Use of cell metabolism modulating compounds in combination with immunotherapy

Abstract

Pharmaceutical compositions and methods of using these compositions are disclosed that show efficacy in the treatment / amelioration of various human diseases, including cancer. The pharmaceutical composition comprises compounds that modulate the function of fatty-acid binding proteins that are used in combination with immunotherapy treatment that demonstrates synergistic efficacy to target and eliminate disease-associated antigens and / or cells.

Description

[0001] USE OF CELL METABOLISM MODULATING COMPOUNDS IN COMBINATION WITH IMMUNOTHERAPY

[0002] The present application claims priority under 35 USC 119(e) to US Provisional Application No. 63 / 673,712 filed July 20, 2024, the entire contents of which is hereby incorporated by reference in its entirety.

[0003] FIELD OF THE INVENTION

[0004] The field of the embodiments of the present invention relate to treatment / amelioration of various human diseases including cancer using the compounds that modulate the function of fatty-acid binding proteins, as described herein, in combination with immunotherapy that demonstrate synergistic efficacy to target and eliminate disease associated antigens or cells.

[0005] BACKGROUND OF THE INVENTION

[0006] Several approved immunotherapies and those under development utilize monoclonal antibodies to target and eliminate disease-associated antigens or cells through mechanisms known as antibody effector functions. However, the success of these therapies is often constrained by the limited effector capacity of innate immune cells. This invention specifically describes a novel class of compounds that bind to FABP4, as well as compounds described in US patent applications 17 / 742,899, 17 / 566,692, 17 / 566,695 (now US Patent No. 12,138,243), 18 / 014,981, 17 / 361,052, 18 / 012,985 that bind to and modulate the function of FABP4 unexpectedly demonstrated significant enhancement in the antibody-dependent phagocytic activity of macrophages, key effector cells in the immune system. Consequently, this invention relates to the use of these compounds in combination with immunotherapies that function by eliminating target antigens or cells via antibody effector functions across different modalities, including but not limited to mono-specific, bi-specific and multi-specific monoclonal antibodies, and antibody-drug conjugates, to treat diseases including cancer, autoimmune, infectious and inflammatory disorders.

[0007] Monoclonal antibodies have been widely used to treat a broad range of diseases. Structurally, they consist of an antigen-binding fragment (Fab), which binds specifically to the target antigen, a hinge region and a fragment crystallizable (Fc) region. The Fc region is responsible for engaging Fc-gamma receptors (FcyRs) on immune cells and thereby modulating the antibody’s mode of action (reviewed in Gogesch et al., 2021 , “The Role of Fc Receptors on the Effectiveness of Therapeutic Monoclonal Antibodies. International Journal of Molecular Sciences, 22(16), 8947). In humans, five FcyRs have been identified. Among them, FcyRI (CD64), FcyRIIa (CD32a), FcyRIIc (CD32c), and FcyRIIIa (CD16a) are classified as activating FcyRs, which transmit immunostimulatory signals that mediate antibody effector functions such as antibody-dependent phagocytosis. In contrast, FcyRIIb (CD32b) is the only inhibitory FcyR and transmits immunosuppressive signals upon antibody binding.

[0008] Immunoglobulin G (IgG) is the most commonly used antibody isotype in immunotherapy due to its favorable pharmaceutical properties. Many IgG antibodies are also capable of combining highly specific antigen binding with the ability to mediate antibody effector functions to eliminate pathogenic antigens or cells through interacting with activating FcyRs in immune cells (reviewed in Gogesch et al., 2021). There are four different subtypes of IgGs in humans: IgGl, IgG2, IgG3, and IgG4 (Yu et al., 2020, “How to select IgG subclasses in developing anti-tumor therapeutic antibodies”, Journal of Hematology & Oncology, 45(13). Among these, IgG2 and IgG4 exhibit little to no effector activity. While IgG3 can engage activating FcyRs and mediate immune effector functions, it is generally not preferred for therapeutic antibodies due to structural limitations that negatively impact its stability, efficacy, and pharmacokinetic properties. In contrast, IgGl can bind to all activating FcyRs and are capable of eliciting strong effector functions such as antibody-dependent phagocytosis. Accordingly, numerous examples in the literature demonstrate that IgGl -based antibodies across various modalities including mono- specific antibodies targeting a single epitope, bi-specific or multi-specific antibodies engaging multiple targets, or antibody-drug conjugates delivering cytotoxic payloads directly to the target cells, consistently maintain the capacity to eliminate target antigens or cells through antibody effector functions. This versatile effector potential, combined with their favorable pharmacological properties underlies their widespread use in oncology, autoimmune diseases, and infectious disease therapies where cellular or antigen depletion is a key therapeutic goal.

[0009] Macrophages play a central role in antibody-dependent phagocytic elimination of pathogens or target cells. Macrophage phagocytosis is a metabolically demanding process. Studies have identified fatty-acid metabolism as a critical energy source for phagosome formation vacuoles that ingest pathogens, antibody opsonized cells, and cellular debris and for subsequent digestion of these materials (Viola et al., 2019, “The Metabolic Signature of Macrophage Responses”. Frontiers in Immunology, 10, 3389). Fatty acid binding proteins (FABP) are a family of proteins that bind fatty acids and other lipids reversibly, regulating their metabolism (Li et al., 2021, “A-FABP in Metabolic Diseases and the Therapeutic Implications: An Update”. International Journal of Molecular Sciences, 22(17), 9386). These proteins are involved in multiple cellular pathways, including lipid storage, degradation, signaling, and cytokine production. There are nine known FABP isoforms in mammals, each exhibiting different tissue-specific expressions. Among human leukocytes, FABP4 (also known as aP2) is prominently expressed in macrophages and dendritic cells. In macrophages, the function of this protein has been linked to numerous pathways that influence the efficiency of phagocytosis such as lipolysis, ER-stress and inflammation. Accordingly, it has been shown that genetic deletion of FABP4 in cultured macrophages increases antibody-dependent phagocytosis, while overexpressing it reduces this activity.

[0010] While the literature and select patent applications (e.g., WO 00 / 47734, WO 00 / 15229, WO 00 / 15230, WO 02 / 40448, WO 01 / 54694, WO 00 / 59506, and WO 2004 / 063156) have provided various presentations of the concept of the FABP inhibition, in general, and that of the FABP4 inhibition, in particular, none of the discussions in these prior art documents provide (a) solution(s) to all of the unmet needs, as does the present invention. For example, the present invention describes that a novel class of compounds that binds to FABP4, and compounds that bind to and modulate the function of FABP4 described in prior art US patent applications 17 / 742,899, 17 / 566,692, 17 / 566,695 (now US Patent No. 12,138,243), 18 / 014,981, 17 / 361,052, 18 / 012,985 increase macrophage mediated antibody effector functions, thereby boosting target depletion when combined with certain immunotherapies.

[0011] SUMMARY OF THE INVENTION

[0012] Pharmaceutical compositions and methods of using these compositions are disclosed that show efficacy in the treatment / amelioration of various human diseases, including cancer. The pharmaceutical composition comprises compounds I, IA, II, IIA as disclosed herein that modulate the function of fatty-acid binding proteins that are used in combination with immunotherapy treatment that demonstrates synergistic efficacy to target and eliminate disease- associated antigens and / or cells. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

[0013] Fig. 1A shows the results of an assay measuring the phagocytic index for a control, an antibody anti-CD47 and various compounds with anti-CD47 using Raji cells.

[0014] Fig. IB shows the results of an assay measuring the phagocytic index for a control, an antibody anti-CD20 and various compounds with anti-CD20 using Raji cells.

[0015] Fig. 1C shows the results of an assay measuring the phagocytic index for a control, an antibody anti-CD20 and various compounds with anti-CD20 using BJAB cells.

[0016] Fig. ID shows the results of an assay measuring the phagocytic index for a control, an antibody anti-HER2 and various compounds with anti-HER2 using SK-BR-3 cells. Fig. IE shows the results of an assay measuring the phagocytic index for a control, an antibody anti-HER2 and various compounds with anti-HER2 using BT-474 cells.

[0017] DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention, in one embodiment, relates to a pharmaceutical composition comprising a compound of Formula (IA) or of Formula (IIA) in combination with an antibody:

[0019] Formula (IA) or pharmaceutically acceptable salts or esters thereof, wherein: wherein each of R1and R6-R9are independently -H, -CN, -COOH, -CONH2, B(0Ra)2, an acid isostere, a halo, Cnalkyl, Cnalkenyl, Cnalkynyl, Cnaryl, Cnaminoalkyl, Cnhaloalkyl, Cnheteroaryl, Cncycloalkyl, or Cnheterocycloalkyl, wherein Raof the B(0Ra)2 is H or an alkyl, wherein B of the B(0Ra)2 is boron, wherein n of the Cnis 1 - 10, wherein each of R2- R5are independently -H, -CN, -COOH, -COOMe, -CONH2, B(ORa)2, the acid isostere, the halo, -CONHOH, -NH-SO2-Cr-C6-alkyl, -NHSO2Ar, the Cn alkyl, the Cn alkyl, the Cnalkenyl, the Cnalkynyl, the Cnaryl, the Cnaminoalkyl, the Cnhaloalkyl, the Cn heteroaryl, the Cncycloalkyl, or the Cnheterocycloalkyl, wherein the Ar of -NHSO2Ar is selected from the group consisting of: phenyl, naphthyl, pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3- benzoxadiazole, benzothiazole, 2,1,3-benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-l,4-benzoxazine, 1,5- naphthyridine, 1,8-naphthyridine, acridine, phenazine, and xanthene, wherein each of the Cnalkyl, the Cnalkenyl, the Cnalkynyl, the Cnaryl, the Cnaminoalkyl, the Cnhaloalkyl, the Cnheteroaryl, the Cncycloalkyl, and the Cnheterocycloalkyl is unsubstituted or substituted with a quantity of substituents being between 1-5, wherein each of the substituents is the same or different, wherein each of the substituents is selected from the group consisting of H,2H, halo, amino, alkoxy, cyano, aminoalkyl-, (amino)alkoxy-, -alkyl, -alkenyl, -alkynyl, alkoxy-, hydroxy, -alkyl hydroxy, aryloxy-, -alkyl(aryl), (alkoxyalkyl)amino-, -aryl, -aryl(halo), -heteroaryl, hydroxyl-alkyl-, hydroxyl-aryl-, (aryl)alkyl-, -S(O)2-alkyl, -S(O)2-aryl, -C(O)alkyl, and -Cq-U- Cq, wherein each q of -Cq-U-Cqis independently 0 to 10, wherein the U of -Cq-U-Cqis any one of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, O, S, SO2, orN(Ri)(Ri), wherein each Ri of N(Ri)(Ri) is independently hydrogen, the Cnalkyl, the Cn alkenyl, the Cnalkynyl, the Cnaryl, the Cnaminoalkyl, the Cnhaloalkyl, the Cn heteroaryl, the Cn cycloalkyl, or the Cnheterocycloalkyl, wherein each Ri of N(Ri)(Ri) is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents which can be the same or different and are independently selected from the group consisting of: H,2H, halo, amino, alkoxy, cyano, aminoalkyl-, (amino)alkoxy-, -alkyl, -alkenyl, - alkynyl, alkoxy-, hydroxy, -alkylhydroxy, aryloxy-, -alkyl(aryl), (alkoxyalkyl)amino-, -aryl, - aryl(halo), -heteroaryl, hydroxyl-alkyl-, hydroxyl-aryl-, (aryl)alkyl-, -S(O)2-alkyl, -S(O)2-aryl, and -C(O)alkyl, wherein Q is a bond or O, wherein X is C, N, O, or S such that R6is not present if X is O or S, wherein “A” is a saturated or unsaturated ring depicted by wherein Y, T, W, and Z are independently a bond, C, N, O, an alkyl having 1 to 4 carbon atoms, or an alkenyl having 1 to 4 carbon atoms, and wherein n is 0, 1, 2, or 3. Wherein:

[0020] Wn-14 are each independently -C, -CH, O, S, orN;

[0021] Z is an 5-6 membered aryl or heteroaryl group;

[0022] Xi is independently CH or N;

[0023] Y is independently CH orN; m is a number between 0 and 3;

[0024] One or more of Ru and RUA on the ring Z is / are independently selected from the group consisting of: CN, OH, COOH, OCH3, CF3, CONH2, B(0H)2, B(0R)2, an acid isostere, a substituted amine, ethers, and a halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cyclic or heterocyclic, substituted or unsubstituted cycloaryl or cycloheteroaryl, wherein the substituted cycloaryl or cycloheteroaryl may be substituted with hydrogen, CN, OH, COOH, OCH3, CF3, CONH2, B(0H)2, B(0R)2, an acid isostere, a substituted amine, ethers, and a halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cyclic or heterocyclic, substituted or unsubstituted cycloaryl or cycloheteroaryl, SO2NH2;

[0025] One or more of R12 or R12A on the ring W is / are independently selected from the group consisting of: CN, OH, CHF2, CH2F, CF3, COOH, CONH2, B(OH)2, B(OR)2, an acid isostere, a halogen, and a bicyclic heteroaryl;

[0026] Rn is hydrogen or CN, COOH, CONH2, B(0H)2, B(0R)2 or an acid isostere;

[0027] R is alkyl;

[0028] R13, R14, R15 or Ri8, or Ri6 when n is not zero, is each independently selected from:

[0029] (1) hydrogen;

[0030] (2) alkyl or ether having 1 to 12 carbon atoms,

[0031] (3) a substituted amine, or

[0032] (4) — (CH2)OG, wherein o is 1 to 12 and G is independently selected from:

[0033] (a) cycloalkyl containing 3 to 6 carbon atoms,

[0034] (b) aryl or heteroaryl,

[0035] (c) CF3, CF2H or CFH2, or

[0036] (d) a heterocycle, provided that R13, R14, R15, Ri8, or Ri6 are not all hydrogen; or pharmaceutically acceptable salts or stereoisomers thereof. The present invention, in one embodiment, relates to a pharmaceutical composition comprising a compound of Formula (I) or of Formula (II) in combination with an antibody:

[0037] Formula II wherein Q is a bond or O,

[0038] Ri is aryl, heterocyclyl, or heteroaryl, wherein each aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more of any of -COOH, -CONH2, an alkyl, a Ci-salkoxy, hydroxyl, cyano, an ether, halo, or CF3;

[0039] R2 is hydrogen or halo;

[0040] R3 is hydrogen, C2-Csalkyl optionally substituted with 1 to 10 halo atoms or a mono or bicyclic heterocyclyl or mono or bicyclic heteroaryl ring, wherein the mono or bicyclic heterocyclyl or mono or bicyclic heteroaryl ring is optionally substituted with hydroxy or Ci.3alkyl; -CF3, - CHF2, -CH2F, -CN, -C2-C8alkyl-N3, -CH2(CH2)6C(O)NH(CH2)2-O(CH2)2-O(CH2)2-NH2, - N(CH2CH3)2, or -N(CH3)(C6HS);

[0041] R4 is hydrogen, halo, or C2-C8alkyl optionally substituted with 1 to 10 halo atoms;

[0042] R5 is hydrogen; with the proviso that all of R2, R3, R4, and R5 are not hydrogen;

[0043] X is CH, O, N, or S, wherein Re is not present when X is O or S;

[0044] Re is hydrogen, alkyl, or cycloalkyl, n is 0 or 1,

[0045] R7 is heterocyclyl, heteroaryl, -C(C8)(C9)(Cio) wherein C8, C9, and C10 are each independently hydrogen, Ci-C3alkyl, -COOH, -C(O)NHCH2COOH, -C(O)NHCH2OH, or any two of C8, C9, and C10 may be =0; or X, Re, R7, and / or any of R8, R9, and Rio together with the atoms to which they are attached optionally form a 3 to 6 membered cycloalkyl ring or a 5 or 6 membered heterocyclyl or heteroaryl ring, which is optionally substituted with Ci-C3alkyl, -COOH, -C(0)NHCH2C00H, - C(0)NHCH20H, or =0,

[0046] Z is phenyl, pyridyl, or a thiophene,

[0047] R11 and RUA are independently -CN, hydrogen, -CF3, -COOH, halo, -O-Ci-3alkyl, -C(0)NH2, R12 and RI2A are independently -COOH, halo, hydrogen, or -C(0)NHCH2C00H, with the proviso that at least one of RI2and RI2A are -COOH or -C(0)NHCH2C00H, m is 1 or 2,

[0048] RI3is hydrogen or Ci-3alkyl,

[0049] Ru is hydrogen or C2.8alkyl optionally substituted with 1 to 10 halo atoms or -COOH,

[0050] R15 is hydrogen or Ci-3alkyl,

[0051] Ri6 is hydrogen or Ci-3alkyl,

[0052] R17 and RI8are independently hydrogen, Ci-3alkyl or together are =0.

[0053] In an embodiment, Ri is phenyl, pyrrolo, piperdinyl, morpholino, oxazolo, or pyridyl.

[0054] In an embodiment, Q is a bond or O,

[0055] Ri is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with an alkyl, an ether, halo, or CF3

[0056] R2is hydrogen or halo, R.3 is hydrogen, C2-C8alkyl optionally substituted with 1 to 10 halo atoms, CF3, CHF2, CH2F, CN, C2-C8alkyl-N3, or (CH2)7C(O)NH(CH2)2-O(CH2)2-O(CH2)2-NH2,

[0057] R4 is hydrogen, halo, or C2-C8alkyl optionally substituted with 1 to 10 halo atoms, R5 is hydrogen, with the proviso that all of R2, R3, R4, and R5 are not hydrogen, X is CH, O, N, or S, wherein Re is not present when X is O or S, Re is hydrogen or alkyl, n is 0 or 1,

[0058] R7 is heterocyclyl, heteroaryl, -C(C8)(C9)(Cio) wherein C8, C9, and C10 are each independently hydrogen, Ci-C3alkyl, -COOH, -C(O)NHCH2COOH, or -C(O)NHCH2OH;

[0059] Z is phenyl, pyridyl, or a thiophene,

[0060] R11 and RUA are independently -CN, hydrogen, -CF3, -COOH, halo, -O-Ci-3alkyl, -C(O)NH2, R12 and R12A are independently -COOH, halo, hydrogen, or -C(O)NHCH2COOH, with the proviso that at least one of R12 and R12A are -COOH or -C(O)NHCH2COOH, m is 1 or 2,

[0061] R13 is hydrogen or Ci-3alkyl,

[0062] Ru is hydrogen or C2-8alkyl optionally substituted with 1 to 10 halo atoms or -COOH,

[0063] R15 is hydrogen or Ci-jalkyl,

[0064] R16 is hydrogen or Ci-3alkyl,

[0065] R17 and RI8are independently hydrogen, Ci-salkyl or together are =0.

[0066] The present invention relates to a pharmaceutical composition using the compound(s) according to Formulas (IA), (IIA), (I) or (II) for use in the treatment of disorders acting on the fatty acid binding protein (FABP4) in combination with an antibody. Moreover, any accompanying method as disclosed herein using this pharmaceutical composition are contemplated and within the scope of the present invention.

[0067] Yet another object of the present invention is a pharmaceutical composition comprising a compound according to Formulas (IA), (IIA), (I) or (II) as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier for use in the treatment of disorders acting on the FABP4. Here, the pharmaceutical composition can further comprise an additional therapeutically active agent. It should be noted that all of the various Formula (1 )s, for example, Formula (I) and Formula (IA) are related in a manner that one is substantially a subgenus of the other. Similarly, all Formula (II)s are related. For example, Formula (II) and Formula (IIA) contain that same genus / subgenus relationship. It should be noted that although there is a genus / subgenus relationship with the various Formulae, there may be instances where the Formula that is substantially the subgenus, may have one or more variables that has / have a greater number of possible substituents and may be broader than the substituents that are present for the comparable variables in the Formula of the genus. Hence, this is the reason why one is “substantially” a subgenus of the other, as the genus / subgenus relationship is not absolute.

[0068] Accordingly, it should be understood that if the variable name is the same (e.g., R17 in Formula (IIA) and Formula (II)), the substituents that are named for R17 in Formulas (IIA) may be moved to R17 in Formula (II) or vice versa. Similarly, the same protocol may be done with Formula (I) and Formula (IA). Moreover, if the relative position of the variable is the same, the same protocol may be done. For example, in Formula (IA), and Formula (I), it should be apparent to those of skill in the art that variables R7, Rs, and R9 in Formula (IA) roughly correspond to variables Rs, R9 and Rio in Formula (I), respectively, so that the various substituents that are named for those variables in one formula may be moved to the other, or vice versa. Alternatively, it is contemplated that any subgenus may be established wherein any Markush member from any variable may be omitted. Furthermore, any proviso that is stated in relation to Formula (I) may be transferred to Formula (IA), or vice versa and any proviso that is stated in relation to Formula (II) may be transferred to Formula (IIA), or vice versa.

[0069] As used herein, the term “acid isostere” includes, but is not limited to, the following functional groups, where R is H or alkyl.

[0070]

[0071] The term “alkyl” refers to a saturated, straight- or branched-chain hydrocarbon group having from 1 to 20 carbon atoms. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3- methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l -pentyl,

[0072] 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l- butyl, 3, 3 -dimethyl -1 -butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like, and longer alkyl groups, such as heptyl, octyl, and the like.

[0073] Moreover, the number of carbons on an alkyl chain can be defined in association with the C atom such as Ci-io, where Ci-io is a carbon chain having 1 to 10 carbon atoms.

[0074] The term “alkoxy” as used herein includes -O-(alkyl), wherein alkyl is defined above.

[0075] The term “amino” as used herein refers to an -NH2 group. The term “aryl” means a mono-, bi-, or tricyclic aromatic group, wherein all rings of the group are aromatic and all ring atoms are carbon atoms. For bi- or tricyclic systems, the individual aromatic rings are fused to one another. Examples of aryl groups are 6 and 10 membered aryls. Further examples of aryl groups include, but are not limited to, phenyl, naphthalene, and anthracene.

[0076] The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond.

[0077] The term “deuterium” as used herein means a stable isotope of hydrogen having one proton and one neutron.

[0078] The term “halo” represents chloro, fluoro, bromo, or iodo. In some embodiments, halo is chloro, fluoro, or bromo. The term “halogen” as used herein refers to fluorine, chlorine, bromine, or iodine.

[0079] The term “hydroxy” or “hydroxyl” means an -OH group.

[0080] The term “oxo” means an =0 group and may be attached to a carbon atom or a sulfur atom.

[0081] The term “N-oxide” refers to the oxidized form of a nitrogen atom.

[0082] The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic, fused polycyclic, bridged polycyclic, or spiro polycyclic carbocycle having from 3 to 15 carbon ring atoms. A non limiting category of cycloalkyl groups are saturated or partially saturated, monocyclic carbocycles having from 3 to 6 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moi eties:

[0083] The term "heterocycloalkyl" or “heterocyclyl” as used herein refers to a monocyclic, or fused, bridged, or spiro polycyclic ring structure that is saturated or partially saturated and has from three to 12 ring atoms selected from carbon atoms and up to three heteroatoms selected from nitrogen, oxygen, and sulfur. The ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members, or an N-oxide. Illustrative heterocycloalkyl entities include, but are not limited to:

[0084] The term “heteroaryl” refers to a monocyclic, or fused polycyclic, aromatic heterocycle having from three to 15 ring atoms that are selected from carbon, oxygen, nitrogen, and sulfur. Suitable heteroaryl groups do not include ring systems that must be charged to be aromatic, such as pyrylium. Suitable 5-membered heteroaryl rings (as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) have one oxygen, sulfur, or nitrogen ring atom, or one nitrogen plus one oxygen or sulfur, or 2, 3, or 4 nitrogen ring atoms. Suitable 6-membered heteroaryl rings (as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) have 1, 2, or 3 nitrogen ring atoms. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The term “fused heteroaryl” refers to a heteroaryl as defined above, having two constituent aromatic rings, wherein the two rings are fused to one another and at least one of the rings is a heteroaryl as defined above. Fused heteroaryls include fused heteroaryl groups comprising 1, 2, 3, or 4 heteroatom ring atoms selected from O, N or S. In certain embodiments, wherein the heteroatom is N it can be an N-oxide. Fused heteroaryls also include 8-, 9-, or 10- membered fused heteroaryl groups. Fused heteroaryls also include 8-, 9-, or 10-membered fused heteroaryl groups that have 1, 2, 3, or 4 heteroatom ring atoms selected from O, N or S. Illustrative examples of fused heteroaryls include, but are not limited to:

[0085] DETAILED DESCRIPTION OF EXPERIMENTS

[0086] Synthetic methods and Data for compounds in Table #1.

[0087] Compound #1 : 5-(3-cyanobenzyl)-7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid

[0088] Step 1: Synthesis of 3-hexylcycloheptan-l-one A suspension of CuBr.Me2S (15 g, 72.3 mmol) in THF (lOOmL) at -78°C under argon atmosphere was added hexyl magnesium bromide (74 mL, 208.2 mmol, 2M in DEE) and HMPA (62 mL, 361.9mmol). The reaction mixture was stirred at -78°C for 0.5 h, before the addition of

[0089] 2-cycloheptene- 1 -one (10 g, 90.5 mmol) in THF (50 mL) and TMS-C1 (52 mL, 407.2 mmol) and continued the stirring at -78 °C for additional 1 h. After completion of the reaction (monitored by T.L.C, Eluent: 10% EtOAc / Hexane, R.f: 0.5), the reaction mixture was quenched with a saturated aqueous ammonium chloride solution (200 mL) and extracted with EtOAc (300 mL). The organic layer was dried NaSCL, fdtered and concentrated under reduced pressure to obtain crude compound. The crude compound was purified by column chromatography over silica gel (100- 200 mesh) using a solvent gradient of 2% EtOAC in Hexane as eluent to afford

[0090] 3-hexylcycloheptan-l-one (14 g, 78%) as a colourless liquid.

[0091] ‘H-NMR (400 MHz, DMSO-d6): 5 2.49-2.45 (m, 3H), 2.40-2.34 (m, 1H), 1.92-1.84 (m, 3H), 1.66-1.58 (m, 3H), 1.42-1.38 (m, 1H), 1.36-1.22 (br s, 10H), 0.88 (t, J = 6.8 Hz, 3H).

[0092] Step 2: Synthesis of 7-hexyl-cyclohepta[b]indole-4-carboxylic acid

[0093] To a stirred solution of 3-hexylcycloheptan-l-one (14 g, 71.4 mmol) in AcOH (100 mL) was added 2-hydrazineylbenzoic acid hydrochloride (14.8 g, 78.4 mmol) and stirred the reaction mixture at 110 °C for 12 h. After completion of the reaction (monitored by T.L.C, Eluent:30% EtOAc / Hexane, R.f: 0.5), the reaction mixture was cooled to RT and excess AcOH was removed by reduced pressure. The resulting residue was diluted with water and extracted with EtOAc (3x 100ml). The combined organic layer was dried over Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (100- 200 mesh) using a solvent gradient of 20% EtOAC in hexane as eluent to afford 7-hexyl- cyclohepta[b]indole-4-carboxylic acid (8 g, 36 %) as an off white solid.

[0094] MS (ESI) m / z: 314 [M+H]+.

[0095] Step 3: Synthesis of methyl 7-hexyl-cyclohepta[b]indole-4-carboxylate

[0096] To a stirred solution of 7-hexyl-cyclohepta[b]indole-4-carboxylic acid (6 g, 19 mmol) in DMF (60 mL) at 0°C was added K2CO3 (3.2 g, 23.1 mmol) and Mel (2.5 mL, 40.1 mol) and stirred the reaction mixture at 0°C for 3 h. After completion of the reaction (monitored by T.L.C, Eluent: 10% EtOAc: Hexane, R.f: 0.8), the reaction mixture was quenched with ice-water (100 mL), the precipitated solid was collected by filtration, washed with ice-water (50 mL) and dried under vacuum to afford methyl 7-hexyl-cyclohepta[b]indole-4-carboxylate (6 g, 96 %) as an off white solid.

[0097] MS (ESI) m / z: 328 [M+H]+.

[0098] Step 4: Synthesis of methyl 5-(3-cyanobenzyl)-7-hexyl-cyclohepta[b]indole-4-carboxylate To a stirred solution of methyl 7-hexyl-cyclohepta[b]indole-4-carboxylate (10 g, 30.5 mmol) in DMF (80 mL) at 0°C was added NaH (1.9 g, 55 % dispersion in mineral oil, 39.6 mmol) In portion wise and stirred at 0°C for 5 mins before the addition of 3 -cy nobenzyl bromide (6.6 g, 33.5 mmol) in DMF (20 mL). The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 0.5 h. After completion of the reaction (monitored by T.L.C, Eluent: 10% EtOAc: Hexane, R.f: 0.6), the reaction mixture was cooled to 0°C, quenched with saturated Ice- water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure (Note: aqueous layer having corresponding carboxylate salt was preserved). The resulting residue was purified by column chromatography over silica gel (100- 200 mesh) using a solvent gradient of 8% EtOAC in hexane as eluent to afford methyl 5-(3-cyanobenzyl)-7- hexyl-cyclohepta[b]indole-4-carboxylate (6.5 g, 44 %;) as an off white solid.

[0099] MS (ESI) m / z 443 [M+H]+.

[0100] Step 5: 5-(3-cyanobenzyl)-7-hexyl-hexahydrocyclohepta[b]indole-4-carboxylic acid

[0101] To a stirred solution of methyl 5-(3-cyanobenzyl)-7-hexyl-cyclohepta[b]indole-4-carboxylate (3.5 g, 7.92 mmol) in THF (22 mL), H2O (9 mL) and MeOH (4 mL) was added LiOH H2O (1.7 g, 40.4 mmol) and heated the reaction mixture at 50 °C for 8 h. After completion of the reaction (monitored by T.L.C, Eluent: EtOAc, R.f: 0.3), reaction mixture was cooled to room temperature, and concentrated under vacuum. Resultant residue was dissolved in water and acidified by the addition of aqueous hydrochloric acid (1 M) at 0°C.The precipitated solid was collected by filtration, washed with cold water, and dried in vacuum to afford 5-(3-cyanobenzyl)- 7-hexyl-hexahydrocyclohepta[b]indole-4-carboxylic acid (2 g, 60 %) as an off white solid. ‘H-NMR (400 MHz, DMSO-d6): 8 12.87 (brs, 1H), 7.70-7.65 (m, 2H), 7.46-7.40 (m, 2H), 7.28 (s, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 5.77 (d, J = 18 Hz, 1H), 5.60 (d, J = 18 Hz, 1H), 2.93-2.88 (tn, 1H), 2.81 -2.79 (m, 1H), 2.73-2.70 (m, 1H), 1.92-1.87 (tn, 2H), 1.55-1.50 (m, 2H), 1.37 (br.s, 1H), 1.23-0.92 (m, 11 H), 0.85 (t, J = 10 Hz, 3H).

[0102] MS (ESI) m / z: 429 [M+H]+.

[0103] Compound #2: Synthesis of 5-(3-cyanobenzyl)-2-fluoro-7-hexyl-5,6,7,8,9,10 hexahydrocyclohepta[b]indole-4-carboxylic acid

[0104] Step 1: Synthesis of 5-fluoro-2-hydrazineylbenzoic acid HC1:

[0105] To a stirred solution of 2-amino-5-fluorobenzoic acid (2 g, 12.9 mmol) in HC1 (7 mL) at 0°C was added NaNCh (0.89 g, 12.9 mmol) in water (7 mL) and stirred the reaction mixture at O’C for 30 mins, before the addition of SnCh (7.3 g, 38.0 mmol) in HC1 (5 mL) and continued the stirring at 0°C for additional 3 h. After completion of the reaction (monitored by T.L.C, Eluent: 20% EtOAc: Hexane, R.f: 0.3), the reaction mixture was quenched with ice-water (100 mL). The precipitated solid was collected by filtration, washed with ice-water (30 mL) and dried under vacuum to afford of 5-fluoro-2-hydrazineylbenzoic acid HC1 (2 g, 91%) as an off white solid.

[0106] 'H-NMR (400 MHz, DMSO-d6): 8 10.38 (brs, 2H), 8.98 (brs, 1H), 7.66-7.62 (m, 1H), 7.56-7.51 (m, 1H), 7.22-7.19 (m, 1H).

[0107] Step 2: Synthesis of 2-fluoro-7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid:

[0108] The process of this step was adopted from step # 2 of Synthesis of #1 to obtain the title compound (1.2 g, 36%) as an off white solid.

[0109] MS (ESI) m / z : 330 (M-H)’.

[0110] Step 3: Synthesis of methyl 2-fluoro-7-hexyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4- carboxylate: The process of this step was adopted from step # 3 of Synthesis of #1 to obtain the title compound (1.0 g, 80%) as an off white solid.

[0111] JH-NMR (400 MHZ,CDC13): 5 9.29 (brs, 1H), 7.48-7.45 (m, 1H), 7.34-7.21 (m, 1H), 3.97 (s, 3H), 2.88-2.79 (m, 2H), 2.70-2.62 (m, 2H), 2.17-2.01 (m, 1H), 1.96-1.93 (m, 1H), 1.69-1.59 (m,lH), 1.58-1.54 (m, 2H), 1.33-1.27 (m, 10H), 0.90-0.86 (t, J = 8.0 Hz, 3H).

[0112] Step 4: Synthesis of methyl 5-(3-cyanobenzyl)-2-fluoro-7-hexyl-5,6,7,8,9,10- hexahy drocy cl oheptafb ]i ndol e-4-carb oxy 1 ate :

[0113] The process of this step was adopted from step # 4 of Synthesis of #1 to obtain the title compound (0.2 g, 50%) as an off white solid. 'H-NMR (400 MHz, CDCI3): 8 7.5-7.4 (m, 1H), 7.36-7.34 (m, 2H), 7.33-7.32 (m, 1H) 7.15 (s, 1H), 7.04-6.99 (m, 1H), 5.64-5.47 (m, 2H), 3.68 (s, 3H), 2.88-2.83 (m, 1H), 2.75-2.67 (m, 2H), 2.50-2.44 (m, 1H), 2.01-1.89 (m, 2H), 1.66-1.60 (m, 1H), 1.25-1.14 (m, 12 H), 0.88-0.84 (t, J = 8.0 Hz, 3H).

[0114] Step 5: Synthesis of 5-(3-cyanobenzyl)-2-fluoro-7-hexyl-5,6,7,8,9,10- hexahy drocy cl ohepta[b]indole-4-carboxylic acid (CRE- 1000166)

[0115] The process of this step was adopted from step # 5 of Synthesis of #1 to obtain the title compound (60 mg, 31%). as off white solid.

[0116] 'H-NMR (400 MHz, DMSO-d6): 8 13.1 (brs, 1H), 7.68-7.66 (m, 1H), 7.52-7.49 (m, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.30 (s, 1H), 7.18-7.15 (m, 1H), 6.97 (d, J = 8.0 Hz, 1H), 5.79-5.74 (m, 1H), 5.61-5.56 (m, 1H), 2.90-2.80 (m, 2H), 2.51-2.50 (m, 2H), 1.91-1.84 (m, 2H), 1.54-1.49 (m, 2H), 1.36 (brs, 1H), 1.23-0.91 (m, 10H), 0.83 (t, J = 7.2 Hz, 3H)

[0117] MS (ESI) m / z: 446 [M+H]+.

[0118] Compound #3 : 7-hexyl-5-((2-(trifluoromethyl)pyridin-4-yl)methyl)-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid

[0119] Synthesis of compound #3 was adopted from synthesis of compound #1 with using 4- (bromomethyl)-2-(trifluoromethyl)pyridine as substrate for Step #4

[0120] ^-NMR (400 MHz, DMSO-d6): 812.89 (brs, 1H), 8.62 (d, J = 4.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.47-7.43 (m, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.99-6.98 (m, 1H), 5.89-5.84 (m, 1H), 5.69-5.65 (m, 1H), 2.95-2.90 (m, 1H), 2.72-2.68 (m, 2H), 1.93-1.87 (m, 2H), 1.55-1.50 (m, 2H), 1.36 (brs, 1H), 1.16-1.11 (m, 2H), 1.09-0.89 (m, 7H), 0.80 (t, J = 7.2 Hz, 3H), MS (ESI) m / z: 472.9 [M+H]+.

[0121] Compound #4: 5-((4-cyanothiophen-2-yl)methyl)-7-hexyl-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid

[0122] Synthesis of compound #4 was adopted from synthesis of compound #1 with 5- (bromomethyl)thiophene-3-carbonitrile as substrate for Step #4

[0123] 'H-NMR (400 MHz, DMSO-d6): 8 13.0(s, 1H), 8.31 (s, J=1.2Hz, 1H), 7.66 (d, J=6.8 Hz, 1H) ,7.49-7.47 (m, 1H), 7.08-7.04 (m, 2H), 5.94 (d, J =18 ,1H ), 5.80 (d, J =17.2 Hz, 1H), 2.96 (d, J=15.6Hz ,1H), 2.89-2.84 (m , 1H), 2.62-2.58 (m, 2H), 1.96-1.84 (m , 2H), 1.55-1.50 (m ,3H), 1.23-1.18 (m, 10H), 0.85 (t , J=6.4 ,3H);

[0124] MS (ESI) m / z: 433 [M - H]’.

[0125] Compound #5: 5-(3-cyanobenzoyl)-7-hexyl-5,6,7,8,9,10-hexahydrocydohepta[b]indole-4- carboxylic acid

[0126] To a stirred solution of 7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid (300 mg, 0.958 mmol) in DMF (10 mL) at 0°C was added NaH (125 mg, 55 % dispersion in mineral oil, 2.87 mmol) in portion wise and stirred at 0°C for 30 mins, then 3 -cyanobenzoyl chloride (317 mg, 1.916 mmol) in DMF (3 mL) was added. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for additional 2h. After completion of the reaction (monitored by T.L.C, Eluent: 10% EtOAc: Hexane, R.f: 0.6), the reaction mixture was cooled to 0°C, quenched with saturated Ice-water (20 mL), The resulting solution was acidified by the addition of aqueous hydrochloric acid (1 M) at 0°C and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by Preparative HPLC. After purification isolated methyl 5-(3-cyanobenzoyl)-7-hexyl-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid (31 mg, 7.65 %) as an off white solid.

[0127] ^-NMR (400 MHz, DMSO-d6): 6 12.90 (s, 1H), 8.12-8.10 (m, 1H), 7.92 (s, 1H), 7.84-7.82 (m, 1H), 7.67 (t, J = 7.60 Hz, 1H), 7.57-7.53 (m, 2H), 7.26 (t, J = 7.60 Hz, 1H), 2.88-2.57 (m, 4H), 1.93-1.84 (m, 2H), 1.63-1.57 (m, 3H), 1.25-1.24 (m, 1H), 1.15-0.80 (m, 12H), MS (ESI) m / z: 441 [M-H]'.

[0128] Prep. HPLC conditions

[0129] Mobile Phase-A: 0.1% Formic Acid in Water , Mobile Phase-B: Acetonitrile, Column: YMC Tri art C-18 (250 x 20 mm), 5micron ; Flow Rate: 14 mL / min ; Gradient: 0.01 / 90, 15 / 95, 20 / 95.

[0130] Compound #6: 5-(3-cyano-2-(trifluoromethyl)benzyl)-7-hexyl-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid Synthesis of compound #6 was adopted from synthesis of compound #1 with 3-(bromomethyl)- 2-(trifluoromethyl)benzonitrile as substrate for Step #4

[0131] ^-NMR (400 MHz, DMSO-d6): 8 12.9 (brs, 1H), 8.10(d, J=8.0Hz, 1H), 7.74 (d, J=8.0Hz, 1H), 7.70 ( t, J=8.0Hz, 1H), 7.48(d, J=7.8Hz, 1H), 7.10 ( t, J=8.0Hz, 1H), 6.47 (d, J = 8.4Hz, 1H), 6.06(br d, J=16.0Hz, 1H), 5.73(br d, J=16.0Hz, 1H), 3.0-2.9(m, 1H), 2.68-2.55(m, 2H), 2.45- 2.40(m, 1H), 1.91-1.88(m, 2H), 1.60-1.45(m, 2H), 1.33-1.20(m, 2H), 1.15-0.95(m, 9H), 0.90- 0.85(m, 1H), 0.82(t, J=6.8Hz, 3H), 0.60-0.45(m, 1H)

[0132] MS (ESI) m / z: 495 [M-H]

[0133] Compound #7: 5-(3-carbamoyl-2-fluorobenzyl)-2-chloro-7-propyl-5,6,7,8,9,10- hexahydrocyclohepta|bJindole-4-carboxylic acid 12.9 (brs, 1H), 7.76 (d, J=2.0Hz, 1H), 7.68 (br s, 1H), 7.63 (br s, 1H), , 7.50-7.46 (m, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.03 ( t, J=7.6Hz, 1H), 6.23 (m, 1H), 5.77 (br d, J=18.0Hz, 1H), 5.65 (br d, J=18.0Hz, 1H), 2.93-2.87(m, 1H), 2.79 (d, J=16Hz, 1H) 2.71- 2.55(m, 1H), 1.93-1.88(m, 2H), 1.57-1.51(m, 3H), 1.15-1.07(m, 4H), 0.72(t, J=6.8Hz, 3H) MS (ESI) m / z: 457 [M+H]

[0134] Compound #8: 2-fluoro-7-hexyl-5-((2-(trifluoromethyl)pyridin-4-yl)methyl)-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid Synthesis of compound #8 was adopted from synthesis of compound #2 with using 4- (bromomethyl)-2-(trifluoromethyl)pyridine as substrate for Step #4

[0135] ^-NMR (400 MHz, DMSO-d6): 8 12.9 (brs, 1H), 8.62 (d, J=8.0Hz, 1H), 7.56 (dd, J=8.0, 2.8Hz, 1H), 7.43(s, 1H), 7.22 (dd, J=8.0, 2.8Hz, 1H), 6.98 (d, J = 8.0Hz, 1H), 5.82(br d, J=19.0Hz, 1H), 5.65(br d, J=19.0Hz, 1H), 3.0-2.9(m, 1H), 2.70-2.55(m, 2H), 2.50-2.45(m, 1H), 1.91-1.88(m, 2H), 1.53-1.48(m, 2H), 1.33-1.20(m, 1H), 1.15-0.95(m, 9H), 0.90-0.85(m, 2H), 0.62(t, J=6.8Hz, 3H),

[0136] MS (ESI) m / z: 491.3 [M+H]

[0137] Compound #9: 2-fluoro-5-(3-fluorobenzyl)-7-hexyl-5,6,7,8,9,10- hexahydrocyclohepta[bJindole-4-carboxylic acid

[0138] Synthesis of compound #9 was adopted from synthesis of compound #2 with using 1- (bromomethyl)-3-fluorobenzene as substrate for Step #4

[0139] 'H-NMR (400 MHz, DMSO-d6): 8 12.9 (brs, 1H), 7.50 (dd, 1=9.2, 2.8 Hz, 1H), 7.56 (dd, J=8.0, 2.8Hz, 1H), 7.29-7.25(m, 1H), 7.15 (dd, J=9.2, 2.8Hz, 1H), 6.99 (dt, J = 8.0, 2.0Hz, 1H), 6.54(t, J=7.2Hz, 2H), 5.74(d, J=17.6Hz, 1H), 5.56(d, J=17.6Hz, 1H)), 3.0-2.8(m, 2H), 2.70-2.63(m, 1H), 2.50-2.45(m, 1H), 1.91-1.84(m, 2H), 1.53-1.48(m, 2H), 1.39-1.33(br s, 1H), 1.23-0.95(m, 10H), 0.82(t, J=6.8Hz, 3H),

[0140] MS (ESI) m / z: 538.5 [M+H]

[0141] Synthesis of methyl 2-chloro-7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate To a stirred solution of 3-hexylcycloheptan-l-one (35 g, 178.2 mmol) in AcOH (350 mL) was added 5-chloro-2-hydrazineylbenzoic acid hydrochloride (59.64 g, 267.4 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by TLC, Eluent: 20% EtOAc: hexane, Rf: 0.3), the reaction mixture was cooled to room temperature. Excess AcOH was removed under reduced pressure. The residue was triturated with water (300 mL) followed by acetonitrile (200 mL) and dried to afford 2-chloro-7-hexyl- 5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid (28 g, 45.1%) as a pale-green solid. MS (ESI) m / z 348.25 [M+H]+. ^-NMR (400 MHz, DMSO-d6): 8 13.21 (s, 1H), 10.80 (s, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 3.21 (d, J=15.2 Hz, 1H), 2.86-2.79 (m, 1H), 2.63-2.52 (m, 2H), 1.99-1.92 (m, 1H), 1.89-1.82 (m, 1H), 1.58-1.21 (m, 13H), 0.87 (t, J=6.8 Hz, 3H).

[0142] To a stirred solution of 2-chloro-7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid (8 g, 22.99 mmol) in DMF (80 mL) was added K2CO3 (6.34 g, 45.99 mmol) followed by addition of Mel (1.71 mL, 27.58 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC (Eluent: 10% EtOAc: Hexane, Ri: 0.8). After completion, the reaction mixture was poured into ice- water (150 mL), the precipitated solid was collected by filtration. The residue was purified by silica gel (100-200 mesh) column chromatography, eluted with 5% EtOAc / Hexane to afford methyl 2-chloro-7-hexyl-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylate (5 g, 60%) as a pale-yellow solid.

[0143] MS (ESI) m / z 362.00 [M+H]+.

[0144] ^-NMR (400 MHz, DMSO-d6): 8 10.85 (s, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 3.93 (s, 3H), 3.21-3.16 (m, 1H), 2.86-2.81 (m, 1H), 2.67-2.57 (m, 2H), 1.99-1.82 (m, 2H), 1.58- 1.21 (m, 13H), 0.85 (t, J =7.2 Hz, 3H).

[0145] MS (ESI) m / z 362.00 [M+H]+.

[0146] Compound #10: 2-chloro-5-(3-fluorobenzyl)-7-hexyl-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid

[0147] Synthesis of compound #10 was adopted from synthesis of compound #1, using methyl 2-chloro- 7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate (described above) and 1- (bromomethyl)-3 -fluorobenzene as substrates for Step #4 followed by Step #5

[0148] ^-NMR (400 MHz, DMSO-d6): 8 13.2 (brs, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.27 (m, 1H), 7.00 (dt, J = 8.4, 2.0Hz, 1H), 6.58-6.54(m,2H), 5.75(d, J=18.0Hz, 1H), 5.57(d, J=18.0Hz, 1H), 2.90-2.80(m, 2H), 2.70-2.66(m, 1H), 2.50-2.47(m, 1H), 1.91-1.84(m, 2H), 1.54-1.49(m, 2H), 1.48-1.35(br s, 1H), 1.22-0.95(m, 10H), 0.82(t, J=6.8Hz, 3H), MS (ESI) m / z 456.0 [M+H]+.

[0149] Compound #11: 2-chloro-7-hexyl-5-((2-(trifluoromethyl)pyridin-4-yl)methyl)-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid

[0150]

[0151] Synthesis of compound #10 was adopted from synthesis of compound #1, using methyl 2-chloro- 7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylate (described above) and 4- (bromomethyl)-2-(trifluoromethyl)pyridine as substrates for Step #4 followed by Step #5

[0152] 'H-NMR (400 MHz, DMSO-d6): 5 13.2 (brs, 1H), 8.62 (d, J=4.8 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.44(s, 1H), 7.38 (d, J=2.4 Hz, 1H), 6.97 (d, J = 4.8Hz, 1H), 5.83 (d, J=18.8Hz, 1H), 5.66(d, J=18.8Hz, 1H), 2.95-2.89(m, 1H), 2.72-2.66(m, 2H), 2.50-2.47(m, 1H), 1.91-1.84(m, 2H), 1.54- 1.49(m, 2H), 1.35(br s, 1H), 1.15-0.95(m, 10H), 0.80(t, J=6.8Hz, 3H), MS (ESI) m / z 505.3 [M+H]+.

[0153] Compound #12: 9-(3-chlorobenzyl)-6-fluoro-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid

[0154] Synthesis of compound #12 was adopted from synthesis of compound #1, except using 5-chloro- 2-hydrazineylbenzoic acid hydrochloride for the formation of the indole moiety in methyl 6- fluoro-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (described below) and 1- (bromomethyl)-3 -chloro-benzene as substrates for Step #4 followed by Step #5

[0155] 'H-NMR (400 MHz, DMSO-d6): 8 13.20 (s, 1H), 7.42 (dd, J=8.8, 2.4Hz, 1H), 7.27-7.22 (m, 2H), 7.18 (dd, J=8.8, 2.4Hz, 1H), 6.75(s, 1H), 6.65-6.63 (m, 1H), 5.60(d, J=17.2 Hz, 1H), 5.52 (d, J=17.2 Hz, 1H), 2.82-2.71(m, 2H), 2.62-2.57(m, Ih), 2.27-2.20 (m, 1H), 1.96-1.93 (m, 1H), 1.84- 1.69 (m, IH), 1.47-1.24 (m, 11H), 0.84 (t, J =7.2 Hz, 3H)

[0156] MS (ESI) m / z 440.4 [M+H]+. Synthesis of methyl 6-chloro-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate

[0157] To a stirred solution of 3-hexylcyclohexan-l-one (30 g, 164.5 mmol) in AcOH (300 mL) was added 5-chloro-2-hydrazineylbenzoic acid hydrochloride (55.05 g, 246.8 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by TLC, Eluent: 20% EtOAc: hexane, Rf: 0.3), the reaction mixture was cooled to room temperature. Excess AcOH was removed under reduced pressure. The residue was triturated with water (300 mL) followed by acetonitrile (200 mL) and dried to afford 6-chloro-2-hexyl- 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid (20 g, 36.4%) as pale-green solid.

[0158] MS (ESI) m / z 334.10 [M+H]+.

[0159] ^-NMR (400 MHz, DMSO-d6): 8 13.23 (s, 1H), 10.80 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 2.96-2.90 (m, 1H), 2.76-2.66 (m, 1H), 2.58-2.51 (m, 1H), 2.37-2.30 (m, 1H), 1.97- 1.91 (m, 1H), 1.83-1.74 (m, 1H), 1.47-1.23 (m, 11H), 0.87 (t, J=6.4 Hz, 3H).

[0160] To a stirred solution of 6-chloro-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid (7 g, 20.96 mmol) in DMF (70 mL) was added K2CO3 (5.78 g, 41.93 mmol) followed by Mel (1.95 mL, 31.44 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC (Eluent: 10% EtOAc: Hexane, Rf 0.8). The reaction mixture was poured into ice-water (60 mL), the precipitated solid was collected by filtration to afford methyl 6-chloro- 2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (6.1 g, 83.6%) as a pale-yellow solid. ^-NMR (400 MHz, DMSO-d6): 8 10.86 (s, 1H), 7.62 (s, 1H), 7.56 (s, 1H), 3.93 (s, 3H), 3.39- 3.31 (m, 1H), 2.95-2.87 (m, 1H), 2.76-2.63 (m, 1H), 2.38-2.28 (m, 1H), 1.96-1.87 (m, 1H), 1.81- 1.69 (m, 1H), 1.46-1.21 (m, 11H), 0.87 (t, J =7.2 Hz, 3H)

[0161] MS (ESI) m / z 348.15 [M+H]+.

[0162] Compound #13: 6-chloro-9-(3-fluorobenzyl)-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid

[0163] Synthesis of compound #13 was adopted from synthesis of compound #1, using methyl 6-chloro-

[0164] 2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (described above) and 1 -(bromomethyl)-

[0165] 3 -fluoro-benzene as substrates for Step #4 followed by Step #5.

[0166] ’H-NMR (400 MHz, DMSO-d6): 8 13.20 (s, 1H), 7.67 (d, J=2.0Hz, 1H), 7.34 (d, J=2.0Hz, 1H), 7.28-7.22(m, 1H), 7.00(dt, J=8.4, 2.4Hz, 1H), 6.54-6.48 (m, 2H), 5.65(d, 1=17.2 Hz, 1H), 5.56 (d, J=17.2 Hz, 1H), 2.84-2.75(m, 2H), 2.64-2.60(m, Ih), 2.27-2.20 (m, 1H), 1.98-1.93 (m, 1H), 1.81- 1.69 (m, IH), 1.46-1.21 (m, 11H), 0.85 (t, J =7.2 Hz, 3H)

[0167] MS (ESI) m / z 440.4 [M+H]+. Compound #14: 6-chloro-2-hexyl-9-((2-(trifluoromethyl)pyridin-4-yl)methyl)-2, 3,4,9- tetrahydro-lH-carbazole-8-carboxylic acid

[0168] Synthesis of compound #14 was adopted from synthesis of compound #1 similar to compound

[0169] #13 using methyl 6-chloro-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylate (described above) and 4-(bromomethyl)-2-(trifluoromethyl)pyridine as substrates for Step #4 followed by Step #5.

[0170] ^-NMR (400 MHz, DMSO-d6): 8 13.20 (bs, 1H), 8.59 (d, 4.8 Hz, 1H), 7.71 (d, >2.0 Hz, 1H), 7.43 (s, 1H), 7.39 (d, >2.4 Hz, 1H), 6.82 (d, >4.4 Hz, 1H), 5.78-5.67 (m, 2H), 2.82-2.71 (m, 2H), 2.68-2.54 (m, 1H), 2.23-2.14 (m, 1H), 1.97-1.91 (m, 1H), 1.88-1.78 (m, 1H), 1.49-1.18 (m, 11H), 0.83 (t, >6.4 Hz, 3H). MS (ESI) m / z : 493.4

[0171] [M+H]+. Yield: 51% (40 mg)

[0172] Compound #15: 7-hexyl-5-((2-(trifluoromethyl)pyridin-4-yl)methyl)-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid*

[0173] *: Stereochemistry has been arbitrarily assigned based on Chiral SFC separation.

[0174] Synthesis of compound #15 was adopted from synthesis of compound #1 with using 4-

[0175] (bromomethyl)-2-(trifluoromethyl)pyridine as substrate for Step #4. Enantiomers were separated by chiral HPLC.

[0176] 'H-NMR (400 MHz, DMSO-d6): 812.89 (brs, 1H), 8.62 (d, J = 4.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.47-7.43 (m, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.99-6.98 (m, 1H), 5.89-5.84 (m, 1H), 5.69-5.65 (m, 1H), 2.95-2.90 (m, 1H), 2.72-2.68 (m, 2H), 1.93-1.87 (m, 2H), 1.55-1.50 (m, 2H), 1.36 (brs, 1H), 1.16-1.11 (m, 2H), 1.09-0.89 (m, 7H), 0.80 (t, J = 7.2 Hz, 3H),

[0177] MS (ESI) m / z: 472.9 [M+H]+.

[0178] Enantiomeric excess: 99%

[0179] Chiral HPLC condition Description

[0180] Column: Chiralpak-IC (4.6 * 250) mm * 5.0pm

[0181] Mobile Phase A -: 0.1%DEA in n-Hexane

[0182] Mobile Phase B -: MeOH:IPA:DCM(l:l: l)

[0183] Method(A:B) :- (85: 15))

[0184] Flow Rate: l.O mL / Min

[0185] Compound #16: 5-(2-chloro-3-cyanobenzyl)-2-fluoro-7-hexyl-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid*

[0186] * Stereochemistry has been arbitrarily assigned based on Chiral SFC separation.

[0187] Synthesis of compound #9 was adopted from synthesis of compound #2 with using 3- (bromomethyl)-2-Chloro-benzonitrile as substrate for Step #4

[0188] 'H-NMR (400 MHz, DMSO-d6): 512.89 (brs, 1H), 7.86 (dd, J = 7.6, 1.6 Hz, 1H), 7.56 (dd, J =

[0189] 9.2, 2.4 Hz, 1H), 7.38 (t, J =8.0Hz, 1H), 7.20 (dd, J = 9.2, 2.4 Hz, 1H), 6.36 (dd, J = 7.6, 1.6 Hz, 1H), 5.65(d, J=14.8 Hz, 1H), 5.56 (d, J=14.8 Hz, 1H), 2.93-2.89 (m, 1H), 2.69-2.63 (m, 2H), 2.45-2.43(m, 1H), 1.93-1.87 (m, 2H), 1.55-1.50 (m, 2H), 1.36 (br s, 1H), 1.18-0.95 (m, 9H), 0.87-0.85(m, 1H), 0.82 (t, J = 7.2 Hz, 3H)

[0190] MS (ESI) m / z: 481.3 [M+H]+.

[0191] Chiral SFC Method: 70% CO2 _30% CO SOLVENT (A)

[0192] Column: Chiralcel OX-H

[0193] Co-solvent: Methanol + 0.1% DEA Flow Rate: 3.0 mL / Min

[0194] Compound #17: 5-(3-cyano-2-methoxybenzyl)-2-fluoro-7-hexyl-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid

[0195] Synthesis of compound #17 was adopted from synthesis of compound #2 with using 3- (bromomethyl)-2-(Methoxy)benzonitrile as substrate for Step #4

[0196] 'H-NMR (400 MHz, DMSO-d6): 512.89 (brs, 1H), 7.65 (dd, J = 7.6, 1.6 Hz, 1H), 7.53 (dd, J = 9.2, 2.4 Hz, 1H), 7.18 (dd, J = 9.2, 2.4 Hz, 1H), 7.08 (t, J =8.0Hz, 1H), 6.28 (dd, J = 7.6, 1.6 Hz, 1H), 5.78 (d, J=18.4 Hz, 1H), 5.57 (d, 1=18.4 Hz, 1H), 4.03(s, 3H), 2.95-2.85 (m, 1H), 2.72-2.60 (m, 2H), 2.45-2.43(m, 1H), 1.93-1.87 (m, 2H), 1.55-1.45 (m, 2H), 1.34 (br s, 1H), 1.18-0.95 (m, 10H), 0.87-0.85(m, 1H), 0.82 (t, J = 7.2 Hz, 3H)

[0197] MS (ESI) m / z: 477.2 [M+H]+.

[0198] Compound #18: 7-(7-carboxyheptyl)-5-(3-cyano-2-fluorobenzyl)-2-fluoro-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid*

[0199] * Stereochemistry has been arbitrarily assigned based on Chiral SFC separation.

[0200] ^-NMR (400 MHz, DMSO-d6): 512.89 (brs, 1H), 7.78 (t, J = 10.4 Hz, 1H), 7.54 (dd, J = 9.2, 2.4 Hz, 1H), 7.24-7.16 (m, 2H), 6.53(t, J=10.4Hz, 1H), 5.80 (d, J=18.4 Hz, 1H), 5.66 (d, J=18.4 Hz, 1H), 2.88 (dd, J=17.2, 7.2 Hz, 1H), 2.79(d, J=15.6Hz, 1H), 2.69-2.63 (m, 1H), 2.55-2.50(m, 1H), 2.17 ( t, J=7.2Hz, 1H), 1.99-1.85 (m, 2H), 1.53-1.45 (m, 2H), 1.45-1.41 (m, 3H), 1.18-0.95 (m, 10H)

[0201] MS (ESI) m / z: 523 [M+H]+. Chiral HPLC Description :

[0202] Column: CHIRALPAK-IC(4.6X250mm) 5. Op

[0203] Mobile phase- A : 0.1% DEA in Hexane

[0204] Mobile phase- B : IPA:MeOH(50:50)

[0205] Flow: 1.5mL / Min

[0206] Method: 70:30 = A:B

[0207] Compound #19: 9-(3-chlorobenzyl)-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic

[0208] * Stereochemistry has been arbitrarily assigned based on Chiral SFC separation.

[0209] Synthesis of compound #17 was adopted from synthesis of compound #2 but with 3-hexyl-l- cyclohexanone for the indole formation in Step #2 and 1 -(brom omethyl)-3 -chloro-benzene as substrate for Step #4. Enantiomers were separated by chiral HPLC.

[0210] 1H-NMR (400 MHz, DMSO-d6): > 12.90 (s, 1H), 7.72-7.69 (m, 2H), 7.14-7.065 (m, 3H), 6.86 (s, 1H), 6.57 (d, J = 7.20 Hz, 1H), 5.63 (d, J = 17.2 Hz, 1H), 2.87-2.84 (m, 1H), 2.78-2.71 (m, 2H), 2.28-2.21 (m, 1H), 2.06-2.01 (m, 1H),1.89 (br s, 1H), 1.58-1.26 (m, 1H), 1.08-1.13 (m, HH), 0.88 (t, J = 7.20 Hz, 3H).

[0211] MS (ESI) m / z: 424.1 [M+H]+.

[0212] Chiral HPLC condition Description

[0213] Column: Chiralpak-AD-H (4.6 x 250) mm * 5.0pm

[0214] Mobile Phase A -: 0.1%TFA in Methanol; (100%)

[0215] Flow Rate: l .O mL / Min

[0216] Compound #20: 8-[(m-chlorophenyl)methyl]-ll-hexyl-8-azatricyclo[7.5.0.02,7]tetradeca- 1 (9),2(7),3,5-tetraene-6-carboxylic acid Synthesis of compound #20 was adopted from synthesis of compound #1 with using 1 - (bromomethyl)-3 -chloro-benzene as substrate for Step #4

[0217] 400MHz-DMSO d6 : 12.90 (br s, 1H), 7.65(d, J =7.6Hz, 1H), 7.38 (d, J =7.6Hz, 1H), 7.27-7.20(m, 2H), 7.04(t, J=7.2Hz, 1H), 6.84 (s, 1H), 6.67 (d, J=7.2Hz, 1H), 5.74 (d, J= 17.6Hz, 1H), 5.54 (d, J= 17.6Hz, 1H), 2.88 (dd, J =15.6, 7.2 Hz, 1H), 2.81(d, J=15.6, 1H), 2.71-2.66(m, 1H), 2.62- 2.46(m, 1H), 1.96-1.82 (m, 2H), 1.56-1.45(m, 2H), 1.43-1.35(m,lH), 1.23-0.97(m, 10H), 0.83 (t, J =7.2Hz, 3H)

[0218] MS (ESI) m / z: 438.1 [M+H]+.

[0219] Compound #21: 9-[(m-fluorophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8- carboxylic acid

[0220] Synthesis of compound #21 was adopted from synthesis of compound #2 but with 3-hexyl-l- cyclohexanone for the indole formation in Step #2 and 1 -(brom om ethyl )-3 -fluoro-benzene as substrate for Step #4

[0221] 1H-NMR (400MHz-DMSO d6) : 12.80(br s, 1H), 7.62 (d, J =7.6Hz, 1H), 7.41 (d, J = 7.6Hz, 1H), 7.25-7.22 (m, 1H), 7.27-6.96 ( m, 2H), 6.52-6.49(m, 2H), 5.65 ( d, J= 17.2Hz, 1H), 5.58 ( d, J= 17.2Hz, 1H) 2.84-2.76 (m, 2H), 2.67-2.60 (m, 1H), 2.27-2.21 (m, 1H), 1.98-1.95 (m, 1H), 1.84 (br s, 1H), 1.46-1.23(m, 11H), 0.85 (t, J =6.4Hz, 3H)

[0222] MS (ESI) m / z: 408.1 [M+H]+.

[0223] Compound #22: 9-(3-chlorobenzyl)-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid

[0224] Synthesis of compound #22 was adopted from synthesis of compound #2 but with 3-hexyl-l- cyclohexanone for the indole formation in Step #2 and 1 -(brom omethyl)-3 -chloro-benzene as substrate for Step #4

[0225] 1H-NMR (400 MHz, DMSO-d6): > 12.90 (s, 1H), 7.72-7.69 (m, 2H), 7.14-7.065 (m, 3H), 6.86 (s, 1H), 6.57 (d, J = 7.20 Hz, 1H), 5.63 (d, I = 17.2 Hz, 1H), 2.87-2.84 (m, 1H), 2.78-2.71 (m, 2H), 2.28-2.21 (m, 1H), 2.06-2.01 (m, 1H),1.89 (br s, 1H), 1.58-1.26 (m, 1H), 1.08-1.13 (m, 11H), O.88 (t, J = 7.20 Hz, 3H). MS (ESI) m / z: 424.1 [M+H]+.

[0226] Compound #23 : N-(6-hexyl-4-phenylquinolin-2-yl)-N-methylglycine

[0227] Step 1: Synthesis of N-(4-hexylphenyl)-3-oxo-3-phenylpropanamide (Int-1):

[0228] A mixture of 4-hexyl aniline (30 g, 0.170 mol) and ethyl 3-oxo-3-phenylpropanoate (37 g, 0.186 mol) was heated at 120°C for 12 h. After completion of the reaction (monitored by T.L.C, Eluent: 10% EtOAc / Hexane, R.f: 0.3), it was cooled to room temperature and diluted with icewater (100 mL), extracted with ethyl acetate (3 X 100 mL) and washed with brine (2 X 50 mL). The combined organic layer was dried over NaiSCh (35g), fdtered and concentrated under reduced pressure to obtain crude compound. The crude compound was purified by column chromatography over silica gel (100- 200 mesh) using a solvent gradient of 4% EtOAC in Hexane as eluent to afford N-(4-hexylphenyl)-3-oxo-3-phenylpropanamide (Int-1) as a white solid.

[0229] LC-MS purity: 99.62% with m / z 324.0 (M + H)+.

[0230] Step 2: Synthesis of 6-hexyl-4-phenylquinolin-2(lH)-one (Int-2):

[0231] To a stirred solution ofN-(4-hexylphenyl)-3-oxo-3-phenylpropanamide, Int-1 (16.5 g, 0.051 mol) in methanesulphonicacid (66.3 mL, 1.022 mol) at room temperature was added phosphorus pentoxide (14.4 g, 0.102 mol) under nitrogen atmosphere. The reaction mixture was heated at 100°C for 3 h. After completion of the reaction (monitored by T.L.C, Eluent: 30% EtOAc / Hexane, R.f: 0.3), it was cooled to room temperature, poured onto ice-water (350 mL), extracted with EtOAc (3 X 150 mL) and washed with brine (1 X 50 mL). The combined organic layer was dried over Na2SO4 (12g), filtered and concentrated under reduced pressure to obtain crude compound. The crude compound was triturated with diethyl ether (2 X 50 mL) to afford 6-hexyl-4- phenylquinolin-2(lH)-one (Int-2) as off-white solid.

[0232] LC-MS: 98.90% with m / z 306 (M+H)+.

[0233] Step 3: Synthesis of 2-chloro-6-hexyl-4-phenylquinoline (Int-3):

[0234] To a stirred solution of 6-hexyl-4-phenylquinolin-2(lH)-one, Int-2 (10g, 0.032 mol) in POCh (61.30 mL, 0.65 mol ) was added N,N-Dimethylaniline (10.3 mL, 0.082 mol ) and heated at 100°C for 5 h. After completion of the reaction (monitored by T.L.C, Eluent: 10% EtOAc / Hexane, R.f: 0.7), excess POCI3 was concentrated under reduceed pressure and the residue was poured onto icewater (150 mL) and the product was extracted with EtOAc (3 X 120 mL) and washed with brine (1 X 50 mL). The combined organic layers were dried over Na2SC>4 (8g), filtered and concentrated under reduced pressure to obtain crude compound. The crude compound was purified by column chromatography over silica gel (100- 200 mesh) using a solvent gradient of 3% EtOAC in Hexane as eluent to afford 2-chloro-6-hexyl-4-phenylquinoline (Int-3) as a colorless liquid.

[0235] LC-MS purity: 99.76% with m / z 324.0 (M + H)+.

[0236] Step 4: Synthesis of N-(6-hexyl-4-phenylquinolin-2-yl)-N-methylglycine

[0237] To a stirred solution of 2-chloro-6-hexyl-4-phenylquinoline, Int-3 (7.2g, 0.022 mol) in DMSO (70 mL) at room temperature was added cesium carbonate (21.7g, 0.067 mol) followed by sarcosine (4.96 g, 0.056 mol). The reaction mixture was heated at 100°C for 24 h. After completion of the reaction (monitored by T.L.C, Eluent: 10% MeOH: DCM, R.f: 0.2), the reaction mixture was cooled to room temperature and portioned between ice-water (100 mL) and EtOAc (40 mL). The aqueous layer was acidified with IN HC1 (250 mL) and the precipitated solid was collected by filtration, washed with ice-water (50 mL) and dried under vacuum to afford N-(6-hexyL4- phenylquinolin-2-yl)-N-methyl glycine as a pale green solid.

[0238] ^-NMR (400 MHz, DMSO-d6): 8 12.67 (br.s, 1H), 7.69 (br.s, 1H), 7.60-7.51 (m, 6H), 7.35 (br.s, 1H), 7.01 (br.s, 1H), 4.51 (br.s, 2H), 3.25 (br.s, 3H), 2.60 (t, J = 7.6 Hz, 2H), 1.52 (t, J = 6.4 Hz, 2H), 1.23 (br.s, 6H), 0.82 (t, J = 6.80 Hz, 3H);

[0239] LC-MS: 99.29% / 215 nm with m / z 377 (M+H)+.

[0240] Compound #24: N-methyl-N-(4-phenyl-6-(trifluoromethyl)quinolin-2-yl)glycine

[0241] Synthesis of compound #24 was adopted from synthesis of compound #23 but with 4-CF3- aniline in Step #1.

[0242] 'I I-NMR (400 MHz, DMSO-d6): 8 12.67 (br.s, 1H), 7.79-7.74 (m, 3H), 7.63-7.54 (m, 4H), 7.1 l(s,

[0243] 1H), 4.48(s, 2H), 3.25(s, 3H)

[0244] MS (ESI) m / z: 361.1 [M+H]+. Compound #25: N-(6-cyano-4-phenylquinolin-2-yl)-N-methyl glycine

[0245] Synthesis of compound #25 was adopted from synthesis of compound #23 but with 4-cyano- aniline in Step #1.

[0246] ^-NMR (400 MHz, DMSO-d6): 5 12.67 (br.s, 1H), 7.8(d, J=1.6Hz, 1H), 7.81(dd, J=8.8, 2.0Hz,

[0247] 1H), 7.67 (d, J=8.4Hz, 1H), 7.63-7.50 (m, 5H), 7.1 l(s, 1H), 4.49(s, 2H), 3.26(s, 3H)

[0248] MS (ESI) m / z: 318 [M+H]+.

[0249] Compound #26: 2-((4-(3-fluorophenyl)-6-hexylquinolin-2-yl)thio)-2-methylpropanoic acid

[0250] ^-NMR (400 MHz, DMSO-d6): 8 12.67 (br.s, 1H), 7.78 (d, J=8.4Hz, 1H), 7.65-7.60 (m, 2H), 7.45(br s, 1H), 7.41-7.35(m, 3H), 7.23 (s, 1H), 2.67 (t, J = 7.6 Hz, 2H), 1.69(s, 6H), 1.57-1.54 (m, 2H), 1.30-1.22 (m, 6H), 0.83 (t, J = 6.80 Hz, 3H);

[0251] MS (ESI) m / z: 426.0 [M + H]+.

[0252] Compound #27 : 5-((4-(2-methoxypyridin-4-yl)-6-pentylquinolin-2-yl)methyl)thiazolidine-

[0253] 2.4-dione

[0254] Stepl-1: To a stirred solution of (E)-5-((4-iodo-6-pentylquinolin-2-yl) methylene) thiazolidine-

[0255] 2.4-dione* (100 mg, 0.24 mmol) in 1,4 dioxane (2 mL), was added (2-methoxypyridin-4-yl) boronic acid (45 mg, 0.29 mmol) at RT followed by the addition of K3PO4 (1 8 mg, 0.74 mmol) and degassed with argon for 15 min. Then added PdCh dppf. DCM (10 mg, 0.01 mmol) and the reaction mixture was continued for 16 h at 100 °C in seal tube. After completion of the reaction (monitored by TLC, Eluent: 20% EtOAc: Hexane, Rf: 0.3), the resultant reaction mixture was filtered through celite pad, washed with ethyl acetate (30 mL) and combined filtrate was concentrated under reduced pressure to get crude (0.13 g). The crude was purified by silica gel column chromatography (100- 200 mesh), eluted with 20% EtOAc in hexane to afford (E)-5-((4- (2-methoxypyridin-4-yl)-6-pentylquinolin-2-yl) methylene) thiazolidine-2, 4-dione (80 mg, 75%) as a pale brown solid.

[0256] MS (ESI) m / z: 434.23 [M+H]+

[0257] Step2-1: To a stirred solution of afford (E)-5-((4-(2-methoxypyridin-4-yl)-6-pentylquinolin-2-yl) methylene) thiazolidine-2, 4-dione (80 mg, 0.18 mmol) in THF (5 mL) was added Pd / C (40 mg) and the reaction mixture was stirred under H2 pressure for 16 h. After completion of the reaction (monitored by TLC, Eluent: 20% EtOAc: Hexane, Rf: 0.3), the reaction mass was diluted with Ethyl acetate (20 ml), filtered through celite and washed with ethyl acetate (20 ml). The combined filtrate was concentrated under reduced pressure. The crude material was purified by prep-HPLC to afford 5-((4-(2-methoxypyridin-4-yl)-6-pentylquinolin-2-yl) methyl) thiazolidine-2, 4-dione (17 mg, 22%) as a pale brown solid.

[0258] 'H-NMR (400 MHz, DMSO-d6): 8 12.07 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.68 (dd, J- 8.8, 1.6 Hz, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 7.15 (dd, > 5.2, 1.2 Hz, 1H), 6.98 (s, 1H), 5.08 - 5.05 (m, 1H), 3.95 (s, 3H), 3.91 - 3.83 (m, 1H), 3.68 - 3.59 (m, 1H), 2.70 (t, J = 7.6 Hz, 2H), 1.61 - 1.52 (m, 2H), 1.32 - 1.20 (m, 4H), 0.84 (t, J = 6.8 Hz, 3H).

[0259] MS (ESI) m / z: 436.23 [M+H]+

[0260] *(E)-5-((4-iodo-6-pentylquinolin-2-yl) methylene) thiazolidme-2,4-dione was prepared using the chemistry shown below but using 4-pentyl aniline instead of 4-hexyl-aniline

[0261] Step 1: Synthesis of dimethyl 2-((4-hexylphenyl)amino)fumarate

[0262] To a stirred solution of 4-hexylaniline (10 g, 56.40 mmol) in MeOH (100 mL) at room temperature was added dimethyl but-2-ynedioate (9.6 g, 67.6 mmol). The reaction mixture was stirred at room temperature for 5 min. After completion of the reaction (monitored by TLC, Eluent: 30% EtOAc: Hexane, Rf: 0.6), the reaction mixture was concentrated under reduced pressure to afford dimethyl 2-((4-hexylphenyl)amino)fumarate (10.8 g, crude) as a yellow gummy liquid. MS (ESI) m / z: 320.3 (M+H)+.

[0263] Step 2: Synthesis of methyl 6-hexyl-4-hydroxyquinoline-2-carboxylate

[0264] To a stirred solution of dimethyl 2-((4-hexylphenyl)amino)fumarate (20 g, 62.61 mmol) in 10% P2O5 solution in methane sulfonic acid (300 mL) at room temperature was heated to 60 °C for 2 h. After completion of the reaction (monitored by TLC, Eluent: 10% MeOH: DCM, Rf: 0.3), the reaction mixture was poured into ice water and fdtered the solid to afford methyl 6-hexyl-4- hydroxyquinoline-2-carboxylate (15 g, 83%) as a pale-yellow solid. MS (ESI) m / z: 288 (M+H)+.

[0265] Step 3: Synthesis of methyl 6-hexyl-4-(((trifluoromethyl)sulfonyl)oxy)quinoline-2- carboxylate

[0266] To a stirred solution of methyl 6-hexyl-4-hydroxyquinoline-2-carboxylate (4 g, 13.91 mmol) in DMF (40 mL) at 0 °C was added EtsN (5.8 mL, 41.8 mmol) and 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (5.9 g, 16.72 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC, Eluent: 50% EtOAc: Hexane, Rf: 0.7), the reaction mixture was diluted with water (20 mL) and fdter the solid to afford methyl methyl 6-hexyl-4-(((trifluoromethyl)sulfonyl)oxy)quinoline-2-carboxylate (5 g, 86%) as an off white solid. MS (ESI) m / z: 420 (M+H)+.

[0267] Step 4: Synthesis of methyl 6-hexyl-4-iodoquinoline-2-carboxylate:

[0268] To a stirred solution of methyl 6-hexyl-4-(((trifluoromethyl)sulfonyl) oxy)quinoline-2-carboxylate (1 g, 2.38 mmol) in DMF (10 ml) was added Con.HCl (0.1ml) followed by addition of Nal (0.43 g, 2.86 mmol) at 0 °C. The reaction was stirred for 16 h at RT. After completion of the reaction (monitored by TLC, Eluent: 20% EtOAc: Hexane, Rf: 0.4), the reaction mixture was diluted with ice cold water (10 mL) and solid was filtered off and dried over vacuum to afford methyl 6-hexyL 4-iodoquinoline-2-carboxylate as a yellow solid (700 mg, 74%), MS (ESI) m / z: 398.24 (M+H)+.

[0269] Step 5: Synthesis of 6-hexyl-4-iodoquinoline-2-carbaldehyde To a stirred solution of methyl 6-hexyl-4-iodoquinoline-2-carboxylate (2.5 g, 6.29 mmol) in DCM (30 mL) was added DIB AL-H (16 mL, 1 M in toluene, 15.74 mmol) at -78 °C. The reaction mixture was stirred for 30 min at -78 °C. After completion of the reaction (monitored by TLC, Eluent: 30% EtOAc: Hexane, Rf: 0.4), the reaction mixture was quenched with sat.aq. Na2SO4 solution, filtered through celite pad, washed the pad with ethyl acetate (30mL) and combined filtrate was concentrated under reduced pressure to get the crude material (3 g). The crude material was purified by silica gel (100-200) column chromatography eluted with 20% EtOAc in hexane to afford 6-hexyl-4-iodoquinoline-2-carbaldehyde (1.75 g, 75%) as a yellow solid. MS (ESI) m / z: 368.14 (M+H)-.

[0270] 1H-NMR (400 MHz, DMSO-d6): 10.13 (s,lH), 8.55 (s, ,1H), 8.09-8.07 (d, . / 8 Hz, 1H 7.83 (s,lH), 7.70-7.68 (m,lH), 2.90-2.88 (t, J=8Hz,2H), 1.79-1.73 (m, 2H), 1.41-1.25 (m,6H), 0.91-0.90 (t, J=4Hz,3H)

[0271] The reaction was repeated as (4 x 2.5g) and obtained 7g as yellow solid.

[0272] Step 6: Synthesis of (E)-5-((6-hexyl-4-iodoquinolin-2-yl) methylene) thiazolidine-2, 4-dione:

[0273] To a stirred solution of 6-hexyl-4-iodoquinoline-2-carbaldehyde (2 g, 5.44 mmol) in EtOH (20 mL, 10 vol), was added piperidine (0.4 mL, 3.81 mmol), and thiazolidine-2, 4-dione (0.7g, 5.99 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 8 h. After completion of the reaction (monitored by TLC, 30% EtOAc: Hexane, Rf: 0.3), the reaction mixture was cooled to room temperature, solid was filtered off and dried over vacuum to afford (E)-5-((6- hexyl-4-iodoquinolin-2-yl)methylene)thiazolidine-2, 4-dione (1 g, 40%) as a pale pink colour solid. MS (ESI) m / z: 467.29 (M+H)+.

[0274] Compound #28: 5-((6-pentyl-4-phenoxyquinolin-2-yl)methyl)thiazolidine-2, 4-dione

[0275] To a stirred solution of (E)-5-((4-iodo-6-pentylquinolin-2-yl)methylene)thiazolidine-2, 4-dione* (300 mg, 0.66 mmol) and phenol (124 mg, 1.32 mmol) in DMF (3 mL) was added CS2CO3 (647 mg, 1 .99 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 16 h in seal tube. The reaction was monitored by TLC, (Eluent: 30% EtOAc: Hexane Rr: 0.3). The reaction mixture was poured into ice water (30 mL), extracted with EtOAc (2 x 20 mL), the combined organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel (100-200 mesh) column chromatography, eluted with EtOAc / Hexane (2 / 8) to afford (E)- 5-((6-pentyl-4-phenoxyquinolin-2-yl)methylene)thiazolidine-2, 4-dione (250 mg, 90%) as an off- white solid.

[0276] MS (ESI) m / z: 419.06 [M+H]+

[0277] To a stirred solution of (E)-5-((4-phenoxy-6-pentylquinolin-2-yl)methylene)thiazolidine-2,4- dione (250 mg, 0.59 mmol) in THF (10 mL) was added Pd / C (250 mg). The reaction mixture was stirred at RT for 16 h under H2 pressure. The reaction was monitored by TLC, (Eluent: 30% EtOAc: Hexane, Rr: 0.3), The reaction mixture was diluted with THF (5 ml) and filtered through a celite pad, the filtrate was concentrated under reduced pressure. The residue was purified Prep HPLC to afford 5-((6-pentyl-4-phenoxyquinolin-2-yl)methyl)thiazolidine-2, 4-dione (60 mg, 24%) as an off-white solid.

[0278] ' H-NMR (400 MHz, DMSO-d6): 12.04 (s, 1H), 8.10 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.57 (t, J=8.4 Hz, 2H), 7.38 (t, J=7.2 Hz, 1H), 7.32 (d, J=7.6 Hz, 2H), 6.66 (s, 1H), 4.96 - 4.92 (m, 1H), 3.68 - 3.63 (m, 1H), 3.52 - 3.46 (m, 1H), 2.82 (t, J=7.6 Hz, 2H), 1.71 - 1.66 (m, 2H), 1.33 - 1.30 (m, 4H), 0.87 (t, J=6.8 Hz, 3H).

[0279] MS (ESI) m / z: 421.16 [M+H]+

[0280] Compound #29: N-(6-(l,l-difluorohexyl)-4-phenylquinolin-2-yl)-N-methyl glycine

[0281] 'H-NMR (400 MHz, DMSO-d6): 5 12.67 (br.s, 1H), 7.69-7.51 (m, 8H), 7.04 (s, 1H), 4.47 (s, 2H), 3.23 (s, 3H), 2.17-2.09 (m,2H), 1.33-1.18 (m, 7H), 0.80 (t, J = 6.80 Hz, 3H);

[0282] MS (ESI) m / z: 413.17 [M+H]+ Compound #30: 5-((4-phenyl-6-(trifluoromethyl)quinolin-2-yl)methyl)thiazolidine-2,4- dione

[0283] Synthesis of compound #30 was adopted from synthesis of compound #27 but with 4-CF3- aniline in Step #1 and phenyl boronic acid in Step #1-1

[0284] 'H-NMR (400 MHz, DMSO-d6): 5 12.11 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.11 - 8.06 (m, 2H), 7.66-7.58 (m, 6H), 5.12 - 5.09 (m, 1H), 3.99 - 3.93 (m, 1H), 3.76 - 3.69 (m, 1H). MS (ESI) m / z : 403.08 [M+H]+.

[0285] Compound #31: 5-((4-(pyridin-3-yl)-6-(trifluoromethyl)quinolin-2-yl)methyl)thiazolidine- 2, 4-dione

[0286] Synthesis of compound #31 was adopted from synthesis of compound #27 but with 4-CF3- aniline in Step #1 and pyridin-3-yl-boronic acid in Step #1-1.

[0287] 'H-NMR (400 MHz, DMSO-d6): 5 12.12 (s, 1H), 8.81 -8.78 (m, 2H), 8.21 (d, J=8.8 Hz, 1H), 8.11 - 8.04 (m, 3H), 7.71 (s, 1H), 7.68 - 7.65 (m, 1H), 5.12 - 5.08 (m, 1H), 3.99 - 3.94 (m, 1H), 3.76 -3.70 (m, 1H).

[0288] MS (ESI) m / z : 404.24 [M+H]+.

[0289] Compound #32: 5-((4-phenoxy-6-(trifluoromethyl)quinolin-2-yl)methyl)thiazolidine-2,4- dione

[0290] Synthesis of compound #32 was adopted from synthesis of compound #28 but with 4-CF3- aniline in Step #1.

[0291] ^-NMR (400 MHz, DMSO-d6): 5 12.03 (s,lH), 8.60 (s, 1H), 8.10 (s, 2H), 7.57 (t, J=7.6 Hz, 2H),

[0292] 7.41 - 7.35 (m, 3H), 6.70 (s, 1H), 4.94 - 4.94 (m, 1H), 3.75 - 3.69 (m, 1H), 3.55 - 3.48 (m, 1H). MS (ESI) m / z: 419.19 [M+H]

[0293] Compound #33: N-methyl-N-(4-phenyl-6-(2,2,2-trifluoroethyl)quinolin-2-yl)glycine

[0294] Synthesis of compound #33 was adopted from synthesis of compound #23 but with 4-(CEsCH2)- aniline in Step #1.

[0295] ’H-NMR (400 MHz, DMSO-d6): 8 12.67 (br.s, 1H), 7.60-7.47 (m, 8H), 6.89(s, 1H), 4.48(s, 2H),

[0296] 4.27(s, 2H), 3.70-3.60(m, 2H), 3.20(s, 3H)

[0297] MS (ESI) m / z: 375.2 [M+H]+.

[0298] Compound #34: 5-((4-((2-methoxypyridin-4-yl)oxy)-6-(trifluoromethyl)quinolin-2- yl)methyl)thiazolidine-2, 4-dione

[0299] Step 1: To a stirred solution of 4-(trifluoromethyl)aniline (5 g, 30.86 mmol) in MeOH (100 mL) was added dimethyl but-2-ynedioate (3.8 mL, 30.86 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 min. The reaction was monitored by TLC (Eluent: 10% EtOAc: Hexane, Rf: 0.6), the reaction mixture was concentrated under reduced pressure to afford dimethyl 2-((4-(trifluoromethyl)phenyl)amino)maleate (9 g, 96%) as a pale-yellow liquid. MS (ESI) m / z: 304.08 [M+H]+.

[0300] Step 2: To a stirred solution of dimethyl 2-((4-(trifluoromethyl)phenyl)amino)maleate (9 g, 29.7 mmol) in methane sulfonic acid (90 mL, 10 vol) was added P2O5 (12.65 g, 89.11 mmol) at 0 °C. The reaction mixture was stirred at 60 °C for 2 h. The reaction was monitored by TLC (Eluent: 70% EtOAc / Hexane, Rf: 0.2), the reaction mixture was poured into ice water and filtered the solid to afford methyl 4-hydroxy-6-(trifluoromethyl)quinoline-2-carboxylate (4.5 g, 55%) as a light brown solid.

[0301] MS (ESI) m / z: 272.07 [M+H]+. Step 3: To a stirred solution of methyl 4-hydroxy-6-(trifluoromethyl)quinoline-2-carboxylate (4.5 g, 16.6 mmol) in DMF (45 mL) was added EtsN (3.47 mL, 24.9 mmol) followed by the addition of l,l,l-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl) methane sulfonamide (6.52 g, 18.26 mmol) at 0 °C. The reaction mixture was stirred at RT for 30 min. The reaction monitored by TLC (Eluent: 50% EtOAc / Hexane, Rt: 0.6), reaction mixture was poured into ice water, solid was filtered and dried under vacuum to afford methyl 6-(trifluoromethyl)-4- (((trifluoromethyl)sulfonyl)oxy)quinoline-2-carboxylate (5 g, 74%) as an off-white solid.

[0302] MS (ESI) m / z: 404.05 [M+H]+

[0303] Step 4: To a stirred solution of methyl 6-(trifluoromethyl)-4-

[0304] (((trifluoromethyl)sulfonyl)oxy)quinoline-2-carboxylate (1.5 g, 3.72 mmol) in Acetonitrile (15 mL, vol) was added Nal (5.58 g, 37.22 mmol) followed by addition of Con.HCl (0.5 mL) at room temperature. The reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC, (Eluent: 50% EtOAc: Hexane Rr: 0.4), the resultant reaction mixture was poured into ice water (30 mL), solid was filtered and dried under vacuum to afford methyl 4-iodo-6- (trifluoromethyl)quinoline-2-carboxylate (690 mg, 48%) as a pale-yellow solid.

[0305] MS (ESI) m / z: 381.98 [M+H]+

[0306] Step 5: To a stirred solution of methyl 4-iodo-6-(trifluoromethyl)quinoline-2-carboxylate (850 mg, 2.23 mmol) in DMF (10 ml) was added CS2CO3 (2.17 g, 6.69 mmol) and 2-methoxypyridin- 4-ol (557 mg, 4.46 mmol) at RT. The reaction mixture was stirred at 100 °C for 16 h. The reaction was monitored by TLC (Eluent: 10% MeOH / DCM, Rr: 0.3), the reaction mixture was diluted with water (10 mL), neutralized with 2N. HC1 and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 4-((2-methoxypyridin-4-yl)oxy)-6-(trifluoromethyl)quinoline-2-carboxylic acid (1 g, crude) as a brown solid,

[0307] MS (ESI) m / z: 365.04 [M+H]+.

[0308] Step 6: To a stirred solution of 4-((2-methoxypyridin-4-yl)oxy)-6-(trifluoromethyl)quinoline-2- carboxylic acid (1 g, 2.74 mmol) in DMF (10 mL) was added CS2CO3 (2.67 g, 8.22 mmol) followed by addition of methyl iodide (0.26 ml, 4.11 mmol) at 0 °C. The reaction mixture was stirred at RT for 2 h. The reaction was monitored by TLC (Eluent: 30% EtOAc: Hexane, Rf: 0.5), the reaction mixture was diluted with water (10 mL), extracted with EtOAc (50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel (100-200) column chromatography eluted at EtOAc / hexane (1 / 9) to afford methyl 4-((2-methoxypyridin-4-yl)oxy)-6-(trifluoromethyl)quinoline-2-carboxylate (490 mg, 58% overall two steps) as an off-white solid,

[0309] MS (ESI) m / z: 379.12 [M+H]+.

[0310] Step 7: To a stirred solution of methyl 4-((2-methoxypyridin-4-yl)oxy)-6- (trifluoromethyl)quinoline-2-carboxylate (400 mg, 1.06 mmol) in DCM (10 mL) at -78 °C was added DIBAL-H (1.76 mL, 1.5 M in toluene, 2.64 mmol). The reaction mixture was stirred for 30 min at -78 °C. The reaction monitored by TLC (Eluent: 20% EtOAc: Hexane, Rf: 0.6), the reaction mixture was quenched with sat. NazSCL solution, filtered through a celite pad and washed with DCM (30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel (100-200) column chromatography eluted at EtOAc / hexane (2 / 8) to afford 4-((2- methoxypyridin-4-yl)oxy)-6-(trifluoromethyl)quinoline-2-carbaldehyde (280 mg, 76%) as a paleyellow solid.

[0311] MS (ESI) m / z: 349.02 [M+H]1.

[0312] Step 8: To a stirred solution of 4-((2-methoxypyridin-4-yl)oxy)-6-(trifluoromethyl)quinoline-2- carbaldehyde (280 mg, 0.8 mmol) and thiazolidine-2, 4-dione (103 mg, 0.88 mmol) in EtOH (2.8 mL, 10 vol) under nitrogen atmosphere, was added piperidine (0.056 mL, 0.56 mmol). The reaction mixture was stirred at 80 °C for 8 h. The reaction monitored by TLC (30% EtOAc: Hexane, Rf: 0.3). The reaction mixture was cooled to room temperature, solid was filtered and dried under vacuum to afford (E)-5-((4-((2-methoxypyridin-4-yl)oxy)-6- (trifluoromethyl)quinolin-2-yl)methylene)thiazolidine-2, 4-dione (75 mg, 21%) as a pale-yellow solid.

[0313] MS (ESI) m / z: 448.04 [M+H]+.

[0314] Step 9: To a stirred solution of (E)-5-((4-((2-methoxypyridin-4-yl)oxy)-6- (trifluoromethyl)quinolin-2-yl)methylene)thiazolidine-2, 4-dione (70 mg, 0.16 mmol) in MeOH (10 mL) and AcOH (1 drop) was added 10% Pd / C (70 mg). The reaction mixture was stirred at RT for 16 h under H2 atmosphere. The reaction was monitored by TLC (eluent:30% EtOAc: Hexane, Rf: 0.4), the reaction mixture was filtered through a celite pad, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford 5-((4-((2- methoxypyridin-4-yl)oxy)-6-(trifluoromethyl)quinolin-2-yl)methyl)thiazolidine-2, 4-dione (19 mg, 27%) as a white solid. ^-NMR (400 MHz, DMSO-d6): 5 12.07 (s,lH), 8.49 (s, 1H), 8.28 (d, J=5.6 Hz, 1H), 8.15 - 8.09 (m, 2H), 7.14 (s, 1H), 6.99 (dd, J=6.0, 2.4 Hz, 1H), 6.78 (d, J=2.0 Hz, 1H), 5.01 - 4.97 (m, 1H), 3.90 (s, 3H), 3.84 - 3.78 (m, 1H), 3.61 - 3.54 (m, 1H).

[0315] MS (ESI) m / z: 450.02 [M+H]+

[0316] Compound #35: N-(5,7-difluoro-6-hexyl-4-phenoxyquinolin-2-yl)-N-methylglycine

[0317] Synthesis of compound #35 was adopted from synthesis of compound #23 and #28 but with 3,5- difluoro-4-hexylaniline in Step #1.

[0318] ^-NMR (400 MHz, DMSO-d6): 6 12.67 (br.s, 1H), 7.49- 7.44(m, 2H), 7.25 (t, J = 7.6Hz, 1H), 7.16-7.09 (m, 3H), 6.20 (s, 1H), 4.27 (br.s, 2H), 2.93 (s, 3H), 2.68-2.63 (m, 2H), 1.54-1.52 (m, 2H), 1.26-1.23 (m, 6H), 0.84 (t, J = 6.80 Hz, 3H);

[0319] MS (ESI) m / z: 429.3 [M+H]+

[0320] Compound #36: 2-methyl-2-((6-pentyl-4-phenylquinolin-2-yl)thio)propanoic acid 12.67 (br.s, 1H), 7.70 (d, J=8.4Hz, 1H), 7.62-7.49 (m, 7H), 7.20 (s, 1H), 2.66 (t, J = 7.6 Hz, 2H), 1.69(s, 6H), 1.59-1.52 (m, 2H), 1.30-1.22 (m, 4H), 0.83 (t, J = 6.80 Hz, 3H);

[0321] MS (ESI) m / z: 394.2 [M + H]+.

[0322] Compound #37: 5-((6-(l,l-difluoroethyl)-4-phenoxyquinolin-2-yl)methyl)thiazolidine-2,4- dione

[0323] Step 1: 4-bromoaniline (20 g, 116.26 mmol) and 2, 2-dimethyl-l,3-dioxane-4, 6-dione (16.76 g, 116.26 mmol) were taken in round bottom flask. The reaction mixture was stirred at 100 °C for 3 h. After completion of the reaction (monitored by TLC, Eluent: 90% EtOAc: hexane, Rf: 0.1), the reaction mixture was cooled to room temperature and the solidified compound was triturated with pentane followed by ether, solid was filtered through buchner funnel under vacuum to afford 3-((4-bromophenyl) amino)-3-oxopropanoic acid (18 g, 60%) as an off-white solid.

[0324] MS (ESI) m / z: 257.8 [M + H]+.

[0325] Step 2: To a stirred solution of 3-((4-bromophenyl) amino)-3-oxopropanoic acid (12.5 g, 48.43 mmol) in CH3SO3H (100 mL) at room temperature, was added P2O5 (27.4 g, 96.65 mmol) and stirred at 100 °C for 3 h. After completion of the reaction (monitored by TLC, Eluent: 10% MeOH: DCM, Rf: 0.5) the reaction mixture was quenched with ice-cold water (200 mL), Basify the reaction mixture with aq Na2CO3 solution and the precipitated solid was filtered through buchner funnel under vacuum to afford 6-bromo-4-hydroxyquinolin-2(lH)-one (11 g, 95%) as a yellow solid.

[0326] MS (ESI) m / z: 240 [M + H]+.

[0327] Step 3: To a stirred solution of 6-bromo-4-hydroxyquinolin-2(lH)-one (2 g, 8.33 mmol) in DMF (20 mL) was added EtsN (2.3 mL, 16.66 mmol) followed by the addition of 1,1,1-trifluoro-N- phenyl-N-((trifluoromethyl)sulfonyl) methane sulfonamide (3.5 g, 10.04 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 10 min. The reaction was monitored by TLC (Eluent: 50% EtOAc / Hexane, Rf: 0.6), reaction mixture was poured into ice water, solid was filtered and dried under vacuum to afford 6-bromo-2-oxo-l,2-dihydroquinolin-4-yl trifluoromethanesulfonate (2.3 g, 74%) as a white solid.

[0328] MS (ESI) m / z: 371.85 [M+H]+

[0329] Step 4: To a stirred solution of 6-bromo-2-oxo-l,2-dihydroquinolin-4-yl trifluoromethanesulfonate (2.5 g, 6.73 mmol) in Acetonitrile (25 mL) was added Nal (5.05 g, 33.69 mmol) followed by addition of Con.HCl (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC, (Eluent: 1% EtOAc: Hexane Rf: 0.6), the resultant reaction mixture was poured into ice water (30 mL), solid was filtered and dried under vacuum to afford 6-bromo-4-iodoquinolin-2(lH)-one (2 g, 85%) as a paleyellow solid.

[0330] MS (ESI) m / z: 349.94 [M+H]+

[0331] Step 5: To a stirred solution of 6-bromo-4-iodoquinolin-2(lH)-one (2 g, 5.73 mmol) and phenol (5.3 g, 57.3 mmol) in DMF (20 mL) was added CS2CO3 (5.6 g, 17.19 mmol) at room temperature. The reaction mixture was stirred at 90 °C in a sealed tube for 16 h. The reaction was monitored by TLC, (Eluent: 50% EtOAc: Hexane Rf: 0.4), the resultant reaction mixture was poured into ice water (30 mL), solid was filtered and dried under vacuum to afford 6-bromo-4-phenoxyquinolin- 2(lH)-one (1.5 g, crude) as an off-white solid.

[0332] MS (ESI) m / z: 315.94 [M+H]+

[0333] Step 6: To a stirred solution of 6-bromo-4-phenoxyquinolin-2(lH)-one (1.5 g, 4.74 mmol) in toluene (30 mL) was added diethyl aniline (1.5 mL, 1 vol), and POCI3 (7.5 mL, 5 vol) at 0 °C. The reaction mixture was stirred at 100 °C for 5 h. The reaction was monitored by TLC, (Eluent: 30% EtOAc: Hexane Rf: 0.6), the reaction mixture was basified with sat. aq. sodium bicarbonate solution and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with brine solution (2 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel (100- 200 mesh) column chromatography, eluted with EtOAc / Hexane (1 / 9) to afford 6-bromo-2-chloro-4-phenoxy quinoline (900 mg, 47% overall two steps) as an off-White solid.

[0334] MS (ESI) m / z: 333.93 [M+H]+

[0335] Step 7: To a stirred solution of 6-bromo-2-chloro-4-phenoxyquinoline (900 mg, 2.70 mmol) and tributyl(l -ethoxy vinyl)stannane (1.37 g, 3.78 mmol) in Toluene (18 mL) was added PdCh(PPh3)2 (95 mg, 0.13 mmol) at room temperature. The reaction mixture was degassed with argon for 15 min. The reaction mixture was stirred at 60 °C in a sealed tube for 48 h. The reaction was monitored by TLC (Eluent: 20% EtOAc: Hexane, Rf: 0.4). The reaction mixture was cooled to room temperature, filtered through a pad of celite and washed with EtOAc (20 mL) and combined filtrate was concentrated under reduced pressure to afford 2-chloro-6-(l -ethoxy vinyl)-4- phenoxyquinoline (950 mg, crude) as a brown gummy.

[0336] MS (ESI) m / z: 326.07 [M+H]+. Step 8: To a stirred solution of 2-chloro-6-(l-ethoxyvinyl)-4-phenoxy quinoline (950 mg, 2.92 mmol) in 1,4 dioxane (10 mL) was added 4M HC1 in 1,4 Dioxane (3 mL, 7.30 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice water (20 mL) and extracted the compound with EtOAc (2 x 100 mL). The combined organic layer was dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by silica gel (100- 200 mesh) column chromatography, eluted with EtOAc / Hexane (1 / 9) to afford l-(2-chloro-4-phenoxyquinolin-6-yl)ethan-l-one (450 mg, 56% overall two steps) as an off-White solid.

[0337] MS (ESI) m / z: 297.91 [M+H]+

[0338] Step 9: To a stirred solution of l-(2-chloro-4-phenoxyquinolin-6-yl)ethan-l-one (420 mg, 1.41 mmol) in DCM (10 mL) was added DAST (2.73 g, 2.73 mmol) at -10 °C. The reaction mixture was stirred at room temperature for 48 h. The reaction was monitored by TLC (Eluent: 10% EtOAc: Hexane, Rr: 0.8), the reaction mixture was quenched with sat. NaHCO solution (20 mL) and extracted the compound with DCM (2 x 50 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel (100-200) column chromatography, eluted at EtOAc / hexane (1 / 9) to afford 2-chloro-6-(l, 1 -difluoroethyl)-4- phenoxy quinoline (180 mg, 40%) as a pale-yellow gummy.

[0339] MS (ESI) m / z: 320.13 [M+H]+.

[0340] Step 10: To a stirred solution of 2-chloro-6-( 1,1 -difluoroethyl)-4-phenoxy quinoline (180 mg, 0.56 mmol) in MeOH (10 mL) was added KOAc (165 mg, 1.69 mmol) at RT. The reaction mixture was degassed with argon for 15 min followed by addition of Pd(dppf)C12.DCM (4 mg, 0.01 mmol) under argon atmosphere. The reaction mixture was stirred under CO pressure at 60 °C in a steel bomb for 16 h. The reaction was monitored by TLC (Eluent: 20% EtOAc: Hexane, Rf 0.3). The reaction mixture was filtered through celite and concentrated the filtrate under reduced pressure. The residue was purified by silica gel (100- 200 mesh) column chromatography, eluted with EtOAc / Hexane (1 / 9) to afford methyl 6-(l,l-difluoroethyl)-4-phenoxyquinoline-2-carboxylate (140 mg, 72%) as an off-white solid.

[0341] MS (ESI) m / z: 344.19 [M+H]+

[0342] Step 11: To a stirred solution of methyl 6-(l,l-difluoroethyl)-4-phenoxyquinoline-2-carboxylate (140 mg, 0.40 mmol) in DCM (3 mL) was added DIBAL-H (0.6 mL, 1.7 M in toluene, 1.02 mmol) at -78 °C. The reaction mixture was stirred for 30 min at -78 °C. The reaction was monitored by TLC (Eluent: 20% EtOAc: Hexane, Rf: 0.7), the reaction mixture was quenched with sat. Na SO4 solution, filtered through a celite pad and washed with DCM (30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel (100-200) column chromatography, eluted with EtOAc / hexane (1 / 9) to afford 6-(l,l-difluoroethyl)-4- phenoxyquinoline-2-carbaldehyde (110 mg, 87%) as an off-white solid. MS (ESI) m / z: 313.99 [M+H]+.

[0343] Step 12: To a stirred solution of 6-(l,l-difluoroethyl)-4-phenoxyquinoline-2-carbaldehyde (110 mg, 0.35 mmol) and thiazolidine-2, 4-dione (45 mg, 0.38 mmol) in EtOH (1.1 mL, 10 vol) was added piperidine (20 mg, 0.24 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 8 h. The reaction was monitored by TLC (30% EtOAc: Hexane, Rf: 0.3). The reaction mixture was cooled to room temperature, solid was filtered and dried under vacuum to afford (E)- 5-((6-(l, l-difluoroethyl)-4-phenoxyquinolin-2-yl)methylene)thiazolidine-2, 4-dione (30 mg, crude) as a light brown solid.

[0344] MS (ESI) m / z: 413.21 [M+H]1.

[0345] Step 13: To a stirred solution of (E)-5-((6-(l,l-difluoroethyl)-4-phenoxyquinolin-2- yl)methylene)thiazolidine-2, 4-dione (30 mg, 0.07 mmol) in MeOH (2 mL) and AcOH (1 drop) was added 10% Pd / C (30 mg). The reaction mixture was stirred at RT for 16 h under H2 pressure. The reaction was monitored by TLC (eluent: 50% EtOAc: Hexane, Rf 0.2), the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford 5-((6-(l,l-difluoroethyl)-4-phenoxyquinolin-2- yl)methyl)thiazolidine-2, 4-dione (17 mg, 12% overall two steps) as an off white solid.

[0346] !H-NMR (400 MHz, DMSO-d6): 8 12.10 (bs, 1H), 8.42 (s, 1H), 8.02 (d, J =8.8 Hz, 1H), 7.98 (dd, J =8.8, 1.6 Hz, 1H), 7.57 (t, J =7.6 Hz, 2H), 7.42-7.32 (m, 3H), 6.64 (s, 1H), 4.89 (dd, I =9.6, 3.6 Hz, 1H), 3.68 (dd, J =16.8, 3.6 Hz, 1H), 3.43 (dd, J =16.8, 9.6 Hz, 1H), 2.10 (t, J = 18.8 Hz, 3H). MS (ESI) m / z: 415.09 [M+H]+

[0347] Compound #38: N-(6-(8-azidooctyl)-4-phenylquinolin-2-yl)-N-methylglycine * methyl N-(6-iodo-4-phenylquinolin-2-yl)-N-methyl glycinate is generated similar to the intermediates for compound #23 except uses 4-iodo-aniline for Step #1

[0348] Step 1: To a solution of methyl N-(6-iodo-4-phenylquinolin-2-yl)-N-methyl glycinate (6 g, 13.9 mmol) in THF (30 mL) in a sealed tube at room temperature, were added Cui (0.264 g, 1.388 mmol) and triethylamine (19.3 mL, 138.88 mmol). The reaction mixture was degassed with argon for 10 min. To the reaction mixture, was added oct-7-yn-l-ol (2.103 g, 16.666 mmol) and Pd(PPhs)2C12 (0.487 g, 0.694 mmol) and again degassed with argon further 5 min. The reaction mixture was stirred at 65 °C for 8 h. After completion of the reaction (monitored by TLC, Eluent: 25 % EtOAc: hexane, Rf: 0.2), the reaction mixture was cooled to room temperature, concentrated under vacuum, diluted with ice water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SC>4, fdtered and concentrated under reduced pressure. The resulting crude compound was purified by column chromatography over silica gel using a solvent gradient of 40-50% EtOAc in hexane as eluent to afford methyl N-(6-(8-hydroxyoct-l-yn-l-yl)-4-phenylquinolin-2-yl)-N- methylglycinate as brown solid (5.8 g, 97%).

[0349] MS (ESI) m / z 431 [M+H]+.

[0350] Step 2: To a stirred solution of methyl N-(6-(8-hydroxyoct-l-yn-l-yl)-4-phenylquinolin-2-yl)-N- methylglycinate (2.3 g, 5.345 mmol) in MeOH (15 mL) and THF (10 mL) at room temperature, was added 10% Pd / C (2.3 g) and stirred at room temperature under H2 atmosphere for 12 h. After completion of the reaction (monitored by TLC, Eluent: 25 % EtOAc: hexane, Rf: 0.6), the reaction mixture was filtered through celite bed, washed with MeOH (200 mL) and concentrated under reduced pressure to afford methyl N-(6-(8-hydroxyoctyl)-4-phenylquinolin-2-yl)-N-methyl glycinate as a green solid (2 g, 86 %).

[0351] MS (ESI) m / z: 435 [M + H]+.

[0352] Step 3: To a stirred solution of methyl N-(6-(8-hydroxyoctyl)-4-phenylquinolin-2-yl)-N-methyl glycinate (1.0 g, 2.304 mmol) in THF (10) at 0 °C, were added EtsN (0.9 mL, 6.906 mmol) and methane sulphonyl chloride (0.35 mL, 4.608 mmol). The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC, Eluent: 50% EtOAc: hexane, Rf: 0.4), the reaction mixture was quenched with ice-cold water (50 mL)and extracted with ethyl acetate (3 x 100 mL), the combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford methyl N-methyl-N-(6-(8-((methylsulfonyl)oxy)octyl)-4- phenylquinolin-2-yl)glycinate (1.1 g, 93%) as a green gum.

[0353] MS (ESI) m / z: 513 [M + H]+.

[0354] Step 4: To a stirred solution of N-methyl-N-(6-(8-( (methyl sulfonyl) oxy) octyl)-4- phenylquinolin-2-yl) glycinate (1.2 g, 5.581 mmol) in DMF (12 mL) at room temperature was added sodium azide (0.72 g, 11.162 mmol) and heated the reaction at 60 °C for 3 h. After completion of the reaction (monitored by TLC, Eluent: 30% EtOAc: hexane, Rf: 0.3), the reaction mixture was cooled to room temperature, quenched with ice-cold water (200 mL) and extracted with ethyl acetate (2 x 200 mL), the combined organic layer was washed with brine, dried over anhydrous Na SO4, fdtered and concentrated under reduced pressure. The resulting crude was purified by column chromatography over silica gel (100- 200 mesh) using a solvent gradient of 5 -10% EtOAc in Hexane as eluent to afford methyl N-(6-(8-azidooctyl)-4-phenylquinolin-2-yl)-N- methyl glycinate (0.7 g, 65%) as a green gum.

[0355] MS (ESI) m / z: 460 [M + H]1.

[0356] Step 5:To a stirred solution of methyl N-(6-(8-azidooctyl)-4-phenylquinolin-2-yl)-N-methyl glycinate (70 mg, 0.152 mmol) in THF (1 mL) and H2O (1 mL) at room temperature, was added LiOH.H2O (12.7 mg, 0.304 mmol). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC, Eluent: 10% MeOH: DCM, Rf: 0.3), the reaction mixture was concentrated under vacuum, diluted with ice water (10 mL), acidified with IN HC1 and the precipitated compound was filtered under vacuum, washed with water to afford N-(6-(8-azidooctyl)-4-phenylquinolin-2-yl)-N-methyl glycine as pale green solid (27 mg, 40%). 'H-NMR (400 MHz, DMSO-d6): 8 7.90-7.92 (m, 7H), 7.40 (s, 1H), 7.29-7.21 (m, 1H), 4.66 (s, 2H), 3.35 (s, 3H), 3.27 (t, J = 6.8 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H), 1.54-1.48 (m, 4H), 1.36-1.20 (m, 8H) (carboxylic acid proton was not observed)

[0357] MS (ESI) m / z: 444 [M - H] '.

[0358] Compound #39: N-(6-(8-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-8-oxooctyl)-4- phenylquinoIin-2-yl)-N-methylglycine

[0359] * methyl N-(6-iodo-4-phenylquinolin-2-yl)-N-methyl glycinate is generated similar to the intermediates for compound #23 except uses 4-iodo-aniline for Step #1

[0360] Step 1: To a stirred solution of methyl N-(6-iodo-4-phenylquinolin-2-yl)-N-methyl glycinate* (1.0 g, 2.313 mmol) in THF (20 mL) at room temperature, were added TEA (3.2 mL, 23.1 mmol) and Cui (43 mg, 0.231 mmol). The resultant reaction mixture was bubbled with nitrogen gas for 15 minutes, followed by addition of oct-7-ynoic acid (324 mg, 2.313 mmol) and PdCh(PPh3)2 (81 mg, 0.115 mmol) and stirred at 70 °C for 12 h. After completion of the reaction (monitored by TLC, Eluent: 70% EtOAc: hexane, Rf: 0.3), the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL), The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by column chromatography over silica gel (100- 200 mesh) using a solvent gradient of EtOAc as eluent to afford 8-(2-((2-methoxy-2-oxoethyl) (methyl)amino)-4-phenylquinolin-6-yl) oct-7-ynoic acid (500 mg, 49%) as a yellow gum, MS (ESI) m / z: 445 [M + H]+.

[0361] Step 2: To a stirred solution of 8-(2-((2-methoxy-2-oxoethyl) (methyl)amino)-4-phenylquinolin- 6-yl) oct-7-ynoic acid (330 mg, 0.742 mmol) and tert-butyl (2-(2-(2- aminoethoxy)ethoxy)ethyl)carbamate (221 mg, 0.890 mmol) in DMF (10 mL) at room temperature, were added N-Methyl morpholine (187 mg, 1.85 mmol), HOBt (300 mg, 2.22 mmol) and EDC.HC1 (424 mg, 2.22 mmol). The resulting reaction mixture was stirred at room temperature for 12 h. After completion of the reaction (monitored by TLC, Eluent: 70% EtOAc: hexane, Rf: 0.2), the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 X 30 mL), the combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by column chromatography over silica gel (100- 200 mesh) using a solvent gradient of EtOAc as eluent to afford methyl N-(6-(2,2-dimethyl-4,15-dioxo-3,8,l l-trioxa-5,14-diazadocos-21-yn-22- yl)-4-phenylquinolin-2-yl)-N-methylglycinate (400 mg, 80%) as a yellow gum, MS (EST) m / z: 675 [M + H]+.

[0362] Step 3: To a stirred solution of methyl N-(6-(2,2-dimethyl-4,15-dioxo-3,8,l l-trioxa-5,14- diazadocos-21-yn-22-yl)-4-phenylquinolin-2-yl)-N-methylglycinate (400 mg, 0.593 mmol) in MeOH (15 mL) under nitrogen atmosphere was added 10% Pd / C (400 mg). The reaction mixture was stirred under hydrogen balloon pressure at room temperature for 12 h. After completion of the reaction (monitored by TLC, Eluent: 70% EtOAc: Hexane, Rf: 0.3), the reaction mixture was filtered through a celite pad, washed with MeOH (30 mL). Filterate was concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100- 200 mesh) using a solvent gradient of 25% EtOAc in hexane as eluent to methyl N-(6-(2,2- dimethyl-4,15-dioxo-3,8,l l-trioxa-5,14-diazadocosan-22-yl)-4-phenylquinolin-2-yl)-N- methylglycinate (350 mg, 87%) as an off-white solid.

[0363] MS (ESI) m / z 679 [M+H]+.

[0364] Step 4: To a stirred solution of N-(6-(2,2-dimethyl-4,15-dioxo-3,8,l l-trioxa-5,14-diazadocosan- 22-yl)-4-phenylquinolin-2-yl)-N-methylglycinate (250 mg, 0.368 mol) in DCM (5 mL) at 0 °C, was added TFA (0.28 mL). The reaction mixture was slowly warmed to room temperature and stirred for 6 h at room temperature. After completion of the reaction (monitored by TLC, Eluent: 70% EtOAc: hexane, Rf: 0.1), the excess solvent was concentrated under reduced pressure. The crude material obtained was triturated with n-pentane (30 mL) to afford methyl N-(6-(8-((2-(2-(2- aminoethoxy) ethoxy) ethyl) amino)-8-oxooctyl)-4-phenylquinolin-2-yl)-N-methyl glycinate TFA salt (250 mg, crude) as a colourless liquid and taken forward for the subsequent step without any purification.

[0365] MS (ESI) m / z: 676 [M + H]+.

[0366] Step 5: To a stirred solution of methyl N-(6-(8-((2-(2-(2-aminoethoxy) ethoxy) ethyl) amino)-8- oxooctyl)-4-phenylquinolin-2-yl)-N-methyl glycinate TFA salt (100 mg, 0.148 mmol) in THF (1 mL), MeOH (1 mL) & H2O (1 mL) at room temperature, was added LiOH.ftO (62 mg, 1.48 mmol) and stirred at room temperature for 12 h. After completion of the reaction (monitored by TLC, Eluent: 10 % MeOH: DCM, Rf: 0.1), the reaction mixture was cooled to room temperature, concentrated under vacuum, diluted with ice water (10 mL), acidified with IN HC1 and extracted with 10% MeOH / DCM (3 X 10 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC to afford N-(6-(8-((2-(2-(2-aminoethoxy) ethoxy) ethyl) amino)-8-oxooctyl)-4-phenylquinolin-2-yl)-N-methyl glycine as an off-white solid (24 mg, 29 %).

[0367] 'H-NMR (400 MHz, DMSO-d6): 8 7.80-7.79 (m, 1H), 7.57-7.49 (m, 4H), 7.49-7.45 (m, 2H), 7.35 (dd, J = 2.00, 8.60 Hz, 1H), 7.27 (s, 1H), 6.77 (s, 1H), 4.03 (s, 2H), 3.49-3.33 (m, 9H), 3.18- 3.10 (m, 6H), 2.75-2.72 (m, 2H), 2.58-2.56 (m, 2H), 1.98-2.01 (m, 2H), 1.53-1.49 (m, 2H), 1.44- 1.40 (m, 2H), 1.28-1.13 (m, 6H), (Carboxylic acid peak was not visible), MS (ESI) m / z 565.2 [M+H]+.

[0368] Compound #40: [(6-bromo-4-phenyl-2-quinolyl)-N-methylamino]acetic acid

[0369] Synthesis of compound #41 was adopted from synthesis of compound #23 but with 4-butyl- aniline in Step #1 and 2-methyl-3-(methylamino)propanoic acid in Step #4

[0370] 'H-NMR (400MHz-DMSO-d6-D2O exchange): 7.80(br s, 1H), 7.64-7.43(m, 6H), 7.37(s, 1H), 7.15 (br s, lH), 4.00(s, 1H), 3.83-3.78 (m, 1H), 3.28 (s, 3H), 2.94(dd, J = 14.8, 7.8Hz, 1H), 2.62(t, J = 8Hz, 2H), 1.53-1.47 (m, 2H), 1.36-1.19(m, 3H), 1.13 (d, J = 6.4Hz, 3H), 0.86 (t, J = 7.2Hz, 3H)

[0371] MS (ESI) m / z: 377.1 [M+H]+. Compound #42: [(7-bromo-4-phenyl-2-quinolyl)-N-methylamino]acetic acid Synthesis of compound #42 was adopted from synthesis of compound #23 but with 3 -bromoaniline in Step #1. iH-NMR (400MHz-DMSO-d6): 12.5 (s, 1H), 7.73(s, 1H), 7.57-7.49 (m, 6H), 7.27(dd, J = 8.8, 2Hz, 1H), 6.92(s, 1H), 4.28 (s, 2H), 3.19 (s, 3H), MS (ESI) m / z: 371.5 [M+H]+.

[0372] The binding of the compounds to FABP4 was assessed using thermal shift assays (Pantoliano, M.W., Petrella, E.C., Kwasnoski, J.D., Lobanov, V.S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B.A., Lane, P., & Salemme, F.R. (2001). "High-Density Miniaturized Thermal Shift Assays as a General Strategy for Drug Discovery." SLAS Discovery, 6(6), 429- 440). Briefly, purified human recombinant FABP4 expressed in E. coli was thawed on ice and diluted in PBS (Gibco) to a stock concentration of 10 uM. Test compounds were dissolved in DMSO (Sigma-Aldrich) and diluted in PBS to a final stock concentration of 50 uM. Compounds (or DMSO as vehicle control) were mixed with FABP4 at a 5: 1 molar ratio (compound-to- protein) and incubated at room temperature for 10 minutes. The final FABP4 concentration was 5 uM, and the final DMSO concentration in each sample was 2.5%. Following incubation, protein unfolding transition temperatures (melting temperatures; Tm) were measured using the Tycho NT.6 instrument (NanoTemper). Compound binding was assessed by calculating the change in melting temperature (deltaTm, °C), defined as the difference between the Tm of the compound-treated FABP4 sample and that of the DMSO control. As shown in Table 1, compounds were categorized based on the magnitude of the shift in FABP4 melting temperature (deltaTm), where a greater shift indicates higher binding affinity. Category “A” includes compounds with deltaTm > 3.00 °C; Category “B” includes those with deltaTm between 1.00 and 3.00 °C; and Category “C” includes those with deltaTm between 0.50 and 0.99 °C. Compounds marked with an asterisk (*) were tested using the same 5: 1 compound-to-protein molar ratio, but with a final FABP4 concentration of 50 uM. Conditions not yet tested are indicated as “n.d.” (not determined). To assess the effect of FABP-modulating compounds on antibody effector functions, a cell-based assay that utilizes RAW264.7 macrophages (ATCC), a mouse cell line known to maintain their macrophage phenotype in culture and widely used in phagocytosis assays, and antibody opsonized bioparticles were used. Briefly, RAW264.7 cells were propagated in the DMEM media containing Ig / L glucose and 10% heat inactivated FBS (Thermo Fisher) were seeded at a density of 2.8E+4 cells / well into each well of a 96 well flat bottom plate at a volume of 100 uL. 20-24 hours later, the media was replaced with RPMI 1640 media (Gibco) with 5% heat inactivated FBS that contains either DMSO (vehicle control) or indicated compounds at a final concentration of 10 uM. After an additional incubation period of 20-24 hours at 37 degrees C, 1.2E+5 of antibody opsonized E. Coli bioparticles (Thermo Fisher) with pHrodo Red conjugate (Thermo Fisher), a pH-sensitive dye used to track the egulfment of particles by phagocytes, or rabbit IgG latex beads (Cayman Chemical) with PE complex diluted 1 :200 were added to the cells to determine phagocytic activity. Following an incubation period of 2-3 hours at 37 degrees C, the cells were thoroughly washed with ice-cold PBS for three times, scraped off and transferred to a new 96 well V bottom plate for flow analysis.

[0373] Phagocytosis index, as a measure of antibody effector function, was calculated as geometric mean of fluorescence (gMFI) times percentage of positive cell populations. Mean fold-change values relative to the DMSO control and corresponding standard deviations (SD) were determined. As shown in Table 1, treatment with FABP modulators resulted in a significant enhancement of antibody effector functions.

[0374] Table 1

[0375] To further validate the synergistic activity of FABP-modulation and cell depleting immunotherapy, FABP-modulating compounds were tested in combination with monoclonal antibodies (mAbs) known to mediate target cell depletion by antibody effector functions. This was assessed using an antibody-dependent cellular phagocytosis assay utilizing cultured macrophages and various cancer cell lines including Raji (Invivogen) and BJAB (ATCC) B-cell lymphoma cells, and SK-BR-3 and BT-474 (ATCC) breast cancer cells. The assay included biosimilars of the anti-CD20 mAb rituximab, approved for the treatment of multiple B-cell nonHodgkin lymphomas; the anti-CD47 mAb magrolimab, an investigational agent evaluated in several hematological malignancies, lymphomas and solid tumors; and the anti-HER2 mAb trastuzumab, approved for HER2 -positive breast cancer, gastric and gastroesophageal junction cancers, and metastatic colorectal cancer. Briefly, RAW264.7 macrophages propagated in the DMEM media containing Ig / L glucose and 10% heat inactivated FBS were seeded at a density of 2.8E+4 cells / well into each well of a 96 well flat bottom plate at a volume of 100 uL. 20-24 hours later, the media was replaced with 100 uL of RPMI 1640 (Gibco) assay media containing 5% heat inactivated FBS (Thermo Fisher). FABP-modulating compounds or DMSO (vehicle in which the compounds were dissolved) were added on the cells at a final concentration of 10 uM (except for the compound 23 which was used at 20 uM) and 0.1%, respectively. The final assay volume was 200 uL. The cells were incubated for an additional period of 20-24 hours at 37 degrees C. Next day, medium of the cells were replaced with 50 uL of fresh assay media, and target cancer cells, were either stained with a cell proliferation dye eFluor-670 (Thermo Fisher; Raji cells in Figure 1 A and IB) or a pHrodo Red conjugate (Thermo Fisher; BJAB, SK-BR-3, and BT474 cells in Figure 1C, ID, and E), washed with assay media, and resuspended at a density of le+6 cells / mL. 50 uL of the stained cells were added on the macrophages at an estimated ratio of 1 :4 to 1:5 (target cell: macrophage). To opsonize target human cancer cells and engage antibody effector functions in RAW264.7 macrophages of murine origin, monoclonal antibodies were used targeting human CD47 (anti-CD47, BioLegend), which carries a mouse IgGl isotype, as well as antibodies against human CD20 (anti-CD20, InvivoGen) and HER2 (anti-HER2; Bioexcell), both of which bear a mouse IgG2a isotype that is functionally analogous to human IgGl. The antibodies and freshly diluted FABP-modulating compounds were sequentially added to the cells in the assay medium, to yield a final assay volume of 200 uL. The final antibody concentration was 0.5, 1, 2, 1, and 1 ug / ml for the experiments in Figure 1A, IB, 1C, ID, and IE, respectively, for the antibodies. Isotype controls for each antibody, mouse IgGl (Biolegend) for anti-CD47 and mouse IgG2a (Biolegend) for anti-CD20 and anti-HER2 served as negative controls. The final assay volume was 200 uL and the final concentration of DMSO was 0.1%. The plates were incubated at 37 degrees C for a time period that allows for antibodydependent phagocytosis, which was 4 hours, 20 hours, 2.5 hours, 2 hours and 2 hours for the experiments shown in Figure 1A, IB, 1C, ID, and IE, respectively. The macrophage-target cell co-cultures were washed with PBS for three times, scraped off and transferred to a new 96 well v-bottom plate. The flow analyses were performed after staining the macrophages with anti-F4- 80 (Biolegend). The phagocytic index was calculated by multiplying the frequency of macrophage / target double-positive cell population and geometric mean fluorescence of target cells and is shown in Figure 1. Statistical significance was determined using one-way ANOVA (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001; ns: not significant)

[0376] The present invention contemplates using other compounds in combination with the compounds disclosed herein. In this vein, the inventors believe that there are a plurality of commercially available immunotherapies or immunotherapies currently undergoing FDA testing that are of IgGl subtype and capable of depleting target antigens or cells expressing those antigens through antibody dependent phagocytosis that can be added to the compounds disclosed herein that will demonstrate the desired enhanced effect. Several examples are listed in Table 2. The synergistic effect that is generated when modulating the FABPs using the compounds of the present invention, alternatively combined with the immunotherapies listed in Table 2 suggest that the methodology described above will work as potential treatments for advanced cancer, autoimmune conditions / diseases, infectious diseases, and conditions / diseases associated with inflammation.

[0377] Table 2

[0378] Immunotherapy Target Use Status

[0379] To the best of the inventors’ knowledge, there have been no reports proposing a potential synergy between immunotherapies that function by eliminating target antigens and / or cells via antibody effector functions and modulating the FABPs using small molecules. The above example shows that FABP4 modulating small molecules will synergistically increase the response rate of immunotherapies that target antibody effector functions.

[0380] In an embodiment, the antibody includes one or more of the following: Depemokimab, Telisotuzumab vedotin, Clesrovimab, Sipavibart, Nipocalimab, Bentracimab, Datopotamab deruxtecan, Zenocutuzumab, Zanidatamab, Patritumab deruxtecan, Tarlatamab, Marstacimab, Garadacimab, Zolbetuximab, Crovalimab, Cosibelimab, Trastuzumab, duocarmazine, Donanemab, Epcoritamab, Glofitamab, Lecanemab, Teplizumab, Ublituximab, Mirvetuximab soravtansine, Nirsevimab, Spesolimab, Mosunetuzumab, Faricimab, Regdanvimab, Tisotumab vedotin, Amivantamab, Anifrolumab, Loncastuximab, tesirine, Bimekizumab, Aducanumab, Dostarlimab, Ansuvimab, Margetuximab, Naxitamab Atoltivimab, Maftivimab, and Odesivimab-ebgn, Belantamab mafodotin, Tafasitamab, Inebilizumab, Sacituzumab govitecan, Teprotumumab, Isatuximab, Eptinezumab, [fam]- trastuzumab deruxtecan, Enfortumab vedotin, Polatuzumab vedotin, Risankizumab, Emapalumab, Moxetumomab pasudotox, Lanadelumab, Mogamulizumab, Tildrakizumab, Burosumab, Durvalumab, Benralizumab, Ocrelizumab, Guselkumab, Sarilumab, Avelumab, Atezolizumab, Bezlotoxumab, Olaratumab, Obiltoxaximab, Daratumumab, Elotuzumab, Necitumumab, Idarucizumab, Alirocumab, Mepolizumab, Dinutuximab, Secukinumab, Blinatumomab, Ramucirumab, Vedolizumab, Siltuximab, Obinutuzumab, Ado-trastuzumab, emtansine, Raxibacumab, Pertuzumab, Brentuximab vedotin, Belimumab, Ipilimumab, Tocilizumab, Ofatumumab, Canakinumab, Golimumab, Ustekinumab, Certolizumab pegol, Ranibizumab, Bevacizumab, Cetuximab, Efalizumab, Omalizumab, Ibritumomab tiuxetan, Adalimumab, Alemtuzumab, Trastuzumab, Infliximab, Palivizumab, Basiliximab, Daclizumab, Rituximab, Abciximab, TG-1801 / NI-1701, IMM0306, Botensilimab, Felzartamab, Efgartigimod, Nipocalimab, Batoclimab, Ociperlimab (BGB-A1217), Litifilimab (BIIB059), BAT5906, Ligelizumab, Clazakizumab, Nirsevimab, SYN023, Afimkibart, APG777, Namilumab, Siltuximab, Cixutumumab / Dalotuzumab, Ublituximab, Depatuxizumab mafodotin, CAP- 100, JBH492, Camidanlumab tesirine, RG-6292, RM-1995, BMS-986340, GS-1811, S-531011, BAY-3375968, BGB-A3055, ABBV-514, RO7502175, QLP2117, ZL-1218, CHS-114, Dacetuzumab, Lucatumumab, MOR202, Milatuzumab, BI-505, AVE1642, F50067, Mapatumumab, Lorvotuzumab mertansine, or Indatuximab Ravtansine.

[0381] All references (including all applications referenced), disclosed herein are incorporated by reference in their entireties for all purposes.

[0382] It should be understood that any feature that is described above can be combined with any other feature as long as they are not incompatible. Moreover, where a variable lists different possible substituents, any genus or subgenus containing the substituents in those various definitions of the variables is contemplated. In one embodiment, he present invention is defined by the below claims.

Claims

We claim:

1. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of Formula (I) or Formula (II), and an antibodyFormula (II) wherein Q is a bond or O,Ri is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with an alkyl, a Ci-3 alkoxy, an ether, halo, or CF3R2 is hydrogen or halo,R3 is hydrogen, Cz-Csalkyl optionally substituted with 1 to 10 halo atoms, CF3, CHF2, CH2F,CN, C2-C8alkyl-N3, or (CH2)7C(O)NH(CH2)2-O(CH2)2-O(CH2)2-NH2,R.4 is hydrogen, halo, or C2-Csalkyl optionally substituted with 1 to 10 halo atoms,Rs is hydrogen, with the proviso that all of R2, R3, R4, and R5 are not hydrogen,X is CH, O, N, or S, wherein Re is not present when X is O or S,Re is hydrogen or alkyl, n is 0 or 1,R7 is heterocyclyl, heteroaryl, -C(Cs)(C9)(Cio) wherein Cs, C9, and C10 are each independently hydrogen, Ci-C3alkyl, -COOH, -C(O)NHCH2COOH, or -C(O)NHCH2OH;Z is phenyl, pyridyl, or a thiophene,R11 and RUA are independently -CN, hydrogen, -CF3, -COOH, halo, -O-Ci-3alkyl, -C(O)NH2, R12 and R12A are independently -COOH, halo, hydrogen, or -C(O)NHCH2COOH, with the proviso that at least one of R12 and R12.4 are -COOH or -C(O)NHCH2COOH, m is 1 or 2,R13 is hydrogen or Ci-3alkyl,Ru is hydrogen or C2-salkyl optionally substituted with 1 to 10 halo atoms or -COOH,R15 is hydrogen or Ci-3alkyl,Ri6 is hydrogen or Ci-3alkyl,R17 and Ris are independently hydrogen, Ci-3alkyl or together are =0.

2. The pharmaceutical composition of claim 1, wherein Ri is phenyl or a 5 to 6 membered heteroaryl optionally substituted with an alkyl, an ether, halo, or CF3.

3. The pharmaceutical composition of claim 2, wherein Ri is phenyl, imidazole, pyrazole, or pyridine optionally substituted with an alkyl, an ether, halo, or CF3.

4. The pharmaceutical composition of claim 1, wherein R7 is a thiazolidinedione, or a thiadiazoldione, or -C(Cs)(C9)(Cio).

5. The pharmaceutical composition of claim 1, wherein either R4 or R5 is Cs-Csalkyl optionally substituted with 1 to 10 halo atoms.

6. The pharmaceutical composition of claim 1, with the proviso that at least one of R13, R14, R15, Ri6 is not hydrogen.

7. The pharmaceutical composition of claim 1, wherein R14 is C3-ealkyl optionally substituted with a COOH group.

8. The pharmaceutical of claim 1, wherein Z is phenyl or pyridyl.

9. The pharmaceutical composition of claim 1, wherein the antibody is an antibody that is implicated in antibody-dependent phagocytosis.

10. The pharmaceutical composition of claim 9, wherein an amount of the compound or pharmaceutically acceptable salt of Formula (I) or Formula (II) is in an amount ideally suited to treat cancer.

11. The pharmaceutical composition of claim 1, wherein the compound or pharmaceutically acceptable salt of Formula (I) or Formula (II) is selected from the group consisting of 5- (3-cyanobenzyl)-7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(3-cyanobenzyl)-2-fluoro-7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid, 7-hexyl-5-((2-(trifluoromethyl)pyridin-4-yl)methyl)-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-((4-cyanothiophen-2-yl)methyl)-7- hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(3-cyanobenzoyl)- 7-hexyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(3-cyano-2- (trifluoromethyl)benzyl)-7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid, 5-(3-carbamoyl-2-fluorobenzyl)-2-chloro-7-propyl-5,6,7,8,9, 10- hexahydrocyclohepta[b]indole-4-carboxylic acid, 2-fluoro-7-hexyl-5-((2- (trifluoromethyl)pyridin-4-yl)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid, 2-fluoro-5-(3-fluorobenzyl)-7-hexyl-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid, 2-chloro-5-(3-fluorobenzyl)-7-hexyl-5, 6, 7, 8, 9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 2-chloro-7-hexyl-5-((2- (trifluoromethyl)pyridin-4-yl)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid, 9-(3-chlorobenzyl)-6-fluoro-2-hexyl-2, 3, 4, 9-tetrahy dro-lH-carbazole-8- carboxylic acid, 6-chloro-9-(3-fluorobenzyl)-2-hexyl -2,3,4, 9-tetrahy dro-lH-carbazol e-8- carboxylic acid, 6-chl oro-2-hexyl-9-((2-(trifluoromethyl)pyridin-4-yl)methyl)-2, 3,4,9- tetrahydro-lH-carbazole-8-carboxylic acid, 7-hexyl-5-((2-(trifluoromethyl)pyridin-4- yl)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(2-chloro-3- cyanobenzyl)-2-fluoro-7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(3-cyano-2-methoxybenzyl)-2-fluoro-7-hexyl-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid, 7-(7-carboxyheptyl)-5-(3-cyano-2- fluorobenzyl)-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 9- (3-chlorobenzyl)-2 -hexyl -2, 3, 4, 9-tetrahy dro-lH-carbazole-8-carboxylic acid, 8-[(m-chlorophenyl)methyl]-l l -hexyl-8-azatricyclo[7.5.0.02,7]tetradeca-l(9),2(7),3,5-tetraene- 6-carboxylic acid, 9-[(m-fluorophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole- 8-carboxylic acid, 9-[(m-chlorophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole- 8-carboxylic acid, N-(6-hexyl-4-phenylquinolin-2-yl)-N-methylglycine, N-methyl-N-(4- phenyl-6-(trifluoromethyl)quinolin-2-yl)glycine, N-(6-cyano-4-phenylquinolin-2-yl)-N- methylglycine, 2-((4-(3-fluorophenyl)-6-hexylquinolin-2-yl)thio)-2-methylpropanoic acid, 5-((4-(2-methoxypyridin-4-yl)-6-pentylquinolin-2-yl)methyl)thiazolidine-2, 4-dione, 5-((6-pentyl-4-phenoxyquinolin-2-yl)methyl)thiazolidine-2, 4-dione, N-(6-(l,l- difluorohexyl)-4-phenylquinolin-2-yl)-N-methylglycine, 5-((4-phenyl-6- (trifluoromethyl)quinolin-2-yl)methyl)thiazolidine-2, 4-dione, 5-((4-(pyridin-3-yl)-6- (trifluoromethyl)quinolin-2-yl)methyl)thiazolidine-2, 4-dione, 5-((4-phenoxy-6- (trifluoromethyl)quinolin-2-yl)methyl)thiazolidine-2, 4-dione, N-methyl-N-(4-phenyl-6- (2,2,2-trifluoroethyl)quinolin-2-yl)glycine, 5-((4-((2-methoxypyridin-4-yl)oxy)-6- (trifluoromethyl)quinolin-2-yl)methyl)thiazolidine-2, 4-dione, N-(5,7-difluoro-6-hexyl-4- phenoxyquinolin-2-yl)-N-methylglycine, 2-methyl-2-((6-pentyl-4-phenylquinolin-2- yl)thio)propanoic acid, 5 -((6-( 1 , 1 -difluoroethyl)-4-phenoxyquinolin-2- yl)methyl)thiazolidine-2, 4-dione, N-(6-(8-azidooctyl)-4-phenylquinolin-2-yl)-N- methylglycine, N-(6-(8-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-8-oxooctyl)-4- phenylquinolin-2-yl)-N-methylglycine, [(6-bromo-4-phenyl-2-quinolyl)-N- m ethyl ami no] acetic acid, 3-[(6-butyl-4-phenyl-2-quinolyl)-N-methylamino]-2- methylpropionic acid, [(7-bromo-4-phenyl-2-quinolyl)-N-methylamino]acetic acid.

12. The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable diluent, excipient, filler, binder, lubricant, coating, flavoring, colorant, surfactant, or preservative.

13. A method of treating cancer, autoimmune diseases, metabolic diseases, infectious diseases or inflammatory disorders comprising administering to an individual in need thereof a pharmaceutically acceptable amount of a pharmaceutical composition that comprises a compound or pharmaceutically acceptable salt of Formula (I) or Formula (II), and an antibodyFormula (II) wherein Q is a bond or O,Ri is aryl, heterocyclyl, or heteroaryl, wherein each aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more of any of -COOH, -CONH2, an alkyl, a Ci-3alkoxy, hydroxyl, cyano, an ether, halo, or CF3;R2 is hydrogen or halo; R3 is hydrogen, C2-Cgalkyl optionally substituted with 1 to 10 halo atoms or a mono or bicyclic heterocyclyl or mono or bicyclic heteroaryl ring, wherein the mono or bicyclic heterocyclyl or mono or bicyclic heteroaryl ring is optionally substituted with hydroxy or Ci-salkyl; -CF3, -CHF2, -CH2F, -CN, -C2-C8alkyl-N3, -CH2(CH2)6C(O)NH(CH2)2-O(CH2)2-O(CH2)2-NH2, - N(CH2CH3)2, or -N(CH3)(C6H5);R4 is hydrogen, halo, or C2-C8alkyl optionally substituted with 1 to 10 halo atoms;R5 is hydrogen; with the proviso that all of R2, R3, R4, and R5 are not hydrogen;X is CH, O, N, or S, wherein Re is not present when X is O or S;Re is hydrogen, alkyl, or cycloalkyl, n is 0 or 1,R7 is heterocyclyl, heteroaryl, -C(C8)(C9)(Cio) wherein C8, C9, and C10 are each independently hydrogen, Ci-C3alkyl, -COOH, -C(O)NHCH2COOH, -C(O)NHCH2OH, or any two of C8, C9, and C10 may be =0; or X, Re, R7, and / or any of R8, R9, and Rio together with the atoms to which they are attached optionally form a 3 to 6 membered cycloalkyl ring or a 5 or 6 membered heterocyclyl or heteroaryl ring, which is optionally substituted with Ci-C3alkyl, -COOH, -C(0)NHCH2C00H, - C(0)NHCH20H, or =0,Z is phenyl, pyridyl, or a thiophene,R11 and RUA are independently -CN, hydrogen, -CF3, -COOH, halo, -O-Ci.3alkyl, -C(0)NH2, RI2and RI2A are independently -COOH, halo, hydrogen, or -C(0)NHCH2C00H, with the proviso that at least one of R12 and RI2A are -COOH or -C(0)NHCH2C00H, m is 1 or 2,Ri3is hydrogen or Ci-3alkyl,Ru is hydrogen or C2-8alkyl optionally substituted with 1 to 10 halo atoms or -COOH,R15 is hydrogen or Ci-3alkyl,Ri6 is hydrogen or Ci-3alkyl,R17 and RI are independently hydrogen, Ci-3alkyl or together are =0.

14. The method of claim 13, wherein Ri is phenyl, pyrrolo, piperdinyl, morpholino, oxazolo, or pyridyl.

15. The method of claim 13, wherein the cancer is ovarian, breast, prostate, lung, bladder, renal, esophageal, hepatocellular carcinoma, melanoma, renal cell carcinoma, mesothelioma, non-Hodgkin lymphoma or multiple myeloma cancer, or the autoimmune disease is multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosusor inflammatory bowel disease, or inflammatory disorder manifests as or is neuroinflammation, Alzheimer’s disease, dermatitis or asthma, or the infectious disease is caused by coronavirus, respiratory syncytial virus, or ebola virus.

16. The method of claim 13, wherein the antibody is a mono-specific, bi-specific or multispecific monoclonal antibody, or antibody-drug conjugate that eliminates a target antigen or target cell by antibody-dependent phagocytosis.

17. The method of claim 16 wherein, the antibody is selected from the group consisting of Depemokimab, Telisotuzumab vedotin, Clesrovimab, Sipavibart, Nipocalimab, Bentracimab, Datopotamab deruxtecan, Zenocutuzumab, Zanidatamab, Patritumab deruxtecan, Tarlatamab, Marstacimab, Garadacimab, Zolbetuximab, Crovalimab, Cosibelimab, Trastuzumab, duocarmazine, Donanemab, Epcoritamab, Glofitamab, Lecanemab, Teplizumab, Ublituximab, Mirvetuximab soravtansine, Nirsevimab, Spesolimab, Mosunetuzumab, Faricimab, Regdanvimab, Tisotumab vedotin, Amivantamab, Anifrolumab, Loncastuximab, tesirine, Bimekizumab, Aducanumab, Dostarlimab, Ansuvimab, Margetuximab, Naxitamab, Atoltivimab, Maftivimab, and Odesivimab-ebgn, Belantamab mafodotin, Tafasitamab, Inebilizumab, Sacituzumab govitecan, Teprotumumab, Isatuximab, Eptinezumab, [fam] -trastuzumab deruxtecan, Enfortumab vedotin, Polatuzumab vedotin, Risankizumab, Emapalumab, Moxetumomab pasudotox, Lanadelumab, Mogamulizumab, Tildrakizumab, Burosumab, Durvalumab, Benralizumab, Ocrelizumab, Guselkumab, Sarilumab, Avelumab, Atezolizumab, Bezlotoxumab, Olaratumab, Obiltoxaximab, Daratumumab, Elotuzumab, Necitumumab, Idarucizumab, Alirocumab, Mepolizumab, Dinutuximab, Secukinumab, Blinatumomab, Ramucirumab, Vedolizumab, Siltuximab, Obinutuzumab, Ado-trastuzumab, emtansine, Raxibacumab, Pertuzumab, Brentuximab vedotin, Belimumab, Ipilimumab, Tocilizumab, Ofatumumab, Canakinumab, Golimumab, Ustekinumab, Certolizumab pegol, Ranibizumab, Bevacizumab, Cetuximab, Efalizumab, Omalizumab, Ibritumomab tiuxetan, Adalimumab, Alemtuzumab, Trastuzumab, Infliximab, Palivizumab, Basiliximab, Daclizumab, Rituximab, Abciximab, TG-1801 / NI-1701, IMM0306, Botensilimab, Felzartamab, Efgartigimod, Nipocalimab, Batoclimab, Ociperlimab (BGB- A1217), Litifilimab (BIIB059), BAT5906, Ligelizumab, Clazakizumab, Nirsevimab, SYN023, Afimkibart, APG777, Namilumab, Siltuximab, Cixutumumab / Dalotuzumab,Ublituximab, Depatuxizumab mafodotin, CAP-100, JBH492, Camidanlumab tesirine, RG-6292, RM-1995, BMS-986340, GS-1811, S-531011, BAY-3375968, BGB-A3O55, ABBV-514, RO7502175, QLP2117, ZL-1218, CHS-114, Dacetuzumab, Lucatumumab, MOR202, Milatuzumab, BI-505, AVE1642, F50067, Mapatumumab, Lorvotuzumab mertansine, and Indatuximab Ravtansine.

18. The method of claim 13, wherein the cancer is advanced cancer.

19. The method of claim 13, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable diluent, excipient, filler, binder, lubricant, coating, flavoring, colorant, surfactant, or preservative.

20. The method of claim 13, wherein the compound is a compound selected from the group consisting of: 5-(3-cyanobenzyl)-7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid, 5-(3-cyanobenzyl)-2-fluoro-7-hexyl-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid, 7-hexyl-5-((2-(trifluoromethyl)pyridin- 4-yl)methyl)-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-((4- cyanothiophen-2-yl)methyl)-7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid, 5-(3-cyanobenzoyl)-7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole- 4-carboxylic acid, 5-(3-cyano-2-(trifluoromethyl)benzyl)-7-hexyl-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(3-carbamoyl-2-fluorobenzyl)-2- chloro-7-propyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 2-fluoro- 7-hexyl-5-((2-(trifluoromethyl)pyridin-4-yl)methyl)-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid, 2-fluoro-5-(3-fluorobenzyl)-7-hexyl- 5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 2-chloro-5-(3- fluorobenzyl)-7-hexyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 2- chloro-7-hexyl-5-((2-(trifluoromethyl)pyridin-4-yl)methyl)-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid, 9-(3-chlorobenzyl)-6-fluoro-2-hexyl- 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 6-chloro-9-(3-fluorobenzyl)-2-hexyl- 2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 6-chloro-2-hexyl-9-((2- (trifluoromethyl)pyridin-4-yl)methyl)-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 7-hexyl-5-((2-(trifluoromethyl)pyridin-4-yl)methyl)-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(2-chl oro-3 -cyanobenzyl)-2-fluoro-7- hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4-carboxylic acid, 5-(3-cyano-2-methoxybenzyl)-2-fluoro-7-hexyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-4- carboxylic acid, 7-(7-carboxyheptyl)-5-(3-cyano-2-fluorobenzyl)-2-fluoro-5,6,7,8,9,10- hexahydrocyclohepta[b]indole-4-carboxylic acid, 9-(3-chl orobenzyl)-2-hexyl-2, 3,4,9- tetrahydro-lH-carbazole-8-carboxylic acid, 8-[(m-chlorophenyl)methyl]-l l-hexyl-8- azatricyclo[7.5.0.02,7]tetradeca-l(9),2(7),3,5-tetraene-6-carboxylic acid, 9-[(m- fluorophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, 9-[(m- chlorophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-lH-carbazole-8-carboxylic acid, N-(6- hexyl-4-phenylquinolin-2-yl)-N-methylglycine, N-methyl-N-(4-phenyl-6- (trifluoromethyl)quinolin-2-yl)glycine, N-(6-cyano-4-phenylquinolin-2-yl)-N- methylglycine, 2-((4-(3-fluorophenyl)-6-hexylquinolin-2-yl)thio)-2-methylpropanoic acid, 5-((4-(2-methoxypyridin-4-yl)-6-pentylquinolin-2-yl)methyl)thiazolidine-2, 4-dione, 5-((6-pentyl-4-phenoxyquinolin-2-yl)methyl)thiazolidine-2, 4-dione, N-(6-(l,l- difluorohexyl)-4-phenylquinolin-2-yl)-N-methylglycine, 5-((4-phenyl-6- (trifluoromethyl)quinolin-2-yl)methyl)thiazolidine-2, 4-dione, 5-((4-(pyridin-3-yl)-6- (trifluoromethyl)quinolin-2-yl)methyl)thiazolidine-2, 4-dione, 5-((4-phenoxy-6- (trifluoromethyl)quinolin-2-yl)methyl)thiazolidine-2, 4-dione, N-methyl-N-(4-phenyl-6- (2,2,2-trifluoroethyl)quinolin-2-yl)glycine, 5-((4-((2-methoxypyridin-4-yl)oxy)-6- (trifluoromethyl)quinolin-2-yl)methyl)thiazolidine-2, 4-dione, N-(5,7-difluoro-6-hexyl-4- phenoxyquinolin-2-yl)-N-methylglycine, 2-methyl-2-((6-pentyl-4-phenylquinolin-2- yl)thio)propanoic acid, 5-((6-(l,l-difluoroethyl)-4-phenoxyquinolin-2- yl)methyl)thiazolidine-2, 4-dione, N-(6-(8-azidooctyl)-4-phenylquinolin-2-yl)-N- methylglycine, N-(6-(8-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-8-oxooctyl)-4- phenylquinolin-2-yl)-N-methylglycine, [(6-bromo-4-phenyl-2-quinolyl)-N- methylamino]acetic acid, 3-[(6-butyl-4-phenyl-2-quinolyl)-N-methylamino]-2- methylpropionic acid, [(7-bromo-4-phenyl-2-quinolyl)-N-methylamino]acetic acid.

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