Compounds targeting RNA-binding proteins or RNA-modifying proteins

Abstract

The invention relates to a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, compositions comprising the same and methods of preparing and using the same. The variables are described herein.

Description

COMPOUNDS TARGETING RNA-BINDING PROTEINS OR RNA-MODIFYING PROTEINS RELATED APPLICATIONS

[0001] This application claims the beneffit of U.S. Provisional Application Serial No.62 / 984,677, filed March 3, 2020, the entire teachings of which are incorporated herein by reference. BACKGROUND OF THE INVENTION

[0002] RNA-binding proteins and RNA-modifying proteins play important roles in post- transcriptional gene regulation processes, such as RNA splicing, transport, translation, and localization. Recent studies have demonstrated that dysregulated expression of some of these proteins can lead to disease occurrence, such as cancers.

[0003] Let 7 miRNA is known as a tumor suppressor of miRNA targeting oncogenes K-Ras, c-myc, and HMGA2. A number of human cancer cell lines and primary tumors express low levels of let-7 family miRNAs. It has been demonstrated that increased let-7 expression can effectively inhibit cancer growth in mouse models of lung and breast cancers. Lin28 proteins play important roles in regulating let-7 miRNA level in cells. Lin28B functions in the nucleus and inhibits the miRNA microprocessor by sequestering primary let-7 transcripts. In contrast, Lin28A-mediated inhibition of let-7 expression involves recruitment of a 3' terminal uridylyl transferase (TUTase) (e.g., Zcchc11 / TUTase4 / TUT4 / Z11 or Zcchc6 / TUTase7 / TUT7 / Z6) to let-7 precursor RNA to block processing by Dicer in the cell cytoplasm. TUTase activity is required for the Lin28-mediated inhibition of let-7 biogenesis. It has been found that Zcchc11 expression is up-regulated in primary human liver and colorectal tumors compared with normal tissues. In addition, Zcchc11 knockdown has been shown to inhibit tumorigenesis of human breast, ovarian, melanoma, prostate, and liver cancer cells in mouse xenograft models and lung metastasis of liver cancer cells.

[0004] As such, there is a need for targeted therapies that modulate the TUTase activities for treating diseases or disorders mediated by let 7 miRNA. SUMMARY OF THE INVENTION

[0005] The present invention provides compounds that can modulate the activities TUTase Zcchc11 (or Z11). In certain embodiments, the compounds of the invention have inhibitory activities against Z11 TUTase. The compounds of the invention have quinolone cores similar to quinolone antibiotics. However, certain compounds of the invention exhibit reduced or minimal antibiotic activity.

[0006] In a first aspect, the present invention is directed to a compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein: W is –CH2Y-R3, -S(O)2R3, -SCH2R3, Y-R3, -OC(=O)NR11R12or –N(C=O)NR11R12; V is -C(=O)-, -S(=O)2- or CR13R14; X is CR4R5, NR6or O; Y is NR7or O; Z is CR8or N; R1is halo, -CN, -OR1a, -C≡CH, a C3-6carbocyclyl, or a C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more R10; R1ais H or C1-6alkyl optionally substituted with one or more R10; R10, for each occurrence, is independently selected from halo, -CN and -OR10a; R10a, for each occurrence, is independently selected from H and C1-6alkyl; R2is -CN,-CHRzCN, -C(O)NH2,-CHRzC(O)NH2, 3- to 12-membered carbocyclyl,–(CHRz)- (3- to 12-membered carbocyclyl), 3- to 12-membered heterocyclyl, or–(CHRz)-(3 to 12-membered heterocyclyl), wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R2or in the group represented by R2are optionally substituted with one or more R20, and Rzis H or methyl; R20, for each occurrence, is independently selected from H, halo, CN, oxo, -C(O)R20a, -C(O)2R20a, -C(O)NR20a, -N(R20a)2, -N(R20a)C(O)R20a, -N(R20a)C(O)2R20a, - N(R20a)C(O)N(R20a)2, -N(R20a)S(O)2R20a, -OR20a, -OC(O)R20a, -OC(O)N(R20a)2, -SR20a, - S(O)2R20a, -S(O)N(R20a)2, -S(O)2N(R20a)2, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R20are each optionally substituted with one or more R25; R20a, for each occurrence, is independently selected from H, C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl and4- to 7-membered monocyclic heterocyclyl represented by R20aare each optionally substituted with one or more R25, or two R20atogether with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or more R25; R25, for each occurrence, is independently H, C1-6alkyl, halo,-C=O,-C(O)O(C1-C6 alkyl), 4- to 6- membered heterocyclyl optionally substituted with OH, -N(R25a)2, –OR25a, phenyl optionally substituted with C1-6alkyl, halo, -N(R25a)2or –OR25a; and R25ais H, C1-6alkyl; or two R25atogether with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl, wherein the C1-6alkyl is optionally substituted with-OCH3; R3is a 3 to 12-membered carbocyclyl or a 3 to 12-membered heterocyclyl, wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R3are optionally substituted with one or more R30; R30, for each occurrence, is independently selected from H, halo, oxo, -CN, -C(O)R30a, -C(O)2R30a, -C(O)NR30a, -N(R30a)2, -N(R30a)C(O)R30a, -N(R30a)C(O)2R30a, - N(R30a)C(O)N(R30a)2, -N(R30a)S(O)2R30a, -OR30a, -OC(O)R30a, -OC(O)N(R30a)2, -SR30a, - S(O)2R30a, -S(O)N(R30a)2, -S(O)2N(R30a)2, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R30are each optionally substituted with one or more R35; R30a, for each occurrence, is independently selected from H, C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R30aare each optionally substituted with one or more R35; R35, for each occurrence, is independently H, -NH2, C1-6alkyl, halo and –OR35a; and R35ais H or C1-6alkyl; alternatively, when Y is NR7, R7and R3together with the N atom from which R7is attached can form a 4 to 12-membered heterocyclyl optionally substituted with or more R30; R4, R5, R15, R16, R17and R18are each independently selected from H, C1-6alkyl, halo, - NHC(O)CH3, 4- to 6- membered carbocyclyl, or 4- to 6-membered heterocyclyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halo, and wherein the heterocyclyl and carbocyclyl are optionally substituted with halo, -CN, -OR4a, C1-C6 alkyl or =O (when the carbocyclyl or heterocyclyl are non-aromatic), or wherein R15and R16taken together or R17and R18taken together are =NOH or =NHOCH3;R4ais H or C1-6alkyl, optionally substitute with one or more halo; R6is H or C1-6alkyl optionally substituted with one or more substituents independently selected from halo, -CN and -OR6a; R6ais H or C1-6alkyl optionally substitute with one or more halo; R7is H or C1-6alkyl optionally substituted with one or more halo; R8is H, halo, -CN, -OR8aor C1-6alkyl optionally substituted with one or more halo; R8ais H or C1-6alkyl optionally substituted with one or more halo; R9, R13and R14are each independently selected from H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl and the C3-6cycloalkyl are each optionally substituted with one or more substituents independently selected from halo, -CN, –OR9aand C1-6alkyl optionally substituted with one or more halo; R9ais H or C1-6alkyl optionally substituted with one or more halo; R11and R12are each independently H or C1-6alkyl, or R11and R12together with the nitrogen atom from which they are attached form a 4- to 7-membered monocyclic heterocyclyl optionally substituted with one or more substituents independently selected from C1-6alkyl, halo, -OH, and C1-6alkoxy; or any two of R4, R5, R9, R13, R14, R15, R16, R17and R18together form a -C1-5alkylene-, optionally substituted with one or more substituents independently selected from halo, -ORa, -N(Ra)2and C1-6alkyl; or R4and R15taken together with their intervening carbon atoms form phenyl or a 6 membered heteroaryl; and Ra, for each occurrence, is independently H or C1-6alkyl optionally substituted with one or more halo; R19aand R19bare each independently H or C1-6alkyl optionally substituted with one or more halo, or R19aand R19btogether with the carbon atom from which they are attached form –C(=O); or one R20group and one R30group taken together form –O-CH2CH2-O- or –O-CH2CH2-NH-; and n1 is 0, 1 or 2; and n2 is 0, 1 or 2, provided when X is NR6or O, n1 and n2 cannot be 0.

[0007] In a second aspect, the present invention is directed to a compound represented by Formula (I’),

[0008] or a pharmaceutically acceptable salt thereof, wherein: W is Y-R3, -OC(=O)NR11R12or –N(C=O)NR11R12; V is -C(=O)-, -S(=O)2- or CR13R14; X is CR4R5, NR6or O; Y is NR7or O; Z is CR8or N; R1is halo, CN, -OR1a,-C≡CH, or a C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more R10; R1ais H or C1-6alkyl optionally substituted with one or more R10; R10, for each occurrence, is independently selected from halo, CN and OR10a; R10a, for each occurrence, is independently selected from H and C1-6alkyl; R2is a 3 to 12-membered carbocyclyl or a 3 to 12-membered heterocyclyl, wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R2are optionally substituted with one or more R20; R20, for each occurrence, is independently selected from H, halo, CN, oxo, -C(O)R20a, -C(O)2R20a, -C(O)NR20a, -N(R20a)2, -N(R20a)C(O)R20a, -N(R20a)C(O)2R20a, - N(R20a)C(O)N(R20a)2, -N(R20a)S(O)2R20a, -OR20a, -OC(O)R20a, -OC(O)N(R20a)2, -SR20a, - S(O)2R20a, -S(O)N(R20a)2, -S(O)2N(R20a)2, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R20are each optionally substituted with one or more R25;R20a, for each occurrence, is independently selected from H, C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R20aare each optionally substituted with one or more R25, or two R20atogether with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or more R25; R25, for each occurrence, is independently H, C1-6alkyl, halo, -N(R25a)2, -OR25a, phenyl optionally substituted with C1-6alkyl, halo, -N(R25a)2or –OR25a; and R25ais H or C1-6alkyl; R3is a 3 to 12-membered carbocyclyl or a 3 to 12-membered heterocyclyl, wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R3are optionally substituted with one or more R30; R30, for each occurrence, is independently selected from H, halo, oxo, -CN, -C(O)R30a, -C(O)2R30a, -C(O)NR30a, -N(R30a)2, -N(R30a)C(O)R30a, -N(R30a)C(O)2R30a, - N(R30a)C(O)N(R30a)2, -N(R30a)S(O)2R30a, -OR30a, -OC(O)R30a, -OC(O)N(R30a)2, -SR30a, - S(O)2R30a, -S(O)N(R30a)2, -S(O)2N(R30a)2, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R30are each optionally substituted with one or more R35; R30a, for each occurrence, is independently selected from H, C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R30aare each optionally substituted with one or more R35; R35, for each occurrence, is independently H, C1-6alkyl, halo and –OR35a; and R35ais H or C1-6alkyl; alternatively, when Y is NR7, R7and R3together with the N atom from which R7is attached can form a 4 to 12-membered heterocyclyl optionally substituted with or more R30; R4, R5, R15, R16, R17and R18are each independently selected from H, C1-6alkyl, halo, -CN and -OR4a, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halo, CN and -OR4a; R4ais H or C1-6alkyl optionally substitute with one or more halo; R6is H or C1-6alkyl optionally substituted with one or more substituents independently selected from halo, CN and -OR6a;R6ais H or C1-6alkyl optionally substitute with one or more halo; R7is H or C1-6alkyl optionally substituted with one or more halo; R8is H, halo, CN, -OR8aor C1-6alkyl optionally substituted with one or more halo; R8ais H or C1-6alkyl optionally substituted with one or more halo; R9, R13and R14are each independently selected from H, C1-6alkyl and C3-6cycloalkyl, wherein the C1-6alkyl and the C3-6cycloalkyl are each optionally substituted with one or more substituents independently selected from halo, CN, -OR9aand C1-6alkyl optionally substituted with one or more halo; R9ais H or C1-6alkyl optionally substituted with one or more halo; R11and R12are each independently H or C1-6alkyl, or R11and R12together with the nitrogen atom from which they are attached form a 4- to 7-membered monocyclic heterocyclyl optionally substituted with one or more substituents independently selected from C1-6alkyl, halo, OH, and C1-6alkoxy; or any two of R4, R5, R9, R13, R14, R15, R16, R17and R18together form a -C1-5alkylene- optionally substituted with one or more substituents independently selected from halo, -ORa, -N(Ra)2and C1-6alkyl; Ra, for each occurrence, is independently H or C1-6alkyl optionally substituted with one or more halo; R19aand R19bare each independently H or C1-6alkyl optionally substituted with one or more halo or R9aand R9btogether with the carbon atom from which they are attached form –C(=O)-; n1 is 0, 1 or 2; and n2 is 0, 1 or 2, provided when X is NR6or O, n1 and n2 cannot be 0.

[0009] In a third aspect, the present invention provides a composition (e.g., a pharmaceutical composition) comprising a compound disclosed herein, or a salt (e.g., a pharmaceutically acceptable salt) thereof. The composition may also include a carrier (e.g., a pharmaceutically acceptable carrier).

[0010] In a fourth aspect, the present invention also includes a method of treating a disease or disorder in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein the disease or disorder is mediated by Z11 TUTase. Also included in the present invention is a compound disclosed herein, or a salt (e.g., a pharmaceutically acceptable salt) thereof for use in a method of treating a disease or disorder in a subject, wherein the disease or disorder is mediated by Z11 TUTase. The present invention also includes use of a compound disclosed herein,or a salt (e.g., a pharmaceutically acceptable salt) thereof for the manufacture of a medicament for treating a disease or disorder in a subject, wherein the disease or disorder is mediated by Z11 TUTase. DETAILED DESCRIPTION OF THE INVENTION

[0011] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulae. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. In the event that one or more of the incorporated literature references, patents or similar materials differ from or contradict this application, including but not limited to defined terms, term usage, described techniques or the like, this application controls.

[0012] It should be understood that any of the embodiments described herein, including those described under different aspects of the invention (e.g., compounds, compositions, methods of making and using) and different parts of the specification can be combined with one or more other embodiments of the invention, unless explicitly disclaimed or improper. Combination of embodiments are not limited to those specific combinations claimed via the multiple dependent claims. Definitions and general terminology

[0013] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having 1 to 20 carbon atoms. Preferably the alkyl comprises 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3- pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, and the like.

[0014] The number of carbon atoms in a group is specified herein by the prefix “Cx-xx”, wherein x and xx are integers. For example, "C1-4alkyl" is an alkyl group which has from 1 to 4 carbon atoms.

[0015] “Alkylene” as used herein refers to a saturated linear or branched-chain divalent hydrocarbon radical of one to twenty carbon atoms (C1-20), examples of which include, but are not limited to, those having the same core structures of the alkyl groups as exemplified above. “Divalent” means that thealkylene has two points of attachment to the remainder of the molecule. Preferably, the alkylene has one to sixteen carbon atoms (C1-16) or one to ten carbon atoms (C1-10). More preferably, the alkylene has one to seven carbon atoms (C1-7), one to six carbon atoms (C1-6), one to five carbon atoms (C1-5), one to four carbon atoms (C1-4) or one to three carbon atoms (C1-3). In certain embodiments, alkylene is preferably –(CH2)–, –(CH2)2– or –(CH2)3–.

[0016] As used herein, the term "carbocyclyl" refers to a saturated or unsaturated monocyclic or bicyclic (e.g., fused, bridged, or spiro bicyclic) hydrocarbon ring having 3-12 ring carbon atoms. The term “carbocyclyl” encompasses cycloalkyl groups and aromatic groups (i.e., aryl). In certain embodiments, the carbocyclyl is a 3- to 7-membered monocyclic carbocyclyl. Exemplary 3- to 7- membered monocyclic carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl and cycloheptatrienyl.

[0017] The term “cycloalkyl” refers to completely saturated monocyclic or bicyclic (e.g., fused, bridged, or spiro bicyclic) hydrocarbon ring having 3-12 ring carbon atoms, 3-8 ring carbon atoms, 3- 6 ring carbon atoms, or 5-7 ring carbon atoms. Exemplary bicyclic carbocyclyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, or 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[2.2]pentanyl, and spiro[3.3]heptanyl. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Preferably, the cycloalkyl is 3 to 8 membered monocyclic ring, 3 to 7 membered monocyclic ring or 3 to 6 membered monocyclic ring. Even more preferably, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0018] The term “aryl” refers to an aromatic hydrocarbon ring system having six to fourteen carbon ring atoms. The term “aryl” may be used interchangeably with the terms “aryl ring” “aromatic ring,” “aryl group” and “aromatic group.” “Aryl group” also includes an aromatic hydrocarbon ring system fused to a non-aromatic carbocyclic ring system, such as a cycloalkyl group. Examples includes phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like. An aryl group is monovalent, i.e., has one point of attachment to the remainder of the molecule. A “substituted aryl group” is substituted at any one or more substitutable ring atom, which is a ring carbon atom bonded to a hydrogen. Preferably, the aryl is phenyl.

[0019] The term "alkoxy" as used herein refers to the group -OR, in which R is an alkyl as defined above. Preferably, the alkyl group has one to sixteen carbon atoms (C1-16) or one to ten carbon atoms (C1-10). More preferably, the alkyl group has one to eight carbon atoms (C1-8), one to seven carbon atoms (C1-7), one to six carbon atoms (C1-6), one to four carbon atoms (C1-4) or one to three carbonatoms (C1-3). Non-limiting examples include: -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, - OCH(CH2)2, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl and -O-cyclohexyl.

[0020] The terms “heterocycle,” “heterocyclyl,” “heterocyclic” and “heterocyclic ring” are used interchangeably herein and refer to a cyclic group which contains at least one heteroatom, e.g., N, O or S, and may be aromatic (heteroaryl) or non-aromatic. It can be monocyclic or bicyclic (e.g., fused, bridged or spiro bicyclic ring) having 3 to 12 ring members, preferably, 4 to 12 ring members, 3 to 7 ring members, 3 to 6 ring members, 4 to 7 ring members, 5 to 7 ring members, or 4 to 6 ring members, at least one of which is a heteroatom, and up to 4 (e.g., 1, 2, 3, or 4) of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein C can be oxidized (e.g., C(O)), N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. Unsaturated heterocyclic rings include heteroaryl rings.

[0021] In one embodiment, a heterocyclyl is a 3- to 7-membered monocyclic heterocyclyl (saturated or partially unsaturated (i.e., non-aromatic)) having 1-2 heteroatoms selected from O, S and N. Examples of 3- to 7-membered monocyclic heterocyclyl include, but are not limited to, aziridinyl, oxiranyl, thirranyl, oxaziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl. In one embodiment, a heterocyclyl is a 4- to 7- membered monocyclic heterocyclyl (saturated or partially unsaturated (i.e., non-aromatic)). In one embodiment, a heterocyclyl is a 5-to 7-membered monocyclic heterocyclyl (saturated or partially unsaturated).

[0022] In one embodiment, a heterocyclyl is a 4- to 6-membered monocyclic heterocyclyl (saturated or partially unsaturated) having 1-2 heteroatoms selected from O, S and N. Examples of a 4- to 6- membered monocyclic heterocyclic include, but are not limited to azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, and tetrazinyl.

[0023] In another embodiment, a heterocyclyl is a 4- to 6-membered saturated monocyclic heterocyclyl. In one embodiment, the 4- to 6-membered saturated monocyclic heterocyclyl contains 1-2 heteroatoms independently selected from O, S and N. Examples of saturated 4- to 6-memberedmonocyclic heterocyclic ring systems include, but are not limited to azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithiinyl. In one embodiment, a saturated 4- to 6-membered monocyclic heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxinyl. In another embodiment, a saturated 4- to 6-membered monocyclic heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0024] In one embodiment, a heterocyclyl is a 7 to 10-membered saturated or partially saturated bicyclic (e.g., fused, bridged or spiro) heterocyclyl. In one embodiment, a 7 to 10-membered saturated or partially saturated bicyclic heterocyclyl is a fused bicyclic heterocyclyl having a monocyclic heterocycle fused to a carbocycle or a heterocycle, wherein at least one of the ring is non- aromatic. Examples of a 7 to 10-membered saturated or partially saturated fused bicyclic heterocyclyl include, but are not limited to, 2,3-dihydrobenzofuranyl, indolinyl (or 2,3-dihydroindolyl), 2,3- dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, 5,6,7,8-tetrahydropyrido[3,4-b]pyrazinyl, 1,3-dihydroisobenzofuranyl, and isochromanyl. In one embodiment, a 7 to 10-membered saturated or partially saturated bicyclic heterocyclyl is a spiro bicyclic heterocyclyl, such as oxaspiro[2.4]heptanyl, 2,6- diazaspiro[3.3]heptanyl, oxa-6-azaspiro[3.3]heptanyl, 2,2,6-diazaspiro[3.3]heptanyl, 3- azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, 7-azaspiro[3.5]nonanyl, 2,6- diazaspiro[3.4]octanyl, 8-azaspiro[4.5]decanyl, 1,6-diazaspiro[3.3]heptanyl, 5-azaspiro[2.5]octanyl, 4,7-diazaspiro[2.5]octanyl, 5-oxa-2-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl, 3- azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, and the like. In one embodiment, the 7 to 10- membered saturated or partially saturated bicyclic heterocyclyl is 2-azaspiro[3.3]heptan-6-yl.

[0025] As used herein, “heteroaryl” can be used interchangeably with “heteroaromatic,” “heteroaryl ring,” “heteroaryl group,” “heteroaromatic ring,” and “heteroaromatic group.” It refers to aromatic ring systems having five to fourteen ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur). “Heteroaryl” includes monocyclic rings and polycyclic rings (e.g., bicyclic) in which a monocyclic heteroaromatic ring is fused to one or more other aromatic or heteroaromatic rings. Preferably, the heteroaryl is 5 to 10-membered.

[0026] In one embodiment, a heteroaryl is “5 or 6-memberedmonocyclic heteroaryl,” which means a monocyclic aromatic ring system having five or six ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur).Examples of a 5 or 6-memberedmonocyclic heteroaryl include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1- pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl (or pyridyl, e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, triazolyl (e.g., 2-triazolyl, 5- triazolyl), tetrazolyl (e.g., tetrazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyranyl, thiopyranyl, pyrazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl and tetrazinyl. Preferably, the 5 or 6-memberedmonocyclic heteroaryl is pyridinyl, pyridazinyl, or pyrazinyl.

[0027] In one embodiment, a heteroaryl is “9 or 10-memberedbicyclic heteroaryl,” which refers to bicyclic aromatic ring system with 9 or 10 ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen or sulfur), in which a monocyclic heteroaromatic ring fused to an aromatic or heteroaromatic ring. Examples of a 9 or 10-membered bicyclic heteroaryl include, but are not limited to, azaindolyl, benzimidazolyl, benzofuryl, benzoisoxazolyl, benzoisothiazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, furopyridinyl, imidazopyridyl, imidazopyrimidinyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, oxazolopyridinyl, purinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyridopyazinyl, pyridopyrimidinyl, pyrrolo[2,3]pyrimidinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolotriazolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, thiazolopyridinyl, thienopyridinyl, thienopyrimidinyl, thienopyrazinyl, napthyridyl, and the like. Preferably, the 9 or 10- membered bicyclic heteroaryl is indolyl, indazolyl, or benzimidazolyl.

[0028] The term “fused ring system”, as used herein, is a ring system that has two rings each of which are independently selected from a carbocyclyl or a heterocyclyl, wherein the two ring structures share two adjacent ring atoms. In one embodiment, a fused ring system have from 9 to 12 ring members.

[0029] The term “bridged ring system”, as used herein, is a ring system that has a carbocyclyl or heterocyclyl ring wherein two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably from one to three) atoms selected from C, N, O, and S. In one embodiment, a bridged ring system have from 6 to 12 ring members.

[0030] The term “spiro ring system,” as used herein, is a ring system that has two rings each of which are independently selected from a carbocyclyl or a heterocyclyl, wherein the two ring structures having one ring atom in common. In one embodiment, spiro ring systems have from 5 to 12 ring members.

[0031] The heterocycle or heteroaryl groups may be carbon (carbon-linked) or nitrogen (nitrogen- linked) attached where such is possible. By way of example and not limitation, carbon bonded heterocycle or heteroaryl groups are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.

[0032] By way of example and not limitation, nitrogen bonded heterocycle or heteroaryl heteroarylene groups are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2- pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole or isoindoline, or position 4 of a morpholine.

[0033] The heteroatoms present in heteroaryl or heterocyclyl can include the oxidized forms such as NO, SO, and SO2.

[0034] The term “Halogen” or “halo” as used herein refers to F, Cl, Br or I. Preferably, halo is F, Cl, or Br.

[0035] If a group is described as being “optionally substituted,” the group may be either (1) not substituted, or (2) substituted. If a carbon of a group is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogen atoms on the carbon (to the extent there are any) may separately and / or together be replaced with an independently selected optional substituent. If a group is substituted with one or more substituents, it can be substituted with 1, 2, 3, 4, 5, 6, or more independently selected substituents. In certain embodiments, it can be substituted with 1, 2, 3, 4, 5 or 6 independently selected substituents. In certain embodiments, it can be substituted with 1, 2 or 3 independently selected substituents.

[0036] Suitable substituents for an alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, and heterocyclyl are those which do not significantly adversely affect the biological activity of the bifunctional compound. Unless otherwise specified, exemplary substituents for these groups include linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, aryl, heteroaryl, heterocyclyl, halogen, guanidinium [-NH(C=NH)NH2], -OR100, NR101R102, -NO2, -NR101COR102, - SR100, a sulfoxide represented by -SOR101, a sulfone represented by -SO2R101, a sulfonate -SO3M, a sulfate -OSO3M, a sulfonamide represented by -SO2NR101R102, cyano, an azido, -COR101, - OCOR101, -OCONR101R102and a polyethylene glycol unit (-OCH2CH2)nR101wherein M is H or a cation (such as Na+or K+); R101, R102and R103are each independently selected from H, linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycolunit (-OCH2CH2)n-R104, wherein n is an integer from 1 to 24, an aryl having from 6 to 10 carbon atoms, a heterocyclic ring having from 3 to 10 carbon atoms and a heteroaryl having 5 to 10 carbon atoms; and R104is H or a linear or branched alkyl having 1 to 4 carbon atoms, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl in the groups represented by R100, R101, R102, R103and R104are optionally substituted with one or more (e.g., 2, 3, 4, 5, 6 or more) substituents independently selected from halogen, -OH, -CN, -NO2, and unsubstituted linear or branched alkyl having 1 to 4 carbon atoms. Preferably, the substituent for the optionally substituted alkyl, alkylene, cycloalkylene, arylene, and heteroarylene described above is selected from the group consisting of halogen, -CN, -NR101R102, -CF3, -OR100, aryl, heteroaryl, heterocyclyl, -SR101, -SOR101, -SO2R101, and -SO3M. Alternatively, the suitable substituent is selected from the group consisting of -halogen, - OH, -NO2, -CN, C1-4alkyl, -OR100, NR101R102, -NR101COR102, -SR100,-SO2R101, - SO2NR101R102, -COR101, -OCOR101, and -OCONR101R102, wherein R100, R101, and R102are each independently -H or C1-4alkyl.

[0037] As used herein, an integer “between” x and y includes integers x and y unless otherwise specified to the contrary. For example, “an integer between 1 and 5” can be 1, 2, 3, 4, or 5.

[0038] The term “salt” as used herein refers to organic or inorganic salts of a bifunctional compound of the invention. Preferably, a salt is a pharmaceutically acceptable salt. Other non-pharmaceutically acceptable salts are also included in the present invention. The salts include salts, formed by reacting a bifunctional compound of the invention, which comprises a basic group, with an inorganic acid or organic acid (such as a carboxylic acid), and salts, formed by reacting a bifunctional compound of the invention, which comprises an acidic group, with an inorganic base or organic base (such as an amine). Exemplary salts include those pharmaceutically acceptable salts described immediately below.

[0039] The term “pharmaceutically acceptable salt” as used herein refers to pharmaceutically acceptable organic or inorganic salts of a bifunctional compound of the invention. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate,” ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence,a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counter ion.

[0040] If the compound of the invention contains one or more basic moieties, desired salts (e.g., pharmaceutically acceptable salts) may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[0041] If the compound of the invention contains one or more acidic moieties, desired salts (e.g., pharmaceutically acceptable salts) may be prepared by any suitable method, for example, treatment of the free acid with an inorganic, such as an alkali metal hydroxide or alkaline earth metal hydroxide, organic base, such as an amine (primary, secondary or tertiary), or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0042] The phrase “pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0043] The term “treat”, “treatment” or “treating” refers to reversing, alleviating, reducing the likelihood of developing, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In some embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.

[0044] The term “effective amount” refers to an amount of an active compound sufficient to carry out a specifically stated purpose, e.g., inhibiting the activity of Z11.

[0045] The term “therapeutically effective amount” means that an amount of an active compound that elicits the desired biological response in a subject, e.g., “treating” a disease or disorder in a subject. Such response includes alleviation of the symptoms of the disease or disorder being treated,inhibition or a delay in the recurrence of symptom of the disease or of the disease itself, an increase in the longevity of the subject compared with the absence of the treatment, or prevention, inhibition or delay in the progression of symptom of the disease or of the disease itself. Determination of the therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Toxicity and therapeutic efficacy of a compound of the present invention can be determined by standard pharmaceutical procedures in cell cultures and in experimental animals. The therapeutically effective amount of a compound of the present invention or other therapeutic agent to be administered to a subject will depend on the stage, category and status of the disease and characteristics of the subject, such as general health, age, sex, body weight and drug tolerance. The therapeutically effective amount of the compound of the present invention or other therapeutic agent to be administered will also depend on administration route and dosage form. Dosage amount and interval can be adjusted individually to provide plasma levels of the active compound that are sufficient to maintain desired therapeutic effects. Exemplary Compounds

[0046] In a first aspect, the present invention is directed to a compound represented by Formula (I) or (I’), or a pharmaceutically acceptable salt thereof, wherein the variables are described above for Formula (I) or (I’).

[0047] In certain embodiments, for compounds of Formula (I) and (I’) described above, any two of R4, R5, R9, R13, R14, R15, R16, R17and R18together form a -C1-5alkylene- optionally substituted with one or more substituents independently selected from halo and C1-6alkyl. For example, R13and R15together with the carbon atoms to which they are attached can form a cycloalkyl that is fused with the ring containing variables V and X. In another example, R13and R9together with the carbon atoms to which they are attached and the ring containing variables V and X form a bridged bicyclic ring.

[0048] In a first embodiment, a compound of the present invention is represented by Formula (Ia) or (Ib):, or a pharmaceutically acceptable salt thereof, wherein:X is CR4R5, NR6or O; Y is NR7or O; Z is CR8or N; R1is halo, CN, -OR1a, -C≡CH, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more R10; R1ais H or C1-6alkyl optionally substituted with one or more R10; R10, for each occurrence, is independently selected from halo, CN and OR10a; R10a, for each occurrence, is independently selected from H and C1-6alkyl; R2is a 3 to 12-membered carbocyclyl or a 3 to 12-membered heterocyclyl, wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R2are optionally substituted with one or more R20; R20, for each occurrence, is independently selected from H, halo, CN, oxo, -C(O)R20a, -C(O)2R20a, -C(O)NR20a, -N(R20a)2, -N(R20a)C(O)R20a, -N(R20a)C(O)2R20a, - N(R20a)C(O)N(R20a)2, -N(R20a)S(O)2R20a, -OR20a, -OC(O)R20a, -OC(O)N(R20a)2, -SR20a, - S(O)2R20a, -S(O)N(R20a)2, -S(O)2N(R20a)2, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R20are each optionally substituted with one or more R25; R20a, for each occurrence, is independently selected from H, C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R20aare each optionally substituted with one or more R25, or two R20atogether with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or more R25; R25, for each occurrence, is independently H, C1-6alkyl, halo, -N(R25a)2, -OR25a, phenyl optionally substituted with C1-6alkyl, halo, -N(R25a)2or –OR25a; and R25ais H or C1-6alkyl; R3is a 3 to 12-membered carbocyclyl or a 3 to 12-membered heterocyclyl, wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R3are optionally substituted with one or more R30; R30, for each occurrence, is independently selected from H, halo, oxo, -CN, -C(O)R30a, -C(O)2R30a, -C(O)NR30a, -N(R30a)2, -N(R30a)C(O)R30a, -N(R30a)C(O)2R30a, -N(R30a)C(O)N(R30a)2, -N(R30a)S(O)2R30a, -OR30a, -OC(O)R30a, -OC(O)N(R30a)2, -SR30a, - S(O)2R30a, -S(O)N(R30a)2, -S(O)2N(R30a)2, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R30are each optionally substituted with one or more R35; R30a, for each occurrence, is independently selected from H, C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R30aare each optionally substituted with one or more R35; R35, for each occurrence, is independently H, C1-6alkyl, halo and –OR35a; and R35ais H or C1-6alkyl; alternatively, when Y is NR7, R7and R3together with the N atom from which R7is attached can form a 4 to 12-membered heterocyclyl optionally substituted with or more R30; R4and R5are each independently selected from H, C1-6alkyl, halo, -CN and -OR4a, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halo, CN and -OR4a; R4ais H or C1-6alkyl optionally substitute with one or more halo; R6is H or C1-6alkyl optionally substituted with one or more substituents independently selected from halo, CN and -OR6a; R6ais H or C1-6alkyl optionally substitute with one or more halo; R7is H or C1-6alkyl optionally substituted with one or more halo; R8is H, halo, CN, -OR8aor C1-6alkyl optionally substituted with one or more halo; R8ais H or C1-6alkyl optionally substituted with one or more halo; n1 is 0, 1 or 2; and n2 is 0, 1 or 2, or, for formula (I) or (Ia), any two of R4, R5, R9, R13, R14, R15, R16, R17and R18together form a -C1-5alkylene- optionally substituted with one or more substituents independently selected from halo, -ORa, -N(Ra)2and C1-6alkyl; wherein Ra, for each occurrence, is independently H or C1-6alkyl optionally substituted with one or more halo.

[0049] In a second embodiment, for compounds of Formula (I), (I’), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof described in the first aspect or first embodiment, X is CH2; and the remaining variables are as defined in the first aspect or the first embodiment.

[0050] In a third embodiment, for compounds of Formula (I), (I’), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof described in the first aspect or the first or second embodiment, n1 and n2 are both 0; n1 and n2 are both 1;n1 is 0 and n2 is 1; or n1 is 1 and n2 is 0; and the remaining variables are as defined in the first aspect or in the first or second embodiment.

[0051] In a fourth embodiment, for compounds of Formula (I), (I’), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof described in the first aspect or the first or second embodiment, X is O; and n1 and n2 are both 1; and the remaining variables are as defined in the first aspect or the first embodiments.

[0052] In a fifth embodiment, the invention provides a compound of Formula (IIa) or (IIb):, or a pharmaceutically acceptable salt thereof, wherein the variables are described for Formula (Ia) or (Ib) in the first embodiment.

[0053] In a sixth embodiment, the compound of Formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof is represented by Formula (II-1a) or (II-1b) respectively:, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (IIa) or (IIb) in the fifth embodiment.

[0054] In a specific embodiment, for compounds of Formula (IIa), (IIb), (II-1a) or (II-1b), or a pharmaceutically acceptable salt thereof described in the fifth or sixth embodiment, Y is NH or O; and the variables are as in the fifth or sixth embodiment.

[0055] In a seventh embodiment, the invention provides a compound of Formula (IIIa) or (IIIb):, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (Ia) or (Ib) in the first embodiment.

[0056] In an eighth embodiment, a compound of Formula (IIIa) or (IIIb) or a pharmaceutically acceptable salt thereof is represented by Formula (IIIa-1a) or (III-1b) respectively:, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the seventh embodiment.

[0057] In a ninth embodiment, a compound of Formula (IIIa) or (IIIb), or a pharmaceutically acceptable salt thereof described in the seventh embodiment is represented by Formula (IVa) or (IVb):, , or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (IIIa) or (IIIb) in the seventh embodiment.

[0058] In a tenth embodiment, a compound of Formula (IVa) or (IVb) or a pharmaceutically acceptable salt thereof described in the ninth embodiment is represented by Formula (IV-1a) or (IV- 1b):, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (IVa) or (IVb) in the ninth embodiment.

[0059] In an eleventh embodiment, for compounds or pharmaceutically acceptable salts described herein (e.g., compounds of Formula (I), (I’), (Ia), (Ib), (IIa), (IIb), (II-1a), (II-1b), (IIIa), (IIIb), (III- 1a), (III-1b), (IVa), (IVb), (IV-1a) and (IV-1b) or a pharmaceutically acceptable salt thereof), R8is H, halo, or OR8a; and the remaining variables are as defined in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment or any specific embodiments described therein.

[0060] In a twelfth embodiment, for compounds or pharmaceutically acceptable salts described herein (e.g., compounds of Formula (I), (I’), (Ia), (Ib), (IIa), (IIb), (II-1a), (II-1b), (IIIa), (IIIb), (III- 1a), (III-1b), (IVa), (IVb), (IV-1a) and (IV-1b) or a pharmaceutically acceptable salt thereof), R8is H, F, Cl or -OCH3; and the remaining variables are as defined in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment or any specific embodiments described therein. In a specific embodiment, R8is H.

[0061] In a thirteenth embodiment, for compounds or pharmaceutically acceptable salts described herein (e.g., compounds of Formula (I), (I’), (Ia), (Ib), (IIa), (IIb), (II-1a), (II-1b), (IIIa), (IIIb), (III- 1a), (III-1b), (IVa), (IVb), (IV-1a) and (IV-b) or a pharmaceutically acceptable salt thereof), R1is F, Cl, Br, CN, -OR9or C1-6alkyl; and the remaining variables are as defined in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiments or any specific embodiments described therein. In a specific embodiment, R1is Cl, Br, CN, -OR9or C1-6alkyl. In a more specific embodiment, R1is Cl, CN or CH3.

[0062] In a fourteenth embodiment, the present invention provides a compound represented by the following formula:or a pharmaceutically acceptable salt thereof, wherein R8is H or F; and the remaining variables are as defined in the first embodiment.

[0063] In a fifteenth embodiment, the invention provides a compound represented by the following formula:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the fourteenth embodiment.

[0064] In a sixteenth embodiment, for compounds or pharmaceutically acceptable salts described herein (e.g., compounds of Formula (I), (I’), (Ia), (Ib), (IIa), (IIb), (II-1a), (II-1b), (IIIa), (IIIb), (III- 1a), (III-1b), (IVa), (IVb), (IV-1a), (IV-1b), (IVAa), (IVBa), (IVCa), (IVDa), (IVAb), (IVBb), (IVCb), (IVDb), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (IVA-1b), (IVB-1b), (IVC-1b), or (IVD- 1b) or a pharmaceutically acceptable salt thereof), R3is phenyl, a 5 or 6-membered monocyclic heteroaryl or a 9 or 10-membered bicyclic heteroaryl, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl represented by R3are eachoptionally substituted with one to three R30; and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment or any specific embodiments described therein.

[0065] In a seventeenth embodiment, for compounds or pharmaceutically acceptable salts described herein (e.g., compounds of Formula (I), (I’), (Ia), (Ib), (IIa), (IIb), (II-1a), (II-1b), (IIIa), (IIIb), (III- 1a), (III-1b), (IVa), (IVb), (IV-1a), (IV-1b), (IVAa), (IVBa), (IVCa), (IVDa), (IVAb), (IVBb), (IVCb), (IVDb), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (IVA-1b), (IVB-1b), (IVC-1b), or (IVD- 1b)) or a pharmaceutically acceptable salt thereof), R3is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1H-pyrrolo[2,3-c]pyridinyl or 1H-imidazo[4,5-c]pyridinyl, each of which is optionally substituted with one to three R30; and the remaining variables are as defined in the sixteenth embodiment.

[0066] In an eighteenth embodiment, for compounds or pharmaceutically acceptable salts thereof described in the sixteenth or seventeenth embodiment, R30, for each occurrence, is H, halo, CN, - C(O)NR30a, -N(R30a)2, -N(R30a)C(O)R30a, -N(R30a)S(O)2R30a, -OR30a, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one to three R35; R30a, for each occurrence, is independently H or C1-6alkyl optionally substituted with one to three R35; R35, for each occurrence, is independently H, halo and –OR35a; and R35ais H or C1-3alkyl; and the remaining variables are as defined in the sixteenth or seventeenth embodiment.

[0067] In a specific embodiment, for compounds or a pharmaceutically acceptable salt thereof described in the eighteenth embodiment, R30, for each occurrence, is H, halo, CN, -OR30aand C1-6alkyl optionally substituted with one to three halo; R30ais H or C1-6alkyl optionally substituted with one to three halo; and the remaining variables are as defined in the eighteenth embodiment.

[0068] In another specific embodiment, for compounds or a pharmaceutically acceptable salt thereof described in the eighteenth embodiment, R30, for each occurrence, is H, F, Cl, Br, CN, -OCH3, -CH3, - CH2CH3or -CF3; and the remaining variables are as defined in the eighteenth embodiment.

[0069] In a nineteenth embodiment, for compounds or pharmaceutically acceptable salts described herein (e.g., compounds of Formula (I), (I’), (Ia), (Ib), (IIa), (IIb), (II-1a), (II-1b), (IIIa), (IIIb), (III- 1a), (III-1b), (IVa), (IVb), (IV-1a), (IV-1b), (IVAa), (IVBa), (IVCa), (IVDa), (IVAb), (IVBb), (IVCb), (IVDb), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (IVA-1b), (IVB-1b), (IVC-1b), or (IVD- 1b) or a pharmaceutically acceptable salt thereof), R3is selected from 3-chloropyridin-2-yl, 3- methylpyridin-2-yl, 3-bromopyridin-2-yl, 3-cyanopyridin-2-yl, 3-ethylpyridin-2-yl, 3-fluoropyridin-2- yl, 3-methoxypyridin-2-yl, 3-trifluoromethylpyridin-2-yl, pyridin-2-yl, 1H-pyrrolo[2,3-c]pyridin-5-yl,1H-pyrrolo[2,3-c]pyridin-7-yl, 1H-pyrrolo[2,3-c]pyridin-6-yl, 1H-imidazo[4,5-c]pyridin-4-yl, 2,6- dimethylphenyl, phenyl, pyradzin-3-yl, pyrimidin-4-yl, 5-methylpyridin-2-yl, 4-methylpyridin-2-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl, and pyridin-3-yl, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment or any specific embodiments described therein.

[0070] In a twentieth embodiment, the invention provides a compound represented by Formula (Va) or (Vb):, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; and the remaining variables are as defined in the first aspect or in the first, eleventh, twelfth or thirteen embodiments or any specific embodiments described therein.

[0071] In a twenty-first embodiment, a compound of Formula (Va) or (Vb) or a pharmaceutically acceptable salt thereof is represented by Formula (V-1a) or (V-1b):, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the twentieth embodiment.

[0072] In a twenty-second embodiment, a compound of Formula (Va) or (Vb) or a pharmaceutically acceptable salt thereof, is represented by Formula (VAa), (VBa), (VCa), (VDa), (VAb), (VBb), (VCb) or (VDb):or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the twentieth embodiment.

[0073] In a twenty-third embodiment, a compound of Formula (Va) or (Vb) or a pharmaceutically acceptable salt thereof is represented by Formula (VA-1a), (VB-1a), (VC-1a), (VD-1a), (VA-1b), (VB-1b), (VC-1b) or (VD-1b):, or a pharmaceutically acceptable salt thereof, wherein R8is H or F; and the remaining variables are as defined in the twentieth embodiment.

[0074] In a twenty-fourth embodiment, the present invention provides a compound of Formula (VIa) or (VIb):, or a pharmaceutically acceptable salt thereof, wherein R30is H, halo, CN, -OR30a, and C1-6alkyl optionally substituted with one to three halo; and R30ais H or C1-6alkyl optionally substituted with one to three halo; and the remaining variables are as defined in the twentieth embodiment

[0075] In a twenty-fifth embodiment, a compound of Formula (VIa) or (VIb) or a pharmaceutically acceptable salt thereof is represented by Formula (VI-1a) or (VI-1b):, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the twenty-fourth embodiment.

[0076] In a twenty-sixth embodiment, a compound of Formula (VIa) or (VIb) or a pharmaceutically acceptable salt thereof is represented by Formula (VIAa), (VIBa), (VICa), (VIDa), (VIAb), (VIBb), (VICb) or (VIDb):,, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the twenty-fourth embodiment.

[0077] In a twenty-seventh embodiment, a compound of Formula (VIa) or (VIb) or a pharmaceutically acceptable salt thereof is represented by Formula (VIA-1a),(VIB-1a), (VIC-1a), (VID-1a), (VIA-1b),(VIB-1b), (VIC-1b) or (VID-1b):, or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the twenty-fourth embodiment.

[0078] In a twenty-eighth embodiment, for compounds of Formula (Va), (Vb), (V-1a), (V-1b), (VAa), (VAb), (VBa), (VBb), (VCa), (VCb), (VDa), (VDb), (VA-1a), (VA-1b), (VB-1a), (VB-1b), (VC-1a), (VC-1b), (VID-1a), (VID-1b), (VIa), (VIb), (VI-1a), (VI-1b), (VIAa), (VIAb), (VIBa), (VIBb), (VICa), (VICb), (VIDa), (VIDb), (VIA-1a), (VIA-1b), (VIB-1a), (VIB-1b), (VIC-1a), (VIC- 1b), (VID-1a) or (VID-1b) or a pharmaceutically acceptable salt thereof, R30, for each occurrence, is independently H, F, Cl, Br, CN, -CH3, -CH2CH3, -OCH3, or -CF3; and the remaining variables are as defined in the twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth or twenty-seventh embodiment or any specific embodiments described therein.

[0079] In a twenty-ninth embodiment, for compounds or pharmaceutically acceptable salts described herein (e.g., compounds of Formula(I), (I’), (Ia), (Ib), (IIa), (IIb), (II-1a), (II-1b), (IIIa), (IIIb), (III-1a), (III-1b), (IVa), (IVb), (IV-1a), (IV-1b), (IVAa), (IVBa), (IVCa), (IVDa), (IVAb), (IVBb), (IVCb),(IVDb), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (IVA-1b), (IVB-1b), (IVC-1b), (IVD-1b), (Va), (Vb), (V-1a), (V-1b), (VAa), (VAb), (VBa), (VBb), (VCa), (VCb), (VDa), (VDb), (VA-1a), (VA-1b), (VB-1a), (VB-1b), (VC-1a), (VC-1b), (VID-1a), (VID-1b), (VIa), (VIb), (VI-1a), (VI-1b), (VIAa), (VIAb), (VIBa), (VIBb), (VICa), (VICb), (VIDa), (VIDb), (VIA-1a), (VIA-1b), (VIB-1a), (VIB-1b), (VIC-1a), (VIC-1b), (VID-1a) or (VID-1b), or a pharmaceutically acceptable salt thereof): R2is C3-8cycloalkyl, phenyl, a 4 to 6-membered saturated monocyclic heterocyclyl, a 7 to 10- membered saturated or partially saturated bicyclic heterocyclyl, a 5 or 6-membered monocyclic heteroaryl or a 9 to 10-membered bicyclic heteroaryl, each of which is optionally substituted with one to three R20; R20, for each occurrence, is independently selected from H, halo, -CN, oxo, -C(O)R20a, - C(O)NR20a, -N(R20a)2, -N(R20a)C(O)R20a, -N(R20a)S(O)2R20a, -OR20a, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered saturated monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7- membered saturated monocyclic heterocyclyl represented by R20are each optionally substituted with one or two R25; R20a, for each occurrence, is independently selected from H and C1-6alkyl, wherein the C1-6alkyl represented by R20ais optionally substituted with one or more R25; R25, for each occurrence, is independently H, C1-6alkyl, halo, -N(R25a)2, –OR25a, phenyl optionally substituted with C1-6alkyl, halo, -N(R25a)2or –OR25a; and R25ais H or C1-6alkyl; and the remaining variables as defined above in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment or any specific embodiments described therein.

[0080] In a thirtieth embodiment, for compounds or pharmaceutically acceptable salts described herein (e.g., compounds of Formula (I), (I’), (Ia), (Ib), (IIa), (IIb), (II-1a), (II-1b), (IIIa), (IIIb), (III- 1a), (III-1b), (IVa), (IVb), (IV-1a), (IV-1b), (IVAa), (IVBa), (IVCa), (IVDa), (IVAb), (IVBb), (IVCb), (IVDb), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (IVA-1b), (IVB-1b), (IVC-1b), (IVD-1b), (Va), (Vb), (V-1a), (V-1b), (VAa), (VAb), (VBa), (VBb), (VCa), (VCb), (VDa), (VDb), (VA-1a), (VA-1b), (VB-1a), (VB-1b), (VC-1a), (VC-1b), (VID-1a), (VID-1b), (VIa), (VIb), (VI-1a), (VI-1b), (VIAa), (VIAb), (VIBa), (VIBb), (VICa), (VICb), (VIDa), (VIDb), (VIA-1a), (VIA-1b), (VIB-1a), (VIB-1b), (VIC-1a), (VIC-1b), (VID-1a) or (VID-1b), or a pharmaceutically acceptable salt thereof), R2is phenyl or a 6-membered monocyclic heteroaryl containing 1 to 3 nitrogen atoms, wherein the phenyl and the 6-membered monocyclic heteroaryl are each optionally substituted with one to three R20; and the remaining variables are as defined in the twenty-ninth embodiment.

[0081] In a thirty-first embodiment, for compounds or pharmaceutically acceptable salts described herein (e.g., compounds of Formula (I), (I’), (Ia), (Ib), (IIa), (IIb), (II-1a), (II-1b), (IIIa), (IIIb), (III- 1a), (III-1b), (IVa), (IVb), (IV-1a), (IV-1b), (IVAa), (IVBa), (IVCa), (IVDa), (IVAb), (IVBb), (IVCb), (IVDb), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (IVA-1b), (IVB-1b), (IVC-1b), (IVD-1b), (Va), (Vb), (V-1a), (V-1b), (VAa), (VAb), (VBa), (VBb), (VCa), (VCb), (VDa), (VDb), (VA-1a), (VA-1b), (VB-1a), (VB-1b), (VC-1a), (VC-1b), (VID-1a), (VID-1b), (VIa), (VIb), (VI-1a), (VI-1b), (VIAa), (VIAb), (VIBa), (VIBb), (VICa), (VICb), (VIDa), (VIDb), (VIA-1a), (VIA-1b), (VIB-1a), (VIB-1b), (VIC-1a), (VIC-1b), (VID-1a) or (VID-1b), or a pharmaceutically acceptable salt thereof), R2is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, 1H-indolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1H- benzo[d]imidazolyl, 1,3,4-thiadiazoly, indolinyl, tetrahydro-2H-pyranyl, pyridinyl, pyridazinyl, pyrazinyl, oxetanyl, tetrahydro-2H-pyranyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, isochromanyl, and 1,3-dihydroisobenzofuranyl, each of which is optionally substituted with one or two R20; and the remaining variables are as defined in the twenty-ninth embodiment.

[0082] In a thirty-second embodiment, for compounds or pharmaceutically acceptable salts described herein (e.g., compounds of Formula (I), (I’), (Ia), (Ib), (IIa), (IIb), (II-1a), (II-1b), (IIIa), (IIIb), (III- 1a), (III-1b), (IVa), (IVb), (IV-1a), (IV-1b), (IVAa), (IVBa), (IVCa), (IVDa), (IVAb), (IVBb), (IVCb), (IVDb), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (IVA-1b), (IVB-1b), (IVC-1b), (IVD-1b), (Va), (Vb), (V-1a), (V-1b), (VAa), (VAb), (VBa), (VBb), (VCa), (VCb), (VDa), (VDb), (VA-1a), (VA-1b), (VB-1a), (VB-1b), (VC-1a), (VC-1b), (VID-1a), (VID-1b), (VIa), (VIb), (VI-1a), (VI-1b), (VIAa), (VIAb), (VIBa), (VIBb), (VICa), (VICb), (VIDa), (VIDb), (VIA-1a), (VIA-1b), (VIB-1a), (VIB-1b), (VIC-1a), (VIC-1b), (VID-1a) or (VID-1b), or a pharmaceutically acceptable salt thereof), R2is selected from phenyl, pyridinyl, and pyrazinyl, each of which is optionally substituted with one or two R20; and the remaining variables are as defined in the twenty-ninth embodiment.

[0083] In a thirty-third embodiment, for compounds or pharmaceutically acceptable salts described herein (e.g., compounds of Formula(I), (I’), (Ia), (Ib), (IIa), (IIb), (II-1a), (II-1b), (IIIa), (IIIb), (III-1a), (III-1b), (IVa), (IVb), (IV-1a), (IV-1b), (IVAa), (IVBa), (IVCa), (IVDa), (IVAb), (IVBb), (IVCb), (IVDb), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (IVA-1b), (IVB-1b), (IVC-1b), (IVD-1b), (Va), (Vb), (V-1a), (V-1b), (VAa), (VAb), (VBa), (VBb), (VCa), (VCb), (VDa), (VDb), (VA-1a), (VA-1b), (VB-1a), (VB-1b), (VC-1a), (VC-1b), (VID-1a), (VID-1b), (VIa), (VIb), (VI-1a), (VI-1b), (VIAa), (VIAb), (VIBa), (VIBb), (VICa), (VICb), (VIDa), (VIDb), (VIA-1a), (VIA-1b), (VIB-1a), (VIB-1b), (VIC-1a), (VIC-1b), (VID-1a) or (VID-1b), or a pharmaceutically acceptable salt thereof), R2is represented by the following formula:, wherein R21is H, halo, -CN, -C(O)R20a, -C(O)NR20a, -N(R20a)2, -N(R20a)C(O)R20a, -N(R20a)S(O)2R20a, - OR21a, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered saturated monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered saturated monocyclic heterocyclyl represented by R21are each optionally substituted with one or two R25; R21ais H or C1-6alkyl, wherein the C1-6alkyl represented by R21ais optionally substituted with one or more R25; R25, for each occurrence, is independently C1-6alkyl, halo, -N(R25a)2, –OR25a, phenyl optionally substituted with C1-6alkyl, halo, -N(R25a)2or –OR25a; R25ais H or C1-6alkyl; and r is 0, 1 or 2; and the remaining variables are as defined in the twenty-ninth embodiment.

[0084] In one embodiment, for compounds or pharmaceutically acceptable salts described in the thirty-third embodiment, R21ais C1-6alkyl optionally substituted with one or more R25; and the remaining variables are as defined in the thirty-third embodiment.

[0085] In another embodiment, or compounds or pharmaceutically acceptable salts described in the thirty-third embodiment, R21is H, -F, -Cl, -CH3, -CH2OH, -OCH3, -OH, -OCH2CH2OCH3, - OCH2CH2OH, -OCH2CH2N(CH3)2, (4-methoxybenzyl)oxy, -NHCH2CH2OMe, -NHSO2CH3, or -NHC(O)CH3; and the remaining variables are as defined in the thirty-third embodiment.

[0086] In a thirty-fourth embodiment, for compounds or pharmaceutically acceptable salts described herein (e.g., compounds of Formula (I), (I’), (Ia), (Ib), (IIa), (IIb), (II-1a), (II-1b), (IIIa), (IIIb), (III- 1a), (III-1b), (IVa), (IVb), (IV-1a), (IV-1b), (IVAa), (IVBa), (IVCa), (IVDa), (IVAb), (IVBb), (IVCb), (IVDb), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (IVA-1b), (IVB-1b), (IVC-1b), (IVD-1b), (Va), (Vb), (V-1a), (V-1b), (VAa), (VAb), (VBa), (VBb), (VCa), (VCb), (VDa), (VDb), (VA-1a), (VA-1b), (VB-1a), (VB-1b), (VC-1a), (VC-1b), (VID-1a), (VID-1b), (VIa), (VIb), (VI-1a), (VI-1b), (VIAa), (VIAb), (VIBa), (VIBb), (VICa), (VICb), (VIDa), (VIDb), (VIA-1a), (VIA-1b), (VIB-1a), (VIB-1b), (VIC-1a), (VIC-1b), (VID-1a) or (VID-1b), or a pharmaceutically acceptable salt thereof), R20, for each occurrence, is independently selected from -F, -OH, -Cl, -CH3, -CH2CH3, -CH2OH, - CH2OCH3, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2N(CH3)2, -CF3, -OCH3, -OCH2CH2OCH3, - OCH2CH2OH, -OCH2CH2N(CH3)2, (4-methoxybenzyl)oxy, oxo, -C(O)CH3, -NH2, -NHCH3, - N(CH3)2, -N(CH3)(CH2CH2OCH3), -NHCH2CH2OMe, -NHCH2CH2NHCH3, -NHCH2CH2N(CH3)2, - NHSO2CH3, -NHSO2CH2CH3, -NHC(O)CH3, azetidin-yl, 3-aminoazeitidin-1-yl, piperidin-1-yl,morpholinyl, and pyrrolidin-1-yl; and the remaining variables are as defined in the twenty-ninth, thirtieth, thirty-first, thirty-second or thirty-third embodiment.

[0087] In a thirty-fifth embodiment, the present invention provides a compound represented by Formula (VIIA-1a), (VIIB-1a), (VIIC-1a), (VIID-1a), (VIIA-1b), (VIIB-1b), (VIIC-1b), (VIID-1b):or a pharmaceutically acceptable salt thereof, wherein:R30is H, halo, CN, -OR30a, and C1-6alkyl optionally substituted with one to three halo; and R30ais H or C1-6alkyl optionally substituted with one to three halo; R2is phenyl or a 6-membered monocyclic heteroaryl containing 1 to 3 nitrogen atoms, wherein the phenyl and the 6-membered monocyclic heteroaryl are each optionally substituted with one to three R20; R20, for each occurrence, is independently selected from halo, and -N(R20a)2; and R20a, for each occurrence, is independently selected from H and C1-3alkyl, or two R20atogether with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or more R25; R25, for each occurrence, is independently H, C1-6alkyl, halo, -N(R25a)2, or –OR25a; and R25ais H or C1-6alkyl.

[0088] In a thirty-sixth embodiment, for compounds of Formula (VIIA-1a), (VIIB-1a), (VIIC-1a), (VIID-1a), (VIIA-1b), (VIIB-1b), (VIIC-1b), (VIID-1b) or a pharmaceutically acceptable salt thereof, R30is halo or C1-3alkyl; R2is phenyl, pyridinyl or pyrazinyl, each of which is optionally substituted with -N(R20a)2; R20a, for each occurrence, is H or methyl, or two R20atogether with the nitrogen atom from which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with one R25; R25is -N(R25a)2; and R25ais H or Me; and the remaining variables are as defined in the thirty-fifth embodiments. In a specific embodiment, R30is Cl or methyl; and R2is phenyl, pyridin-3-yl, or pyrazin-2-yl, each of which is optionally substituted with –NH2, azetidin-1-yl, 3-aminoazetidin-1-yl or 3-(dimethylamino)azetidin-1-yl.

[0089] In a thirty-seventh embodiment, for compounds of Formula (I), (I’), (IIa), (II-1a), (IIIa), (III- 1a), (IVa), (IV-1a), (IVAa), (IVBa), (IVCa), (IVDa), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (Va), (V-1a), (VAa), (VBa), (VCa), (VDa), (VA-1a), (VB-1a), (VC-1a), (VD-1a), (VIa), (VI-1a), (VIAa), (VIBa), (VICa), (VIDa), (VIA-1a), (VIB-1a), (VIC-1a), (VID-1a), (VIIA-1a), (VIIB-1a), (VIIC-1a), or (VIID-1a) or a pharmaceutically acceptable salt thereof described in any one of the fifth to thirty- sixth embodiments, R4, R5, R13, R14, R17and R18are all H, and R9is C1-6alkyl or C3-6cycloalkyl, wherein the C1-6alkyl and the C3-6cycloalkyl are each optionally substituted with one or more substituents independently selected from halo, CN, -OR9aand C1-6alkyl optionally substituted with one or more halo; wherein R9ais H or C1-6alkyl optionally substituted with one or more halo; and the remaining variables are as defined in the fifth to thirty-sixth embodiments. In a specific embodiment, R9is C1-6alkyl optionally substituted with one to three halo. In a more specific embodiment, R9is – CH3.

[0090] In a thirty-eighth embodiment, for compounds of Formula (I), (I’), (Ia), (IIa), (II-1a), (IIIa), (III-1a), (IVa), (IV-1a), (IVAa), (IVBa), (IVCa), (IVDa), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a),(Va), (V-1a), (VAa), (VBa), (VCa), (VDa), (VA-1a), (VB-1a), (VC-1a), (VD-1a), (VIa), (VI-1a), (VIAa), (VIBa), (VICa), (VIDa), (VIA-1a), (VIB-1a), (VIC-1a), (VID-1a), (VIIA-1a), (VIIB-1a), (VIIC-1a), or (VIID-1a) or a pharmaceutically acceptable salt thereof described in any one of the fifth to thirty-sixth embodiments, R5, R9, R13, R14, R17and R18are all H, and R4is C1-6alkyl, halo, -CN or - OR4a, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halo, CN and -OR4a; and R4ais H or C1-6alkyl optionally substitute with one or more halo; and the remaining variables are as defined in the fifth to thirty-sixth embodiments. In a specific embodiment, R4is halo. In a more specific embodiment, R4is F.

[0091] In a thirty-ninth embodiment, for compounds of Formula (I), (I’), (Ia), (IIa), (II-1a), (IIIa), (III-1a), (IVa), (IV-1a), (IVAa), (IVBa), (IVCa), (IVDa), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (Va), (V-1a), (VAa), (VBa), (VCa), (VDa), (VA-1a), (VB-1a), (VC-1a), (VD-1a), (VIa), (VI-1a), (VIAa), (VIBa), (VICa), (VIDa), (VIA-1a), (VIB-1a), (VIC-1a), (VID-1a), (VIIA-1a), (VIIB-1a), (VIIC-1a), or (VIID-1a) or a pharmaceutically acceptable salt thereof described in any one of the fifth to thirty-sixth embodiments, R4, R5, R14, R17and R18are all H, and R13and R9together form a -C1-3alkylene- optionally substituted with one or more substituents independently selected from halo, -ORa, -N(Ra)2and C1-6alkyl; wherein Ra, for each occurrence, is independently H or C1-6alkyl optionally substituted with one or more halo; and the remaining variables are as defined in the fifth to thirty-sixth embodiments. In a specific embodiment, R13and R9together form a –CH2CH2-, optionally substituted with one or two substituents independently selected from halo, -ORa, -N(Ra)2and C1-3alkyl; wherein Ra, for each occurrence, is independently H or C1-3alkyl optionally substituted with one or more halo. In a more specific embodiment, R13and R9together form a –CH2CH2-.

[0092] In a fortieth embodiment, the compound is represented by Formula (IV-1a):or a pharmaceutically acceptable salt thereof,wherein: R1is F, Cl, CN or CH3; R2is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, 1H-indolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1H-benzo[d]imidazolyl, 1,3,4-thiadiazoly, indolinyl, tetrahydro-2H-pyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxetanyl, tetrahydro-2H-pyranyl, 1H-benzo[d]imidazolyl, 1H-indazolyl,isochromanyl, and 1,3-dihydroisobenzofuranyl, each of which is optionally substituted with one or two R20; R20, for each occurrence, is independently selected from H, halo, -CN, oxo, -C(O)R20a, - C(O)NR20a, -N(R20a)2, -N(R20a)C(O)R20a, -N(R20a)S(O)2R20a, -OR20a, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered saturated monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7- membered saturated monocyclic heterocyclyl represented by R20 are each optionally substituted with one or two R25; R20a, for each occurrence, is independently selected from H and C1-6alkyl, wherein the C1-6alkyl represented by R20ais optionally substituted with one or more R25; R25, for each occurrence, is independently H, C1-6alkyl, halo, -N(R25a)2, –OR25a, phenyl optionally substituted with C1-6alkyl, halo, -N(R25a)2or –OR25a; and R25ais H, C1-6alkyl, or C1-6alkyl substituted with –OCH3; R3is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H- imidazo[4,5-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-imidazo[4,5-b]pyridinyl, 1H-pyrrolo[3,2- b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl,or 1H-imidazo[4,5-c]pyridinyl, each of which is optionally substituted with one to three R30; R30, for each occurrence, is H, halo, CN, -C(O)NR30a, -N(R30a)2, -N(R30a)C(O)R30a, - N(R30a)S(O)2R30a, -OR30a, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one to three R35; R30a, for each occurrence, is independently H, C1-6alkyl optionally substituted with one to three R35or C3-6cycloalkyl; R35, for each occurrence, is independently H, halo and –OR35a; and R35ais H or C1-3alkyl; R4is H, halo, CN, -OR4a, C1-6alkyl, pyridinyl, or pyrazolyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halo, CN and -OR4a; wherein the pyridinyl, or pyrazolyl is optionally substituted with –OH, -C1-C6alkyl or –O-C1-C6alkyl; and R4ais H, C1-6alkyl optionally substituted with one or more halo, or C3-C6cycloalkyl; R5is H or halo, or R4and R5taken together are =NOH, or =NHOCH3, or R4and R5taken together with the carbon to which they are connected form a C3-C6 cycloalkyl, or R5and R13taken together with their intervening atoms form a cyclopropyl; and; R8, R13and R14are each H;R9is H, C1-C6 alkoxy or C1-C6 alkyl, or R9and R13together form a C1-3alkylene- optionally substituted with one or more substituents independently selected from halo, ORa, N(Ra)2and C1-6alkyl; wherein Ra, for each occurrence, is independently H or C1-6alkyl optionally substituted with one or more halo; R17is H, halo or C1-6alkyl; and R18is H, -OH, -O(C1-C6 alkyl) or C1-6alkyl, or R17and R18taken together are =NOH or =NHOCH3).

[0093] In a forty-first embodiment, the compound is represented by Formula (IV-1a):or a pharmaceutically acceptable salt thereof, wherein: R1is F, Cl, CN or CH3; R2is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, 1H-indolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1H-benzo[d]imidazolyl, 1,3,4-thiadiazoly, indolinyl, tetrahydro-2H-pyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxetanyl, tetrahydro-2H-pyranyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, isochromanyl, and 1,3-dihydroisobenzofuranyl, each of which is optionally substituted with one or two R20; R20, for each occurrence, is independently selected from -F, -OH, -Cl, -CH3, -CH2CH3, - CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2N(CH3)2, -CF3, -OCH3, - OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, (4-methoxybenzyl)oxy, oxo, -C(O)CH3, -NH2, -NHCH3, -N(CH3)2, -N(CH3)(CH2CH2OCH3), -NHCH2CH2OMe, -NHCH2CH2NHCH3, - NHCH2CH2N(CH3)2, -NHSO2CH3, -NHSO2CH2CH3, -NHC(O)CH3, azetidin-yl, 3-aminoazeitidin-1- yl, piperidin-1-yl, morpholinyl, pyrrolidin-1-yl; and 3-(dimethylamino)azetidin-1-yl orR3is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H- pyrrolo[3,2-c]pyridinyl, or 1H-imidazo[4,5-c]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrrolo[2,3- b]pyridinyl,1H-imidazo[4,5-b]pyridinyl; 1H-pyrrolo[3,2-b]pyridinyl, or 3H-imidazo[4,5-b]pyridinyl each of which is optionally substituted with one to three R30; R30, for each occurrence, is H, F, Cl, Br, CN, -OCH3, -O(cyclopropyl), -NH2, -NH(CH3)2, - CH3, -CH2CH3or -CF3; R4is H, halo, -CN, OR4a, C1-6alkyl, pyridinyl, or pyrazolyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halo, CN and -OR4a; wherein the pyridinyl, or pyrazolyl is optionally substituted with –OH, -CH3or -OCH3; and R4ais H, -CH3, cyclopropyl or -CH2CH3optionally substituted with one or more halo, or cyclopropyl; R5is H or F, or R4and R5taken together are =NHOCH3, or R4and R5taken together with the carbon to which they are connected form cyclopropyl, or R5and R13taken together with their intervening atoms form a cyclopropyl; and R8, R13and R14are each H; R9is H or -CH3, or R9and R13together form a –C2alkylene-; R17is H, F or –CH3; and R18is H, -OH, -OCH3or –CH3, or R17and R18taken together are =NHOCH3.

[0094] In a forty-second embodiment, the compound is represented by Formula (IV-1a):or a pharmaceutically acceptable salt thereof, wherein: R1is F or Cl; R2is selected from pyridinyl, pyriminidinyl and pyridazinyl, each of which is substituted with R20; R20, for each occurrence, is independently selected from -NH2,-NHCH3, N(CH3)2, and 4- to 7-membered saturated monocyclic heterocyclyl, wherein the 4- to 7-membered saturated monocyclic heterocyclyl represented by R20substituted with -N(R25a)2;R25ais H, C1-6alkyl, or C1-6alkyl substituted with –OCH3; R3is pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2- b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, each of which is optionally substituted with one to three R30; R30, for each occurrence, is H, halo, C1-C6alkyl, -N(R30a)2or -OR30a; R30a, for each occurrence, is independently H, C1-6alkyl or C3-6cycloalkyl; R4is H, halo, -OR4a, C1-6alkyl, pyridinyl, or pyrazolyl, wherein the pyridinyl, or pyrazolyl is optionally substituted with –OH, -C1-C6alkyl or –O-(C1-C6 alkyl); R4ais H, C1-6alkyl or C3-C6 cycloalkyl; R5is H or halo, or R4and R5taken together are =NOH or =NHOCH3, or R4and R5taken together with the carbon to which they are connected form a C3-C6 cycloalkyl, or R5and R13taken together with their intervening atoms form a cyclopropyl; and; R8, R13and R14are each H; R9is H or C1-C6alkyl; R17is H, halo, C1-C6alkoxy or C1-6alkyl; R18is H, or C1-6alkyl

[0095] In a forty-third embodiment, the compound is represented by Formula (IV-1a):or a pharmaceutically acceptable salt thereof, wherein: R1is F or Cl; R2is selected from pyridinyl, pyrimidinyl and pyridazinyl, each of which is substituted withR20is -NH2, -NHCH3, N(CH3)2, 3-(dimethylamino)azetidin-R3is pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2- b]pyridinyl, or 3H-imidazo[4,5-b]pyridinyl each of which is optionally substituted with one to three R30; R30, for each occurrence, is H, Cl, CH3, -OCH3, -O(cyclopropyl), -NH2, -NHCH3or -N(CH3)2; R4is H, F, OH, -OCH3, -O-(cyclopropyl), -C1-C3alkyl, pyridinyl, or pyrazolyl, wherein the pyridinyl or pyrazolyl is optionally substituted with –OH, -CH3, -OCH3or –O(Cyclopropyl); R5is H or F, or R4and R5taken together are =NHOCH3, or R4and R5taken together with the carbon to which they are connected form cyclopropyl, or R5and R13taken together with their intervening atoms form a cyclopropyl; and R8, R13and R14are each H; R9is H or -CH3; R17is H, F, -OCH3or –CH3; and R18is H or –CH3.

[0096] In one embodiment, the invention provides a compound selected from those described in Example section, e.g., Examples 1-1 to 1-43, Examples 2-1 to 2-89, and Examples 3-1 to 3-116, including pharmaceutically acceptable salts thereof and the neutral form.

[0097] The compounds or pharmaceutically acceptable salts thereof as described herein, can contain one or more asymmetric centers in the molecule. In accordance with the present disclosure any structure that does not designate the stereochemistry is to be understood as embracing all the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture, or an enantiomerically enriched mixture). It is well known in the art how to prepare such optically active forms (for example, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, by chiral synthesis, or chromatographic separation using a chiral stationary phase).

[0098] When a particular stereoisomer of a compound is depicted by name or structure, the stereoisomeric purity of the compounds is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. “Stereoisomeric purity” means the weight percent of the desired stereoisomer relative to the combined weight of all stereoisomers.

[0099] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. The stereoisomeric purity is the weight percent of the desired stereoisomers encompassed by the name or structure relative to the combined weight of all of the stereoisomers.

[0100] When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has one or more chiral centers, it is to be understood that the name or structure encompasses one enantiomer of compound in pure or substantially pure form, as well as mixtures thereof (such as a racemic mixture of the compound, mixtures enriched in one enantiomer relative to its corresponding optical isomer, mixtures of stereoisomers, and mixtures of stereoisomers in which one or more stereoisomers is enriched relative to the other stereoisomer(s)).

[0101] The disclosed compounds may exist in tautomeric forms and mixtures and separate individual tautomers are contemplated. In addition, some compounds may exhibit polymorphism. Pharmaceutical compositions and methods of administration

[0102] In the second aspect, the compounds herein disclosed, and their pharmaceutically acceptable salts thereof may be formulated as pharmaceutical compositions or “formulations.”

[0103] A typical formulation is prepared by mixing a compound described herein, or a pharmaceutically acceptable salt thereof, and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art. The particular carrier, diluent or excipient used will depend upon the means and purpose for which a compound described herein is being formulated.

[0104] The formulations may be prepared using conventional dissolution and mixing procedures.

[0105] The terms “administer”, “administering” or “administration” in reference to a compound, composition or dosage form of the invention means introducing the compound into the system of the subject or patient in need of treatment. When a compound of the invention is provided in combination with one or more other active agents, “administration” and its variants are each understood to include concurrent and / or sequential introduction of the compound and the other active agents.

[0106] The compositions described herein may be administered systemically or locally, e.g. orally (including, but not limited to solid dosage forms including hard or soft capsules (e.g. gelatincapsules), tablets, pills, powders, sublingual tablets, troches, lozenges, and granules; and liquid dosage forms including, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, aqueous or oil solutions, suspensions, syrups and elixirs, by inhalation (e.g. with an aerosol, gas, inhaler, nebulizer or the like), to the ear (e.g. using ear drops), topically (e.g. using creams, gels, inhalants, liniments, lotions, ointments, patches, pastes, powders, solutions, sprays, transdermal patches, etc.), ophthalmically (e.g. with eye drops, ophthalmic gels, ophthalmic ointments), rectally (e.g. using enemas or suppositories), nasally, buccally, vaginally (e.g. using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets, etc.), via ear drops, via an implanted reservoir or the like, or parenterally depending on the severity and type of the disease being treated. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

[0107] In another aspect, a compound described herein or a pharmaceutically acceptable salt thereof may be formulated in a veterinary composition comprising a veterinary carrier. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert. In the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route. Therapeutic methods

[0108] In the third aspect, the invention also provides a method of treating a disease or disorder in a subject, wherein the disease or disorder is mediated by Z11 TUTase. The method comprises administering to the subject a therapeutically effective amount of the compound or the composition described herein, solvates thereof, and salts thereof.

[0109] The term "disease" or "disorder" is used interchangeably herein, refers to any alternation in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and / or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person. A disease or disorder can also related to a distemper, ailing, ailment, malady, disorder, sickness, illness, complaint, indisposition, or affection.

[0110] The term "malignancy" and "cancer" are used interchangeably herein, refers to diseases that are characterized by uncontrolled, abnormal growth of cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. The term "malignancy" or "cancer" are used interchangeably herein and refers to any disease of an organ or tissue in mammals characterized by poorly controlled or uncontrolled multiplication of normal or abnormal cells in thattissue and its effect on the body as a whole. Cancer diseases within the scope of the definition comprise benign neoplasms, dysplasias, hyperplasias as well as neoplasms showing metastatic growth or any other transformations like e.g. leukoplakias which often precede a breakout of cancer. The term "tumor" or "tumor cell" are used interchangeably herein, refers to the tissue mass or tissue type of cell that is undergoing abnormal proliferation.

[0111] A "cancer cell" refers to a cancerous, pre-cancerous or transformed cell, either in vivo, ex vivo, and in tissue culture, that has spontaneous or induced phenotypic changes that do not necessarily involve the uptake of new genetic material. Although transformation can arise from infection with a transforming virus and incorporation of new genomic nucleic acid, or uptake of exogenous nucleic acid, it can also arise spontaneously or following exposure to a carcinogen, thereby mutating an endogenous gene. Transformation / cancer is associated with, e.g., morphological changes, immortalization of cells, aberrant growth control, foci formation, anchorage dependence, proliferation, malignancy, contact inhibition and density limitation of growth, growth factor or serum dependence, tumor specific markers levels, invasiveness, tumor growth or suppression in suitable animal hosts such as nude mice, and the like, in vitro, in vivo, and ex vivo. See also Freshney, Culture Animal Cells: A Man. Basic Tech. (3rd ed., 1994).

[0112] The term "biological sample" as used herein may mean a sample of biological tissue or fluid that comprises nucleic acids. Such samples include, but are not limited to, tissue isolated from animals. Biological samples may also include sections of tissues such as biopsy and autopsy samples, frozen sections taken for histologic purposes, blood, plasma, serum, sputum, stool, tears, mucus, hair, and skin. Biological samples also include explants and primary and / or transformed cell cultures derived from patient tissues. A biological sample may be provided by removing a sample of cells from an animal, but can also be accomplished by using previously isolated cells (e.g., isolated by another person, at another time, and / or for another purpose), or by performing the methods of the invention in vivo. As used herein, the term "biological sample" also refers to a cell or population of cells or a quantity of tissue or fluid from a subject. "Biological sample" can also refer to cells or tissue analyzed in vivo, i.e., without removal from the subject. The term "tissue" is intended to include intact cells, blood, blood preparations such as plasma and serum, bones, joints, muscles, smooth muscles, and organs.

[0113] The terms "patient", "subject" and "individual" are used interchangeably herein, and refer to an animal, particularly a human, to whom treatment is provided. The term "subject" as used herein refers to human and non-human animals, such as apes, monkeys, horses, cattle, sheep, goats, dogs, cats, rabbits, guinea pigs, rats, and mice. In one embodiment, the subject is human.

[0114] As used herein, a “reference level” refers to the protein (e.g., Z11, Lin28A, Lin28B) level or RNA level (e.g., let 7 miRNA) in a biological sample free of disease or disorder described herein(e.g., cancer). In certain embodiments, the biological sample is obtained from a healthy subject (e.g., healthy human) who is free of cancer. In certain embodiments, the biological sample is obtained from the same subject (e.g., patient to be treated) from an earlier time when the subject is free of cancer. Alternatively, the biological sample is non-cancerous tissue obtained from the same subject (e.g., patient to be treated), preferably of the same tissue type as the cancerous tissue.

[0115] In certain embodiments, the disease or disorder is characterized by an increase in Lin28A or Lin28B level as compared to a reference level. In certain embodiments, the disease or disorder is characterized by a decrease in let 7 miRNA level as compared to the reference level. In yet another embodiment, the decrease in let 7 miRNA level is mediated by Z11 TUTase.

[0116] In certain embodiments, the compounds or compositions of the present invention can be used in a method of increasing let 7 miRNA level in a cancer cell.

[0117] In certain embodiments, the compounds or compositions of the present invention can be used for the treatment of adult and / or pediatric oncology including in solid phase tumors / malignancies, locally advanced tumors, human soft tissue sarcomas, metastatic cancer, including lymphatic metastases, blood cell malignancies including multiple myeloma, acute and chronic leukemias, lymphomas, head and neck cancers including mouth cancer, larynx cancer and thyroid cancer, lung cancers including small cell carcinoma and non-small cell cancers, breast cancers including small cell carcinoma and ductal carcinoma, gastrointestinal cancers including esophageal cancer, stomach cancer, colon cancer, colorectal cancer and polyps associated with colorectal neoplasia, pancreatic cancers, liver cancer, urologic cancers including bladder cancer and prostate cancer, malignancies of the female genital tract including ovarian carcinoma, uterine (including endometrial) cancers, and solid tumor in the ovarian follicle, kidney cancers including renal cell carcinoma, brain cancers including intrinsic brain tumors, neuroblastoma, askocytic brain tumors, gliomas, metastatic tumor cell invasion in the central nervous system, bone cancers including osteomas, skin cancers including malignant melanoma, tumor progression of human skin keratinocytes, squamous cell carcinoma, basal cell carcinoma, hemangiopericytoma and Kaposi's sarcoma.

[0118] In certain embodiments, the compounds or compositions described herein can be used for treating a cancer. Cancers include, but are not limited to, biliary tract cancer; bladder cancer; breast cancer; brain cancer including glioblastomas and medulloblastomas; cervical cancer; choriocarcinoma; colon cancer including colorectal carcinomas; endometrial cancer; esophageal cancer; gastric cancer; head and neck cancer; hematological neoplasms including acute lymphocytic and myelogenous leukemia, multiple myeloma, AIDS-associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms including Bowen's disease and Paget's disease, liver cancer; lung cancer including small cell lung cancer and non- small cell lung cancer; lymphomas including Hodgkin's disease and lymphocytic lymphomas; neuroblastomas; oral cancer including squamous cellcarcinoma; osteosarcomas; ovarian cancer including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells; pancreatic cancer; prostate cancer; rectal cancer; sarcomas including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, synovial sarcoma and osteosarcoma; skin cancer including melanomas, Kaposi's sarcoma, basocellular cancer, and squamous cell cancer; testicular cancer including germinal tumors such as seminoma, non-seminoma (teratomas, choriocarcinomas), stromal tumors, and germ cell tumors; thyroid cancer including thyroid adenocarcinoma and medullar carcinoma; transitional cancer and renal cancer including adenocarcinoma and Wilms' s tumor. In certain embodiments, the cancer is breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer or brain cancer. In some embodiments, the cancer cells are metastatic. In some embodiments, the cancer does not express LIN28A / B.

[0119] In certain embodiments, the compounds or compositions of the present invention can be used for treating breast cancer. In certain embodiments, the compounds or compositions of the present invention can be used for treating a lung cancer, a hepatic cancer or leukemia, for example but not limited to lung carcinoma, chronic myelogenous leukemia (CML) and HCC (hepatic cell carcinoma).

[0120] In certain embodiments, the compounds or compositions described herein are useful to be administered to a subject who has cancer regression. In certain embodiments, the compounds or compositions described herein are useful to be administered to a subject who has a therapy-resistant cancer, for example a chemotherapy resistant cancer. In some embodiments, the compounds or compositions described herein are useful to be administered to a subject who has cancer and has been exposed to adjuvant cancer therapies.

[0121] In some embodiments, the compounds or compositions described herein are useful to be administered to a subject with a malignant cancer. In some embodiments, the compounds or compositions described herein are also useful to be administered to and for the treatment of a subject with a cancer or tumor comprising a cancer stem cell.

[0122] In some embodiments, the compounds or compositions described herein are also useful in the treatment of other disease or disorders associated with abnormal cellular proliferation or differentiation of stem cells. Thus, treatment can be directed to a subject who is affected but asymptomatic with cancer, for example, a disease of an organ or tissue in a subject characterized by poorly controlled or uncontrolled multiplication of normal or abnormal cells in that tissue and its effect on the body as a whole. Cancer diseases which can be treated by the compounds or compositions described herein include, for example but are not limited to, benignneoplasms, dysplasias, hyperplasias as well as neoplasms showing metastatic growth or any other transformations,e.g., leukoplakias which often precede a breakout of cancer.

[0123] In some embodiments, the compounds or compositions described herein can be used for treating inflammatory disorders, such as asthma (Kumar, M., Ahmad, T., Sharma, A. et al. Let-7microRNA-mediated regulation of IL-13 and allergic airway inflammation. J. Allergy Clin. Immunol. 128(5), 1077-1085 (2011)), chronic obstructive pulmonary disease (COPD) (Van Pottelberge, G.R., Mestdagh, P., Bracke, K.R. et al. MicroRNA Expression in Induced Sputum of Smokers and Patients with Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med.183, 898-906, (2010); Conickx, G., Cogos, F.A., van den Berge, M. et al. Sci Rep 7, 12871 (2017)), endometriosis (Sahin, C., Mamillapalli, R., Yi, K.W., and Taylor, H.S. microRNA Let-7b: A Novel treatment for endometriosis. J Cell Mol Med.22, 5346-5353 (2018)), and the like.

[0124] In some embodiments, the compounds or compositions described herein can be used for treating atherosclerosis, such as diabetes-associated atherosclerosis (Brennan, E., Wang, Bo., McClelland, A. et al. Protective Effect of let-7 miRNA Family in Regulating Inflammation in Diabetes-Associated Atherosclerosis. Diabetes 66, 2266-2277 (2017)).

[0125] In some embodiments, the compounds or compositions described herein can be used for treating liver diseases (McDaniel, K., Hall, C., Sato, K. et al. Lin28 and let-7: roles and regulation in liver diseases. Am J Physiol Gastrointes Liver Physiol.310(10), G757 (2016)). Examples of liver diseases include, but are not limited to, liver fibrosis (Matsuura K., De Giorgi, V., Schechterly, C. et al. Circulating let-7 levels in plasma and extracellular vesicles correlate with hepatic fibrosis progression in chronic hepatitis C. Hepatology 64(3), 732-745 (2016); Matsuura K., Aizawa, N., Enomoto, H., et al. Circulating let-7 Levels in Serum Correlate With the Severity of Hepatic Fibrosis in Chronic Heptatis C. Open Forum Infectious Diseases 5, 11 (2018); Zhang, Y., Guo, J., Li, Y. et al. let-7a suppresses liver fibrosis via TGFβ / SMAD signaling transduction pathway. Experimental and Therapeutic Medicine 17, 3935-3942 (2019)), hepatitis, alcoholic liver disease (ALD) (McDanile K., Huang L., Sato, K. et al. The let-7 / Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury. J. Biol. Chem.292(27), 11336-11347 (2017)), nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), biliary diseases (e.g., primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)), polycystic liver diseases (PCLD), and the like.

[0126] In some embodiments, the compounds or compositions described herein can be used for treating kidney diseases, such as renal fibrosis (Wang, B., Ja, J.C., Hagiwara, S. et al. Transforming growth factor-β1-mediated renal fibrosis is dependent on the regulation of transforming growth factor receptor 1 expression by let-7b. Kidney International, 85, 352-361 (2014); Nagai, T., Kanasaki, M., Srivastava, S.P. et al. N-acetyl-seryl-aspartyl-lysyl-proline Inhibits Diabetes-Associated Kidney Fibrosis and Endothelial-Mesenchymal Transition. BioMed Research International, 2014, 696475 (2014); Brenna, E.P., Nolan, K.A., Borgeson, E. et al. Lipoxins Attenuate Renal Fibrosis by Inducing let-7c and Suppressing TGFβR1. J Am Soc Nephrol 24, 627-637 (2013)), diabetic nephropathy ( Bhatt, K., Kato, Mi., and Natarajan, R. Mini-review: emerging roles of microRNAs in the pathophysiology of renal diseases. Am J Physiol Renal Physiol 310, F109-F118 (2016); Park, J.T., Kato, M., Lating, L. et al. Repression of let-7 by transforming growth factor-β1-induced Lin28upregulates collagen expression in glomerular mesangial cells under diabetic conditions. Am J Physiol Renal Physiol, 307, F1390-F1403 (2014)), chronic kidney disease (CKD) (Lv, W., Fan, F., Wang, Y. et al. Therapeutic potential of microRNAs for the treatment of renal fibrosis and CKD. Physiol Genomics.50(1), 20-34 (2018)), diabetic kidney disease (DKD) (Kato, M. Noncoding RNAs as therapeutic targets in early stage diabetic kidney disease. Kidney Res Clin Pract 37, 197-200 (2018)).

[0127] In some embodiments, the compounds or compositions described herein can be used for treating systemic scleroderma (SSc) (see, for example, Makino, K., Jinnin, M., Hirano, A. et al. The Downregulation of microRNA let-7a Contributes to the Excessive Expression of Type I Collagen in Systemic and Localized Scleroderma. J Immunol 190, 3905-3915 (2013)). In some embodiments, the compounds or compositions described herein can be used for treating pulmonary hypertension in patients with systemic scleroderma (SSc) (Izumiya, Y., Jinnn, M., Kimura, Y. et al. Expression of Let-7 family microRNAs in skin correlates negatively with severity of pulmonary hypertension in patients with systemic scleroderma. IJC Heart & Vasculature 8, 98-102 (2015)).

[0128] In some embodiments, the compounds or compositions described herein can be used for treating lung fibrosis (Huleihel, L., Ben-Yehudah, A., Milosevic, J. et al. Let-7d microRNA affects mesenchymal phenotypic properties of lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 306, L534-542 (2014)), such as idiopathic pulmonary fibrosis (IPF) (Liang, H., Liu, S., Chen, Y. et al. miR-26a suppresses EMT by disrupting the Lin28B / let-7d axis: potential cross-talks among miRNAs in IPF. J. Mol. Med.94, 655-665 (2016); Pandit, K.V., Corcoran, D., Yousef, H. et al. Inhibition and Role of Let-7d in Idiopathic Pulmonary Fibrosis. Am J respire Crit Care Med 182, 220-229 (2010)).

[0129] In some embodiments, the compounds or compositions described herein can be used for treating multiple sclerosis (Angelou, C.C., Wells, A.C., Vijayaraghavan, J. et al. Differentiation of Pathogenic Th17 Cells Is Negative Regulated by Let-7 MicroRNAs in a Mouse Model of Multiple Sclerosis. Front. Immunol.10, 3125 (2019); Kimura, K., Hohjoh, H., Fukuoka, M. et al. Circulating exosomes suppress the induction of regulatory T cells via let-7i in multiple sclerosis. Nature Communications 9, 17 (2018)).

[0130] In some embodiments, the compounds or compositions described herein can be used in preventing bone loss and / or stimulating bone healing in a subject in need thereof. In certain embodiments, the compounds or compositions described herein can be used in accelerating fracture healing, including bone regeneration in large bony defects, prevention and / or treatment of osteoarthritis and other osteopathy-related conditions (e.g., inflammation-induced bone loss associated with aging and rheumatoid arthritis), prevention and / or treatment of osteogenesis imperfect and osteomalacia, spinal fusion, and craniofacial re-construction of the mandible, maxilla, and cranial bones (Ansari, M.Y., Khan, N.M., Ahmad, N. et al. Genetic Inactivation of ZCCHC6 Suppresses Interleukin-6 Expression and Reduces the Severity of Experimental Osteoarthritis in Mice. Arthritis &Rheumatology 71 (4), pp583-593 (2019); US2019 / 0101533; US2019 / 0101533; WO 2017 / 156557; and WO 2018 / 005608).

[0131] In some embodiments, the compounds or compositions described herein can be used in treating IL-6 mediated diseases, for example, those described in US756011, US2012 / 0253016 and WO 92 / 19759, all of which are incorporated by reference herein. Examples of IL-6 mediated diseases include, but are not limited to, rheumatoid arthritis, juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, Castleman's disease, systemic lupus erythematosus (SLE), lupus nephritis, Crohn's disease, lymphoma, ulcerative colitis, anemia, vasculitis, Kawasaki disease, Still's disease, amyloidosis, multiple sclerosis, transplantation, age-related macular degeneration, ankylosing spondylitis, psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease (COPD), IgA nephropathy, osteoarthritis, asthma, diabetic nephropathy, GVHD, endometriosis, hepatitis (NASH), myocardial infarction, arteriosclerosis, sepsis, osteoporosis, diabetes, multiple myeloma, prostate cancer, kidney cancer, B-cell non-Hodgkin's lymphoma, pancreatic cancer, lung cancer, esophageal cancer, colon cancer, cancer cachexia, cancer neuroinvasion, myocardial infarction, myopic choroidal neovascularization, idiopathic choroidal neovascularization, uveitis, chronic thyroiditis, delayed hypersensitivity, contact dermatitis, atopic dermatitis, mesothelioma, polymyositis, dermatomyositis, panuveitis, anterior uveitis, intermediate uveitis, scleritis, keratitis, orbital inflammation, optic neuritis, diabetic retinopathy, proliferative vitreoretinopathy, dry eye, and post-operative inflammation.

[0132] In some embodiments, the IL-6 mediated diseases is an IL-6 mediated immune related disease selected from rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis, gastric ulcer, seronegative arthropathies, osteoarthritis, osteolysis, aseptic loosening of orthopedic implants, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, antiphospholipid syndrome, iridocyclitis / uveitis / optic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis / wegener's granulomatosis, sarcoidosis, orchitis / vasectomy reversal procedures, allergic / atopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, trauma / hemorrhage, burns, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathologies, sarcoidosis, Crohn's pathology, sickle cell anemia, diabetes, nephrosis, atopic diseases, hypersensitity reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphalaxis, dermatitis, pernicious anemia, hemolytic disesease, thrombocytopenia, graft rejection of any organ or tissue, kidney transplant rejection, heart transplantrejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT) rejection, skin allograft rejection, cartilage transplant rejection, bone graft rejection, small bowel transplant rejection, fetal thymus implant rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reactions, Graves disease, Raynaud's disease, type B insulin-resistant diabetes, asthma, myasthenia gravis, antibody-meditated cytotoxicity, type III hypersensitivity reactions, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes syndrome, antiphospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison's disease, diabetes mellitus, chronic active hepatitis, primary billiary cirrhosis, vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, drug sensitivity, metabolic / idiopathic, Wilson's disease, hemachromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, hashimoto's thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis evaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial hematophagocytic lymphohistiocytosis, dermatologic conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, hemodialysis, uremia, toxicity and preeclampsia.

[0133] In some embodiments, the IL-mediated disease is a cardiovascular disease, such as cardiac stun syndrome, myocardial infarction, congestive heart failure, stroke, ischemic stroke, hemorrhage, acute coronary syndrome, arteriosclerosis, atherosclerosis, restenosis, diabetic aterioscierotic disease, hypertension, arterial hypertension, renovascular hypertension, syncope, shock, syphilis of the cardiovascular system, heart failure, cor pulmonale, primary pulmonary hypertension, cardiac arrhythmias, atrial ectopic beats, atrial flutter, atrial fibrillation (sustained or paroxysmal), post perfusion syndrome, cardiopulmonary bypass inflammation response, chaotic or multifocal atrial tachycardia, regular narrow QRS tachycardia, specific arrythmias, ventricular fibrillation, His bundle arrythmias, atrioventricular block, bundle branch block, myocardial ischemic disorders, coronary artery disease, angina pectoris, myocardial infarction, cardiomyopathy, dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart diseases, endocarditis, pericardial disease, cardiac tumors, aordic and peripheral aneuryisms, aortic dissection, inflammation of the aorta, occlusion of the abdominal aorta and its branches, peripheral vascular disorders, occlusive arterial disorders, peripheral atherlosclerotic disease, thromboangitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and disease, acrocyanosis, erythromelalgia, venous diseases, venous thrombosis, varicose veins, arteriovenous fistula, lymphederma, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemia-reperfusion injury, and the like.

[0134] In some embodiments, the IL-mediated disease is an infectious disease, such as, acute or chronic bacterial infection, acute and chronic parasitic or infectious processes, including bacterial, viral and fungal infections, HIV infection / HIV neuropathy, meningitis, hepatitis (e.g., A, B or C, or the like), septic arthritis, peritonitis, pneumonia, epiglottitis, E. coli O157:h7, hemolytic uremic syndrome / thrombolytic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, leprosy, toxic shock syndrome, streptococcal myositis, gas gangrene, mycobacterium tuberculosis, mycobacterium avium intracellulare, pneumocystis carinii pneumonia, pelvic inflammatory disease, orchitis / epidydimitis, legionella, lyme disease, influenza a, epstein-barr virus, viral-associated hemaphagocytic syndrome, viral encephalitis / aseptic meningitis, and the like.

[0135] In some embodiments, the IL-mediated disease is a malignant disease, such as, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), acute lymphocytic leukemia, B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML), acute myelogenous leukemia, chromic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome (MDS), a lymphoma, Hodgkin's disease, a malignant lymphoma, non-Hodgkin’s lymphoma, Burkett’s lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal carcinoma, pancreatic carcinoma, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic syndrome / hypercalcemia of malignancy, solid tumors, bladder cancer, breast cancer, colorectal cancer, endometrial cancer, head cancer, neck cancer, hereditary nonpolyposis cancer, Hodgkin's lymphoma, liver cancer, lung cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, testicular cancer, adenocarcinomas, sarcomas, malignant melanoma, hemangioma, metastatic disease, cancer related bone resorption, cancer related bone pain, and the like.

[0136] In some embodiments, the IL-mediated disease is a neurologic disease, such as, neurodegenerative diseases, multiple sclerosis, migraine headache, AIDS dementia complex, demyelinating diseases, such as multiple sclerosis and acute transverse myelitis; extrapyramidal and cerebellar disorders, such as lesions of the corticospinal system; disorders of the basal ganglia; hyperkinetic movement disorders, such as Huntington's Chorea and senile chorea; drug-induced movement disorders, such as those induced by drugs which block CNS dopamine receptors; hypokinetic movement disorders, such as Parkinson's disease; Progressive supranucleo Palsy; structural lesions of the cerebellum; spinocerebellar degenerations, such as spinal ataxia, Friedreich's ataxia, cerebellar cortical degenerations, multiple systems degenerations (Mencel, Dejerine-Thomas, Shi-Drager, and Machado-Joseph); systemic disorders (Refsum's disease, abetalipoprotemia, ataxia, telangiectasia, and mitochondrial multi-system disorder); demyelinating core disorders, such as multiple sclerosis, acute transverse myelitis; and disorders of the motor unit' such as neurogenic muscular atrophies (anterior horn cell degeneration, such as amyotrophic lateral sclerosis, infantile spinal muscular atrophy and juvenile spinal muscular atrophy); Alzheimer's disease; Down'sSyndrome in middle age; Diffuse Lewy body disease; Senile Dementia of Lewy body type; Wernicke- Korsakoff syndrome; chronic alcoholism; Creutzfeldt-Jakob disease; Subacute sclerosing panencephalitis, Hallerrorden-Spatz disease; Dementia pugilistica; neurotraumatic injury (e.g., spinal cord injury, brain injury, concussion, repetitive concussion); pain; inflammatory pain; autism; depression; stroke; cognitive disorders; epilepsy; and the like.

[0137] In some embodiments, the IL-mediated disease includes, for example, bodily injury or a trauma associated with oral surgery including periodontal surgery, tooth extraction(s), endodontic treatment, insertion of tooth implants, application and use of tooth prosthesis; or wherein the wound is selected from the group consisting of aseptic wounds, contused wounds, incised wounds, lacerated wounds, non-penetrating wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, infarctions and subcutaneous wounds; or wherein the wound is selected from the group consisting of ischemic ulcers, pressure sores, fistulae, severe bites, thermal burns and donor site wounds; or wherein the wound is an aphthous wound, a traumatic wound or a herpes associated wound.

[0138] The dose for the treatment methods described herein above ranges from 1 µg to 1000 mg of compound or pharmaceutically acceptable salt thereof per kg of subject body mass. EXEMPLIFICATION

[0139] Abbreviations: d doublet dd doublet of doublet m multiplet s singlet t triplet q quartet brs / bs broad singlet dd doublet of doublet td triplet of doublet dt doublet of triplet DEAD diethyl azadicarboxylate DCM dichloromethane DIPEA N,N-diisopropylethylamine DMF N, N-dimethyl formamide DMSO dimethyl sulfoxide eq equivalent (s) g gram (s)h hour (s) NaH sodium hydride THF tetrahydrofuran BBr3 boron tribromide CDI carbonyl diimidazole EtOAc ethyl acetate ACN acetonitrile TLC thin layer chromatography RT room temperature °C degree Celsius mmol millimoles µmol micromoles ESI electrospray ionization EtOAc ethyl acetate HCl hydrochloric acid IPA isopropyl alcohol K2CO3potassium carbonate LiOH lithium hydroxide MeOH methanol MS mass spectrometry RBF round bottomed flask TEA triethyl amine General Analytical methods LC-MS conditionsPrep. HPLC conditionsHPLC conditionsExample 1: Synthesis of (R)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-7-(2-((pyridin-2- yloxy)methyl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of 3,4,6-trifluoro-2-methylbenzoyl chlorideTo a mixture of 3,4,6-trifluoro-2-methylbenzoic acid (100 mg, 0.52 mmol, 1.0 equiv) and (COCl)2(133 mg, 1.05 mmol, 2.0 equiv) in DCM (2 mL) was added DMF (0.1 mL) at 0 °C. The resulting mixture was stirred overnight at 25 °C. The resulting mixture was concentrated under vacuum. The residue was used for next step directly. Step 2. Synthesis of ethyl 3-oxo-3-(3,4,6-trifluoro-2-methylphenyl)propanoateTo a mixture of 3,4,6-trifluoro-2-methylbenzoyl chloride (100 mg, 0.48 mmol, 1.0 equiv) and 1-ethyl 3-potassium propanedioate (163 mg, 0.96 mmol, 2.0 equiv) in MeCN (5 mL) was added TEA (97 mg, 0.96 mmol, 2.0 equiv) and MgCl2(91 mg, 0.96 mmol, 2.00 equiv). The resulting mixture was stirred for 4 h at 25 °C. The resulting mixture was concentrated under vacuum. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 4 with HCl (aq.). The aqueous layer was extracted with methylbenzene (10 mL x 3). The organic solution was concentrated under vacuum. This resulted in ethyl 3-oxo-3-(3,4,6-trifluoro-2-methylphenyl)propanoate (100 mg, 80.15%) as a yellow oil. Step 3. Synthesis of Ethyl 1-cyclopropyl-6,7-difluoro-5-methyl-4-oxoquinoline-3-carboxylateTo a mixture of ethyl 3-oxo-3-(3,4,6-trifluoro-2-methylphenyl)propanoate (100 mg, 0.38 mmol, 1.0 equiv) in acetic anhydride (117 mg, 1.15 mmol, 3.0 equiv) was added triethyl orthoformate (85 mg, 0.57 mmol, 1.5 equiv). The resulting mixture was stirred for 2 h at 100 °C. The resulting mixture was concentrated under vacuum. Then the resulting mixture in DMSO (3 mL) was added aminocyclopropane (22 mg, 0.38 mmol, 1.0 equiv). The resulting mixture was stirred for 2 h at 25 °C. Then, the resulting mixture was added K2CO3(26 mg, 0.19 mmol, 0.5 equiv). The resulting mixturewas stirred for 1 h at 100 °C. The reaction was quenched by the addition of 20 mL water. The precipitated solids were collected by filtration. This resulted in ethyl 1-cyclopropyl-6,7-difluoro-5- methyl-4-oxoquinoline-3-carboxylate (100 mg, 84.68%) as a yellow solid. Step 4. Synthesis of 1-cyclopropyl-6,7-difluoro-5-methyl-4-oxoquinoline-3-carboxylic acidTo a mixture of ethyl 1-cyclopropyl-6,7-difluoro-5-methyl-4-oxoquinoline-3-carboxylate (100 mg, 0.325 mmol, 1.0 equiv) in THF (2 mL) and H2O (0.5 mL) was added LiOH (39 mg, 1.62 mmol, 5.0 equiv). The resulting mixture was stirred overnight at 25 °C. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 4 with HCl (aq.). The precipitated solids were collected by filtration and washed with water (10 mL x 3). This resulted in 1-cyclopropyl-6,7- difluoro-5-methyl-4-oxoquinoline-3-carboxylic acid (90 mg, 99.0%) as a yellow solid. Step 5. Synthesis of 1-cyclopropyl-6-fluoro-5-methyl-4-oxo-7-[(2R)-2-[(pyridin-2- yloxy)methyl]pyrrolidin-1-yl]quinoline-3-carboxylic acidTo a mixture of 1-cyclopropyl-6,7-difluoro-5-methyl-4-oxoquinoline-3-carboxylic acid (40 mg, 0.14 mmol, 1.0 equiv) in DMSO (2 mL) was added 2-[(2R)-pyrrolidin-2-ylmethoxy]pyridine (25 mg, 0.14 mmol, 1.0 equiv). The resulting mixture was stirred for 1 h at 100 °C. The mixture was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column,, 5um,19*150mm ; Mobile Phase A:Water(0.05%FA), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:48 B to 67 B in 8 min; 254 nm; RT1:7.02; RT2:; Injection Volumn: ml; Number Of Runs:;) to afford 1-cyclopropyl-6-fluoro-5-methyl-4-oxo-7-[(2R)-2-[(pyridin-2-yloxy)methyl]pyrrolidin-1- yl]quinoline-3-carboxylic acid (11.6 mg) as a yellow solid. LCMS (ESI) [M+H]+: 438.11H NMR (300 MHz, DMSO-d6) δ 15.99 (s, 1H), 8.56 (s, 1H), 8.14 – 7.99 (m, 1H), 7.75 – 7.63 (m, 1H), 7.19 (d, J = 8.1 Hz, 1H), 6.99 – 6.89 (m, 1H), 6.77 – 6.70 (m, 1H), 4.65 (s, 1H), 4.51 – 4.40 (m, 1H), 4.38 –4.20 (m, 1H), 3.71 (d, J = 25.2 Hz, 2H), 3.53 (d, J = 8.7 Hz, 1H), 2.74 (d, J = 3.5 Hz, 3H), 2.20 – 1.88 (m, 4H), 1.24 (d, J = 6.3 Hz, 2H), 1.18 – 0.91 (m, 2H). Potency Lin28a-dep Z11 IC50(µM) + Example 2: Synthesis of (R)-6-chloro-4-oxo-7-(2-((pyridin-2-yloxy)methyl)pyrrolidin-1-yl)-1- (pyrimidin-2-yl)-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of 5-chloro-2,4-difluorobenzoyl chlorideTo a stirred mixture of 5-chloro-2,4-difluorobenzoic acid (5.0 g, 26.0 mmol, 1.0 equiv) and (COCl)2(19.8 g, 155.80 mmol, 6.0 equiv) in DCM (50 mL) was added DMF (1 mL) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. Step 2. Synthesis of ethyl 3-(5-chloro-2,4-difluorophenyl)-3-oxopropanoateTo a stirred mixture of 1-ethyl 3-potassium propanedioate (8.07 g, 47.41 mmol, 2.00 equiv) and MgCl2(5.64 g, 49.25 mmol, 2.5 equiv) in MeCN (100 mL) was added TEA (4.80 g, 47.41 mmol, 2.0 equiv) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. To the above mixture was added 5-chloro-2,4- difluorobenzoyl chloride (5.0 g, 23.70 mmol, 1.00 equiv) in portions at 0 °C. The resulting mixturewas stirred for additional 2.5 h at room temperature. The mixture was acidified to pH 5 with conc. HCl. The resulting mixture was extracted with toluene (40 mL x 3). The combined organic layers were washed with water (20 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with hexane / EtOAc (6:1) to afford ethyl 3-(5-chloro-2,4-difluorophenyl)-3-oxopropanoate (3.1g, 48%) as a white solid. LCMS (ESI) [M+H]+: 263.1. Step 3. Synthesis of ethyl 6-chloro-7-fluoro-4-oxo-1-(pyrimidin-2-yl)quinoline-3-carboxylateA solution of ethyl 3-(5-chloro-2,4-difluorophenyl)-3-oxopropanoate (2.0 g, 7.62 mmol, 1.0 equiv) and triethyl orthoformate (1.7 g, 11.40 mmol, 1.5 equiv) in Ac2O (2.3 g, 22.85 mmol, 3.0 equiv) was stirred for 1.5 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (20 mL). To the above mixture was added 2- aminopyrimidine (720 mg, 7.62 mmol, 1.0 equiv) in portions over 2 min at room temperature. The resulting mixture was stirred overnight at room temperature. To the above mixture was added K2CO3(530 mg, 3.81 mmol, 0.5 equiv) in portions at room temperature. The resulting mixture was stirred for additional 2 h at 40 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (15 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford ethyl 6-chloro-7-fluoro-4-oxo-1-(pyrimidin-2-yl)quinoline-3-carboxylate (500 mg, 19%) as a red solid. LCMS (ESI) [M+H]+: 348.1. Step 4. Synthesis of 6-chloro-7-fluoro-4-oxo-1-(pyrimidin-2-yl)quinoline-3-carboxylic acidA mixture of ethyl 6-chloro-7-fluoro-4-oxo-1-(pyrimidin-2-yl)quinoline-3-carboxylate (300 mg, 0.86 mmol, 1.0 equiv) and LiOH (83 mg, 3.45 mmol, 4.0 equiv) in THF (4.0 mL) and H2O (1.0 mL) was stirred for 5 h at room temperature under nitrogen atmosphere. The mixture was acidified to pH 6 with conc. HCl. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organiclayers were washed with water (5 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was washed with (5 mL x 3) of hexane / EtOAc (5:1), to afford 6-chloro-7-fluoro-4-oxo-1-(pyrimidin-2-yl)quinoline-3-carboxylic acid (160 mg, 58%) as a red solid. LCMS (ESI) [M+H]+: 320.2. Step 5. Synthesis of 6-chloro-4-oxo-7-[(2R)-2-[(pyridin-2-yloxy)methyl]pyrrolidin-1-yl]-1- (pyrimidin-2-yl)quinoline-3-carboxylic acidA solution of 6-chloro-7-fluoro-4-oxo-1-(pyrimidin-2-yl)quinoline-3-carboxylic acid (80 mg, 0.25 mmol, 1.0 equiv) and 2-[(2R)-pyrrolidin-2-ylmethoxy]pyridine (357 mg, 2.00 mmol, 8.0 equiv) in DMSO (4.0 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column,, 5um,19*150mm ; Mobile Phase A:Water(0.05%FA), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:42 B to 73 B in 8 min; 254 nm; RT1:7.67) to afford 6-chloro-4-oxo-7-[(2R)-2-[(pyridin-2- yloxy)methyl]pyrrolidin-1-yl]-1-(pyrimidin-2-yl)quinoline-3-carboxylic acid (25.7 mg, 21.5%) as a yellow solid. LCMS (ESI) [M+H]+: 478.1.1H NMR (300 MHz, DMSO-d6) δ 14.73 (s, 1H), 9.18 (s, 1H), 8.98 (s, 2H), 8.14 (s, 1H), 8.00 – 7.85 (m, 1H), 7.74 (s, 1H), 7.67 – 7.53 (m, 1H), 7.47 (s, 1H), 6.87 (t, J = 5.7 Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 4.58 (s, 1H), 4.40 – 4.11 (m, 2H), 3.74 (s, 1H), 3.33 – 3.30 (m, 1H), 2.23 (s, 1H), 2.10 – 1.65 (m, 3H). Potency Lin28a-dep Z11 IC50(µM) +++ Example 3: Synthesis of (R)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(2-((pyridin-2- yloxy)methyl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of 2,4,5-trifluoro-3-methoxybenzoyl chlorideTo a solution of 2,4,5-trifluoro-3-methoxybenzoic acid (500 mg, 2.43 mmol, 1.0 equiv) in toluene (8.0 mL) at 0 °C was added SOCl2 (866 mg, 7.28 mmol, 3.0 equiv). The resulting mixture was stirred overnight at 25 °C. The resulting mixture was concentrated under vacuum. This resulted in 2,4,5- trifluoro-3-methoxybenzoyl chloride (500 mg, crude) as a yellow semi-solid. Step 2. Synthesis of ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoateA stirred solution of 1-ethyl 3-potassium propanedioate (758 mg, 4.45 mmol, 2.0 equiv) in anhydrous acetonitrile (10 mL) under nitrogen was cooled to 10-15 °C. To this mixture was added TEA (451 mg, 4.45 mmol, 2.0 equiv) followed by MgCl2 (530 mg, 5.57 mmol, 2.5 equiv), and stirring continued at 20-25 °C for 2.5 h. The resultant slurry was re-cooled to 0 °C and 2,4,5-trifluoro-3-methoxybenzoyl chloride (500 mg, 2.23 mmol, 1.0 equiv) added dropwise over 15 min followed by the addition of TEA (23 mg, 0.22 mmol, 0.1 equiv). The mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure to remove acetonitrile. Toluene (8 mL) was added and the mixture concentrated under reduced pressure. More toluene (8 mL) was added and the mixture stirred and cooled to 10-15 °C. Aqueous HCl (13%, 10 mL) was added while the temperature was kept below 25 °C. The aqueous layer was separated and the organic layer washed with aqueous HCl (12%, 10 mL) followed by water (8 mL) and then concentrated under reduced pressure to give ethyl 3-oxo-3- (2,4,5-trifluoro-3-methoxyphenyl)propanoate (1.0 g, crude) as a yellow oil. LCMS (ESI) [M+H]+: 276.Step 3. Synthesis of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxoquinoline-3-carboxylateTo a mixture of ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate (1.0 g, 3.62 mmol, 1.0 equiv) in acetic anhydride (1.1 g, 10.86 mmol, 3.0 equiv) was added triethyl orthoformate (0.8 g, 5.43 mmol, 1.5 equiv). The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under vacuum. To the resulting mixture in DMSO (12 mL) was added aminocyclopropane (0.2 g, 3.62 mmol, 1.0 equiv). The resulting mixture was stirred at 25 °C for 2 h. To the resulting mixture was added K2CO3(0.3 g, 1.81 mmol, 0.5 equiv). The resulting mixture was stirred at 100 °C for 1 h. The reaction was quenched by the addition of 15 mL water. The precipitated solids were collected by filtration. This resulted in ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4- oxoquinoline-3-carboxylate (300 mg, 26 %) as a yellow solid. LCMS (ESI) [M+H]+: 324. Step 4. Synthesis of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxoquinoline-3-carboxylic acidTo a mixture of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxoquinoline-3-carboxylate (300 mg, 0.93 mmol, 1.0 equiv) in THF (5.0 mL) was added LiOH (89 mg, 3.71 mmol, 4.0 equiv) and H2O (1.0 mL). The resulting mixture was stirred for 3 h at room temperature. The mixture was neutralized to pH 6 with HCl (aq.). The resulting mixture was filtered. This resulted in 1-cyclopropyl-6,7-difluoro-8- methoxy-4-oxoquinoline-3-carboxylic acid (250 mg, 91 %) as a white solid. LCMS (ESI) [M+H]+: 296. Step 5. Synthesis of 1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-[(2R)-2-[(pyridine-2- yloxy)methyl]pyrrolidin-1-yl]quinoline-3-carboxylic acidTo a mixture of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid (220 mg, 0.75 mmol, 1.0 equiv) in DMSO (8.0 mL) was added 2-[(2R)-pyrrolidin-2-ylmethoxy]pyridine (199 mg, 1.12 mmol, 1.5 equiv). The resulting mixture was stirred for 48 h at 80 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 5um,19*150mm;Mobile Phase A:Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 60% B to 90% B in 8 min; 254 / 220 nm; Rt: 7.31 min) to afford 1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-[(2R)-2-[(pyridin-2-yloxy)methyl]pyrrolidin-1- yl]quinoline-3-carboxylic acid (56.9 mg, 16.84%) as a light yellow solid. LCMS (ESI) [M+H]+: 454.35.1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.04 – 7.95 (m, 1H), 7.68 – 7.53 (m, 2H), 6.88 (d, J = 7.1, 5.0, 1.0 Hz, 1H), 6.55 (s, 1H), 4.62 – 4.53 (m, 1H), 4.36 – 4.21 (m, 2H), 4.14 (d, J = 7.4, 4.0 Hz, 1H), 3.92 – 3.83 (m, 1H), 3.59 (s, 3H), 3.37 (s, 1H), 2.37 – 2.21 (m, 1H), 2.06 (d, J = 12.5 Hz, 1H), 2.01 – 1.72 (m, 2H), 1.29 – 1.06 (m, 2H), 0.99 – 0.67 (m, 2H). Potency Lin28a-dep Z11 IC50(µM) + Example 4: Synthesis of (R)-6-fluoro-4-oxo-7-(2-(phenoxymethyl)pyrrolidin-1-yl)-1-phenyl-1,4- dihydroquinoline-3-carboxylic acidStep 1. Synthesis of tert-butyl (2R)-2-(2-chlorophenoxymethyl)pyrrolidine-1-carboxylateTo a mixture of phenol (3.0 g, 31.87 mmol, 1.0 equiv), tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine- 1-carboxylate (6.4 g, 31.87 mmol, 1.0 equiv) and PPh3(16.7 g, 63.75 mmol, 2.0 equiv) in THF (50 mL) was added DIAD (8.2 g, 63.75 mmol, 2.0 equiv). The resulting solution was stirred overnight at 25 °C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluting with 5- 60% acetonitrile in water to afford tert-butyl (2R)-2- (phenoxymethyl)pyrrolidine (1.1 g, 20%) as colorless oil. LCMS (ESI) [M+H]+: 278.1Step 2. Synthesis of (2R)-2-(phenoxymethyl)pyrrolidineTo a mixture of tert-butyl (2R)-2-(phenoxymethyl)pyrrolidine (500 mg, 1.60 mmol, 1.0 equiv) in DCM (10 mL) was added TFA (2 mL). The resulting solution was stirred for 1 h at 25 °C. The resulting mixture was concentrated. This resulted in (2R)-2-(phenoxymethyl)pyrrolidine (840 mg, crude) as yellow oil. LCMS (ESI) [M+H]+:178.1. Step 3. Synthesis of 6-fluoro-4-oxo-7-[(2R)-2-(phenoxymethyl)pyrrolidin-1-yl]-1- phenylquinoline-3-carboxylic acidTo a mixture of 6,7-difluoro-4-oxo-1-phenylquinoline-3-carboxylic acid (100 mg, 0.33 mmol, 1.0 equiv) in DMSO (2 mL) was added (2R)-2-(phenoxymethyl)pyrrolidine (58 mg, 0.33 mmol, 1.0 equiv). The resulting solution was stirred for 1 h at 80 °C. The precipitated solids were collected and purified by Prep.-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column,, 5um,19*150mm ; Mobile Phase A:Water(0.05%FA), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:50 B to 75 B in 8 min; 254 nm; RT1:6.86). This resulted in 6-fluoro-4-oxo-7-[(2R)- 2-(phenoxymethyl)pyrrolidin-1-yl]-1-phenylquinoline-3-carboxylic acid (59.4 mg 39.0%) as a yellow solid. LCMS (ESI) [M+H]+: 459.1.1H NMR (300 MHz, DMSO-d6) δ 15.41 (s, 1H), 8.53 (s, 1H), 7.92 (d, J = 14.5 Hz, 1H), 7.66 (m, 4H), 7.41 (t, J = 7.7 Hz, 1H), 7.26 (t, J = 7.7 Hz, 2H), 6.94 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 8.0 Hz, 2H), 6.09 (d, J = 7.5 Hz, 1H), 4.34 – 4.24 (m, 1H), 3.90 (q, J = 3.7 Hz, 1H), 3.82 (t, J = 8.4 Hz, 1H), 3.38 – 3.36 (m, 1H), 3.27 – 3.14 (m, 1H), 2.20 – 1.76 (m, 4H). Potency Lin28a-dep Z11 IC50(µM) + Example 5: Synthesis of (R)-6-fluoro-7-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)- 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acidTo a mixture of ethyl 3-oxo-3-(2,4,5-trifluorophenyl)propanoate (5.0 g, 20.31 mmol, 1.0 equiv), in acetic anhydride (6.2 g, 60.93 mmol, 3.0 equiv) was added triethyl orthoformate (4.5 g, 30.46 mmol, 1.5 equiv). The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under vacuum. To the resulting mixture in DMSO (50 mL) was added aniline (2.2 g, 24.37 mmol, 1.2 equiv), The resulting mixture was stirred at 25 °C for 2 h. To the resulting mixture was added K2CO3(2.8 g, 20.31 mmol, 1.0 equiv). The resulting mixture was stirred at 100 °C for 1 h. The reaction was quenched by the addition of 500 mL water. The precipitated solids were collected by filtration. This resulted in ethyl 6,7-difluoro-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylate (4.7 g 70.2%) as a yellow solid. LCMS (ESI) [M+H]+: 330.1. Step 2. Synthesis of 6,7-difluoro-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acidTo a mixture of ethyl 6,7-difluoro-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylate (2.0 g, 6.07 mmol, 1.0 equiv) in THF (100 mL) and H2O (10 mL) was added LiOH (1.1 g, 48.58 mmol, 8.0 equiv). The resulting mixture was stirred at 25 °C overnight. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 4 with HCl (aq.). The precipitated solids were collected by filtration and washed with water (50 mL x 3). This resulted in 6,7-difluoro-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid (1.6 g 89.6%) as a yellow solid. LCMS (ESI) [M+H]+: 302.1 Step 3. Synthesis of (R)-6-fluoro-7-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo- 1-phenyl-1,4-dihydroquinoline-3-carboxylic acidTo a solution of 6,7-difluoro-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid (100 mg, 0.33 mmol, 1.0 equiv) in DMSO (10 mL) was added (R)-3-methyl-2-(pyrrolidin-2-ylmethoxy)pyridine (63 mg, 0.33 mmol, 1.0 equiv). The resulting solution was stirred for 1 h at 100 °C. The mixture was purified by Prep.-HPLC (Column: SunFire Prep C18 OBD Column, 19×150mm 5um 10nm; Mobile Phase A:Water(0.05%FA), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:52 B to 82 B in 8 min; 254 / 220 nm; RT1:7.77; RT2:; Injection Volumn: ml; Number Of Runs:;). This resulted in (R)-6- fluoro-7-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1-phenyl-1,4- dihydroquinoline-3-carboxylic acid (42.6 mg, 27%) as a yellow solid. LCMS (ESI) [M+H]+: 474.1.1H NMR (300 MHz, DMSO-d6) δ 15.51 – 15.37 (m, 1H), 8.54 – 8.50 (m, 1H), 7.95 – 7.82 (m, 2H), 7.73 – 7.55 (m, 4H), 7.54 – 7.41 (m, 2H), 6.93 – 6.82 (m, 1H), 6.09 – 5.99 (m, 1H), 4.47 – 4.34 (m, 1H), 4.30 – 4.16 (m, 2H), 3.36 – 3.35 (m, 1H), 3.24 – 3.11 (m, 1H), 2.15 – 1.84 (m, 7H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 6: Synthesis of (R)-7-(2-(((3-ethylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-6-fluoro-4- oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of tert-butyl (2R)-2-[[(3-iodopyridin-2-yl)oxy]methyl]pyrroledine-1- carboxylateTo a mixture of 2-fluoro-3-iodopyridine (5.0 g, 22.42 mmol, 1.0 equiv) in THF (50 mL) was added NaH (1.6 g, 67.26 mmol, 3.0 equiv) and tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (22.56 g, 112.11 mmol, 1.0 equiv). The resulting mixture was stirred overnight at 70 °C. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were collected and dried with anhydrous Na2SO4. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with Petroleum ether / EtOAc (1:1). This resulted in tert-butyl (2R)-2-[[(3-iodopyridin-2- yl)oxy]methyl]pyrrolidine-1-carboxylate (5.2 g, 11%) as a colorless oil. LCMS (ESI) [M+H]+: 405.0 Step 2. Synthesis of tert-butyl (R)-2-(((3-vinylpyridin-2-yl)oxy)methyl)pyrrolidine-1-carboxylateTo a mixture of tert-butyl (2R)-2-[[(3-iodopyridin-2-yl)oxy]methyl]pyrrolidine-1-carboxylate (2.0 g, 4.94 mmol, 1.0 equiv) in toluene (7 mL), EtOH (2 mL), H2O (1 mL) was added K2CO3(2.0 g, 14.84 mmol, 3.0 equiv), Pd(dppf)Cl2 (360 mg, 0.49 mmol, 0.1 equiv) and ethenyltrifluoro-lambda4-borane potassium (990 mg, 7.42 mmol, 1.5 equiv). The resulting mixture was stirred for additional 1 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with Petroleum ether / EtOAc (1:1). This resulted in tert-butyl (R)-2-(((3-vinylpyridin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate (1.0 g, 69%) as a colorless oil. LCMS (ESI) [M+H]+: 307.1 Step 3. Synthesis of tert-butyl (R)-2-(((3-ethylpyridin-2-yl)oxy)methyl)pyrrolidine-1-carboxylateTo a mixture of tert-butyl (R)-2-(((3-vinylpyridin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate (1.0 g, 3.28 mmol, 1.0 equiv) in MeOH (100 mL), Pd / C (349 mg, 0.328 mmol, 0.1 equiv, 10%), Theresulting mixture was stirred for 0.5 h at room temperature under a hydrogen atmosphere. The resulting mixture was filtered; the filter cake was washed with DCM (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1). This resulted in tert-butyl (R)-2-(((3-ethylpyridin-2- yl)oxy)methyl)pyrrolidine-1-carboxylate (507 mg, 50%) as a colorless oil. LCMS (ESI) [M+H]+: 307.1 Step 4. Synthesis of (R)-3-ethyl-2-(pyrrolidin-2-ylmethoxy)pyridineTo a solution of tert-butyl (R)-2-(((3-ethylpyridin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate (200 mg, 0.65 mmol, 1.0 equiv) in DCM (5 mL) was added TFA (2 mL) dropwise. The resulting mixture was stirred for 0.5 h at room temperature. The resulting mixture was concentrated. This resulted in (R)-3- ethyl-2-(pyrrolidin-2-ylmethoxy)pyridine (206 mg, crude) as a colorless oil. LCMS (ESI) [M+H]+: 207.1 Step 5. Synthesis of 7-[(2R)-2-[[(3-ethylpyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-6-fluoro-4-oxo- 1-phenylquinoline-3-carboxylic acidTo a mixture of 3-ethyl-2-[(2R)-pyrrolidin-2-ylmethoxy]pyridine (68 mg, 0.33 mmol, 1.0 equiv) in DMSO (5 mL) was added TEA (100 mg, 0.98 mmol, 3 equiv) and 6,7-difluoro-4-oxo-1- phenylquinoline-3-carboxylic acid (99 mg, 0.33 mmol, 1.0 equiv). The resulting mixture was stirred for additional 1 h at 80 °C. The precipitated solids were collected and crude product was purified by Prep.-HPLC with the following conditions (Column: SunFire Prep C18 OBD Column, 19×150 mm 5um 10nm; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:62 B to 70 B in 10 min; 254 nm; RT1:9.48). This resulted in 7-[(2R)-2-[[(3-ethylpyridin-2- yl)oxy]methyl]pyrrolidin-1-yl]-6-fluoro-4-oxo-1-phenylquinoline-3-carboxylic acid (25.1 mg, 15.3%)as a yellow solid. LCMS (ESI) [M+H]+: 488.11H NMR (300 MHz, DMSO-d6) δ 15.42 (s, 1H), 8.52 (s, 1H), 7.99 – 7.81 (m, 2H), 7.76 – 7.55 (m, 4H), 7.49 (d, J = 7.3 Hz, 2H), 6.90 (dd, J = 7.2, 4.9 Hz, 1H), 6.05 (d, J = 7.4 Hz, 1H), 4.50 – 4.33 (m, 1H), 4.17 (qd, J = 10.9, 9.9, 3.4 Hz, 2H), 3.24 – 3.14 (m, 2H), 2.37 (q, J = 7.6 Hz, 2H), 2.14 – 1.84 (m, 4H), 1.01 (t, J = 7.5 Hz, 3H) Potency Lin28a-dep Z11 IC50(µM) + Example 7: Synthesis of 6-fluoro-1-(4-hydroxyphenyl)-7-((2R)-4-methyl-2-(((3-methylpyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of 1-tert-butyl 2-methyl (2R)-4-(oxan-2-yloxy)pyrrolidine-1,2-dicarboxylateTo a mixture of 1-tert-butyl 2-methyl (2R)-4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.77 mmol) in DCM (100.00 mL) was added DHP (5.14 g, 61.10 mmol) and TsOH-Py (1.02 g, 4.05 mmol). The resulting mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with 500 ml H2O. The resulting solution was extracted with DCM (300 mL x 3) and the organic layers were combined. The organic layer was washed with brine (200 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / Petroleum ether (0-50%) to afford 1-tert-butyl 2- methyl (2R)-4-(oxan-2-yloxy)pyrrolidine-1,2-dicarboxylate (13 g, 89.0% yield) as a yellow oil. LCMS (ESI) [M+H]+: 330.20. Step 2. Synthesis of tert-butyl (2R)-2-(hydroxymethyl)-4-(oxan-2-yloxy)pyrroledine-1- carboxylateTo a mixture of 1-tert-butyl 2-methyl (2R)-4-(oxan-2-yloxy)pyrrolidine-1,2-dicarboxylate (6 g, 18.21 mmol) in THF (50.00 mL) were added LiAlH4 (0.83 g, 21.85 mmol) at 0 °C, The mixture was stirred at room temperature for 0.5 h. The reaction was quenched with Na2SO4.10 H2O at 0 °C. The mixture was filtered and the filter cake was washed with EtOAc. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / Petroleum ether (40%-50%) to afford tert-butyl (2R)-2-(hydroxymethyl)-4- (oxan-2-yloxy)pyrrolidine-1-carboxylate (2.5 g, 41.0% yield) as a yellow oil. LCMS (ESI) [M+H]+: 302.21. Step 3. Synthesis of tert-butyl (2R)-2-[(benzyloxy)methyl]-4-(oxan-2-yloxy)pyrrolidine-1- carboxylateTo a mixture of tert-butyl (2R)-2-(hydroxymethyl)-4-(oxan-2-yloxy)pyrrolidine-1-carboxylate (2.50 g, 8.29 mmol) in THF (30.00 mL) was added NaH (0.80 g, 33.33 mmol) at 0 °C. The mixture was stirred at room temperature for 0.5 h. Thebenzyl bromide (1.70 g, 9.93 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction was quenched with H2O at 0 °C. Then the reaction mixture was diluted with 200 mL H2O. The resulting solution was extracted with EtOAc (200 mL x 3) and the organic layers were combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep.-HPLC to afford tert-butyl (2R)-2-[(benzyloxy)methyl]-4-(oxan-2-yloxy)pyrrolidine-1-carboxylate (1.3 g, 41.0% yield) as a yellow oil. LCMS (ESI) [M+H]+: 392.25. Step 4. Synthesis of tert-butyl (2R)-2-[(benzyloxy)methyl]-4-hydroxypyrrolidine-1-carboxylateTo a mixture of tert-butyl (2R)-2-[(benzyloxy)methyl]-4-(oxan-2-yloxy)pyrrolidine-1-carboxylate (1.3 g, 3.32 mmol) in THF (4.00 mL) were added AcOH (4 mL) and H2O (4.00 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with 50 ml H2O. The resulting solution was extracted with EtOAc (300 mL x 3) and the organic layers were combined. The organiclayer was washed with brine (200 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / Petroleum ether (40-60%) to afford tert-butyl (2R)-2-[(benzyloxy)methyl]-4- hydroxypyrrolidine-1-carboxylate (800 mg, 70 % yield) as a yellow oil. LCMS (ESI) [M+H]+: 308.15. Step 5. Synthesis of tert-butyl (2R)-2-[(benzyloxy)methyl]-4-oxopyrrolidine-1-carboxylateTo a mixture of tert-butyl (2R)-2-[(benzyloxy)methyl]-4-hydroxypyrrolidine-1-carboxylate (800 mg, 2.60 mmol) in ACN (10.00 mL) was added IBX (1.09 g, 3.90 mmol). The mixture was stirred at 80 °C for 2 h. The residue was purified by reverse phase flash chromatography to afford tert-butyl (2R)-2- [(benzyloxy)methyl]-4-oxopyrrolidine-1-carboxylate (500 mg, 59 % yeild) as a yellow oil. LCMS (ESI) [M+H]+: 306.15. Step 6. Synthesis of tert-butyl (2R)-2-[(benzyloxy)methyl]-4-methylidenepyrrolidine-1- carboxylateTo a mixture of methyltriphenylphosphonium bromide (874 mg, 2.45 mmol) in THF (3.00 mL) were added t-BuOK (551 mg, 4.91 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. Then tert-butyl (2R)-2-[(benzyloxy)methyl]-4-oxopyrrolidine-1-carboxylate (500 mg, 1.63 mmol) was added and the mixture was stirred for 3 h at room temperature. The residue was purified by reverse phase flash chromatography to afford tert-butyl (2R)-2-[(benzyloxy)methyl]-4- methylidenepyrrolidine-1-carboxylate (450 mg, 90% yield) as a colorless oil. LCMS (ESI) [M+H]+: 304.18. Step 7. Synthesis of tert-butyl (2R)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylateUnder hydrogen, to a mixture of tert-butyl (2R)-2-[(benzyloxy)methyl]-4-methylidenepyrrolidine-1- carboxylate (450 mg, 1.48 mmol) in MeOH (10 mL) was added Pd / C (60 mg, 0.56 mmol). The resulting mixture was stirred for 1 h at room temperature. After filtration, the filtrate was concentrated to afford tert-butyl (2R)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate (300 mg, 93%) as a colorless oil. LCMS (ESI) [M+H]+: 216.19 Step 8. Synthesis of 3-methyl-2-(((2R)-4-methylpyrrolidin-2-yl)methoxy)pyridineTo a mixture of tert-butyl (2R)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate (300 mg, 1.39 mmol) in THF (10 mL) was added NaH (133 mg, 5.54 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h. Then 2-bromo-3-methylpyridine was added and stirred at 70 °C overnight. The reaction was quenched with 20 mL water at 0 °C. The resulting mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluting with ACN / H2O(0.1%FA) (80%~90%) to afford 3-methyl-2-(((2R)-4-methylpyrrolidin-2- yl)methoxy)pyridine (200 mg, 69%) as a dark yellow oil. LCMS (ESI) [M+H]+: 307.21 Step 9. Synthesis of 6-fluoro-1-(4-hydroxyphenyl)-7-[(2R)-4-methyl-2-[[(3-methylpyridin-2- yl)oxy]methyl]pyrrolidin-1-yl]-4-oxoquinoline-3-carboxylic acidTo a mixture of 6,7-difluoro-1-(4-hydroxyphenyl)-4-oxoquinoline-3-carboxylic acid (150 mg, 0.47 mmol) in DMSO (3 mL) was added 3-methyl-2-[[(2R)-4-methylpyrrolidin-2-yl]methoxy]pyridine (117 mg, 0.56 mmol) and TEA (287 mg, 2.83 mmol). The resulting mixture was stirred for 16 h at room temperature. The residue was purified by Prep.-HPLC (Column: SunFire Prep C18 OBD Column, 19×150mm 5um 10nm; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:50 B to 70 B in 8 min; 254 / 220 nm; RT1:7.73 / 8.22) to afford 6-fluoro-1-(4- hydroxyphenyl)-7-[(2R)-4-methyl-2-[[(3-methylpyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-4-oxoquinoline-3-carboxylic acid (8.2 mg, 3.4% yield) as a yellow solid. LCMS (ESI) [M+H]+: 504.2.1H NMR (300 MHz, DMSO-d6) δ 15.41 (s, 1H), 8.51 (s, 1H), 7.98 – 7.82 (m, 2H), 7.76 – 7.54 (m, 4H), 7.49 (d, J = 7.3 Hz, 2H), 7.02 – 6.81 (m, 1H), 6.04 (d, J = 7.4 Hz, 1H), 4.39 (m, 1H), 4.29 – 4.04 (m, 2H), 3.23 – 3.12 (m, 2H), 2.36 (q, J = 7.6 Hz, 2H), 2.14 – 1.85 (m, 4H), 1.00 (t, J = 7.5 Hz, 3H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 8: Synthesis of (R)-6-chloro-7-(2-(1-((3-chloropyridin-2-yl)oxy) ethyl)pyrrolidin-1-yl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1- carboxylateTo a mixture of (2R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.0 g, 4.65 mmol, 1.0 equiv) in DMF (12 mL) was added N,O-dimethylhydroxylamine (0.3 g, 5.58 mmol, 1.2 equiv), DIEA (2.4 g, 18.58 mmol, 4.0 equiv) and HATU (2.7 g, 6.97 mmol, 1.5 equiv). The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL). The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 5% to 100% gradient in 30 min; detector, UV 254 nm and UV 220 nm. This resulted in tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (1.0 g, 83.3%) as a colorless oil. LCMS (ESI) [M+H]+: 259.Step 2. Synthesis of tert-butyl (2R)-2-acetylpyrrolidine-1-carboxylateTo a mixture of tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (900 mg, 3.48 mmol, 1.0 equiv) in THF (9 mL) at -78 °C was added MeMgBr (1.2 g, 10.45 mmol, 3.0 equiv). The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (8 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After concentration, the residue was purified by silica gel column chromatography eluting with Petroleum ether / EtOAc (3:1) to afford tert-butyl (2R)-2-acetylpyrrolidine-1-carboxylate (700 mg, 94.2%) as a light yellow oil. Step 3. Synthesis of tert-butyl (2R)-2-(1-hydroxyethyl) pyrrolidine-1-carboxylateTo a mixture of tert-butyl (2R)-2-acetylpyrrolidine-1-carboxylate (700 mg, 3.28 mmol, 1.0 equiv) in MeOH (7 mL) was added NaBH4 (248 mg, 6.56 mmol, 2.0 equiv) at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of water (6 mL). The resulting mixture was extracted with EtOAc (3 x 8 mL). The combined organic layers were dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography eluting with Petroleum ether / EtOAc (1:1) to afford tert-butyl (2R)-2-(1-hydroxyethyl) pyrrolidine-1-carboxylate (600 mg, 84.9%) as a colorless oil. LCMS (ESI) [M+H]+: 216. Step 4. Synthesis of tert-butyl (2R)-2-[1-[(3-chloropyridin-2-yl) oxy] ethyl] pyrrolidine-1- carboxylateTo a mixture of tert-butyl (2R)-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (500 mg, 2.32 mmol, 1.0 equiv) in THF (6 mL) was added NaH (167 mg, 6.97 mmol, 3.0 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogenatmosphere. To the above mixture was added 3-chloro-2-fluoropyridine (367 mg, 2.79 mmol, 1.2 equiv). The resulting mixture was stirred for additional 2.5 h at 70 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (6 mL) at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 5% to 100% gradient in 30 min; detector, UV 254 nm UV 220 nm. This resulted in tert-butyl (2R)-2-[1-[(3-chloropyridin-2-yl) oxy] ethyl] pyrrolidine-1-carboxylate (126 mg, 29.6%) as a light yellow oil. LCMS (ESI) [M+H]+: 327. Step 5. Synthesis of 3-chloro-2-[1-[(2R)-pyrrolidin-2-yl]ethoxy]pyridineTo a mixture of tert-butyl (2R)-2-[1-[(3-chloropyridin-2-yl) oxy] ethyl] pyrrolidine-1-carboxylate (126 mg, 0.39 mmol, 1.0 equiv) in DCM (3 mL) was added TFA (0.6 mL). The resulting mixture was stirred for 1.5 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 3-chloro-2-[1-[(2R)-pyrrolidin-2-yl]ethoxy]pyridine (100 mg, crude) as a light yellow oil. LCMS (ESI) [M+H]+: 227. Step 6. Synthesis of 6-chloro-7-[(2R)-2-[1-[(3-chloropyridin-2-yl)oxy]ethyl]pyrrolidin-1-yl]-4- oxo-1-phenylquinoline-3-carboxylic acidTo a mixture of 6-chloro-7-fluoro-4-oxo-1-phenylquinoline-3-carboxylic acid (80 mg, 0.25 mmol, 1.0 equiv) in DMSO (3.5 mL) was added TEA (127 mg, 1.26 mmol, 5.0 equiv) and 3-chloro-2-[1-[(2R)- pyrrolidin-2-yl]ethoxy]pyridine (86 mg, 0.38 mmol, 1.5 equiv). The resulting mixture was stirred for 2 h at 80 °C. The mixture was allowed to cool down to room temperature. The resulting mixture wasconcentrated under vacuum. The crude product was purified by Prep.-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 5um,19*150mm;Mobile Phase A:Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 60% B to 90% B in 8 min; 254 / 220 nm; Rt: 7.31 min) to afford 6-chloro-7-[(2R)-2-[1-[(3-chloropyridin-2- yl)oxy]ethyl]pyrrolidin-1-yl]-4-oxo-1-phenylquinoline-3-carboxylic acid (14.4 mg, 10.91%) as a light yellow solid. LCMS (ESI) [M+H]+: 524.0.1H NMR (300 MHz, DMSO-d6) δ 15.07 (s, 1H), 8.53 (s, 1H), 8.12 (s, 1H), 7.82 (dd, J = 7.7, 1.7 Hz, 1H), 7.78 – 7.53 (m, 5H), 7.34 (d, J = 7.2 Hz, 1H), 6.78 (dd, J = 7.7, 4.9 Hz, 1H), 6.06 (s, 1H), 5.44 – 5.31 (m, 1H), 4.50 – 4.37 (m, 1H), 3.28 – 3.15 (m, 1H), 3.03 (t, J = 7.8 Hz, 1H), 2.25 – 2.07 (m, 2H), 2.01 (dd, J = 9.9, 4.1 Hz, 1H), 1.81 – 1.66 (m, 1H), 1.17 (d, J = 6.5 Hz, 3H). Potency Lin28a-dep Z11 IC50(µM) +++ Example 9: Synthesis of (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-8- fluoro-1-(1-methylcyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of methyl 2,3,4-trifluoro-5-nitrobenzoateA solution of 2,3,4-trifluoro-5-nitrobenzoic acid (5.00 g, 22.62 mmol) in methanol (30.0 mL) was added thionyl chloride (8.07 g, 67.84 mmol) and stirred at 60 °C for 4 hours. The solvent was concentrated under vacuum. The residue was dissolved in DCM and washed with sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford methyl 2,3,4-trifluoro-5-nitrobenzoate (5.1 g, 95.9%) as a light yellow oil. Step 2. Synthesis of methyl 5-amino-2,3,4-trifluorobenzoateUnder hydrogen, a solution of methyl 2,3,4-trifluoro-5-nitrobenzoate (5.80 g, 24.67 mmol) in ethyl acetate (100.0 mL) was added Pd / C (1.00 g, 9.39 mmol) at room temperature. The resulting solution was stirred at room temperature for 3 hours. The solid was filtered out. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / Petroleum ether (0%-20%) to afford methyl 5-amino-2,3,4-trifluorobenzoate (4.5 g, 88.9%) as a white solid. LCMS: m / z = 206 [M+H]+Step 3. Synthesis of methyl 5-chloro-2,3,4-trifluorobenzoateUnder nitrogen, a solution of methyl 5-amino-2,3,4-trifluorobenzoate (5.00 g, 24.37 mmol) and CuCl2 (6.55 g, 48.75 mmol) in ACN (100.0 mL) was added t-BuONO (5.03 g, 48.78 mmol) at 70 °C. The resulting solution was stirred at 70 °C for 1 hour. The solvent was cooled and added hydrochloric acid (3 M) to adjust the pH to 3. The mixture was quenched with water, extracted with DCM and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / Petroleum ether (0%-10%) to afford methyl 5-chloro-2,3,4-trifluorobenzoate (3.5 g, 63.9%) as a white solid. Step 4. Synthesis of 5-chloro-2,3,4-trifluorobenzoic acidA solution of methyl 5-chloro-2,3,4-trifluorobenzoate (5.00 g, 22.26 mmol) in THF (50.0 mL) was added lithium hydroxide hydrate (3.74 g, 89.13 mmol) in H2O (25.0 mL) and stirred at room temperature for 2 hours. The solvent was concentrated under vacuum. The residue was dissolved in water. The pH was adjusted to 3 with hydrochloric acid (3 M). The solid was filtered, washed with water and concentrated under vacuum to afford 5-chloro-2,3,4-trifluorobenzoic acid (3.7 g, 78.9%) asa white solid. Step 5. Synthesis of 5-chloro-2,3,4-trifluorobenzoyl chlorideA solution of 5-chloro-2,3,4-trifluorobenzoic acid (600.0 mg, 2.85 mmol) in thionyl chloride (10.0 mL) was stirred at 80 °C for 3 hours. The solvent was concentrated under vacuum to afford 5-chloro- 2,3,4-trifluorobenzoyl chloride (630 mg, 96.5%) as a light yellow oil. Step 6. Synthesis of ethyl 3-(5-chloro-2,3,4-trifluorophenyl)-3-oxopropanoateUnder nitrogen, a solution of 1-ethyl 3-potassium propanedioate (936.58 mg, 5.50 mmol) and MgCl2 (654.9 mg, 6.88 mmol) in ACN (50.0 mL) was added TEA (835.2 mg, 8.25 mmol) at 5 °C and stirred at room temperature for 2 hours. Then 5-chloro-2,3,4-trifluorobenzoyl chloride (630.0 mg, 2.75 mmol) in ACN was added dropwise at 5 °C and stirred at room temperature for 16 hours. The reaction mixture was quenched with hydrochloric acid (3 M) to adjust the pH to 3. The reaction mixture was extracted with DCM and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0%-30%) to afford ethyl 3-(5-chloro-2,3,4-trifluorophenyl)- 3-oxopropanoate (450 mg, 58.2%) as a white solid. Step 7. Synthesis of ethyl (Z)-2-(5-chloro-2,3,4-trifluorobenzoyl)-3-ethoxyacrylateA solution of ethyl 3-(5-chloro-2,3,4-trifluorophenyl)-3-oxopropanoate (450.0 mg, 1.60 mmol) and triethyl orthoformate (356.4 mg, 2.41 mmol) in acetic anhydride (982.2 mg, 9.62 mmol) was stirred at 100 °C for 2 hours. The solvent was concentrated under vacuum to afford ethyl (2Z)-2-[(Z)-5-chloro-2,3,4-trifluorobenzoyl]-3-ethoxyprop-2-enoate (500 mg, 92.6%) as a yellow oil. LCMS: m / z = 337 [M+H]+Step 8. Synthesis of ethyl 6-chloro-7,8-difluoro-1-(1-methylcyclopropyl)-4-oxo-1,4- dihydroquinoline-3-carboxylateA solution of ethyl (2Z)-2-[(Z)-5-chloro-2,3,4-trifluorobenzoyl]-3-ethoxyprop-2-enoate (500.0 mg, 1.49 mmol) and 1-methylcyclopropan-1-amine (105.6 mg, 1.49 mmol) in DMSO (8.0 mL) was stirred at room temperature for 2 hours. Then K2CO3(205.2 mg, 1.49 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was quenched with water, extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0%-60%) to afford ethyl 6-chloro-7,8-difluoro-1-(1-methylcyclopropyl)-4- oxoquinoline-3-carboxylate (200 mg, 39.4%) as a white solid. LCMS: m / z = 342 [M+H]+Step 9. Synthesis of 6-chloro-7,8-difluoro-1-(1-methylcyclopropyl)-4-oxo-1,4-dihydroquinoline- 3-carboxylic acidInto a 10-mL sealed tube, was placed ethyl 6-chloro-7,8-difluoro-1-(1-methylcyclopropyl)-4- oxoquinoline-3-carboxylate (100.0 mg, 0.29 mmol), THF (2.0 mL), H2O (1.0 mL), lithium hydroxide hydrate (61.4 mg, 1.46 mmol). The resulting solution was stirred for 2 hours at room temperature. The solids were collected by filtration. This resulted in 90 mg (98.05%) of 6-chloro-7,8-difluoro-1-(1- methylcyclopropyl)-4-oxoquinoline-3-carboxylic acid as a white solid. LCMS: m / z = 314 [M+H]+Step 10. Synthesis of (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrolidin-1-yl)-8- fluoro-1-(1-methylcyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidInto a 10-mL sealed tube, was placed 6-chloro-7,8-difluoro-1-(1-methylcyclopropyl)-4-oxoquinoline- 3-carboxylic acid (80.0 mg, 0.26 mmol), DMSO (2.0 mL), 3-chloro-2-[(2R)-pyrrolidin-2- ylmethoxy]pyridine (65.1 mg, 0.31 mmol), N,N-diisopropylethylamine (98.9 mg, 0.77 mmol). The resulting solution was stirred for 5 hours at 60 °C. The residue was purified by reverse phase flash chromatography eluting with ACN / water (0%-40%, basic system). This resulted in 30 mg (20.65%) of 6-chloro-7-[(2R)-2-[[(3-chloropyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-8-fluoro-1-(1- methylcyclopropyl)-4-oxoquinoline-3-carboxylic acid as a white solid. LCMS: m / z = 506 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ 14.63 (s, 1H), 8.86 (d, J = 1.7 Hz, 1H), 8.19 – 7.91 (m, 2H), 7.71 (m, 1H), 6.92 (m, 1H), 4.65 (s, 1H), 4.42 – 4.11 (m, 2H), 3.91 – 3.72 (m, 1H), 3.23 (s, 1H), 2.27 (m, 1H), 2.08 (s, 1H), 2.00 – 1.75 (m, 2H), 1.61 (s, 3H), 1.28 (d, J = 16.3 Hz, 2H), 1.11 (m, 2H). Potency Lin28a-dep Z11 IC50(µM) +++ Example 10: Synthesis of (R)-7-(2-(((3-chloropyridin-2-yl)(methyl)amino)methyl)pyrrolidin-1- yl)-6-fluoro-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of tert-butyl (2R)-2-[[(3-chloropyridin-2-yl)(methyl)amino]methyl]pyrroledine- 1-carboxylateTo a solution of tert-butyl (2R)-2-[[(3-chloropyridin-2-yl) amino] methyl] pyrrolidine-1-carboxylate (1.0 g, 3.21 mmol, 1.0 equiv) in DMF (10 mL) was added NaH (120 mg, 4.81 mmol, 1.5 equiv) and CH3I (910 mg, 6.41 mmol, 2.0 equiv). The reaction was stirred at 0 °C for 2 h. The reaction was then quenched by the addition of water. The resulting solution was extracted with 30 mL x 3 of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column chromatography eluting with ethyl acetate / Petroleum ether (1 / 3). This resulted in tert-butyl (2R)-2-[[(3-chloropyridin-2- yl)(methyl)amino]methyl]pyrrolidine-1-carboxylate (850 mg, 81.3%) as yellow oil. LCMS (ESI) [M+H]+: 326. Step 2. Synthesis of 3-chloro-N-methyl-N-[(2R)-pyrrolidin-2-ylmethyl]pyridin-2-amineTo a solution of tert-butyl (2R)-2-[[(3-chloropyridin-2-yl)(methyl)amino]methyl]pyrrolidine-1- carboxylate (800 mg, 2.46 mmol, 1.0 equiv) in DCM (5 mL) was added TFA (1 mL). The resulting solution was stirred at room temperature for 2 h. The pH value of the solution was adjusted to 10. The resulting mixture was concentrated under vacuum. This resulted in 3-chloro-N-[(2R)-pyrrolidin-2- ylmethyl] pyridin-2-amine (500 mg, crude) as yellow oil. LCMS (ESI) [M+H]+: 226. Step 3. Synthesis of 7-[(2R)-2-[[(3-chloropyridin-2-yl)(methyl)amino]methyl]pyrrolidin-1-yl]-6- fluoro-1-(4-hydroxyphenyl) -4-oxoquinoline-3-carboxylic acidTo a solution of 6,7-difluoro-1-(4-hydroxyphenyl)-4-oxoquinoline-3-carboxylic acid (100 mg, 0.32 mmol, 1.0 equiv), in DMSO (2 mL) was added TEA (96 mg, 0.95 mmol, 3.0 equiv) and 3-chloro-N- methyl-N-[(2R)-pyrrolidin-2-ylmethyl]pyridin-2-amine (85 mg, 0.38 mmol, 1.2 equiv). The reactionwas stirred at 80 ° C for 2 h. The mixture was purified by Prep.-HPLC with the following conditions: Column: X Bridge Shield RP18 OBD Column, 5um, 19*150mm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 25 B to 45 B in 15 min; 254 nm. This resulted in 7-[(2R)-2-[[(3-chloropyridin-2-yl) amino] methyl] pyrrolidin-1-yl]-6-fluoro-1-(4- hydroxyphenyl)-4-oxoquinoline-3-carboxylic acid (60.8 mg, 36.88%) as a yellow solid. LCMS (ESI): [M+H]+: 523.1.1H NMR (300 MHz, DMSO-d6) δ 15.53 (s, 1H), 10.15 (s, 1H), 8.42 (s, 1H), 7.84 – 7.72 (m, 2H), 7.49 – 7.35 (m, 3H), 7.01 (d, J = 7.9 Hz, 1H), 6.96 – 6.86 (m, 1H), 6.53 – 6.44 (m, 1H), 6.43 – 6.35 (m, 1H), 6.02 (d, J = 7.4 Hz, 1H), 4.45 (s, 1H), 3.59 – 3.49 (m, 1H), 3.32 – 3.29 (m, 1H), 3.28 – 3.22 (m, 1H),3.13 – 3.04 (m, 1H), 2.06 – 1.79 (m, 4H). Potency Lin28a-dep Z11 IC50(µM) +++ Example 11: Synthesis of (R)-7-(2-((1H-pyrrolo[3,2-b]pyridin-1-yl)methyl)pyrroledin-1-yl)-6- fluoro-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of tert-butyl (2R)-2-[[(4-methylpyridin-2-yl)oxy]methyl]pyrrolidine-1- carboxylateTo a mixture of tert-butyl (2R)-2-[[(4-methylbenzenesulfonyl)oxy]methyl]pyrrolidine-1-carboxylate (200 mg, 0.56 mmol, 1.0 equiv) and 4-azaindole (133 mg, 1.13 mmol, 2.0 equiv) in DMSO (2.0 mL) was added Cs2CO3(550 mg, 1.69 mmol, 3.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. The reaction was quenched by the addition of water (1 mL) at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in w ater, 5% to 95% gradient in 30 min; detector, UV 254 nm and UV 220 nm. This resulted in tert-butyl(2R)-2-[[(4-methylpyridin-2-yl)oxy]methyl]pyrrolidine-1-carboxylate (100 mg, 59% yield). LCMS (ESI) [M+H]+: 302.1 Step 2. Synthesis of (2R)-2-[pyrrolo[3,2-b]pyridin-1-ylmethyl]pyrrolidineTo a mixture of tert-butyl (2R)-2-[pyrrolo[3,2-b]pyridin-1-ylmethyl]pyrrolidine-1-carboxylate (100 mg, 0.33 mmol, 1.0 equiv) in DCM (5 mL) was added TFA (2 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1.5 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product (2R)-2-[pyrrolo[3,2-b]pyridin- 1-ylmethyl]pyrrolidine (160 mg, crude) was used in the next step directly without further purification. LCMS (ESI) [M+H]+: 202.12. Step 3. Synthesis of 6-fluoro-1-(4-hydroxyphenyl)-4-oxo-7-[(2R)-2-[pyrrolo[3,2-b]pyridin-1- ylmethyl]pyrrolidin-1-yl]quinoline-3-carboxylic acidTo a mixture of (2R)-2-[pyrrolo[3,2-b]pyridin-1-ylmethyl]pyrrolidine (60 mg, 0.30 mmol, 1.0 equiv) and 6,7-difluoro-1-(4-hydroxyphenyl)-4-oxoquinoline-3- carboxylic acid (32 mg, 0.10 mmol, 0.3equiv) in DMSO (1.0 mL) was added TEA (181 mg, 1.79 mmol, 6.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column,, 5um,19*150mm ; Mobile Phase A:Water (0.05% FA), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:9 B to 30 B in 8 min; 254 nm; RT1:7.9) to afford 6- fluoro-1-(4-hydroxyphenyl)-4-oxo-7-[(2R)-2-[pyrrolo[3,2-b]pyridin-1-ylmethyl]pyrrolidin-1- yl]quinoline-3-carboxylic acid (46.9 mg, 31.3 %) as a white solid. LCMS (ESI) [M+H]+: 499.20.1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.48 (s, 1H), 8.35 (d, J = 4.8 Hz, 1H), 7.90 – 7.76 (m,2H), 7.52 – 7.43 (m, 3H), 7.21 (s, 1H), 7.09 – 6.99 (m, 2H), 6.59 (d, J = 3.2 Hz, 1H), 6.12 (d, J = 7.5 Hz, 1H), 4.47 (d, J = 6.7 Hz, 1H), 4.27 (d, J = 6.0 Hz, 2H), 3.15 (d, J = 8.7 Hz, 2H), 1.94 – 1.72 (m, 3H), 1.71 – 1.60 (m, 1H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 12: Synthesis of (R)-7-(2-(((1H-pyrrolo[3,2-c]pyridine-6-yl)oxy)methyl)pyrrolidin-1- yl)-6-fluoro-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of 6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridineTo a mixture of 6-chloro-1H-pyrrolo[3,2-c]pyridine (2.0 g, 13.11 mmol, 1.0 equiv) in DMF (15 mL) was added NaH (0.4 g, 15.73 mmol, 1.2 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 15 min at room temperature under nitrogen atmosphere. To the above mixture was added SEM-Cl (2.6 g, 15.73 mmol, 1.2 equiv) at 0 °C. The resulting mixture was stirred for additional 1.5 h at room temperature. The reaction was quenched by the addition of water (15 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (5 x 10 mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with Petroleum ether / EtOAc (4:1) to afford 6-chloro-1-[[2- (trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridine (2.7 g, 72.8%) as a yellow oil. LCMS (ESI) [M+H]+: 283. Step 2. Synthesis of tert-butyl (2R)-2-[[(1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2- c]pyridin-6-yl)oxy]methyl]pyrrolidine-1-carboxylateBocCs2CO3, toluene SEM To a mixture of 6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridine (1.0 g, 3.54 mmol, 1.0 equiv) in toluene (12 mL) was added tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1- carboxylate (4.3 g, 21.21 mmol, 6.0 equiv), Cs2CO3(3.5 g, 10.61 mmol, 3.0 equiv), Pd2(allyl)2Cl2 (0.1 g, 0.35 mmol, 0.1 equiv) and t-BuBrettPhos (0.2 g, 0.35 mmol, 0.1 equiv). The resulting mixture was stirred for 3.5 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 8 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with Petroleum ether / EtOAc (2:1) to afford tert-butyl (2R)-2-[[(1-[[2- (trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6-yl)oxy]methyl]pyrrolidine-1-carboxylate (590 mg, 37.3%) as a light yellow oil. LCMS (ESI) [M+H]+: 448. Step 3. Synthesis of (2R)-2-([1H-pyrrolo[3,2-c]pyridin-6-yloxy]methyl)pyrrolidineTo a mixture of tert-butyl (2R)-2-[[(1-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[3,2-c]pyridin-6- yl)oxy]methyl]pyrrolidine-1-carboxylate (590 mg, 1.32 mmol, 1.0 equiv) in HCl (gas) in 1,4-dioxane (6 mL) at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. To the above mixture was added the solution of ammonia (5 mL, 7M in MeOH) at 0 °C. The resulting mixture was stirred for additional 3.5 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in (2R)-2-([1H- pyrrolo[3,2-c]pyridin-6-yloxy]methyl)pyrrolidine (300 mg, crude) as a light yellow oil. LCMS (ESI) [M+H]+: 218. Step 4. Synthesis of 6-fluoro-1-(4-hydroxyphenyl)-4-oxo-7-[(2R)-2-([1H-pyrrolo[3,2-c]pyridin-6- yloxy]methyl)pyrrolidin-1-yl]quinoline-3-carboxylic acidTo a mixture of 6,7-difluoro-1-(4-hydroxyphenyl)-4-oxoquinoline-3-carboxylic acid (300 mg, 0.95 mmol, 1.0 equiv) in DMSO (6 mL) was added TEA (287 mg, 2.84 mmol, 3.0 equiv) and (2R)-2-([1H- pyrrolo[3,2-c]pyridin-6-yloxy]methyl)pyrrolidine (411 mg, 1.89 mmol, 2.0 equiv). The resulting mixture was stirred for 2 h at 80 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep.-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 5um,19*150mm;Mobile Phase A:Water(0.05%FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 60% B to 90% B in 8 min; 254 / 220 nm; Rt: 7.31 min) to afford 6-fluoro-1-(4-hydroxyphenyl)-4-oxo-7-[(2R)-2-([1H- pyrrolo[3,2-c]pyridin-6-yloxy]methyl)pyrrolidin-1-yl]quinoline-3-carboxylic acid (25.0 mg, 5.14%) as a yellow solid. LCMS (ESI) [M+H]+: 515.25.1H NMR (300 MHz, DMSO-d6) δ 15.49 (s, 1H), 11.12 (s, 1H), 10.16 (s, 1H), 8.43 (s, 1H), 8.22 (d, J = 19.7 Hz, 1H), 7.88 (d, J = 14.5 Hz, 1H), 7.40 (d, J = 8.5, 2.7 Hz, 1H), 7.31 – 7.19 (m, 2H), 6.96 (s, 1H), 6.90 – 6.78 (m, 1H), 6.52 – 6.38 (m, 2H), 6.07 (d, J = 7.5 Hz, 1H), 4.45 (s, 1H), 4.25 (d, J = 5.3 Hz, 2H), 3.13 (d, J = 7.0 Hz, 2H), 2.13 – 1.87 (m, 4H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 13: Synthesis of (R)-1-(6-aminopyridin-3-yl)-6-fluoro-7-(2-(((3-methylpyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of ethyl (R)-1-(6-acetamidopyridin-3-yl)-6-fluoro-7-(2-(((3-methylpyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylateTo a mixture of ethyl (R,Z)-2-(2,5-difluoro-4-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1- yl)benzoyl)-3-ethoxyacrylate (350 mg, 0.63 mmol ) in DMSO (5 mL) was added N-(5-aminopyridin- 2-yl)acetamide (114 mg, 0.75 mmol). The resulting mixture was stirred for 1 h at room temperature. Then K2CO3(87 mg, 0.62 mmol) was added and stirred at 100 °C for 1 h. The reaction was quenched with water at room temperature. The solid was collected by filtration, washed by water and dried to afford ethyl (R)-1-(6-acetamidopyridin-3-yl)-6-fluoro-7-(2-(((3-methylpyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (200 mg ,crude) as a yellow solid. LCMS (ESI) [M+H]+: 560.3. Step 2. Synthesis of (R)-1-(6-aminopyridin-3-yl)-6-fluoro-7-(2-(((3-methylpyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a mixture of ethyl (R)-1-(6-acetamidopyridin-3-yl)-6-fluoro-7-(2-(((3-methylpyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (200 mg, 0.12mmol) in THF (3 mL) were added LiOH.H2O (131 mg, 3.12 mmol ) in H2O (1 mL) under nitrogen. The mixture was stirred at 100 °C for 2 h. The residue was purified by Prep.-HPLC (Column: Gemini-NX C18 AXAI Packed, 21.2*150mm 5um; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:51 B to 71 B in 15 min; 254 nm; RT1:17.1; RT2:; Injection Volumn: ml; Number Of Runs:;) to afford (R)-1-(6-aminopyridin-3-yl)-6-fluoro-7-(2-(((3-methylpyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (79.2 mg, 29.5% yield) as a yellow solid. LCMS (ESI) [M+H]+: 490.15.1H NMR (300 MHz, DMSO-d6) δ 15.41 (s, 1H), 8.48 (s, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.94 – 7.81 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 6.93 – 6.79 (m, 1H), 6.71 – 6.36 (m, 3H), 6.16 (d, J = 7.4 Hz, 1H), 4.66 – 4.45 (m, 1H), 4.34 – 4.16 (m, 2H), 3.31 – 3.15 (m, 2H), 2.19 – 1.84 (m, 7H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 14: Synthesis of 6-fluoro-7-[(2R)-2-[[(3-methylpyridin-2-yl)oxy]methyl]pyrrolidin-1- yl]-1-(oxan-4-yl)-4-oxoquinoline-3-carboxylic acidStep 1. Synthesis of 3-methyl-2-[(2R)-pyrrolidin-2-ylmethoxy]pyridineTo a mixture of tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (10.0 g, 49.71 mmol, 1.0 equiv) in THF (20 mL) was added NaH (7.9 g, 199.22 mmol, 4.0 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h. Then 2-bromo-3-methylpyridine was added and stirred at 70 °C overnight. The reaction was quenched with 20 mL water at 0 °C. The resulting mixture was extracted with EtOAc (200 mL x 3) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluting with ACN / H2O(0.1%FA) (80%- 90%) to afford 3-methyl-2-[(2R)-pyrrolidin-2-ylmethoxy]pyridine (7.50 g, 78%) as a dark yellow oil. LCMS (ESI) [M+H]+:193.1 and tert-butyl (2R)-2-[[(3-methylpyridin-2-yl)oxy]methyl]pyrrolidine-1-carboxylate (1.6 g) as a light yellow oil. LCMS (ESI) [M+H]+:293.1. Step 2. Synthesis of 3-[2,5-difluoro-4-[(2R)-2-[[(3-methylpyridin-2-yl)oxy]methyl]pyrolidin-1- yl]phenyl]-3-oxopropanoateTo a mixture of methyl 3-methyl-2-[(2R)-pyrrolidin-2-ylmethoxy]pyridine (1.00 g, 5.20 mmol, 1.0 equiv) in ACN (10 mL) was added ethyl 3-oxo-3-(2,4,5-trifluorophenyl)propanoate (1.28 g, 5.20 mmol, 1.0 equiv) and TEA (1.58 g, 15.60 mmol, 3.0 equiv). The resulting mixture was stirred for 2 h at 80 °C. The residue was purified by reverse phase flash chromatography eluting with ACN / H2O (0.05%NH4HCO3) (60%-80%) to afford ethyl 3-[2,5-difluoro-4-[(2R)-2-[[(3-methylpyridin-2- yl)oxy]methyl]pyrrolidin-1-yl]phenyl]-3-oxopropanoate (600 mg, 25.4% yield) as a yellow oil. LCMS (ESI) [M+H]+: 419.17. Step 3. Synthesis of ethyl (2Z)-2-[(Z)-2,5-difluoro-4-[(2R)-2-[[(3-methylpyridin-2- yl)oxy]methyl]pyrrolidin-1-yl]benzoyl]-3-ethoxyprop-2-enoateTo a mixture of ethyl 3-[2,5-difluoro-4-[(2R)-2-[[(3-methylpyridin-2-yl)oxy]methyl]pyrrolidin-1- yl]phenyl]-3-oxopropanoate (200 mg, 0.47 mmol, 1.0 equiv) in acetic anhydride (146 mg, 1.43 mmol, 2.99 equiv) were added triethyl orthoformate (106 mg, 0.71 mmol, 1.5 equiv). The resulting mixture was stirred for 8 h at 80 °C. The solvent was concentrated under vacuum to afford ethyl (2Z)-2-[(Z)- 2,5-difluoro-4-[(2R)-2-[[(3-methylpyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]benzoyl]-3-ethoxyprop-2- enoate (250 mg, crude) as a yellow oil. LCMS (ESI) [M+H]+: 475.20.Step 4. Synthesis of ethyl 6-fluoro-7-[(2R)-2-[[(3-methylpyridin-2-yl)oxy]methyl]pyrrolidin-1- yl]-1-(oxan-4-yl)-4-oxoquinoline-3-carboxylateTo a mixture of ethyl (2Z)-2-[(Z)-2,5-difluoro-4-[(2R)-2-[[(3-methylpyridin-2- yl)oxy]methyl]pyrrolidin-1-yl]benzoyl]-3-ethoxyprop-2-enoate (250 mg, 0.52 mmol, 1.0 equiv) in DMSO (5.00 mL) was added oxan-4-amine (64 mg, 0.63 mmol, 1.20 equiv). The resulting mixture was stirred for 1 h at room temperature. Then K2CO3(73 mg, 0.52 mmol, 1.00 equiv) was added and stirred at 100 °C for 1 h. The reaction was quenched with water at room temperature. The solid was collected by filtration, washed by water and dried to afford ethyl 6-fluoro-7-[(2R)-2-[[(3- methylpyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-1-(oxan-4-yl)-4-oxoquinoline-3-carboxylate (200 mg ,crude) as a yellow solid. LCMS (ESI) [M+H]+: 510.23. Step 5. Synthesis of 6-fluoro-7-[(2R)-2-[[(3-methylpyridin-2-yl)oxy]methyl]pyrolidin-1-yl]-1- (oxan-4-yl)-4-oxoquinoline-3-carboxylic acidTo a mixture of ethyl 6-fluoro-7-[(2R)-2-[[(3-methylpyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-1- (oxan-4-yl)-4-oxoquinoline-3-carboxylate (200 mg, 0.39 mmol, 1.0 equiv) in THF (3.00 mL) was added LiOH.H2O (131.0 mg,3.12 mmol, 8.0 equiv) and H2O (1.00 mL). The mixture was stirred at room temperature for 2 h. The residue was purified by Prep.-HPLC to afford 6-fluoro-7-[(2R)-2-[[(3- methylpyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-1-(oxan-4-yl)-4-oxoquinoline-3-carboxylic acid (34.4 mg, 18%) as a yellow solid. LCMS (ESI) [M+H]+: 482.20.1H NMR (300 MHz, DMSO-d6) δ 15.52 (s, 1H), 8.65 (s, 1H), 7.92 – 7.81 (m, 2H), 7.48 (d, J = 7.1 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.86 – 6.82 (m, 1H), 5.01 (s, 1H), 4.79 (s, 1H), 4.39 – 4.28 (m, 2H), 4.02 (d, J = 11.2 Hz, 1H), 3.91 (d, J = 11.3 Hz, 1H), 3.79 (s, 1H), 3.65 – 3.48 (m, 3H), 2.19 (s, 2H), 2.03 (d, J = 10.4 Hz, 9H).Potency Lin28a-dep Z11 IC50(µM) ++++ Example 15: Synthesis of (R)-6-fluoro-7-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)- 4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of ethyl (R,Z)-2-(2,5-difluoro-4-(2-(((3-methylpyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)benzoyl)-3-ethoxyacrylateTo a mixture of ethyl (R)-3-(2,5-difluoro-4-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1- yl)phenyl)-3-oxopropanoate (300 mg, 0.69 mmol, 1.0 equiv) in acetic anhydride (220 mg, 2.65 mmol, 2.99 equiv) were added triethyl orthoformate (159 mg, 106 mmol, 1.5 equiv). The resulting mixture was stirred for 8 h at 80 °C. The solvent was concentrated under vacuum to afford ethyl (R,Z)-2-(2,5- difluoro-4-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)benzoyl)-3-ethoxyacrylate (350 mg, crude) as a yellow oil. LCMS (ESI) [M+H]+: 475.20. Step 2. Synthesis of ethyl (R)-6-fluoro-7-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)- 4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylateTo a mixture of ethyl (R,Z)-2-(2,5-difluoro-4-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1- yl)benzoyl)-3-ethoxyacrylate (350 mg, 0.73 mmol, 1.0 equiv) in DMSO (5.00 mL) was added 2- aminopyrazine (84 mg, 0.88 mmol, 1.20 equiv). The resulting mixture was stirred for 1 h at room temperature. Then K2CO3(101 mg, 0.73 mmol, 1.00 equiv) was added and stirred at 100 °C for 1 h. The reaction was quenched with water at room temperature. The solid was collected by filtration, washed by water and dried to afford ethyl (R)-6-fluoro-7-(2-(((3-methylpyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylate (350 mg, crude) as a yellow solid. LCMS (ESI) [M+H]+: 504.20. Step 3. Synthesis of (R)-6-fluoro-7-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo- 1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylic acidTo a mixture of ethyl (R)-6-fluoro-7-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1- (pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylate (350 mg, 0.69 mmol, 1.0 equiv) in THF (5.00 mL) was added LiOH.H2O (233 mg, 5.55 mmol, 7.99 equiv) and H2O (1.70 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the residue which was purified by Prep.-HPLC to afford (R)-6-fluoro-7-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1- (pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylic acid (69.7 mg, 23%) as a yellow solid. LCMS (ESI) [M+H]+: 476.10.1H NMR (300 MHz, DMSO-d6) δ 15.18 (s, 1H), 9.15 (s, 1H), 8.92 (d, J = 2.4 Hz, 1H), 8.91 (s, 1H), 8.75 (s, 1H), 7.90 (d, J = 14.5 Hz, 1H), 7.85 (dd, J = 5.1, 1.8 Hz, 1H), 7.49 (d, J = 7.1 Hz, 1H), 6.85 (dd, J = 7.1, 5.0 Hz, 1H), 6.29 (d, J = 7.3 Hz, 1H), 4.62 – 4.48 (m, 1H), 4.32 – 4.12 (m, 2H), 3.52 – 3.40 (m, 1H), 3.30 – 3.21 (m, 1H), 2.17 – 1.82 (m, 7H). Potency Lin28a-dep Z11 IC50(µM) ++++Example 16: Synthesis of (R)-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-1-(5-(2- (dimethylamino)ethoxy)pyrazin-2-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of tert-butyl N-(5-chloropyrazin-2-yl)carbamateTo a mixture of 5-chloro-pyrazinamine (5 g, 38.59 mmol) in dioxane (50 mL) was added Boc2O (12 g, 54.98 mmol), DMAP (9 g, 73.66 mmol) and TEA (3.51 g, 10.78 mmol). The resulting mixture was stirred for 1 h at 100 °C. The reaction mixture was diluted with 500 ml H2O. The resulting solution was extracted with EtOAc (300 mL x 3) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluting with ACN / H2O (0.05% NH4HCO3) (80%-100%) to afford tert-butyl N-(5-chloropyrazin-2-yl)carbamate (8 g, 90% yield) as a yellow solid. LCMS (ESI) [M+H]+: 230.27. Step 2. Synthesis of tert-butyl N-[5-[2-(dimethylamino)ethoxy]pyrazin-2-yl]carbamateTo a mixture of tert-butyl N-(5-chloropyrazin-2-yl)carbamate (1 g, 4.35 mmol) in Toluene (10 mL) was added dimethylaminoethanol (1.55 g, 17.41 mmol), t-BuBrettPhos (211 mg, 0.43 mmol) , Pd2(allyl)2Cl2(159 mg, 0.43 mmol) and Cs2CO3(4.26 g, 13.06 mmol). The resulting mixture was stirred for 2 h at 80 °C. The reaction mixture was diluted with 200 mL H2O. The resulting solution was extracted with EtOAc (100 mL x 3) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified byreverse phase flash chromatography eluting with ACN / H2O (0.05% NH4HCO3) (80%-100%) to afford tert-butyl N-[5-[2-(dimethylamino)ethoxy]pyrazin-2-yl]carbamate (300 mg, 22 % yield) as a yellow oil. LCMS (ESI) [M+H]+: 601.24. Step 3. Synthesis of 5-[2-(dimethylamino)ethoxy]pyrazin-2-amineTo a mixture of tert-butyl N-[5-[2-(dimethylamino)ethoxy]pyrazin-2-yl]carbamate (180 mg, 0.63 mmol) in DCM (2 mL) was added TFA (2 mL). The resulting mixture was stirred for 1 h at room temperature. The filtrate was collected by filtration and concentrated to afford 5-[2- (dimethylamino)ethoxy]pyrazin-2-amine (200 mg, crude) as a yellow oil. LCMS (ESI) [M+H]+: 183.24. Step 4. Synthesis of ethyl (R)-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-1-(5-(2- (dimethylamino)ethoxy)pyrazin-2-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylateTo a mixture of ethyl (R,Z)-2-(4-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-2,5- difluorobenzoyl)-3-ethoxyacrylate (200 mg, 0.42 mmol) in DMSO (5.00 mL) was added 5-[2- (dimethylamino)ethoxy]pyrazin-2-amine (92 mg, 0.50 mmol). The resulting mixture was stirred for 1 h at room temperature. Then K2CO3(58 mg, 0.42 mmol) was added and stirred at 100 °C for 1 h. The reaction was quenched with water at room temperature. The solid was collected by filtration, washed by water and dried to afford ethyl (R)-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-1-(5- (2-(dimethylamino)ethoxy)pyrazin-2-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (100 mg, crude) as a yellow solid. LCMS (ESI) [M+H]+: 589.24. Step 5. Synthesis of (R)-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-1-(5-(2- (dimethylamino)ethoxy)pyrazin-2-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a mixture of ethyl (R)-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-1-(5-(2- (dimethylamino)ethoxy)pyrazin-2-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (100 mg, 0.17 mmol) in THF (3 mL) was added LiOH.H2O (35 mg, 0.83 mmol,) and H2O (1.00 mL). The mixture was stirred at room temperature for 2 h. The residue was purified by Prep.-HPLC (Column: YMC-Actus Triart C18, 20*250mm,5um,12nm; Mobile Phase A:Water(10mmol / L NH4HCO3), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:5 B to 61 B in 2 min; 254 nm; RT1:8.72) to afford (R)-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-1-(5-(2- (dimethylamino)ethoxy)pyrazin-2-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (6.0 mg, 6%) as a yellow solid. LCMS (ESI) [M+H]+:583.25.1H NMR (400 MHz, DMSO-d6) δ 8.89 – 8.48 (m, 2H), 8.30 (s, 1H), 8.14 – 7.53 (m, 3H), 6.99 (s, 1H), 6.28 – 6.17 (m, 1H), 4.65 – 4.40 (m, 3H), 4.35 – 4.15 (m, 2H), 3.35 (s, 1H), 3.21 (s, 1H), 2.68 (s, 2H), 2.27 – 2.22 (m, 6H), 2.08 (s, 2H), 1.99 – 1.81 (m, 2H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 17: Synthesis of (R)-1-(4-(2-(dimethylamino)ethoxy)phenyl)-6-fluoro-7-(2-(((3- methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of dimethyl[2-(4-nitrophenoxy)ethyl]amineTo a mixture of 4-nitrophenol (500 mg, 3.59 mmol) in DMF (10 mL) was added dimethylaminoethyl chloride hydrochloride (776 mg, 5.38 mmol) and Cs2CO3(3.51 g, 10.78 mmol). The resulting mixture was stirred for 1 h at 100 °C. The reaction mixture was diluted with 50 ml H2O. The resulting solution was extracted with EtOAc (100 mL x 3) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluting with ACN / H2O (0.05% NH4HCO3)(80%-100%) to afford dimethyl[2-(4-nitrophenoxy)ethyl]amine (400 mg, 47% yield) as a white solid. LCMS (ESI) [M+H]+: 211.24. Step 2. Synthesis of 4-[2-(dimethylamino)ethoxy]anilineUnder nitrogen, to a mixture of dimethyl[2-(4-nitrophenoxy)ethyl]amine (400 mg, 1.90 mmol) in MeOH (10 mL) was added Pd / C (99 mg, 0.93 mmol). Then the nitrogen atmosphere was replaced by hydrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature. The filtrate was collected by filtration and concentrated to afford 4-[2-(dimethylamino)ethoxy]aniline (250 mg, crude) as a yellow oil. LCMS (ESI) [M+H]+: 181.24. Step 3. Synthesis of ethyl 1-[4-[2-(dimethylamino)ethoxy]phenyl]-6-fluoro-7-[(2R)-2-[[(3- methylpyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-4-oxoquinoline-3-carboxylateTo a mixture of ethyl (2Z)-2-[(Z)-2,5-difluoro-4-[(2R)-2-[[(3-methylpyridin-2- yl)oxy]methyl]pyrrolidin-1-yl]benzoyl]-3-ethoxyprop-2-enoate (200 mg, 0.42 mmol) in DMSO (5.00 mL) was added 4-[2-(dimethylamino)ethoxy]aniline (91 mg, 0.50 mmol). The resulting mixture was stirred for 1 h at room temperature. Then K2CO3(58 mg, 0.42 mmol) was added and stirred at 100 °C for 1 h. The reaction was quenched with water at room temperature. The solid was collected byfiltration, washed by water and dried to afford ethyl 1-[4-[2-(dimethylamino)ethoxy]phenyl]-6-fluoro- 7-[(2R)-2-[[(3-methylpyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-4-oxoquinoline-3-carboxylate (250 mg ,crude) as a yellow solid. LCMS (ESI) [M+H]+: 589.24. Step 4. Synthesis of (R)-1-(4-(2-(dimethylamino)ethoxy)phenyl)-6-fluoro-7-(2-(((3- methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a mixture of ethyl 1-[4-[2-(dimethylamino)ethoxy]phenyl]-6-fluoro-7-[(2R)-2-[[(3-methylpyridin- 2-yl)oxy]methyl]pyrrolidin-1-yl]-4-oxoquinoline-3-carboxylate (250 mg, 0.42 mmol) in THF (3 mL) was added LiOH.H2O (142 mg, 3.38 mmol) and H2O (1.00 mL). The mixture was stirred at room temperature for 2 h. The residue was purified by Prep.-HPLC (Column: Gemini-NX C18 AXAI Packed, 21.2*150mm 5um; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:23 B to 30 B in 9 min; 254 nm; RT1:6.67) to afford (R)-1-(4-(2- (dimethylamino)ethoxy)phenyl)-6-fluoro-7-(2-(((3-methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-4- oxo-1,4-dihydroquinoline-3-carboxylic acid (46.2 mg, 19%) as a yellow solid. LCMS (ESI) [M+H]+: 561.25.1H NMR (300 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.19 (s, 1H), 7.94 – 7.83 (m, 2H), 7.57 – 7.45 (m, 3H), 7.21 (s, 1H), 6.98 (s, 1H), 6.92 – 6.82 (m, 1H), 6.10 (m, 1H), 4.43 (s, 1H), 4.23 (m, 1H), 4.13 (m, 3H), 3.37 (s, 1H), 3.21 (s, 1H), 2.69 (m, 2H), 2.06 (s, 6H), 2.04 (s, 2H), 1.99 – 1.85 (s, 5H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 18: Synthesis of (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)- 1-(1,3-dihydroisobenzofuran-5-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of ethyl (R)-3-(5-chloro-4-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1- yl)-2-fluorophenyl)-3-oxopropanoatTo a mixture of ethyl 3-(5-chloro-2,4-difluorophenyl)-3-oxopropanoate (500 mg, 1.90 mmol) in ACN (5 mL) was added 3-chloro-2-[(2R)-pyrrolidin-2-ylmethoxy]pyridine (485 mg, 2.28 mmol) and TEA (1.16 g, 11.42 mmol). The resulting mixture was stirred for 2 h at 80 °C. The residue was purified by reverse phase flash chromatography eluting with ACN / H2O (0.05%NH4HCO3) (60%-80%) to afford ethyl (R)-3-(5-chloro-4-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-2-fluorophenyl)-3- oxopropanoate (300 mg, 33% yield) as a yellow oil. LCMS (ESI) [M+H]+: 455.24. Step 2. Synthesis of ethyl (R,Z)-2-(5-chloro-4-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin- 1-yl)-2-fluorobenzoyl)-3-ethoxyacrylateTo a mixture of ethyl (R)-3-(5-chloro-4-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-2- fluorophenyl)-3-oxopropanoate (300 mg, 0.65 mmol) in acetic anhydride (146 mg, 1.43 mmol) were added triethyl orthoformate (106 mg, 0.71 mmol). The resulting mixture was stirred for 8 h at 80 °C.The solvent was concentrated under vacuum to afford ethyl (R,Z)-2-(5-chloro-4-(2-(((3-chloropyridin- 2-yl)oxy)methyl)pyrrolidin-1-yl)-2-fluorobenzoyl)-3-ethoxyacrylate (360 mg, crude) as a yellow oil. LCMS (ESI) [M+H]+: 511.24. Step 3. Synthesis of ethyl (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrolidin-1-yl)-1- (1,3-dihydroisobenzofuran-5-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylateTo a mixture of ethyl (R,Z)-2-(5-chloro-4-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-2- fluorobenzoyl)-3-ethoxyacrylate (360 mg, 0.70 mmol) in DMSO (5.00 mL) was added 1,3-dihydro-2- benzofuran-5-amine (114 mg, 0.84 mmol). The resulting mixture was stirred for 1 h at 100 °C. Then K2CO3(97 mg, 0.70 mmol) was added and stirred at 100 °C for 1 h. The reaction was quenched with water at room temperature. The solid was collected by filtration, washed by water and dried to afford ethyl (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-1-(1,3- dihydroisobenzofuran-5-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (350 mg, crude) as a yellow solid. LCMS (ESI) [M+H]+: 580.20. Step 4. Synthesis of (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrolidin-1-yl)-1-(1,3- dihydroisobenzofuran-5-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a mixture of ethyl (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-1-(1,3- dihydroisobenzofuran-5-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (350 mg, 0.60 mmol) in THF (3 mL) was added LiOH.H2O (57 mg, 2.38 mmol) and H2O (1.00 mL). The mixture was stirred at room temperature for 2 h. The residue was purified by Prep.-HPLC(Column: XSelect CSH Prep C18 OBD Column,, 5um,19*150mm ; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:53 B to 77 B in 8 min; 254 nm; RT1:7.2) to afford (R)-6-chloro-7-(2-(((3- chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-1-(1,3-dihydroisobenzofuran-5-yl)-4-oxo-1,4- dihydroquinoline-3-carboxylic acid (70 mg, 21%) as a yellow solid. LCMS (ESI) [M+H]+: 552.0.1HNMR (300 MHz, DMSO-d6) δ 15.08 (s, 1H), 8.55 (s, 1H), 8.17 (s, 1H), 7.89 (d, J = 4.8 Hz, 1H), 7.83 (dd, J = 7.7, 1.6 Hz, 1H), 7.74 – 7.27 (m, 3H), 7.03 – 6.87 (m, 1H), 6.37 (d, J = 4.3 Hz, 1H), 5.11 (s, 3H), 5.04 – 4.84 (m, 1H), 4.71 – 4.55 (m, 1H), 4.36 – 4.19 (m, 2H), 3.58 – 3.40 (m, 1H), 3.26 – 3.09 (m, 1H), 2.26 (d, J = 15.5 Hz, 1H), 2.05 – 1.65 (m, 3H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 19: Synthesis of (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)- 4-oxo-1-(pyrazin-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acidStep 1. Synthesis of ethyl 3-oxo-3-(2,5,6-trichloropyridin-3-yl)propanoateUnder a nitrogen atmosphere, a mixture of 2,5,6-trichloropyridine-3-carboxylic acid (1.8 g, 7.95 mmol) and CDI (1.6 g, 9.54 mmol) in THF (40 mL) was stirred for 3 h at 60 °C. Then the mixture was added to a suspension of 1-ethyl 3-potassium propanedioate (1.4 g, 7.93 mmol), Et3N (116 mg, 1.15 mmol), MgCl2(1.1 g, 12.00 mmol) in THF (40 mL) and the mixture was stirred overnight at room temperature. Then the reaction was adjusted pH to 3-4 with 1N HCl (aq.). The mixture was diluted with EtOAc (200 mL), washed with water (80 mL), brine (80 mL), dried over Na2SO4, filtrated, concentrated and purified by flash chromatography on silica gel eluting with EtOAc / Petroleum ether (0-100%) to afford ethyl 3-oxo-3-(2,5,6-trichloropyridin-3-yl)propanoate (300 mg,12.73%) as a light yellow oil. LCMS (ESI) [M+H]+: 296. Step 2. Synthesis of ethyl 6,7-dichloro-4-oxo-1-(pyrazin-2-yl)-1,8-naphthyridine-3-carboxylateUnder a nitrogen atmosphere, a mixture of ethyl 3-oxo-3-(2,5,6-trichloropyridin-3-yl)propanoate (300 mg, 1.01 mmol) and triethyl orthoformate (225 mg, 1.52 mmol) in Ac2O (620 mg, 6.07 mmol) was stirred for 1 h at 100 °C. Then the mixture was evaporated to give the residue. The residue was dissolved in DMSO (5 mL) and 2-aminopyrazine (96 mg, 1.01 mmol) was added and the mixture was stirred for 1 h. Then K2CO3(140 mg, 1.01 mmol) was added into the mixture and stirred for additional 1 h at room temperature. Then the reaction was adjusted pH to 3-4 with 1N HCl (aq.). The mixture was diluted with EtOAc (200 mL), washed with water (80 mL), brine (80 mL), dried over Na2SO4, filtrated, concentrated and purified by flash chromatography on silica gel eluting with EtOAc / Petroleum ether (0-100%) to afford ethyl 6,7-dichloro-4-oxo-1-(pyrazin-2-yl)-1,8- naphthyridine-3-carboxylate (240 mg, 64.96%) as a red solid. LCMS (ESI) [M+H]+: 365. Step 3. Synthesis of ethyl (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)- 4-oxo-1-(pyrazin-2-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylateUnder a nitrogen atmosphere, a mixture of ethyl 6,7-dichloro-4-oxo-1-(pyrazin-2-yl)-1,8- naphthyridine-3-carboxylate (70 mg, 0.19 mmol), 3-chloro-2-[(2R)-pyrrolidin-2-ylmethoxy]pyridine (61 mg, 0.29 mmol), Et3N (116 mg, 1.15 mmol) and ACN (3 mL) was stirred overnight at 80 °C. The reaction was cooled to room temperature and used directly without further purification. LCMS (ESI) [M+H]+: 541. Step 4. Synthesis of 6-chloro-7-[(2R)-2-[[(3-chloropyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-4- oxo-1-(pyrazin-2-yl)-1,8-naphthyridine-3-carboxylic acidLiOH.H2O (1N, 0.38 mL, 0.38 mmol) in water was added into the mixture from the previous step and the mixture was stirred for 2 h. Then the reaction was adjusted pH to 3-4. The mixture was filtrated, washed with water and ACN. The filtrate was evaporated under reduced pressure to afford 6- chloro-7-[(2R)-2-[[(3-chloropyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-4-oxo-1-(pyrazin-2-yl)-1,8- naphthyridine-3-carboxylic acid (23.4 mg, 22.59%) as a light yellow solid. LCMS (ESI) [M+H]+: 513.1.1H NMR (300 MHz, Chloroform-d) δ 14.60 (s, 1H), 9.09 (d, J = 1.4 Hz, 1H), 9.02 (s, 1H), 8.61 (d, J = 2.5 Hz, 1H), 8.53 (dd, J = 2.5, 1.5 Hz, 1H), 8.48 (s, 1H), 7.91 (dd, J = 4.9, 1.7 Hz, 1H), 7.63 (dd, J = 7.6, 1.7 Hz, 1H), 6.85 (dd, J = 7.6, 4.9 Hz, 1H), 4.86 (m, 1H), 4.34 – 4.19 (m, 2H), 4.15 – 3.97 (m, 1H), 3.95 – 3.78 (m, 1H), 2.28 – 2.03 (m, 3H), 2.02 – 1.84(m, J = 7.2 Hz, 1H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 20: Synthesis of (R)-6,8-difluoro-1-(2-fluoro-4-hydroxyphenyl)-7-(2-(((3- methylpyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of ethyl 6,7,8-trifluoro-1-(2-fluoro-4-hydroxyphenyl)-4-oxoquinoline-3- carboxylateA mixture of ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propanoate (300 mg, 1.13 mmol), triethyl orthoformate (252 mg, 1.70 mmol) and acetic anhydride (347 mg, 3.40 mmol) at 100 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. To the residue in DMSO (5 mL) was added 4-amino-3-fluorophenol (129 mg, 1.02 mmol) and the mixture was stirred for 12 h at room temperature. Then K2CO3(156 mg, 1.13 mmol) was added and the resulting mixture was stirred for 2 h at room temperature. Then the reaction was quenched with water (5 mL). The precipitated solids were collected by filtration and washed with water (2x10 mL). This resulted in ethyl 6,7,8-trifluoro-1-(2-fluoro-4-hydroxyphenyl)-4-oxoquinoline-3-carboxylate (140 mg, 32.4%) as a yellow solid. LCMS (ESI) [M+H]+: 382. Step 2. Synthesis of ethyl 6,8-difluoro-1-(2-fluoro-4-hydroxyphenyl)-7-[(2R)-2-[[(3- methylpyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-4-oxoquinoline-3-carboxylateA mixture of 3-methyl-2-[(2R)-pyrrolidin-2-ylmethoxy]pyridine (212 mg, 1.10 mmol), Et3N (223 mg, 2.20 mmol), DMSO (2 mL) and ethyl 6,7,8-trifluoro-1-(2-fluoro-4-hydroxyphenyl)-4-oxoquinoline-3- carboxylate (210 mg, 0.55 mmol) was stirred for 12 h at 100 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The aqueous layer was extracted with EtOAc (3x10 mL). The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography eluting with ACN / H2O (0-95%) to afford ethyl 6,8-difluoro-1-(2-fluoro-4-hydroxyphenyl)-7-[(2R)-2-[[(3- methylpyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-4-oxoquinoline-3-carboxylate (60 mg, 19.7%) as a light yellow solid. LCMS (ESI) [M+H]+: 554. Step 3. Synthesis of 6,8-difluoro-1-(2-fluoro-4-hydroxyphenyl)-7-[(2R)-2-[[(3-methylpyridin-2- yl)oxy]methyl]pyrrolidin-1-yl]-4-oxoquinoline-3-carboxylic acidTo a stirred solution of ethyl 6,8-difluoro-1-(2-fluoro-4-hydroxyphenyl)-7-[(2R)-2-[[(3- methylpyridin-2-yl)oxy]methyl]pyrrolidin-1-yl]-4-oxoquinoline-3-carboxylate (60.0 mg, 0.10 mmol) in THF (2 mL) was added LiOH.H2O (23 mg, 0.54 mmol) and H2O (0.5 mL) and the mixture was stirred for 2 h at room temperature. The resulting mixture was purified by Prep.-HPLC with the following conditions (Column: Gemini-NX C18 AXAI Packed, 21.2*150mm 5um; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:60 B to 65 B in 8 min; 254 nm) to afford 6,8-difluoro-1-(2-fluoro-4-hydroxyphenyl)-7-[(2R)-2-[[(3-methylpyridin-2- yl)oxy]methyl]pyrrolidin-1-yl]-4-oxoquinoline-3-carboxylic acid (10.4 mg, 18.26%) as a light yellow solid. LCMS (ESI) [M+H]+: 526.2.1H NMR (300 MHz, DMSO-d6) δ 14.75 (s, 1H), 10.51 (s, 1H), 8.47 (s, 1H), 7.90 – 7.71 (m, 2H), 7.62 – 7.47 (m, 1H), 7.43 (d, J = 7.3 Hz, 1H), 6.91 – 6.64 (m, 3H), 4.61 – 4.42 (m, 1H), 4.33 – 4.12 (m, 2H), 3.77 – 3.61 (m, 1H), 3.41 – 3.36 (m, 1H), 2.25 – 2.13 (m, 1H), 2.03 – 1.90 (m, 1H), 1.86 – 1.71 (m, 5H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 21: Synthesis of (R)-7-(2-(((3-bromopyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-6-fluoro- 1-(4-(2-hydroxyethoxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of 2-(4-nitrophenoxy)ethan-1-olTo a mixture of 1-fluoro-4-nitrobenzene (3.0 g, 21.27 mmol) and ethane-1,2-diol (2.6 g, 42.55 mmol) in DMF (40 mL) was added K2CO3(8.8 g, 63.81 mmol). The mixture was stirred at room temperature for 16 h. The mixture was poured into ice water. The mixture was filtered. The filtrate was extracted with EtOAc (50 mL x 3). The combined organic phase was dried over Na2SO4and concentrated to afford 2-(4-nitrophenoxy)ethan-1-ol (1.0 g, 26%) as yellow solid.1H NMR (300 MHz, DMSO-d6) δ 8.26 – 8.16 (m, 2H), 7.21 – 7.12 (m, 2H), 4.97 (t, J = 5.5 Hz, 1H), 4.19 – 4.10 (m, 2H), 3.75 (q, J = 5.1 Hz, 2H). Step 2. Synthesis of 2-(4-aminophenoxy)ethan-1-olTo a solution of 2-(4-nitrophenoxy)ethan-1-ol (1.0 g, 5.46 mmol) in MeOH (15 mL) was added Pd / C (200 mg). The mixture was degassed and stirred at room temperature under H2for 1.5 h. The mixture was filtered. The filtrate was concentrated to afford 2-(4-aminophenoxy)ethan-1-ol (700 mg, 84%) as yellow oil. LCMS (ESI) [M+H]+: 154. Step 3. Synthesis of ethyl 6,7-difluoro-1-(4-(2-hydroxyethoxy)phenyl)-4-oxo-1,4- dihydroquinoline-3-carboxylateTo a solution of ethyl (Z)-3-ethoxy-2-(2,4,5-trifluorobenzoyl)acrylate (1.2 g, 4.07 mmol) in DMSO (25 mL) was added 2-(4-aminophenoxy)ethan-1-ol (622 mg, 4.07 mmol). The solution was stirred at room temperature for 1 h. K2CO3(673 mg, 4.88 mmol) was then added. The mixture was stirred at room temperature for another 1 h. The reaction mixture was poured into water. The solid was collected by filtration and dried to afford ethyl 6,7-difluoro-1-(4-(2-hydroxyethoxy)phenyl)-4-oxo- 1,4-dihydroquinoline-3-carboxylate (1.4 g, 88%) as light yellow solid. LCMS (ESI) [M+H]+: 390.Step 4. Synthesis of ethyl (R)-7-(2-(((3-bromopyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-6-fluoro- 1-(4-(2-hydroxyethoxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylateTo a solution of ethyl 6,7-difluoro-1-(4-(2-hydroxyethoxy)phenyl)-4-oxo-1,4-dihydroquinoline-3- carboxylate (500 mg, 1.28 mmol) and TEA (648 mg, 6.40 mmol) in DMSO (10 mL) was added (R)-3- bromo-2-(pyrrolidin-2-ylmethoxy)pyridine (987 mg, 3.85 mmol). The mixture was stirred at 100 °C for 3 h. The reaction solution was purified by reverse phase flash column with 40- 80% acetonitrile in water to afford ethyl (R)-7-(2-(((3-bromopyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-6-fluoro-1-(4-(2- hydroxyethoxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (670 mg, 84%) as light yellow solid. LCMS (ESI) [M+H]+: 626. Step 5. Synthesis of (R)-7-(2-(((3-bromopyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-6-fluoro-1-(4- (2-hydroxyethoxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a stirred solution of ethyl (R)-7-(2-(((3-bromopyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-6-fluoro-1- (4-(2-hydroxyethoxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (60 mg, 0.10 mmol) in THF (1 mL) at room temperature under nitrogen was added LiOH.H2O (16 mg, 0.38 mmol) in water (1 mL). The mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of HOAc to adjust pH 5. The mixture was purified by prep-HPLC (Column: XSelect CSH Prep C18 OBD Column,, 5um,19*150mm ; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:25 mL / min; Gradient:38 B to 68 B in 8 min; 254 nm; RT1:7.65) to afford (R)-7-(2-(((3-bromopyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-6-fluoro-1-(4-(2-hydroxyethoxy)phenyl)-4-oxo-1,4- dihydroquinoline-3-carboxylic acid (32.3 mg, 54%) as off-white solid. LCMS (ESI) [M+H]+: 600.10.1H NMR (300 MHz, DMSO-d6) δ 15.43 (s, 1H), 8.47 (s, 1H), 8.06 – 7.95 (m, 2H), 7.88 (d, J = 14.4 Hz, 1H), 7.58 – 7.49 (m, 2H), 7.24 – 7.14 (m, 1H), 7.09 – 6.99 (m, 1H), 6.98 – 6.88 (m, 1H), 6.08 (d, J = 7.5 Hz, 1H), 4.97 (t, J = 5.4 Hz, 1H), 4.50 – 4.44 (m, 1H), 4.35 – 4.29 (m, 2H), 4.11 – 4.02 (m, 2H), 3.83 – 3.72 (m, 2H), 3.33 – 3.25 (m, 1H), 3.21 – 3.13 (m, 1H), 2.14 – 2.02 (m, 2H), 2.04 – 1.81 (m, 2H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 22: Synthesis of (R)-6-fluoro-1-(2-fluoro-4-hydroxyphenyl)-4-oxo-7-(2-((pyrimidin-2- yloxy)methyl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of ethyl 6,7-difluoro-1-[2-fluoro-4-[(4-methoxyphenyl)methoxy]phenyl]-4- oxoquinoline-3-carboxylateTo a solution of ethyl 6,7-difluoro-1-(2-fluoro-4-hydroxyphenyl)-4-oxoquinoline-3-carboxylate (10.0 g, 27.53 mmol, 1.0 equiv) in DMF (100 mL) was added K2CO3(11.4 g, 82.58 mmol, 3.0 equiv) and 4-methoxybenzyl chloride (6.5 g, 41.29 mmol, 1.5 equiv). The reaction was stirred at 70 ° C for 2 h. The reaction was then quenched by water. The resulting solution was extracted with 150 x 3 mL of ethyl acetate. The organic layers combined and dried over anhydrous sodium sulfate, concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane / ethyl acetate (1 / 2). This resulted in ethyl 6,7-difluoro-1-[2-fluoro-4-[(4-methoxyphenyl)methoxy]phenyl]-4- oxoquinoline-3-carboxylate (4.2 g, 31.6%) as yellow oil. LCMS (ESI) [M+H]+: 484.Step 2. Synthesis of ethyl 6-fluoro-7-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-1-[4-[(4- methoxyphenyl)methoxy]phenyl]-4-oxoquinoline-3-carboxylateTo a solution of ethyl 6,7-difluoro-1-[4-[(4-methoxyphenyl)methoxy]phenyl]-4-oxoquinoline-3- carboxylate (2.0 g, 4.30 mmol, 1.0 equiv) in DMSO (25 mL) was added K2CO3(1.8 g, 12.89 mmol, 3.0 equiv) and (R)-pyrrolidin-2-ylmethanol (650 mg, 6.45 mmol, 1.5 equiv). The reaction was stirred at 100 °C for 2 h under N2atmosphere. The crude product was purified by Flash-Prep-HPLC with the NH4HCO3 / acetonitrile = 40% increasing to 50% within 15 min; Detector, 254 / 220 nm. This resulted in ethyl 6-fluoro-7-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]-1-[4-[(4- methoxyphenyl)methoxy]phenyl]-4-oxoquinoline-3-carboxylate (1.5 g, 63.9%) as yellow oil. LCMS (ESI) [M+H]+: 547. Step 3. Synthesis of (R)-6-fluoro-1-(2-fluoro-4-((4-methoxybenzyl)oxy)phenyl)-4-oxo-7-(2- ((pyrimidin-2-yloxy)methyl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acidTo a solution of ethyl 6-fluoro-1-[2-fluoro-4-[(4-methoxyphenyl) methoxy] phenyl]-7-[(2R)-2- (hydroxymethyl) pyrrolidin-1-yl]-4-oxoquinoline-3-carboxylate (150 mg, 0.27 mmol, 1.0 equiv) in THF (5 mL) was added NaH (10 mg, 0.40 mmol, 1.5 equiv). The reaction was stirred at room temperature for 0.5 h. Then, 2-chloropyrimidine (37 mg, 0.32 mmol, 1.2 equiv) was added into the solution. The reaction was stirred at room temperature for 2 h. The reaction was then quenched by the addition of water. The residue was purified by reverse phase flash chromatography to afford (R)-6- fluoro-1-(2-fluoro-4-((4-methoxybenzyl)oxy)phenyl)-4-oxo-7-(2-((pyrimidin-2- yloxy)methyl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (12.3 mg, 7.53%) as a light yellow solid. LCMS (ESI): [M+H]+: 615.15.1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.7 Hz,2H), 8.38 (s, 1H), 7.82 (d, J = 14.8 Hz, 1H), 7.69 – 7.57 (m, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.34 – 7.26 (m, 0.5H), 7.16 – 7.03 (m, 2H), 7.03 – 6.96 (m, 2H), 6.92 – 6.86 (m, 0.5H), 6.00 – 5.91 (m, 1H), 5.19 – 5.04 (m, 2H), 4.37 – 4.17 (m, 3H), 3.79 (s, 3H), 3.31 – 3.29 (m, 1H), 3.21 – 3.13 (m, 1H), 2.14 – 1.85 (m, 4H). Step 4. Synthesis of (R)-6-fluoro-1-(2-fluoro-4-hydroxyphenyl)-4-oxo-7-(2-((pyrimidin-2- yloxy)methyl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acidTo a solution of (R)-6-fluoro-1-(2-fluoro-4-((4-methoxybenzyl)oxy)phenyl)-4-oxo-7-(2-((pyrimidin- 2-yloxy)methyl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (30 mg, 0.05 mmol, 1.0 equiv) in DCM (2 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 2 h. The solution concentrated under vacuum. The residue was purified by the prep-HPLC with the following conditions: Column: X Select CSH Prep C18 OBD Column, 5um, 19*150mm; Mobile Phase A: Water (0.05%FA), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 30 B to 55 B in 8 min; 254 nm. This resulted in (R)-6-fluoro-1-(2-fluoro-4-hydroxyphenyl)-4-oxo-7-(2- ((pyrimidin-2-yloxy)methyl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (10.3 mg, 42.68%) as a yellow solid. LCMS (ESI) [M+H]+: 495.30.1H NMR (400 MHz, DMSO-d6) δ 15.29 (s, 1H), 10.62 (s, 1H), 8.60 (d, J = 2.8 Hz, 1H), 8.52 (dd, J = 4.8, 1.8 Hz, 2H), 7.88 (dd, J = 14.5, 2.2 Hz, 1H), 7.60 – 7.50 (m, 1H), 7.17 – 7.08 (m, 4.8 Hz, 1H), 6.94 – 6.81 (m, 1H), 6.73 – 6.65 (m, 1H), 6.08 – 6.00 (m, 1H), 4.44 (s, 1H), 4.35 – 4.22 (m, 2H), 3.32 – 3.30 (m, 1H), 3.26 – 3.17 (m, 1H), 2.17 – 1.88 (m, 4H). Potency Lin28a-dep Z11 IC50(µM) +++ Example 23: Synthesis of (R)-6-fluoro-1-(4-hydroxyphenyl)-7-(2-((5-methyl-6-oxopyridazin- 1(6H)-yl)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of ethyl (R)-6-fluoro-7-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-(4-((4- methoxybenzyl)oxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylateInto a 10-mL sealed tube, was placed ethyl 6,7-difluoro-1-(4-((4-methoxybenzyl)oxy)phenyl)-4-oxo- 1,4-dihydroquinoline-3-carboxylate (820.0 mg, 1.762 mmol), DMSO (5.0 mL), Et3N (1782.7 mg, 17.617 mmol), (R)-pyrrolidin-2-ylmethanol (213.8 mg, 2.114 mmol). The resulting solution was stirred for 15 hour at 80 °C. The residue was purified by reverse phase flash chromatography eluting with ACN / water (0%-70%, basic system). This resulted in 780 mg (81.00%) of ethyl (R)-6-fluoro-7- (2-(hydroxymethyl)pyrrolidin-1-yl)-1-(4-((4-methoxybenzyl)oxy)phenyl)-4-oxo-1,4- dihydroquinoline-3-carboxylate as a yellow solid. LCMS (ESI) [M+H]+: 547. Step 2. Synthesis of ethyl (R)-7-(2-(bromomethyl)pyrrolidin-1-yl)-6-fluoro-1-(4-((4- methoxybenzyl)oxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylateInto a 40-mL sealed tube, was placed ethyl (R)-6-fluoro-7-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-(4- ((4-methoxybenzyl)oxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (500.0 mg, 0.915 mmol), DCM (10.0 mL), PPh3 (719.8 mg, 2.744 mmol), CBr4 (910.1 mg, 2.744 mmol). The resulting solution was stirred for 2 hours at 0 °C. The resulting solution was extracted with 3x50 mL of dichloromethane. The organic phase was combined and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with ethyl acetate / petroleum ether (1:2). This resulted in 400 mg(71.74%, crude) of ethyl (R)-7-(2-(bromomethyl)pyrrolidin-1-yl)-6-fluoro-1-(4-((4- methoxybenzyl)oxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a brown solid. LCMS (ESI) [M+H]+: 569. Step 3. Synthesis of ethyl (R)-6-fluoro-1-(4-((4-methoxybenzyl)oxy)phenyl)-7-(2-((5-methyl-6- oxopyridazin-1(6H)-yl)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylateInto a 40-mL sealed tube, was placed ethyl (R)-7-(2-(bromomethyl)pyrrolidin-1-yl)-6-fluoro-1-(4-((4- methoxybenzyl)oxy)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (300.0 mg, 0.492 mmol), DMF (10.0 mL), K2CO3(204.1 mg, 1.477 mmol), 4-methylpyridazin-3-ol (54.2 mg, 0.492 mmol). The resulting solution was stirred for 2 hour at 80 °C. The residue was purified by reverse phase flash chromatography eluting with ACN / water (0%-50%, basic system). This resulted in 200 mg (63.62%, crude) of ethyl (R)-6-fluoro-1-(4-((4-methoxybenzyl)oxy)phenyl)-7-(2-((5-methyl-6-oxopyridazin- 1(6H)-yl)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellow solid. LCMS (ESI) [M+H]+: 639. Step 4. Synthesis of (R)-6-fluoro-1-(4-((4-methoxybenzyl)oxy)phenyl)-7-(2-((5-methyl-6- oxopyridazin-1(6H)-yl)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidInto a 10-mL sealed tube, was placed ethyl (R)-6-fluoro-1-(4-((4-methoxybenzyl)oxy)phenyl)-7-(2- ((5-methyl-6-oxopyridazin-1(6H)-yl)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylate (200.0 mg, 0.313 mmol), LiOH.H2O (65.7 mg, 1.566 mmol), THF (4.0 mL), H2O (2.0 mL). The resulting solution was stirred for 2 hours at room temperature. The pH value of the solution was adjusted to 4-5 with AcOH. The solids were collected by filtration. This resulted in 160 mg (83.68%) of (R)-6-fluoro-1-(4-((4-methoxybenzyl)oxy)phenyl)-7-(2-((5-methyl-6-oxopyridazin- 1(6H)-yl)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a yellow solid. LCMS (ESI) [M+H]+: 611.Step 5. Synthesis of (R)-6-fluoro-1-(4-hydroxyphenyl)-7-(2-((5-methyl-6-oxopyridazin-1(6H)- yl)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidInto a 10-mL sealed tube, was placed (R)-6-fluoro-1-(4-((4-methoxybenzyl)oxy)phenyl)-7-(2-((5- methyl-6-oxopyridazin-1(6H)-yl)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (80.0 mg, 0.131 mmol) and TFA (2.0 mL). The resulting solution was stirred for 2 hours at room temperature. The residue was purified by reverse phase flash chromatography eluting with ACN / water (0%-40%, basic system). This resulted in 20 mg (31.12%) of (R)-6-fluoro-1-(4-hydroxyphenyl)-7-(2- ((5-methyl-6-oxopyridazin-1(6H)-yl)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylic acid as a solid. LCMS (ESI) [M+H]+: 491.1H NMR (300 MHz, DMSO-d6) δ 15.42 (s, 1H), 10.17 (s, 1H), 8.45 (s, 1H), 7.80 (d, J = 14.4 Hz, 1H), 7.66 (d, J = 3.9 Hz, 1H), 7.45 (s, 2H), 7.20 (d, J = 3.7 Hz, 1H), 7.00 (m, 2H), 6.31 (d, J = 7.4 Hz, 1H), 4.38 (s, 1H), 4.27 – 4.07 (m, 1H), 3.96 – 3.72 (m, 1H), 3.52 (s, 1H), 3.28 (s, 1H), 2.00 (s, 3H), 1.92 (s, 3H), 1.76 (s, 1H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 24: Synthesis of (R)-6-chloro-1-(1-methylcyclopropyl)-4-oxo-7-(2-oxo-5-((pyridin-2- yloxy)methyl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acidStep 1. Synthesis of (R)-5-((pyridin-2-yloxy)methyl)pyrrolidin-2-oneUnder nitrogen, into a 40-mL sealed tube, was placed (R)-5-(hydroxymethyl)pyrrolidin-2-one (500.0 mg, 4.343 mmol), DMF (10.0 mL), 2-fluoropyridine (506.0 mg, 5.211 mmol), tert-butoxypotassium (1462.0 mg, 13.029 mmol). The resulting solution was stirred for 5 hour at 80 °C. The residue was purified by reverse phase flash chromatography eluting with ACN / water (0%-40%, basic system). This resulted in 600 mg (71.9%) of (R)-5-((pyridin-2-yloxy)methyl)pyrrolidin-2-one as an off-white solid. LCMS (ESI) [M+H]+: 193. Step 2. Synthesis of (R)-6-chloro-1-(1-methylcyclopropyl)-4-oxo-7-(2-oxo-5-((pyridin-2- yloxy)methyl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acidUnder nitrogen, into a 10-mL sealed tube was placed 6-chloro-7-fluoro-1-(1-methylcyclopropyl)-4- oxo-1,4-dihydroquinoline-3-carboxylic acid (100.0 mg, 0.338 mmol), DMSO (3.0 mL), (R)-5- ((pyridin-2-yloxy)methyl)pyrrolidin-2-one (78.0 mg, 0.406 mmol), tert-butoxypotassium (113.9 mg, 1.015 mmol). The resulting solution was stirred for 15 hour at room temperature. The residue was purified by reverse phase flash chromatography eluting with ACN / water (0%-50%, basic system). This resulted in 36.8 mg (23.26%) of (R)-6-chloro-1-(1-methylcyclopropyl)-4-oxo-7-(2-oxo-5- ((pyridin-2-yloxy)methyl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid as a white solid. LCMS (ESI) [M+H]+: 468.2.1H NMR (300 MHz, DMSO-d6) δ 14.66 (s, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 8.29 – 8.05 (m, 2H), 7.56 (d, J = 9.0 Hz, 1H), 6.92 (m, 1H), 6.46 (d, J = 8.0 Hz, 1H), 4.71 (s, 1H), 4.54 – 4.19 (m, 2H), 2.82 – 2.55 (m, 3H), 2.12 (m, 1H), 1.42 (m, 4H), 1.22 – 0.90 (m, 3H). Potency Lin28a-dep Z11 IC50(µM) +Example 25: 6-fluoro-1-[3-(methoxymethyl) cyclobutyl]-4-oxo-7-[(2R)-2-[(pyridin-2-yloxy) methyl] pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of N, N-dibenzyl-3-(methoxymethyl) cyclobutan-1-amineTo a stirred suspension of sodium hydride (63.5 mg, 2.65 mmol) in THF (10 mL), was added [3- (dibenzylamino) cyclobutyl] methanol (500 mg, 1.77 mmol) at 0 °C and stirred for 30 min at same temperature before the addition of dimethyl sulfate (200 µL, 2.12 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 2h. The reaction mixture was quenched with ice cold saturated ammonium chloride solution and the product was extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The obtained crude material was purified by silica gel column chromatography using 10% EtOAc / hexane. The relevant fractions containing the product were combined and distilled under vaccum to N, N- dibenzyl-3-(methoxymethyl) cyclobutan-1-amine (300 mg, 56%) as a colorless liquid. MS (ESI) m / z: 296.5 [M+H]+. Step 2: Synthesis of 3-(methoxymethyl)cyclobutan-1-amine hydrochlorideTo a stirred solution of N, N-dibenzyl-3-(methoxymethyl) cyclobutan-1-amine (2.4 g, 8.12 mmol) in EtOH (30 mL), was added acetic acid (1 mL) followed by 10% Pd / C (864 mg, 8.12 mmol) under nitrogen atmosphere. The reaction mixture was hydrogenated under balloon pressure at room temperature for 16 h. The reaction mixture was filtered through celite pad and the filtrate was evaporated to afford crude. The crude was dissolved in dioxane and added 4M HCl in dioxane, stirred for 10 min. The volatiles were evaporated and the crude residue was triturated with diethyl ether, dried under vacuum to afford 3-(methoxymethyl) cyclobutan-1-amine hydrochloride (800 mg, 65%) as a colorless sticky gum which was taken forward for the next step without any purification. Step 3: Synthesis of ethyl 6-fluoro-1-[3-(methoxymethyl)cyclobutyl]-4-oxo-7-[(2R)-2-[(pyridin-2- yloxy)methyl]pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylateTo a stirred solution of ethyl (R, Z)-2-(2,5-difluoro-4-(2-((pyridin-2-yloxy) methyl) pyrrolidin-1-yl) benzoyl)-3-ethoxyacrylate (300 mg, 0.652 mmol) in DMSO (3 mL), were added 3-(methoxymethyl) cyclobutan-1-amine hydrochloride (134 mg, 889 µmol), triethyl amine (0.18 ml, 1.78 mmol) then stirred for 1 h. Potassium carbonate (153 mg, 1.11 mmol) was added, the reaction mixture was heated to 80 °C and stirred for 2 h. After completion of reaction, the reaction mixture was cooled to room temperature and diluted with ice cold water. The precipitated solid was collected by filtration washed with water and dried under vacuum to afford ethyl 6-fluoro-1-[3-(methoxymethyl)cyclobutyl]-4-oxo- 7-[(2R)-2-[(pyridin-2-yloxy) methyl]pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylate (77.7 mg, 20.6%) as an off white solid.MS (ESI) m / z: 510.2 [M+H]+Step 4: Synthesis of 6-fluoro-1-[3-(methoxymethyl)cyclobutyl]-4-oxo-7-[(2R)-2-[(pyridin-2- yloxy)methyl]pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylic acidExperimental procedure as described above to obtain 6-fluoro-1-[3-(methoxymethyl) cyclobutyl]-4- oxo-7-[(2R)-2-[(pyridin-2-yloxy) methyl] pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylic acid (17.4 mg, 23%) as a pale brown solid.1H NMR (400 MHz, DMSO-d6) 15.55 (s, 1H), 8.53 (s, 1H), 8.08-8.05 (m, 1H), 7.84 (d, J = 14.8 Hz, 1H), 7.69-7.65 (m, 1H), 6.96-6.93 (m, 1H), 6.81 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 7.2 Hz, 1H), 5.00- 4.92 (m, 1H), 4.72-4.64 (m, 1H), 4.45-4.38 (m, 1H), 4.31-4.22 (m, 1H), 3.80-3.70 (m, 1H), 3.54-3.46 (m, 1H), 3.34-3.28 (m, 2H), 3.24 (s, 3H), 2.77-2.67 (m, 2H), 2.43-2.30 (m, 1H), 2.25-1.95 (m, 6H), MS (ESI) m / z: 482.4 [M+H]+. Potency Lin28a-dep Z11 IC50(µM) ++ Example 26: 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl) oxy] methyl} pyrrolidin-1-yl]-1-(6- methanesulfonamidopyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1- yl]-1-[6-(N-methanesulfonylmethanesulfonamido)pyridin-3-yl]-4-oxo-1,4-dihydroquinoline-3- carboxylateTo a stirred solution of ethyl 1-(6-aminopyridin-3-yl)-6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl) oxy] methyl} pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate hydrochloride (180 mg, 0.304 mmol) in DCM (5 mL), was added triethylamine (0.13 mL, 0.914 mmol) and cooled to 0 °C before the addition of methane sulfonyl chloride (0.03 mL, 0.365 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 2 h at room temperature. The reaction mixture was quenched with water and the product was extracted with DCM (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulphate and evaporated to afford ethyl 6-chloro-7-[(2R)-2- {[(3-chloropyridin-2-yl) oxy] methyl} pyrrolidin-1-yl]-1-[6-(N-methanesulfonylmethanesulfonamido) pyridin-3-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (200 mg, crude) as a pale brown solid. MS (ESI) m / z: 710.2 [M+H]+. Step 2. Synthesis of 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-1-(6- methanesulfonamidopyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidExperimental procedure as described above to obtain 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl) oxy] methyl}- pyrrolidin-1-yl]-1-(6-methanesulfon amidopyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (20 mg, 12%) as an off white solid.1H NMR (400 MHz, DMSO-d6) 15.03 (brs, 1H), 11.15 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.54 (t, J = 6.4 Hz, 1H), 8.17 (s, 1H), 8.02-7.95 (m, 1H), 7.90-7.89 (dd, J = 5.2, 1.6 Hz, 1H), 7.79 (d, J = 5.6 Hz, 1H), 7.19-7.03 (m, 1H), 6.94 (dd, J = 7.6, 5.2 Hz, 1H), 6.37 (s, 1H), 4.78 (s, 1H), 4.34-4.25 (m, 2H), 3.51-3.47 (m, 1H), 3.40 (s, 3H), 3.19-3.18 (m, 1H), 2.34-2.24 (m, 1H), 1.99-1.91 (m, 2H), 1.85-1.78 (m, 1H), MS (ESI) m / z: 604.2 [M+H]+.Potency Lin28a-dep Z11 IC50(µM) ++++ Example 27: Synthesis of (R)-6-fluoro-1-(6-hydroxypyrazin-2-yl)-4-oxo-7-(2-((pyridin-2-yloxy) methyl) pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of ethyl 6-fluoro-1-(6-hydroxypyrazin-2- yl)-4-oxo-7-[(2R)-2-[(pyridin-2-yloxy) methyl] pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylateTo a stirred solution of ethyl 1-[6-(benzyloxy) pyrazin-2-yl]-6-fluoro-4-oxo-7-[(2R)-2-[(pyridin-2- yloxy) methyl] pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylate (300 mg, 503 µmol) in MeOH (10 mL), was added 10% Pd / C (106 mg, 1.00 mmol) under nitrogen atmosphere. The reaction mixture was subjected to hydrogenation (under hydrogen, balloon pressure) at room temperature for 6 h. The reaction mixture was filtered through a pad of celite, washed the celite pad with 10% MeOH in DCM (100 mL). The combined filtrate was concentrated under reduced pressure to afford ethyl 6-fluoro-1- (6-hydroxypyrazin-2- yl)-4-oxo-7-[(2R)-2-[(pyridin-2-yloxy) methyl] pyrrolidin-1-yl]-1,4- dihydroquinoline-3-carboxylate (140 mg, 55.1%) as an off white solid. MS (ESI) m / z : 506.1 [M+H]+Step 2: Synthesis of 6-fluoro-1-(6-hydroxypyrazin-2-yl)-4-oxo-7-[(2R)-2-[(pyridin-2-yloxy) methyl] pyrrolidin-1-yl]-1,4- dihydroquinoline-3-carboxylic acidTo a stirred solution of ethyl 6-fluoro-1-(6-hydroxypyrazin-2-yl)-4-oxo-7-[(2R)-2-[(pyridin-2-yloxy) methyl] pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylate (150 mg, 296 µmol) in THF (5 mL) and water (1 mL) was cooled to 0 °C, was added LiOH.H2O (62.1 mg, 1.48 mmol) and the reaction mixture was slowly warmed to room temperature and stirred for 16 h. The excess solvents were distilled under reduced pressure. The obtained residue was diluted with water and acidified with 1N HCl to pH 3-4 and the product was extracted with 10% MeOH in DCM. The combined organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude material obtained was triturated with IPA and ether (1:1 ratio, 50 mL) and dried under vacuum to afford 6-fluoro-1-(6-hydroxypyrazin-2-yl)-4-oxo-7-[(2R)-2-[(pyridin-2-yloxy) methyl] pyrrolidin-1- yl]-1,4- dihydroquinoline-3-carboxylic acid (58.1 mg, 41.2%) as pale green solid.1H NMR (400 MHz, DMSO-d6): δ 15.20 (s, 1H), 12.80 (brs, 1H), 8.81 (s, 1H), 8.41 (brs, 1H), 8.25 (brs, 1H), 8.01-7.99 (m, 1H), 7.88 (d, J = 14.8 Hz, 1H), 7.67-7.63 (m, 1H), 6.94-6.91 (m, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 7.6 Hz, 1H), 4.52-4.48 (m, 1H), 4.27-4.19 (m, 2H), 3.47-3.42 (m, 1H), 3.16 (brs, 1H), 2.09-1.89 (m, 4H), MS: 478.3 [M+H]+Potency Lin28a-dep Z11 IC50(µM) +++ Example 28: Synthesis of (R)-1-(6-(3-aminoazetidin-1-yl) pyridin-3-yl)-6-chloro-7-(2-(((3- chloropyridin-2-yl) oxy) methyl) pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of tert-butyl (1-(5-nitropyridin-2-yl) azetidin-3-yl) carbamateTo a stirred solution of 2-chloro-5-nitropyridine (1 g, 6.30 mmol) in ACN (10 mL) at 0 °C, were added tert-butyl N-(azetidin-3-yl)carbamate (1.30 g, 7.56 mmol) and potassium carbonate (1.74 g, 12.6 mmol). The reaction mixture was heated to 80°C and stirred for 16 h. The reaction mixture was cooled to room temperature, ice-cold water was added and the product was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (eluted in 20- 25%EtOAc in Hexane). The relevant fractions containing the product were combined and evaporated to dryness under reduced pressure to afford tert-butyl (1-(5-nitropyridin-2-yl) azetidin-3-yl) carbamate (800 mg, 44%) as a yellow solid, MS (ESI) m / z: 294.9 [M+H]+Step 2: Synthesis of (tert-butyl (1-(5-aminopyridin-2-yl)azetidin-3-yl)carbamate)To a stirred solution of tert-butyl N-[1-(5-nitropyridin-2-yl) azetidin-3-yl] carbamate (800 mg, 2.71 mmol) in MeOH (20 mL), was added Pd / C (433 mg, 2.71 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was hydrogenated using H2balloon for a period of 6 h. After completion of reaction, the reaction mixture was filtered through a celite pad, the celite pad was further washed with MeOH and the filtrate was concentrated under reduced pressure to afford tert- butyl N-[1-(5-aminopyridin-2-yl) azetidin-3-yl] carbamate (600 mg, 85%) as a brown liquid and taken forward without purification. Step 3: Synthesis of ethyl (R)-1-(6-(3-((tert-butoxycarbonyl)amino)azetidin-1-yl)pyridin-3-yl)-6- chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylateTo a stirred solution of ethyl (2Z)-2-[(Z)-5-chloro-4-[(2R)-2-{[(3-chloropyridin-2-yl) oxy] methyl} pyrrolidin-1-yl]-2-fluorobenzoyl]-3-ethoxyprop-2-enoate (400 mg, 782 µmol) in DMSO (3 mL), was added tert-butyl N-[1-(5-aminopyridin-2-yl) azetidin-3-yl] carbamate (399 mg, 1.51 mmol) at room temperature and stirred at room temperature for 2 h. Then, potassium carbonate (161 mg, 1.25 mmol) was added to reaction mixture at same temperature, the mixture was heated to 80 °C and stirred for 6 h. The reaction mixture was cooled to room temperature and ice-cold water was added, the precipitated solid was collected by filtration, washed with water and dried. The resulting material was treated with charcoal in ethyl acetate and stirred for 10 mins, filtered through celite pad and washed the celite pad with EtOAc. The combined filtrate was concentrated under reduced pressure to afford ethyl 1-[6-(3-{[(tert-butoxy) carbonyl]amino}azetidin-1-yl)pyridin-3-yl]-6-chloro-7-[(2R)-2- {[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate as a brown solid (280 mg, 50%), MS (ESI) m / z: 709.3 [M+H]+Step 4: Synthesis of (R)-1-(6-(3-((tert-butoxycarbonyl)amino)azetidin-1-yl)pyridin-3-yl)-6- chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylic acidTo a stirred solution of ethyl 1-[6-(3-{[(tert-butoxy) carbonyl] amino} azetidin-1-yl) pyridin-3-yl]-6- chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl) oxy] methyl} pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (250 mg, 352 µmol) in THF (2 mL) and water (2 mL), was added LiOH.H2O (41.9 mg, 1.75 mmol) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 4 h. The excess solvents were removed under reduced pressure, the resulting crude material was diluted with water (5 mL) and acidified with 1N HCl. The precipitated solid was collected by filtration, washed with water and dried under vacuum to afford 1-[6-(3-{[(tert- butoxy)carbonyl]amino}azetidin-1-yl)pyridin-3-yl]-6-chloro-7-[(2R)-2-{[(3-chloropyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg, 74%) as brown solid, MS m / z: 681.2 [M+H]+Step 5: Synthesis of (R)-1-(6-(3-aminoazetidin-1-yl)pyridin-3-yl)-6-chloro-7-(2-(((3- chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid4M HCl in Dioxane (2 mL) was added to a stirred solution of 1-[6-(3-{[(tert-butoxy) carbonyl] amino} azetidin-1-yl) pyridin-3-yl]-6-chloro-7-[(2R)-2-{[(3-chloropyridin-2yl) oxy] methyl} pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg, 366 µmol) at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 6 h. The solvents were removed under reduced pressure and purified the crude material by prep-HPLC. The fractions were lyophilized to afford 1-[6-(3-aminoazetidin-1-yl) pyridin-3-yl]-6-chloro-7-[(2R)-2-{[(3-chloropyridin- 2-yl) oxy] methyl} pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. (50.0 mg, 29%) as an off white solid.1H-NMR (400 MHz, DMSO-d6): δ 8.48 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.15 (s, 1H), 7.89-7.90 (m, 1H), 7.81 (dd, J = 8.0, 1.60 Hz, 1H), 7.71-7.64 (m, 1H), 6.96-6.91 (m, 1H), 6.58- 6.33 (m, 2H), 4.76-4.66 (m, 1H), 4.36-4.19 (m, 4H), 3.99-3.93 (m, 1H), 3.76-3.72 (m, 2H), 3.57-3.47 (m, 1H), 3.21-3.17 (m, 1H), 2.26-2.24 (m, 1H), 1.98-1.90 (m, 2H), 1.81-1.78(m, 1H). (COOH & NH2Protons not observed) MS m / z: 581.3 [M+H]+. Potency Lin28a-dep Z11 IC50(µM) ++++ Example 29: Synthesis of (R)-1-cyclopropyl-6,8-difluoro-4-oxo-7-(2-((pyridazin-3-yloxy)methyl)pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acidTo a stirred solution of 3-{[(2R)-pyrrolidin-2-yl] methoxy} pyridazine hydrochloride (200 mg, 927 µmol) in DMSO (4 mL), were added triethylamine (233 mg, 2.31 mmol) followed by 1-cyclopropyl- 6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (131 mg, 463 µmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. Then, was cooled to room temperature, water (10 ml) was added and the product was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with H2O (15 mL), followed by brine solution (15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was subjected to silica gel chromatography (100-200 mesh) and eluted the column by using 5-10% MeOH / DCM. The relevant fractions containing the product were combined and evaporated to dryness to afford 1-cyclopropyl-6,8-difluoro-4-oxo-7-[(2R)-2-[(pyridazin-3-yloxy) methyl] pyrrolidin-1-yl]- 1,4-dihydroquinoline-3-carboxylic acid (7.71 mg, 2%) as pale-yellow solid.1H NMR (400 MHz, DMSO-d6): δ 14.89 (s, 1H), 8.80 (dd, J = 4.4, 1.2 Hz, 1H), 8.63 (s, 1H), 7.71 (dd, J = 12.8, 1.2 Hz, 1H), 7.49 (dd, J = 8.8, 1.2 Hz, 1H), 6.90 (dd, J = 8.8, 1.2 Hz, 1H), 4.67 (brs, 1H), 4.56- 4.54 (m, 1H), 4.49-4.47 (m, 1H), 4.10-4.02 (m, 1H), 3.90-3.82 (m, 1H), 3.50-3.40 (m, 1H), 2.38-2.28 (m, 1H), 2.10- 2.00 (m, 1H), 1.92-1.82 (m, 2H), 1.18-1.11 (m, 4H), MS (ESI) m / z: 443.3 [M+H]+Potency Lin28a-dep Z11 IC50(µM) +++ Example 30: Synthesis of 3 (R)-6-fluoro-1-(3-methoxycyclobutyl)-7-(2-(((3-methylpyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of ethyl (2Z)-2-[(Z)-2,5-difluoro-4-[(2R)-2-{[(3-methylpyridin-2-yl) oxy] methyl} pyrrolidin-1-yl] benzoyl]-3-(dimethylamino) prop-2-enoateTo a stirred solution of ethyl 3-{2,5-difluoro-4-[(2R)-2-{[(3-methylpyridin-2-yl) oxy] methyl} pyrrolidin-1-yl] phenyl}-3-oxopropanoate (300 mg, 716 µmol) in toluene (5 mL), was added (dimethoxy methyl) dimethylamine (85.3 mg, 716 µmol), the reaction mixture heated to 80 °C and stirred for 6 h. The reaction mixture was cooled to RT, solvents were evaporated and the obtained residue was azeotroped with toluene (10 mL) to afford ethyl (2Z)-2-[(Z)-2,5-difluoro-4-[(2R)-2-{[(3- methylpyridin-2-yl) oxy] methyl} pyrrolidin-1-yl] benzoyl]-3-(dimethylamino) prop-2-enoate (248 mg, crude) as brown liquid. The material was used for next step without further purification. MS (ESI) 474.1 [M+H]+. Step 2: Synthesis of (R)-ethyl 6-fluoro-1-(3-methoxycyclobutyl)-7-(2-(((3-methylpyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylateTo a stirred solution of ethyl (2Z)-2-[(Z)-2,5-difluoro-4-[(2R)-2-{[(3-methylpyridin-2-yl) oxy] methyl} pyrrolidin-1-yl] benzoyl]-3-(dimethylamino) prop-2-enoate (250 mg, 527 µmol) in THF (5 mL), was added 3-methoxycyclobutan-1-amine hydrochloride (86.9 mg, 632 µmol) and triethylamine (95.5 µL, 685 µmol). The reaction mixture was stirred at room temperature for 6 h. After completion of reaction, solvents were removed under reduced pressure. The obtained crude material was dissolved in DMF (5 mL), potassium carbonate (72.8 mg, 527 µmol) was added and the reaction mixture was heated to 85 °C, stirred for 2 h. The reaction mixture was cooled, ice-cold water (10 mL) was added and the product was extracted with Ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine solution (15 mL), dried over sodium sulfate and evaporated to afford crude product. The crude product was purified by silica gel column chromatography (100-200 mesh) using 45-50% EtOAc / Hexanes. The relevant fractions containing the product were combined and distilled under reduced pressure to afford ethyl 6-fluoro-1-(3- methoxycyclobutyl)-7-[(2R)-2-{[(3-methylpyridin-2-yl) oxy] methyl} pyrrolidin-1-yl]-4-oxo-1,4- dihydroquinoline-3-carboxylate (163 mg, 61%) as brown solid. MS (ESI) 510.2 [M+H]+. Step 3: Synthesis of (R)-6-fluoro-1-(3-methoxycyclobutyl)-7-(2-(((3-methylpyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a stirred solution of ethyl 6-fluoro-1-(3-methoxycyclobutyl)-7-[(2R)-2-{[(3-methylpyridin-2-yl) oxy] methyl} pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (115 mg, 225 µmol) in THF: Water (1:1, 6 mL), was added LiOH.H2O (28.3 mg, 675 µmol) at 0 °C and the reaction mixture wasstirred at room temperature for 6 h. The reaction mixture was re-cooled to 0 °C and pH was adjusted to 2-3 by using 1N HCl, the precipitated solid was filtered, washed with 10% IPA in diethyl ether and dried under vacuum. Further the solid material was lyophilized using ACN / water to afford 6-fluoro-1- (3-methoxycyclobutyl)-7-[(2R)-2-{[(3-methylpyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4- dihydroquinoline-3-carboxylic acid (50.8 mg 47%) as pale brown solid.1H NMR (400 MHz, DMSO- d6): δ 15.52 (s, 1H), 8.52 (s, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.83 (d, J = 14.8 Hz, 1H), 7.48 (d, J = 6.4 Hz, 1H), 6.86–6.83 (m, 1H), 6.78 (d, J = 7.2 Hz, 1H), 4.73–4.68 (m, 2H), 4.40–4.37 (m, 1H), 4.32– 4.28 (m, 1H), 3.83–3.76 (m, 2H), 3.59–3.50 (m, 1H), 3.18 (s, 3H), 3.12–3.03 (m, 2H), 2.32–2.12 (m, 4H), 2.10–2.03 (m, 2H), 2.01 (s, 3H). MS (ESI) m / z: 482.4 [M+H]+. Potency Lin28a-dep Z11 IC50(µM) ++++ Example 31: (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl) oxy)methyl)pyrrolidin-1-yl)-1-(4- (ethylsulfonamido)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of (R)-ethyl 6-chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)- 1-(4-(ethylsulfonamido)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylateTo a stirred solution of ethyl 1-(4-aminophenyl)-6-chloro-4-oxo-7-[(2R)-2-[(pyridin-2-yloxy) methyl] pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylate hydrochloride (100 mg, 169 µmol) in DCM (5 mL) at 0 °C, was added pyridine (41.2 µL, 507 µmol) followed by ethane sulfonyl chloride (32.2 µL, 338 µmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 h. After completion of reaction, ice cold water (15 mL) was added and the product was extracted withDCM (2 x 15 mL). The combined organic layers were washed with brine (15 mL) and dried over sodium sulphate and evaporated to dryness. The resulting crude material was triturated with diethyl ether & pentane to afford ethyl (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1- yl)-1-(4-(ethylsulfonamido)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (73.3 mg, 71.1%) as pale-yellow solid. MS (ESI) m / z: 645.2 [M+H]+. Step 2: Synthesis of (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin-1-yl)-1-(4- (ethylsulfonamido)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidExperimental procedure described above to obtain (R)-6-chloro-7-(2-(((3-chloropyridin-2-yl) oxy) methyl) pyrrolidin-1-yl)-1-(4-(ethylsulfonamido) phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (42.7 mg, 61.2%) as pale-yellow solid.1H-NMR (400 MHz, DMSO-d6):δ 15.07 (s, 1H), 10.26 (bs, 1H), 8.55 (s, 1H), 8.16 (s, 1H), 7.87-7.88 (m, 1H), 7.81-7.79 (m, 1H), 7.58-7.46 (m, 3H), 7.35 (d, J = 8.0 Hz, 1H), 6.94-6.91 (m, 1H), 6.34 (s, 1H), 4.74 (bs, 1H), 4.29-4.25 (m, 2H), 3.42-3.38 (m, 1H), 3.22 (q, J = 7.2 Hz, 2H), 3.14 (t, J = 8.0 Hz, 1H), 2.33-2.21 (m, 1H), 2.02-1.88 (m, 2H), 1.82-1.75 (m, 1H), 1.23 (t, J = 7.6 Hz, 3H), MS (ESI) m / z: 617.2 [M+H]+. Potency Lin28a-dep Z11 IC50(µM) ++++ Example 32: (R)-6-fluoro-1-(4-fluoroindolin-5-yl)-4-oxo-7-(2-((pyridin-2-yloxy) methyl) pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of 4-fluoroindolin-5-amineTo a stirred solution of 4-fluoro-5-nitro-2,3-dihydro-1H-indole (550 mg, 3.01 mmol, Ref: WO2017 / 153952) in ethyl acetate (5 mL) and water (5 mL), was added iron (670 mg, 12.0 mmol) and ammonium chloride (1.28 g, 24.0 mmol) at RT and the reaction mixture was stirred at 60°C for 12 h. The reaction mixture was cooled to RT and filtered through celite bed, washed the celite pad with EtOAc (50 mL). The organic layer was washed with brine, dried over sodium sulphate and evaporated to dryness. The crude product was purified by silica gel column chromatography (100-200 mesh) by using 10-15% EtOAc / Hexanes as an eluent. The relevant fractions containing the product were combined and evaporated to dryness to afford 4-fluoro-2,3- dihydro-1H-indol-5-amine (280 mg, 61%) as brown solid. MS (ESI) m / z :153.5 Step 2: Synthesis of ethyl (R)-6-fluoro-1-(4-fluoroindolin-5-yl)-4-oxo-7-(2-((pyridin-2-yloxy) methyl) pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylateExperimental procedure as described above to obtain ethyl (R)-6-fluoro-1-(4-fluoroindolin-5-yl)-4- oxo-7-(2-((pyridin-2-yloxy) methyl) pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylate (200 mg, 56.17%) as a brown solid. MS (ESI) m / z: 547.3 [M+H]+. Step 3: Synthesis of (R)-6-fluoro-1-(4-fluoroindolin-5-yl)-4-oxo-7-(2-((pyridin-2-yloxy) methyl) pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acidExperimental procedure as described above to obtain (R)-6-fluoro-1-(4-fluoroindolin-5-yl)-4-oxo-7- (2-((pyridin-2-yloxy) methyl) pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (45 mg, 23.8%) as a pale brown solid.1H-NMR (400 MHz, DMSO-d6): δ 15.32 (bs, 1H), 8.52 (bs, 1H), 8.04 (bs, 1H), 7.88 (d, J = 13.6 Hz, 1H), 7.68-7.66 (m, 1H), 7.24-7.18 (m, 1H), 6.96 (s, 1H), 6.72-6.67 (m, 1H), 6.45 (d, J = 8.0 Hz, 0.5H), 6.34 (bs, 1H), 6.26 (d, J = 8.0 Hz, 0.5H), 6.19-6.16 (m, 1H), 4.41-4.33 (m, 1H), 4.23-4.16 (m, 2H), 3.64-3.51 (m, 2H), 3.42 (s, 1H), 3.10-5.08 (m, 1H), 2.93-2.90 (m, 1H), 2.68-2.50 (m, 1H), 2.06-1.93 (m, 4H), MS (ESI) m / z: 519.3 [M+H]+. Potency Lin28a-dep Z11 IC50(µM) ++++ Example 33: 6-chloro-1-(5-hydroxypyrazin-2-yl)-4-oxo-7-[(2R)-2-[(pyridin-2- yloxy)methyl]pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of ethyl 1-[5-(benzyloxy)pyrazin-2-yl]-6-chloro-4-oxo-7-[(2R)-2-[(pyridin-2- yloxy)methyl]pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylateTo a stirred solution of ethyl (R,Z)-2-(5-chloro-2-fluoro-4-(2-((pyridin-2-yloxy)methyl)pyrrolidin-1- yl)benzoyl)-3-ethoxyacrylate (450 mg, 1.06 mmol) in DMSO (7 mL) was added 5-(benzylox- y)pyrazin-2-amine (213 mg, 1.06 mmol) and stirred the reaction mixture at room temperature for 2 h. After completion of starting material (monitored by TLC), added potassium carbonate (146 mg, 1.06 mmol) and stirred the reaction mixture at 80 °C for 2 h. The reaction mixture was cooled to room temperature, poured into ice-cold water (15 mL) which resulted in precipitation. The precipitated solid was collected by filtration and washed with water (50 mL) & hexane (10 mL) to afford ethyl 1-[5- (benzyloxy)pyrazin-2-yl]-6-chloro-4-oxo-7-[(2R)-2-[(pyridin-2-yloxy)methyl]pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylate (260 mg, 424 µmol, 40%) as pale brown solid. MS (ESI) m / z: 612.3 [M+H]+. Step 2: Synthesis of [6-chloro-1-(5-hydroxypyrazin-2-yl)-4-oxo-7-[(2R)-2-[(pyridin-2- yloxy)methyl]pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylic acid]To a stirred solution of ethyl 1-[5-(benzyloxy)pyrazin-2-yl]-6-chloro-4-oxo-7-[(2R)-2-[(pyridin-2- yloxy)methyl]pyrrolidin-1-yl]-1,4-dihydroquinoline-3-carboxylate (500 mg, 816 µmol) in DCM (30 mL), was added boron tribromide solution 1.0 M in DCM (20.7 mL, 122 mmol) at 0 °C under N2 atmosphere. The resulting mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layer was treated with charcoal (200 mg) then filtered through celite pad and concentrated under reduced pressure to get the crude compound, which was purified by Prep HPLC purification to afford 6-chloro-1-(5-hydroxypyrazin-2-yl)-4-oxo-7- [(2R)-2-[(pyridin-2-yloxy)methy-l]pyrrolidine-1-yl]-1,4-dihydro quinoline-3-carboxylic acid (27.3 mg, 7%) as an off white solid.1H NMR (400 MHz, DMSO-d6): δ 15.05 (brs, 1H), 8.79 (s, 1H), 8.16 (s, 1H), 8.08 (brs, 1H), 8.00–7.97 (m, 1H), 7.75 (brs, 1H), 7.65–7.59 (m, 1H), 6.92–6.88 (m, 1H), 6.67 (s, 1H), 6.60 (d, J = 8.0 Hz, 1H), 4.70–4.60 (m, 1H), 4.25–4.13 (m, 2H), 3.71–3.67 (m, 1H), 3.53– 3.43 (m, 1H), 2.24–2.21 (m, 1H), 1.92–1.89 (m, 1H), 1.88–1.77 (m, 2H); MS (ESI) m / z: 494.3 [M+H]+. Potency Lin28a-dep Z11 IC50(µM) ++++ Example 34: 6-Chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-1-[1-(2- hydroxyethyl)azetidin-3-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of ethyl 1-{1-[(tert-butoxy) carbonyl] azetidin-3-yl}-6-chloro-7-[(2R)-2-{[(3- chloropyridin-2-yl) oxy] methyl} pyrrolidin-1-yl]-4-oxo-1,4- dihydroquinoline-3-carboxylateTo a stirred solution of ethyl (2Z)-2-[(Z)-5-chloro-4-[(2R)-2-{[(3-chloropyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-2-fluorobenzoyl]-3-ethoxyprop-2-enoate (800 mg, 1.56 mmol) in DMSO (8 mL ) was added tert-butyl 3-aminoazetidine-1-carboxylate (322 mg, 1.87 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After completion of starting material (monitored by TLC), potassium carbonate (538 mg, 3.90 mmol) was added and stirred at 80 °C for 16 h. After completion of reaction (monitored by LCMS), the reaction mixture was gradually cooled, quenched with ice-cold water and precipitated solid was filtered and washed with water (20 ml). The obtained solid product was dissolved in EtOAc (25 ml) and treated with charcoal and filtered through celite bed. The filtrate was concentrated under vacuum and triturated with 10% EtOAc in pentane (20 ml) to afford ethyl 1-{1-[(tertbutoxy)carbonyl]azetidin-3-yl}-6- chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3- carboxylate (398 mg, 41%) as a brown solid. MS (ESI) m / z 617.3 [M+H]+Step 2: Synthesis of ethyl 1-(azetidin-3-yl)-6-chloro-7-[(2R)-2-{[(3-chloropyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylateTo a stirred solution of ethyl 1-{1-[(tert-butoxy) carbonyl] azetidin-3-yl}-6-chloro-7-[(2R)-2-{[(3- chloropyridin-2-yl) oxy] methyl} pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (500 mg, 809 µmol) in dioxane (5 mL) was cooled with ice bath and added 4.0 M HCl in Dioxane (5 mL). The reaction mixture was stirred at room temperature for 2 h. The excess of solvent was removed under vacuum and triturated with diethyl ether (2 X 20 ml) to afford ethyl 1-(azetidin-3-yl)-6-chloro-7- [(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3- carboxylate (328 mg, 78%) as a yellow solid. MS (ESI) m / z 517.2 [M+H]+Step 3: Synthesis of ethyl 1-(1-{2-[(tert-butyldimethylsilyl)oxy] ethyl}azetidin-3-yl)-6-chloro-7- [(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3- carboxylateTo a stirred solution of ethyl 1-(azetidin-3-yl)-6-chloro-7-[(2R)-2-{[(3-chloropyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (150 mg, 289 µmol) in ACN (5 mL), was added triethylamine (200 µL, 1.44 mmol) and stirred at room temperature for 15 minutes and added (2-bromoethoxy)(tert-butyl)dimethylsilane (82.7 mg, 346 µmol) at room temperature. The reaction mixture was stirred at 80 °C for 24 h. After completion of reaction (monitored by TLC), the excess of solvent was removed under vacuum and diluted with EtOAc (20 ml) and washed with water (20 ml) and brine (20 ml). The organic layer was dried over anhydrous sodium sulfate and treated with charcoal and filtered through celite bed and concentrated under vacuum to afford ethyl 1-(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}azetidin-3-yl)-6-chloro-7-[(2R)-2- {[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (100 mg, 46%) as a yellow oil. MS (ESI) m / z 675.4 [M+H]+.Step 4: Synthesis of 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl} pyrrolidin-1-yl]-1- [1-(2-hydroxyethyl)azetidin-3-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a stirred solution of ethyl 1-(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}azetidin-3-yl)-6-chloro-7- [(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3- carboxylate (100 mg, 132 µmol) in DCM (10 mL), was added BBr31.0 M in DCM (1 mL) drop wise at 10-15 °C. The reaction mixture was stirred at room temperature for 4 h. After completion of reaction (monitored by TLC), the excess of solvent was removed under vacuum and diluted with EtOAc (30 ml) and washed with water (2 x 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford crude compound. The crude product was purified by Prep HPLC and collected pure fractions were lyophilized to afford 6-chloro-7-[(2R)-2- {[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-1-[1-(2-hydroxyethyl)azetidin-3-yl]-4-oxo-1,4- dihydroquinoline-3-carboxylic acid (10.6 mg, 15%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) 15.25 (brs, 1H), 8.66 (s, 1H), 8.13 (s, 1H), 7.97 (dd, J = 4.8, 1.6 Hz, 1H), 7.79 (dd, J = 7.9, 1.6 Hz, 1H), 6.98 (brs, 1H), 6.92 (dd, J = 7.6, 4.8 Hz, 1H), 5.26‒5.15, (m, 1H), 4.97‒4.92 (m, 1H), 4.48 (t, J = 5.6 Hz, 1H), 4.42‒4.36 (m, 2H), 3.95 (t, J = 6.8 Hz, 1H), 3.88‒3.19 (m, 2H), 3.43‒3.28 (m, 5H), 2.68‒2.49 (m, 2H), 2.34‒2.29 (m, 1H), 2.09‒1.85 (m, 3H). MS (ESI) m / z 533.3 [M+H]+Potency Lin28a-dep Z11 IC50(µM) +++ Example 35: 6-Cyano-1-(1-methylcyclopropyl)-7-[(2R)-2-{[(3-methylpyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of ethyl 3-(5-bromo-2,4-difluorophenyl)-3-oxopropanoateTo a stirred solution of 5-bromo-2,4-difluorobenzoic acid (2.5 g, 10.5 mmol) in THF (50 mL) was added carbonyldiimidazole (3.40 g, 21.0 mmol) at 0 °C and stirred at rt for 2 h. Then, triethylamine (4.38 mL, 31.5 mmol), 1-ethyl 3-potassium propanedioate (2.67 g, 15.7 mmol) and magnesium chloride (799 mg, 8.40 mmol) were added to the reaction mixture and stirred at rt for 16 h. After completion of reaction, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated under vaccum to afford the crude compound. The crude compound was purified by column chromatography with 10% EtOAC in hexane as eluent to afford ethyl 3-(5-bromo-2,4-difluorophenyl)-3-oxopropanoate (2.00 g, 62%) as pale yellow solid.1H NMR (400 MHz, CDCl3): δ 8.20 (t, J = 7.6 Hz, 1H), 7.00–6.93 (m, 1H), 4.23 -4.18 (m, 2H), 3.94 (d, J = 3.6 Hz, 2H), 1.28 (t, J = 3.2 Hz, 3H) Step 2: Synthesis of ethyl 6-bromo-7-fluoro-1-(1-methylcyclopropyl)-4-oxo-1,4- dihydroquinoline-3-carboxylateTo a stirred solution of ethyl 3-(5-bromo-2,4-difluorophenyl)-3-oxopropanoate (1.5 g, 4.88 mmol) in triethyl orthoformate (1.21 mL, 7.32 mmol) was added acetic anhydride (691 µL, 7.32 mmol) at room temperature. The reaction was then heated to 155 °C and stirred for 4 h. After completion of starting material (monitored by TLC), reaction mixture was concentrated under reduced pressure and codistilled with toluene (2 x 5mL) to afford the crude compound. The crude compound was dissolved in DMSO (15 mL), were added 1-methylcyclopropan-1-amine. HCl (347 mg, 4.88 mmol) and triethylamine (882 µL, 6.34 mmol) at room temperature and stirred for 2 h. Then, potassium carbonate (674 mg, 4.88 mmol) was added to the reaction mixture at RT. The mixture was stirred at 80 °C for 2 h. After completion of reaction, the reaction mixture was cooled to RT, quenched with ice-cold water (50 mL), which resulted in precipitation. The precipitated solid was filtered, washedwith water & diethyl ether, dried under reduced pressure to afford ethyl 6-bromo-7-fluoro-1-(1- methylcyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.47 g, 82%) as brown solid. MS (ESI) m / z: 367.9 [M+H]+Step 3: Synthesis of ethyl 6-bromo-1-(1-methylcyclopropyl)-7-[(2R)-2-{[(3-methylpyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylateTo a stirred solution of 3-methyl-2-{[(2S)-pyrrolidin-2-yl] methoxy} pyridine hydrochloride (651 mg, 2.85 mmol) in DMF (14 mL), were added triethylamine (264 µL, 1.90 mmol) and potassium tert- butoxide (639 mg, 5.70 mmol) at room temperature and stirred for 10 min. Then, ethyl 6-bromo-7- fluoro-1-(1-methylcyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (700 mg, 1.90 mmol) was added to the reaction mixture at RT and the reaction was stirred at 130 °C for 16 h. After completion of reaction, the reaction mixture was cooled to 0 °C, quenched with ice-cold water (5 mL), which resulted in precipitation. The precipitated solid was filtered, washed with water & diethyl ether, dried over under reduced pressure to afford ethyl 6-bromo-1-(1-methylcyclopropyl)-7-[(2R)-2-{[(3- methylpyridin-2- yl) oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (108 mg, 10%) as brown solid. MS (ESI) m / z: 540.2 [M+H]+Step 4: Synthesis of ethyl 6-cyano-1-(1-methylcyclopropyl)-7-[(2R)-2-{[(3-methylpyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylateTo a stirred solution of ethyl 6-bromo-1-(1-methylcyclopropyl)-7-[(2R)-2-{[(3-methylpyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (108 mg, 199 µmol) inNMP (3 mL), was added copper(I) cyanide (35.6 mg, 398 µmol) at room temperature and degassed with argon for 10 min in a sealed tube. The reaction was stirred at 160 °C for 16 h. After completion of reaction, the reaction mixture was cooled to RT, diluted with ice-cold water (10 mL) and extracted with 10% MeOH in DCM (2 X 10 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford ethyl 6-cyano-1- (1-methylcyclopropyl)-7-[(2R)-2-{[(3-methylpyridin-2-yl)oxy]methyl} pyrrolidin-1-yl]-4-oxo-1,4- dihydroquinoline-3-carboxylate (72.0 mg, 74%) as brown solid. MS (ESI) m / z: 487.4 [M+H]+Step 5: Synthesis of 6-cyano-1-(1-methylcyclopropyl)-7-[(2R)-2-{[(3-methylpyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a stirred solution of ethyl 6-cyano-1-(1-methylcyclopropyl)-7-[(2R)-2-{[(3-methylpyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (72 mg, 147 µmol) in a mixture of THF (0.72 mL), EtOH (0.72 mL) & water (0.72 mL), was LiOH.H2O (30.8 mg, 735 µmol). The reaction mixture was stirred at room temperature for 2 h. After completion of starting material, the reaction mixture was concentrated under reduced pressure and the crude compound was quenched with ice-cold water and acidified with 1N HCl (pH~3) which resulted in precipitation. The precipitated solid was filtered, dried and purified by prep HPLC and the fractions were lyophilized to afford 6-cyano-1-(1-methylcyclopropyl)-7-[(2R)-2-{[(3-methylpyridin-2-yl)oxy]methyl}pyrrolidin-1- yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (44.5 mg, 66%) as an off white solid.1H NMR (400 MHz, DMSO-d6, VT): δ 14.78 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.84–7.82 (m, 1H), 7.46–7.43 (m, 1H), 7.14 (s, 1H), 6.80 (dd, J = 6.8, 4.8 Hz 1H), 4.93– 4.90 (m, 1H), 4.50 (d, J = 5.2 Hz, 2H), 3.94– 3.91 (m, 1H), 3.73–3.69 (m, 1H), 2.35–2.06 (m, 4H), 2.07 (s, 3H), 1.57 (s, 3H), 1.41–1.16 (m, 4H). MS (ESI) m / z: 459.4 [M+H]+Potency Lin28a-dep Z11 IC50(µM) ++++ Example 36: 1-(1-Acetylazetidin-3-yl)-6-chloro-7-[(2R)-2-{[(3-methylpyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a stirred solution of 1-(azetidin-3-yl)-6-chloro-7-[(2R)-2-{[(3-methylpyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg, 196 µmol) in DCM (6 mL), was added triethylamine (81.9 µL, 588 µmol) followed by acetyl chloride (13.9 µL, 196 µmol) at 0 °C, then the reaction mixture was stirred at room temperature for 3 h. After completion of the starting material, the reaction mixture was quenched with ice cold water and extracted with DCM (2 x 50 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL) solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude compound. The crude compound was purified by prep HPLC to afford desired 1-(1-acetylazetidin-3- yl)-6-chloro-7-[(2R)-2-{[(3-methylpyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4- dihydroquinoline-3-carboxylic acid (19.6 mg, 20%) as pinkish brown solid.1H NMR (400 MHz, DMSO-d6, VT) δ 14.90 (s, 1H), 8.73 (s, 1H), 8.16 (s, 1H), 7.81 (dd, J = 3.6, 1.2 Hz, 1H), 7.39 (dd, J = 7.2, 0.8 Hz, 1H), 6.91 (s, 1H), 6.76 (dd, J = 7.2, 4.8 Hz, 1H), 5.59–5.09 (m, 1H), 4.98–4.91 (m, 1H), 4.69–4.49 (m, 3H), 4.39 (dd, J = 11.2, 4.8 Hz, 1H), 4.29 (dd, J = 11.2, 5.2 Hz, 1H), 3.91–3.82 (m, 1H), 3.46–3.39 (m, 1H), 2.32–2.28 (m, 1H), 2.08–1.92 (m, 4H),1.98 (s, 3H), 1.80 (s, 3H), MS (ESI) m / z: 511.3 [M+H]+. Potency Lin28a-dep Z11 IC50(µM) +++ Example 37: 6-Chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-1-[1-(2- methoxyethyl)-3-methylazetidin-3-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of ethyl 1-{1-[(tert-butoxy)carbonyl]-3-methylazetidin-3-yl}-6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydro quinoline-3- carboxylateTo the stirred solution of ethyl (2Z)-2-[(Z)-5-chloro-4-[(2R)-2-{[(3-chloropyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-2-fluorobenzoyl]-3-ethoxyprop-2-enoate (300 mg, 586 µmol) in DMSO (6 mL) was added tert-butyl 3-amino-3-methylazetidine-1-carboxylate (109 mg, 586 µmol) and stirred at room temperature for 2 h under N2atmosphere. After completion of starting material, potassium carbonate (80.9 mg, 586 µmol) was added and the resulting mixture was stirred at 80 °C for 2 h. After completion of reaction, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with ice-cold water (2 x 10 mL), brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the ethyl 1-{1-[(tert-butoxy)carbonyl]-3-methylazetidin-3-yl}-6-chloro-7-[(2R)-2- {[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (210 mg, 57%) as pale brown solid. MS (ESI) m / z: 631.3 [M+H]+. Step 2: Synthesis of ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1- yl]-1-(3-methylazetidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate HCl.4N HCl in dioxane was added to ethyl 1-{1-[(tert-butoxy)carbonyl]-3-methylazetidin-3-yl}-6-chloro- 7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo-1,4-dihydro quinoline-3- carboxylate (300 mg, 332 µmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. After completion of reaction, reaction mixture was concentrated under reduced pressure to get crude residue which was washed with diethyl ether to afford ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-1-(3-methylazetidin-3-yl)-4-oxo-1,4-dihydro quinoline-3-carboxylate. HCl (180 mg, 96%) as off-white solid. MS (ESI) m / z: 531.2 [M+H]+.Step 3: Synthesis of ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1- yl]-1-[1-(2-methoxyethyl)-3-methylazetidin-3-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylate.To a stirred solution of ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]- 1-(3-methylazetidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (250 mg, 338 µmol) in acetonitrile (5 mL) were added triethylamine (47.1 µL, 338 µmol) and 1-bromo-2-methoxyethane (31.7 µL, 338 µmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. After completion of reaction, reaction mixture was quenched with ice cold water (5 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was washed with water (10 mL) and brine solution (10 mL), filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by column chromatography over silica gel (60-120 mesh) eluted with 30% ethyl acetate to afford ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-1-[1-(2-methoxyethyl)-3-methylazetidin-3-yl]-4-oxo-1,4-dihydro quinoline-3-carboxylate (250 mg, 93%) as yellow solid. MS (ESI) m / z: 589.2 [M+H]+. Step 4: Synthesis of 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl} pyrrolidin-1-yl]-1- [1-(2-methoxyethyl)-3-methylazetidin-3-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a stirred solution of ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]- 1-[1-(2-methoxyethyl)-3-methylazetidin-3-yl]-4-oxo-1,4-dihydro quinoline-3-carboxylate (250 mg, 317 µmol) in THF (2.5 mL) was added a solution of LiOH.H2O (66.2 mg, 1.58 mmol) in water (2.5 mL). The resulting mixture was stirred at room temperature for 6 h. After completion of the reaction, concentrated under reduced pressure until to remove THF, then aqueous layer was acidified with 1N HCl (pH>2), which resulted in precipitation. The precipitated solid was filtered and washed withwater followed by hexane to get the crude compound. The crude compound triturated with mixture of isopropyl alcohol, diethyl ether and n-pentane to afford 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2- yl)oxy]methyl} pyrrolidin-1-yl]-1-[1-(2-methoxyethyl)-3-methylazetidin-3-yl]-4-oxo-1,4- dihydroquinoline-3-carboxylic acid (27 mg, 15%) as an off white solid.1H NMR (400 MHz, DMSO- d6): δ 15.16 (s, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 7.92 (d, J =4.0 Hz, 1H), 7.80 (dd, J = 8.0, 1.6 Hz, 1H), 6.94‒6.91 (m, 1H), 6.47 (s, 1H), 4.92‒4.87 (m, 1H), 4.38‒4.34 (m, 2H), 3.93‒3.79 (m, 3H), 3.52‒3.38 (m, 5H), 3.21 (s, 3H), 2.67‒2.54 (m, 2H), 2.36‒2.29 (m, 1H), 2.10‒2.01 (m, 2H), 1.99‒1.92 (m, 1H), 1.88 (s, 3H). MS (ESI) m / z: 561.3 [M+H]+Potency Lin28a-dep Z11 IC50(µM) +++ Example 38: 6-Chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}-pyrrolidin-1-yl]-1-[1-(2- methoxyethyl)pyrrolidin-3-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of tert-butyl N-[1-(2-methoxyethyl) pyrrolidin-3-yl] carbamateTo a solution of tert-butyl N-(pyrrolidin-3-yl)carbamate (200 mg, 1.07 mmol) in MeCN (5 mL) were added potassium carbonate (147 mg, 1.07 mmol), potassium iodide (177 mg, 1.07 mmol) and 1- bromo-2-methoxyethane (162 mg, 1.17 mmol) at room temperature under N2 atmosphere. Then resulting solution was stirred at 80 °C for 16 h. Excess solvent was concentrated under reduced pressure and quenched with ice cold water. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford tert-butyl N-[1-(2-methoxyethyl)pyrrolidin-3-yl]carbamate (240 mg crude) as yellow liquid. The product was proceeded to next step without purification. MS (ESI) m / z: 245.5 [M+H]+. Step 2: Synthesis of 1-(2-methoxyethyl)pyrrolidin-3-amine hydrochlorideTo a stirred solution of tert-butyl N-[1-(2-methoxyethyl)pyrrolidin-3-yl]carbamate (250 mg, 1.02 mmol) in dioxane (3 mL), was added 4M HCl in 1,4-dioxane (354 µL, 10.2 mmol) at 0 °C under N2 atmosphere. The resulting mixture was slowly warmed to room temperature and stirred for 6 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude solid was triturated with diethyl ether (3 x 10 mL) to afford 1-(2-methoxyethyl)pyrrolidin-3-amine hydrochloride (150 mg, 81%) as pale yellow solid. MS (ESI) m / z: 145.5 [M+H]+. Step 3: Synthesis of ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]me-thyl}pyrrolidin-1- yl]-1-[1-(2-methoxyethyl)pyrrolidin-3-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylateTo a stirred solution of ethyl (2Z)-2-[(Z)-5-chloro-4-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]- methyl}pyrrolidin-1-yl]-2-fluorobenzoyl]-3-ethoxyprop-2-enoate (300 mg, 586 µmol) in DMSO (4 mL) was added 1-(2-methoxyethyl)pyrrolidin-3-amine hydrochloride (105 mg, 586 µmol), followed by triethylamine (59.2 mg, 586 µmol) and stirred the reaction mixture at rt for 2 h under N2 atmosphere. Then, potassium carbonate (80.9 mg, 586 µmol) was added. The resulting mixture was stirred at 80 °C for 2 h. After completion of reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (5 mL), which resulted in precipitation. Precipitated solid was collected by filtration and washed with water followed by hexane, then dried under vacuum filtration to get solid. The solid was dissolved in EtOH, treated with charcoal and filtered through celite pad. The filtrate was concentrated under reduced pressure to afford ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-1-[1-(2-methoxyethyl)pyrrolidin-3-yl]-4-oxo-1,4- dihydroquinoline-3-carboxylate (114 mg, 33%) as pale brown solid. MS (ESI) m / z: 589.2 [M+H]+. Step 4: Synthesis of 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}-pyrrolidin-1-yl]-1- [1-(2-methoxyethyl)pyrrolidin-3-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a stirred solution of ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}-pyrrolidin-1- yl]-1-[1-(2-methoxyethyl)pyrrolidin-3-yl]-4-oxo-1,4-dihydroquinoline-3-carbox-ylate (125 mg, 212 µmol) in THF (3 mL) was added a solution of LiOH.H2O (44.0 mg, 1.05 mmol) in water (2 mL). The resulting mixture was stirred at room temperature for 6 h. After completion of the reaction (monitored by LCMS), reaction mixture was concentrated under reduced pressure, then aqueous layer was acidified with 1N HCl (pH ~3), which resulted in precipitation. The precipitated solid was collected by filtration and washed with water followed by hexane to get the crude compound. It was triturated with mixture of isopropyl alcohol, diethyl ether and n-pentane to afford desired to 6-chloro-7-[(2R)-2- {[(3-chloropyridin-2-yl)oxy]methyl}-pyrrolidin-1-yl]-1-[1-(2-methoxyethyl)pyrrolidin-3-yl]-4-oxo- 1,4-dihydro quinoline-3-carboxylic acid (24.0 mg, 20%) as off white solid.1H NMR (400 MHz, DMSO-d6,VT) δ 8.93 (brs, 1H), 8.15 (s, 1H), 7.92‒7.88 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.26 (brs, 1H), 6.90–6.86 (m, 1H), 5.50 (brs, 1H), 5.04 (brs, 1H), 4.47–4.39 (m, 2H), 3.95–3.90 (m, 1H), 3.75– 3.50 (m, 5H), 3.49–3.40 (m, 5H), 3.34–3.20 (m, 2H), 2.65–2.55 (m, 1H), 2.55–2.50 (m, 1H), 2.38– 2.30 (m, 1H), 2.17–1.85 (m, 3H). MS (ESI) m / z: 561.3 [M+H]+. Potency Lin28a-dep Z11 IC50(µM) +++ Example 39: 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-1-{1-[2- (dimethylamino)ethyl]pyrrolidin-3-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of tert-butyl N-{1-[2-(dimethylamino)ethyl]pyrrolidin-3-yl}carbamateTo a solution of tert-butyl N-(pyrrolidin-3-yl)carbamate (500 mg, 2.68 mmol) in acetonitrile (20 mL) were added triethylamine (1.11 mL, 8.04 mmol), and 1-(2-bromoethyl)dimethylamine (407 mg, 2.68 mmol) at room temperature under N2atmosphere. The resulting reaction mixture was stirred at 80 °C for 8 h under N2atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and quenched with ice cold water. The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers was dried over sodium sulfate and concentrated under reduced pressure to afford tert-butyl N-{1-[2- (dimethylamino)ethyl]pyrrolidin-3-yl}carbamate (550 mg, crude) as yellow liquid. The product was proceeded to next step without purification.1H NMR (400 MHz, DMSO-d6) δ 6.91 (s, 1H), 3.93–3.82 (m, 1H), 2.72–2.66 (m, 1H), 2.56–2.40 (m, 4H), 2.30–2.19 (m, 3H), 2.12 (s, 6H), 2.02–1.94 (m, 1H), 1.55–1.48 (m, 1H), 1.37 (s, 9H). Step 2: Synthesis of 1-[2-(dimethylamino)ethyl]pyrrolidin-3-amine hydrochloride4N HCl in dioxane (5 mL) was added to tert-butyl N-{1-[2-(dimethylamino)ethyl]pyrrolidin-3- yl}carbamate (500 mg, 1.94 mmol) at 0 °C under N2 atmosphere and stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated underreduced pressure to remove volatile solvent. The crude solid was washed with diethyl ether (3 x 50 mL) and n-pentane to get 1-[2-(dimethylamino)ethyl]pyrrolidin-3-amine hydrochloride (250 mg, 67%) as brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.50 (brs, 2H), 3.93–3.87 (m, 1H), 3.56–3.39 (m, 4H), 3.29–3.21 (m, 4H), 2.81 (s, 6H), 2.33–2.16 (m, 1H), 2.08–1.98 (m, 1H). Step 3: Synthesis of ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1- yl]-1-{1-[2-(dimethylamino)ethyl]pyrrolidin-3-yl}-4-oxo-1,4-di- hydroquinoline-3-carboxylateTo a stirred solution of ethyl (2Z)-2-[(Z)-5-chloro-4-[(2R)-2-{[(3-chloropyridin-2- yl)oxy]methyl}pyrrolidin-1-yl]-2-fluorobenzoyl]-3-ethoxyprop-2-enoate (300 mg, 586 µmol) in DMSO (3 mL) was added 1-[2-(dimethylamino)ethyl]pyrrolidin-3-amine hydrochloride (138 mg, 878 µmol), followed by triethylamine (162 µL, 1.17 mmol) and stirred the reaction mixture at room temperature for 2 h under N2atmosphere. After completion of starting material, potassium carbonate (241 mg, 1.75 mmol) was added and the mixture was stirred at 80 °C for 2 h. Then, the reaction mixture was cooled and quenched with ice-cold water (5 mL), which resulted in precipitation. The precipitated solid was collected by filtration and washed with water followed by hexane, then dried under vacuum filtration to get solid. The solid was dissolved in EtOH, treated with charcoal and filtered through celite pad. The filtrate was concentrated under reduced pressure to afford ethyl 6- chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-1-{1-[2- (dimethylamino)ethyl]pyrrolidin-3-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylate (124 mg, 35%) as pale brown solid. MS (ESI) m / z: 602.3 [M+H]+. Step 4: Synthesis of 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-1-{1- [2-(dimethylamino)ethyl]pyrrolidin-3-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a stirred solution of ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]- 1-{1-[2-(dimethylamino)ethyl]pyrrolidin-3-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylate (100 mg, 165 µmol) in mixture of THF (3 mL): water (3 mL), was added LiOH.H2O (34.6 mg, 825 µmol). The resulting reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure, then aqueous layer was acidified with 1N HCl (pH~3), which resulted in precipitation. The precipitated solid was collected by filtration and was purified by prep HPLC to afford 6-chloro-7-[(2R)-2-{[(3- chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-1-{1-[2-(dimethylamino) ethyl]pyrrolidin-3-yl}-4- oxo-1,4-dihydroquinoline-3-carboxylic acid (14.2 mg, 15%) as yellow solid.1H NMR (400 MHz, DMSO-d6,VT) δ 15.31 (brs, 1H), 9.04 (s, 1H), 8.14 (s, 1H), 7.90‒7.88 (m, 1H), 7.73‒7.70 (m, 1H), 7.52‒7.41 (m, 1H), 6.90–6.86 (m, 1H), 5.41 (brs, 1H), 4.95 (brs, 1H), 4.44–4.41 (m, 2H), 3.92–3.89 (m, 1H), 3.37–3.32 (m, 2H), 3.19–3.15 (m, 1H), 2.68–2.54 (m, 4H), 2.49–2.42 (m, 2H), 2.32–2.27 (m, 3H), 2.19 (s, 6H), 2.07–2.01 (m, 1H), 1.92–1.85 (m, 2H), MS (ESI) m / z: 574.3 [M+H]+Potency Lin28a-dep Z11 IC50(µM) ++ Example 40: (R)-1-(6-aminopyridin-3-yl)-6-chloro-7-(2-(((3-chloropyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of ethyl 3-(5-chloro-2,4-difluorophenyl)-3-oxopropanoateTo a stirred solution of 5-chloro-2,4-difluorobenzoic acid (100 g, 519 mmol) in THF (1000 mL), was added CDI (168 g, 1.03 mol) in THF (1000 mL) drop wise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred at same temperature for 1 h. After completion of reaction by TLC, potassium mono ethyl malonate (132.6 g, 775 mmol), magnesium chloride (39.4 g, 413 mmol) followed by triethylamine (220 mL, 1.57 mmol) were added at room temperature and continued the stirring for a period of 16 h. After completion of the reaction by TLC, the reaction mixture was evaporated under reduced pressure. The resulting residue was diluted with water (4000 mL) and extracted with EtOAc (3 x 3000 mL). The combined organic layers were washed with brine solution (2000 mL), dried over anhydrous sodium sulphate and evaporated to dryness afforded a sticky mass. Further it was triturated with methanol (400 mL), the precipitated solid was collected by filtration and dried under vacuum to afford ethyl 3-(5-chloro-2,4-difluorophenyl)-3-oxopropanoate (85.8 g, 63%) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ 7.86 (dd, J = 8.8, 1.2 Hz, 1H), 7.47 (t, J = 10.4 Hz, 1H), 5.12 (s, 1H), 4.01 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H). Step 2: Synthesis of (R)-tert-butyl 2-(((3-chloropyridin-2-yl) oxy) methyl)pyrrolidine-1- carboxylatetert-butyl (R)-2-(hydroxymethyl) pyrrolidine-1-carboxylate (80 g, 397 mmol) in THF (500 mL) was added to a stirred suspension of sodium hydride (15 g, 357 mmol) in THF (150 mL) at 0 °C and continued the stirring at same temperature for 1h before the addition of 2,3-dichloro pyridine (64.6 g, 437 mmol) in THF (30 mL). The reaction mixture was stirred at 65 °C for a period of 16h. After completion of reaction, the reaction mixture was slowly poured in to ice water (500 mL) and the product was extracted with ethyl acetate (2 x 500 mL), the combined organic layers were successively washed with brine (250 mL), dried over sodium sulfate and evaporated under reduced pressure afforded crude material. The crude compound was subjected to silica gel column chromatography (100-200 mesh) and eluted with 5-10% EtOAc-Hexane. The relevant fractions containing the product were combined and evaporated to dryness afforded tert-butyl (R)-2-(((3-chloropyridin-2-yl) oxy)methyl) pyrrolidine-1-carboxylate (61 g, 50%) as pale-yellow liquid. MS (ESI) m / z: 313.0 [M+H]+relevant fractions were combined and concentrated under reduced pressure to afford tert-butyl (2R)-2- [(pyridin-3-yloxy) methyl] pyrrolidine-1-carboxylate (2.75 g, 99%) as an off white solid, MS (ESI) m / z: 279.4 [M+H]+. Step 3: Synthesis of (R)-3-chloro-2-(pyrrolidin-2-ylmethoxy) pyridine. HClTo a stirred solution of tert-butyl (R)2-{[(3-chloropyridin-2-yl) oxy] methyl} pyrrolidine-1- carboxylate (61.0 g, 195.01 mmol) in 4M 1,4 Dioxane-HCl (30 mL) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred at RT for a period of 12h. The excess solvent was removed under reduced pressure afforded a crude material. Further the crude material was triturated with diethyl ether (2x 150 ml) and pentane (2x 150 ml), finally dried under vacuum afforded (R)-3- chloro-2-[(pyrrolidin-2-yl) methoxy] pyridine. HCl (49 g, quantitative) as a white solid. MS (ESI) m / z: 213.1 [M+H]+( for Free base). Step 4: Synthesis of ethyl (R)-3-(5-chloro-4-(2-(((3-chloropyridin-2-yl) oxy) methyl) pyrrolidin- 1-yl)-2-fluorophenyl)-3-oxopropanoate.Triethyl amine (28.7 mL, 206.1 mmol) was added to the stirred solution of ethyl 3-(5-chloro-2,4- difluorophenyl)-3-oxopropanoate (36 g, 138.679 mmol) and (R)-3-chloro-2-(pyrrolidin-2-ylmethoxy) pyridine (49 g, 231.132 mmol) in ACN (200 mL), then the reaction mixture was stirred at 80°C for a period of 16 h. Then, the reaction mixture was cooled to room temperature, the excess solvent was removed under reduced pressure, the residue was diluted with water (300 ml) and the product was extracted with DCM (2 x 500 ml). The combined organic layers were washed with brine (500 mL), dried over Na2SO4and evaporated. The obtained crude material was subjected to silica gel column chromatography (100-200 mesh) and eluted the column with 10% EtOAc / Hexane. The relevantfractions containing the product were combined and evaporated to dryness afforded ethyl 3-{5-chloro- 4-[(2R)-2- {[(3-chloropyridin-2-yl) oxy] methyl} pyrrolidin-1-yl]-2-fluorophenyl}-3-oxopropanoate (30 g, 77%) as green liquid, MS (ESI) m / z: 455.0 [M+H]+.Step 5: Synthesis of ethyl (R,Z)-2-(5-chloro-4-(2-(((3-chloropyridin-2-yl)oxy)methyl)pyrrolidin- 1-yl)-2-fluorobenzoyl)-3-ethoxyacrylateTo a stirred solution of ethyl 3-{5-chloro-4-[(2R)-2-{[(3-chloropyridin-2-yl) oxy] methyl} pyrrolidin- 1-yl]-2-fluorophenyl}-3-oxopropanoate (900 mg, 1.97 mmol) in acetic anhydride (117 µL, 2.07 mmol) at room temperature was added triethyl orthoformate (184 µL, 1.11 mmol) and stirred the reaction mixture at 155 °C for 4 h. After completion of reaction, the reaction mixture was cooled to room temperature, solvents were removed and the residue was azeotrope with toluene (2 x 10 mL) to afford ethyl (R, Z)-2-(5-chloro-4-(2-(((3-chloropyridin-2-yl) oxy) methyl) pyrrolidin-1-yl)-2- fluorobenzoyl)-3-ethoxyacrylate (747 mg, 74%) as brown liquid. The crude compound was used for the next step without further purification. Step 6: Synthesis of (R)-ethyl 1-(6-acetamidopyridin-3-yl)-6-chloro-7-(2-(((3-chloropyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylateTo a stirred solution of ethyl (2Z)-2-[(Z)-5-chloro-4-[(2R)-2-{[(3-chloropyridin-2-yl) oxy] methyl} pyrrolidin-1-yl]-2-fluorobenzoyl]-3-ethoxyprop-2-enoate (5 g, 9.77 mmol) in DMSO (40 mL) was added N-(5-aminopyridin-2-yl) acetamide (1.76 g, 11.7 mmol) and stirred at 27 °C for 1 h. Potassium carbonate (1.35 g, 9.77 mmol) was added to the above reaction mixture and heated the reaction mixture to 90 °C and stirred for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted the reaction mixture with ice-cold water and the product was extractedwith Ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine solution (70 mL), dried over sodium sulphate and evaporated to afford crude product. The crude product was purified by silica gel column chromatography (100- 200 mesh) and eluted the column by using 60- 70% EtOAc / Hexanes. The relevant fractions containing the required product were combined and distilled under reduced pressure to afford ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl) oxy] methyl} pyrrolidin-1-yl]-1-(6-acetamidopyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.71 g, 29%) as brown solid. MS (ESI) m / z: 596.5 [M+H]+Step 7: Synthesis of (R)-1-(6-aminopyridin-3-yl)-6-chloro-7-(2-(((3-chloropyridin-2- yl)oxy)methyl)pyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acidTo a stirred solution of ethyl 6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl) oxy] methyl} pyrrolidin-1- yl]-1-(6-acetamidopyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (2.4 g, 4.02 mmol) in THF and water (1:1, 50 mL) was added sodium hydroxide (479 mg, 12.0 mmol) at 0 °C. The reaction mixture was heated to 50 °C for a period of 6 h. The reaction mixture was cooled to rt, the excess solvents were removed under reduced pressure, was diluted with water (20 ml) and acidified the aq. layer with 1N HCl at 0 °C. The precipitated solid was collected by filtration, washed with water and dried under vacuum. The resulting material was triturated with washed with 10% IPA in diethyl ether (50 ml) and acetone (2 x 50 mL) and dried under vacuum and finally lyophilized to afford 1-(6- aminopyridin-3-yl)-6-chloro-7-[(2R)-2-{[(3-chloropyridin-2-yl)oxy]methyl}pyrrolidin-1-yl]-4-oxo- 1,4-dihydroquinoline-3-carboxylic acid (1.23 g, 58%) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.69 (d, J = 16.4 Hz, 1H), 8.35 (s, 1H), 8.15 (d, J = 2.8 Hz, 1H), 7.95–7.82 (m, 2H), 7.81–7.78 (m, 1H), 7.01–6.89 (m, 2H), 6.45 (d, J = 8.4 Hz, 1H), 4.84–4.80 (m, 1H), 4.30 (s, 2H), 3.66–3.52 (m, 1H), 3.25–3.16 (m, 1H), 2.28–2.22 (m, 1H), 2.00–1.91 (m, 2H), 1.89–1.83 (m, 1H) (- CO2H & -NH2protons were not observed); MS (ESI) m / z: 526.2 [M+H]+. Potency Lin28a-dep Z11 IC50(µM) ++++ Example 41: 6-chloro-7-[(2R,4S)-2-{[(3-chloropyridin-2-yl)oxy]methyl}-4-fluoropyrrolidin-1- yl]-4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylic acidStep 1: Synthesis of 1-tert-butyl 2-methyl (2R,4S)-4-fluoropyrrolidine-1,2-dicarboxylateTo a solution of 1-tert-butyl 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (3 g, 12.2 mmol) in methylene chloride (30 mL) at -78 °C, was added diethyl amino sulfur trifluoride (2.40 mL, 18.2 mmol) drop wise. The mixture was stirred at -78 °C for 2 h and then at RT for another 16 h. After completion of the reaction, the reaction was quenched with NH4Cl aqueous solution (5 mL) and was extracted with DCM (25 mL x 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by a nutral alumina column chromatography (PE / EtOAc (v / v) = 20 / 1) to afford 1-tert-butyl 2-methyl (2R,4S)-4-fluoropyrrolidine- 1,2-dicarboxylate (1.89 g, 7.64 mmol, 63% yield) as a colour less liquid. TLC System: 10% EtOAc / Hexanes, Rf: 0.5.1H NMR (400 MHz, CDCl3): δ 5.28–5.13 (m, 1H), 4.49–4.38 (m, 1H), 3.95– 3.86 (m, 1H), 3.74 (s, 3H), 3.69–3.55 (dd, J = 12.8, 3.2 Hz, 1H), 2.62–2.54 (m, 1H), 2.19–2.02 (m, 1H), 1.42 (s, 9H). Step 2: Synthesis of tert-butyl (2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylateTo a stirred solution of 1-tert-butyl 2-methyl (2R,4S)-4-fluoropyrrolidine-1,2-dicarboxylate (2.1 g, 7.64 mmol) in THF (50 mL), was added lithium borohydride (10.9 mL, 21.8 mmol) at 0 °C. After 10 min, reaction mixture was allowed to room temperature and stirred for 5 h. After completion of reaction, reaction mixture quenched with acetic acid (1 mL) and water (3 mL) extract with ethyl acetate. The combined organic layer was washed with water, saturated NaHCO3solution and brine solution, dried over sodium sulfate filtered and concentrated to get tert-butyl (2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.62 g, 7.38 mmol, 97% yield) as a colourless liquid. Which was used in next step with out any further purifications. TLC System: 20% EtOAc / Hexanes, Rf: 0.3.1H NMR (400 MHz, CDCl3): δ 5.16–5.03 (d, J = 52.8 Hz, 1H), 4.84 (d, J = 4.0 Hz, 1H), 4.16–4.14 (m, 1H), 3.89–3.74 (m, 2H), 3.60–3.55 (m, 2H), 2.36–2.29 (m, 1H), 1.81–1.70 (m, 1H), 1.48 (s, 9H). Step 3: Synthesis of (2R,4S)-4-fluoropyrrolidin-2-yl]methanol hydrochlorideTo a stirred solution of tert-butyl (2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.8 g, 7.38 mmol) in 1,4-Dioxane (15 mL) was added Hydrochloric acid (3.67 mL, 14.7 mmol) at 0 °C. The reaction was allowed to room temperature and stirred for 5 h. After completion of reaction, all volatiles were removed under vacuum, obtained solid was washed with diethylether (2 X 15 mL) to afford [(2R,4S)-4-fluoropyrrolidin-2-yl]methanol hydrochloride (888 mg, 5.70 mmol,78%) as a off- white solid. TLC System: 5% MeOH in DCM, Rf: 0.2.1H NMR (400 MHz, DMSO-d6): δ 9.96 (bs, 1H), 9.33 (bs, 1H), 5.51–5.36 (d, J = 57.2 Hz, 1H), 3.78- 3.72 (m, 2H), 3.62–3.53 (m, 1H), 3.51–3.40 (m, 2H), 2.29–2.19 (m, 1H), 2.06–1.88 (m, 1H). Step 4: Synthesis of ethyl 6-chloro-7-fluoro-4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3- carboxylate .To a stirred solution of ethyl 3-(5-chloro-2,4-difluorophenyl)-3-oxopropanoate (2.0 g, 7.61 mmol) in triethyl orthoformate (1.88 mL, 11.4 mmol) was added acetic anhydride (1.07 mL, 11.4 mmol) and the resulting mixture was stirred at 155 °C for 2 h. After completion of reaction, concentrated under reduced pressure and azeotrope with toluene (2 x 25 ml ) to get crude compoundas brown liquid. To a stirred solution of above crude compound in DMSO (20 mL) was added pyrazin-2-amine (868 mg, 9.13 mmol) at room temperature and stirred for 1 h. After completion of SM (monitored by TLC) was added potassium carbonate (1.05 g, 7.61 mmol) to the reaction mixture at RT. The reaction mixture was heated to 80°C and stirred for 2h. After completion of reaction, the reaction mixture was quenched with ice-cold water (50 mL), which resulted in precipitation. The precipitated solid was filtered and washed with water followed by diethyl ether and dried under vaccuo to afford ethyl 6- chloro-7-fluoro-4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylate (1.98 g, 5.69 mmol, 75%) as pale yellow solid. TLC system : 70% EtOAc in Hexane ; Rf : 0.3. MS (ESI) calcd for C16H11ClFN3O3: 347.05; found: 347.9 [M+H]+(rt: 2.74 min). Step 5: Synthesis of ethyl 6-chloro-7-[(2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]-4-oxo- 1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylate.To a stirred solution of [(2R,4S)-4-fluoropyrrolidin-2-yl]methanol hydrochloride (1.11 g, 5.70 mmol) in dimethyl sulfoxide (15 mL), was added triethylamine (1.88 mL, 14.3 mmol) and stirred for 5min. After 5 min, was added ethyl 6-chloro-7-fluoro-4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3- carboxylate (1 g, 2.87 mmol) and stirred at 130 °C for 16 h in sealed tube. After completion of reaction, reaction mixture was quenched with water and extracted with EtOAc (3X 25 mL). The combined organic layer was washed with cold water, brine solution, dried over anhydrous Na2SO4filtered and concentrated to get crude compound. The obtained crude compound was purified by column chromatography (eluted with 5% MeOH in DCM) to afford ethyl 6-chloro-7-[(2R,4S)-4- fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]-4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3- carboxylate (445 mg, 995 µmol, 35%) as yellowish gummy material. TLC System: 5% MeOH / DCM, Rf: 0.5 MS (ESI) calcd for C21H20ClFN4O4: 446.1; found: 447.0 [M+H]+(rt: 2.50 min). Step 6: Synthesis of ethyl 6-chloro-7-((2R,4S)-2-(((3-chloropyridin-2-yl)oxy)methyl)-4-fluoropyrrolidin-1-yl)-4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylateTo a stirred solution of ethyl 6-chloro-7-[(2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]-4-oxo- 1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylate (500 mg, 995 µmol) in DMSO (10 mL) were added 3-chloro-2-fluoropyridine (653 mg, 4.97 mmol) and potassium carbonate (686 mg, 4.97 mmol) at room temperature. The reaction mixture was stirred at 130 °C for 3 h. After completion of reaction, reaction mixture was quenched with water and extracted with EtOAc (3X 20 mL). The combined organic layer was washed with cold water, brine solution, dried over anhydrous Na2SO4filtered and concentrated to get crude compound. The obtained crude compound was purified by column chromatography to afford ethyl 6-chloro-7-[(2R,4S)-2-{[(3-chloropyridin-2-yl)oxy]methyl}-4- fluoropyrrolidin-1-yl]-4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylate (105 mg, 188 µmol, 19%) as pale yellow gummy material. TLC System: 100% EtOAc, Rf: 0.5 MS (ESI) calcd for C26H22Cl2FN5O4: 557.10; found: 558.1 [M+H]+(rt: 3.21 min). Step 7: Synthesis of 6-chloro-7-[(2R,4S)-2-{[(3-chloropyridin-2-yl)oxy]methyl}-4- fluoropyrrolidin-1-yl]-4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylic acidTo a stirred solution of ethyl 6-chloro-7-[(2R,4S)-2-{[(3-chloropyridin-2-yl)oxy]methyl}-4- fluoropyrrolidin-1-yl]-4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylate (300 mg, 188 µmol) in ethylene dichloride (10 mL) was added trimethyl tin hydroxide (136 mg, 752 µmol) at room temperature. The reaction mixture was heated to 80 °C and stirred for 16 h. After completion of reaction, reaction mixture was diluted with DCM (20 mL) and organic layer was washed with water,brine solution, dried over anhydrous Na2SO4filtered and concentrated to get crude. The obtained crude compound was purified by reverse phase prep HPLC and pure fractions were dried under lypholization to afford 6-chloro-7-[(2R,4S)-2-{[(3-chloropyridin-2-yl)oxy]methyl}-4- fluoropyrrolidin-1-yl]-4-oxo-1-(pyrazin-2-yl)-1,4-dihydroquinoline-3-carboxylic acid (25.4 mg, 48.0 µmol, 25% yield) as an off-white solid. TLC System: 10% MeOH / DCM, Rf: 0.5 MS (ESI): calcd for C24H18Cl2FN5O4: 529.07; found: 530.3 [M+H]+(rt: 5.977 min).1H NMR (400 MHz, DMSO-d6): δ 14.8 (bs, 1H), 9.13 (s, 1H), 8.95 (d, J = 3.2 Hz, 2H), 8.79 (d, J =1.2 Hz, 2H), 8.21 (s, 1H), 7.86‒7.85 (dd, J = 4.8, 1.6 Hz, 1H), 7.80‒7.77 (dd, J = 4.0, 1.4 Hz, 1H), 6.94‒6.91 (q, J = 5.2 Hz, 1H), 6.67 (s, 1H), 5.46‒5.33 (d, J = 53.2 Hz, 1H), 4.85‒4.83 (m, 1H), 4.43- 4.39 (dd, J = 12.0, 3.8 Hz, 1H), 4.29-4.26 (dd, J = 11.8, 3.4 Hz, 1H), 3.91‒3.75 (m, 1H), 2.42‒2.40 (m, 1H), 2.24‒2.20 (m, 1H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 42: Synthesis of 6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-7-(1-(((3- fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylic acidStep 1: Synthesis of (trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonateTo a stirred solution of tert-butyl ((trans)-4-hydroxycyclohexyl)carbamate (4.0 g, 18.59 mmol) and TEA (5.6 g, 55.77 mmol) in DCM (50 mL) at 0 °C was added MsCl (3.2 g, 27.89 mmol). The mixture was stirred at room temperature for 3 h. The reaction was quenched by the addition of 100 mL water.The aqueous solution was extracted with DCM (50 mL x 3). The combined organic phase was dried over Na2SO4and concentrated to give the residue which was purified by flash column with 0- 50 % EtOAc in Petroleum ether to afford (trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate (3.3 g, 61%) as white solid. LCMS (ESI) [M+H]+:294. Step 2: Synthesis of tert-butyl 7-azabicyclo[2.2.1]heptane-7-carboxylateTo a stirred solution of (trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate (4.0 g, 13.65 mmol) in anhydrous THF (100 mL) was added t-BuOK (4.6 g, 40.94 mmol) under N2. The mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to give the residue which was purified by flash chromatography eluting with 0- 50% EtOAc in Petroleum ether to afford tert-butyl 7-azabicyclo[2.2.1]heptane-7-carboxylate (1.5 g, 56%) as colorless oil. LCMS (ESI) [M+H]+: 198. Step 3: Synthesis of tert-butyl 1-formyl-7-azabicyclo[2.2.1]heptane-7-carboxylateTo a stirred solution of tert-butyl 7-azabicyclo[2.2.1]heptane-7-carboxylate (1.4 g, 7.10 mmol) and TMEDA (989 mg, 8.52 mmol) in anhydrous THF (20 mL) at -78 °C was added s-BuLi (4.3 mL, 10.65 mmol) under N2. The mixture was stirred at this temperature for 1 h. DMF (622 mg, 8.52 mmol) was then added. The resultant was stirred for 1 h. The reaction was quenched by the addition of 40 mL water. The aqueous solution was extracted with EtOAc (50 mL x 3). The combined organic phase was dried over Na2SO4and concentrated under reduced pressure to give the residue which was purified by flash chromatography eluting with 0- 50 % EtOAc in Petroleum ether to afford tert-butyl 1-formyl-7- azabicyclo[2.2.1]heptane-7-carboxylate (700 mg, 44%) as colorless oil. LCMS (ESI) [M+H]+:226. Step 4: Synthesis of tert-butyl 1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylateTo a stirred solution of tert-butyl 1-formyl-7-azabicyclo[2.2.1]heptane-7-carboxylate (700 mg, 3.10 mmol) in EtOH (10 mL) at 0 °C was added NaBH4 (236 mg, 6.20 mmol). The mixture was stirred atroom temperature for 1 h. The reaction was quenched by the addition of 20 mL water. The aqueous solution was extracted with EtOAc (20 mL x 3). The combined organic solution was dried over Na2SO4and concentrated under reduced pressure to give the residue which was purified by flash chromatography eluting with 0- 50 % EtOAc in Petroleum ether to afford tert-butyl 1- (hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (500 mg, 71%) as colorless oil. LCMS (ESI) [M+H]+:228. Step 5: Synthesis of tert-butyl 1-(((3-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane- 7-carboxylateTo a solution of tert-butyl 1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (500 mg, 2.20 mmol) in anhydrous THF (10 mL) was added NaH (264 mg, 6.60 mmol) and 2,3- difluoropyridine (380 mg, 3.30 mmol) under N2. The mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of 20 mL water. The aqueous solution was extracted with EtOAc (20 mL x 3). The combined organic phase was dried over Na2SO4and concentrated under reduced pressure to give the residue which was purified by flash chromatography eluting with 0- 50 % EtOAc in Petroleum ether to afford tert-butyl 1-(((3-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptane-7-carboxylate (520 mg, 73%) as light yellow oil. LCMS (ESI) [M+H]+: 323. Step 6: Synthesis of 1-(((3-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptaneTo a solution of tert-butyl 1-(((3-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7- carboxylate (520 mg, 1.61 mmol) in DCM (10 mL) was added TFA (5 mL). The solution was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to give the residue which was dissolved in MeOH. NH3.H2O was added to adjust pH 9. The mixture was concentrated under reduced pressure to give the residue which was purified by flash chromatography eluting with 0- 10% MeOH in DCM to afford 1-(((3-fluoropyridin-2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptane (400 mg, crude) as light yellow oil. LCMS (ESI) [M+H]+: 223.Step 7: Synthesis of ethyl 6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-7-(1-(((3- fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylateTo a 8-mL sealed tube was added ethyl 6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)- 7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (200 mg, 0.46 mmol), 1-(((3-fluoropyridin-2- yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane (204 mg, 0.92 mmol) and DMSO (0.2 mL). The resulting mixture was heated at about 50 °C under vacuum for 1 h. Then DIEA (119 mg, 0.92 mmol, 2 equiv) was added into the mixture. The resulting mixture was stirred at 100 °C for 3 days under N2. The mixture was purified by reverse phase flash chromatography eluting with 20- 80 % acetonitrile in water to afford ethyl 6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-7-(1-(((3- fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylate (55 mg, 19%) as yellow solid. LCMS (ESI) [M+H]+: 638. Step 8: Synthesis of 6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-7-(1-(((3- fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylic acidTo a stirred solution of ethyl 6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-7-(1-(((3- fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylate (85 mg, 0.13 mmol) in THF (2 mL) was added a solution of LiOH.H2O (56 mg, 1.33 mmol) in H2O (2 mL) at room temperature under N2. The resulting mixture was stirred at room temperature overnight. The mixture was acidified by AcOH. The mixture was purified by Prep.- HPLC to afford 6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-7-(1-(((3-fluoropyridin- 2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (45.5 mg, 57%) as yellow solid. LCMS (ESI) [M+H]+:610.35.1H NMR (300 MHz, DMSO-d6) δ 8.59 (d, J = 14.4 Hz, 2H), 8.24 (m, 1H), 7.89 (d, J = 4.7 Hz, 1H), 7.78 – 7.52 (m, 2H), 7.10 – 6.96 (m, 1H), 6.74 (s, 1H), 6.42 (d, J = 8.9 Hz, 1H), 4.62 (s, 2H), 4.31 (s, 1H), 3.98 (t, J = 7.8 Hz, 2H), 3.81 – 3.68 (m, 2H), 3.26 – 3.11 (m, 1H), 2.12 (s, 6H), 1.73 (dd, J = 24.4, 14.4 Hz, 6H), 1.54 (d, J = 9.2 Hz, 2H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 43: Synthesis of (S)-6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-7-(2- (((3-fluoropyridin-2-yl)oxy)methyl)-2-methylpyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylic acidStep 1: Synthesis of (S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acidTo a stirred solution of (S)-2-methylpyrrolidine-2-carboxylic acid (3.6 g, 27.87 mmol) in DCM (100 mL) was added (Boc)2O (18.25 g, 83.61 mmol, 3 equiv) and Et3N (8.46 g, 83.61 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 5 h. Then the reaction was quenched by the addition of brine (200 mL). The mixture was extracted with DCM (100 mL x 3). The combined organic phase was dried over MgSO4. After filtration, the filtrate was concentrated under reducedpressure. This resulted in the crude product (S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2- carboxylic acid (6.38 g, 27.8 mmol) as colorless crystal. LCMS (ESI) [M+H]+:230. Step 2: Synthesis of tert-butyl (S)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylateTo a solution of (S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (6.38 g, 27.8 mmol) in anhydrous THF (100 mL) was added BH3.Me2S (10.56 g, 139 mmol, 5 equiv) at room temperature under N2. Then the resulting mixture was stirred at 70 °C for 1 h. After cooling down to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with Petroleum ether / EtOAc = 1:1 to afford tert-butyl (S)-2- (hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (4.1 g, 19.04 mmol) as colorless oil. LCMS (ESI) [M+H]+:216. Step 3: Synthesis of tert-butyl (S)-2-(((3-fluoropyridin-2-yl)oxy)methyl)-2-methylpyrrolidine-1- carboxylateTo a stirred solution of tert-butyl (S)-2-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (4.1 g, 19.04 mmol) in anhydrous THF (100 mL) was added KOtBu (6.41 g, 57.12 mmol, 3 equiv) at 0 °C under N2. After 10 min, 2,3-difluoropyridine (2.63 g, 22.85 mmol, 1.2 equiv) was added into the mixture and the resulting mixture was stirred at 0 °C for half an hour and followed by room temperature for 4 h. Then the reaction was quenched by the addition of brine (200 mL). The mixture was extracted with EtOAc (100 mL x 3). The combined organic phase was dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with Petroleum ether / EtOAc = 2:1 to afford tert-butyl (S)-2-(((3- fluoropyridin-2-yl)oxy)methyl)-2-methylpyrrolidine-1-carboxylate (4.3 g, 13.85 mmol) as colorless oil. LCMS (ESI) [M+H]+:311. Step 4: Synthesis of (S)-3-fluoro-2-((2-methylpyrrolidin-2-yl)methoxy)pyridineTo a stirred solution of tert-butyl (S)-2-(((3-fluoropyridin-2-yl)oxy)methyl)-2-methylpyrrolidine-1- carboxylate (4.3 g, 13.85 mmol) in DCM (10 mL) was added TFA (15 mL). The mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure. The residue was dissolved in sat. NaHCO3(200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the (S)-3-fluoro-2-((2-methylpyrrolidin-2-yl)methoxy)pyridine (2.6 g, 12.36 mmol) as colorless oil. LCMS (ESI) [M+H]+:211. Step 5: Synthesis of ethyl (S)-6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-7-(2- (((3-fluoropyridin-2-yl)oxy)methyl)-2-methylpyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylateTo a 8-mL sealed tube was added ethyl 6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)- 7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (500 mg, 1.148 mmol), (S)-3-fluoro-2-((2- methylpyrrolidin-2-yl)methoxy)pyridine (724 mg, 3.445 mmol, 3 equiv) and DMSO (1 mL). The resulting mixture was heated at about 50 °C under vacuum for 1 h. Then DIEA (297 mg, 2.296 mmol, 2 equiv) was added into the mixture. The resulting mixture was stirred at 100 °C for 48 h under N2. The mixture was purified by reverse phase chromatography eluting with Acetonitrile / water = 7:3 to afford ethyl (S)-6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-7-(2-(((3-fluoropyridin- 2-yl)oxy)methyl)-2-methylpyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (150 mg, 0.2397 mmol) as yellow solid. LCMS (ESI) [M+H]+:626. Step 6: Synthesis of (S)-6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-7-(2-(((3- fluoropyridin-2-yl)oxy)methyl)-2-methylpyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylic acidTo a stirred solution of ethyl (S)-6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-7-(2- (((3-fluoropyridin-2-yl)oxy)methyl)-2-methylpyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3- carboxylate (150 mg, 0.2397 mmol) in THF (4 mL) was added a solution of NaOH (19 mg, 0.4794 mmol, 2 equiv) in H2O (2 mL) at room temperature under N2. The resulting mixture was stirred at room temperature overnight. The mixture was acidified by AcOH. The mixture was purified by Prep.- HPLC to afford (S)-6-cyano-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-7-(2-(((3- fluoropyridin-2-yl)oxy)methyl)-2-methylpyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (32.8 mg) as yellow solid. LCMS (ESI) [M+H]+:598.25.1H NMR (300 MHz, DMSO-d6) δ 14.69 (s, 1H), 8.63 – 8.07 (m, 3H), 7.91 – 7.51 (m, 3H), 7.01 (m, 1H), 6.60 – 6.25 (m, 2H), 4.34 (m, 2H), 4.08 – 3.83 (m, 4H), 3.81 – 3.59 (m, 2H), 3.21 (d, J = 4.7 Hz, 1H), 2.28 – 2.19 (m, 1H), 2.13 (s, 6H), 1.97 (dd, J = 19.6, 9.9 Hz, 3H), 1.22 (d, J = 11.5 Hz, 3H). Potency Lin28a-dep Z11 IC50(µM) ++++ Example 44: Synthesis of rac-6-chloro-7-((2R,3S)-2-(((3-chloropyridin-2-yl)oxy)methyl)-3- methylpyrrolidin-1-yl)-1-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-4-oxo-1,4- dihydroquinoline-3-carboxylic acidStep 1: Synthesis of 1-tert-butyl 2-methyl 3-bromopyrrole-1,2-dicarboxylateA mixture of methyl 3-bromo-1H-pyrrole-2-carboxylate (5.0 g, 24.51 mmol, 1.0 equiv), di-tert- butyl dicarbonate (8.0 g, 36.76 mmol, 1.5 equiv), DMAP (299 mg, 2.45 mmol, 0.1 equiv) and Et3N (7.4 g, 73.52 mmol, 3 equiv) in DCM (45 mL) was stirred for 1h at room temperature under nitrogen atmosphere. The resulting mixture was con centrated under vacuum. The residue was purified by silica gel column chromatography, eluted with P E / EtOAc (5:1) to afford 1-tert-butyl 2-methyl 3-bromopyrrole-1,2- dicarboxylate (6.5 g, 87.21%) as a yellow oil. Step 2: Synthesis of 1-tert-butyl 2-methyl 3-methylpyrrole-1,2-dicarboxylateA mixture of 1-tert-butyl 2-methyl 3-bromopyrrole-1,2- dicarboxylate (6.50 g, 21.372 mmol, 1.00 equiv) and trimethyl-1,3,5,2,4,6- trioxatriborinane (26827.94 g, 213.717 mmol, 10 equiv) and K2CO3(...

Claims

CLAIMS What is claimed is:

1. In a first aspect, the present invention is directed to a compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein: W is –CH2Y-R3, -S(O)2R3, -SCH2R3, Y-R3, -OC(=O)NR11R12or –N(C=O)NR11R12; V is -C(=O)-, -S(=O)2- or CR13R14; X is CR4R5, NR6or O; Y is NR7or O; Z is CR8or N; R1is halo, -CN, -OR1a, -C≡CH, a C3-6carbocyclyl, or a C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more R10; R1ais H or C1-6alkyl optionally substituted with one or more R10; R10, for each occurrence, is independently selected from halo, -CN and -OR10a; R10a, for each occurrence, is independently selected from H and C1-6alkyl; R2is -CN,-CHRzCN, - C(O)NH2, -CHRzC(O)NH2, 3- to 12-membered carbocyclyl,–(CHRz)- (3- to 12-membered carbocyclyl), 3- to 12-membered heterocyclyl, or–(CHRz)-(3 to 12-membered heterocyclyl), wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R2or in the group represented by R2are optionally substituted with one or more R20, and Rzis H or methyl; R20, for each occurrence, is independently selected from H, halo, CN, oxo, -C(O)R20a, -C(O)2R20a, -C(O)NR20a, -N(R20a)2, -N(R20a)C(O)R20a, -N(R20a)C(O)2R20a, - N(R20a)C(O)N(R20a)2, -N(R20a)S(O)2R20a, -OR20a, -OC(O)R20a, -OC(O)N(R20a)2, -SR20a, -S(O)2R20a, -S(O)N(R20a)2, -S(O)2N(R20a)2, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R20are each optionally substituted with one or more R25; R20a, for each occurrence, is independently selected from H, C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R20aare each optionally substituted with one or more R25, or two R20atogether with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or more R25; R25, for each occurrence, is independently H, C1-6alkyl, halo,-C=O,-C(O)O(C1-C6 alkyl), 4- to 6- membered heterocyclyl optionally substituted with OH, -N(R25a)2, –OR25a, phenyl optionally substituted with C1-6alkyl, halo, -N(R25a)2or –OR25a; and R25ais H, C1-6alkyl; or two R25atogether with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl, wherein the C1-6alkyl is optionally substituted with-OCH3; R3is a 3 to 12-membered carbocyclyl or a 3 to 12-membered heterocyclyl, wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R3are optionally substituted with one or more R30; R30, for each occurrence, is independently selected from H, halo, oxo, -CN, -C(O)R30a, -C(O)2R30a, -C(O)NR30a, -N(R30a)2, -N(R30a)C(O)R30a, -N(R30a)C(O)2R30a, - N(R30a)C(O)N(R30a)2, -N(R30a)S(O)2R30a, -OR30a, -OC(O)R30a, -OC(O)N(R30a)2, -SR30a, - S(O)2R30a, -S(O)N(R30a)2, -S(O)2N(R30a)2, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R30are each optionally substituted with one or more R35; R30a, for each occurrence, is independently selected from H, C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R30aare each optionally substituted with one or more R35; R35, for each occurrence, is independently H, -NH2, C1-6alkyl, halo and –OR35a; and R35ais H or C1-6alkyl; alternatively, when Y is NR7, R7and R3together with the N atom from which R7is attached can form a 4 to 12-membered heterocyclyl optionally substituted with or more R30;R4, R5, R15, R16, R17and R18are each independently selected from H, C1-6alkyl, halo, - NHC(O)CH3, 4- to 6- membered carbocyclyl, or 4- to 6-membered heterocyclyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halo, and wherein the heterocyclyl and carbocyclyl are optionally substituted with halo, -CN, -OR4a, C1-C6 alkyl or =O (when the carbocyclyl or heterocyclyl are non-aromatic), or wherein R15and R16taken together or R17and R18taken together are =NOH or =NHOCH3; R4ais H or C1-6alkyl, optionally substitute with one or more halo; R6is H or C1-6alkyl optionally substituted with one or more substituents independently selected from halo, -CN and -OR6a; R6ais H or C1-6alkyl optionally substitute with one or more halo; R7is H or C1-6alkyl optionally substituted with one or more halo; R8is H, halo, -CN, -OR8aor C1-6alkyl optionally substituted with one or more halo; R8ais H or C1-6alkyl optionally substituted with one or more halo; R9, R13and R14are each independently selected from H, C1-6alkyl, and C3-6cycloalkyl, wherein the C1-6alkyl and the C3-6cycloalkyl are each optionally substituted with one or more substituents independently selected from halo, -CN, –OR9aand C1-6alkyl optionally substituted with one or more halo; R9ais H or C1-6alkyl optionally substituted with one or more halo; R11and R12are each independently H or C1-6alkyl, or R11and R12together with the nitrogen atom from which they are attached form a 4- to 7-membered monocyclic heterocyclyl optionally substituted with one or more substituents independently selected from C1-6alkyl, halo, -OH, and C1-6alkoxy; or any two of R4, R5, R9, R13, R14, R15, R16, R17and R18together form a -C1-5alkylene-, optionally substituted with one or more substituents independently selected from halo, -ORa, -N(Ra)2and C1-6alkyl; or R4and R15taken together with their intervening carbon atoms form phenyl or a 6 membered heteroaryl; and Ra, for each occurrence, is independently H or C1-6alkyl optionally substituted with one or more halo; R19aand R19bare each independently H or C1-6alkyl optionally substituted with one or more halo, or R19aand R19btogether with the carbon atom from which they are attached form –C(=O); orone R20group and one R30group taken together form –O-CH2CH2-O- or –O-CH2CH2-NH-; and n1 is 0, 1 or 2; and n2 is 0, 1 or 2, provided when X is NR6or O, n1 and n2 cannot be 0.

2. The compound of claim 1, represented by Formula (I’):, or a pharmaceutically acceptable salt thereof, wherein: W is Y-R3, -OC(=O)NR11R12or –N(C=O)NR11R12; V is -C(=O)-, -S(=O)2- or CR13R14; X is CR4R5, NR6or O; Y is NR7or O; Z is CR8or N; R1is halo, CN, -OR1a, -C≡CH, or a C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more R10; R1ais H or C1-6alkyl optionally substituted with one or more R10; R10, for each occurrence, is independently selected from halo, CN and OR10a;occurrence, is independently selected from H and C1-6alkyl; R2is a 3 to 12-membered carbocyclyl or a 3 to 12-membered heterocyclyl, wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R2are optionally substituted with one or more R20; R20, for each occurrence, is independently selected from H, halo, CN, oxo, -C(O)R20a, -C(O)2R20a, -C(O)NR20a, -N(R20a)2, -N(R20a)C(O)R20a, -N(R20a)C(O)2R20a, - N(R20a)C(O)N(R20a)2, -N(R20a)S(O)2R20a, -OR20a, -OC(O)R20a, -OC(O)N(R20a)2, -SR20a, - S(O)2R20a, -S(O)N(R20a)2, -S(O)2N(R20a)2, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-memberedmonocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R20are each optionally substituted with one or more R25; R20a, for each occurrence, is independently selected from H, C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R20aare each optionally substituted with one or more R25, or two R20atogether with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or more R25; R25, for each occurrence, is independently H, C1-6alkyl, halo, -N(R25a)2, –OR25a, phenyl optionally substituted with C1-6alkyl, halo, -N(R25a)2or –OR25a; and R25ais H or C1-6alkyl; R3is a 3 to 12-membered carbocyclyl or a 3 to 12-membered heterocyclyl, wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R3are optionally substituted with one or more R30; R30, for each occurrence, is independently selected from H, halo, oxo, -CN, -C(O)R30a, -C(O)2R30a, -C(O)NR30a, -N(R30a)2, -N(R30a)C(O)R30a, -N(R30a)C(O)2R30a, - N(R30a)C(O)N(R30a)2, -N(R30a)S(O)2R30a, -OR30a, -OC(O)R30a, -OC(O)N(R30a)2, -SR30a, - S(O)2R30a, -S(O)N(R30a)2, -S(O)2N(R30a)2, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R30are each optionally substituted with one or more R35; R30a, for each occurrence, is independently selected from H, C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R30aare each optionally substituted with one or more R35; R35, for each occurrence, is independently H, C1-6alkyl, halo and –OR35a; and R35ais H or C1-6alkyl; alternatively, when Y is NR7, R7and R3together with the N atom from which R7is attached can form a 4 to 12-membered heterocyclyl optionally substituted with or more R30; R4, R5, R15, R16, R17and R18are each independently selected from H, C1-6alkyl, halo, -CN and -OR4a, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halo, CN and -OR4a;R4ais H or C1-6alkyl optionally substitute with one or more halo; R6is H or C1-6alkyl wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from halo, CN and -OR4a; R6ais H or C1-6alkyl optionally substitute with one or more halo; R7is H or C1-6alkyl optionally substituted with one or more halo; R8is H, halo, CN, -OR8aor C1-6alkyl optionally substituted with one or more halo; R8ais H or C1-6alkyl optionally substituted with one or more halo; R9, R13and R14are each independently selected from H, C1-6alkyl and C3-6cycloalkyl, wherein the C1-6alkyl and the C3-6cycloalkyl are each optionally substituted with one or more substituents independently selected from halo, CN, –OR9aand C1-6alkyl optionally substituted with one or more halo; R9ais H or C1-6alkyl optionally substituted with one or more halo; R11and R12are each independently H or C1-6alkyl, or R11and R12together with the nitrogen atom from which they are attached form a 4- to 7-membered monocyclic heterocyclyl optionally substituted with one or more substituents independently selected from C1-6alkyl, halo, OH, and C1-6alkoxy; or any two of R4, R5, R9, R13, R14, R15, R16, R17and R18together form a -C1-5alkylene- optionally substituted with one or more substituents independently selected from halo, -ORa, -N(Ra)2and C1-6alkyl; Ra, for each occurrence, is independently H or C1-6alkyl optionally substituted with one or more halo; R19aand R19bare each independently H or C1-6alkyl optionally substituted with one or more halo or R19aand R19btogether with the carbon atom from which they are attached form –C(=O)-; n1 is 0, 1 or 2; and n2 is 0, 1 or 2, provided when X is NR6or O, n1 and n2 cannot be 0.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (Ia) or (Ib):, or a pharmaceutically acceptable salt thereof, wherein: X is CR4R5, NR6or O; Y is NR7or O; Z is CR8or N; R1is halo, CN, -OR1a, -C≡CH, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more R10; R1ais H or C1-6alkyl optionally substituted with one or more R10; R10, for each occurrence, is independently selected from halo, CN and OR10a;occurrence, is independently selected from H and C1-6alkyl; R2is a 3 to 12-membered carbocyclyl or a 3 to 12-membered heterocyclyl, wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R2are optionally substituted with one or more R20; R20, for each occurrence, is independently selected from H, halo, CN, oxo, -C(O)R20a, -C(O)2R20a, -C(O)NR20a, -N(R20a)2, -N(R20a)C(O)R20a, -N(R20a)C(O)2R20a, - N(R20a)C(O)N(R20a)2,--N(R20a)S(O)2R20a, -OR20a, -OC(O)R20a, -OC(O)N(R20a)2, -SR20a, - S(O)2R20a, -S(O)N(R20a)2, -S(O)2N(R20a)2, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R20are each optionally substituted with one or more R25; R20a, for each occurrence, is independently selected from H, C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R20aare each optionally substituted with one or more R25, or two R20atogether with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or more R25;R25, for each occurrence, is independently H, C1-6alkyl, halo, -N(R25a)2, –OR25a, phenyl optionally substituted with C1-6alkyl, halo, -N(R25a)2or –OR25a; and R25ais H or C1-6alkyl; R3is a 3 to 12-membered carbocyclyl or a 3 to 12-membered heterocyclyl, wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R3are optionally substituted with one or more R30; R30, for each occurrence, is independently selected from H, halo, oxo, -CN, -C(O)R30a, -C(O)2R30a, -C(O)NR30a, -N(R30a)2, -N(R30a)C(O)R30a, -N(R30a)C(O)2R30a, - N(R30a)C(O)N(R30a)2, -N(R30a)S(O)2R30a, -OR30a, -OC(O)R30a, -OC(O)N(R30a)2, -SR30a, - S(O)2R30a, -S(O)N(R30a)2, -S(O)2N(R30a)2, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R30are each optionally substituted with one or more R35; R30a, for each occurrence, is independently selected from H, C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R30aare each optionally substituted with one or more R35; R35, for each occurrence, is independently H, C1-6alkyl, halo and –OR35a; and R35ais H or C1-6alkyl; alternatively, when Y is NR7, R7and R3together with the N atom from which R7is attached can form a 4 to 12-membered heterocyclyl optionally substituted with or more R30; R4and R5are each independently selected from H, C1-6alkyl, halo, -CN and -OR4a, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halo, CN and -OR4a; R4ais H or C1-6alkyl optionally substitute with one or more halo; R6is H or C1-6alkyl optionally substituted with one or more substituents independently selected from halo, CN and -OR6a; R6ais H or C1-6alkyl optionally substitute with one or more halo; R7is H or C1-6alkyl optionally substituted with one or more halo; R8is H, halo, CN, -OR8aor C1-6alkyl optionally substituted with one or more halo; R8ais H or C1-6alkyl optionally substituted with one or more halo; n1 is 0, 1 or 2; andn2 is 0, 1 or 2, or, for formula (Ia), any two of R4, R5, R9, R13, R14, R15, R16, R17and R18together form a -C1-5 alkylene- optionally substituted with one or more substituents independently selected from halo, -ORa, -N(Ra)2and C1-6alkyl; wherein Ra, for each occurrence, is independently H or C1-6alkyl optionally substituted with one or more halo.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein X is CH2.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein n1 and n2 are both 0; n1 and n2 are both 1; or n1 is 1 and n2 is 0.

6. The compound of claim 1, 2, or 3, or a pharmaceutically acceptable salt thereof, wherein X is O; and n1 and n2 are both 1.

7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IIa) or (IIb):, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (II-1a) or (II-1b):, or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein Y is NH or O.

10. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IIIa) or (IIIb):, o , or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (III-1a) or (III-1b):or a pharmaceutically acceptable salt thereof.

12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IVa) or (IVb):, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IV-1a) or (IV-1b):, or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R8is H, halo, or OR8a.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R8is H, F, Cl or –OCH3.

16. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R8is H.

17. The compound of any one of claim 1-16, or a pharmaceutically acceptable salt thereof, wherein R1is Cl, Br, CN, -OR9or C1-6alkyl.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R1is Cl, CN or CH3.

19. The compound of any one of claims 1-7, 9, 10, 12, 14 and 15, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IVAa) , (IVBa), (IVCa), (IVDa), (IVAb), (IVBb), (IVCb) or (IVDb):,20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a ), (IVA-1b), (IVB-1b), (IVC-1b), or (IVD-1b):,or a pharmaceutically acceptable salt thereof.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R3is phenyl, a 5 or 6-membered monocyclic heteroaryl or a 9 or 10-membered bicyclic heteroaryl, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl and 9 or 10- membered bicyclic heteroaryl represented by R3are each optionally substituted with one to three R30.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R3is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1H-pyrrolo[2,3-c]pyridinyl or 1H- imidazo[4,5-c]pyridinyl, each of which is optionally substituted with one to three R30.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R30, for each occurrence, is H, halo, CN, -C(O)NR30a, -N(R30a)2, -N(R30a)C(O)R30a, - N(R30a)S(O)2R30a, -OR30a, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one to three R35;R30a, for each occurrence, is independently H or C1-6alkyl optionally substituted with one to three R35; R35, for each occurrence, is independently H, halo and –OR35a; and R35ais H or C1-3alkyl.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R30, for each occurrence, is H, halo, CN, -OR30aand C1-6alkyl optionally substituted with one to three halo; and R30ais H or C1-6alkyl optionally substituted with one to three halo.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein R30, for each occurrence, is H, F, Cl, Br, CN, -OCH3, -CH3, -CH2CH3or -CF3.

26. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R3is selected from 3-chloropyridin-2-yl, 3-methylpyridin-2-yl, 3-bromopyridin-2-yl, 3-cyanopyridin-2- yl, 3-ethylpyridin-2-yl, 3-fluoropyridin-2-yl, 3-methoxypyridin-2-yl, 3-trifluoromethylpyridin-2-yl, pyridin-2-yl, 1H-pyrrolo[2,3-c]pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-7-yl, 1H-pyrrolo[2,3-c]pyridin- 6-yl, 1H-imidazo[4,5-c]pyridin-4-yl, 2,6-dimethylphenyl, phenyl, pyradzin-3-yl, pyrimidin-4-yl, 5- methylpyridin-2-yl, 4-methylpyridin-2-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl, and pyridin-3- yl.

27. The compound of any one of claims 1-7, 9, 10, 12, 14 and 15, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (Va) or (Vb):, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (V-1a) or (V-1b):, or a pharmaceutically acceptable salt thereof.

29. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VAa), (VBa), (VCa), (VDa), (VAb), (VBb), (VCb) or (VDb):, or a pharmaceutically acceptable salt thereof.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VA-1a), (VB-1a), (VC-1a), (VD-1a), (VA-1b), (VB-1b), (VC- 1b) or (VD-1b):, or a pharmaceutically acceptable salt thereof, wherein R8is H or F.

31. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VIa) or (VIb):, or a pharmaceutically acceptable salt thereof, wherein R30is H, halo, CN, -OR30a, and C1-6alkyl optionally substituted with one to three halo; and R30ais H or C1-6alkyl optionally substituted with one to three halo.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VI-1a) or (VI-1b):, or a pharmaceutically acceptable salt thereof.

33. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VIAa), (VIBa), (VICa), (VIDa), (VIAb), (VIBb), (VICb) or (VIDb):, or a pharmaceutically acceptable salt thereof.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VIA-1a),(VIB-1a), (VIC-1a), (VID-1a), (VIA-1b), (VIB-1b), (VIC-1b) or (VID-1b):, or a pharmaceutically acceptable salt thereof.

35. The compound of any one of claims 27-34, or a pharmaceutically acceptable salt thereof, wherein R30, for each occurrence, is independently H, F, Cl, Br, CN, -CH3, -CH2CH3, -OCH3, or -CF3.

36. The compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, wherein R2is C3-8cycloalkyl, phenyl, a 4 to 6-membered saturated monocyclic heterocyclyl, a 7 to 10-membered saturated or partially saturated bicyclic heterocyclyl, a 5 or 6-membered monocyclic heteroaryl or a 9 to 10-membered bicyclic heteroaryl, each of which is optionally substituted with one to three R20; R20, for each occurrence, is independently selected from H, halo, -CN, oxo, -C(O)R20a, - C(O)NR20a, -N(R20a)2, -N(R20a)C(O)R20a, -N(R20a)S(O)2R20a, -OR20a, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered saturated monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7- membered saturated monocyclic heterocyclyl represented by R20are each optionally substituted with one or two R25; R20a, for each occurrence, is independently selected from H and C1-6alkyl, wherein the C1-6alkyl represented by R20ais optionally substituted with one or more R25; R25, for each occurrence, is independently H, C1-6alkyl, halo, -N(R25a)2, –OR25a, phenyl optionally substituted with C1-6alkyl, halo, -N(R25a)2or –OR25a; and R25ais H or C1-6alkyl.

37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl or a 6-membered monocyclic heteroaryl containing 1 to 3 nitrogen atoms, wherein the phenyl and the 6-membered monocyclic heteroaryl are each optionally substituted with one to three R20.

38. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein R2is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, 1H-indolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1H- benzo[d]imidazolyl, 1,3,4-thiadiazoly, indolinyl, tetrahydro-2H-pyranyl, pyridinyl, pyridazinyl, pyrazinyl, oxetanyl, tetrahydro-2H-pyranyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, isochromanyl, and 1,3-dihydroisobenzofuranyl, each of which is optionally substituted with one or two R20.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R2is selected from phenyl, pyridinyl, and pyrazinyl, each of which is optionally substituted with one or two R20.

40. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R2is represented by the following formula:,wherein R21is H, halo, -CN, -C(O)R20a, -C(O)NR20a, -N(R20a)2, -N(R20a)C(O)R20a, -N(R20a)S(O)2R20a, - OR21a, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered saturated monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered saturated monocyclic heterocyclyl represented by R21are each optionally substituted with one or two R25; R21ais H or C1-6alkyl, wherein the C1-6alkyl represented by R21ais optionally substituted with one or more R25; R25, for each occurrence, is independently C1-6alkyl, halo, -N(R25a)2, –OR25a, phenyl optionally substituted with C1-6alkyl, halo, -N(R25a)2or –OR25a; R25ais H or C1-6alkyl; and r is 0, 1 or 2.

41. The compound of claim 40, wherein R21ais C1-6alkyl optionally substituted with one or more R25.

42. The compound of claim 40, wherein R21is H, -F, -Cl, -CH3, -CH2OH, -OCH3, -OH, - OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, (4-methoxybenzyl)oxy, -NHCH2CH2OMe, - NHSO2CH3, or -NHC(O)CH3.

43. The compound of any one of claims 36-42, or a pharmaceutically acceptable salt thereof, wherein R20, for each occurrence, is independently selected from -F, -OH, -Cl, -CH3, - CH2CH3, -CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2N(CH3)2, -CF3, -OCH3, - OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, (4-methoxybenzyl)oxy, oxo, -C(O)CH3, -NH2, -NHCH3, -N(CH3)2, -N(CH3)(CH2CH2OCH3), -NHCH2CH2OMe, -NHCH2CH2NHCH3, - NHCH2CH2N(CH3)2, -NHSO2CH3, -NHSO2CH2CH3, -NHC(O)CH3, azetidin-yl, 3-aminoazeitidin-1- yl, piperidin-1-yl, morpholinyl, and pyrrolidin-1-yl.

44. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VIIA-1a), (VIIB-1a), (VIIC-1a), (VIID-1a), (VIIA-1b), (VIIB- 1b), (VIIC-1b) or (VIID-1b):,or a pharmaceutically acceptable salt thereof, wherein: R30is H, halo, CN, -OR30a, and C1-6alkyl optionally substituted with one to three halo; and R30ais H or C1-6alkyl optionally substituted with one to three halo; and R2is phenyl or a 6-membered monocyclic heteroaryl containing 1 to 3 nitrogen atoms, wherein the phenyl and the 6-membered monocyclic heteroaryl are each optionally substituted with one to three R20; R20, for each occurrence, is independently selected from halo, and -N(R20a)2; and R20a, for each occurrence, is independently selected from H and C1-3alkyl, or two R20atogether with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or more R25; R25, for each occurrence, is independently H, C1-6alkyl, halo, -N(R25a)2, or –OR25a; and R25ais H or C1-6alkyl.

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein: R30is halo or C1-3alkyl; R2is phenyl, pyridinyl or pyrazinyl, each of which is optionally substituted with -N(R20a)2; and R20a, for each occurrence, is H or methyl, or two R20atogether with the nitrogen atom from which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with one R25; R25is -N(R25a)2; and R25ais H or Me.

46. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein R30is Cl or methyl; and R2is phenyl, pyridin-3-yl, or pyrazin-2-yl, each of which is optionally substituted with –NH2, azetidin-1-yl, 3-aminoazetidin-1-yl or 3-(dimethylamino)azetidin-1-yl.

47. The compound of any one of claims 7-46, or a pharmaceutically acceptable salt thereof, wherein, for formula (IIa), (II-1a), (IIIa), (III-1a), (IVa), (IV-1a), (IVAa), (IVBa), (IVCa), (IVDa), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (Va), (V-1a), (VAa), (VBa), (VCa), (VDa), (VA- 1a), (VB-1a), (VC-1a), (VD-1a), (VIa), (VI-1a), (VIAa), (VIBa), (VICa), (VIDa), (VIA-1a), (VIB-1a), (VIC-1a), (VID-1a), (VIIA-1a), (VIIB-1a), (VIIC-1a), or (VIID-1a), R4, R5, R13, R14, R17and R18are all H, and R9is C1-6alkyl or C3-6cycloalkyl, wherein the C1-6alkyl and the C3-6cycloalkyl are each optionally substituted with one or more substituents independently selected from halo, CN, –OR9aand C1-6alkyl optionally substituted with one or more halo; wherein R9ais H or C1-6alkyl optionally substituted with one or more halo.

48. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein R9is C1-6alkyl optionally substituted with one to three halo.

49. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein R9is –CH3.

50. The compound of any one of claims 7-46, or a pharmaceutically acceptable salt thereof, wherein, for formula (IIa), (II-1a), (IIIa), (III-1a), (IVa), (IV-1a), (IVAa), (IVBa), (IVCa), (IVDa), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (Va), (V-1a), (VAa), (VBa), (VCa), (VDa), (VA- 1a), (VB-1a), (VC-1a), (VD-1a), (VIa), (VI-1a), (VIAa), (VIBa), (VICa), (VIDa), (VIA-1a), (VIB-1a), (VIC-1a), (VID-1a), (VIIA-1a), (VIIB-1a), (VIIC-1a), or (VIID-1a), R5, R9, R13, R14, R17and R18are all H, and R4is C1-6alkyl, halo, -CN or -OR4a, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halo, CN and -OR4a; and R4ais H or C1-6alkyl optionally substitute with one or more halo.

51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein R4is halo.

52. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein R4is F.

53. The compound of any one of claims 7-46, or a pharmaceutically acceptable salt thereof, wherein, for formula (IIa), (II-1a), (IIIa), (III-1a), (IVa), (IV-1a), (IVAa), (IVBa), (IVCa), (IVDa), (IVA-1a), (IVB-1a), (IVC-1a), (IVD-1a), (Va), (V-1a), (VAa), (VBa), (VCa), (VDa), (VA- 1a), (VB-1a), (VC-1a), (VD-1a), (VIa), (VI-1a), (VIAa), (VIBa), (VICa), (VIDa), (VIA-1a), (VIB-1a), (VIC-1a), (VID-1a), (VIIA-1a), (VIIB-1a), (VIIC-1a), or (VIID-1a), R4, R5, R14, R17and R18are all H, and R13and R9together form a -C1-3alkylene- optionally substituted with one or more substituents independently selected from halo, -ORa, -N(Ra)2and C1-6alkyl; wherein Ra, for each occurrence, is independently H or C1-6alkyl optionally substituted with one or more halo.

54. The compound of claim 53, or a pharmaceutically acceptable salt thereof, wherein R13and R9together form a –CH2CH2-, optionally substituted with one or two substituents independently selected from halo, -ORa, -N(Ra)2and C1-3alkyl; wherein Ra, for each occurrence, is independently H or C1-3alkyl optionally substituted with one or more halo.

55. The compound of claim 53, or a pharmaceutically acceptable salt thereof, wherein R13and R9together form a –CH2CH2-.

56. A pharmaceutical composition, comprising a compound of any one of claims 1-55 or 62-65 and a pharmaceutically acceptable carrier.

57. A method of treating a disease or disorder in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1- 55 or 62-65, wherein the disease or disorder is mediated by RNA-modifying protein Z11.

58. The method of claim 57, wherein the disease or disorder is characterized by an increase in Lin28A or Lin28B level as compared to a reference level.

59. The method of claim 57, wherein the disease or disorder is characterized by a decrease in let 7 miRNA level as compared to the reference level.

60. The method of claim 57, wherein the decrease in let 7 miRNA level is mediated by Z11.

61. The method of any one of claims 57-60, wherein the method is for treating cancer.

62. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IV-1a):wherein: R1is F, Cl, CN or CH3; R2is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, 1H-indolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1H-benzo[d]imidazolyl, 1,3,4-thiadiazoly, indolinyl, tetrahydro-2H-pyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxetanyl, tetrahydro-2H-pyranyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, isochromanyl, and 1,3-dihydroisobenzofuranyl, each of which is optionally substituted with one or two R20; R20, for each occurrence, is independently selected from H, halo, -CN, oxo, -C(O)R20a, - C(O)NR20a, -N(R20a)2, -N(R20a)C(O)R20a, -N(R20a)S(O)2R20a, -OR20a, C1-6alkyl, C3-8cycloalkyl, and 4- to 7-membered saturated monocyclic heterocyclyl, wherein the C1-6alkyl, C3-8cycloalkyl, and 4- to 7- membered saturated monocyclic heterocyclyl represented by R20are each optionally substituted with one or two R25; R20a, for each occurrence, is independently selected from H and C1-6alkyl, wherein the C1-6alkyl represented by R20ais optionally substituted with one or more R25; R25, for each occurrence, is independently H, C1-6alkyl, halo, -N(R25a)2, –OR25a, phenyl optionally substituted with C1-6alkyl, halo, -N(R25a)2or –OR25a; and R25ais H, C1-6alkyl, or C1-6alkyl substituted with –OCH3; R3is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H- imidazo[4,5-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-imidazo[4,5-b]pyridinyl, 1H-pyrrolo[3,2- b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl,or 1H-imidazo[4,5-c]pyridinyl, each of which is optionally substituted with one to three R30; R30, for each occurrence, is H, halo, CN, -C(O)NR30a, -N(R30a)2, -N(R30a)C(O)R30a, - N(R30a)S(O)2R30a, -OR30a, and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one to three R35;R30a, for each occurrence, is independently H, C1-6alkyl optionally substituted with one to three R35or C3-6cycloalkyl; R35, for each occurrence, is independently H, halo or –OR35a; and R35ais H or C1-3alkyl; R4is H, halo, -CN, -OR4a, C1-6alkyl, pyridinyl, or pyrazolyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halo, CN and -OR4a; wherein the pyridinyl, or pyrazolyl is optionally substituted with –OH, -C1-C6 alkyl or –O-C1-C6 alkyl; and R4ais H, C1-6alkyl optionally substituted with one or more halo, or C3-C6 cycloalkyl; R5is H or halo, or R4and R5taken together are =NOH, or =NHOCH3, or R4and R5taken together with the carbon to which they are connected form a C3-C6 cycloalkyl, or R5and R13taken together with their intervening atoms form a cyclopropyl; and; R8, R13and R14are each H; R9is H, C1-C6alkoxy or C1-C6alkyl, or R9and R13together form a -C1-3alkylene- optionally substituted with one or more substituents independently selected from halo, -ORa, -N(Ra)2and C1-6alkyl; wherein Ra, for each occurrence, is independently H or C1-6alkyl optionally substituted with one or more halo; R17is H, halo or C1-6alkyl; and R18is H, -OH, -O(C1-C6alkyl) or C1-6alkyl, or R17and R18taken together are =NOH or =NHOCH3).

63. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IV-1a):wherein: R1is F, Cl, CN or CH3; R2is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, 1H-indolyl, 2,3-dihydro-1H-benzo[d]imidazolyl,1H-benzo[d]imidazolyl, 1,3,4-thiadiazoly, indolinyl, tetrahydro-2H-pyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxetanyl, tetrahydro-2H-pyranyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, isochromanyl, and 1,3-dihydroisobenzofuranyl, each of which is optionally substituted with one or two R20; R20, for each occurrence, is independently selected from -F, -OH, -Cl, -CH3, -CH2CH3, - CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2N(CH3)2, -CF3, -OCH3, - OCH2CH2OCH3, -OCH2CH2OH, -OCH2CH2N(CH3)2, (4-methoxybenzyl)oxy, oxo, -C(O)CH3, -NH2, -NHCH3, -N(CH3)2, -N(CH3)(CH2CH2OCH3), -NHCH2CH2OMe, -NHCH2CH2NHCH3, - NHCH2CH2N(CH3)2, -NHSO2CH3, -NHSO2CH2CH3, -NHC(O)CH3, azetidin-yl, 3-aminoazeitidin-1- yl, piperidin-1-yl, morpholinyl, pyrrolidin-1-yl; and 3-(dimethylamino)azetidin-1-yl orR3is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H- pyrrolo[3,2-c]pyridinyl, or 1H-imidazo[4,5-c]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrrolo[2,3- b]pyridinyl,1H-imidazo[4,5-b]pyridinyl; 1H-pyrrolo[3,2-b]pyridinyl, or 3H-imidazo[4,5-b]pyridinyl each of which is optionally substituted with one to three R30; R30, for each occurrence, is H, F, Cl, Br, CN, -OCH3, -O(cyclopropyl), -NH2, -NH(CH3)2, - CH3, -CH2CH3or -CF3; R4is H, halo, -CN, OR4a, C1-6alkyl, pyridinyl, or pyrazolyl, wherein the C1-6alkyl is optionally substituted with one or more substituents independently selected from halo, CN and -OR4a; wherein the pyridinyl, or pyrazolyl is optionally substituted with –OH, -CH3or -OCH3; and R4ais H, -CH3, cyclopropyl or -CH2CH3optionally substituted with one or more halo, or cyclopropyl; R5is H or F, or R4and R5taken together are =NHOCH3, or R4and R5taken together with the carbon to which they are connected form cyclopropyl, or R5and R13taken together with their intervening atoms form a cyclopropyl; and R8, R13and R14are all H; R9is H or -CH3, or R9and R13together form a –C2 alkylene-; R17is H, F or –CH3; and R18is H, -OH, -OCH3or –CH3, or R17and R18taken together are =NHOCH3.

64. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IV-1a):wherein: R1is F or Cl; R2is selected from pyridinyl, pyriminidinyl and pyridazinyl, each of which is substituted with R20; R20, for each occurrence, is independently selected from -NH2,-NHCH3, N(CH3)2, and 4- to 7-membered saturated monocyclic heterocyclyl, wherein the 4- to 7-membered saturated monocyclic heterocyclyl represented by R20substituted with -N(R25a)2; R25ais H, C1-6alkyl, or C1-6alkyl substituted with –OCH3; R3is pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2- b]pyridinyl or 3H-imidazo[4,5-b]pyridinyl, each of which is optionally substituted with one to three R30; R30, for each occurrence, is H, halo, C1-C6alkyl, -N(R30a)2and -OR30a; R30a, for each occurrence, is independently H, C1-6alkyl or C3-6cycloalkyl; R4is H, halo, -OR4a, C1-6alkyl, pyridinyl, or pyrazolyl, wherein the pyridinyl, or pyrazolyl is optionally substituted with –OH, -C1-C6alkyl or –O-(C1-C6alkyl); R4ais H, C1-6alkyl or C3-C6cycloalkyl; R5is H or halo, or R4and R5taken together are =NOH or =NHOCH3, or R4and R5taken together with the carbon to which they are connected form a C3-C6 cycloalkyl, or R5and R13taken together with their intervening atoms form a cyclopropyl; and; R8, R13and R14are each H; R9is H or C1-C6 alkyl; R17is H, halo, C1-C6 alkoxy or C1-6alkyl; R18is H, or C1-6alkyl.

65. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IV-1a):wherein: R1is F or Cl; R2is selected from pyridinyl, pyrimidinyl and pyridazinyl, each of which is substituted with R20; R20is -NH2, -NHCH3, N(CH3)2, 3-(dimethylamino)azetidin-1-yl oR3is pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2- b]pyridinyl, or 3H-imidazo[4,5-b]pyridinyl each of which is optionally substituted with one to three R30; R30, for each occurrence, is H, Cl, CH3, -OCH3, -O(cyclopropyl), -NH2, -NHCH3or -N(CH3)2; R4is H, F, OH, -OCH3, -O-(cyclopropyl), -C1-C3 alkyl, pyridinyl, or pyrazolyl, wherein the pyridinyl or pyrazolyl is optionally substituted with –OH, -CH3, -OCH3or –O(Cyclopropyl); R5is H or F, or R4and R5taken together are =NHOCH3, or R4and R5taken together with the carbon to which they are connected form cyclopropyl, or R5and R13taken together with their intervening atoms form a cyclopropyl; and R8, R13and R14are each H; R9is H or -CH3; R17is H, F, -OCH3or –CH3; and R18is H or –CH3.