-3-(naphthalen-2- yl)propan-2-yl)carbamoyl)cyclohexyl)methyl)carbamate (0.15 g, 0.174 mmol, 1.0 eq) in DCM (5 mL) was added TFA (1.2 mL) drop wise at 0 °C and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture wasconcentrated under reduced pressure to obtain a crude residue which was triturated with diethyl to afford the title compound as a trifluoroacetate salt (0.13 g, 85 %).

[0521] LCMS: 759 [M+H]+

[0522] Step-7: Preparation of 2,2',2"-(10-(2-((((lS,4r)-4-(((S)-1-(4-(4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)-3-(naphthalen-2- yl)propan-2-yl)carbamoyl)cyclohexyl)methyl)amino)-2-oxoethyl)- 1,4, 7,10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0523] To a stirred solution of 6-(4-((S)-2-((lr,4S)-4-(aminomethyl)cyclohexanecarboxamido)-3-(naphthalen-2-yl)propoxy)phenyl)-N-(2-((S)-2- cyano-4,4-difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide, 2,2,2-trifluoroacetate salt (0.08 g, 0.11 mmol, 1.0 eq) in DMF (0.5 mL) were added TEA (0.04 mL, 0.316 mmol, 3 eq) followed by the addition of 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl)triacetic acid (0.06 g, 0.13 mmol, 1.2 eq) and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure, triturated with diethyl ether and further purified by Reversed Phase HPLC to afford the title compound (0.027 g, 28.5 %)

[0524] LCMS: 1045 [M+H]+

[0525] 'H NMR: (400 MHz, DMSO-d6) δ 9. 22-9.14 (m, 1H), 8.95 (d, J = 4.29 Hz, 1H), 8.75-8.68 (m, 1H), 8.21-8.07 (m, 3H), 8.00-7.93(m, 1H), 7.92-7.78 (m, 5H), 7.72 (s, 1H), 7.57 (d, J = 4.29 Hz, 1H), 7.51-7.37 (m, 3H), 7.13 (d, J = 9.06 Hz, 2H), 5.19 (dd, J = 2.86, 9.06 Hz, 1H), 4.41-4.32 (m, 2H), 4.28 (dd, J = 4.53, 5.48 Hz, 2H), 4.23-4.06 (m, 1H), 4.06 -3.94(m, 2H), 3.46- 3.38 (m, 7H), 3.18-3.04 (m, 6H), 3.02 -2.84 (m, 14H), 2.63 (br. s., 4H), 2.11-1.98 (m, 2H), 1.75- 1.60 (m, 4H), 1.55 (d, J = 13.35 Hz, 1H), 0.90-0.76 (m, 2H)Compound 17

[0526] Synthesis of 2,2',2"-(10-(2-(((lR,4r)-4-((R)-4-(2-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)- 1 -(naphthalen-2-yl)butan-2-ylcarbamoyl)cyclohexyl)methylamino)-2-oxoethyl)- 1 ,4,7, 10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0527] Step- 1 : Synthesis of methyl 6-(2-hydroxy-4-methoxyphenyl)quinoline-4-carboxylate

[0528] To a solution of 2-bromo-5-methoxyphenol (0.70 g, 3.44 mmol, leq) and methyl 6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline-4-carboxylate (1.09 g, 3.44 mmol, l.Oeq.) in 1,4-dioxane (4.8 mL) were added K2CO3 (1.40 g, 10.34 mmol, 3.0 eq) and water (0.3 ml) and the mixture was degassed under nitrogen for 10 min. Pd(dppf)C12 (0.13 g, 0.17 mmol, 0.05 eq) was then added to the mixture and the mixture was further degassed for 5 min. The resultant mixture was irradiated under MW radiation at 120 °C for 1.5 h. The reaction was monitored by TLC. After completion, the mixture was diluted with water (20 mL) and extracted using ethyl acetate (40 mL x 2). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated to obtain a crude residue which was purified using CombiFlash Chromatography to afford the title compound (0.50 g, 46.7 %).

[0529] LCMS: 310[M+H]

[0530] Step-2c: Preparation of (S)-methyl 3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl) butanoate

[0531] To a stirred solution of (S)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (3.0 g, 9.11 mmol, 1.0 eq) in acetone (60 mL) was added KHCO3 (1.4g, 14.58 mmol, 1.6 eq) followed by the addition of Mel (1.4 mL, 22.8 mmol, 2.5 eq) at RT and the mixture was refluxed at 70 °C for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (200 mL) and extract by ethyl acetate (200 mL x 2). The combined organic layers were washed with saturated NaHCO3solution (200 mL), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (2.8 g, 89.7% ).

[0532] LCMS: 344 [M+H]+

[0533] Step-2b: Preparation of (S)-tert-butyl 4-hydroxy-1-(naphthalen-2-yl)butan-2- ylcarbamate

[0534] To a stirred solution of (S)-methyl 3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl) butanoate (2.8 g, 8.15 mmol, 1.0 eq) in THF (30 mL) was added LiA1H4(0.93g, 24.5 mmol, 3.0 eq) at -10 °C and the mixture was stirred at same temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was quenched using saturated Na2SO4 solution at 0 °C slowly. The reaction mixture was then filtered over a pad of celite and washed with EtOAc (200 mL x 2). The filtrate obtained was washed with H2O (100 mL x 2), brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (2.3 g, 89.5 %).

[0535] LCMS: 316 [M+H]+

[0536] Step-2a: Preparation of (S)-tert-butyl 4-bromo-1-(naphthalen-2-yl)butan-2- ylcarbamate

[0537] To a stirred solution of triphenylphosphine (3.18 g, 12.15 mmol, 2.0 eq) in CCI4 (50 mL) was added CBr4 (8.0 g, 24.32 mmol, 4 eq) and the mixture was stirred at RT for 30 min followed by the addition of (S)-tert-butyl 4-hydroxy- 1 -(naphthalen-2-yl)butan-2-ylcarbamate (2.3g, 6.079 mmol,l eq). The resultant mixture was stirred at RT for 16 h. The progress of thereaction was monitored by TLC. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (2.5 g, 90.6 %).

[0538] LCMS: 378 [M+H]+

[0539] Step-2: Synthesis of (R)-methyl 6-(2-(3-(tert-butoxycarbonylamino)-4-(naphthalen-2- yl)butoxy)-4-methoxyphenyl)quinoline-4-carboxylate

[0540] To a stirred solution of methyl 6-(2-hydroxy-4-methoxyphenyl)quinoline-4- carboxylate (0.50 g, 1.61 mmol, 1.0 eq) in DMF (10 mL) was added CsCCL (1.6 g, 4.85 mmol, 3 eq) at RT and the mixture was stirred at same temperature for 10 min. (S)-tert-butyl 4-bromo-1- (naphthalen-2-yl)butan-2-ylcarbamate (1.3 g, 3.5 mmol, 2 eq) was then added to the mixture and the resultant mixture was heated at 90 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (20 mL) to obtain a precipitate which was filtered under vacuum to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.26 g, 26.53 %)

[0541] LCMS: 607 [M+H]+

[0542] Step-3: Preparation of (R)-methyl 6-(2-(3-amino-4-(naphthalen-2-yl)butoxy)-4- methoxyphenyl)quinoline-4-carboxylate, 2,2,2-trifluoroacetate salt

[0543] To a stirred solution of (R)-methyl 6-(2-(3-(tert-butoxycarbonylamino)-4-(naphthalen- 2-yl)butoxy)-4-methoxyphenyl)quinoline-4-carboxylate (0.26 g, 0.43 mmol, 1.0 eq) in DCM (5 mL) was added TFA (0.8 mL) dropwise at 0 °C and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was evaporated under reduced pressure to obtain a crude residue which was triturated with diethyl ether (10 mL x 3) to afford the title compound as a trifluoroacetate salt (0.23 g, 87.6 % )

[0544] LCMS: 507 [M+H]+

[0545] Step-4: Preparation of methyl 6-(2-((R)-3-((lr,4R)-4-((tert-butoxycarbonylamino) methyl) cyclohexanecarboxamido)-4-(naphthalen-2-yl)butoxy)-4-methoxyphenyl)quinoline-4- carboxylate

[0546] To a stirred solution of (lr,4r)-4-((tert- butoxycarbonylamino)methyl)cyclohexanecarboxylic acid (0.08 g, 0.31 mmol, 1.0 eq) in DMF(15 mL) was added HATU (0.17 g, 0.46 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. DIPEA (0.2 mL, 1.24 mmol, 4 eq) and (R)-methyl 6-(2-(3-amino-4- (naphthalen-2-yl)butoxy)-4-methoxyphenyl)quinoline-4-carboxylate, 2,2,2-trifluoroacetate salt (0.23g, 0.37 mmol, 1.2 eq) were then added to the mixture and the mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion, water (30 mL) was added to the mixture to obtain a precipitate which was filtered over vacuum and dried to obtain a crude residue. The crude product was purified by CombiFlash Chromatography to afford the title compound (0.09 g, 38.96 %).

[0547] LCMS: 746 [M+H]+

[0548] Step-5: Preparation of 6-(2-((R)-3-((lr,4R)-4-((tert-butoxycarbonylamino)methyl) cyclohexanecarboxamido)-4-(naphthalen-2-yl)butoxy)-4-methoxyphenyl)quinoline-4-carboxylic acid

[0549] To a stirred solution of methyl 6-(2-((R)-3-((lr,4R)-4-((tert- butoxycarbonylamino)methyl) cyclohexanecarboxamido)-4-(naphthalen-2-yl)butoxy)-4- methoxyphenyl)quinoline-4-carboxylate (0.09 g, 0.12 mmol, 1.0 eq) in THF (6 mF) was added EiOH.PLO (0.025 g, 0.60 mmol, 5 eq) dissolved in water (1 mF) and methanol (3 mF) and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was acidified using 2N-HC1 (pH~l-2) to obtain a precipitate which was filtered over vacuum to afford the title compound (0.084 g, 95.5 %).

[0550] LCMS: 732 [M+H]+

[0551] Step-6: Preparation of tert-butyl ((lR,4r)-4-((R)-4-(2-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)- 1 -(naphthalen- 2-yl)butan-2-ylcarbamoyl)cyclohexyl)methylcarbamate

[0552] To a stirred solution of 6-(2-((R)-3-((lr,4R)-4-((tert-butoxycarbonylamino)methyl) cyclohexanecarboxamido)-4-(naphthalen-2-yl)butoxy)-4-methoxyphenyl)quinoline-4-carboxylic acid (0.084 g, 0.12 mmol, 1.0 eq) in DMF (4 mL) was added HATU (0.065g, 0.171 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. DIPEA (0.08 mF, 0.46 mmol, 4.0 eq) and (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (0.03 g, 0.14 mmole, 1.2 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. Theprogress of the reaction was monitored by TLC and LCMS. After completion, H2O (30 mL) was added to the mixture to obtain the precipitate which was filtered over vacuum to obtain a crude residue. The crude product was purified by CombiFlash Chromatography to afford the title compound (0.095 g, 92.2 %).

[0553] LCMS: 903 [M+H]+

[0554] Step-7: Preparation of 6-(2-((R)-3-((lr,4R)-4-(aminomethyl)cyclohexanecarboxamido)-4-(naphthalen-2-yl)butoxy)-4-methoxyphenyl)-N-(2- ((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide

[0555] To a stirred solution of tert-butyl ((lR,4r)-4-((R)-4-(2-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)- 1 -(naphthalen- 2-yl)butan-2-ylcarbamoyl)cyclohexyl)methylcarbamate (0.095 g, 0.11 mmol, 1.0 eq) in DCM (5 mL) was added TFA (1.2 mL) drop wise at 0 °C and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue which was triturated with diethyl to afford the title compound as a trifluoroacetate salt (0.085 g, 88.5 %)

[0556] LCMS: 803 [M+H]+

[0557] Step-8: Preparation of 2,2',2"-(10-(2-(((lR,4r)-4-((R)-4-(2-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-6-yl)-5-methoxyphenoxy)- 1 -(naphthalen- 2-yl)butan-2-ylcarbamoyl)cyclohexyl)methylamino)-2-oxoethyl)- 1 ,4,7, 10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0558] To a stirred solution of 6-(2-((R)-3-((lr,4R)-4-(aminomethyl)cyclohexanecarboxamido)-4-(naphthalen-2-yl)butoxy)-4-methoxyphenyl)-N-(2- ((S)-2-cyano-4,4-difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide trifluoroacetate salt (0.085 g, 0.105mmol, 1.0 eq) in DMF (0.2 mL) were added 2,2',2"-(10-(2-(4-nitrophenoxy)- 2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (0.07 g, 0.13 mmol, 1.2 eq) and TEA (0.07 ml, 0.525 mmol, 5.0 eq) and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure, triturated with diethyl ether and further purified by Reversed Phase HPLC to afford the title compound (0.038 g, 35.8 %)

[0559] LCMS: 1189 [M+H]+

[0560] 'H NMR: (400 MHz, DMSO-d6) δ 9.16-9.08 (m, 1H), 8.99 (d, J = 4.3 Hz, 1H), 8.42- 8.34 (m, 1H), 8.15 (d, J = 9.1 Hz, 2H), 8.06 (d, J = 8.6 Hz, 1H), 7.84-7.78 (m, 1H), 7.74-7.67 (m, 2H), 7.65-7.55 (m, 3H), 7.46-7.36 (m, 3H), 7.26 (d, J = 10.0 Hz, 1H), 6.68-6.60 (m, 2H), 5.13 (dd, J = 3.3, 9.5 Hz, 1H), 4.35-4.15 (m, 5H), 4.11 (d, J = 11.0 Hz, 1H), 4.01 (br. s., 3H), 3.79 (s, 3H), 3.62-3.52 (m, 4H), 2.97 (br. s., 8H), 2.95-2.82 (m, 12H), 2.80 (br. s., 2H), 1.94-1.74 (m, 4H), 1.72- 1.56 (m, 3H), 1.52 (d, J = 13.4 Hz, 1H), 1.32-1.19 (m, 3H), 1.13 (d, J = 13.8 Hz, 1H)Compound 18

[0561] Synthesis of (S)-4-((2-(4-(3-(5-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)-2-methoxyphenoxy)propyl)piperazin-1-yl)-2- oxoethyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0562] Stepl: Preparation of (S)-tert-butyl (2-(4-(3-(5-(4-((2-(2-cyano-4,4-difluoropyrrolidin- 1 -yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-2-methoxyphenoxy)propyl)piperazin- 1 -yl)-2- oxoethyl)carbamate

[0563] To a stirred solution of 2-(tert-butoxycarbonylamino)acetic acid (0.14 g, 0.78 mmol, 1.1 eq) in DMF (10 mF) was added HATU (0.40 g, 1.06 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 15 min. DIPEA (0.5 mL, 2.83 mmol, 4.0 eq) and (S)-N-(2-(2- cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-methoxy-3-(3-(piperazin-1- yl)propoxy)phenyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.500 g, 0.708 mmol, 1.0 eq) were then added to the mixture and the mixture was stirred at RT for 1.5 h. The progress of the reaction was monitored by TLC and LC-MS. After completion, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined combined organic layers were washed with water (20 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.25 g , 47.73 % )

[0564] LCMS: 750 [M+l]+

[0565] Step-2: Preparation of (S)-6-(3-(3-(4-(2-aminoacetyl)piperazin-1-yl)propoxy)-4- methoxyphenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide 2,2,2-trifluoroacetate

[0566] To a stirred solution of (S)-tert-butyl (2-(4-(3-(5-(4-((2-(2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-2- methoxyphenoxy)propyl)piperazin-1-yl)-2-oxoethyl)carbamate (0.250 g, 0.333 mmol, 1.0 eq) in DCM (4 mL) was added TFA (1.1 mL) drop wise at 0 °C and the mixture was stirred at RT for 1 h. The reaction was monitored by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure and triturated in diethyl ether to afford the title compound as trifluoroacetate salt (0.25 g, 98.42 %).

[0567] LCMS: 650 [M+l]+

[0568] Step-3: Preparation of (S)-4-((2-(4-(3-(5-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-2-methoxyphenoxy)propyl)piperazin-1-yl)-2- oxoethyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0569] To a stirred solution of 3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-l,9'-xanthene]- 6-carboxylic acid (0.110 g, 0.29 mmol, 1.0 eq) in DMF (2 mL) was added HATU (0.17 g, 0.44 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 15 min. DIPEA (0.2mL, 1.17 mmol, 4.0 eq) and (S)-6-(3-(3-(4-(2-aminoacetyl)piperazin-1-yl)propoxy)-4- methoxyphenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide 2,2,2-trifluoroacetate (0.25 g, 0.07 mmol, 1.0 eq) were the added to the mixture and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC and LC-MS. After completion, the mixture was concentrated under vacuum, the residue obtained was triturated with diethyl ether (10 mL x 3), concentrated under reduced pressure to obtain a crude residue was purified by Reversed Phase HPLC to afford the title compound (0.01 g, 3.4 %).

[0570] LCMS: 1008 [M+l]+

[0571] 'H NMR: (400 MHz, DMSO-d6) δ 10.16 (br. s., 1H), 9.18 (t, J = 6.0 Hz, 1H), 8.94 (d, J= 4.3 Hz, 1H), 8.83 (t, J= 5.7 Hz, 1H), 8.70-8.58 (m, 1H), 8.23-8.02 (m, 4H), 7.70 (s, 1H), 7.56 (d, J = 4.3 Hz, 1H), 7.49-7.38 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 2.4 Hz, 2H), 6.63- 6.46 (m, 3H), 5.15 (dd, J = 3.1, 8.8 Hz, 1H), 4.34 (br. s., 1H), 4.26 (dd, J = 2.9, 5.7 Hz, 2H), 4.22- 4.12 (m, 3H), 4.05 (d, J= 5.7 Hz, 2H), 3.85-3.75 (m, 3H), 3.48 - 3.37 (m, 6H), 2.96 (d, J = 9.5 Hz, 1H), 2.86 (d, J = 16.7 Hz, 2H), 2.40 (d, J = 12.4 Hz, 4H), 1.93 (dd, J = 6.4, 7.4 Hz, 2H)Compound 19

[0572] Synthesis of (S)-4-(2-(2-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl) quinolin-6-yl)-5-methoxyphenoxy)ethylamino)-2-oxoethylcarbamoyl)-2-(6- hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0573] Stepl: Preparation of (S)-tert-butyl (2-(4-(3-(2-(4-((2-(2-cyano-4,4-difluoropyrrolidin- l-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-5-methoxyphenoxy)propyl)piperazin-1-yl)-2- oxoethyl)carbamate

[0574] To a stirred solution of 2-(tert-butoxycarbonylamino)acetic acid (0.06 g, 0.34 mmol, 1.1 eq) in DMF (0.8 mL) was added HATU (0.18 g, 0.47 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 15 min. DIPEA (0.22 mL, 1.24 mmol, 4.0 eq) and (S)-N-(2- (2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-methoxy-2-(3-(piperazin-1- yl)propoxy)phenyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.22 g, 0.31 mmol, 1.0 eq) were the added to the mixture and the mixture was stirred at RT for 1.5 h. The progress of the reaction was monitored by TLC and LC-MS. After completion, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (20 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.10 g , 42.8 % )

[0575] LCMS: 750 [M+l]+

[0576] Step-2: Preparation of ((S)-6-(2-(3-(4-(2-aminoacetyl)piperazin-1-yl)propoxy)-4- methoxyphenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide 2,2,2-trifluoroacetate

[0577] To a stirred solution of (S)-tert-butyl (2-(4-(3-(2-(4-((2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-5- methoxyphenoxy)propyl)piperazin-1-yl)-2-oxoethyl)carbamate (0.10 g, 0.13 mmol, 1.0 eq) in DCM (4 mL) was added TFA (0.03 mL) drop wise at 0 °C and the mixture was stirred at RT for 1 h. The reaction was monitored by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure and triturated in diethyl ether to afford the title compound as trifluoroacetate salt (0.10 g, 98.17 %).

[0578] LCMS: 650 [M+l]+

[0579] Step-3: Preparation of (S)-4-((2-(4-(3-(2-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-5 -methoxyphenoxy )propyl)piperazin-1-yl)-2- oxoethyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0580] To a stirred solution of 3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-l,9'-xanthene]- 6-carboxylic acid (0.03 g, 0.08 mmol, 1.2 eq) in DMF (2 mL) was added HATU (0.04 g, 0.10 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 15 min. DIPEA (0.04 mL, 0.27 mmol, 4.0 eq) and ((S)-6-(2-(3-(4-(2-aminoacetyl)piperazin-1-yl)propoxy)-4- methoxyphenyl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide 2,2,2-trifluoroacetate (0.05 g, 0.07 mmol, 1.0 eq) were the added to the mixture and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC and LC-MS. After completion, the mixture was concentrated under reduced pressure and the residue obtained was triturated with diethyl ether (10 mL x 3), concentrated under reduced pressure to obtain a crude residue which was purified by Reversed Phase HPLC to afford the title compound (0.002 g, 3.03 % ).

[0581] LCMS: 1008 [M+l]+

[0582] 'H NMR: (400 MHz, DMSO-d6) δ 10.16 (br. s., 1H), 9.10 (t, J= 6.0 Hz, 1H), 8.95 (d, J = 4.3 Hz, 1H), 8.86 -8.77 (m, 1H), 8.37 (d, J = 1.9 Hz, 1H), 8.21-8.15 (m, 2H), 8.12-8.02 (m, 2H), 8.02-7.93 (m, 1H), 7.70 (s, 1H), 7.56 (d, J = 4.3 Hz, 1H), 7.43-7.33 (m, 1H), 6.74-6.64 (m,4H), 6.61-6.51 (m, 3H), 5.13 (dd, J= 3.1, 9.3 Hz, 1H), 4.36-4.19 (m, 3H), 4.19-4.08 (m, 2H), 4.06- 4.00 (m, 3H), 3.81 (s, 3H), 2.65-2.58 (m, 3H), 2.95-2.76 (m, 3H), 2.29-2.24 (m, 2H), 2.22-2.17 (m, 2H), 1.87-1.77 (m, 2H), 1.58 (br. s., 1H), 1.50 (br. s., 2H)Compound 20

[0583] Step- 1 : Synthesis of methyl 6-vinylquinoline-4-carboxylate

[0584] To a stirred solution of methyl 6-bromoquinoline-4-carboxylate (0.300 g, 1.127 mmol, 1.0 equiv) in Dioxane:Water (3 : 03 mL) was added K2CO3 (0.311 g, 2.254 mmol, 2.0 equiv), followed by the addition of potassium vinyltrifluoroborate (0.180 g, 1.352 mmol,1.2equiv). The reaction mixture was degassed with N2 for 5-10 minutes, followed by the addition of Bis(triphenylphosphine)palladium dichloride (0.039 g, 0.056 mmol, 0.05 equiv). The resulting reaction mixture was heated at 90 °C for 16 h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20 ml) and passed through Celite®. The filtrate was concentrated and the residue was purified by Flash chromatography (0- 20 % ethyl acetate in hexane as an eluent) to obtain methyl 6- vinylquinoline-4-carboxylate (0.160 g, 66 % Yield) as a yellow oil.

[0585] LCMS: 214 [M+l]

[0586] 'H NMR (400 MHz, DMSO-76) δ 8.94 - 9.10 (m, 1 H) 8.61 (s, 1 H) 8.15 (s, 2 H)7.90 - 7.98 (m, 1 H) 6.87 - 7.10 (m, 1 H) 6.09 (m, 1 H) 5.49 (d, 7=10.97 Hz, 1 H) 4.00 (s, 3 H).

[0587] Step-2: Synthesis of methyl (E)-6-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)styryl)quinoline-4-carboxylate

[0588] To a stirred solution of tert-butyl 4-(3-(4-iodophenoxy)propyl)piperazine-1- carboxylate (0.250 g, 0.560 mmol, 1.0 equiv) in DMF(2.5mL) was added methyl 6-vinylquinoline- 4-carboxylate (0.143 g, 0.672 mmol, 1.2 equiv), followed by the addition of TEA (0.24 ml, 1.681 mmol, 3.0 equiv). The reaction mixture was purged with N2 for 5-10 minutes, followed by the addition of Pd(dppf)C12(0.040 g, 0.056 mmol, 0.1 equiv). The resulting reaction mixture was heated at 100 °C for 6 h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 ml) and passed through Celite®. The filtrate was washed with water(2 x 10ml), brine ( 10ml ), dried over anhydrous sodium sulfate and concentrated under reduced pressure .The residue was purified by Flash chromatography (0-5 % MeOH in DCM as an eluent) to obtain methyl (E)-6-(4-(3-(4-(tert- butoxycarbonyl)piperazin-1-yl)propoxy)styryl)quinoline-4-carboxylate (0.150 g, 50 % Yield) as light brown oil.

[0589] LCMS: 532 [M+l]+

[0590] 'H NMR (400 MHz, CHLOROFORM-d) δ 8.94 (d, 7=4.29 Hz, 1 H) 8.78 (d, 7=1.43 Hz, 1 H) 8.08 - 8.17 (m, 1 H) 7.95 - 8.08 (m, 1 H) 7.90 (d, 7=4.29 Hz, 1 H) 7.51 (d, 7=8.58 Hz, 2 H) 7.11 - 7.36 (m, 2 H) 6.92 (d, 7=9.06 Hz, 2 H) 4.03 - 4.16 (m, 5 H) 3.46 (br. s., 4 H) 2.56 (br. s., 2 H) 2.43 (br. s., 4 H) 1.92 - 2.10 (m, 2 H) 1.47 (s, 9 H).

[0591] Step-3: Synthesis of lithium (E)-6-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)styryl)quinoline-4-carboxylate

[0592] To a stirred solution of methyl (E)-6-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)styryl)quinoline-4-carboxylate (0.120 g, 0.225 mmol, 1.0 equiv) in THF (2 mL) was added LiOH.H2O (0.018 g, 0.451 mmol, 2.0 equiv) in water (0.8 ml). The Reaction mixture was allowed to stir at RT for 2h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the solvent was removed under reduced pressure and the resultingresidue was freeze dried on to obtain lithium (E)-6-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)styryl)quinoline-4-carboxylate (0.100 g, 84 % Yield) as a yellow solid.

[0593] LCMS: 523 [M+l]+

[0594] 'H NMR (400 MHz, DMSO-76) δ 8.62 - 8.71 (m, 2 H) 7.97 (d, 7=6.20 Hz, 1 H) 7.87 (d, 7=9.06 Hz, 1 H) 7.60 (d, 7=9.06 Hz, 2 H) 7.36 (d, 7=4.29 Hz, 1 H) 7.26 (s, 2 H) 6.95 (d, 7=8.58 Hz, 2 H) 3.95 - 4.10 (m, 2 H) 3.46 (br. s., 4 H) 2.56 (br. s., 2 H) 2.43 (br. s., 4 H) 1.92 - 2.10 (m, 2 H) 1.47 (s, 9 H).

[0595] Step-4: Synthesis of tert-butyl (S,E)-4-(3-(4-(2-(4-((2-(2-cyano-4,4-difhroropyrrolidin- 1 -yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)vinyl)phenoxy)propyl)piperazine- 1 -carboxylate

[0596] To a stirred solution of lithium (E)-6-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)styryl)quinoline-4-carboxylate (0.100 g, 0.191 mmol, 1.0 equiv) in DMF (1 mL) was added EDC.HC1 (0.047 g, 0.248 mmol, 1.3 equiv), HOBT(0.033 g, 0.248 mmol, 1.3 equiv) and (S)- l-(2-aminoacetyl)-4,4-difhroropyrrolidine-2-carbonitrile hydrochloride (0.064 g, 0.286 mmol, 1.5 equiv) followed by the addition of DIPEA(0.1mL, 0.573 mmol, 3.0 equiv). The resulting reaction mixture was allowed to stir at RT for 16h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers was washed with water (5 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure The crude product was purified by Flash chromatography (0-5 % MeOH in DCM as an eluent) to obtain tertbutyl (S,E)-4-(3-(4-(2-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)vinyl)phenoxy)propyl)piperazine-l -carboxylate (0.020 g 15 % Yield) as an off white solid.

[0597] LCMS: 689 [M+l]+

[0598] 'H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1 H) 8.92 (d, 7=4.29 Hz, 2 H) 8.52 (s, 1 H) 8.01 - 8.15 (m, 1 H) 7.65 (d, 7=8.58 Hz, 2 H) 7.44 - 7.58 (m, 2 H) 7.28 (d, 7=16.69 Hz, 1 H) 6.97 (d, 7=9.06 Hz, 2 H) 5.19 (d, 7=18.12 Hz, 1 H) 4.21 (t, 7=11.44 Hz, 2 H) 3.94 - 4.11 (m, 4 H) 3.17 (d, 7=5.25 Hz, 2 H) 2.75 - 2.97 (m, 2 H) 2.61 - 2.75 (m, 2 H) 2.44 (t, 7=7.39 Hz, 2 H) 2.33 (br. s., 4 H) 1.81 - 1.94 (m, 2 H) 1.35 - 1.45 (m, 9H).

[0599] Step-5: Synthesis of (S,E)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6- (4-(3 -(piperazin- 1 -yl)propoxy)styryl)quinoline-4-carboxamide 2,2,2-trifluoroacetate

[0600] To a stirred solution of tert-butyl (S,E)-4-(3-(4-(2-(4-((2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)vinyl)phenoxy)propyl)piperazine- 1-carboxylate (0.020 g, 0.029 mmol, 1.0 equiv) in DCM (0.2 mL) was added TFA (0.08 mL) drop wise at 0°C. The Reaction mixture was allowed to stir at RT for 2h. The product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and crystallized with diethyl ether to obtain (S,E)-N-(2-(2- cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-(3-(piperazin-1- yl)propoxy)styryl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.018 g, 94 % Yield) as a yellow solid.

[0601] LCMS: 589 [M+l]+

[0602] 'H NMR (400 MHz, DMSO-76) δ 9.17 (s, 1 H) 8.92 (d, 7=4.29 Hz, 2 H) 8.52 (s, 1 H) 8.01 - 8.15 (m, 2 H) 7.65 (d, 7=8.58 Hz, 2 H) 7.44 - 7.58 (m, 2 H) 7.28 (d, 7=16.69 Hz, 1 H) 6.97 (d, 7=9.06 Hz, 2 H) 5.19 (d, 7=18.12 Hz, 1 H) 4.21 (t, 7=11.44 Hz, 2 H) 3.94 - 4.11 (m, 4 H) 3.17 (d, 7=5.25 Hz, 2 H) 2.75 - 2.97 (m, 2 H) 2.61 - 2.75 (m, 2 H) 2.44 (t, 7=7.39 Hz, 2 H) 2.33 (br. s., 4 H) 1.81 - 1.94 (m, 2 H).

[0603] Step-6: Synthesis of (S,E)-2,2',2"-(10-(2-(4-(3-(4-(2-(4-(2-(2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-6-yl) vinyl)phenoxy)propyl)piperazin- 1 - yl)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7-triyl)triacetic acid

[0604] To a stirred solution of (S,E)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)- 6-(4-(3-(piperazin-1-yl)propoxy)styryl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.018 g, 0.026 mmol, 1.0 equiv) in DMF (0.3 mL) was added 2,2',2"-(10-(2-(4-nitrophenoxy)-2- oxoethyl)- 1,4, 7, 10-tetraazacyclododecane- 1, 4, 7-triyl)triacetic acid (0.020 g, 0.039 mmol, 1.5 equiv) and TEA (0.02 ml, 0.156 mmol, 6.0 equiv). The Reaction mixture was allowed to stir at room temperature for 16 h. The product formation was confirmed by LCMS. After completion of the reaction, the mixture was concentrated under reduced pressure, crystallized in diethyl ether and further purified by reversed phase HPLC to obtain (S,E)-2,2',2"-(10-(2-(4-(3-(4-(2-(4-(2-(2-cyano- 4,4-difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-6-yl)vinyl)phenoxy)propyl)piperazin- 1 -yl)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7- triyl)triacetic acid (0.002 g, 7 % Yield) as an off-white solid.

[0605] LCMS: 975 [M+l]+

[0606] 'H NMR (400 MHz, DEUTERIUM OXIDE) δ 8.77 (br. s., 1 H) 8.16 (br. s., 1 H) 7.92 (br. s., 2 H) 7.59- 7.53 (br. s., 3 H) 7.28 (br. s., 1 H) 7.16 (br. s., 1 H) 6.94 (br. s., 2 H) 5.16 (br. s., 1 H) 4.28 (br. s.,2 H) 4.10 (br. s., 4H) 3.83 -3.69 (s, 8 H) 3.53 (br. s., 2 H) 3.32 - 3.48 (m,12 H) 3.32 - 3.21 (m, 4 H) 3.15 - 2.81 (m, 8 H) 2.22 - 2.06 (m, 4 H).Compound 21Synthesis of (S)-2,2',2"-(10-(2-(4-(3-(4-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-7-yl)phenoxy)propyl)piperazin- 1 -yl)-2-oxoethyl)- 1 ,4,7, 10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0607] Step-1: Preparation of methyl 7-(4-hydroxyphenyl)quinoline-4-carboxylate

[0608] To a stirred solution of methyl 7-bromoquinoline-4-carboxylate (0.5 g, 1.87 mmol, 1.0 eq) and (4-hydroxyphenyl)boronic acid (0.31 g, 2.24 mmol, 1.2 eq) in 1 ,4-Dioxane-H2O (4.5 mL : 0.5 mL) was added K2CO3 (0.77 g, 5.61 mmol, 3 eq) and the mixture was degassed under nitrogen for 10 min. Pd(dppf)C12 (0.07 g, 0.09 mmol, 0.05 eq) was then added to the mixture and the mixture was further degassed for 5 min. The resultant mixture was irradiated under MW radiation at 100 °C for 1.5 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (20 mL) and extracted using ethyl acetate (40 mL x 2). Thecombined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated to obtain a crude residue which was purified using CombiFlash Chromatography to afford the title compound (0.430 g, 81.65 %).

[0609] LCMS: 280 [M+H]+

[0610] Step-2: Preparation of methyl 7-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy) phenyl)quinoline-4-carboxylate

[0611] To a stirred solution of methyl 7-(4-hydroxyphenyl)quinoline-4-carboxylate (0.38 g, 1.36 mmol, 1.0 eq) in DMF (4 mL) was added CS2CO3 (0.88 g, 2.71 mmol, 2 eq) at RT and the mixture was stirred at same temperature for 30 min. Tert-butyl 4-(3-bromopropyl)piperazine-1- carboxylate (0.83 g, 2.71 mmol, 2 eq) was then added to the mixture and the mixture was heated at 70 °C for 2 h. After completion, the mixture was diluted with water (20 mL) to obtain a precipitate which was filtered under vacuum to obtain a crude residue. The crude residue was purified by CombiFlash Chromatography to afford the title compound (0.30 g, 43.6%).

[0612] LCMS: 506 [M+H]+

[0613] Step-3: Preparation of 7-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)phenyl) quinoline-4-carboxylic acid

[0614] To a stirred solution of methyl 7-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)phenyl)quinoline-4-carboxylate (0.32 g, 0.63 mmol, 1.0 eq) in THF (12 mL) was added LiOH.H2O (0.26 g, 6.33 mmol, 10 eq) dissolved in water (2 mL) and methanol (6 mL) and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was acidified using 2N-HC1 (pH~l-2) to obtain a precipitate which was filtered over vacuum and dried to afford the title compound (0.30 g, 100 %).

[0615] LCMS: 492 [M+H]+

[0616] Step-4: Preparation of (S)-tert-butyl 4-(3-(4-(4-(2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)phenoxy)propyl)piperazine-1- carboxylate

[0617] To a stirred solution of 7-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)phenyl) quinoline-4-carboxylic acid (0.3 g, 1.02 mmol, 1.0 eq) in DMF (12 mL) was added TBTU (0.49 g, 1.52 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperaturefor 30 min. NMM (0.3 mL, 3.05 mmol, 3 eq) and (S)-1-(2-aminoacetyl)-4,4-difluoropyrrolidine- 2-carbonitrile hydrochloride (0.27 g, 1.22 mmol, 1.5 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with ice-cold water (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.082 g, 20.29 %).

[0618] LCMS: 663 [M+H]+

[0619] Step-5: Preparation of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)-7-(4-(3-(piperazin-1-yl)propoxy)phenyl)quinoline-4-carboxamide

[0620] To a stirred solution of (S)-tert-butyl 4-(3-(5-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-2-methoxyphenoxy)propyl)piperazine-1-carboxylate (0.082 g, 0.12 mmol, 1.0 eq) in DCM (4 mL) was added TFA (0.5 mL) dropwise at 0 °C and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was evaporated under reduced pressure to obtain a crude residue which was triturated with diethyl ether (10 mL x 3) to afford the title compound (0.080 g, 95.54 %).

[0621] LCMS: 563 [M+H]+

[0622] Step-6: Preparation of (S)-2.2'.2"-( 10-(2-(4-(3-(4-(4-(2-(2-cyano-4.4- difluoropy rrolidin- 1 -y l)-2-oxoethylcarbamoy l)quinolin-7 -y l)phenoxy )propyl)piperazin- 1 - yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid

[0623] To a stirred solution of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-7- (4-(3 -(piperazin- l-yl)propoxy)phenyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate (0.080 g, 0.14 mmol, 1.0 eq) in DMF (2 mL) were added TEA (0.08 mL, 0.56 mmol, 5 eq) and 2,2',2"-(10- (2-(4-nitrophenoxy)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1,4,7 -triyl)triacetic acid (0.09 g, 0.17 mmol, 1.2 eq) and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure, triturated with diethyl ether and further purified by Reversed Phase HPLC to afford the title compound (0.009 g, 14 %).

[0624] LCMS: 949 [M+H]+

[0625] 'H NMR: (400 MHz, DMSO-d6) δ 9.15 (br. s., 1H), 8.99 (d, J = 4.3 Hz, 1H), 8.40 (d, J = 8.6 Hz, 1H), 8.28 (s, 1H), 8.07-7.99 (m, 1H), 7.89-7.82 (m, J = 8.6 Hz, 2H), 7.54 (d, J = 4.8 Hz, 1H), 7.13-7.04 (m, J = 8.6 Hz, 2H), 5.19 (dd, J = 2.6, 9.3 Hz, 1H), 4.39-4.19 (m, 4H), 4.19- 4.03 (m, 4H), 3.61 (br. s., 6H), 3.00 (br. s., 6H), 2.97-2.89 (m, 5H), 2.89-2.78 (m, 6H), 1.93 (br. s., 3H)Compound 22Synthesis of 2,2',2"-(10-(2-((lr,4r)-4-(2-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethylcarbamoyl)cyclohexylamino)-2-oxoethyl)-1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7-triyl)triacetic acid

[0626] Step-1 : Preparation of methyl 6-(4-(2-(tert-butoxycarbonylamino)ethoxy) phenyl) quinoline-4-carboxylate

[0627] To a stirred solution of methyl 6-(4-hydroxyphenyl)quinoline-4-carboxylate (0.400 g, 1.432 mmol, 1.0 eq) in DMF (10 rnL) was added CS2CO3 (0.93 g, 2.87 mmol, 2.0 eq) at RT and the mixture was allowed to stirred for 30 min. Tert-butyl 2-bromoethylcarbamate (0.48 g, 2.41 mmol, 1.5 eq) was then added to the mixture and the resultant mixture was heated at 70 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixturewas diluted with water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL) dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.55 g, 91 %)

[0628] LCMS: 423 [M+H]+

[0629] Step-2: Preparation of methyl 6-(4-(2-aminoethoxy)phenyl)quinoline-4- carboxylate

[0630] To a stirred solution of methyl 6-(4-(2-(tert-butoxycarbonylamino)ethoxy) phenyl) quinoline-4-carboxylate (0.77 g, 1.82 mmol, 1.0 eq) in DCM (15 mL) was added TFA (2.0 mL) drop wise at 0 °C and the mixture was allowed to stir at RT for 2 h. The product formation was confirmed by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure and triturated in diethyl ether (10 mL x2) to afford the title compound (0.71 g, 89 %).

[0631] LCMS: 323 [M+H]+

[0632] Step-3: Preparation of methyl 6-(4-(2-((lr,4r)-4-(tert-butoxycarbonylamino) cyclohexane carboxamido)ethoxy)phenyl)quinoline-4-carboxylate

[0633] To a stirred solution of (lr,4r)-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (0.445 g, 1.831 mmol, 1.0 eq) in DMF (10 mL) was added HATU (1.04 g, 2.75 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. DIPEA (0.95 mL, 5.49 mmol, 3 eq) and methyl 6-(4-(2-aminoethoxy)phenyl)quinoline-4-carboxylate (0.709 g, 2.197 mmol, 1.2 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, water (30 mL) was added to the mixture to obtain a precipitate which was filtered over Buchner funnel to obtain to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.80 g, 80 %).

[0634] LCMS: 548 [M+H]+

[0635] Step-4: Preparation of 6-(4-(2-((lr,4r)-4-(tert-butoxycarbonylamino) cyclohexane carboxamido)ethoxy)phenyl)quinoline-4-carboxylic acid

[0636] To a stirred solution of methyl 6-(4-(2-((lr,4r)-4-(tert-butoxycarbonylamino) cyclohexane carboxamido)ethoxy)phenyl)quinoline-4-carboxylate (0.80 g, 1.46 mmol, 1.0 eq) inTHF (24 mL) was added LiOH.H2O (0.306 g, 7.31 mmol, 5.0 eq) dissolved in MeOH : Water (12 mL : 4.0 mL) and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was acidified with 2N-HC1 (pH ~l-2) to obtain a precipitate which was filtered over Buchner funnel and dried to afford the title compound (0.30 g, 38%).

[0637] LCMS: 534 [M+H]+

[0638] Step-5: Preparation of tert-butyl (lr,4r)-4-(2-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6- yl)phenoxy)ethylcarbamoyl)cyclohexylcarbamate

[0639] To a stirred solution of 6-(4-(2-((lr,4r)-4-(tert-butoxycarbonylamino) cyclohexane carboxamido)ethoxy)phenyl)quinoline-4-carboxylic acid (0.30 g, 0.56 mmol, 1.0 eq) in DMF (10 mL) was added HATU (0.32 g, 0.84 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. DIPEA (0.29 mL, 1.68 mmol, 3 eq) and ((S)-1-(2-aminoacetyl)-4,4- difhroropyrrolidine-2-carbonitrile hydrochloride (0.15 g, 0.67 mmol, 1.2 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, water (30 mL) was added to the mixture to obtain a precipitate which was filtered over Buchner funnel and dried to obtain a crude residue. The crude product was purified by CombiFlash Chromatography to afford the title compound (0.195 g, 49 %).

[0640] LCMS: 705 [M+H]+

[0641] Step-6: Preparation of 6-(4-(2-((lr,4r)-4- aminocyclohexanecarboxamido)ethoxy)phenyl)-N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethyl)quinoline-4-carboxamide

[0642] To a stirred solution of tert-butyl (lr,4r)-4-(2-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-6- yl)phenoxy)ethylcarbamoyl)cyclohexylcarbamate (0.19 g, 0.27 mmol, 1.0 eq) in DCM (5.0 mL) was added TFA (0.8 mL) drop wise at 0 °C and the mixture was allowed to stir at RT for 2 h. The product formation was confirmed by TLC and LCMS. After completion, the mixture wasconcentrated under reduced pressure and triturated with diethyl ether to afford the title compound (0.11 g, 56 %).

[0643] LCMS: 605 [M+l]+

[0644] Step-7: Preparation of 2,2',2"-(10-(2-((lr,4r)-4-(2-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethylcarbamoyl) cyclohexylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid

[0645] To a stirred solution of 6-(4-(2-((lr,4r)-4- aminocyclohexanecarboxamido)ethoxy)phenyl)-N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)- 2-oxoethyl)quinoline-4-carboxamide (0.11 g, 0.18 mmol, 1.0 eq) in DMF (3.0 mL) was added 2,2',2"-( 10-(2-(4-nitrophenoxy)-2-oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid (0.115 g, 0.220 mmol, 1.2 eq) and TEA (0.10 mL, 0.735 mmol, 4.0 eq) and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and triturated with diethyl ether and further purified by Reversed Phase HPLC to afford the title compound (0.044 g, 24 %)

[0646] LCMS: 991 [M+H]+

[0647] 'H NMR: (400 MHz, DMSO-d6) 8 9.22-9.14 (m, 1H), 8.94 (d, J = 4.3 Hz, 1H), 8.76- 8.69 (m, 1H), 8.19-8.09 (m, 2H), 8.09-8.01 (m, 2H), 7.91-7.83 (m, 2H), 7.60-7.52 (m, 1H), 7.14- 7.04 (m, 2H), 5.19 (dd, J = 2.9, 9.5 Hz, 1H), 4.39-4.09 (m, 4H), 4.09-3.97 (m, 2H), 3.50 (br. s., 4H), 3.04 (br. s., 2H), 3.01-2.81 (m, 10H), 2.67 (br. s., 1H), 2.61 (br. s., 3H), 2.18-2.05 (m, 2H), 1.85-1.66 (m, 4H)Compound 23Synthesis of (S,E)-4-(2-(4-(3-(4-(2-(4-(2-(2-cyano-4,4-difluoropyrrolidin- l-yl)-2-oxoethyl carbamoyl)quinolin-6-yl)vinyl)phenoxy)propyl)piperazin-1-yl)-2-oxoethylcarbamoyl)-2-(6- hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0648] Step-1: Preparation of methyl 6-vinylquinoline-4-carboxylate

[0649] To a stirred solution of methyl 6-bromoquinoline-4-carboxylate (1.7 g, 6.41 mmol, 1.0 eq) in Dioxane:Water (3 mL : 0.3 mL) was added K2CO3 (1.78 g, 12.83 mmol, 2.0 eq) followed by the addition of potassium vinyltrifluoroborate (1.0 g, 7.69 mmol, 1.2 eq) and the mixture was degassed with N2 for 5-10 min. Bis(triphenylphosphine) palladium dichloride (0.224 g, 0.320 mmol, 0.05 eq) was then added to the mixture and the mixture was further degassed under N2 for 10 min. The resultant mixture was heated at 90 °C for 6 h. Product formation was confirmed by TLC and LCMS. After completion, the mixture was diluted with ethyl acetate (20 mL) and passed through Celite®. The filtrate was concentrated and the residue was purified by CombiFlash Chromatography to obtain the title compound (0.80 g, 61 %).

[0650] LCMS: 214 [M+l]+

[0651] Step-2: Preparation of (E)-methyl 6-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy) styryl)quinoline-4-carboxylate

[0652] To a stirred solution of tert-butyl 4-(3-(4-iodophenoxy)propyl)piperazine-1- carboxylate (1.0 g, 2.23 mmol, 1.0 eq) in DMF (5mL) was added methyl 6-vinylquinoline-4- carboxylate (0.478 g, 2.23 mmol, 1.0 eq) followed by the addition of K3PO4 (1.18 g, 5.59 mmol,2.5 eq) and the mixture was degassed under N2 for 5-10 min. Pd(OAC)2 (0.035 g, 0.16 mmol, 0.07 eq) and the added to the mixture and the mixture was further degassed N2 for 5 min. The resultant mixture was irradiated under MW radiation at 100 °C for 1 h. Product formation was confirmed by TLC and LCMS. After completion, the mixture was diluted with ethyl acetate (30 mL) and passed through celite®. The filtrate was washed with water (2 x 20 mL), brine ( 10 mL ), dried over anhydrous sodium sulfate and concentrated under reduced pressure .The crude product was purified by CombiFlash Chromatography to afford the title compound (0.45 g, 37 %) .

[0653] LCMS: 533 [M+l]+

[0654] Step-3: Preparation of (E)-methyl 6-(4-(3-(piperazin-1- yl)propoxy)styryl)quinoline-4-carboxylate

[0655] To a stirred solution of methyl (E)-6-(4-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)styryl)quinoline-4-carboxylate (0.45 g, 0.85 mmol, 1.0 eq) in DCM (15 mL) was added TFA (2.0 mL) drop wise at 0 °C and the mixture was allowed to stir at RT for 1 h. The product formation was confirmed by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure and triturated in diethyl ether (10 mL x2) to afford the title compound (0.43 g, 93 %).

[0656] LCMS: 433 [M+l]+

[0657] Step-4: Preparation of (E)-methyl 6-(4-(3-(4-(2-(tert-butoxycarbonylamino) acetyl)piperazin-1-yl)propoxy)styryl)quinoline-4-carboxylate

[0658] To a stirred solution of 2-(tert-butoxycarbonylamino)acetic acid (0.21 g, 1.19 mmol, 1.2 eq) in DMF (7 mL) was added HATU (0.57 g, 1.49 mmol, 1.5 eq) at 0 °C and the mixture was allowed to stir for 30 minutes at the same temperature. DIPEA (0.6 mL, 3.98 mmo1,4.0 eq) and (E)-methyl 6-(4-(3 -(piperazin- l-yl)propoxy)styryl)quinoline-4-carboxylate (0.43 g, 1.0 mmol, 1.0 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. Product formation was confirmed by TLC and LCMS. After completion, the mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers was washed with water (5 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure The crude product was purified by CombiFlash Chromatography to afford the title compound (0.40 g 68 %) .

[0659] LCMS: 589 [M+l]

[0660] Step-5: Preparation of (E)-6-(4-(3-(4-(2-(tert- butoxycarbonylamino)acetyl)piperazin-1-yl)propoxy)styryl)quinoline-4-carboxylic acid

[0661] To a stirred solution of (E)-methyl 6-(4-(3-(4-(2-(tert-butoxycarbonylamino) acetyl)piperazin-1-yl)propoxy)styryl)quinoline-4-carboxylate (0.40 g, 0.68 mmol, 1.0 eq) in THF (9 mL) was added LiOH.FEO (0.14 g, 3.40 mmol, 5.0 eq) in MeOH and water (4.5 : 1.5 mL) and the mixture was allowed to stir at RT for 2 h. Product formation was confirmed by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure and the resulting residue was dried on to obtain to afford the title compound (0.27 g, 70 %).

[0662] LCMS: 575 [M+l]+

[0663] Step-6: Preparation of (S,E)-tert-butyl 2-(4-(3-(4-(2-(4-(2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6- yl)vinyl)phenoxy)propyl)piperazin-1-yl)-2-oxoethylcarbamate

[0664] To a stirred solution of (E)-6-(4-(3-(4-(2-(tert-butoxycarbonylamino)acetyl)piperazin- l-yl)propoxy)styryl)quinoline-4-carboxylic acid (0.27 g, 0.48 mmol, 1.0 eq) in DMF (10 mL) was added TBTU (0.23 g, 0.72 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. NMM (0.15 mL, 1.43 mmol, 3.0 eq) and (S)-1-(2-aminoacetyl)-4,4- difhioropyrrolidine-2-carbonitrile hydrochloride (0.13 g, 0.57 mmol, 1.2 eq) were then added to the mixture and the resultant mixture was stirred at RT for 2 h. Product formation was confirmed by TLC and LCMS. After completion, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers was washed with ice-cold water (10 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by CombiFlash Chromatoraphy to afford the title compound (0.28 g, 78%).

[0665] LCMS: 746 [M+l]+

[0666] Step-7: Preparation of (S,E)-6-(4-(3-(4-(2-aminoacetyl)piperazin-1- yl)propoxy)styryl)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide

[0667] To a stirred solution of (S,E)-tert-butyl 2-(4-(3-(4-(2-(4-(2-(2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-6-yl) vinyl)phenoxy)propyl)piperazin- 1 -yl)-2-oxoethylcarbamate (0.28 g, 0.37 mmol, 1.0 eq) in DCM (10 mL) was added TFA (1.0 mL) drop wise at 0 °C and the mixture was allowed to stir at RT for 1 h. The product formation was confirmed by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure and triturated in diethyl ether (10 mL x2) to afford the title compound (0.23 g, 95 %).

[0668] LCMS: 646 [M+l]+

[0669] Step-8: Preparation of (S,E)-4-(2-(4-(3-(4-(2-(4-(2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6- yl)vinyl)phenoxy)propyl)piperazin-1-yl)-2-oxoethyl carbamoyl)-2-(6-hydroxy-3-oxo-3H- xanthen-9-yl)benzoic acid

[0670] To a stirred solution of 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)terephthalic acid (0.13 g, 0.33 mmol, 1.0 eq) in DMF (5 mL) was added HATU (0.19 g, 0.5 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 4h . DIPEA (0.2 mL, 1.33 mmol, 4.0 eq) and (S,E)- 6-(4-(3-(4-(2-aminoacetyl)piperazin-1-yl)propoxy)styryl)-N-(2-(2-cyano-4,4-difluoropyrrolidin- l-yl)-2-oxoethyl)quinoline-4-carboxamide (0.25 g, 0.33 mmol, 1.0 eq) were then added to the mixture and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the excess solvent was evaporated under reduced pressure and triturated with diethyl ether to obtain a solid which was purified by Reversed Phase HPLC to afford the title compound (0.023 g, 14 %).

[0671] LCMS: 1004 [M+l]+

[0672] 'H NMR: (400 MHz, DMSO-d6) δ 10.21-10.18 (m, 1H), 9.21-9.12 (m, 1H), 8.91 (d, J = 4.3 Hz, 1H), 8.88-8.79 (m, 1H), 8.52 (s, 1H), 8.25-8.15 (m, 1H), 8.14-7.99 (m, 3H), 7.71 (s, 1H), 7.67-7.58 (m, J = 9.1 Hz, 2H), 7.57-7.44 (m, 2H), 7.27 (d, J = 16.2 Hz, 1H), 7.02-6.88 (m, J = 8.6 Hz, 2H), 6.69 (d, J = 2.4 Hz, 2H), 6.61-6.49 (m, 4H), 5.22 (dd, J = 2.9, 9.1 Hz, 1H), 4.41- 4.11 (m, 4H), 4.11-3.97 (m, 4H), 3.50 (br. s., 1H), 3.43 (d, J = 11.0 Hz, 3H), 3.44 (d, J = 10.5 Hz, 2H), 2.98-2.78 (m, 2H), 2.42-2.35 (m, 2H), 2.35-2.29 (m, 2H), 1.96-1.84 (m, 2H)Compound 24Synthesis of N-(2-((S)-2-cyano-4,4-difhioropyrrolidin- 1 -yl)-2-oxoethyl)-6-(4-(2-(( lr,4r)-4-(2-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-l,9'-xanthene]-6-ylcarboxamido) acetamido)cyclohexanecarboxamido)ethoxy)phenyl)quinoline-4-carboxamide

[0673] Step-1: Preparation of methyl 6-(4-(2-(tert- butoxycarbonylamino)ethoxy)phenyl)quinoline-4-carboxylate

[0674] To a stirred solution of methyl 6-(4-hydroxyphenyl)quinoline-4-carboxylate (0.40 g, 1.43 mmol, 1.0 eq) in DMF (10 mL) was added CS2CO3 (0.93 g, 2.86 mmol, 2.0 eq) at RT and the mixture was stirred for 30 min. Tert-butyl 2-bromoethylcarbamate (0.48 g, 2.42 mmol, 1.5 eq) was then added to the mixture and the mixture was heated at 70 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.55 g, 91 %)

[0675] LCMS: 423 [M+H]+

[0676] Step-2: Preparation of methyl 6-(4-(2-aminoethoxy)phenyl)quinoline-4- carboxylate

[0677] To a stirred solution of 6-(4-(2-(tert-butoxycarbonylamino)ethoxy)phenyl)quinoline-4- carboxylate (0.77 g, 1.82 mmol, 1.0 eq) in DCM (15 mL) was added TFA (2.0 mL) drop wise at 0 °C and the mixture was allowed to stir at RT for 2 h. The product formation was confirmed by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure and triturated in diethyl ether (10 mL x2) to afford the title compound (0.71 g, 89 %).

[0678] LCMS: 323 [M+H]+

[0679] Step-3: Preparation of methyl 6-(4-(2-((lr,4r)-4-(tert-butoxycarbonylamino) cyclohexanecarboxamido)ethoxy)phenyl)quinoline-4-carboxylate

[0680] To a stirred solution of (lr,4r)-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (0.44 g, 1.83 mmol, 1.0 eq) in DMF (10 mL) was added HATU (1.04 g, 2.75 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. DIPEA (0.95 mL, 5.49 mmol, 3 eq) and methyl 6-(4-(2-aminoethoxy)phenyl)quinoline-4-carboxylate (0.71 g, 2.2 mmol, 1.2 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, water (30 mL) was added to the mixture to obtain a precipitate which was filtered over Buchner funnel and dried to obtain a crude residue. The crude product was purified by CombiFlash Chromatography to afford the title compound (0.80 g, 80 %).

[0681] LCMS: 548 [M+H]+

[0682] Step-4: Preparation of 6-(4-(2-((lr,4r)-4-(tert-butoxycarbonylamino) cyclohexane carboxamido)ethoxy)phenyl)quinoline-4-carboxylic acid

[0683] To a stirred solution of methyl 6-(4-(2-((lr,4r)-4-(tert-butoxycarbonylamino) cyclohexanecarboxamido)ethoxy)phenyl)quinoline-4-carboxylate (0.80 g, 1.46 mmol, 1.0 eq) in THF (24 mL) was added LiOH.H2O (0.30 g, 7.31 mmol, 5.0 eq) dissolved in MeOH : Water (12 mL : 4.0 mL) and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was acidified with 2N-HC1 (pH ~ 1-2) to obtain a precipitate which was filtered over Buchner funnel and dried to afford the title compound which was taken to next step without further purification (0.30 g, 38%).

[0684] LCMS: 534 [M+H]

[0685] Step-5: Preparation of tert-butyl (lr,4r)-4-(2-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6- yl)phenoxy)ethylcarbamoyl)cyclohexylcarbamate

[0686] To a stirred solution of 6-(4-(2-((lr,4r)-4-(tert-butoxycarbonylamino) cyclohexane carboxamido)ethoxy)phenyl)quinoline-4-carboxylic acid (0.30 g, 0.56 mmol, 1.0 eq) in DMF (10 mL) was added HATU (0.320 g, 0.84 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. DIPEA (0.29 mL, 1.68 mmol, 3 eq) and (S)-1-(2-aminoacetyl)-4,4- difhioropyrrolidine-2-carbonitrile hydrochloride (0.15 g, 0.67 mmol, 1.2 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, water (30 mL) was added to the mixture to obtain a precipitate which was filtered over Buchner funnel and dried to obtain a crude residue. The crude product was purified by CombiFlash Chromatography to afford the title compound (0.195 g, 49 %).

[0687] LCMS: 705 [M+H]+

[0688] Step-6: Preparation of 6-(4-(2-((lr,4r)-4- aminocyclohexanecarboxamido)ethoxy)phenyl)-N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethyl)quinoline-4-carboxamide

[0689] To a stirred solution of tert-butyl (lr,4r)-4-(2-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-6- yl)phenoxy)ethylcarbamoyl)cyclohexylcarbamate (0.19 g, 0.27 mmol, 1.0 eq) in DCM (5.0 mL) was added TFA (0.8 mF) drop wise at 0 °C and the mixture was allowed to stir at RT for 2 h. The product formation was confirmed by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure and triturated in diethyl ether (10 mL x2) to afford the title compound (0.11 g, 55 %).

[0690] LCMS: 605 [M+l]+

[0691] Step-7: Preparation of tert-butyl 2-((lr,4r)-4-(2-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethylcarbamoyl) cyclohexylamino)-2-oxoethylcarbamate

[0692] To a stirred solution of 2-(tert-butoxycarbonylamino)acetic acid (0.035 g, 0.19 mmol, 1.2 eq) in DMF (5 mF) was added HATU (0.094 g, 0.248 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. DIPEA (0.11 mL, 0.66 mmol, 4 eq) and 6-(4-(2- ((lr,4r)-4-aminocyclohexanecarboxamido)ethoxy)phenyl)-N-(2-((S)-2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide (0.10 g, 0.165 mmol, 1.0 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, water (20 mL) was added to the mixture to obtain a precipitate which was filtered over Biichner funnel and dried to obtain a crude residue. The crude product was purified by CombiFlash Chromatography to afford the title compound (0.95 g, 91 %).

[0693] LCMS: 762 [M+H]+

[0694] Step-8: Preparation of 6-(4-(2-((lr,4r)-4-(2- aminoacetamido)cyclohexanecarboxamido) ethoxy)phenyl)-N-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide

[0695] To a stirred solution of tert-butyl 2-((lr,4r)-4-(2-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)ethylcarbamoyl) cyclohexylamino)-2-oxoethyl carbamate (0.095 g, 0.143 mmol, 1.0 eq) in DCM (5.0 mL) was added TFA (0.5 mF) drop wise at 0 °C and the mixture was allowed to stir at RT for 2 h. The product formation was confirmed by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure and crystallized in diethyl ether to afford the title compound (0.093 g, 89 %).

[0696] LCMS: 662 [M+l]+

[0697] Step-9: Preparation of N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)-6-(4-(2-((lr,4r)-4-(2-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-l,9'- xanthene]-6-ylcarboxamido)acetamido)cyclohexanecarboxamido)ethoxy)phenyl)quinoline- 4-carboxamide

[0698] To a stirred solution of 3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-l,9'-xanthene]- 6-carboxylic acid (0.045 g, 0.119 mmol, 1.0 eq) in DMF (2 mF) was added HATU (0.068 g, 0.18 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 1 h . DIPEA (0.2 mF,1.196 mmol, 10 eq) and 6-(4-(2-((lr,4r)-4-(2-aminoacetamido)cyclohexanecarboxamido) ethoxy )phenyl)-N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide (0.092 g, 0.117 mmol, 1.0 eq) were then added to the mixture and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and triturated with diethyl ether to obtain a solid which was purified by Reversed Phase HPLC to afford the title compound (0.026 g, 21 %).

[0699] LCMS: 1020 [M+H]+

[0700] 'H NMR: (400 MHz, DMSO-d6) δ 9. 16 (s, 1H), 8.94 (d, J= 4.3 Hz, 1H), 8.88 (s, 1H), 8.72 (d, J= 1.9 Hz, 1H), 8.20-8.02 (m, 4H), 7.98 (s, 1H), 7.92-7.84 (m, J= 8.6 Hz, 2H), 7.83-7.75 (m, 1H), 7.69 (s, 1H), 7.56 (d, J = 4.3 Hz, 1H), 7.16-6.99 (m, 2H), 6.71-6.48 (m, 7H), 5.19 (d, J = 6.2 Hz, 1H), 4.33-4.24 (m, 2H), 4.2-4.07 (m, 1H), 4.06-3.94 (m, 2H), 3.75 (d, J = 6.2 Hz, 2H), 3.43 (d, J = 6.2 Hz, 4H), 2.85-2.75 (m, 1H), 2.07 (s, 1H), 1.84-1.65 (m, 5H), 1.44-1.29 (m, 2H), 1.15 (d, J = 14.3 Hz, 2H)Compound 25Synthesis of (S)-2,2',2"-(10-(2-(4-(3-(3-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-7-yl)phenoxy)propyl)piperazin- 1 -yl)-2-oxoethyl)- 1 ,4,7, 10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0701] Step-1: Preparation of methyl 7-(3-hydroxyphenyl)quinoline-4-carboxylate

[0702] To a stirred solution of methyl 7-bromoquinoline-4-carboxylate (0.80 g, 3.0 mmol, leq) and 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (0.49 g, 3.6 mmol, 1.2eq) in 1,4-dioxane and H2O (6 : 1 mL) was added K2CO3 (1.24 g, 8.98 mmol, 3.0 eq) and the mixture was degassed under nitrogen for 10 min. Pd(dppf)C12 (0.109 g, 0.149 mmol, 0.05 eq) was then added to the mixture and the mixture was further degassed for 5 min. The resultant mixture was then irradiated in microwave at 100 °C for Ih. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (20 mL) and extracted using ethyl acetate (40 mL x 2). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified using Combi-Flash Chromatography to afford the title compound (0.480 g, 57%).

[0703] LCMS: 280 [M+H]+

[0704] Step-2: Preparation of methyl 7-(3-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)phenyl)quinoline-4-carboxylate

[0705] To a stirred solution of methyl 7-(3-hydroxyphenyl)quinoline-4-carboxylate (0.183 g, 0.655 mmol, 1.0 eq) in DMF (10 mL) was added CS2CO3 (0.426 g, 1.31 mmol, 2.0 eq) at RT. The mixture was allowed to stirred for 30 min. Tert-butyl 4-(3-bromopropyl)piperazine-l -carboxylate (0.40 g, 1.31 mmol, 2 eq) and the mixture was heated at 70 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.24 g, 72 %)

[0706] LCMS: 506 [M+H]+

[0707] Step-3: Preparation of 7-(3-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)phenyl) quinoline-4-carboxylic acid

[0708] To a stirred solution of methyl 7-(3-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)phenyl)quinoline-4-carboxylate (0.24 g, 0.47 mmol, 1.0 eq) in THF (6.0 mL) was added LiOH.H2O (0.08 g, 1.90 mmol, 4.0 eq) dissolved in MeOH : Water (3.0 mL : 1.0 mL) and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was acidified with 2N-HC1 (pH ~ 1-2) to obtain a precipitatewhich was filtered over Buchner funnel and dried to afford the title compound which was taken to next step without further purification (0.200 g, 85 %).

[0709] LCMS: 492 [M+H]+

[0710] Step-4: Preparation of (S)-tert-butyl 4-(3-(3-(4-(2-(2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)phenoxy)propyl)piperazine-1- carboxylate

[0711] To a stirred solution of 7-(3-(3-(4-(tert-butoxycarbonyl)piperazin-1- yl)propoxy)phenyl) quinoline-4-carboxylic acid (0.20 g, 0.41 mmol, 1.0 eq) in DMF (5 mL) was added TBTU (0.195 g, 0.610 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperature for 30 min. NMM (0.13 mL, 1.221 mmol, 3 eq) and (S)-1-(2-aminoacetyl)-4,4- difluoropyrrolidine-2-carbonitrile hydrochloride (0.091 g, 0.407 mmol, 1.0 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, water (30 mL) was added to the mixture to obtain a precipitate which was filtered over Buchner funnel and dried to obtain a crude residue. The crude product was purified by CombiFlash Chromatography to afford the title compound (0.190 g, 70 %)

[0712] LCMS: 663 [M+H]+

[0713] Step-5: Preparation of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)-7-(3-(3-(piperazin-1-yl)propoxy)phenyl)quinoline-4-carboxamide

[0714] To a stirred solution (S)-tert-butyl 4-(3-(3-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-7-yl)phenoxy)propyl)piperazine-l -carboxylate (0.19 g, 0.27 mmol, 1.0 eq) in DCM (10 mL) was added TFA (0.8 mL) drop wise at 0 °C and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure and triturated the crude with diethyl-ether (10 mL x2) to afford the title compound (0.19 g, 97 %).

[0715] LCMS: 563 [M+H]+

[0716] Step-6: Preparation of (S)-2.2'.2"-( 10-(2-(4-(3-(3-(4-(2-(2-cyano-4.4- difluoropy rrolidin- 1 -y l)-2-oxoethylcarbamoy l)quinolin-7 -y l)phenoxy )propyl)piperazin- 1 - yl)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid

[0717] To a stirred solution of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-7- (3-(3-(piperazin-1-yl)propoxy)phenyl)quinoline-4-carboxamide (0.19 g, 0.28 mmol, 1.0 eq) in DMF (3.0 mL) was added 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraaza cyclododecane- 1,4, 7-triyl)triacetic acid (0.177 g, 0.337 mmol, 1.2 eq) and TEA (0.11 mL, 0.84 mmol, 3.0 eq) and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and triturated with diethyl ether and further purified by Reversed Phase HPLC to afford the title compound (0.042 g, 30 %)

[0718] LCMS: 949 [M+H]+

[0719] 'H NMR: (400 MHz, DMSO-d6) δ 9.19 (t, J = 6.04 Hz, 1H), 9.02 (d, J = 4.45 Hz, 1H), 8.43 (d, J = 8.90 Hz, 1H), 8.34 (s, 1H), 8.02 - 8.11 (m, 1H), 7.58 (d, J = 4.45 Hz, 1H), 7.35- 7.49 (m, 3H), 6.96-7.06 (m, 1H), 5.18 (dd, J = 2.54, 9.54 Hz, 1H), 4.09-4.39 (m, 9H), 3.73-4.00 (m, 6H), 3.64 (br. s., 3H), 2.77-3.07 (m, 17H), 2.35-2.48 (m, 4H), 2.33 (br. s., 1H), 1.87-2.01 (m, 2H)Compound 34

[0720] Synthesis of 4-(((lS,4r)-4-((S)-1-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethylcarbamoyl)quinolin-6-yl)phenoxy)-3-(naphthalen-2-yl)propan-2-ylcarbamoyl) cyclohexyl)methylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0721] Step-1: Preparation of 4-(((lS,4r)-4-((S)-1-(4-(4-(2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)-3-(naphthalen-2- yl)propan-2-ylcarbamoyl)cyclohexyl)methylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9- yl)benzoic acid

[0722] To a stirred solution of 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)terephthalic acid (0.046 g, 0.122 mmol, 1.0 eq) in DMF (1 mL) was added NHS (0.03 g, 0.24 mmol, 2.0 eq) and EDC.HC1 (0.03 g, 0.24 mmol, 2.0 eq) at 0 °C and the mixture was stirred at same temperatureerature for 4 h. DIPEA (0.1 mL, 0.48 mmol, 4.0 eq) and 6-(4-((S)-2-((lr,4S)-4-(aminomethyl) cyclohexane carboxamido)-3-(naphthalen-2-yl)propoxy)phenyl)-N-(2-((S)-2-cyano-4,4-difluoro pyrrolidin-1- yl)-2-oxoethyl)quinoline-4-carboxamide trifluoroacetate salt (0.182 g, 0. mmol, L2 eq) were then added to the mixture and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and triturated with diethyl ether to obtain a solid which was purified by Reversed Phase HPLC to afford the title compound (0.025 g, 11.3 %).

[0723] LCMS: 1117 [M+H]+

[0724] 'H NMR: (400 MHz, DMSO-d6) δ 9..17 (t, J = 6.0 Hz, 1H), 8.95 (d, J = 4.5 Hz, 1H), 8.71 (s, 1H), 8.67-8.56 (m, 1H), 8.20-8.03 (m, 4H), 7.94-7.75 (m, 7H), 7.66 (s, 1H), 7.70 (s, 1H), 7.57 (d, J = 4.5 Hz, 1H), 7.49-7.35 (m, 3H), 7.17-7.07 (m, 2H), 6.67 (br. s., 2H), 6.62-6.51 (m, 4H), 5.19 (dd, J = 2.9, 9.2 Hz, 1H), 4.40-4.12 (m, 5H), 4.05-3.94 (m, 2H), 3.12 (dd, J = 5.4, 13.7 Hz, 2H), 3.08-2.78 (m, 4H), 2.04-1.97 (m, 1H), 1.71-1.58 (m, 3H), 1.56-1.48 (m, 1H), 1.40 (br. s., 2H), 1.26-1.17 (m, 3H).Compound 97

[0725] Synthesis of 2,2',2"-(10-(2-(bis(3-(4-(4-((2-((S)-2-cyano-4,4-difluoropyrrohdin-1-yl)- 2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)amino)-2-oxoethyl)- 1 ,4,7, 10- tetraazacyclododecane- 1 ,4,7 -triyl)triacetic acid

[0726] Step- Id: Synthesis of ethyl 3-((3-hydroxypropyl)amino)propanoate

[0727] To a stirred solution of 3-aminopropan-1-ol (5.0 g, 35.82 mmol, 1.0 eq) in ethanol (50 mL) was added ethyl acrylate (4.9 ml, 35.82 mmol, 1.0 eq) and the mixture was stirred at RT for 24 h. The progress of the reaction was monitored by TLC and NMR. After completion, the mixture was concentrated under reduced pressure to afford the title compound (7.0 g, 63 %).

[0728] LCMS: 176 [M+H]+

[0729] Step- 1c: Synthesis of ethyl 3-((tert-butoxycarbonyl)(3- hydroxypropyl)amino)propanoate

[0730] To a stirred solution of ethyl 3-((3-hydroxypropyl)amino)propanoate (7.0 g, 40.2 mmol, 1.0 eq) in DCM (50 mL), TEA (9.98 ml, 71.64 mmol, 2.0 eq) and Di-tert-butyl dicarbonate (10.09 ml, 48.00 mmol, 1.2 eq) was added drop wise at 0 °C. The reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC and NMR. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue. The crude product was purified by CombiFlash Chromatography to afford the title compound (7.0 g, 64.22 %).

[0731] LCMS: 276 [M+H]+

[0732] Step- lb: Synthesis of tert-butyl bis(3-hydroxypropyl)carbamate

[0733] The solution of ethyl 3-((tert-butoxycarbonyl)(3-hydroxypropyl)amino)propanoate (7.0 g, 25.45 mmol, l.Oeq.) in THF (60 mL) was added lithium aluminum hydride (2.2 g, 50.90 mmol, 2.0eq) at -10 °C slowly and the mixture was stirred at same temperatureerature for 2 h. The reaction was monitored by TLC. Upon completion, the mixture was quenched using saturated solution of sodium sulphate (60 mL) and filtered through celite bed and washed with ethyl acetate (50 ml). Water (150 mL) was added to filtrate and extracted using ethyl acetate (150 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated to obtain crude residue which was purified by CombiFlash Chromatography to afford the title compound (3.0 g , 50.7 %) .

[0734] LCMS: 234 [M+H]+

[0735] Step-la: Synthesis of (tert-butoxycarbonyl)azanediyl)bis(propane-3,l-diyl) dimethane sulfonate

[0736] To a stirred solution of tert-butyl bis(3-hydroxypropyl)carbamate (1.0 g, 4.29 mmol, 1.0 eq) in DCM (50 mL), TEA (2.9 mL, 21.45 mmol, 5.0 eq) and methanesulfonyl chloride (0.9 mL, 12.8 mmol, 3.0 eq) was added drop wise at 0 °C and the mixture was stirred at same temperatureerature for 1 h. The progress of the reaction was monitored by TLC and NMR. After completion, the mixture was diluted with water (30 mL) and extracted with DCM (50mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated to obtain crude residue which was purified by CombiFlash Chromatography to afford the title compound (1.6 g, 93.7 %) .

[0737] LCMS: 390[M+H]+

[0738] Step-1: Preparation of dimethyl 6,6'-(4,4'-(3,3'-(tert- butoxycarbonylazanediyl)bis(propane-3,l-diyl)bis(oxy))bis(4,l-phenylene))diquinoline-4- carboxylate

[0739] To a stirred solution of methyl 6-(4-hydroxyphenyl)quinoline-4-carboxylate (0.5 g, 1.8 mmol, 1.0 eq) in DMF (10 mL) was added CsCCL (1.7 g, 5.37 mmol, 3 eq) at RT and the mixture was stirred at same temperatureerature for 20 min. (tert-butoxycarbonyl)azanediyl)bis(propane- 3,1-diyl) dimethane sulfonate (0.52 g, 1.3 mmol, 0.75 eq) was then added to the mixture and the resultant mixture was heated at 90 °C for 2 h. The progress of the reaction was monitored by TLCand LCMS. After completion, the mixture was diluted with water (20 mL) to obtain a precipitate which was filtered under vacuum to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.26 g, 20 %)

[0740] LCMS: 756 [M+H]+

[0741] Step-2: Preparation of 6,6'-(4,4'-(3,3'-(tert-butoxycarbonylazanediyl)bis(propane-3,l- diyl)bis(oxy))bis(4, l-phenylene))diquinoline-4-carboxylic acid

[0742] To a stirred solution of dimethyl 6,6'-(4,4'-(3,3'-(tert- butoxycarbonylazanediyl)bis(propane-3 , 1 -diyl)bis(oxy ))bis(4, 1 -phenylene))diquinoline-4- carboxylate (0.26 g, 0.35 mmol, 1.0 eq) in THF (12 mL) was added LiOH.FEO (0.107 g, 3.52 mmol, 10 eq) in water (2 mL) and methanol (6 mL) and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was acidified using 2N-HC1 (pH~l-2) to obtain a precipitate which was filtered over vacuum to afford the title compound (0.21 g, 78 %).

[0743] LCMS: 728 [M+H]+

[0744] Step-3: Preparation of tert-butyl bis(3-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)propyl)carbamate

[0745] To a stirred solution of 6,6'-(4,4'-(3,3'-(tert-butoxycarbonylazanediyl)bis(propane-3,l- diyl)bis(oxy))bis(4,l-phenylene))diquinoline-4-carboxylic acid (0.550 g, 0.756 mmol, 1.0 eq) in DMF (12 mL) was added HATU (1.1 g, 3.026 mmol, 4.0 eq) at 0 °C and the mixture was stirred at same temperatureerature for 30 min. DIPEA (1.3 mL, 7.56 mmol, 10.0 eq) and (S)-1-(2- aminoacetyl)-4,4-difhroropyrrolidine-2-carbonitrile hydrochloride (0.510 g, 2.27 mmol, 3.0 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, H2O (30 mL) was added to the mixture to obtain the precipitate which was filtered over vacuum to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.65 g 80 %) .

[0746] LCMS: 1070 [M+H]+

[0747] Step-4: Preparation of 6,6'-(4,4'-(3,3'-azanediylbis(propane-3,l-diyl)bis(oxy))bis(4,l- phenylene))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide)

[0748] To a stirred solution of tert-butyl bis(3-(4-(4-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethylcarbamoyl)quinolin-6-yl)phenoxy)propyl)carbamate (0.65 g, 0.61 mmol, 1.0 eq) in DCM (5 mL) was added TFA (1.5 mL) drop wise at 0 °C and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue which was triturated with diethyl to afford the title compound (0.60 g, 92 %).

[0749] LCMS: 970 [M+H]+

[0750] Step-5: Preparation of 2,2',2"-(10-(2-(bis(3-(4-(4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)amino)-2- oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7-triyl)triacetic acid

[0751] To a stirred solution of 6,6'-(4,4'-(3,3'-azanediylbis(propane-3,l-diyl)bis(oxy))bis(4,l- phenylene))bis(N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide) (0.25 g, 0.23 mmol, 1.0 eq) in DMF (0.05 mL) were added TEA (0.1 mL, 1.15 mmol, 5 eq) followed by the addition of 2, 2', 2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-l, 4, 7, 10- tetraazacyclododecane- 1,4, 7-triyl)triacetic acid (0.15 g, 0.27 mmol, 1.2 eq) and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure, triturated with diethyl ether and further purified by Reversed Phase HPLC to afford the title compound (0.033 g, 10.5 %)

[0752] LCMS: 1355 [M+H]+

[0753] 'H NMR: (400 MHz, DMSO-d6) δ 9.19 (t, J = 6.7 Hz, 2H), 8.95 (d, J = 4.5 Hz, 2H), 8.71 (s, 2H), 8.18-8.07 (m, 4H), 7.86 (d, J = 8.3 Hz, 4H), 7.57 (d, J = 4.5 Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 5.24-5.12 (m, 2H), 4.38-4.24 (m, 6H), 4.22-4.02 (m, 6H), 3.57- 3.44 (m, 14H), 3.02-2.81 (m, 18H), 2.12-1.95 (m, 4H)Compound 98

[0754] Synthesis of 4-((2-(bis(3-(4-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)amino)-2-oxoethyl)carbamoyl)-2-(6- hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0755] Step-1: Preparation of tert-butyl (2-(bis(3-(4-(4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)amino)-2- oxoethyl)carbamate

[0756] To a stirred solution of 2-((tert-butoxycarbonyl)amino)acetic acid (0.05 g, 0.27 mmol, 1.0 eq) in DMF (12 mL) was added HATU (0.13 g, 0.04 mmol, 1.5 eq) at 0 °C and the mixture was stirred at same temperatureerature for 30 min. DIPEA (0.15 mL, 0.33 mmol, 1.5 eq) and 6,6'- ((azanediylbis(propane-3,l-diyl))bis(oxy))bis(4,l-phenylene))bis(N-(2-((S)-2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide) 2,2,2-trifluoroacetate (0.24 g, 0.22 mmol, 1.0 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, H2O (30 mL) was added to the mixture to obtain the precipitate which was filtered over vacuum to obtain a crude residue. The crude product was purified by CombiFlash Chromatography to afford the title compound (0.240 g 96 %).

[0757] LCMS: 1127 [M+H]+

[0758] Step-2: Preparation of 6-(4-(3-(2-amino-N-(3-(4-(4-((2-((S)-2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)phenoxy)propyl)acetamido)propoxy)phenyl)-N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)- 2-oxoethyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate

[0759] To a stirred solution of tert-butyl (2-(bis(3-(4-(4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)amino)-2- oxoethyl)carbamate (0.24 g, 0.21 mmol, 1.0 eq) in DCM (5 mL) was added TFA (0.8 mL) drop wise at 0 °C and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue which was triturated with diethyl ether to afford the title compound (0.18 g, 71 %).

[0760] LCMS: 1027 [M+H]+

[0761] Step-3: Preparation 4-((2-(bis(3-(4-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)amino)-2-oxoethyl)carbamoyl)-2-(6- hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0762] To a stirred solution of 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)terephthalic acid (0.046 g, 0.122 mmol, 1.0 eq) in DMF (1 mL) was added NHS (0.03 g, 0.24 mmol, 2.0 eq) and EDC.HC1 (0.03 g, 0.24 mmol, 2.0 eq) at 0 °C and the mixture was stirred at same temperatureerature for 4 h . DIPEA (0.1 mL, 0.48 mmol, 4.0 eq) and 6-(4-(3-(2-amino-N-(3-(4-(4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)acetamido) propoxy )phenyl)-N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4- carboxamide 2,2,2-trifluoroacetate (0.18 g, 0.15 mmol, 1.2 eq) were then added to the mixture and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and triturated with diethyl ether to obtain a solid which was purified by Reversed Phase HPLC to afford the title compound (0.025 g, 11.3 %).

[0763] LCMS: 1385 [M+H]+

[0764] 'H NMR: (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.16 (t, J = 5.7 Hz, 2H), 8.98-8.88 (m, 3H), 8.71 (br. s., 2H), 8.16-8.05 (m, 6H), 7.84 (dd, J = 3.2, 8.9 Hz, 4H), 7.56 (d, J = 4.5 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 6.72-6.50 (m, 6H), 5.18 (d, J = 7.0 Hz, 2H), 4.34 (br. s., 2H), 4.3- 4.23 (m, 4H), 4.19 (br. s., 1H), 4.17-4.06 (m, 4H), 4.02 (t, J = 6.0 Hz, 2H), 3.54 (d, J = 7.6 Hz, 2H), 3.45 (br. s., 3H), 3.02-2.75 (m, 4H), 2.08 (br. s., 2H), 1.96 (br. s., 2H)Compound 99

[0765] Synthesis of 4-((((lR,4r)-4-(((R)-4-(2-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-5-methoxyphenoxy)-1-(naphthalen-2-yl)butan-2- yl)carbamoyl)cyclohexyl)methyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid

[0766] Step-1: Preparation of 4-((((lS,4r)-4-(((S)-1-(4-(4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)-3-(naphthalen-2- yl)propan-2-yl)carbamoyl)cyclohexyl)methyl)carbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9- yl)benzoic acid

[0767] To a stirred solution of 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)terephthalic acid (0.025 g, 0.07 mmol, 1.0 eq) in DMF (1 mL) was added NHS (0.016 g, 0.13 mmol, 2.0 eq) and EDC.HC1 (0.03 g, 0.13 mmol, 2.0 eq) at 0 °C and the mixture was stirred at same temperatureerature for 4 h . DIPEA (0.05 mL, 0.26 mmol, 4.0 eq) and 6-(2-((R)-3-((lr,4R)-4-(aminomethyl)cyclohexane carboxamido)-4-(naphthalen-2-yl)butoxy)-4-methoxyphenyl)-N-(2-((S)-2-cyano-4,4- difluoropyrrolidin- 1 -yl)-2-oxoethyl)quinoline-4-carboxamide, 2,2,2-trifluoroacetate salt (0.060 g, 0.079 mmol, 1.2 eq) were then added to the mixture and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and triturated with diethyl ether to obtain a solid which was purified by Reversed Phase HPLC to afford the title compound (0.021 g, 27.6 %).

[0768] LCMS: 1161 [M+H]+

[0769] 'H NMR: (400 MHz, DMSO-d6) 810.18 (br. s., 1H), 9.13 (t, J = 6.0 Hz, 1H), 9.00 (d, J= 4.5 Hz, 1H), 8.62 (t, J = 5.7 Hz, 1H), 8.38 (s, 1H), 8.20-8.11 (m, 2H), 8.10-8.03 (m, 2H), 7.83- 7.75 (m, 1H), 7.72-7.63 (m, 3H), 7.63-7.52 (m, 3H), 7.44-7.34 (m, 3H), 7.28-7.20 (m, 1H), 6.71- 6.51 (m, 8H), 5.12 (dd, J = 2.9, 9.2 Hz, 1H), 4.33-4.06 (m, 5H), 4.05-3.94 (m, 2H), 3.77 (s, 3H),3.01 (t, J = 6.4 Hz, 2H), 2.90 (br. s., 1H), 2.87-2.76 (m, 4H), 2.11-2.02 (m, 2H), 1.91-1.73 (m, 4H), 1.70-1.51 (m, 4H), 1.48 (d, J = 14.0 Hz, 1H)Compound 100

[0770] 2,2',2"-(10-(2-((2-(4-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)ethyl)(3-(4-(4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)amino)-2- oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7-triyl)triacetic acid

[0771] Step-la: Synthesis of ethyl 3-((2-ethoxy-2-oxoethyl)amino)propanoate

[0772] To a stirred solution of ethyl 2-aminoacetate (5.0 g, 35.82 mmol, 1.0 eq) in ethanol (50 mL) was added and ethyl acrylate (4.9 ml, 35.82 mmol, 1.0 eq) and the mixture was stirred at RT for 24 h. The progress of the reaction was monitored by TLC and NMR. After completion, the mixture was concentrated under reduced pressure to afford the title compound (5.0 g, 50.80 %).

[0773] LCMS: 204 [M+H]+

[0774] Step- lb: Synthesis of ethyl 3-((tert-butoxycarbonyl)(2-ethoxy-2- oxoethyl)amino)propanoate

[0775] To a stirred solution of ethyl 3-((2-ethoxy-2-oxoethyl)amino)propanoate (5.0 g, 35.82 mmol, 1.0 eq) in DCM (50 mL), TEA (9.98 ml, 71.64 mmol, 2.0 eq) and Di-tert-butyl dicarbonate (12.34 ml, 53.73 mmol, 1.2 eq) was added drop wise at 0 °C and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC and NMR. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue. The crude product was purified by CombiFlash Chromatography to afford the title compound (7.0 g, 93.45 %).

[0776] LCMS: 304 [M+H]+

[0777] Step-lc: Synthesis of tert-butyl (2-hydroxyethyl)(3-hydroxypropyl)carbamate

[0778] The solution of ethyl 3-((tert-butoxycarbonyl)(2-ethoxy-2-oxoethyl)amino)propanoate(6.0 g, 19.77 mmol, l.Oeq.) in THF (60 mF) was added lithium aluminum hydride (1.5 g, 32.55 mmol, 2.0 eq) at -10 °C slowly and the mixture was stirred at same temperatureerature for 2 h. The reaction was monitored by TLC. Upon completion, the mixture was quenched using saturated solution of sodium sulphate (60 mF) and the mixture was filtered through celite and washed with ethyl acetate (50 ml). Water (150 mF) was added to filtrate and extracted using ethyl acetate (150 mF x 2). The combined organic layer washed with brine solution (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain crude product. The crude product was purified by CombiFlash Chromatography to afford the title compound (4.0 g, 92.37 %).

[0779] LCMS: 220 [M+H]+

[0780] Step- Id: Synthesis of 3-((tert-butoxycarbonyl)(2-((methylsulfonyl)oxy)ethyl)amino)propyl methanesulfonate

[0781] To a stirred solution of tert-butyl (2-hydroxyethyl)(3-hydroxypropyl)carbamate (1.0 g, 4.56 mmol, 1.0 eq) in DCM (50 mL), TEA (3.0 ml, 22.8 mmol, 5.0 eq) and methanesulfonyl chloride (1.05 ml, 13.68 mmol, 3.0 eq) was added drop wise at 0 °C and the mixture was stirred at 0 °C for 1 h. The progress of the reaction was monitored by TLC and NMR. After completion, the mixture was diluted with water (30 mL) and extracted with DCM (50 mLx 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate andconcentrated to obtain crude residue which was purified by CombiFlash Chromatography to afford the title compound (1.6 g, 94.1 %) .

[0782] LCMS: 376 [M+H]+

[0783] Step-1: Synthesis of methyl 6-(4-(3-((tert-butoxycarbonyl)(2-(4-(4-(methoxycarbonyl)quinolin-6-yl)phenoxy)ethyl)amino)propoxy)phenyl)quinoline-4-carboxylate

[0784] To a stirred solution of methyl 6-(4-hydroxyphenyl)quinoline-4-carboxylate (0.5 g, 1.8 mmol, 1.0 eq) in DMF (10 mL) was added CsCCL (1.7 g, 5.37 mmol, 3 eq) at RT and the mixture was stirred at same temperatureerature for 30 min. 3-((tert-butoxycarbonyl)(2-((methylsulfonyl) oxy)ethyl)amino)propyl methanesulfonate (0.67 g, 1.0 mmol, 0.75 eq) was then added to the mixture and the resultant mixture was heated at 70 °C for 2.0 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was diluted with water (20 mL) to obtain a precipitate which was filtered under vacuum to obtain a crude residue which was purified by CombiFlash Chromatography to afford the title compound (0.40 g, 30 %)

[0785] LCMS: 742 [M+H]+

[0786] Step-2: Synthesis of 6-(4-(3-((tert-butoxycarbonyl)(2-(4-(4-carboxyquinolin-6- yl)phenoxy)ethyl)amino)propoxy)phenyl)quinoline-4-carboxylic acid

[0787] To a stirred solution of methyl 6-(4-(3-((tert-butoxycarbonyl)(2-(4-(4- (methoxycarbonyl) quinolin-6-yl)phenoxy)ethyl)amino)propoxy)phenyl)quinoline-4-carboxylate (0.50 g, 0.67 mmol, 1.0 eq) in THF (12 mL) was added LiOH.H2O (0.276 g, 6.74 mmol, 10 eq) in water (2 mL) and methanol (6 mL) and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was acidified using 2N-HC1 (pH~l-2) to obtain a precipitate which was filtered over vacuum to afford the title compound (0.40 g, 83.16 %).

[0788] LCMS: 714 [M+H]+

[0789] Step-3: Synthesis of tert-butyl (2-(4-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)ethyl)(3-(4-(4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)carbamate

[0790] To a stirred solution of afford 6-(4-(3-((tert-butoxycarbonyl)(2-(4-(4-carboxyquinolin- 6-yl)phenoxy)ethyl)amino)propoxy)phenyl)quinoline-4-carboxylic acid (0.40 g, 0.56 mmol, 1.0eq) in DMF (10 mF) was added HATU (0.85 g, 2.24 mmol, 4.0 eq) at 0 °C and the mixture was stirred at same temperatureerature for 30 min. DIPEA (0.97 mL, 5.60 mmol, 10.0 eq) and (S)-1- (2-aminoacetyl)-4,4-difluoropyrrolidine-2-carbonitrile hydrochloride (0.379 g, 1.68 mmol, 3.0 eq) were then added to the mixture and the mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, ice water (30 mL) was added to the mixture to obtain the precipitate which was filtered over vacuum to obtain a crude residue, which was purified by CombiFlash Chromatography to afford the title compound (0.20 g, 33.82 %) .

[0791] LCMS: 1056 [M+H]+

[0792] Step-4: Synthesis of N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-(3-((2-(4-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6- yl)phenoxy)ethyl)amino)propoxy)phenyl)quinoline-4-carboxamide 2,2,2-trifluoroacetate

[0793] To a stirred solution of tert-butyl (2-(4-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1- yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)ethyl)(3-(4-(4-((2-((S)-2-cyano-4,4-difluoro pyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)carbamate (0.20 g, 0.19 mmol, 1.0 eq) in DCM (4mL) was added TFA (0.7 mF) drop wise at 0 °C and the mixture was stirred at RT for 1 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the mixture was concentrated under reduced pressure to obtain a crude residue which was triturated with diethyl to afford the title compound (0.180 g, 88.88 %).

[0794] LCMS: 956 [M+H]+

[0795] Step-5: Synthesis of 2,2',2"-(10-(2-((2-(4-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidin- l-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)ethyl)(3-(4-(4-((2-((S)-2-cyano-4,4- difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)propyl)amino)-2- oxoethyl)- 1 ,4,7, 10-tetraazacyclododecane- 1 ,4,7-triyl)triacetic acid

[0796] To a stirred solution of afford N-(2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)-6-(4-(3-((2-(4-(4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2- oxoethyl)carbamoyl)quinolin-6-yl)phenoxy)ethyl)amino)propoxy)phenyl)quinoline-4- carboxamide 2,2,2-trifluoroacetate (0.100g, 0.104 mmol, 1.0 eq) in DMF (0.04 mL) were added TEA (0.06 mF, 1.15 mmol, 4 eq) followed by the addition of 2,2',2"-(10-(2-(4-nitrophenoxy)-2- oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (0.066g, 0.125 mmol, 1.2 eq)and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure, triturated with diethyl ether and further purified by Reversed Phase HPLC to afford the title compound (0.023 g, 16.42 %)

[0797] LCMS: 1342 [M+H]+

[0798] 'H NMR: (400 MHz, DMSO-d6) δ 9.18 (t, J = 6.7 Hz, 2H), 8.99-8.91 (m, 2H), 8.70 (dd, J = 1.3, 5.1 Hz, 2H), 8.18-8.08 (m, 4H), 7.91-7.82 (m, 4H), 7.62-7.55 (m, 2H), 7.17-7.06 (m, 4H), 5.17 (d, J = 9.5 Hz, 2H), 4.36-4.17 (m, 11H), 4.16-4.06 (m, 4H), 3.70-3.82 (m, 5H), 3.14- 2.89 (m, 14H), 2.88-2.80 (m, 3H), 2.36-2.26 (m, 1H), 2.21-2.11 (m, 2H), 2.1- 2.02 (m, 2H), 1.48 (d, J = 6.36 Hz, 2H), 1.10-1.18 (m, 2H)Compound 101

[0799] Synthesis of (S)-4-(2-(4-(3-(3-(4-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl carbamoyl)quinolin-7-yl)phenoxy)propyl)piperazin-1-yl)-2-oxoethylcarbamoyl)-2-(6-hydroxy-3- oxo-3H-xanthen-9-yl)benzoic acid

[0800] Stepl: Preparation of (S)-tert-butyl 2-(4-(3-(3-(4-(2-(2-cyano-4,4-difluoropyrrolidin- 1 -yl)-2-oxoethylcarbamoyl)quinolin-7 -yl)phenoxy )propyl)piperazin- 1 -yl)-2-oxoethylcarbamate

[0801] To a stirred solution of 2-(tert-butoxycarbonylamino)acetic acid (0.08 g, 0.44 mmol, 1.2 eq) in DMF(10 mL) was added HATU (0.21 g, 0.67 mmol, 1.5 eq) at 0 °C and the mixture was allowed to stirred at same temperature for 30 min. DIPEA (0.03 mL, 1.78 mmol, 4.0 eq) and (S)- N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-7-(3-(3-(piperazin-1- yl)propoxy)phenyl)quinoline-4-carboxamide (0.250 g, 0.369 mmol, 1.0 eq) were then successively added to the mixture and the mixture was allowed to stir at RT for 1 h. The product formation was confirmed by TLC and LCMS. After completion, the mixture was poured in ice cold water (10 mL). The resulting solid was filtered off and dried under vacuum to get the crude residue which was purified by Combi-flash chromatography to afford the title compound (0.130 g, 40 %) as an off white solid.

[0802] LCMS: 720 [M+l]+

[0803] Step-2: Synthesis ...

Claims

CLAIMS1. A compound of formula (I):formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein,Q is a bondX is N or CR2;A is -O-;D is, independently at each occurrence, a payload;L is, independently at each occurrence, a linker;R1and R2are independently hydrogen, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6alkoxy, C1-C6haloalkoxy, Ci- C6haloalkyl, -OR3, -SR3, -S(O)2R3, -S(O)2NR4R5, -NR3S(O)2R4, -NR4R5,-C(O)R3, -NR3C(O)R4, -NR3C(O)NR4R5, -C(O)OR3, -C(O)ONR4R5or-C(O)NR4R5, wherein each of R1and R2is independently optionally substituted by R10; each R3, R4and R5is independently hydrogen, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6alkoxy, Ci- C6haloalkoxy, C1-C6haloalkyl, -OR7, -SR7, -S(O)2R7, -S(O)2NR8R9, -NR7S(O)2R8, -NR8R9, -C(O)R7, -NR7C(O)R8, -NR7C(O)NR8R9, -C(O)OR7, -C(O)ONR8R9or -C(O)NR8R9; or R4andR5are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl which is optionally substituted by R10; each R7, R8and R9is independently hydrogen or C1-C6alkyl optionally substituted by oxo, -OH or -NH2;or R8and R9are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl which is optionally substituted by oxo, -OH or -NH2;R10is oxo, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6- membered heterocyclyl, -CN, halogen, C1-C6alkoxy, C1-C6haloalkoxy, Ci- C6haloalkyl, -OR14, -SR14, -S(O)2R14, -S(O)2NR15R16, -NR14S(O)2R15, -NR15R16, -C(O)R14, -NR14C(O)R15, -NR14C(O)NR15R16, -C(O)OR14, -C(O)ONR15R16or-C(O)NR15R16; each R14, R15and R16is independently hydrogen or C1-C6alkyl optionally substituted by oxo, -OH or -NH2; or R15and R16are taken together with the atom to which they attached to form a 3- to 6- membered heterocyclyl which is optionally substituted by oxo, -OH or -NH2; m is 0 or 1 ; and n is 0 or 1 ; provided that m + n is greater than 0.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (1-1):

3. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (1-2):

4. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (1-3):

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Q is a bond.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (II- 1) or formula (II-2):

7. The compound of claim 6, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (Il-a):

8. The compound of claim 6, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (Il-b):

9. The compound of claim 6, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (II-c):

10. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (III):

11. The compound of claim 10, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (Ill-a):

12. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Q is13. The compound of any one of claims 1-4 and 12, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (IV- 1) or formula (IV-2):

14. The compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (IV-a):

15. The compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (IV-b):

16. The compound of claim 13, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (IV-c):

17. The compound of any one of claims 1-4 and 12, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (V):

18. The compound of claim 17, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (V-a):The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein X is CR2.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2is H.

21. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein X is N.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1is hydrogen, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6alkoxy, Ci- C6haloalkoxy, or C1-C6haloalkyl.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R2is hydrogen, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6alkoxy, Ci- C6haloalkoxy, or C1-C6haloalkyl.

24. The compound of any one of claims 1-5, 12 and 19-23, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein m is 1 and n is 0.

25. The compound of any one of claims 1-5, 12 and 19-23, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein m is 0 and n is i.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein L comprises or has the structure:wherein L1and L2are optionally substituted by Z; wherein t is an integer from 1 to 10; denotes attachment to D and - denotes attachment to A;L1is, independently at each occurrence, absent or C3-C6cycloalkyl, C6- aryl, 5- to 6- membered heterocyclyl or 5- to 6-membered heteroaryl, each of which is optionally substituted by R12;L2is, independently at each occurrence, absent or O, S, NR6, C1-C10 alkylene, 2- to 14- membered heteroalkylene, -C(=O)O-, -O(C=O)-, -CONR6-, -NR6CO-, SO2, -SO2NR6-, -NR6SO2-, -S-S-, -(OCH2CH2)V-, -(CH2CH2O)V-, or -C(Rm)=N-, wherein the C1-C10 alkylene and 2- to 14- membered heteroalkylene of each L2, when present, are optionally and independently substituted with Rmand Rn, wherein v is independently an integer from 1 to 3;R6is hydrogen or C1-C6alkyl;Rmand Rnare independently hydrogen, carboxyl, C1-C6alkyl, C3-C6cycloalkyl, C6-C10aryl, 5- to 6-membered heterocyclyl or 5- to 10-membered heteroaryl, -C1-C3-alkylene(C3- C6cycloalkyl), -C1-C3-alkylene(C6-C10aryl), -C1-C3-alkylene(5- to 6-membered heterocyclyl), - C1-C3-alkylene(5- to 10-membered heteroaryl), or -C1-C3-alkylene(NHC(O)NH2) , each of which is optionally substituted by R17; andR12and R17are independently oxo, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6alkoxy, C1-C6haloalkoxy, Ci-C6haloalkyl, -OR14, -SR14, -S(O)2R14, -S(O)2NR15R16, -NR14S(O)2R15, -NR15R16, -C(O)R14, -NR14C(O)R15, -NR14C(O)NR15R16, -C(O)OR14, -C(O)ONR15R16or-C(O)NR15R16; and27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein L comprises or is 5- to 6-membered heterocyclyl,the ■Aww lines denote attachment points to D;- lines denote attachment points to A; ring B is C3-C6cycloalkyl, C6-C10aryl, 5- to 6-membered heterocyclyl or 5- to 6- membered heteroaryl, each of which is optionally substituted by Rb; ring C is C3-C6cycloalkyl, C6-C10aryl, 5- to 6-membered heterocyclyl or 5- to 6- membered heteroaryl, each of which is optionally substituted by Rc; andRband Rcare independently oxo, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 3- to 6-membered heterocyclyl, -CN, halogen, C1-C6alkoxy, C1-C6haloalkoxy, Ci- C6haloalkyl, -OR14, -SR14, -S(O)2R14, -S(O)2NR15R16, -NR14S(O)2R15, -NR15R16, -C(O)R14, -NR14C(O)R15, -NR14C(O)NR15R16, -C(O)OR14, -C(O)ONR15R16or-C(O)NR15R16, and each q is independently an integer from 1 to 3.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt,, wherein the lines denote attachment points toD and - lines denote attachment points to A.

29. The compound of claims 26-28, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Z is present and comprises30. The compound of claim 29, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Z is present and comprises31. The compound of any one of claims 26-29, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein Z is present and represented by32. The compound of claim 31 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (VI):

33. The compound of claim 32, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is of formula (VI- la) or formula (VI-2a):

34. The compound of claim 31 or 32, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the moietysymmetric with respect to the payload.

35. The compound of claim 34, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the moiety is selected from the group consisting of36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the payload comprises or is, independently at each occurrence, one or more drugs and agents.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the payload comprises or is, independently at each occurrence, a cytotoxic drug.

38. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the payload comprises or is, independently at each occurrence, a radioactive component, a metal chelating group, a chelating agent, a fluorescent dye, a contrast agent, or any combination thereof.

39. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the payload comprises or is, independently at each occurrence, a radionuclide.

40. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the payload comprises or is, independently at eachthereof, wherein the <~vwv lines denote attachment points to L.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the payload further comprises one or more motifs.

42. The compound of claim 41, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the motif is an albumin-binding motif.

43. The compound of claim 42, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the motif is an ibuprofen motif.

44. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound is a compound of Table 1.

45. A pharmaceutical composition comprising a compound of any one of claims 1-44, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

46. A method of treating a disease or disorder mediated by fibroblast activation protein (FAP) in an individual in need thereof comprising administering to the individual a compound of any one of claims 1-44, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

47. The method of claim 46, wherein the disease or disorder is breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, esophagus cancer, thyroid cancer, brain cancer, neuroblastoma, glioma, melanoma, lymphoma, fibrosarcoma, osteosarcoma, bone sarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, gastrointestinal carcinoma, or adenocarcinoma.

48. A method of inhibiting FAP in an individual comprising administering to the individual a compound of any one of claims 1-44, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

49. A method of imaging, diagnosing, or detecting a disease or disorder mediated by FAP in an individual in need thereof comprising administering to the individual a compound of any one of claims 1-44, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

50. The method of claim 49, wherein the disease or disorder is a chronic inflammatory and / or destructive process, fibrosis, or a benign tumor.

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