COMPOUNDS, COMPOSITIONS AND METHODS FOR HISTONE LYSINE DEMETHYLASE INHIBITION CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application Number 63/238,042, filed August 27, 2021, which is incorporated by reference in its entirety. FIELD [0002] Provided herein are compounds and pharmaceutical compositions suitable for the selective inhibition of histone lysine demethylase-5 (KDM5), particularly KDM5B, and methods for their use in treating conditions and diseases modulated by KDM5 activity. BACKGROUND [0003] Epigenetic enzymes modify DNA or histones by adding or removing chemical markers including methylation, acetylation, phosphorylation, and ubiquitination. These alterations modify the interactions between histones and DNA and lead to local changes in chromatin structure that silence or activate local genes. Histone Demethylases (HDMs) are a class of epigenetic enzyme that remove methyl groups from histone lysine residues, in particular lysine residues 4 (H3K4), 9 (H3K9), 27 (H3K27), 36 (H3K36), and 79 (H3K79) on histone 3, and lysine residue 20 (H4K20) on histone 4. Although there is some literature on the roles of HDMs in non-cancer settings (e.g. inflammation and wound healing), the vast majority of the current HDM literature is in cancer where HDMs are frequently over-expressed and where genetic approaches support pro-tumorigenic HDM functions. [0004] At least 17 different HDMs have been identified so far. While the first and most studied HDMs belong to the lysine-specific demethylase 1 (LSD1; also known as KDM1) family of amine oxidases, the remainder are all Jumonji C (JmjC) domain containing Fe(II)-dependent and oxoglutarate (2OG)-dependent dioxygenases. The JmjC domain is responsible for the demethylation activity by first hydroxylating histone lysine methylamine groups utilizing oxygen and 2-OG, which is then followed by the spontaneous loss of the unstable hydroxymethyl group. (See, e.g., Loenarz and Schofield (2008) Nat Chem Biol 4(3):152-6; Ozer et al (2007) Nat Chem Biol 3(3):144-53.) [0005] The KDM5, or JARID1, family of JmjC HDMs includes KDM5A (JARID1A/RBP2), KDM5B (JARID1B/PLU-1), KDM5C (JARID1C/SMCX), and KDM5D (JARID1D/SMCY). These enzymes can act on di- and trimethylated H3K4 and demethylate H3K4me3/me2/me. There are numerous reports of pro-tumorigenic functions for KDM5A, KDM5B, and KDM5C. (See, e.g., Tang et al (2015) Oncotarget 6(14):12723-39.) For example, KDM5B has been implicated in the development of prostate, breast, and skin cancer and also has been associated with melanoma maintenance. (See, e.g., Han et al. (2017) Oncotarget 8(5):8980-8991.) KDM5B is also overexpressed in non-small cell lung cancer (NSCLC) cells and is associated with tumor size, lymph node metastasis, advanced stages, and poor overall survival in NSCLC patients. (Kuo et al. (2018) Clin Epigenetics 10(1):107.) [0006] There remains a need for compounds that are effective in the treatment and prevention of conditions and disorders associated with KDM5 and, in particular KDM5B, including various cancers. The compounds provided herein inhibit KDM5 activity and can be used to treat and prevent KDM5- associated disorders such as cancer. SUMMARY [0007] The present disclosure is directed to compounds, compositions comprising the same, and methods of using the compounds to selectively modulate the activity of histone demethylases (HDMs), in particular, histone lysine demethylase-5. In one aspect, provided are compounds of Formula I: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: n is 0, 1, 2, 3, or 4; R ¹ is hydrogen, -P(O)(OR ²⁰ )2, -CH2P(O)(OR ²⁰ )2, -P(O)(R ²⁰ )(OR ²⁰ ), -CH2P(O)(R ²⁰ )(OR ²⁰ ), -P(O)(N(R ²⁰ )2)(OR ²⁰ ), -CH2P(O)(N(R ²⁰ )2)(OR ²⁰ ), -P(O)(R ²⁰ )(N(R ²⁰ )2), -CH2P(O)(R ²⁰ )(N(R ²⁰ )2), -C(O)R ²⁰ , -C(O)N(R ²¹ )(R ²² ), -CH2P(O)(N(R ²⁰ )2)2, or -P(O)(N(R ²⁰ )2)2; R ² is -OH, -OR ⁵ , -OCH ₂ P(O)(OR ²⁰ ) ₂ , -OCH ₂ P(O)(R ²⁰ )(N(R ²⁰ ) ₂ ), -OCH ₂ P(O)(R ²⁰ )(OR ²⁰ ), -OCH2P(O)(N(R ²⁰ )2)(OR ²⁰ ), -OCH2P(O)(N(R ²⁰ )2)2, -N(R ²¹ )(R ²² ), -N(R ²⁰ )C(O)R ²⁰ , -N(R ²⁰ )C(O)OR ²⁰ , -N(R ²⁰ )C(O)N(R ²¹ )(R ²¹ ), -N(R ²⁰ )S(O)2(R ²⁰ ), -NR ²⁰ S(O)2N(R ²¹ )(R ²² ), or -NR ²⁰ S(O)2O(R ²⁰ ); R ³ is hydrogen, halo, cyano, or C _1-6 haloalkyl; each R ⁴ is independently halo, cyano, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R ⁴ is independently optionally substituted with 1-5 R ¹⁴ ; L is a bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C1-6 heteroalkylene, -O-, -S-, -S(O)-, -S(O)2-, -NR ¹⁶ -, -C(O)NR ¹⁶ -, -NR ¹⁶ C(O)-, -C(O)-, -OC(O)-, -C(O)O-, -NR ¹⁶ S(O)-, -S(O)NR ¹⁶ -, -NR ¹⁶ S(O)NR ¹⁶ -, -NR ¹⁶ S(O) ₂ -, -S(O) ₂ NR ¹⁶ -, -NR ¹⁶ S(O) ₂ NR ¹⁶ -, -NR ¹⁶ C(O)NR ¹⁶ -, -OC(O)NR ¹⁶ -, or -NR ¹⁶ C(O)O-; wherein each C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, or C _1-6 heteroalkylene of L is independently optionally substituted with 1-5 R ¹⁴ ; each R ⁵ is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R ⁵ is independently optionally substituted with 1-5 R ¹⁵ ; each of R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently hydrogen, deuterium, C1-6 alkyl, or C1-6 haloalkyl; each R ¹⁴ and R ¹⁵ are independently hydroxy, halo, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, benzyl, heteroaryl, -N(R ¹⁶ )2, -C(O)R ¹⁶ , -C(O)OR ¹⁶ , -S-R ¹⁶ , S(O)R ¹⁶ , -NR ¹⁶ S(O)R ¹⁶ , -S(O)N(R ¹⁶ )2, -NR ¹⁶ S(O)N(R ¹⁶ )2, -S(O)2R ¹⁶ , -NR ¹⁶ S(O)2R ¹⁶ , -S(O)2N(R ¹⁶ )2, -NR ¹⁶ S(O)2N(R ¹⁶ )2, -NR ¹⁶ C(O)N(R ¹⁶ )2, -C(O)N(R ¹⁶ )2, -NR ¹⁶ C(O)R ¹⁶ , -OC(O)N(R ¹⁶ )2, or -NR ¹⁶ C(O)OR ¹⁶ ; each R ¹⁶ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 heteroalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 heteroalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R ¹⁶ is independently optionally substituted with 1-5 halo, cyano, -NO ₂ , oxo, -SF ₅ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-10 cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl; or two R ¹⁶ together with the atom to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted with 1-5 R ³⁰ ; each R ²⁰ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with 1-5 R ³⁰ ; or two R ²⁰ together with the atom to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted with 1-5 R ³⁰ ; each R ²¹ and R ²² is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C3-10 cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with 1-5 R ³⁰ groups; or R ²⁰ and R ²¹ together with the nitrogen to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted with 1-5 R ³⁰ ; or R ²¹ and R ²² together with the nitrogen to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted with 1-5 R ³⁰ ; each R ³⁰ is independently oxo, thioxo, hydroxy, halo, -NO2, -N3, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-6 haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C1-6 alkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-10 cycloalkyl), -O(C1-6 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH ₂ , -NH(C _1-6 alkyl), -NH(C _2-6 alkenyl), -NH(C _2-6 alkynyl), -NH(C _3-10 cycloalkyl), -NH(C _1-6 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C _1-6 alkyl) ₂ , -N(C _3-10 cycloalkyl) ₂ , -N(C _2-6 alkenyl) ₂ , -N(C _2-6 alkynyl) ₂ , -N(C _3-10 cycloalkyl) ₂ , -N(C _1-6 haloalkyl) ₂ , -N(aryl)2, -N(heteroaryl)2, -N(heterocyclyl)2, -N(C1-6 alkyl)(C3-10 cycloalkyl), -N(C1-6 alkyl)(C2-6 alkenyl), -N(C1-6 alkyl)(C2-6 alkynyl), -N(C1-6 alkyl)(C3-10 cycloalkyl), -N(C1-6 alkyl)(C1-6 haloalkyl), -N(C1-6 alkyl)(aryl), -N(C1-6 alkyl)(heteroaryl), -N(C1-6 alkyl)(heterocyclyl), -C(O)(C1-6 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-10 cycloalkyl), -C(O)(C1-6 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C _1-6 alkyl), -C(O)O(C _2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-10 cycloalkyl), -C(O)O(C1-6 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclyl), -C(O)NH2, -C(O)NH(C1-6 alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C _2-6 alkynyl), -C(O)NH(C _3-10 cycloalkyl), -C(O)NH(C _1-6 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), -C(O)N(C _1-6 alkyl) ₂ , -C(O)N(C _3-10 cycloalkyl) ₂ , -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-10 cycloalkyl)2, -C(O)N(C1-6 haloalkyl)2, -C(O)N(aryl)2, -C(O)N(heteroaryl)2, -C(O)N(heterocyclyl)2, -NHC(O)(C1-6 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-10 cycloalkyl), -NHC(O)(C1-6 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C1-6 alkyl), -NHC(O)O(C _2-6 alkenyl), -NHC(O)O(C _2-6 alkynyl), -NHC(O)O(C _3-10 cycloalkyl), -NHC(O)O(C _1-6 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C1-6 alkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-10 cycloalkyl), -NHC(O)NH(C1-6 haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C1-6 alkyl), -S(C2-6 alkenyl), -S(C _2-6 alkynyl), -S(C _3-10 cycloalkyl), -S(C _1-6 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclyl), -NHS(O)(C _1-6 alkyl), -N(C _1-6 alkyl)(S(O)(C _1-6 alkyl), -S(O)N(C _1-6 alkyl) ₂ , -S(O)(C _1-6 alkyl), -S(O)(NH)(C _1-6 alkyl), -S(O)(C _2-6 alkenyl), -S(O)(C _2-6 alkynyl), -S(O)(C _3-10 cycloalkyl), -S(O)(C1-6 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O)2(C1-6 alkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-10 cycloalkyl), -S(O)2(C1-6 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C1-6 alkyl), or -S(O)2N(C1-6 alkyl)2; wherein each alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R ³⁰ is optionally substituted with one to four substituents independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, -OH, -NH ₂ , -NH(C _1-6 alkyl), -NH(C _3-10 cycloalkyl), -NH(C _1-6 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C1-6 alkyl)2, -N(C3-10 cycloalkyl)2, -NHC(O)(C3-10 cycloalkyl), -NHC(O)(C1-6 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C1-6 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-10 cycloalkyl), -NHC(O)O(C1-6 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C _1-6 alkyl), -S(O)(NH)(C _1-6 alkyl), S(O) ₂ (C _1-6 alkyl), -S(O) ₂ (C _3-10 cycloalkyl), -S(O) ₂ (C _1-6 haloalkyl), -S(O) ₂ (aryl), -S(O) ₂ (heteroaryl), -S(O) ₂ (heterocyclyl), -S(O) ₂ NH(C _1-6 alkyl), -S(O)2N(C1-6 alkyl)2, -O(C1-6 alkyl), -O(C3-10 cycloalkyl), -O(C1-6 haloalkyl), -O(aryl), -O(heteroaryl), or -O(heterocyclyl). [0008] This disclosure also provides pharmaceutical compositions comprising one or more compounds of formula I and a pharmaceutically acceptable excipient. [0009] This disclosure is also directed to methods for inhibiting the activity of histone lysine demethylase and treating, pretreating, or delaying onset of a condition associated with histone lysine demethylase. In one aspect, provided is a method of treating, pretreating, or delaying onset of a condition associated with undesirable cellular proliferation. DETAILED DESCRIPTION [0010] Before the present compounds and methods are described, it is to be understood that the disclosure is not limited to the methodologies, protocols, cell lines, assays, and reagents described, as these may vary. It is also to be understood that the terminology used herein is intended to describe embodiments of the present disclosure, and is in no way intended to limit the scope of the present disclosure as set forth in the appended claims. 1. Definitions [0011] It must be noted that as used herein, and in the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. [0012] Unless defined otherwise, all technical, and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods, devices, and materials are now described. All publications cited herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing the methodologies, reagents, and tools reported in the publications that might be used in connection with the disclosure. [0013] The practice of the present disclosure will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, cell biology, genetics, immunology, and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. (See, e.g., Gennaro, A.R., ed. (1990) Remington’s Pharmaceutical Sciences, 18 ^th ed., Mack Publishing Co.; Colowick, S. et al., eds., Methods In Enzymology, Academic Press, Inc.; D.M. Weir, and C.C. Blackwell, eds. (1986) Handbook of Experimental Immunology, Vols. I-IV, Blackwell Scientific Publications; Maniatis, T. et al., eds. (1989) Molecular Cloning: A Laboratory Manual, 2 ^nd edition, Vols. I-III, Cold Spring Harbor Laboratory Press; Ausubel, F. M. et al., eds. (1999) Short Protocols in Molecular Biology, 4 ^th edition, John Wiley & Sons; Ream et al., eds. (1998) Molecular Biology Techniques: An Intensive Laboratory Course, Academic Press; Newton & Graham eds. (1997) PCR (Introduction to Biotechniques Series), 2nd ed., Springer Verlag. [0014] The terms “disorders,” “diseases,” and “conditions” are used inclusively and refer to any condition deviating from normal. [0015] The term “alkyl” refers to saturated monovalent straight or branched chain hydrocarbyl groups having from 1 to 10 carbon atoms, from 1 to 6 carbon atoms, or 1 to 3 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, and the like. [0016] The term “alkoxy” refers to -O-alkyl, where alkyl is as defined above. [0017] The term “alkenyl” refers to a vinyl unsaturated monovalent hydrocarbyl group having from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms, and having at least 1, or from 1 to 2 sites of vinyl (>C=C<) unsaturation. Such groups are exemplified by vinyl (ethen-1-yl), allyl, but-3-enyl and the like. [0018] The term “alkynyl” refers to an acetylinic unsaturated monovalent hydrocarbyl groups having from 2 to 6 carbon atoms, or 2 to 3 carbon atoms, and having at least 1, or from 1 to 2 sites of acetylenic (-C≡C-) unsaturation. This group is exemplified by ethyn-1-yl, propyn-1-yl, propyn-2-yl, and the like. [0019] The terms “alkylene,” “alkenylene,” and “alkynylene” refer to divalent alkyl, alkenyl, and alkynyl groups, respectively, where each is as defined herein. [0020] The term “aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)- one-7-yl, benzo[1,3]-dioxol-5-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 2,3-dihydro-benzofuran-5-yl, dibenzofuran-4-yl, and the like) provided that the point of attachment is the aryl group. [0021] The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including, by way of example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. [0022] The term “cycloalkenyl” refers to cyclic alkenyl (but not aromatic) groups of from 5 to 10 carbon atoms having single or multiple cyclic rings and having at least one site of vinyl (>C=C<) unsaturation within the ring including, by way of example, cyclopentenyl, cyclooctenyl, and the like. [0023] The term “halo” or “halogen” refers to fluoro, chloro, bromo, and iodo, and in certain embodiments, is fluoro, chloro or bromo. [0024] The term “heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms, or from 1 to 10 carbon atoms, and 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl, furyl, or thienyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). The nitrogen and/or sulfur ring atoms can optionally be oxidized to provide for the N-oxide or the sulfoxide, and sulfone derivatives. Exemplary heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, thienyl, and furyl. [0025] The term “haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like. [0026] The term “haloalkoxy” refers to -O-haloalkyl, where haloalkyl is as defined above. [0027] The term “heteroalkyl” refers to a C _1-6 alkyl group in which one or two of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NH-, -O-, -S-, -S(O)-, -S(O) ₂ -, and the like. [0028] The term “heteroalkylene” refers to a linear, divalent C _1-6 alkyl group (i.e., C _1-6 alkylene) in which one or two of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NH-, -O-, -S-, -S(O)-, -S(O)2-, and the like. [0029] The term “heterocyclyl” or “heterocyclic” refers to a saturated or unsaturated (but not aromatic) group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms, and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more of the rings can be aryl or heteroaryl provided that the point of attachment is at the heterocycle. The nitrogen and/or sulfur ring atoms can optionally be oxidized to provide for the N-oxide or the sulfoxide, and sulfone derivatives. [0030] The term “substituted heterocyclyl” or “substituted heterocyclic” refers to heterocycle groups that are substituted with from 1 to 3 of the same substituents as defined for substituted cycloalkyl. [0031] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7- tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like. [0032] The term “oxo” refers to the atom (=O) or (-O-). [0033] The term “amino acid” refers to any of the naturally occurring amino acids, as well as synthetic analogs (e.g., D-stereoisomers of the naturally occurring amino acids, such as D-threonine), and derivatives thereof. α-Amino acids comprise a carbon atom to which is bonded an amino group, a carboxyl group, a hydrogen atom, and a distinctive group referred to as a “side chain.” The side chains of naturally occurring amino acids are well known in the art, and include, for example, hydrogen (e.g., as in glycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine, proline), substituted alkyl (e.g., as in threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine), arylalkyl (e.g., as in phenylalanine, and tryptophan), substituted arylalkyl (e.g., as in tyrosine), and heteroarylalkyl (e.g., as in histidine). Unnatural amino acids are also known in the art, as set forth in, for example, Williams, ed. (1989) Synthesis of Optically Active α-Amino Acids, Pergamon Press; Evans et al. (1990) J. Amer. Chem. Soc.112:4011-4030; Pu et al. (1991) J. Amer. Chem. Soc.56:1280-1283; Williams et al. (1991) J. Amer. Chem. Soc.113:9276-9286; and all references cited therein. [0034] The term “pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt of a compound, which salt can be derived from a variety of organic, and inorganic counter ions well known in the art, and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, a salt of an organic or inorganic acid, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. [0035] The term “excipient” as used herein means an inert or inactive substance used in the production of pharmaceutical products or other tablets, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, parenteral, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. [0036] It is understood that the substituents as defined herein are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups or a hydroxy group attached to an ethenylic or acetylenic carbon atom). Such impermissible substitution patterns are well known to the skilled artisan. 2. Compounds [0037] Provided herein are compounds of Formula I: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein: n is 0, 1, 2, 3, or 4; R ¹ is hydrogen, -P(O)(OR ²⁰ ) ₂ , -CH ₂ P(O)(OR ²⁰ ) ₂ , -P(O)(R ²⁰ )(OR ²⁰ ), -CH ₂ P(O)(R ²⁰ )(OR ²⁰ ), -P(O)(N(R ²⁰ )2)(OR ²⁰ ), -CH2P(O)(N(R ²⁰ )2)(OR ²⁰ ), -P(O)(R ²⁰ )(N(R ²⁰ )2), -CH2P(O)(R ²⁰ )(N(R ²⁰ )2), -C(O)R ²⁰ , -C(O)N(R ²¹ )(R ²² ), -CH2P(O)(N(R ²⁰ )2)2, or -P(O)(N(R ²⁰ )2)2; R ² is -OH, -OR ⁵ , -OCH2P(O)(OR ²⁰ )2, -OCH2P(O)(R ²⁰ )(N(R ²⁰ )2), -OCH2P(O)(R ²⁰ )(OR ²⁰ ), -OCH2P(O)(N(R ²⁰ )2)(OR ²⁰ ), -OCH2P(O)(N(R ²⁰ )2)2, -N(R ²¹ )(R ²² ), -N(R ²⁰ )C(O)R ²⁰ , -N(R ²⁰ )C(O)OR ²⁰ , -N(R ²⁰ )C(O)N(R ²¹ )(R ²¹ ), -N(R ²⁰ )S(O) ₂ (R ²⁰ ), -NR ²⁰ S(O) ₂ N(R ²¹ )(R ²² ), or -NR ²⁰ S(O) ₂ O(R ²⁰ ); R ³ is hydrogen, halo, cyano, or C1-6 haloalkyl; each R ⁴ is independently halo, cyano, -L-C _1-6 alkyl, -L-C _2-6 alkenyl, -L-C _2-6 alkynyl, -L-C _1-6 haloalkyl, -L-C _3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R ⁴ is independently optionally substituted with 1-5 R ¹⁴ ; L is a bond, C _1-6 alkylene, C _2-6 alkenylene, C _2-6 alkynylene, -C _1-6 heteroalkylene, -O-, -S-, -S(O)-, -S(O)2-, -NR ¹⁶ -, -C(O)NR ¹⁶ -, -NR ¹⁶ C(O)-, -C(O)-, -OC(O)-, -C(O)O-, -NR ¹⁶ S(O)-, -S(O)NR ¹⁶ -, -NR ¹⁶ S(O)NR ¹⁶ -, -NR ¹⁶ S(O)2-, -S(O)2NR ¹⁶ -, -NR ¹⁶ S(O)2NR ¹⁶ -, -NR ¹⁶ C(O)NR ¹⁶ -, -OC(O)NR ¹⁶ -, or -NR ¹⁶ C(O)O-; wherein each C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or -C1-6 heteroalkylene of L is independently optionally substituted with 1-5 R ¹⁴ ; each R ⁵ is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R ⁵ is independently optionally substituted with 1-5 R ¹⁵ ; each of R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently hydrogen, deuterium, C _1-6 alkyl, or C _1-6 haloalkyl; each R ¹⁴ and R ¹⁵ are independently hydroxy, halo, cyano, -NO2, C1-6 alkyl, C2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-10 cycloalkyl, heterocyclyl, aryl, benzyl, heteroaryl, -N(R ¹⁶ ) ₂ , -C(O)R ¹⁶ , -C(O)OR ¹⁶ , -S-R ¹⁶ , S(O)R ¹⁶ , -NR ¹⁶ S(O)R ¹⁶ , -S(O)N(R ¹⁶ ) ₂ , -NR ¹⁶ S(O)N(R ¹⁶ ) ₂ , -S(O) ₂ R ¹⁶ , -NR ¹⁶ S(O) ₂ R ¹⁶ , -S(O) ₂ N(R ¹⁶ ) ₂ , -NR ¹⁶ S(O) ₂ N(R ¹⁶ ) ₂ , -NR ¹⁶ C(O)N(R ¹⁶ ) ₂ , -C(O)N(R ¹⁶ )2, -NR ¹⁶ C(O)R ¹⁶ , -OC(O)N(R ¹⁶ )2, or -NR ¹⁶ C(O)OR ¹⁶ ; each R ¹⁶ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R ¹⁶ is independently optionally substituted with 1-5 halo, cyano, -NO2, oxo, -SF5, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, aryl, benzyl, heteroaryl, or heterocyclyl; or two R ¹⁶ together with the atom to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted with 1-5 R ³⁰ ; each R ²⁰ is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with 1-5 R ³⁰ ; or two R ²⁰ together with the atom to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted with 1-5 R ³⁰ ; each R ²¹ and R ²² is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is independently optionally substituted with 1-5 R ³⁰ groups; or R ²⁰ and R ²¹ together with the nitrogen to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted with 1-5 R ³⁰ ; or R ²¹ and R ²² together with the nitrogen to which they are attached form a heterocyclyl; wherein said heterocyclyl is independently optionally substituted with 1-5 R ³⁰ ; each R ³⁰ is independently oxo, thioxo, hydroxy, halo, -NO ₂ , -N ₃ , cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, C _1-6 haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C _1-6 alkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-10 cycloalkyl), -O(C1-6 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH2, -NH(C1-6 alkyl), -NH(C2-6 alkenyl), -NH(C2-6 alkynyl), -NH(C3-10 cycloalkyl), -NH(C1-6 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C1-6 alkyl)2, -N(C3-10 cycloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-10 cycloalkyl)2, -N(C1-6 haloalkyl)2, -N(aryl) ₂ , -N(heteroaryl) ₂ , -N(heterocyclyl) ₂ , -N(C _1-6 alkyl)(C _3-10 cycloalkyl), -N(C _1-6 alkyl)(C _2-6 alkenyl), -N(C _1-6 alkyl)(C _2-6 alkynyl), -N(C _1-6 alkyl)(C _3-10 cycloalkyl), -N(C _1-6 alkyl)(C _1-6 haloalkyl), -N(C _1-6 alkyl)(aryl), -N(C _1-6 alkyl)(heteroaryl), -N(C _1-6 alkyl)(heterocyclyl), -C(O)(C1-6 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-10 cycloalkyl), -C(O)(C1-6 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C1-6 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-10 cycloalkyl), -C(O)O(C1-6 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclyl), -C(O)NH ₂ , -C(O)NH(C _1-6 alkyl), -C(O)NH(C _2-6 alkenyl), -C(O)NH(C _2-6 alkynyl), -C(O)NH(C _3-10 cycloalkyl), -C(O)NH(C _1-6 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), -C(O)N(C1-6 alkyl)2, -C(O)N(C3-10 cycloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-10 cycloalkyl)2, -C(O)N(C1-6 haloalkyl)2, -C(O)N(aryl)2, -C(O)N(heteroaryl)2, -C(O)N(heterocyclyl)2, -NHC(O)(C1-6 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3-10 cycloalkyl), -NHC(O)(C _1-6 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C _1-6 alkyl), -NHC(O)O(C _2-6 alkenyl), -NHC(O)O(C _2-6 alkynyl), -NHC(O)O(C _3-10 cycloalkyl), -NHC(O)O(C1-6 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C1-6 alkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-10 cycloalkyl), -NHC(O)NH(C1-6 haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C1-6 alkyl), -S(C2-6 alkenyl), -S(C _2-6 alkynyl), -S(C _3-10 cycloalkyl), -S(C _1-6 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclyl), -NHS(O)(C _1-6 alkyl), -N(C _1-6 alkyl)(S(O)(C _1-6 alkyl), -S(O)N(C _1-6 alkyl) ₂ , -S(O)(C _1-6 alkyl), -S(O)(NH)(C _1-6 alkyl), -S(O)(C _2-6 alkenyl), -S(O)(C _2-6 alkynyl), -S(O)(C _3-10 cycloalkyl), -S(O)(C1-6 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O)2(C1-6 alkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-10 cycloalkyl), -S(O)2(C1-6 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C1-6 alkyl), or -S(O)2N(C1-6 alkyl)2; wherein each alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R ³⁰ is optionally substituted with one to four substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, -OH, -NH2, -NH(C _1-6 alkyl), -NH(C _3-10 cycloalkyl), -NH(C _1-6 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C _1-6 alkyl) ₂ , -N(C _3-10 cycloalkyl) ₂ , -NHC(O)(C _3-10 cycloalkyl), -NHC(O)(C1-6 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C1-6 alkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-10 cycloalkyl), -NHC(O)O(C1-6 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C1-6 alkyl), -S(O)(NH)(C1-6 alkyl), S(O)2(C1-6 alkyl), -S(O)2(C3-10 cycloalkyl), -S(O) ₂ (C _1-6 haloalkyl), -S(O) ₂ (aryl), -S(O) ₂ (heteroaryl), -S(O) ₂ (heterocyclyl), -S(O) ₂ NH(C _1-6 alkyl), -S(O) ₂ N(C _1-6 alkyl) _2, -O(C _1-6 alkyl), -O(C _3-10 cycloalkyl), -O(C _1-6 haloalkyl), -O(aryl), -O(heteroaryl), or -O(heterocyclyl). [0038] In certain embodiments, n is 0 or 1. In certain embodiments, n is 1. In certain embodiments, n is 0. [0039] In certain embodiments, provided herein is a compound of Formula IA: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0040] In certain embodiments, provided herein is a compound of Formula IB: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0041] In certain embodiments, provided herein is a compound of Formula IC: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0042] In certain embodiments, provided herein is a compound of Formula ID: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0043] In certain embodiments, R ³ is halo, cyano, or C1-6 haloalkyl. In certain embodiments, R ³ is hydrogen, cyano, or C1-6 haloalkyl. [0044] In certain embodiments, provided herein is a compound of Formula II: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ¹ , R ² , R ⁴ , n, R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0045] In certain embodiments, n is 0 or 1. In certain embodiments, n is 1. In certain embodiments, n is 0. [0046] In certain embodiments, provided herein is a compound of Formula IIA: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ¹ , R ² , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0047] In certain embodiments, provided herein is a compound of Formula IIB: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ¹ , R ² , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0048] In certain embodiments, provided herein is a compound of Formula IIC: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ¹ , R ² , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0049] In certain embodiments, provided herein is a compound of Formula IID: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ¹ , R ² , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0050] In certain embodiments, R ¹ is hydrogen. [0051] In certain embodiments, provided herein is a compound of Formula IIIA: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ² , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0052] In certain embodiments, provided herein is a compound of Formula IIIB: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ² , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0053] In certain embodiments, provided herein is a compound of Formula IIIC: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ² , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0054] In certain embodiments, provided herein is a compound of Formula IIID: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ² , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0055] In certain embodiments, R ² is -OH, -OR ⁵ , -OCH2P(O)(OR ²⁰ )2, -OCH2P(O)(R ²⁰ )(N(R ²⁰ )2), -OCH2P(O)(R ²⁰ )(OR ²⁰ ), -OCH2P(O)(N(R ²⁰ )2)(OR ²⁰ ), or -OCH2P(O)(N(R ²⁰ )2)2. In certain embodiments, R ² is -N(R ²¹ )(R ²² ), -N(R ²⁰ )C(O)R ²⁰ , -N(R ²⁰ )C(O)OR ²⁰ , -N(R ²⁰ )C(O)N(R ²¹ )(R ²¹ ), -N(R ²⁰ )S(O)2(R ²⁰ ), -NR ²⁰ S(O) ₂ N(R ²¹ )(R ²² ), or -NR ²⁰ S(O) ₂ O(R ²⁰ ). [0056] In certain embodiments, R ² is -OH, -OR ⁵ , or -N(R ²¹ )(R ²² ). In certain embodiments, R ² is -OH or -OR ⁵ . In certain embodiments, R ² is -OH. In certain embodiments, R ² is -OR ⁵ or -N(R ²¹ )(R ²² ). In certain embodiments, R ² is -OR ⁵ . In certain embodiments, R ² is -N(R ²¹ )(R ²² ). [0057] In certain embodiments, provided herein is a compound of Formula IVA: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0058] In certain embodiments, provided herein is a compound of Formula IVB: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0059] In certain embodiments, provided herein is a compound of Formula IVC: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0060] In certain embodiments, provided herein is a compound of Formula IVD: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are independently as defined herein. [0061] In certain embodiments, R ⁶ is hydrogen. In certain embodiments, R ⁷ is hydrogen. In certain embodiments, R ⁸ is hydrogen. In certain embodiments, R ⁹ is hydrogen. In certain embodiments, R ⁶ and R ⁷ are hydrogen. In certain embodiments, R ⁸ and R ⁹ are hydrogen. In certain embodiments, R ⁶ , R ⁷ , R ⁸ , and R ⁹ are hydrogen. [0062] In certain embodiments, provided herein is a compound of Formula VA: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ² and R ⁴ are independently as defined herein. [0063] In certain embodiments, provided herein is a compound of Formula VB: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ² and R ⁴ are independently as defined herein. [0064] In certain embodiments, provided herein is a compound of Formula VC: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ² and R ⁴ are independently as defined herein. [0065] In certain embodiments, provided herein is a compound of Formula VD: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, where each of R ² and R ⁴ are independently as defined herein. [0066] In certain embodiments, R ⁴ is cyano, -L-C _3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl of R ⁴ is optionally substituted with 1-3 R ¹⁴ . [0067] In certain embodiments, R ⁴ is cyano, -L-cycloalkyl, -L-aryl, or -L-heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl of R ⁴ is optionally substituted with 1-3 R ¹⁴ . [0068] In certain embodiments, R ⁴ is cyano or -L-aryl; wherein the aryl of R ⁴ is optionally substituted with 1-3 R ¹⁴ . [0069] In certain embodiments, R ⁴ is cyano. In certain embodiments, R ⁴ is -L-cycloalkyl optionally substituted with 1-3 R ¹⁴ . In certain embodiments, R ⁴ is -L-aryl optionally substituted with 1-3 R ¹⁴ . In certain embodiments, R ⁴ is -L-heteroaryl optionally substituted with 1-3 R ¹⁴ . In certain embodiments, L is a bond, C1-2 alkylene, C2 alkynylene, -O-, -S-, or -S(O)2-. [0070] In certain embodiments, L is a bond, C _1-2 alkylene, C ₂ alkynylene, -O-, -S-, or -S(O) ₂ -. [0071] In certain embodiments, L is a bond. In certain embodiments, L is a C1-2 alkylene. In certain embodiments, L is C2 alkynylene. In certain embodiments, L is -O-, -S-, or -S(O)2-. In certain embodiments, L is -O-. In certain embodiments, L is -S-. In certain embodiments, L is -S(O) ₂ -. [0072] In certain embodiments, R ⁴ is cyano, -L-cycloalkyl, -L-aryl, or -L-heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl of R ⁴ is optionally substituted with 1-3 R ¹⁴ ; and L is a bond, C1-2 alkylene, C2 alkynylene, -O-, -S-, or -S(O)2-. [0073] In certain embodiments, R ⁴ is cycloalkyl optionally substituted with 1-3 R ¹⁴ . In certain embodiments, R ⁴ is aryl optionally substituted with 1-3 R ¹⁴ . In certain embodiments, R ⁴ is heteroaryl optionally substituted with 1-3 R ¹⁴ . [0074] In certain embodiments, each R ¹⁴ is independently selected from the group consisting of halo, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and aryl. [0075] In certain embodiments, R ⁴ is cyano, -L-cycloalkyl, -L-aryl, or -L-heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl of R ⁴ is optionally substituted with 1-3 R ¹⁴ independently selected from the group consisting of halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy; and L is a bond, C _1-2 alkylene, C ₂ alkynylene, -O-, -S-, or -S(O) ₂ -. [0076] In certain embodiments, R ⁴ is cyano or -L-aryl; wherein the aryl of R ⁴ is optionally substituted with 1-3 R ¹⁴ ; and L is a bond, C1-2 alkylene, C2 alkynylene, -O-, -S-, or -S(O)2-. [0077] In certain embodiments, each R ¹⁴ is independently selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy. [0078] In certain embodiments, R ⁴ is cyano or -L-aryl; wherein the aryl of R ⁴ is optionally substituted with 1-3 R ¹⁴ independently selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; and L is a bond, C1-2 alkylene, C2 alkynylene, -O-, -S-, or -S(O)2-. [0079] In certain embodiments, R ⁴ is cyano, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4- isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3- trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, naphthalen-1-yl, 4-fluoro-3-methylphenyl, 2-fluoro- 3-methylphenyl, 2-fluoro-5-methylphenyl, 2-p-tolyl-ethyl, 2-chloro-phenylethynyl, 2-(2-chloro-phenyl)- ethyl, 2-fluoro-4-methoxy-phenyl, 2,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2-fluoro-3-methoxyphenyl, 1,1'-biphenyl]-2-yl, 1,1'-biphenyl]-3-yl, 1,1'-biphenyl]-4-yl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2- chloro-4-(trifluoromethoxy)phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methoxyphenyl, 2-fluoro-5- methoxyphenyl, 2-fluoro-5-methylphenyl, 2-methyl-4-(trifluoromethoxy)phenyl, 3,4-dimethylphenyl, 3,5-difluorophenyl, 3,5-difluoropyridin-4-yl, 3-cyanophenyl, 3-fluoropyridin-4-yl, 4-cyanophenyl, 4- fluoro-3-methylphenyl, 6-(trifluoromethoxy)pyridin-3-yl, or cyclopropyl. [0080] In certain embodiments, R ⁴ is cyano, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4- isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3- trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, naphthalen-1-yl, 4-fluoro-3-methylphenyl, 2-fluoro- 3-methylphenyl, 2-fluoro-5-methylphenyl, 2-p-tolyl-ethyl, 2-chloro-phenylethynyl, 2-(2-chloro-phenyl)- ethyl, 2-fluoro-4-methoxy-phenyl, 2,4-difluoro-phenyl, or 2,5-difluoro-phenyl. [0081] In certain embodiments, R ¹ is hydrogen; R ² is -OH; R ³ is hydrogen, cyano, or C1-6 haloalkyl; and each of R ⁶ , R ⁷ , R ⁸ , and R ⁹ is hydrogen. [0082] In certain embodiments, R ¹ is hydrogen; R ² is -OH; R ³ is hydrogen, cyano, or C1-6 haloalkyl; each of R ⁶ , R ⁷ , R ⁸ , and R ⁹ is hydrogen; R ⁴ is cyano, -L-cycloalkyl, -L-aryl, or -L-heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl of R ⁴ is optionally substituted with 1-3 R ¹⁴ independently selected from the group consisting of halo, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C1-6 haloalkoxy; and L is a bond, C1-2 alkylene, C2 alkynylene, -O-, -S-, or -S(O)2-. In certain embodiments, each R ¹⁴ is independently selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy. [0083] In certain embodiments, R ¹ is hydrogen; R ² is -OH; R ³ is hydrogen, cyano, or C _1-6 haloalkyl; each of R ⁶ , R ⁷ , R ⁸ , and R ⁹ is hydrogen; and R ⁴ is cyano, phenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4- isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3- trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, naphthalen-1-yl, 4-fluoro-3-methylphenyl, 2-fluoro- 3-methylphenyl, 2-fluoro-5-methylphenyl, 2-p-tolyl-ethyl, 2-chloro-phenylethynyl, 2-(2-chloro-phenyl)- ethyl, 2-fluoro-4-methoxy-phenyl, 2,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2-fluoro-3-methoxyphenyl, 1,1'-biphenyl]-2-yl, 1,1'-biphenyl]-3-yl, 1,1'-biphenyl]-4-yl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2- chloro-4-(trifluoromethoxy)phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methoxyphenyl, 2-fluoro-5- methoxyphenyl, 2-fluoro-5-methylphenyl, 2-methyl-4-(trifluoromethoxy)phenyl, 3,4-dimethylphenyl, 3,5-difluorophenyl, 3,5-difluoropyridin-4-yl, 3-cyanophenyl, 3-fluoropyridin-4-yl, 4-cyanophenyl, 4- fluoro-3-methylphenyl, 6-(trifluoromethoxy)pyridin-3-yl, or cyclopropyl. [0084] In certain embodiments, R ¹ is hydrogen; R ² is -OH; R ³ is hydrogen, cyano, or C _1-6 haloalkyl; each of R ⁶ , R ⁷ , R ⁸ , and R ⁹ is hydrogen; and R ⁴ is cyano, phenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4- isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethoxyphenyl, 3- trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, naphthalen-1-yl, 4-fluoro-3-methylphenyl, 2-fluoro- 3-methylphenyl, 2-fluoro-5-methylphenyl, 2-p-tolyl-ethyl, 2-chloro-phenylethynyl, 2-(2-chloro-phenyl)- ethyl, 2-fluoro-4-methoxy-phenyl, 2,4-difluoro-phenyl, or 2,5-difluoro-phenyl. [0085] In certain embodiments, provided is a compound selected from Table 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof: TABLE 1

3. Compositions and Methods [0086] This disclosure provides compounds, compositions and methods of inhibiting the activity of a histone lysine demethylase-5 (KDM5) enzyme, as well as compounds and compositions for the manufacture of a medicament, for use in treating various conditions or disorders as described herein. The compound or composition can be used in methods to treat, pretreat, or delay progression or onset of a condition associated with a KDM5, particularly KDM5B. In certain embodiments, the composition is a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and a therapeutically effective amount of one or more compounds of formula I. In the present disclosure, each of the various embodiments above also relate to a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug of the compound (e.g., a compound of formula I). [0087] In certain embodiments, provided is a method of inhibiting the activity of a KDM5, particularly KDM5B, comprising bringing into contact the KDM5 and an inhibitory-effective amount of a compound or pharmaceutical composition disclosed herein. [0088] In certain embodiments, provided is a method of treating, pretreating, or delaying onset of a condition associated with KDM5, particularly KDM5B, the method comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein. [0089] In certain embodiments, provided is a method of treating, pretreating, or delaying onset of a condition associated with undesirable cellular proliferation, the method comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein. [0090] In certain embodiments, the condition is cancer. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangio sarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B- cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T- lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM), myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrinetumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva). [0091] In certain embodiments, the condition is a neoplasm, a tumor, or leukemia. In certain embodiments, the condition is histocytoma, glioma, astrocytoma, osteoma, lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carcinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, or melanoma. In certain embodiments, the cancer is embryonic carcinoma, teratoma, seminoma, germ cell tumors, prostate cancer, breast cancer, stomach cancer, gastrointestinal cancer, neuroblastoma, choriocarcinoma, yolk sac tumors, ovarian cancer, endometrial cancer, cervical cancer, retinoblastoma, kidney cancer, liver cancer, gastric cancer, brain cancer, medulloblastoma, medulloepithelioma, glioma, glioblastoma, multiple myeloma, lung cancer, bronchial cancer, mesothelioma, skin cancer, colon and rectal cancer, bladder cancer, pancreatic cancer, lip and oral cancer, laryngeal and pharyngeal cancer, melanoma, pituitary cancer, penile cancer, parathyroid cancer, thyroid cancer, pheochromocytoma and paraganglioma, thymoma and thymic carcinoma, leukemia, lymphoma, plasma cell neoplasms, myeloproliferative disorders, islet cell tumor, small intestine cancer, transitional cell cancer, pleuropulmonary blastoma, gestational trophoblastic cancer, esophageal cancer, central nervous system cancer, head and neck cancer, endocrine cancer, cardiovascular cancer, rhabdomyosarcoma, soft tissue carcinomas, carcinomas of bone, cartilage, fat, vascular, neural, and hematopoietic tissues or an AIDS-related cancer. [0092] In certain embodiments, provided is a method of treating, pretreating, or delaying onset of a hematologic cancer, in particular a B-cell acute lymphocytic leukemia (B-ALL) or B-cell lymphoma, comprising administering a therapeutically effective amount of a compound or composition disclosed herein to a patient in need thereof. In certain embodiments, provided is a method of treating, pretreating, or delaying onset of a lung cancer, in particular a non-small cell lung cancer (NSCLC), comprising administering a therapeutically effective amount of a compound or composition disclosed herein to a patient in need thereof. In certain embodiments, provided is a method of treating, pretreating, or delaying onset of a breast cancer, in particular an estrogen receptor positive (ER+) breast cancer, comprising administering a therapeutically effective amount of a compound or composition disclosed herein to a patient in need thereof. [0093] In certain embodiments, provided is a method of preventing or treating a viral infection, the method comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein. [0094] In certain embodiments, the patient has a viral infection or is at risk for viral infection but is free from cancer. The viral infection may be due to a nuclear DNA viral infection such as a herpes viral infection. The herpesvirus may be, e.g., herpes simplex virus (HSV) type 1, herpes simplex virus type 2, varicella zoster virus (VZV), or cytomegalovirus (CMV). The herpesvirus may be Epstein-Barr virus (EBV), Kaposi's Sarcoma-Associated herpesvirus, herpes simiae virus, herpes lymphotropic virus, human herpesvirus-7 (HHMV-7), or human herpesvirus-8 (HHMV-8). Viral infections especially pose a threat to individuals that have suppressed (immunosuppressed) or otherwise compromised (immunocompromised) immune systems. For example, individuals with HIV/AIDS, diabetes, or cancer often have reduced ability to ward off additional and/or opportunistic viral infections due to immune systems that are adversely affected by the underlying, primary infection or condition. Therefore, preventing or treating viral infection or re-activation is especially important for these individuals. [0095] In certain embodiments, the viral infection involves reactivation of a virus after latency in the patient. In certain embodiments, the patient has undergone, is undergoing, or will undergo, immunosuppression. In certain embodiments, the method prevents or treats viral-induced encephalitis, viral-induced keratitis, or reduces the severity of infection. In certain embodiments, the patient is an immunocompromised mammal. [0096] In certain embodiments, provided is a method for treating a hepatitis B virus (HBV) infection, comprising administering a therapeutically effective amount of a compound or composition disclosed herein to a patient in need thereof. In certain embodiments, provided is a method for treating a hepatocellular carcinoma derived from persistent HBV or HCV infection, comprising administering a therapeutically effective amount of a compound or composition disclosed herein to a patient in need thereof. [0097] In certain embodiments, the condition is cardiovascular disease. In certain embodiments, the cardiovascular disease is heart disease. In certain embodiments, the cardiovascular disease is coronary heart disease. In certain embodiments, the cardiovascular disease is stroke or cerebrovascular disease. In certain embodiments, the cardiovascular disease is a congenital heart defect. In certain embodiments, the cardiovascular disease is peripheral artery disease. In certain embodiments, the cardiovascular disease is heart disease associated with atherosclerosis. In certain embodiments, the cardiovascular disease is ischemic heart disease. In certain embodiments, the cardiovascular disease is hypertensive heart disease. In certain embodiments, the cardiovascular disease is cardiac arrhythmia. In certain embodiments, the cardiovascular disease is heart failure or congenital heart disease. In certain embodiments, the cardiovascular disease is inflammatory heart disease. In certain embodiments, the cardiovascular disease is cardiomyopathy. [0098] In certain embodiments, the compound is administered in combination with one or more additional pharmaceutical agents described herein. The additional pharmaceutical agent may be an anti- proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. The additional pharmaceutical agent may also be a kinase inhibitor. In certain embodiments, the additional pharmaceutical agent is an inhibitor of histone lysine demethylase. In certain embodiments, the additional pharmaceutical agent includes an anti-cancer agent, anti-inflammatory agent, steroids, immunosuppressant, radiation therapy, or other agents. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is a non-selective inhibitor of a histone demethylase. In certain embodiments, the additional pharmaceutical agent is an immunotherapy agent. In certain embodiments, the additional pharmaceutical agent is an immune checkpoint inhibitor. In certain embodiments, the anti-cancer agent is a chemotherapeutic. In certain embodiments, the immunotherapy agent is a PD1 inhibitor. In certain embodiments, the immunotherapy agent is a PDL1 inhibitor. In certain embodiments, the additional pharmaceutical agent is a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a BRCA1 inhibitor, BRCA2 inhibitor, HER1 inhibitor, HER2 inhibitor, a CDK9 inhibitor, a Jumonji histone demethylase inhibitor, or a DNA damage inducer. In certain embodiments, the additional pharmaceutical agent is etoposide, obatoclax, navitoclax, JQ1, 4-(((5’- chloro-2’-(((lR,4R)-4- (((R)-l-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4’-b ipyridin]-6- yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile, JIB04, or cisplatin. Exemplary chemotherapeutic agents include alkylating agents such as nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates, nitrosoureas, and triazenes; antimetabolites such as folic acid analogs, pyrimidine analogs, in particular fluorouracil and cytosine arabinoside, and purine analogs; natural products such as vinca alkaloids epi-podophyllotoxins, antibiotics, enzymes, and biological response modifiers; and miscellaneous products such as platinum coordination complexes, anthracenedione, substituted urea such as hydroxyurea, methyl hydrazine derivatives, and adrenocorticoid suppressant. Exemplary chemotherapeutic agents also include anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, paclitaxel, colchicine, cytochalasin B, emetine, maytansine, amsacrine, cisplatin, carboplatin, mitomycin, altretamine, cyclophosphamide, lomustine, and carmustine. In certain embodiments, a pharmaceutical composition described herein further comprises a combination of the additional pharmaceutical agents described herein. 4. Formulations and Administration [0099] The compositions of the present disclosure can be delivered directly or in pharmaceutical compositions along with suitable carriers or excipients, as is well known in the art. Present methods of treatment can comprise administration of an effective amount of a compound of the disclosure to a subject in need; e.g., a subject having or at risk for a hyperproliferative disease or cancer. In certain embodiments, the subject is a mammalian subject. In certain embodiments, the subject is a human subject. [0100] An effective amount of such agents can readily be determined by routine experimentation, as can the most effective and convenient route of administration and the most appropriate formulation. Various formulations and drug delivery systems are available in the art. See, e.g., Gennaro, A.R., ed. (1995) Remington’s Pharmaceutical Sciences, supra. [0101] Suitable routes of administration may, for example, include oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral administration. The indication to be treated, along with the physical, chemical, and biological properties of the drug, dictate the type of formulation and the route of administration to be used, as well as whether local or systemic delivery would be desired. [0102] Pharmaceutical compositions are often composed of the drug and an excipient(s). Pharmaceutical dosage forms are often composed of the drug, an excipient(s), and a container/closure system. One or multiple excipients, also referred to as inactive ingredients, can be added to a compound of the disclosure to improve or facilitate manufacturing, stability, administration, and safety of the drug, and can provide a means to achieve a desired drug release profile. Therefore, the type of excipient(s) to be added to the drug can depend on various factors, such as, for example, the physical and chemical properties of the drug, the route of administration, and the manufacturing procedure. Pharmaceutically acceptable excipients are available in the art and include those listed in various pharmacopoeias. (See, e.g., the U.S. Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British pharmacopeia (BP); the U.S. Food and Drug Administration (fda.gov) Center for Drug Evaluation and Research (CEDR) publications, e.g., Inactive Ingredient Guide (1996); Ash and Ash, Eds. (2002) Handbook of Pharmaceutical Additives, Synapse Information Resources, Inc., Endicott NY; etc.) [0103] Pharmaceutical dosage forms of a compound of the present disclosure may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extruding, spray- drying, levigating, emulsifying, (nano/micro-) encapsulating, entrapping, or lyophilization processes. As noted above, the compositions of the present disclosure can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use. [0104] Proper formulation is dependent upon the desired route of administration. For intravenous injection, for example, the composition may be formulated in aqueous solution, if necessary using physiologically compatible buffers, including, for example, phosphate, histidine, or citrate for adjustment of the formulation pH, and a tonicity agent, such as, for example, sodium chloride or dextrose. For transmucosal or nasal administration, semisolid, liquid formulations, or patches may be desired, possibly containing penetration enhancers. Such penetrants are generally known in the art. For oral administration, the compounds can be formulated in liquid or solid dosage forms, and as instant or controlled/sustained release formulations. Suitable dosage forms for oral ingestion by a subject include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions. The compounds may also be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. [0105] Solid oral dosage forms can be obtained using excipients, which may include fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, antiadherants, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring, and flavoring agents. These excipients can be of synthetic or natural source. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatine, magnesium carbonate, magnesium/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicates, silicium dioxide, sodium benzoate, sorbitol, starches, stearic acid or a salt thereof, sugars (i.e. dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oils (hydrogenated), and waxes. Ethanol and water may serve as granulation aides. In certain instances, coating of tablets with, for example, a taste-masking film, a stomach acid resistant film, or a release-retarding film is desirable. Natural and synthetic polymers, in combination with colorants, sugars, and organic solvents or water, are often used to coat tablets, resulting in dragees. When a capsule is desired over a tablet, the drug powder, suspension, or solution thereof can be delivered in a compatible hard or soft shell capsule. [0106] A therapeutically effective dose can be estimated initially using a variety of techniques well-known in the art. Initial doses used in animal studies may be based on effective concentrations established in cell culture assays. Dosage ranges appropriate for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays. [0107] An effective amount or a therapeutically effective amount or dose of an agent, e.g., a compound of the disclosure, refers to that amount of the agent or compound that results in amelioration of symptoms or a prolongation of survival in a subject. Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the ratio LD ₅₀ /ED ₅₀ . Agents that exhibit high therapeutic indices are generally desired. [0108] The effective amount or therapeutically effective amount is the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Dosages typically fall within a range of circulating concentrations that includes the ED ₅₀ with little or no toxicity. Dosages may vary within this range depending upon the dosage form employed and/or the route of administration utilized. Dosages are typically expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 900 mg/kg may be appropriate. In some embodiments, about 1 and 500 mg/kg may be appropriate. In other embodiments, a dosage of between 10 and 250 mg/kg may be appropriate. In some embodiments, a dosage of from about 1 to about 100 mg per kg of body weight, from about 1 to about 50 mg of compound per kg of body weight, or from about 1 to about 10 mg of compound per kg of body weight may be appropriate. In some embodiments, a dosage of from about 25 to about 500 mg per kg of body weight, from about 50 to about 500 mg of compound per kg of body weight, or from about 25 to about 250 mg of compound per kg of body weight may be appropriate. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject’s condition. [0109] The amount of agent or composition administered may be dependent on a variety of factors, including the sex, age, and weight of the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. [0110] These and other embodiments of the present disclosure will readily occur to those of ordinary skill in the art in view of the disclosure herein and are specifically contemplated. 5. General Synthetic Methods [0111] The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods, and procedures. It will be appreciated that where certain process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0112] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting certain functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein. [0113] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. [0114] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance CA USA), EMKA-Chemie Gmbh & Co. KG (Eching Germany), or Millipore Sigma (Burlington MA USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5 ^th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). [0115] Scheme I illustrates a general method which can be employed for the synthesis of compounds described herein, where n, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are defined herein, Z is halo (such as Cl, Br, or I), PG is a suitable protecting group (e.g., benzyl), and R ⁵² and R ⁵³ are independently C1-6 alkoxy, -O-C2-6 alkenyl, -O-C2-6 alkynyl, -O-C1-6 haloalkyl, -O-C3-10 cycloalkyl, -O-C3-10 cycloalkenyl, -O-heterocyclyl, -O-aryl, or –O-heteroaryl.

[0116] Compounds of Formula I, where R ³ is other than hydrogen, can be provided by functionalization of Formula I-1 (e.g., compounds of Formula I where R ³ is hydrogen). For example, halogenation of Formula I-1 provides Formula I-2 (e.g., compounds of Formula I where R ³ is halo). Further derivatization of Formula I-2, such as with a compound of formula B-C _1-6 haloalkyl or M-CN, where B is a suitable functional group such as, but not limited to, a boronic acid or a derivative thereof, such as a boronic ester, zinc or magnesium halide, an organotin compound, and M is a metal, such as zinc or magnesium halide, provides compounds of Formula I where R ³ is cyano or C1-6 haloalkyl. [0117] Compounds of Formula I-1 can be provided from Formula I-3. For example, contacting appropriately substituted Formula I-3 with oxalyl chloride in the presence of DMF, followed by 2-tert- butoxycarbonyl-succinic acid 1-tert-butyl ester 4-ethyl ester provides Formula I-4. Formula I-1 is then provided from Formula I-4 using an acid (e.g., p-toluenesulfonic acid) followed by appropriate deprotection and/or functionalization, such as at R ¹ . Alternatively, compounds of Formula I-1 where one or more of R ⁶ -R ⁹ are other than hydrogen can be provided from Formula I-3. [0118] Referring to Scheme I, exposing Formula I-5 to a base, for example n-butyl lithium, then with a compound of Formula I-3, produces phosphine oxide I-6. Formula I-6 can then be treated with a compound of Formula I-7, to provide compounds of Formula I-8. In certain embodiments, when control of stereochemistry is desired, proper control of reaction conditions and selection of substituents for the reagents and compounds of Formula I-6 and Formula I-7 can at least partially dictate the formation of E or Z isomers of Formula I-7, allowing for the stereocontrol of substituents R ⁶ , R ⁷ , R ⁸ , and R ⁹ on subsequent fully-saturated compounds of Formula I-1. Further derivatization of α,β-unsaturated dioxo compounds of Formula I-8, transformations which are known to those of skill in the art, or exposure to standard reducing conditions, provides compounds of Formula I-1. [0119] For any compound shown in Scheme I, it should be understood that various derivatives can be provided by functional group interconversion at any step. For example with R ² , various compounds of Formula I can be provided via transesterification or hydrolysis using methods known to one of skill in the art. Likewise, various compounds of Formula I can be prepared by contacting compounds where one or more R ⁴ is a leaving group (e.g., halo, such as Cl, Br, or I, or a pseudohalide, such as a triflate, sulfonate, or phosphate), with a compound of Formula R ⁴ -B, wherein B is a suitable functional group such as, but not limited to, a boronic acid or a derivative thereof, such as a boronic ester, zinc or magnesium halide, an organotin compound, such as tributylstannane or trimethylstannane, fluorosulfonyl esters, tin, sodium, hydrogen, and the like. Such reactions are commonly utilized for aromatic functionalization, and are typically conducted in the presence of suitable catalyst such as, but not limited to, a palladium catalyst including [1,1’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCl2(PPh3)2 or tris(dibenzylideneacetone)dipalladium(0), and the like, or a copper catalyst such as CuCl or CuI, and if required suitable mediator, co-catalyst and/or base known to one skilled in the art using suitable solvents/solvent mixtures. Upon reaction completion, compounds of Formula I can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like. [0120] In some embodiments, the various substituents of Formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, or I-8 (e.g., n, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , Z, R ⁵² , and R ⁵³ ) are as defined herein. However, derivatization of compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, and I-8 prior to reacting in any step, and/or further derivatization of the resulting reaction product, provides various compounds of Formula I. Appropriate starting materials and reagents can be purchased or prepared by methods known to one of skill in the art. Upon each reaction completion, each of the intermediate or final compounds can be recovered, and optionally purified, by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like. Other modifications to arrive at compounds of this disclosure are within the skill of the art. EXAMPLES [0121] This disclosure is further understood by reference to the following examples, which are intended to be purely exemplary of the disclosure. The present disclosure is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the disclosure only. Any methods that are functionally equivalent are within the scope of the disclosure. Various modifications of the disclosure in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications fall within the scope of the appended claims. Example 1 4-(4-Cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid a) (2-Amino-4-bromo-phenyl)-methanol [0122] To an ice cooled solution of LiAlH4 (5.2 g, 0.135 mol) in THF (125 mL), methyl 2- amino-4-bromobenzoate (25 g, 0.108 mol) in THF (125 mL) was added at 0 ⁰ C and stirred at RT for 4h. The reaction mixture was slowly quenched using saturated aqueous solution of sodium thiosulfate and filtered. The obtained filtrate was concentrated to afford the crude product, which was purified by crystallization using ethyl acetate and hexane to yield 15.3 g of the title compound. ¹ H NMR (CDCl ₃ , 400 MHz): δ = 6.93 (d, J = 8 Hz, 1H), 6.80-6.90 (m, 2H), 4.64 (s, 2H), 4.27 (br s, 2H). b) 2-Amino-4-bromo-benzaldehyde [0123] To a solution of (2-amino-4-bromo-phenyl)-methanol (15 g, 74.2 mmol) in DCM (750 mL), activated manganese (IV) oxide (64 g, 742 mmol) was added portion wise with stirring at room temperature (mechanical stirrer). The resulting reaction mixture was stirred at room temperature for 5 h. On reaction completion the mixture was filtered through a celite pad and the filter cake was washed thoroughly with DCM (1L). The combined filtrates were concentrated in vacuo to give 13 g of crude product. This material was mixed with hexane and stirred for 30 min and filtered to get 11 g of the title compound. ¹ H NMR (CDCl3, 400 MHz): δ = 9.83 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.85-6.91 (m, 2H), 6.20 (br s, 2H). c) 3-Amino-7-bromo-quinoline-2-carboxylic acid ethyl ester [0124] A solution of ethyl bromopyruvate (3.4 mL, 26.8 mmol) in ethanol (23 mL) was added dropwise to a mixture of pyridine (2 mL, 25.4 mmol) and ethanol (23 mL) at room temperature for a period of more than 30 minutes and reaction mixture was stirred at rt for 1h to ensure the reaction was complete. The mixture was stirred at 60 ⁰ C for 2h and was cooled to room temperature. To the mixture was added 2-Amino-4-bromo-benzaldehyde (5 g, 25.4 mmol) and pyridine (6 mL). The mixture was refluxed at 85 ⁰ C for 4 hours. Pyrrolidine (5.2 mL, 63.5 mmol) was added and the mixture was refluxed at 85 ⁰ C for 4 hours. The reaction mixture was concentrated and purified by column chromatography using 5% ethyl acetate in DCM as eluent to yield 3.4 g of the title compounds. MS: (+) m/z 295, 297 (M+H, ^79/81 Br). d) 7-Bromo-3-hydroxy-quinoline-2-carboxylic acid ethyl ester [0125] 3-Amino-7-bromo-quinoline-2-carboxylic acid ethyl ester (3.4 g, 11.5 mmol) was dissolved in anhydrous THF (35 mL) and placed in an ice bath. With vigorous stirring, concentrated H2SO4 (1.4 mL, 34.5 mmol) was slowly added to give a thick suspension. Butyl nitrite (4 mL, 34.5 mmol) was then added dropwise, and the resulting suspension was stirred vigorously in the ice bath for 2 h. The mixture was diluted with 2 mL of cold THF and the solid was isolated by filtration and dried under high vacuum for several hours. In a separate flask, glacial acetic acid (80 mL) was heated to 115 ^o C. The solid from above was suspended in glacial acetic acid (80 mL) and added to the pre-heated acetic acid, and the resulting homogeneous mixture was then stirred at 115-120 ^o C for 16 h. The reaction was completed. The mixture was allowed to come to room temperature and concentrated to dryness. The residue was re-dissolved in absolute EtOH (35 mL) and placed in ice bath. Thionyl chloride (3.5 mL) was added, and the mixture was warmed to room temperature and refluxed for 16 h, Ethanol was evaporated and residue was dissolved in DCM and washed with water followed by saturated solution of bicarbonate, organic layer was separated, dried over sodium sulfate and filtered, filtrate was concentrated to give crude product. This material was purified by column chromatography using 5% ethyl acetate in hexane as eluent to yield 450 mg of the title compound. MS: (+) m/z 296, 298 (M+H, ^79/81 Br). e) 3-Benzyloxy-7-bromo-quinoline-2-carboxylic acid ethyl ester [0126] Benzyl bromide (0.91 mL, 1.31 g, 7.5 mmol, 1.5 eq.) was added to a mixture of 7- Bromo-3-hydroxy-quinoline-2-carboxylic acid ethyl ester (1.48 g, 5.0 mmol, 1.0 eq.) and cesium carbonate (1.96 g, 6.0 mmol, 1.2 eq.) in anhydrous DMF (15 mL) at room temperature. After 3 hours at room temperature, TLC shows the completion of the reaction. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (4 x 50 mL). The combined extracts were washed with brine (2 x 100 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound. MS-(+)-ion, M+H = 387.89, 385.99. f) [2-(3-Benzyloxy-7-bromo-quinolin-2-yl)-2-oxo-ethyl]-phosphon ic acid dimethyl ester [0127] At -78 °C, to a solution of dimethyl methylphosphonate (1.1 mL, 10.0 mmol, 2.2 eq.) in THF (20 mL) was added n-BuLi (2.5 M in hexanes, 3.7 mL, 9.2 mmol, 2.0 eq) over 10 min under N2 atmosphere. After 30 min, a solution of 3-Benzyloxy-7-bromo-quinoline-2-carboxylic acid ethyl ester (1.17 g, 4.6 mmol) in THF (10 mL) was added slowly over 10 min. After stirring for 2 h at -78 °C, the mixture was treated with half saturated aq. NH4Cl (20 mL) and extracted with ethyl acetate (4 x 15 mL). The combined extracts were dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hex (0% - 100%) to give 1.89 g of the title compound. MS-(+)-ion, M+H = 465.80, 463.85. g) 4-(3-Benzyloxy-7-bromo-quinolin-2-yl)-4-oxo-but-2-enoic acid ethyl ester [0128] To a solution of [2-(3-Benzyloxy-7-bromo-quinolin-2-yl)-2-oxo-ethyl]-phosphon ic acid dimethyl ester (1.88 g, 4.0 mmol) in THF (20 mL) at -78 °C was added t-BuOK (1 M in THF, 5.2 mmol, 5.2 mL, 1.3 eq). After stirring at -78 °C for 10 min, ethyl glyoxalate (50 wt % in toluene, 1.63 g, 8.0 mmol, 2.0 eq.) was added dropwise over 20 min via a dropping funnel. The mixture was stirred at -78 °C for 3 h, then was treated with half saturated aq. NH4Cl (20 mL) and extracted with ethyl acetate (4 x 15 mL). The combined extracts were dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/hexane (0% - 20%) to give the title compound, 1.05 g. MS-(+)-ion, M+H = 441.85, 439.90. E/Z = 3/1. h) 4-Hydroxy-4-(3-hydroxy-quinolin-2-yl)-butyric acid ethyl ester [0129] To a solution of 4-(3-Benzyloxy-7-bromo-quinolin-2-yl)-4-oxo-but-2-enoic acid ethyl ester (0.98 g, 2.2 mmol) in ethyl acetate (20 mL) was added Pd/C (200 mg, 0.10eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 70 hr at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography to give the title compound, 0.61 g, contains impurities. MS-(+)-ion, M+H = 275.96. i) 4-(3-Hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0130] The mixture of 4-Hydroxy-4-(3-hydroxy-quinolin-2-yl)-butyric acid ethyl ester (0.61 g, 2.2 mmol) and manganese dioxide (2.9 g, 33 mmol) in anhydrous toluene (20 mL) was heated at 80 °C under N ₂ atmosphere for 16 hours. After cooling down to room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound.48 mg, MS-(-)-ion, M+H = 273.96. j) 4-(4-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0131] To a solution of 4-(3-Hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (48 mg, 0.18 mmol) in acetonitrile (3 mL) was added N-Bromosuccinimide (35 mg, 0.2 mmol). The mixture was stirred at room temperature for 2h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to afford the crude product. This material was purified by column chromatography using 0- 10% ethyl acetate in hexane as eluent gave 45 mg of the title compound. MS-(+)-ion, M+H = 353.88, 351.93. k) 4-(4-Cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0132] A mixture of 4-(4-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (45 mg, 0.13 mmol), zinc cyanide (30 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium(0) (11.9 mg, 0.013 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 14.4 mg, 0.026 mmol), and zinc dust (2.5 mg, 0.039 mmol) in anhydrous dimethylacetamide (2 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 23 mg. MS-(+)-ion, M+H = 298.92. l) 4-(4-Cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid [0133] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (24 mg, 0.08 mmol) in THF/H2O (2 mL/1 mL) was added lithium hydroxide monohydrate (16.4 mg, 0.4 mmol). After 20 hours at room temperature, the reaction was diluted with 15 mL of water and extracted with ethyl acetate (10 mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound, 15 mg. MS-(+)-ion, M+H = 270.91. Example 2 4-(4-Cyano-3-hydroxy-7-phenyl-quinolin-2-yl)-4-oxo-butyric acid a) 3-Hydroxy-7-phenyl-quinoline-2-carboxylic acid ethyl ester [0134] A round bottom flask was charged with 7-Bromo-3-hydroxy-quinoline-2-carboxylic acid ethyl ester (930 mg, 3.0 mmol), phenylboronic acid (550 mg, 4.5 mmol, 1.5 eq), S-Phos (98 mg, 0.24 mmol, 0.08 eq), palladium acetate (40.3 mg, 0.18 mmol, 0.06 eq), and tripotassium phosphate (1.27 g, 6.0 mmol, 2.0 eq). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (10 mL) and water (108 mg, 6.0 mmol, 2.0 eq) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH=4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 890 mg.MS-(+)-ion, M+H = 294.02. b) 3-Benzyloxy-7-phenyl-quinoline-2-carboxylic acid ethyl ester [0135] Benzyl bromide (0.54 mL, 0.78 g, 4.5 mmol, 1.5 eq.) was added to a mixture of 3- Hydroxy-7-phenyl-quinoline-2-carboxylic acid ethyl ester (0.90 g, 3.0 mmol, 1.0 eq.) and cesium carbonate (1.17 g, 3.6 mmol, 1.2 eq.) in anhydrous DMF (20 mL) at room temperature. After 3 hours at room temperature, TLC shows the completion of the reaction. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (4 x 50 mL). The combined extracts were washed with brine (2 x 100 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 1.1 g. MS-(+)-ion, M+H = 384.09. c) [2-(3-Benzyloxy-7-phenyl-quinolin-2-yl)-2-oxo-ethyl]-phospho nic acid dimethyl ester [0136] At -78 °C, to a solution of dimethyl methylphosphonate (0.67 mL, 6.2 mmol, 2.2 eq.) in THF (20 mL) was added n-BuLi (2.5 M in hexanes, 2.3 mL, 5.6 mmol, 2.0 eq.) over 10 min under N2 atmosphere. After 30 min, a solution of 3-Benzyloxy-7-phenyl-quinoline-2-carboxylic acid ethyl ester (1.1 g, 2.8 mmol) in THF (10 mL) was added slowly over 10 min. After stirring for 2 h at -78 °C, the mixture was treated with half saturated aq. NH ₄ Cl (20 mL) and extracted with ethyl acetate (4 x 15 mL). The combined extracts were dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hex (0% - 100%) to give 1.04 g of the title compound. MS-(+)-ion, M+H = 462.10. d) 4-(3-Benzyloxy-7-phenyl-quinolin-2-yl)-4-oxo-but-2-enoic acid ethyl ester [0137] To an ice cooled solution of [2-(3-Benzyloxy-7-phenyl-quinolin-2-yl)-2-oxo-ethyl]- phosphonic acid dimethyl ester (1.04 g, 2.2 mmol) in acetonitrile was added ethyl glyoxalate (3.3 mmol, 50% in toluene) and triethyl amine (263 mg, 2.6 mmol). After 1 hour at 0 ⁰ C, the reaction mixture was quenched using saturated aq solution of ammonium chloride. The mixture was extracted with ethyl acetate (3x30 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 0.84 g. MS- (+)-ion, M+H = 438.15. e) 4-(3-Benzyloxy-7-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0138] To a solution of 4-(3-Benzyloxy-7-phenyl-quinolin-2-yl)-4-oxo-but-2-enoic acid ethyl ester (0.8 g, 1.8 mmol) in ethyl acetate (30 mL) was added Pd/C (38 mg, 0.01eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 1 hr at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography to give the title compound, 0.49 g. MS-(+)-ion, M+H = 440.15. f) 4-(3-Hydroxy-7-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0139] The mixture of 4-(3-Benzyloxy-7-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (0.49 g, 1.1 mmol) and thioanisole (1.4 g, 11 mmol) in trifluoroacetic acid (5 mL) was heated at 80°C for 6 hours. After cooling down to room temperature, the reaction mixture was slowly quenched with sodium bicarbonate aqueous solution to pH = 7~8. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 0.30 g. MS-(+)-ion, M+H = 350.04. g) 4-(4-Bromo-3-hydroxy-7-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0140] To a solution of 4-(3-Hydroxy-7-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (258 mg, 0.74 mmol) in acetonitrile (10 mL) was added N-Bromosuccinimide (145 mg, 0.84 mmol). The mixture was stirred at room temperature for 3h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to afford the crude product. This material was purified by column chromatography using 0-10% ethyl acetate in hexane as eluent to give the title compound, 255 mg. MS- (+)-ion, M+H = 429.87, 427.92. h) 4-(4-Cyano-3-hydroxy-7-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0141] A mixture of 4-(4-Bromo-3-hydroxy-7-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (129 mg, 0.3 mmol), zinc cyanide (70 mg, 0.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 33 mg, 0.06 mmol), and zinc dust (6.0 mg, 0.09 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 37 mg. MS-(+)-ion, M+H = 375.04. i) 4-(4-Cyano-3-hydroxy-7-phenyl-quinolin-2-yl)-4-oxo-butyric acid [0142] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-7-phenyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (60 mg, 0.16 mmol) in THF/H ₂ O (3 mL/1 mL) was added lithium hydroxide monohydrate (33 mg, 0.80 mmol). After 1h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound. 35 mg. MS-(+)-ion, M+H = 346.93. Example 3 4-(3-Hydroxy-7-phenyl-quinolin-2-yl)-4-oxo-butyric acid a) 4-(3-hydroxy-7-phenyl-quinolin-2-yl)-4-oxo-butyric acid [0143] At room temperature, to a solution of 4-(3-hydroxy-7-phenyl-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (50 mg, 0.14 mmol) in THF/H ₂ O (3 mL/1 mL) was added lithium hydroxide monohydrate (24 mg, 0.57 mmol). After 6h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound. 34 mg. MS-(+)-ion, M+H = 321.97. Example 4 4-(4-Cyano-3-hydroxy-5-phenyl-quinolin-2-yl)-4-oxo-butyric acid a) (2-Amino-6-bromo-phenyl)-methanol [0144] To a solution of 2-amino-6-bromo benzoic acid (10 g, 46.2 mmol) in THF (100 mL), LiAlH ₄ (2.5 g, 69.3 mmol) was added at 0 ^o C and stirred at RT for 8 h, water (7.7 mL) was added, followed by 15% NaOH (7.7 mL) and water (23 mL). The slurry was stirred at room temperature for 1h. The salts were filtered off and washed with THF. The combined filtrates were concentrated under vacuo to get crude which was purified by column chromatography using 0-40% ethyl acetate in hexane as eluent to give 5.5 g of the title compound. ¹ H NMR (400 MHz, CDCl ₃ ): δ = 6.9-7.0 (m, 2H), 6.6-6.7 (m, 1H), 4.9 (s, 2H), 3.0 (br s). b) 2-Amino-6-bromo-benzaldehyde [0145] To a solution of (2-Amino-6-bromo-phenyl)-methanol (5.5 g, 29.46 mmol) in DCM (50 mL) at room temperature was added MnO2 (25.61 g, 294.66 mmol) in portions. Reaction mixture was stirred at room temperature for 4 h. Reaction mixture was filtered through a pad of celite and washed with DCM, filtrate was concentrated under vacuo to get crude; The obtained crude was purified by column chromatography (0-30% EtOAc/hexane) to yield 4 g of the title compound. MS: (+) m/z 200, 202 (M+1). c) 3-Amino-5-bromo-quinoline-2-carboxylic acid ethyl ester [0146] A solution of ethyl bromopyruvate (1.32 mL, 10.49 mmol) in ethanol (10 mL) was added dropwise to a mixture of pyridine (0.8 mL, 9.99 mmol) and ethanol (10 mL) at room temperature for a period of more than 30 minutes and reaction mixture was stirred at rt for 1h to ensure the reaction was complete. The mixture was stirred at 60 ^o C for 2h and was cooled to room temperature. To the mixture was added 2-Amino-6-bromo-benzaldehyde (2 g, 9.99 mmol) and pyridine (5 mL). The mixture was refluxed for 4 hours. Pyrrolidine (2 mL, 24.97 mmol) was added and the mixture was refluxed for 4 hours. The reaction mixture was concentrated under vacuo to remove ethanol, crude was diluted with ethyl acetate and washed with excess water. The organic layer was separated, dried over sodium sulfate and concentrated to get crude. The obtained crude was purified by column chromatography using 0-5% ethyl acetate in DCM as eluent followed by trituration from pentane to give 1.2 g of the title compound. MS: (+) m/z 295, 297 (M+1). d) 5-Bromo-3-hydroxy-quinoline-2-carboxylic acid ethyl ester [0147] 3-Amino-5-bromo-quinoline-2-carboxylic acid ethyl ester (1.2 g, 4.06 mmol) was dissolved in anhydrous THF (12 mL) and placed in an ice bath. With vigorous stirring, concentrated H ₂ SO ₄ (0.64 mL, 12.19 mmol) was slowly added to give a thick suspension. Butyl nitrite (1.42 mL, 12.19 mmol) was then added dropwise, and the resulting suspension was stirred vigorously in the ice bath for 2 h. The mixture was diluted with 10 mL of cold THF and the solid was isolated by filtration and dried under high vacuum for several hours. In a separate flask, glacial acetic acid (8 mL) was heated to 115 ^o C. The solid from above was suspended in glacial acetic acid (7 mL) and added to the pre-heated acetic acid, and the resulting homogeneous mixture was then stirred at 115-120 ^o C for 16 h. The reaction mixture was allowed to come to room temperature and concentrated to dryness. The residue was re- dissolved in absolute EtOH (58 mL) and placed in ice bath. Thionyl chloride (1.66 mL) was added, and the mixture was warmed to room temperature and refluxed for 16h. The mixture was concentrated under vacuo. The crude was diluted with water and neutralized with sat. NaHCO3 solution and extracted with DCM. The organic layer was separated, dried over sodium sulfate and concentrated to get crude. The obtained crude was purified by column chromatography using 0-2% ethyl acetate in hexane as eluent followed by trituration from pentane to yield 560 mg of title compound. MS: (+) m/z 296, 298 (M+1). e) 3-Hydroxy-5-phenyl-quinoline-2-carboxylic acid ethyl ester [0148] A round bottom flask was charged with 5-Bromo-3-hydroxy-quinoline-2-carboxylic acid ethyl ester (1.55 g, 5.0 mmol), phenylboronic acid (915 mg, 7.5 mmol, 1.5 eq), S-Phos (164 mg, 0.4 mmol, 0.08 eq), palladium acetate (67 mg, 0.3 mmol, 0.06 eq), and tripotassium phosphate (2.12 g, 10 mmol, 2.0 eq). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (20 mL) and water (180 mg, 10 mmol, 2.0 eq) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture was filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 690 mg. MS-(+)-ion, M+H = 293.97. f) 3-Benzyloxy-5-phenyl-quinoline-2-carboxylic acid ethyl ester [0149] Benzyl bromide (0.45 mL, 0.64 g, 3.7 mmol) was added to a mixture of 3-Hydroxy-5- phenyl-quinoline-2-carboxylic acid ethyl ester (0.68 g, 2.3 mmol) and cesium carbonate (0.98 g, 3.0 mmol) in anhydrous DMF (15 mL) at room temperature. After 3 hours at room temperature, TLC shows the completion of the reaction. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (4 x 50 mL). The combined extracts were washed with brine (2 x 100 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 0.64 g. MS-(+)-ion, M+H = 384.09. g) [2-(3-Benzyloxy-5-phenyl-quinolin-2-yl)-2-oxo-ethyl]-phospho nic acid dimethyl ester [0150] At -78 °C, to a solution of dimethyl methylphosphonate (0.38 mL, 3.5 mmol, 2.2 eq.) in THF (10 mL) was added n-BuLi (2.5 M in hexanes, 1.3 mL, 3.2 mmol, 2.0 eq) over 10 min under N2 atmosphere. After 30 min, a solution of 3-Benzyloxy-5-phenyl-quinoline-2-carboxylic acid ethyl ester (0.64 g, 1.6 mmol) in THF (10 mL) was added slowly over 10 min. After stirring for 2 h at -78 °C, the mixture was treated with half saturated aq. NH ₄ Cl (20 mL) and extracted with ethyl acetate (4 x 15 mL). The combined extracts were dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hex (0% - 100%) to give 0.66 g of the title compound. MS-(+)-ion, M+H = 462.05. h) 4-(3-Benzyloxy-5-phenyl-quinolin-2-yl)-4-oxo-but-2-enoic acid ethyl ester [0151] To an ice cooled solution of [2-(3-Benzyloxy-5-phenyl-quinolin-2-yl)-2-oxo-ethyl]- phosphonic acid dimethyl ester (0.65 g, 1.4 mmol) in acetonitrile (15 mL) was added ethyl glyoxalate (2.1 mmol, 50% in toluene) and triethyl amine (171 mg, 1.7 mmol). After 1 hour at 0 ⁰ C, the reaction mixture was quenched using saturated aq solution of ammonium chloride. The mixture was extracted with ethyl acetate (3x30 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 0.49 g. MS- (+)-ion, M+H = 438.10. i) 4-(3-Benzyloxy-5-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0152] To a solution of 4-(3-Benzyloxy-5-phenyl-quinolin-2-yl)-4-oxo-but-2-enoic acid ethyl ester (0.49 g, 1.1 mmol) in ethyl acetate (20 mL) was added Pd/C (23 mg, 0.01eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 1 hr at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography to give the title compound, 0.34 g. MS-(+)-ion, M+H = 440.05. j) 4-(3-Hydroxy-5-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0153] The mixture of 4-(3-Benzyloxy-5-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (0.34 g, 0.77 mmol) and thioanisole (0.96 g,7.7 mmol) in trifluoroacetic acid (5 mL) was heated at 80°C for 6 hours. After cooling down to room temperature, the reaction mixture was slowly quenched with sodium bicarbonate aqueous solution to pH = 7~8. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 0.27 g. MS-(+)-ion, M+H = 350.04. k) 4-(4-Bromo-3-hydroxy-5-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0154] To a solution of 4-(3-Hydroxy-5-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (270 mg, 0.77 mmol) in acetonitrile (10 mL) was added N-Bromosuccinimide (151 mg, 0.85 mmol). The mixture was stirred at room temperature for 3h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to get crude; purified by column chromatography using 0-10% ethyl acetate in hexane as eluent gave the title compound, 172 mg. MS-(+)-ion, M+H = 429.85, 427.95. l) 4-(4-Cyano-3-hydroxy-5-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0155] A mixture of 4-(4-Bromo-3-hydroxy-5-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (86 mg, 0.2 mmol), zinc cyanide (47 mg, 0.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 22 mg, 0.04 mmol), and zinc dust (3.9 mg, 0.06 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 37 mg. MS-(+)-ion, M+H = 375.05. m) 4-(4-Cyano-3-hydroxy-5-phenyl-quinolin-2-yl)-4-oxo-butyric acid [0156] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-5-phenyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (32 mg, 0.09 mmol) in THF/H2O (3 mL/1 mL) was added lithium hydroxide monohydrate (15 mg, 0.36 mmol). After 1h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound. 25 mg. MS-(+)-ion, M+H = 346.98. Example 5 4-(3-Hydroxy-5-phenyl-4-trifluoromethyl-quinolin-2-yl)-4-oxo -butyric acid a) 4-(3-Benzyloxy-4-bromo-5-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0157] Benzyl bromide (0.036 mL, 52 mg, 0.3 mmol) was added to a mixture of 4-(4-Bromo-3- hydroxy-5-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (86 mg, 0.2 mmol) and cesium carbonate (78 mg, 0.24 mmol) in anhydrous DMF (3 mL) at room temperature. After 3 hours at room temperature, TLC shows the completion of the reaction. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (4 x 20 mL). The combined extracts were washed with brine (2 x 20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 93 mg. MS-(+)-ion, M+H = 384.09. b) 4-(3-Benzyloxy-5-phenyl-4-trifluoromethyl-quinolin-2-yl)-4-o xo-butyric acid ethyl ester [0158] The mixture of 4-(3-Benzyloxy-4-bromo-5-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (92 mg, 0.18 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (207 mg, 1.08 mmol), and copper(I) iodide (103 mg, 0.54 mmol), in anhydrous 1-methyl-2-pyrrolidone (3 mL) was heated at 100 °C under N2 atmosphere for 3 hours. After cooling down to room temperature, the reaction mixture was diluted with water (30 mL), quenched with 5 mL 1 N HCl and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound.61 mg, MS-(+)-ion, M+Na = 508.11. c) 4-(3-Hydroxy-5-phenyl-4-trifluoromethyl-quinolin-2-yl)-4-oxo -butyric acid ethyl ester [0159] The mixture of 4-(3-Benzyloxy-5-phenyl-4-trifluoromethyl-quinolin-2-yl)-4-o xo-butyric acid ethyl ester (60 mg, 0.12 mmol) and thioanisole (75 mg, 0.6 mmol) in trifluoroacetic acid (2 mL) was stirred at room temperature for 18 hours. The reaction mixture was slowly quenched with sodium bicarbonate aqueous solution to pH = 7~8. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 31 mg. MS-(+)-ion, M+H = 417.94. d) 4-(3-Hydroxy-5-phenyl-4-trifluoromethyl-quinolin-2-yl)-4-oxo -butyric acid [0160] At room temperature, to a solution of 4-(3-Hydroxy-5-phenyl-4-trifluoromethyl- quinolin-2-yl)-4-oxo-butyric acid ethyl ester (30 mg, 0.07 mmol) in THF/H ₂ O (3 mL/1 mL) was added lithium hydroxide monohydrate (15 mg, 0.36 mmol). After 4h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.21 mg. MS-(+)-ion, M+H = 389.99. Example 6 4-(5-Cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid a) 2-tert-Butoxycarbonyl-succinic acid 1-tert-butyl ester 4-ethyl ester [0161] A solution of di-tert-butyl malonate (9.66 g, 44.7 mmol) in anhydrous tetrahydrofuran (15 mL) was added to a suspension of sodium hydride (1.8 g, 45 mmol, 60% dispersion) in anhydrous tetrahydrofuran (50 mL) at room temperature. After stirring for 2 hours at room temperature, the suspension mixture was further heated at 60°C for 16 hours. After cooling back to room temperature, a solution of ethyl bromoacetate (5.97 g, 35.7 mmol) in anhydrous tetrahydrofuran (25 mL) was added, and the mixture was stirred for 4 h. Then the mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined extract was washed with brine (50 mL), dried over sodium sulfate, and concentrated to give crude product. The obtained crude was purified by column chromatography using 5% ethyl acetate in hexane as eluent to yield 7.1 g of the title compound. ¹ H NMR (CDCl ₃ , 200 MHz): δ = 1.25 (3H, t, J = 6.4 Hz), 1.46 (18H, s), 2.81 (2H, d, J = 7.4 Hz), 3.65 (1H, t, J = 7.4 Hz), 4.13 (2H, q, J = 6.4 Hz). b) 3-Benzyloxy-5-bromo-quinoline-2-carboxylic acid ethyl ester [0162] Benzyl bromide (0.91 mL, 1.31 g, 7.5 mmol) was added to a mixture of 5-Bromo-3- hydroxy-quinoline-2-carboxylic acid ethyl ester (1.48 g, 5.0 mmol) and cesium carbonate (1.96 g, 6.0 mmol) in anhydrous DMF (20 mL) at room temperature. After 3 hours at room temperature, TLC shows the completion of the reaction. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (4 x 30 mL). The combined extracts were washed with brine (2 x 30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 1.86 g. MS- (+)-ion, M+H = 387.89, 385.94. c) 4-(3-Benzyloxy-5-bromo-quinolin-2-yl)-4-oxo-butyric acid [0163] At room temperature, to a solution of 4-(3-Benzyloxy-5-bromo-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (1.86 g, 4.8 mmol) in THF/H2O (15 mL/5 mL) was added lithium hydroxide monohydrate (0.59 g, 14.6 mmol). After 4h at room temperature, most of the organic solvent was evaporated off.100 mL of water was the reaction mixture, followed by treatment with 1N HCl to pH = 3. The precipitation was filtrated off and dried under vacuum for overnight to afford the title compound. 1.68 g. MS-(+)-ion, M+H = 359.78, 357.88. d) 3-Benzyloxy-5-bromo-quinoline-2-carbonyl chloride [0164] At 0 °C, to the solution of 3-Benzyloxy-5-bromo-quinoline-2-carboxylic acid (1.68 g, 4.7 mmol, 1.0 eq) in anhydrous THF (15 mL) was added oxalyl chloride (0.82 mL, 9.4 mmol, 2.0 eq), followed by 2 drops of DMF. The reaction was stirred at 0 °C for 1 hour, and then at room temperature for 1 hour. The solvent was evaporated in vacuo and further dried under high vacuum for 1 hour. The residue was used directly in the next step. e) 4-(3-Benzyloxy-5-bromo-quinolin-2-yl)-3,3-bis-tert-butoxycar bonyl-4-oxo-butyric acid ethyl ester [0165] A solution of 2-tert-Butoxycarbonyl-succinic acid 1-tert-butyl ester 4-ethyl ester (2.13 g, 7.05 mmol) in anhydrous tetrahydrofuran (15 mL) was added to a suspension of sodium hydride (0.28 g, 7.05 mmol, 60% dispersion) in anhydrous tetrahydrofuran (30 mL) at room temperature. The mixture was then stirred at 40 ^o C for 16 h. After cooling down to room temperature, a solution of 3-Benzyloxy-5- bromo-quinoline-2-carbonyl chloride (4.7 mmol) in anhydrous tetrahydrofuran (20 mL) was added, and the mixture was stirred at room temperature for 2 h. Then the mixture was treated with aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL X 3). The combined extract was washed with brine (100 mL), dried over sodium sulfate, and concentrated to a crude residue. The obtained crude was purified by column chromatography using 0-15% ethyl acetate in hexane as eluent to yield 3.01 g of the title compound. MS-(+)-ion, M+H = 643.88, 641.98. f) 4-(3-Benzyloxy-5-bromo-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0166] p-Toluenesulfonic acid monohydrate (0.09 g, 0.47 mmol) was added to a solution of 4- (3-Benzyloxy-5-bromo-quinolin-2-yl)-3,3-bis-tert-butoxycarbo nyl-4-oxo-butyric acid ethyl ester (3.0 g, 4.7 mmol) in toluene (18 mL), and the mixture was refluxed for 2 h. After cooling to room temperature, the mixture was treated with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (30 mL X 3). The combined extract was dried over sodium sulfate, and concentrated to a crude residue. The obtained crude was purified by column chromatography using 0-15% ethyl acetate in hexane as eluent to yield 0.83 g of the title compound. MS-(+)-ion, M+H = 441.90, 443.85. g) 4-(5-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0167] The mixture of 4-(3-Benzyloxy-5-bromo-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (360 mg, 1.1 mmol) and thioanisole (682 mg, 5.5 mmol) in trifluoroacetic acid (4 mL) was heated at 80°C for 6 hours. After cooling down to room temperature, the reaction mixture was slowly quenched with sodium bicarbonate aqueous solution to pH = 7~8. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 245 mg. MS-(+)-ion, M+H = 353.68, 351.88. h) 4-(5-Cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0168] A mixture of 4-(5-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (237 mg, 0.67 mmol), zinc cyanide (117 mg, 1.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (61 mg, 0.067 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 74 mg, 0.134 mmol), and zinc dust (13 mg, 0.2 mmol) in anhydrous dimethylacetamide (5 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 136 mg. MS-(+)-ion, M+H = 298.97. i) 4-(5-Cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid [0169] At room temperature, to a solution of 4-(5-Cyano-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (9 mg, 0.03 mmol) in THF/H2O (1 mL/0.5 mL) was added lithium hydroxide monohydrate (6 mg, 0.15 mmol). After 3h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound. 3.0 mg. MS-(+)-ion, M+H = 270.91. Example 7 4-(4-Cyano-3-hydroxy-6-phenyl-quinolin-2-yl)-4-oxo-butyric acid a) (2-Amino-5-bromo-phenyl)-methanol [0170] To a solution of 2-amino-5-bromo benzoic acid (10 g, 46.2 mmol) in THF (100 ml), LiAlH4 (2.5 g, 69.3 mmol) was added at 0 ^o C and stirred at RT for 8h, The reaction was quenched using saturated solution of sodium sulfate and filtered through celite bed to yield 6 g of title compound. MS: (+) m/z 202, 204 (M+1). b) 2-Amino-5-bromo-benzaldehyde [0171] To a solution of (2-Amino-5-bromo-phenyl)-methanol (6 g, 29.7 mmol) in DCM (400 mL) at room temperature was added MnO2 (25.5 g, 297 mmol) in portions. Reaction mixture was stirred at room temperature for 4 h. Reaction mixture was filtered through a pad of celite and washed with DCM, filtrate was concentrated under vacuo to yield the crude product. The obtained crude was purified by column chromatography using 10 to 15% ethyl acetate in hexane as eluent to yield 3.8 g of the title compound. MS: (+) m/z 200, 202 (M+1). c) 3-Amino-6-bromo-quinoline-2-carboxylic acid ethyl ester [0172] A solution of ethyl bromopyruvate (2.5 mL, 20.9 mmol) in ethanol (20 mL) was added dropwise to a mixture of pyridine (1.5mL, 19 mmol) and ethanol (20 mL) at room temperature for a period of more than 30 minutes and reaction mixture was stirred at rt for 1h to ensure the reaction was complete. The mixture was stirred at 60 ^o C for 2h and was cooled to room temperature. To the mixture was added 2-amino-5-bromo-benzaldehyde (3.8g, 19 mmol) and pyridine (10 mL). The mixture was refluxed at 85 ^o C for 4 hours. Pyrrolidine (3.9 mL, 47.5 mmol) was added and the mixture was refluxed at 85 ^o C for 4 hours. The reaction mixture was concentrated on rotavapor, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to get crude. The obtained crude was purified by column chromatography using 0-5% ethyl acetate in DCM as eluent gave 3 g of the title compound. MS: (+) m/z 295, 297 (M+1). d) 6-Bromo-3-hydroxy-quinoline-2-carboxylic acid ethyl ester [0173] 3-Amino-7-bromo-quinoline-2-carboxylic acid ethyl ester (3 g, 10.2 mmol) was dissolved in anhydrous THF (30 mL) and placed in an ice bath. With vigorous stirring, concentrated H2SO4 (1.6 mL, 30 mmol) was slowly added to give a thick suspension. Butyl nitrite (3.5 mL, 30 mmol) was then added dropwise, and the resulting suspension was stirred vigorously in the ice bath for 2 h. The mixture was diluted with 10 mL of cold THF and the solid was isolated by filtration and dried under high vacuum for several hours. In a separate flask, glacial acetic acid (20 mL) was heated to 115 ^o C. The reaction mixture was allowed to come to room temperature and concentrated to dryness. The residue was re-dissolved in absolute EtOH (30 mL) and placed in ice bath. Thionyl chloride (3.7 mL) was added, and the mixture was warmed to room temperature and refluxed for 16h. The reaction mixture was concentrated on rotavapor. Ethyl acetate was added to the reaction mixture and extracted with water and aq. sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated to get crude. The obtained crude was purified by column chromatography using 5% ethyl acetate in DCM as eluent to yield 1.5 g of the target compound. MS: (+) m/z 296, 298 (M+1). e) 3-Benzyloxy-6-bromo-quinoline-2-carboxylic acid ethyl ester [0174] Benzyl bromide (0.91 mL, 1.31 g, 7.5 mmol) was added to a mixture of 6-Bromo-3- hydroxy-quinoline-2-carboxylic acid ethyl ester (1.48 g, 5.0 mmol) and cesium carbonate (1.96 g, 6.0 mmol) in anhydrous DMF (20 mL) at room temperature. After 3 hours at room temperature, TLC shows the completion of the reaction. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (4 x 30 mL). The combined extracts were washed with brine (2 x 30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 1.74 g. MS- (+)-ion, M+H = 385.94, 387.89. f) 3-Benzyloxy-6-bromo-quinoline-2-carboxylic acid [0175] At room temperature, to a solution of 3-Benzyloxy-6-bromo-quinoline-2-carboxylic acid ethyl ester (1.74 g, 0.45 mmol) in THF/H2O (25 mL/15 mL) was added lithium hydroxide monohydrate (0.55 g, 13.5 mmol). After 4 hours at room temperature, most of the THF was evaporated in vacuo. The residue diluted in 150 mL water and treated with 1N HCl to pH = 3. After filtration and drying in vacuo for overnight, 1.52 g of the title compound was obtained. MS-(+)-ion, M+H = 357.83, 359.83. g) 3-Benzyloxy-6-bromo-quinoline-2-carbonyl chloride [0176] At 0 °C, to the solution of 3-Benzyloxy-6-bromo-quinoline-2-carboxylic acid (1.52 g, 4.3 mmol, 1.0 eq) in anhydrous THF (15 mL) was added oxalyl chloride (0.80 mL, 8.6 mmol, 2.0 eq), followed by 2 drops of DMF. The reaction was stirred at 0 °C for 1 hour, and then at room temperature for 1 hour. The solvent was evaporated in vacuo and further dried under high vacuum for 1 hour. The residue was used directly in the next step. h) 4-(3-Benzyloxy-6-bromo-quinolin-2-yl)-3,3-bis-tert-butoxycar bonyl-4-oxo-butyric acid ethyl ester [0177] A solution of 2-tert-Butoxycarbonyl-succinic acid 1-tert-butyl ester 4-ethyl ester (1.96 g, 6.5 mmol) in anhydrous tetrahydrofuran (15 mL) was added to a suspension of sodium hydride (0.26 g, 6.5 mmol, 60% dispersion) in anhydrous tetrahydrofuran (30 mL) at room temperature. The mixture was then stirred at 40 ^o C for 16 h. After cooling down to room temperature, a solution of 3-Benzyloxy-6- bromo-quinoline-2-carbonyl chloride (4.3 mmol) in anhydrous tetrahydrofuran (20 mL) was added, and the mixture was stirred at room temperature for 2 h. Then the mixture was treated with aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL X 3). The combined extract was washed with brine (100 mL), dried over sodium sulfate, and concentrated to a crude residue. The obtained crude was purified by column chromatography using 0-15% ethyl acetate in hexane as eluent to yield 2.41 g of the title compound. MS-(+)-ion, M+H = 643.98. i) 4-(3-Benzyloxy-6-bromo-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0178] p-Toluenesulfonic acid monohydrate (0.14 g, 0.74 mmol) was added to a solution of 4- (3-Benzyloxy-6-bromo-quinolin-2-yl)-3,3-bis-tert-butoxycarbo nyl-4-oxo-butyric acid ethyl ester (2.4 g, 3.7 mmol) in toluene (18 mL), and the mixture was refluxed for 2 h. After cooling to room temperature, the mixture was treated with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (30 mL X 3). The combined extract was dried over sodium sulfate, and concentrated to a crude residue. The obtained crude was purified by column chromatography using 0-10% ethyl acetate in hexane as eluent to yield 0.31 g of the title compound. MS-(+)-ion, M+H = 441.90, 443.85. j) 4-(6-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0179] The mixture of 4-(3-Benzyloxy-6-bromo-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (300 mg, 0.67 mmol) and thioanisole (246 mg, 2.0 mmol) in trifluoroacetic acid (4 mL) was heated at 80°C for 6 hours. After cooling down to room temperature, the reaction mixture was slowly quenched with sodium bicarbonate aqueous solution to pH = 7~8. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 118 mg. MS-(+)-ion, M+H = 353.88, 351.88. k) 4-(3-Hydroxy-6-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0180] A round bottom flask was charged with 4-(6-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (105 mg, 0.3 mmol), phenylboronic acid (55 mg, 0.45 mmol, 1.5 eq), S-Phos (9.9 mg, 0.024 mmol, 0.08 eq), palladium acetate (4.0 mg, 0.018 mmol, 0.06 eq), and tripotassium phosphate (127 mg, 0.6 mmol, 2.0 eq). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (3 mL) and water (10.8 mg, 0.6 mmol, 2.0 eq) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 99 mg. MS-(+)-ion, M+H = 350.03. l) 4-(4-Bromo-3-hydroxy-6-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0181] To a solution of 4-(3-Hydroxy-6-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (99 mg, 0.28 mmol) in acetonitrile (5 mL) was added N-Bromosuccinimide (55 mg, 0.31 mmol). The mixture was stirred at room temperature for 3h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to yield crude product; purified by column chromatography using 0-10% ethyl acetate in hexane as eluent gave 94 mg of the title compound. MS-(+)-ion, M+H = 429.85, 427.95. m) 4-(4-Cyano-3-hydroxy-6-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0182] A mixture of 4-(4-Bromo-3-hydroxy-6-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (86 mg, 0.2 mmol), zinc cyanide (47 mg, 0.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 22 mg, 0.04 mmol), and zinc dust (3.9 mg, 0.06 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 51 mg. MS-(+)-ion, M+H = 375.04. n) 4-(4-Cyano-3-hydroxy-6-phenyl-quinolin-2-yl)-4-oxo-butyric acid [0183] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-6-phenyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (48 mg, 0.13 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.39 mL, 0.39 mmol). After 2h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.17 mg. MS-(+)-ion, M+H = 346.98. Example 8 4-(6-Benzyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid a) 4-(6-Benzyl-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0184] At 0°C, to a solution of 4-(6-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (110 mg, 0.32 mmol), Pd(OAc)2 (7.2 mg, 0.032 mmol) and S-Phos (26 mg, 0.064 mmol) in dry THF (3 mL) was added dropwise a solution of benzylzinc(II) bromide in THF (0.8 mmol, 1.6 mL, 0.5 M) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour, then quenched by half saturated NH4Cl aqueous solution (20 mL) and extracted with ethyl acetate (20 mL X 3). The combined organic layers were dried (Na2SO4), concentrated under reduced pressure, and purified by flash column chromatography to give the 4-(6-Benzyl-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester, 79 mg. MS-(+)-ion, M+H = 364.03. b) 4-(6-Benzyl-4-bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0185] To a solution of 4-(6-Benzyl-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (76 mg, 0.21 mmol) in acetonitrile (5 mL) was added N-Bromosuccinimide (61 mg, 0.34 mmol). The mixture was stirred at room temperature for 3h. Silica gel was added to the reaction. The mixture was concentrated under vacuo yield crude product, which was purified by column chromatography using 0- 10% ethyl acetate in hexane as eluent gave 74 mg of the title compound. MS-(+)-ion, M+H = 443.80, 441.85. c) 4-(6-Benzyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0186] A mixture of 4-(6-Benzyl-4-bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (74 mg, 0.17 mmol), zinc cyanide (40 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.017 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 19 mg, 0.034 mmol), and zinc dust (3.3 mg, 0.05 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 51 mg. MS- (+)-ion, M+H = 389.04. d) 4-(6-Benzyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid [0187] At room temperature, to a solution of 4-(6-Benzyl-4-cyano-3-hydroxy-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (50 mg, 0.13 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.39 mL, 0.39 mmol). After 2h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.31 mg. MS-(+)-ion, M+H = 361.03. Example 9 4-(7-Benzyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid a) 3-Benzyloxy-7-bromo-quinoline-2-carboxylic acid [0188] At room temperature, to a solution of 3-Benzyloxy-7-bromo-quinoline-2-carboxylic acid ethyl ester (7.7 g, 20 mmol) in THF/H2O (60 mL/30 mL) was added lithium hydroxide monohydrate (2.46 g, 60 mmol). After 4 hours at room temperature, most of the THF was evaporated in vacuo. The residue diluted in 300 mL water and treated with 1N HCl to pH = 3. After filtration and drying in vacuo for overnight, 6.92 g of the title compound was obtained. MS-(+)-ion, M+H = 359.83, 357.88. b) 3-Benzyloxy-7-bromo-quinoline-2-carbonyl chloride [0189] At 0 °C, to the solution of 3-Benzyloxy-7-bromo-quinoline-2-carboxylic acid (6.9 g, 19.3 mmol, 1.0 eq) in anhydrous THF (60 mL) was added oxalyl chloride (3.3 mL, 4.9 mmol, 2.0 eq). The reaction was then at room temperature for 2 hours. The solvent was evaporated in vacuo and further dried under high vacuum for 1 hour. The residue was used directly in the next step. c) 4-(3-Benzyloxy-7-bromo-quinolin-2-yl)-3,3-bis-tert-butoxycar bonyl-4-oxo-butyric acid ethyl ester [0190] A solution of 2-tert-Butoxycarbonyl-succinic acid 1-tert-butyl ester 4-ethyl ester (8.76 g, 29 mmol) in anhydrous tetrahydrofuran (100 mL) was added to a suspension of sodium hydride (1.16 g, 29 mmol, 60% dispersion) in anhydrous tetrahydrofuran (100 mL) at room temperature. The mixture was then stirred at 40 ^o C for 16 h. After cooling down to room temperature, a solution of 3-Benzyloxy-7- bromo-quinoline-2-carbonyl chloride (19.3 mmol) in anhydrous tetrahydrofuran (60 mL) was added, and the mixture was stirred at room temperature for 18 h. Then the mixture was treated with aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (200 mL X 3). The combined extract was washed with brine (200 mL), dried over sodium sulfate, and concentrated to a crude residue. The obtained crude was purified by column chromatography using 0-15% ethyl acetate in hexane as eluent to yield 8.5 g of the title compound. MS-(+)-ion, M+H = 643.99, 642.04. d) 4-(3-Benzyloxy-7-bromo-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0191] p-Toluenesulfonic acid monohydrate (0.25 g, 1.32 mmol) was added to a solution of 4- (3-Benzyloxy-7-bromo-quinolin-2-yl)-3,3-bis-tert-butoxycarbo nyl-4-oxo-butyric acid ethyl ester (8.5 g, 13.2 mmol) in toluene (80 mL), and the mixture was refluxed for 3 h. After cooling to room temperature, the mixture was treated with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (100 mL X 3). The combined extract was dried over sodium sulfate, and concentrated to a crude residue. The obtained crude was purified by column chromatography using 0-15% ethyl acetate in hexane as eluent to yield 4.3 g of the title compound. MS-(+)-ion, M+H = 443.90. e) 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0192] The mixture of 4-(3-Benzyloxy-7-bromo-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (3.95 g, 11.3 mmol) and thioanisole (6.9 g, 56 mmol) in trifluoroacetic acid (10 mL) was heated at 80°C for 6 hours. After cooling down to room temperature, the reaction mixture was slowly quenched with sodium bicarbonate aqueous solution to pH = 7~8. The mixture was extracted with ethyl acetate (3x100 mL). The combined extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 2.45 g. MS-(+)-ion, M+H = 353.88. f) 4-(7-Benzyl-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0193] At 0°C, to a solution of 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (160 mg, 0.45 mmol), Pd(OAc)2 (20 mg, 0.09 mmol) and S-Phos (49 mg, 0.12 mmol) in dry THF (3 mL) was added dropwise a solution of benzylzinc(II) bromide in THF (1.15 mmol, 2.3 mL, 0.5 M) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour, then quenched by half saturated NH ₄ Cl aqueous solution (20 mL) and extracted with ethyl acetate (20 mL X 3). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and purified by flash column chromatography to give the 4-(7-Benzyl-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester, 151 mg. MS-(+)-ion, M+H = 364.08. g) 4-(7-Benzyl-4-bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0194] To a solution of 4-(7-Benzyl-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (150 mg, 0.45 mmol) in acetonitrile (5 mL) was added N-Bromosuccinimide (121 mg, 0.68 mmol). The mixture was stirred at room temperature for 3h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to get crude; purified by column chromatography using 0-10% ethyl acetate in hexane as eluent gave 116 mg of the title compound. MS-(+)-ion, M+H = 443.90, 441.95. h) 4-(7-Benzyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0195] A mixture of 4-(7-Benzyl-4-bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (110 mg, 0.25 mmol), zinc cyanide (58 mg, 0.50 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 28 mg, 0.05 mmol), and zinc dust (4.9 mg, 0.075 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 59 mg. MS- (+)-ion, M+H = 389.14. i) 4-(7-Benzyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid [0196] At room temperature, to a solution of 4-(7-Benzyl-4-cyano-3-hydroxy-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (58 mg, 0.15 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.45 mL, 0.45 mmol). After 18h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.11 mg. MS-(+)-ion, M+H = 361.08. Example 10 4-(4-Cyano-3-hydroxy-7-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid a) 4-(3-Hydroxy-7-phenylsulfanyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0197] To a round-bottom-flask were added 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (352mg, 1.0 mmol), Pd2(dba)3 (35.4 mg, 0.05 mmol), Xantphos (58 mg, 0.1 mmol), benzenethiol (165 mg, 1.5 mmol), and N,N-Diisopropylethylamine (0.35 mL, 2.0 mmol) in anhydrous 1,4-dioxane (5 mL). The mixture was heated at 105 °C under N2 atmosphere for 6 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 30 mL H ₂ O, treated with 1N HCl to pH = 3, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (100 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound 338 mg. MS-(+)-ion, M+H = 382.04. b) 4-(4-Bromo-3-hydroxy-7-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0198] At room temperature, to a solution of 4-(3-Hydroxy-7-phenylsulfanyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (291 mg, 0.76 mmol) and sodium acetate (125 mg, 1.52 mmol) in anhydrous CHCl ₃ (7 mL) was added bromine (184 mg, 1.14 mmol). After 30 min at room temperature, the reaction was quenched by saturated NaHSO ₃ aqueous solution and extracted with DCM (15mL x 3). The combined organics were washed with aqueous sodium bicarbonate, brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound.312 mg (~80% purity). MS-(+)-ion, M+H = 461.80. c) 4-(4-Cyano-3-hydroxy-7-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0199] A mixture of 4-(4-Bromo-3-hydroxy-7-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (311 mg, 0.67 mmol), zinc cyanide (149 mg, 1.35 mmol), tris(dibenzylideneacetone)dipalladium(0) (61 mg, 0.067 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 75 mg, 0.135 mmol), and zinc dust (13 mg, 0.20 mmol) in anhydrous dimethylacetamide (5 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (25 mL) and ethyl acetate (25 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 25 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 146 mg. MS-(+)-ion, M+H = 407.04. d) 4-(4-Cyano-3-hydroxy-7-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid [0200] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-7-phenylsulfanyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (61 mg, 0.15 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.45 mL, 0.45 mmol). After 18h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.23 mg. MS-(+)-ion, M+H = 378.99. Example 11 4-(7-Benzenesulfonyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid a) 4-(7-Benzenesulfonyl-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0201] At 0 ^o C, RuCl3.XH2O (0.02 mmol, 4 mg) was added to the mixture of 4-(3-Hydroxy-7- phenylsulfanyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (150 mg, 0.39 mmol) and NaIO4 (247 mg, 1.17 mmol) in CH3CN (10mL)/H2O (5mL). 20 min later, the reaction was diluted in 20 mL H2O, extracted with ethyl acetate (20 mL x 3). The combined organics were washed with brine (30 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 40%) to give the title compound 102 mg. MS-(+)-ion, M+H = 414.04. b) 4-(7-Benzenesulfonyl-4-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester [0202] To a solution of 4-(7-Benzenesulfonyl-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (100 mg, 0.24 mmol) in acetonitrile (5 mL) was added N-Bromosuccinimide (68 mg, 0.38 mmol). The mixture was stirred at room temperature for 1h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to get crude; purified by column chromatography using 0-10% ethyl acetate in hexane as eluent gave 84 mg of the title compound. MS-(+)-ion, M+H = 493.81. c) 4-(7-Benzenesulfonyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester [0203] A mixture of 4-(7-Benzenesulfonyl-4-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (84 mg, 0.17 mmol), zinc cyanide (40 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.017 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 19 mg, 0.034 mmol), and zinc dust (3.3 mg, 0.051 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 18 mg. MS-(+)-ion, M+H = 439.00. d) 4-(7-Benzenesulfonyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid [0204] At room temperature, to a solution of 4-(7-Benzenesulfonyl-4-cyano-3-hydroxy- quinolin-2-yl)-4-oxo-butyric acid ethyl ester (18 mg, 0.044 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.45 mL, 0.45 mmol). After 18h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.15 mg. MS-(+)-ion, M+H = 411.03. Example 12 4-[4-Cyano-3-hydroxy-7-(2-methyl-benzyl)-quinolin-2-yl]-4-ox o-butyric acid a) 4-[3-Hydroxy-7-(2-methyl-benzyl)-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester [0205] At 0°C, to a solution of 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (176 mg, 0.45 mmol), Pd(OAc)2 (22.4 mg, 0.10 mmol) and S-Phos (61 mg, 0.15 mmol) in dry THF (3 mL) was added dropwise a solution of 2-methylbenzyl zinc(II) bromide in THF (1.25 mmol, 2.5 mL, 0.5 M) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour, then quenched by half saturated NH ₄ Cl aqueous solution (20 mL) and extracted with ethyl acetate (20 mL X 3). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and purified by flash column chromatography to give the title compound, 156 mg. MS-(+)-ion, M+H = 378.09. b) 4-[4-Bromo-3-hydroxy-7-(2-methyl-benzyl)-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0206] To a solution of 4-[3-Hydroxy-7-(2-methyl-benzyl)-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester (155 mg, 0.41 mmol) in acetonitrile (5 mL) was added N-bromosuccinimide (109 mg, 0.61 mmol). The mixture was stirred at room temperature for 18h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to get crude; purified by column chromatography using 0-10% ethyl acetate in hexane as eluent gave 122 mg of the title compound. MS-(+)-ion, M+H = 457.88, 455.95. c) 4-[4-Cyano-3-hydroxy-7-(2-methyl-benzyl)-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0207] A mixture of 4-[4-Bromo-3-hydroxy-7-(2-methyl-benzyl)-quinolin-2-yl]-4-ox o-butyric acid ethyl ester (120 mg, 0.26 mmol), zinc cyanide (61 mg, 0.52 mmol), tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 29 mg, 0.052 mmol), and zinc dust (5.1 mg, 0.078 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 46 mg. MS-(+)-ion, M+H = 403.04. d) 4-[4-Cyano-3-hydroxy-7-(2-methyl-benzyl)-quinolin-2-yl]-4-ox o-butyric acid [0208] At room temperature, to a solution of 4-[4-Cyano-3-hydroxy-7-(2-methyl-benzyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester (45 mg, 0.09 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.36 mL, 0.36 mmol). After 5h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.27 mg. MS-(+)-ion, M+H = 375.09. Example 13 4-(4-Cyano-3-hydroxy-8-phenyl-quinolin-2-yl)-4-oxo-butyric acid a) (2-Amino-3-bromo-phenyl)-methanol [0209] To a solution of 2-amino-3-bromo benzoic acid (10 g, 46.2 mmol) in THF (100 mL), LiAlH ₄ (2.5 g, 69.3 mmol) was added at 0 ^o C and stirred at RT for 8 h, The reaction was quenched using saturated solution of sodium sulfate and filtered through celite bed to yield 7 g of title compound after trituration with hexane. MS: (+) m/z 202, 204 (M+1). b) 2-Amino-3-bromo-benzaldehyde [0210] To a solution of (2-Amino-3-bromo-phenyl)-methanol (7 g, 34.65 mmol) in DCM (200 mL) at room temperature was added MnO ₂ (30.14 g, 346 mmol) in portions. Reaction mixture was stirred at room temperature for 10 h. Reaction mixture was filtered through a pad of celite and washed with DCM, filtrate was concentrated under vacuo to get crude; The obtained crude was purified by column chromatography (10% EtOAc/hexane) to yield 5 g of the title compound. MS: (+) m/z 200, 202 (M+1). c) 3-Amino-8-bromo-quinoline-2-carboxylic acid ethyl ester [0211] A solution of ethyl bromopyruvate (3.57 mL, 27.5 mmol) in ethanol (25 mL) was added dropwise to a mixture of pyridine (2.2 mL, 27.5 mmol) and ethanol (20 mL) at room temperature for a period of more than 30 minutes and reaction mixture was stirred at rt for 1h to ensure the reaction was complete. The mixture was stirred at 60 ^o C for 2h and was cooled to room temperature. To the mixture was added 2-Amino-3-bromo-benzaldehyde (5 g, 25 mmol) and pyridine (20 mL). The mixture was refluxed at 85 ^o C for 4 hours. Pyrrolidine (5 mL, 62.5 mmol) was added and the mixture was refluxed at 85 ^o C for 4 hours. The reaction mixture was concentrated on rotavapor, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to get crude. The obtained crude was purified by column chromatography using 0-2% ethyl acetate in DCM as eluent gave 1 g of the title compound. MS: (+) m/z 295, 297 (M+1). d) 8-Bromo-3-hydroxy-quinoline-2-carboxylic acid ethyl ester [0212] 3-Amino-8-bromo-quinoline-2-carboxylic acid ethyl ester (2 g, 6.77 mmol) was dissolved in anhydrous THF (20 mL) and placed in an ice bath. With vigorous stirring, concentrated H ₂ SO ₄ (1.08 mL, 20.33 mmol) was slowly added to give a thick suspension. Butyl nitrite (2.3 mL, 20.33 mmol) was then added dropwise, and the resulting suspension was stirred vigorously in the ice bath for 2 h. The mixture was diluted with 10 mL of cold THF and the solid was isolated by filtration and dried under high vacuum for several hours. In a separate flask, glacial acetic acid (20 mL) was heated to 115 ^o C. The solid from above was suspended in glacial acetic acid (20 mL) and added to the pre-heated acetic acid, and the resulting homogeneous mixture was then stirred at 115-120 ^o C for 16 h. The reaction mixture was allowed to come to room temperature and concentrated to dryness. The residue was re- dissolved in absolute EtOH (30 mL) and placed in ice bath. Thionyl chloride (1 mL) was added, and the mixture was warmed to room temperature and refluxed for 16 h. The mixture was concentrated on rotavapor. Ethyl acetate was added to the reaction mixture and extracted with water and aq. sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated to get crude. The obtained crude was purified by column chromatography using 5% ethyl acetate in DCM as eluent to yield 415 mg of the title compound. MS: (+) m/z 296, 298 (M+1). e) 3-Benzyloxy-8-bromo-quinoline-2-carboxylic acid ethyl ester [0213] Benzyl bromide (2.1 mL, 2.98 g, 17.1 mmol) was added to a mixture of 8-Bromo-3- hydroxy-quinoline-2-carboxylic acid ethyl ester (3.63 g, 12.2 mmol) and cesium carbonate (4.8 g, 14.7 mmol) in anhydrous DMF (25 mL) at room temperature. After 3 hours at room temperature, TLC shows the completion of the reaction. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (4 x 30 mL). The combined extracts were washed with brine (2 x 30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 4.52 g. MS- (+)-ion, M+H = 387.94, 385.89. f) 3-Benzyloxy-8-bromo-quinoline-2-carboxylic acid [0214] At room temperature, to a solution of 4-(3-Benzyloxy-8-bromo-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (4.52 g, 12 mmol) in THF/H ₂ O (60 mL/30 mL) was added lithium hydroxide monohydrate (1.48 g, 36 mmol). After 5h at room temperature, most of the organic solvent was evaporated off.200 mL of water was the reaction mixture, followed by treatment with 1N HCl to pH = 3. The precipitation was filtrated off and dried under vacuum for overnight to afford the title compound. 3.86 g. MS-(+)-ion, M+H = 359.88. g) 3-Benzyloxy-8-bromo-quinoline-2-carbonyl chloride [0215] At 0 °C, to the solution of 3-Benzyloxy-8-bromo-quinoline-2-carboxylic acid (3.964 g, 11 mmol, 1.0 eq) in anhydrous THF (40 mL) was added oxalyl chloride (1.9 mL, 22 mmol, 2.0 eq). The reaction was stirred at room temperature for 2 hour. The solvent was evaporated in vacuo and further dried under high vacuum for 1 hour. The residue was used directly in the next step. h) 4-(3-Benzyloxy-8-bromo-quinolin-2-yl)-3,3-bis-tert-butoxycar bonyl-4-oxo-butyric acid ethyl ester [0216] A solution of 2-tert-Butoxycarbonyl-succinic acid 1-tert-butyl ester 4-ethyl ester (4.98 g, 16.5 mmol) in anhydrous tetrahydrofuran (40 mL) was added to a suspension of sodium hydride (0.66 g, 16.5 mmol, 60% dispersion) in anhydrous tetrahydrofuran (40 mL) at room temperature. The mixture was then stirred at 40 ^o C for 16 h. After cooling down to room temperature, a solution of 3-Benzyloxy-8- bromo-quinoline-2-carbonyl chloride (11 mmol) in anhydrous tetrahydrofuran (30 mL) was added, and the mixture was stirred at room temperature for 2 h. Then the mixture was treated with aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL X 3). The combined extract was washed with brine (100 mL), dried over sodium sulfate, and concentrated to a crude residue. The obtained crude was purified by column chromatography using 0-15% ethyl acetate in hexane as eluent to yield 4.3 g of the title compound. MS-(+)-ion, M+H = 644.05, 642.08. i) 4-(3-Benzyloxy-8-bromo-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0217] p-Toluenesulfonic acid monohydrate (0.12 g, 0.66 mmol) was added to a solution of 4- (3-Benzyloxy-8-bromo-quinolin-2-yl)-3,3-bis-tert-butoxycarbo nyl-4-oxo-butyric acid ethyl ester (4.28 g, 6.6 mmol) in toluene (30 mL), and the mixture was refluxed for 3 h. After cooling to room temperature, the mixture was treated with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (100 mL X 3). The combined extract was dried over sodium sulfate, and concentrated to a crude residue. The obtained crude was purified by column chromatography using 0-15% ethyl acetate in hexane as eluent to yield 2.62 g of the title compound. MS-(+)-ion, M+H = 443.90, 441.95. j) 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0218] The mixture of 4-(3-Benzyloxy-8-bromo-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (2.62 g, 4.8 mmol) and thioanisole (1.8 g, 14.4 mmol) in trifluoroacetic acid (6 mL) was heated at 80°C for 6 hours. After cooling down to room temperature, the reaction mixture was slowly quenched with sodium bicarbonate aqueous solution to pH = 7~8. The mixture was extracted with ethyl acetate (3x100 mL). The combined extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 1.59 g. MS-(+)-ion, M+H = 353.88, 351.83. k) 4-(3-Hydroxy-8-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0219] A round bottom flask was charged with 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.5 mmol), phenylboronic acid (98 mg, 0.8 mmol, 1.5 eq), S-Phos (16.5 mg, 0.04 mmol, 0.08 eq), palladium acetate (6.7 mg, 0.03 mmol, 0.06 eq), and tripotassium phosphate (212 mg, 1.0 mmol, 2.0 eq). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (3 mL) and water (18 mg, 1.0 mmol, 2.0 eq) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 157 mg. MS-(+)-ion, M+H = 350.03. l) 4-(4-Bromo-3-hydroxy-8-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0220] To a solution of 4-(3-Hydroxy-8-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (150 mg, 0.44 mmol) in acetonitrile (5 mL) was added N-bromosuccinimide (117 mg, 0.66 mmol). The mixture was stirred at room temperature for 18 h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to get crude; purified by column chromatography using 0-10% ethyl acetate in hexane as eluent gave 146 mg of the title compound. MS-(+)-ion, M+H = 429.80. m) 4-(4-Cyano-3-hydroxy-8-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0221] A mixture of 4-(4-Bromo-3-hydroxy-8-phenyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (145 mg, 0.34 mmol), zinc cyanide (80 mg, 0.68 mmol), tris(dibenzylideneacetone)dipalladium(0) (31 mg, 0.034 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 35 mg, 0.064 mmol), and zinc dust (6.5 mg, 0.1 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 81 mg. MS- (+)-ion, M+H = 375.04. n) 4-(4-Cyano-3-hydroxy-8-phenyl-quinolin-2-yl)-4-oxo-butyric acid [0222] At room temperature, to a solution of 4-(4-cyano-3-hydroxy-8-phenyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (80 mg, 0.21 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.05 mL, 1.05 mmol). After 5h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.27 mg. MS-(+)-ion, M+H = 346.98. Example 14 4-[4-Cyano-7-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid a) 4-[7-(2,6-Dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-bu tyric acid ethyl ester [0223] A round bottom flask was charged with 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (210 mg, 0.6 mmol), 2,6-dimethylphenylboronic acid (125 mg, 0.9 mmol, 1.5 eq), S-Phos (20 mg, 0.048 mmol, 0.08 eq), palladium acetate (8.1 mg, 0.036 mmol, 0.06 eq), and tripotassium phosphate (254 mg, 1.2 mmol, 2.0 eq). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (4 mL) and water (22 mg, 1.2 mmol, 2.0 eq) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 152 mg. MS-(+)-ion, M+H = 378.09. b) 4-[4-Bromo-7-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester [0224] To a solution of 4-[7-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-bu tyric acid ethyl ester (150 mg, 0.39 mmol) in acetonitrile (5 mL) was added N-bromosuccinimide (84 mg, 0.47 mmol). The mixture was stirred at room temperature for 18 h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to get crude; purified by column chromatography using 0-10% ethyl acetate in hexane as eluent gave 125 mg of the title compound. MS-(+)-ion, M+H = 453.95, 455.95. c) 4-[4-Cyano-7-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester [0225] A mixture of 4-[4-bromo-7-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo- butyric acid ethyl ester (125 mg, 0.27 mmol), zinc cyanide (63 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium(0) (25 mg, 0.027 mmol), 1,1’-bis(diphenylphosphino)ferrocene (dppf, 30 mg, 0.054 mmol), and zinc dust (5.3 mg, 0.081 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 42 mg. MS-(+)-ion, M+H = 403.14. d) 4-[4-Cyano-7-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid [0226] At room temperature, to a solution of 4-[4-cyano-7-(2,6-dimethyl-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester (41 mg, 0.1 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.5 mL, 0.5 mmol). After 20h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.27 mg. MS-(+)-ion, M+H = 375.04. Example 15 4-(4-Cyano-3-hydroxy-7-phenoxy-quinolin-2-yl)-4-oxo-butyric acid a) 4-(3-Benzyloxy-7-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0227] To a round-bottom-flask were added 4-(3-benzyloxy-7-bromo-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (221mg, 0.5 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol), t-BuXPhos (32 mg, 0.075 mmol), phenol (71 mg, 0.75 mmol), and K3PO4 (212 mg, 1.0 mmol) in anhydrous toluene (4 mL). The mixture was heated at 100 °C under N2 atmosphere for 2 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 30 mL H ₂ O, treated with 1N HCl to pH = 3, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (100 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 15%) to give the title compound 122 mg. MS-(+)-ion, M+H = 456.10. b) 4-(3-Hydroxy-7-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0228] The mixture of 4-(3-benzyloxy-7-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (120 mg, 0.26 mmol) and thioanisole (161 mg, 1.3 mmol) in trifluoroacetic acid (5 mL) was heated at 90°C for 6 hours. After cooling down to room temperature, the reaction mixture was slowly quenched with sodium bicarbonate aqueous solution to pH = 7~8. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 74 mg. MS-(+)-ion, M+H = 366.03. c) 4-(4-Bromo-3-hydroxy-7-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0229] At room temperature, to a solution of 4-(3-hydroxy-7-phenoxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (73 mg, 0.20 mmol) and sodium acetate (33 mg, 0.40 mmol) in anhydrous CHCl3 (4 mL) was added bromine (48 mg, 0.30 mmol). After 30 min at room temperature, the reaction was quenched by saturated NaHSO ₃ aqueous solution and extracted with DCM (15mL x 3). The combined organics were washed with aqueous sodium bicarbonate, brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound.71 mg (~70% purity). MS-(+)- ion, M+H = 443.95, 445.85. d) 4-(4-Cyano-3-hydroxy-7-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0230] A mixture of 4-(4-bromo-3-hydroxy-7-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (70 mg, 0.16 mmol), zinc cyanide (37 mg, 0.32 mmol), tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.016 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 18 mg, 0.038 mmol), and zinc dust (3.1 mg, 0.048 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 22 mg. MS- (+)-ion, M+H = 391.09. e) 4-(4-Cyano-3-hydroxy-7-phenoxy-quinolin-2-yl)-4-oxo-butyric acid [0231] At room temperature, to a solution of 4-(4-cyano-3-hydroxy-7-phenoxy-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (20 mg, 0.05 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.3 mL, 0.3 mmol). After 20h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.12 mg. MS-(+)-ion, M+H = 362.98. Example 16 4-(8-Benzyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid a) 4-(8-Benzyl-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0232] At 0°C, to a solution of 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (176 mg, 0.5 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol) and S-Phos (61 mg, 0.15 mmol) in dry THF (3 mL) was added dropwise a solution of benzylzinc(II) bromide in THF (1.25 mmol, 2.5 mL, 0.5 M) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour, then quenched by half saturated NH ₄ Cl aqueous solution (20 mL) and extracted with ethyl acetate (20 mL X 3). The combined organic layers were dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and purified by flash column chromatography to give the title compound, 136 mg. MS-(+)-ion, M+H = 364.08 b) 4-(8-Benzyl-4-bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0233] To a solution of 4-(8-Benzyl-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (134 mg, 0.37 mmol) in acetonitrile (5 mL) was added N-bromosuccinimide (79 mg, 0.44 mmol). The mixture was stirred at room temperature for 18 h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to get crude; purified by column chromatography using 0-10% ethyl acetate in hexane as eluent gave 99 mg of the title compound. MS-(+)-ion, M+H = 443.80, 441.90. c) 4-(8-Benzyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0234] A mixture of 4-(8-Benzyl-4-bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (98 mg, 0.22 mmol), zinc cyanide (51 mg, 0.44 mmol), tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.022 mmol), 1,1'-bis(diphenylphosphino)ferrocene (dppf, 24 mg, 0.044 mmol), and zinc dust (4.3 mg, 0.066 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 30%) to give the title compound, 42 mg. MS- (+)-ion, M+H = 389.09. d) 4-(8-Benzyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid [0235] At room temperature, to a solution of 4-(8-benzyl-4-cyano-3-hydroxy-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (40 mg, 0.05 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.5 mL, 0.5 mmol). After 20h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.25 mg. MS-(+)-ion, M+H = 361.08. Example 17 4-(4-Cyano-3-hydroxy-7-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid a) 4-(3-Hydroxy-7-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0236] A round bottom flask was charged with 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.5 mmol), 2-methylphenylboronic acid (136 mg, 1.0 mmol), S-Phos (16.5 mg, 0.04 mmol), palladium acetate (6.7 mg, 0.03 mmol), and tripotassium phosphate (212 mg, 1.0 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (4 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 163 mg. MS-(+)-ion, M+H = 364.08. b) 4-(4-Bromo-3-hydroxy-7-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0237] To a solution of 4-(3-Hydroxy-7-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (160 mg, 0.44 mmol) in acetonitrile (5 mL) was added N-bromosuccinimide (95 mg, 0.53 mmol). The mixture was stirred at room temperature for 48 h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to get crude; purified by column chromatography using 0-10% ethyl acetate in hexane as eluent gave 165 mg of the title compound. MS-(+)-ion, M+H = 443.85. c) 4-(4-Cyano-3-hydroxy-7-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0238] A mixture of 4-(4-bromo-3-hydroxy-7-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (165 mg, 0.37 mmol), zinc cyanide (87 mg, 0.74 mmol), tris(dibenzylideneacetone)dipalladium(0) (34 mg, 0.037 mmol), 1,1'-bis(diphenylphosphino)ferrocene (dppf, 41 mg, 0.074 mmol), and zinc dust (7.1 mg, 0.11 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 106 mg. MS- (+)-ion, M+H = 389.09. d) 4-(4-Cyano-3-hydroxy-7-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid [0239] At room temperature, to a solution of 4-(4-cyano-3-hydroxy-7-o-tolyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (105 mg, 0.27 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.35 mL, 1.35 mmol). After 20h at room temperature, the reaction was diluted in 35 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.76 mg. MS-(+)-ion, M+H = 361.03. Example 18 4-(4-Cyano-3-hydroxy-7-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid a) 4-(3-Hydroxy-7-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0240] A round bottom flask was charged with 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.5 mmol), 3-methylphenylboronic acid (136 mg, 1.0 mmol), S-Phos (16.5 mg, 0.04 mmol), palladium acetate (6.7 mg, 0.03 mmol), and tripotassium phosphate (212 mg, 1.0 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (4 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 172 mg. MS-(+)-ion, M+H = 364.08. b) 4-(4-Bromo-3-hydroxy-7-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0241] To a solution of 4-(3-hydroxy-7-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (172 mg, 0.48 mmol) in acetonitrile (5 mL) was added N-bromosuccinimide (111 mg, 0.62 mmol). The mixture was stirred at room temperature for 48 h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to get crude; purified by column chromatography using 0-10% ethyl acetate in hexane as eluent gave 146 mg of the title compound. MS-(+)-ion, M+H = 443.80, 441.95. c) 4-(4-Cyano-3-hydroxy-7-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0242] A mixture of 4-(4-bromo-3-hydroxy-7-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (145 mg, 0.33 mmol), zinc cyanide (77 mg, 0.66 mmol), tris(dibenzylideneacetone)dipalladium(0) (30 mg, 0.033 mmol), 1,1'-bis(diphenylphosphino)ferrocene (dppf, 37 mg, 0.066 mmol), and zinc dust (6.5 mg, 0.10 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 68 mg. MS- (+)-ion, M+H = 389.07. d) 4-(4-Cyano-3-hydroxy-7-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid [0243] At room temperature, to a solution of 4-(4-cyano-3-hydroxy-7-m-tolyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (68 mg, 0.27 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.9 mL, 0.9 mmol). After 20h at room temperature, the reaction was diluted in 35 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.45 mg. MS-(+)-ion, M+H = 361.03. Example 19 4-(4-Cyano-3-hydroxy-7-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid a) 4-(3-Hydroxy-7-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0244] A round bottom flask was charged with 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.5 mmol), 4-methylphenylboronic acid (136 mg, 1.0 mmol), S-Phos (16.5 mg, 0.04 mmol), palladium acetate (6.7 mg, 0.03 mmol), and tripotassium phosphate (212 mg, 1.0 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (4 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 161 mg. MS-(+)-ion, M+H = 364.13. b) 4-(4-Bromo-3-hydroxy-7-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0245] To a solution of 4-(3-hydroxy-7-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (160 mg, 0.44 mmol) in acetonitrile (5 mL) was added N-bromosuccinimide (111 mg, 0.62 mmol). The mixture was stirred at room temperature for 48 h. Silica gel was added to the reaction. The mixture was concentrated under vacuo to get crude; purified by column chromatography using 0-10% ethyl acetate in hexane as eluent gave 146 mg of the title compound. MS-(+)-ion, M+H = 443.85, 441.95. c) 4-(4-Cyano-3-hydroxy-7-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0246] A mixture of 4-(4-Bromo-3-hydroxy-7-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (118 mg, 0.27 mmol), zinc cyanide (63 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium(0) (25 mg, 0.027 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 30 mg, 0.054 mmol), and zinc dust (5.3 mg, 0.08 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 61 mg. MS- (+)-ion, M+H = 389.04. d) 4-(4-Cyano-3-hydroxy-7-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid [0247] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-7-p-tolyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (60 mg, 0.16 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.8 mL, 0.8 mmol). After 20h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.43 mg. MS-(+)-ion, M+H = 361.03. Example 20 4-(4-Cyano-3-hydroxy-6-phenoxy-quinolin-2-yl)-4-oxo-butyric acid a) 4-(3-Benzyloxy-6-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0248] To a round-bottom-flask were added 4-(3-Benzyloxy-6-bromo-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (221mg, 0.5 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol), t-BuXPhos (32 mg, 0.075 mmol), phenol (71 mg, 0.75 mmol), and K ₃ PO ₄ (212 mg, 1.0 mmol) in anhydrous toluene (4 mL). The mixture was heated at 100 °C under N ₂ atmosphere for 2 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 30 mL H2O, treated with 1N HCl to pH = 3, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (100 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 15%) to give the title compound 146 mg. MS-(+)-ion, M+H = 456.15. b) 4-(3-Hydroxy-6-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0249] The mixture of 4-(3-Benzyloxy-6-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (145 mg, 0.32 mmol) and thioanisole (200 mg, 1.6 mmol) in trifluoroacetic acid (3 mL) was heated at 90°C for 6 hours. After cooling down to room temperature, the reaction mixture was slowly quenched with sodium bicarbonate aqueous solution to pH = 7~8. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 109 mg. MS-(+)-ion, M+H = 366.03. c) 4-(4-Bromo-3-hydroxy-6-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0250] To a solution of 4-(3-Hydroxy-6-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (136 mg, 0.37 mmol) in DMF (4 mL) was added N-Bromosuccinimide (73 mg, 0.41 mmol). The mixture was stirred at room temperature for 1h and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 83 mg. MS-(+)-ion, M+H = 445.85, 443.90. d) 4-(4-Cyano-3-hydroxy-6-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0251] A mixture of 4-(4-Bromo-3-hydroxy-6-phenoxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (82 mg, 0.18 mmol), zinc cyanide (42 mg, 0.36 mmol), tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.018 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 20 mg, 0.036 mmol), and zinc dust (3.5 mg, 0.054 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 33 mg. MS- (+)-ion, M+H = 391.04. e) 4-(4-Cyano-3-hydroxy-6-phenoxy-quinolin-2-yl)-4-oxo-butyric acid [0252] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-6-phenoxy-quinolin-2-yl)- 4-oxo-butyric acid ethyl ester (30 mg, 0.077 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.46 mL, 0.46 mmol). After 20h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.17 mg. MS-(+)-ion, M+H = 363.08. Example 21 4-(4-Cyano-3-hydroxy-6-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid a) 4-(3-Hydroxy-6-phenylsulfanyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0253] To a round-bottom-flask were added 4-(6-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (352mg, 1.0 mmol), Pd2(dba)3 (35.4 mg, 0.05 mmol), Xantphos (58 mg, 0.1 mmol), benzenethiol (165 mg, 1.5 mmol), and N,N-Diisopropylethylamine (0.35 mL, 2.0 mmol) in anhydrous 1,4-dioxane (5 mL). The mixture was heated at 105 °C under N ₂ atmosphere for 6 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 30 mL H ₂ O, treated with 1N HCl to pH = 3, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (100 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound 356 mg. MS-(+)-ion, M+H = 381.99. b) 4-(4-Bromo-3-hydroxy-6-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0254] To a solution of 4-(3-Hydroxy-6-phenylsulfanyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (196 mg, 0.51 mmol) in DMF (6 mL) was added N-Bromosuccinimide (99 mg, 0.56 mmol). The mixture was stirred at room temperature for 20 min and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 232 mg. MS-(+)-ion, M+H = 461.80. c) 4-(4-Cyano-3-hydroxy-6-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0255] A mixture of 4-(4-Bromo-3-hydroxy-6-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (230 mg, 0.50 mmol), zinc cyanide (117 mg, 1.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 55 mg, 0.10 mmol), and zinc dust (9.7 mg, 0.15 mmol) in anhydrous dimethylacetamide (5 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (25 mL) and ethyl acetate (25 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 116 mg. MS-(+)-ion, M+H = 407.04. d) 4-(4-Cyano-3-hydroxy-6-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid [0256] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-6-phenylsulfanyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (30 mg, 0.07 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.46 mL, 0.46 mmol). After 20h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.26 mg. MS-(+)-ion, M+H = 378.94. Example 22 4-(6-Benzenesulfonyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid a) 4-(6-Benzenesulfonyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester [0257] To a solution of 4-(4-Cyano-3-hydroxy-6-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (70 mg, 0.17 mmol) in DCM (6 mL) was added meta-chloroperoxybenzoic acid (88 mg, 0.51 mmol). The mixture was stirred at room temperature for 3h and then quenched with saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (50% - 100%) to give the title compound, 53 mg. MS-(+)-ion, M+H = 439.00 b) 4-(6-Benzenesulfonyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid [0258] At room temperature, to a solution of 4-(6-Benzenesulfonyl-4-cyano-3-hydroxy- quinolin-2-yl)-4-oxo-butyric acid ethyl ester (52 mg, 0.12 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.6 mL, 0.6 mmol). After 20h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.17 mg. MS-(+)-ion, M+H = 410.97. Example 23 4-[4-Cyano-6-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid a) 4-[6-(2,6-Dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-bu tyric acid ethyl ester [0259] A round bottom flask was charged with 4-(6-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.5 mmol), 2,6-dimethylphenylboronic acid (136 mg, 1.0 mmol), S- Phos (16.5 mg, 0.04 mmol), palladium acetate (6.7 mg, 0.03 mmol), and tripotassium phosphate (212 mg, 1.0 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (4 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 161 mg. MS-(+)-ion, M+H = 378.09. b) 4-[4-Bromo-6-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester [0260] To a solution of 4-[6-(2,6-Dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-bu tyric acid ethyl ester (160 mg, 0.42 mmol) in DMF (4 mL) was added N-bromosuccinimide (83 mg, 0.46 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 173 mg. MS- (+)-ion, M+H = 455.95, 457.90. c) 4-[4-Cyano-6-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester [0261] A mixture of 4-[4-Bromo-6-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo- butyric acid ethyl ester (173 mg, 0.38 mmol), zinc cyanide (89 mg, 0.76 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 42 mg, 0.076 mmol), and zinc dust (8.2 mg, 0.13 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (25 mL) and ethyl acetate (25 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 92 mg. MS-(+)-ion, M+H = 403.08. d) 4-[4-Cyano-6-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid [0262] At room temperature, to a solution of 4-[4-Cyano-6-(2,6-dimethyl-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester (90 mg, 0.22 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.1 mL, 1.1 mmol). After 20h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.57 mg. MS-(+)-ion, M+H = 375.07. Example 24 4-(4-Cyano-3-hydroxy-7-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid a) 4-(3-Hydroxy-7-phenylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0263] To a round-bottom-flask were added 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (71 mg, 0.20 mmol), PdCl2(PPh3)2 (28 mg, 0.04 mmol), and tributyl- phenylethynyl-stannane (0.12 mL, 0.32 mmol) in anhydrous DMF (3 mL). The mixture was heated at 120 °C under N2 atmosphere for 2 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 20 mL H ₂ O, and extracted with ethyl acetate (20 mL x 3). The combined organics were washed with brine (20 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 77 mg, MS-(+)-ion, M+H = 374.12. b) 4-(3-Hydroxy-7-phenethyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0264] To a solution of 4-(3-Hydroxy-7-phenylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (77 mg, 0.21 mmol) in ethyl acetate (6 mL) was added Pd/C (11 mg, 0.05eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 16 hr at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hexane (0% - 20%) to give the title compound, 46 mg, MS-(+)-ion, M+H = 378.10. c) 4-(4-Bromo-3-hydroxy-7-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid ethyl ester [0265] To a solution of from 4-(3-Hydroxy-7-phenethyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (38 mg, 0.10 mmol) in DMF (2 mL) was added N-Bromosuccinimide (21 mg, 0.12 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x10 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 38 mg. MS-(+)-ion, M+H = 457.93, 455.93. d) 4-(4-Cyano-3-hydroxy-7-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid ethyl ester [0266] A mixture of 4-(4-Bromo-3-hydroxy-7-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid ethyl ester (37 mg, 0.08 mmol), zinc cyanide (19 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium(0) (7.3 mg, 0.008 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 8.9 mg, 0.016 mmol), and zinc dust (1.7 mg, 0.024 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 14 mg. MS- (+)-ion, M+H = 403.09. e) 4-(4-Cyano-3-hydroxy-7-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid [0267] At room temperature, to a solution of 4-(4-cyano-3-hydroxy-7-phenethyl-quinolin-2-yl)- 4-oxo-butyric acid ethyl ester (12 mg, 0.03 mmol) in methanol(1 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.15 mL, 0.15 mmol). After 3h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.3.0 mg. MS-(+)-ion, M+H = 375.09. Example 25 4-(4-Cyano-3-hydroxy-6-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid a) 4-(3-Hydroxy-6-phenylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0268] To a round-bottom-flask were added 4-(6-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.50 mmol), PdCl ₂ (PPh ₃ ) ₂ (71 mg, 0.2 mmol), and tributyl- phenylethynyl-stannane (0.31 mL, 0.8 mmol) in anhydrous DMF (5 mL). The mixture was heated at 120 °C under N2 atmosphere for 2 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 20 mL H2O, and extracted with ethyl acetate 2 x 3). The combined organics were washed with brine (20 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 156 mg, MS-(+)-ion, M+H = 374.08. b) 4-(3-Hydroxy-6-phenethyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0269] To a solution of 4-(3-Hydroxy-6-phenylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (155 mg, 0.42 mmol) in ethyl acetate (8 mL) was added Pd/C (22 mg, 0.05eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 16 hr at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hexane (0% - 20%) to give the title compound, 112 mg, MS-(+)-ion, M+H = 378.09. c) 4-(4-Bromo-3-hydroxy-6-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid ethyl ester [0270] To a solution of from 4-(3-Hydroxy-6-phenethyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (112 mg, 0.30 mmol) in DMF (5 mL) was added N-Bromosuccinimide (64 mg, 0.36 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 114 mg. MS-(+)-ion, M+H = 457.93, 455.93. d) 4-(4-Cyano-3-hydroxy-6-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid ethyl ester [0271] A mixture of 4-(4-Bromo-3-hydroxy-6-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid ethyl ester (112 mg, 0.25 mmol), zinc cyanide (59 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 28 mg, 0.05 mmol), and zinc dust (4.9 mg, 0.075 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 42 mg. MS- (+)-ion, M+H = 403.09. e) 4-(4-Cyano-3-hydroxy-6-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid [0272] At room temperature, to a solution of 4-(4-cyano-3-hydroxy-6-phenethyl-quinolin-2-yl)- 4-oxo-butyric acid ethyl ester (40 mg, 0.1 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.5 mL, 0.5 mmol). After 3h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.15 mg. MS-(+)-ion, M+H = 375.09. Example 26 4-(4-Cyano-3-hydroxy-6-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid a) 4-(3-Hydroxy-6-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0273] A round bottom flask was charged with 4-(6-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.5 mmol), 2-methylphenylboronic acid (136 mg, 1.0 mmol), S-Phos (16.5 mg, 0.04 mmol), palladium acetate (6.7 mg, 0.03 mmol), and tripotassium phosphate (212 mg, 1.0 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (4 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 161 mg. MS-(+)-ion, M+H = 364.08. b) 4-(4-Bromo-3-hydroxy-6-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0274] To a solution of from 4-(3-hydroxy-6-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (175 mg, 0.48 mmol) in DMF (5 mL) was added N-bromosuccinimide (90 mg, 0.51 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 170 mg. MS-(+)-ion, M+H = 443.90, 441.95. c) 4-(4-Cyano-3-hydroxy-6-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0275] A mixture of 4-(4-bromo-3-hydroxy-6-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (170 mg, 0.23 mmol) and zinc(II) cyanide (54 mg, 0.46 mmol), tris(dibenzylideneacetone)dipalladium(0) (21 mg, 0.023 mmol), 1,1'-bis(diphenylphosphino)ferrocene (dppf, 25 mg, 0.046 mmol), and zinc dust (4.6 mg, 0.07 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 96 mg. MS-(+)-ion, M+H = 389.07. d) 4-(4-Cyano-3-hydroxy-6-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid [0276] At room temperature, to a solution of 4-(4-cyano-3-hydroxy-6-o-tolyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (95 mg, 0.25 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.25 mL, 1.25 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.52 mg. MS-(+)-ion, M+H = 361.08. Example 27 4-(4-Cyano-3-hydroxy-6-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid a) 4-(3-Hydroxy-6-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0277] A round bottom flask was charged with 4-(6-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.5 mmol), 3-methylphenylboronic acid (136 mg, 1.0 mmol), S-Phos (16.5 mg, 0.04 mmol), palladium acetate (6.7 mg, 0.03 mmol), and tripotassium phosphate (212 mg, 1.0 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (4 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 156 mg. MS-(+)-ion, M+H = 364.08. b) 4-(4-Bromo-3-hydroxy-6-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0278] To a solution of from 4-(3-Hydroxy-6-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (156 mg, 0.43 mmol) in DMF (5 mL) was added N-Bromosuccinimide (78 mg, 0.44 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 176 mg. MS-(+)-ion, M+H = 443.85, 442.00. c) 4-(4-Cyano-3-hydroxy-6-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0279] A mixture of 4-(4-Bromo-3-hydroxy-6-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (170 mg, 0.38 mmol) and zinc(II) cyanide (89 mg, 0.76 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 42 mg, 0.076 mmol), and zinc dust (7.4 mg, 0.114 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 96 mg. MS-(+)-ion, M+H = 389.07. d) 4-(4-Cyano-3-hydroxy-6-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid [0280] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-6-m-tolyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (95 mg, 0.25 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.25 mL, 1.25 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.52 mg. MS-(+)-ion, M+H = 361.03. Example 28 4-(4-Cyano-3-hydroxy-6-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid a) 4-(3-Hydroxy-6-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0281] A round bottom flask was charged with 4-(6-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (106 mg, 0.3 mmol), 4-methylphenylboronic acid (82 mg, 0.6 mmol), S-Phos (9.8 mg, 0.024 mmol), palladium acetate (4.0 mg, 0.018 mmol), and tripotassium phosphate (127 mg, 0.6 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (4 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 110 mg. MS-(+)-ion, M+H = 364.08. b) 4-(4-Bromo-3-hydroxy-6-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0282] To a solution of from 4-(3-Hydroxy-6-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (110 mg, 0.3 mmol) in DMF (4 mL) was added N-Bromosuccinimide (55 mg, 0.31 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 116 mg. MS-(+)-ion, M+H = 443.91, 441.94. c) 4-(4-Cyano-3-hydroxy-6-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0283] A mixture of 4-(4-Bromo-3-hydroxy-6-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (115 mg, 0.26 mmol) and zinc(II) cyanide (61 mg, 0.52 mmol), tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 29 mg, 0.052 mmol), and zinc dust (5.1 mg, 0.078 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 69 mg. MS-(+)-ion, M+H = 389.04. d) 4-(4-Cyano-3-hydroxy-6-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid [0284] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-6-p-tolyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (68 mg, 0.18 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.9 mL, 0.9 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.43 mg. MS-(+)-ion, M+H = 361.08. Example 29 4-(4-Cyano-3-hydroxy-8-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid a) 4-(3-Hydroxy-8-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0285] A round bottom flask was charged with 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (106 mg, 0.3 mmol), 2-methylphenylboronic acid (82 mg, 0.6 mmol), S-Phos (9.8 mg, 0.024 mmol), palladium acetate (4.0 mg, 0.018 mmol), and tripotassium phosphate (127 mg, 0.6 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (4 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 116 mg. MS-(+)-ion, M+H = 364.08. b) 4-(4-Bromo-3-hydroxy-8-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0286] To a solution of from 4-(3-Hydroxy-8-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (115 mg, 0.31 mmol) in DMF (4 mL) was added N-Bromosuccinimide (57 mg, 0.32 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 132 mg. MS-(+)-ion, M+H = 443.85, 441.95. c) 4-(4-Cyano-3-hydroxy-8-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0287] A mixture of 4-(4-bromo-3-hydroxy-8-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (130 mg, 0.3 mmol) and zinc(II) cyanide (70 mg, 0.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol), 1,1'-bis(diphenylphosphino)ferrocene (dppf, 33 mg, 0.06 mmol), and zinc dust (6.0 mg, 0.09 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 52 mg. MS-(+)-ion, M+H = 389.09. d) 4-(4-Cyano-3-hydroxy-8-o-tolyl-quinolin-2-yl)-4-oxo-butyric acid [0288] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-8-o-tolyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (50 mg, 0.13 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.65 mL, 0.65 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.26 mg. MS-(+)-ion, M+H = 361.08. Example 30 4-(4-Cyano-3-hydroxy-8-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid a) 4-(3-Hydroxy-8-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0289] A round bottom flask was charged with 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (106 mg, 0.3 mmol), 3-methylphenylboronic acid (82 mg, 0.6 mmol), S-Phos (9.8 mg, 0.024 mmol), palladium acetate (4.0 mg, 0.018 mmol), and tripotassium phosphate (127 mg, 0.6 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (4 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 105 mg. MS-(+)-ion, M+H = 364.08. b) 4-(4-Bromo-3-hydroxy-8-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0290] To a solution of from 4-(3-Hydroxy-8-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (104 mg, 0.29 mmol) in DMF (4 mL) was added N-Bromosuccinimide (52 mg, 0.30 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 115 mg. MS-(+)-ion, M+H = 443.85, 441.90. c) 4-(4-Cyano-3-hydroxy-8-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0291] A mixture of 4-(4-Bromo-3-hydroxy-8-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (112 mg, 0.25 mmol) and zinc(II) cyanide (59 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 28 mg, 0.05 mmol), and zinc dust (4.9 mg, 0.075 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 77 mg. MS-(+)-ion, M+H = 389.09. d) 4-(4-Cyano-3-hydroxy-8-m-tolyl-quinolin-2-yl)-4-oxo-butyric acid [0292] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-8-m-tolyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (76 mg, 0.20 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.0 mL, 1.0 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.21 mg. MS-(+)-ion, M+H = 361.03. Example 31 4-(4-Cyano-3-hydroxy-8-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid a) 4-(3-Hydroxy-8-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0293] A round bottom flask was charged with 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (106 mg, 0.3 mmol), 4-methylphenylboronic acid (82 mg, 0.6 mmol), S-Phos (9.8 mg, 0.024 mmol), palladium acetate (4.0 mg, 0.018 mmol), and tripotassium phosphate (127 mg, 0.6 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (4 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 89 mg. MS-(+)-ion, M+H = 364.08. b) 4-(4-Bromo-3-hydroxy-8-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0294] To a solution of from 4-(3-Hydroxy-8-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (88 mg, 0.24 mmol) in DMF (4 mL) was added N-Bromosuccinimide (44 mg, 0.25 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 101 mg. MS-(+)-ion, M+H = 443.85, 441.95. c) 4-(4-Cyano-3-hydroxy-8-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0295] A mixture of 4-(4-Bromo-3-hydroxy-8-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (99 mg, 0.22 mmol) and zinc(II) cyanide (52 mg, 0.44 mmol), tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.022 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 24 mg, 0.044 mmol), and zinc dust (4.3 mg, 0.066 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 54 mg. MS-(+)-ion, M+H = 389.09. d) 4-(4-Cyano-3-hydroxy-8-p-tolyl-quinolin-2-yl)-4-oxo-butyric acid [0296] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-8-p-tolyl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester (53 mg, 0.14 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.7 mL, 0.7 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.23 mg. MS-(+)-ion, M+H = 361.08. Example 32 4-[4-Cyano-3-hydroxy-7-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-7-(2-trifluoromethyl-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0297] A round bottom flask was charged with 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.5 mmol), 2-trifluoromethylphenylboronic acid (190 mg, 1.0 mmol), S- Phos (33 mg, 0.08 mmol), palladium acetate (13.4 mg, 0.06 mmol), and tripotassium phosphate (212 mg, 1.0 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (3 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 195 mg. MS-(+)-ion, M+H = 418.09. b) 4-[4-Bromo-3-hydroxy-7-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0298] To a solution of from 4-[3-Hydroxy-7-(2-trifluoromethyl-phenyl)-quinolin-2-yl]-4-o xo- butyric acid ethyl ester (193 mg, 0.46 mmol) in DMF (6 mL) was added N-Bromosuccinimide (85 mg, 0.47 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 208 mg. MS- (+)-ion, M+H = 497.86. c) 4-[4-Cyano-3-hydroxy-7-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0299] A mixture of 4-[4-Bromo-3-hydroxy-7-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo- butyric acid ethyl ester (206 mg, 0.40 mmol) and zinc(II) cyanide (94 mg, 0.80 mmol), tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 44 mg, 0.08 mmol), and zinc dust (7.8 mg, 0.12 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 119 mg. MS-(+)-ion, M+H = 443.00. d) 4-[4-Cyano-3-hydroxy-7-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid [0300] At room temperature, to a solution of 4-[4-Cyano-3-hydroxy-7-(2-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester (118 mg, 0.27 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.35 mL, 1.35 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.73 mg. MS-(+)-ion, M+H = 414.99. Example 33 4-[4-Cyano-3-hydroxy-7-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-7-(4-trifluoromethyl-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0301] A round bottom flask was charged with 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (106 mg, 0.3 mmol),4-trifluoromethylphenylboronic acid (114 mg, 0.6 mmol), S- Phos (19.7 mg, 0.048 mmol), palladium acetate (8.1 mg, 0.036 mmol), and tripotassium phosphate (127 mg, 0.6 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (3 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 68 mg. MS-(+)-ion, M+H = 418.04. b) 4-[4-Bromo-3-hydroxy-7-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0302] To a solution of from 4-[3-Hydroxy-7-(4-trifluoromethyl-phenyl)-quinolin-2-yl]-4-o xo- butyric acid ethyl ester (65 mg, 0.16 mmol) in DMF (3 mL) was added N-Bromosuccinimide (29 mg, 0.17 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 61 mg. MS- (+)-ion, M+H = 495.76, 497.81. c) 4-[4-Cyano-3-hydroxy-7-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0303] A mixture of 4-[4-Bromo-3-hydroxy-7-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo- butyric acid ethyl ester (60 mg, 0.12 mmol) and zinc(II) cyanide (28 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.012 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 13 mg, 0.074 mmol), and zinc dust (2.4 mg, 0.036 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 38 mg. MS-(+)-ion, M+H = 443.05. d) 4-[4-Cyano-3-hydroxy-7-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid [0304] At room temperature, to a solution of 4-[4-Cyano-3-hydroxy-7-(4-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester (35 mg, 0.08 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.48 mL, 0.48 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.20 mg. MS-(+)-ion, M+H = 414.99. Example 34 4-[4-Cyano-3-hydroxy-7-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-7-(3-trifluoromethyl-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0305] A round bottom flask was charged with 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.5 mmol), 3-trifluoromethylphenylboronic acid (190 mg, 1.0 mmol), S- Phos (33 mg, 0.08 mmol), palladium acetate (13.4 mg, 0.06 mmol), and tripotassium phosphate (212 mg, 1.0 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (3 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 169 mg. MS-(+)-ion, M+H = 417.99. b) 4-[4-Bromo-3-hydroxy-7-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0306] To a solution of from 4-[3-Hydroxy-7-(3-trifluoromethyl-phenyl)-quinolin-2-yl]-4-o xo- butyric acid ethyl ester (168 mg, 0.40 mmol) in DMF (6 mL) was added N-Bromosuccinimide (73 mg, 0.41 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 173 mg. MS- (+)-ion, M+H = 497.86, 495.91. c) 4-[4-Cyano-3-hydroxy-7-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0307] A mixture of 4-[4-Bromo-3-hydroxy-7-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo- butyric acid ethyl ester (170 mg, 0.35 mmol) and zinc(II) cyanide (82 mg, 0.70 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.035 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 39 mg, 0.07 mmol), and zinc dust (6.8 mg, 0.105 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 87 mg. MS-(+)-ion, M+H = 443.05. d) 4-[4-Cyano-3-hydroxy-7-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid [0308] At room temperature, to a solution of 4-[4-Cyano-3-hydroxy-7-(3-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester (87 mg, 0.20 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.0 mL, 1.0 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.37 mg. MS-(+)-ion, M+H = 414.99. Example 35 4-[4-Cyano-3-hydroxy-7-(2-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo-butyric acid a) 4-[3-Hydroxy-7-(2-isopropyl-phenyl)-quinolin-2-yl]-4-oxo-but yric acid ethyl ester [0309] A round bottom flask was charged with 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.5 mmol), 2-isopropylphenylboronic acid (164 mg, 1.0 mmol), S-Phos (33 mg, 0.08 mmol), palladium acetate (13.4 mg, 0.06 mmol), and tripotassium phosphate (212 mg, 1.0 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (3 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 190 mg. MS-(+)-ion, M+H = 392.14. b) 4-[4-Bromo-3-hydroxy-7-(2-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo-butyric acid ethyl ester [0310] To a solution of from 4-[3-Hydroxy-7-(2-isopropyl-phenyl)-quinolin-2-yl]-4-oxo-but yric acid ethyl ester (180 mg, 0.46 mmol) in DMF (6 mL) was added N-Bromosuccinimide (85 mg, 0.47 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 192 mg. MS- (+)-ion, M+H = 471.85. c) 4-[4-Cyano-3-hydroxy-7-(2-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo-butyric acid ethyl ester [0311] A mixture of 4-[4-Bromo-3-hydroxy-7-(2-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo- butyric acid ethyl ester (190 mg, 0.40 mmol) and zinc(II) cyanide (94 mg, 0.80 mmol), tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 44 mg, 0.08 mmol), and zinc dust (7.8 mg, 0.12 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 116 mg. MS-(+)-ion, M+H = 417.14. d) 4-[4-Cyano-3-hydroxy-7-(2-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo-butyric acid [0312] At room temperature, to a solution of 4-[4-Cyano-3-hydroxy-7-(2-isopropyl-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester (115 mg, 0.28 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.4 mL, 1.4 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.75 mg. MS-(+)-ion, M+H = 389.09. Example 36 4-[4-Cyano-3-hydroxy-7-(3-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo-butyric acid a) 4-[3-Hydroxy-7-(3-isopropyl-phenyl)-quinolin-2-yl]-4-oxo-but yric acid ethyl ester [0313] A round bottom flask was charged with 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.5 mmol), 3-isopropylphenylboronic acid (164 mg, 1.0 mmol), S-Phos (33 mg, 0.08 mmol), palladium acetate (13.4 mg, 0.06 mmol), and tripotassium phosphate (212 mg, 1.0 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (3 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 169 mg. MS-(+)-ion, M+H = 392.09. b) 4-[4-Bromo-3-hydroxy-7-(3-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo-butyric acid ethyl ester [0314] To a solution of from 4-[3-Hydroxy-7-(3-isopropyl-phenyl)-quinolin-2-yl]-4-oxo-but yric acid ethyl ester (169 mg, 0.44 mmol) in DMF (6 mL) was added N-Bromosuccinimide (81 mg, 0.46 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 182 mg. MS- (+)-ion, M+H = 470.15. c) 4-[4-Cyano-3-hydroxy-7-(3-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo-butyric acid ethyl ester [0315] A mixture of 4-[4-Bromo-3-hydroxy-7-(3-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo- butyric acid ethyl ester (180 mg, 0.38 mmol) and zinc(II) cyanide (89 mg, 0.76 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 42 mg, 0.076 mmol), and zinc dust (7.4 mg, 0.11 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 105 mg. MS-(+)-ion, M+H = 417.09. d) 4-[4-Cyano-3-hydroxy-7-(3-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo-butyric acid [0316] At room temperature, to a solution of 4-[4-Cyano-3-hydroxy-7-(3-isopropyl-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester (102 mg, 0.25 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.4 mL, 1.4 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.46 mg. MS-(+)-ion, M+H = 389.04. Example 37 4-[4-Cyano-3-hydroxy-7-(4-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo-butyric acid a) 4-[3-Hydroxy-7-(4-isopropyl-phenyl)-quinolin-2-yl]-4-oxo-but yric acid ethyl ester [0317] A round bottom flask was charged with 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (176 mg, 0.5 mmol), 4-isopropylphenylboronic acid (164 mg, 1.0 mmol), S-Phos (33 mg, 0.08 mmol), palladium acetate (13.4 mg, 0.06 mmol), and tripotassium phosphate (212 mg, 1.0 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (3 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 86 mg. MS-(+)-ion, M+H = 392.14. b) 4-[4-Bromo-3-hydroxy-7-(4-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo-butyric acid ethyl ester [0318] To a solution of from 4-[3-Hydroxy-7-(4-isopropyl-phenyl)-quinolin-2-yl]-4-oxo-but yric acid ethyl ester (85 mg, 0.42 mmol) in DMF (4 mL) was added N-Bromosuccinimide (41 mg, 0.23 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 81 mg. MS- (+)-ion, M+H = 470.15. c) 4-[4-Cyano-3-hydroxy-7-(4-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo-butyric acid ethyl ester [0319] A mixture of 4-[4-Bromo-3-hydroxy-7-(4-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo- butyric acid ethyl ester (80 mg, 0.17 mmol) and zinc(II) cyanide (40 mg, 0.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.017 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 19 mg, 0.034 mmol), and zinc dust (3.3 mg, 0.051 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 46 mg. MS-(+)-ion, M+H = 417.14. d) 4-[4-Cyano-3-hydroxy-7-(4-isopropyl-phenyl)-quinolin-2-yl]-4 -oxo-butyric acid [0320] At room temperature, to a solution of 4-[4-Cyano-3-hydroxy-7-(4-isopropyl-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester (45 mg, 0.11 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.55 mL, 0.55 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.46 mg. MS-(+)-ion, M+H = 389.04. Example 38 4-[4-Cyano-8-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid a) 4-[8-(2,6-Dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-bu tyric acid ethyl ester [0321] A round bottom flask was charged with 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (142 mg, 0.4 mmol), 2,6-dimethylphenylboronic acid (120 mg, 0.8 mmol), S- Phos (26 mg, 0.064 mmol), palladium acetate (11 mg, 0.048 mmol), and tripotassium phosphate (170 mg, 0.8 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (4 mL) and water (18 mg, 1.0 mmol) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 106 mg. MS-(+)-ion, M+H = 378.04. b) 4-[4-Bromo-8-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester [0322] To a solution of from 4-[8-(2,6-Dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo- butyric acid ethyl ester (104 mg, 0.28 mmol) in DMF (4 mL) was added N-Bromosuccinimide (51 mg, 0.29 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 102 mg. MS- (+)-ion, M+H = 457.80, 455.90. c) 4-[4-Cyano-8-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester [0323] A mixture of 4-[4-Bromo-8-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo- butyric acid ethyl ester (100 mg, 0.25 mmol) and zinc(II) cyanide (58 mg, 0.50 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 28 mg, 0.05 mmol), and zinc dust (4.9 mg, 0.075 mmol) in anhydrous dimethylacetamide (3 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 39 mg. MS-(+)-ion, M+H = 403.09. d) 4-[4-Cyano-8-(2,6-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid [0324] At room temperature, to a solution of 4-[4-Cyano-8-(2,6-dimethyl-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester (39 mg, 0.10 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.4 mL, 0.4 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.17 mg. MS-(+)-ion, M+H = 375.09. Example 39 4-[4-Cyano-7-(3,5-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid a) 4-[7-(3,5-Dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-bu tyric acid ethyl ester [0325] A round bottom flask was charged with 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (530 mg, 1.5 mmol), 3,5-dimethylphenylboronic acid (450 mg, 3.0 mmol), S- Phos (98 mg, 0.24 mmol), palladium acetate (41 mg, 0.18 mmol), and tripotassium phosphate (636 mg, 3.0 mmol). The flask was evacuated and backfilled with nitrogen three times. Anhydrous toluene (6 mL) and water (60 mg) were added to the reaction. The reaction was heated at 100 °C for 6 hours, until TLC shows the completion of the reaction. After cooling back to room temperature, the reaction was diluted with water (50 mL) and acidified to pH = 4 with 1N HCl. The mixture filtrate through celite. The filtrate was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 520 mg. MS-(+)-ion, M+H = 378.09. b) 4-[4-Bromo-7-(3,5-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester [0326] To a solution of from 4-[7-(3,5-Dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo- butyric acid ethyl ester (520 mg, 1.38 mmol) in DMF (20 mL) was added N-Bromosuccinimide (250 mg, 1.4 mmol). The mixture was stirred at room temperature for 1 hour and then quenched with saturated aqueous sodium sulfite (10 mL) and diluted with 30 mL water. The mixture was extracted with ethyl acetate (3x30 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 530 mg. MS- (+)-ion, M+H = 456.10, 457.90. c) 4-[4-Cyano-7-(3,5-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester [0327] A mixture of 4-[4-Bromo-7-(3,5-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo- butyric acid ethyl ester (183 mg, 0.4 mmol) and zinc(II) cyanide (94 mg, 0.8 mmol), tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 44 mg, 0.08 mmol), and zinc dust (7.8 mg, 0.12 mmol) in anhydrous dimethylacetamide (5 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and ethyl acetate (15 mL).1 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 92 mg. MS-(+)-ion, M+H = 403.09. d) 4-[4-Cyano-7-(3,5-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid [0328] At room temperature, to a solution of 4-[4-Cyano-7-(3,5-dimethyl-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester (92 mg, 0.23 mmol) in methanol(4 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.1 mL, 1.1 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.47 mg. MS-(+)-ion, M+H = 375.19. Example 40 4-(4-Cyano-3-hydroxy-8-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid a) 4-(3-Hydroxy-7-phenylsulfanyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0329] To a round-bottom-flask were added 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (246 mg, 0.7 mmol), Pd2(dba)3 (50 mg, 0.07 mmol), Xantphos (81 mg, 0.14 mmol), benzenethiol (154 mg, 1.4 mmol), and N,N-Diisopropylethylamine (0.25 mL, 1.4 mmol) in anhydrous 1,4-dioxane (5 mL). The mixture was heated at 105 °C under N ₂ atmosphere for 6 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 30 mL H2O, treated with 1N HCl to pH = 3, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (100 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound 230 mg. MS-(+)-ion, M+H = 382.04. b) 4-(4-Bromo-3-hydroxy-8-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0330] To a solution of 4-(3-Hydroxy-8-phenylsulfanyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (230 mg, 0.6 mmol) in DMF (6 mL) was added N-Bromosuccinimide (108 mg, 0.61 mmol). The mixture was stirred at room temperature for 20 min and then quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 252 mg. MS-(+)-ion, M+H = 459.85, 461.85. c) 4-(4-Cyano-3-hydroxy-8-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0331] A mixture of 4-(4-Bromo-3-hydroxy-8-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (251 mg, 0.54 mmol), zinc cyanide (126 mg, 1.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (49 mg, 0.054 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 60 mg, 0.108 mmol), and zinc dust (10.5 mg, 0.112 mmol) in anhydrous dimethylacetamide (5 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (25 mL) and ethyl acetate (25 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 128 mg. MS-(+)-ion, M+H = 407.04. d) 4-(4-Cyano-3-hydroxy-8-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid [0332] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-8-phenylsulfanyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (50 mg, 0.12 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.6 mL, 0.6 mmol). After 20h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.31 mg. MS-(+)-ion, M+H = 379.04. Example 41 4-(8-Benzenesulfonyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid a) 4-(8-Benzenesulfonyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester [0333] To a solution of 4-(4-Cyano-3-hydroxy-8-phenylsulfanyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (75 mg, 0.19 mmol) in DCM (6 mL) was added meta-chloroperoxybenzoic acid (99 mg, 0.57 mmol). The mixture was stirred at room temperature for 3h and then quenched with saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (50% - 100%) to give the title compound, 42 mg. MS-(+)-ion, M+H = 438.95. b) 4-(8-Benzenesulfonyl-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid [0334] At room temperature, to a solution of 4-(8-Benzenesulfonyl-4-cyano-3-hydroxy- quinolin-2-yl)-4-oxo-butyric acid ethyl ester (42 mg, 0.10 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.5 mL, 0.5 mmol). After 20h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.22 mg. MS-(+)-ion, M+H = 410.99. Example 42 4-[7-(3,5-Dimethyl-phenyl)-3-hydroxy-4-trifluoromethyl-quino lin-2-yl]-4-oxo-butyric acid a) 4-[3-Benzyloxy-4-bromo-7-(3,5-dimethyl-phenyl)-quinolin-2-yl ]-4-oxo-butyric acid ethyl ester [0335] Benzyl bromide (0.13 mL, 185 mg, 1.05 mmol) was added to a mixture of 4-[4-Bromo- 7-(3,5-dimethyl-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyr ic acid ethyl ester (321 mg, 0.7 mmol) and potassium carbonate (145 mg, 1.05 mmol) in anhydrous DMF (7 mL) at room temperature. After 20 hours at room temperature, TLC shows the completion of the reaction. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (4x15 mL). The combined extracts were washed with brine (2x20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 355 mg. MS-(+)-ion, M+H = 546.07, 548.07. b) 4-[3-Benzyloxy-7-(3,5-dimethyl-phenyl)-4-trifluoromethyl-qui nolin-2-yl]-4-oxo-butyric acid ethyl ester [0336] The mixture of 4-[3-Benzyloxy-4-bromo-7-(3,5-dimethyl-phenyl)-quinolin-2-yl ]-4-oxo- butyric acid ethyl ester (350 mg, 0.64 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (611 mg, 3.2 mmol), and copper(I) iodide (367 mg, 1.92 mmol), in anhydrous 1-methyl-2-pyrrolidone (10 mL) was heated at 100 °C under N2 atmosphere for 3 hours. After cooling down to room temperature, the reaction mixture was diluted with water (30 mL), quenched with 5 mL 1 N HCl and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound.92 mg, MS-(+)-ion, M+H = 536.11. c) 4-[7-(3,5-Dimethyl-phenyl)-3-hydroxy-4-trifluoromethyl-quino lin-2-yl]-4-oxo-butyric acid ethyl ester [0337] The mixture of 4-[3-Benzyloxy-7-(3,5-dimethyl-phenyl)-4-trifluoromethyl-qui nolin-2- yl]-4-oxo-butyric acid ethyl ester (90 mg, 0.17 mmol) and thioanisole (105 mg, 0.85 mmol) in trifluoroacetic acid (5 mL) was stirred at room temperature for 2h, the reaction mixture was slowly quenched with sodium bicarbonate aqueous solution to pH = 7~8. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 69 mg. MS- (+)-ion, M+H = 446.00. d) 4-[7-(3,5-Dimethyl-phenyl)-3-hydroxy-4-trifluoromethyl-quino lin-2-yl]-4-oxo-butyric acid [0338] At room temperature, to a solution of 4-[7-(3,5-Dimethyl-phenyl)-3-hydroxy-4- trifluoromethyl-quinolin-2-yl]-4-oxo-butyric acid ethyl ester (67 mg, 0.15 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.75 mL, 0.75 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.20 mg. MS-(+)-ion, M+H = 417.99. Example 43 4-(4-Cyano-3-hydroxy-7-phenylethynyl-quinolin-2-yl)-4-oxo-bu tyric acid a) 4-(3-Hydroxy-7-phenylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0339] To a round-bottom-flask were added 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (353 mg, 1.0 mmol), PdCl2(PPh3)2 (142 mg, 0.2 mmol), and tributyl- phenylethynyl-stannane (626 mg, 1.6 mmol) in anhydrous DMF (8 mL). The mixture was heated at 120 °C under N ₂ atmosphere for 2 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 50 mL H2O, and extracted with ethyl acetate (50 x 3). The combined organics were washed with brine (50 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 290 mg, MS-(+)-ion, M+H = 374.09. b) 4-(4-Bromo-3-hydroxy-7-phenylethynyl-quinolin-2-yl)-4-oxo-bu tyric acid ethyl ester [0340] At 0°C, to a solution of 4-(3-Hydroxy-7-phenylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (270 mg, 0.73 mmol) in DMF (20 mL) was added N-Bromosuccinimide (130 mg, 0.73 mmol). The mixture was stirred then at room temperature for 30 min and quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 10%) to give the title compound, 346 mg. MS-(+)-ion, M+H = 453.85. c) 4-(4-Cyano-3-hydroxy-7-phenylethynyl-quinolin-2-yl)-4-oxo-bu tyric acid ethyl ester [0341] A mixture of 4-(4-Bromo-3-hydroxy-7-phenylethynyl-quinolin-2-yl)-4-oxo-bu tyric acid ethyl ester (136 mg, 0.3 mmol), zinc cyanide (70 mg, 0.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 33 mg, 0.06 mmol), and zinc dust (6.0 mg, 0.09 mmol) in anhydrous dimethylacetamide (4 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (25 mL) and ethyl acetate (25 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 15 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 82 mg. MS-(+)-ion, M+H = 399.04. d) 4-(4-Cyano-3-hydroxy-7-phenylethynyl-quinolin-2-yl)-4-oxo-bu tyric acid [0342] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-7-phenylethynyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (80 mg, 0.23 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.15 mL, 1.05 mmol). After 20h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.22 mg. MS-(+)-ion, M+H = 371.08. Example 44 4-(4-Cyano-3-hydroxy-7-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid a) 4-(3-Hydroxy-7-o-tolylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0343] To a round-bottom-flask were added 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (530 mg, 1.5 mmol), PdCl ₂ (PPh ₃ ) ₂ (53 mg, 0.075 mmol), CuI (29 mg, 015 mmol), Et ₃ N (757 mg, 7.5 mmol), and 1-ethynyl-2-methyl-benzene (348 mg, 3.0 mmol) in anhydrous DMF (8 mL). The mixture was heated at 100 °C under N2 atmosphere for 2 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 50 mL H2O, treated with 5 mL 1N HCl, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (50 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 540 mg, MS-(+)-ion, M+H = 388.04. b) 4-(4-Bromo-3-hydroxy-7-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0344] At 0°C, to a solution of 4-(3-Hydroxy-7-o-tolylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (540 mg, 1.4 mmol) in DMF (20 mL) was added N-Bromosuccinimide (253 mg, 1.42 mmol). The mixture was stirred then at room temperature for 30 min and quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x30 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 598 mg. MS-(+)-ion, M+H = 465.90, 468.10. c) 4-(4-Cyano-3-hydroxy-7-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0345] A mixture of 4-(4-Bromo-3-hydroxy-7-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (595 mg, 1.3 mmol), zinc cyanide (304 mg, 2.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (119 mg, 0.13 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 144 mg, 0.26 mmol), and zinc dust (25 mg, 0.39 mmol) in anhydrous dimethylacetamide (12 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 266 mg. MS-(+)-ion, M+H = 413.14. d) 4-(4-Cyano-3-hydroxy-7-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid [0346] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-7-o-tolylethynyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (65 mg, 0.15 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.75 mL, 0.75 mmol). After 20h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (20mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.21 mg. MS-(+)-ion, M+H = 385.04. Example 45 4-[4-Cyano-3-hydroxy-7-(2-o-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid a) 4-(4-Cyano-3-hydroxy-7-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0347] To a solution of 4-(4-Bromo-3-hydroxy-7-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (200 mg, 0.47 mmol) in ethyl acetate (20 mL) was added Pd/C (25 mg, 0.025eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 4 hr at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hexane (0% - 20%) to give the title compound, 91 mg, MS-(+)-ion, M+H = 417.09. b) 4-[4-Cyano-3-hydroxy-7-(2-o-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid [0348] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-7-o-tolylethynyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (90 mg, 0.21 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.05 mL, 1.05 mmol). After 3h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.48 mg. MS-(+)-ion, M+H = 389.09. Example 46 4-(4-Cyano-3-hydroxy-7-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid a) 4-(3-Hydroxy-7-m-tolylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0349] To a round-bottom-flask were added 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (530 mg, 1.5 mmol), PdCl2(PPh3)2 (53 mg, 0.075 mmol), CuI (29 mg, 015 mmol), Et3N (757 mg, 7.5 mmol), and 1-ethynyl-3-methyl-benzene (348 mg, 3.0 mmol) in anhydrous DMF (8 mL). The mixture was heated at 100 °C under N2 atmosphere for 3 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 50 mL H ₂ O, treated with 5 mL 1N HCl, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (50 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 490 mg, MS-(+)-ion, M+H = 388.09. b) 4-(4-Bromo-3-hydroxy-7-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0350] At 0°C, to a solution of 4-(3-Hydroxy-7-m-tolylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (490 mg, 1.26 mmol) in DMF (20 mL) was added N-Bromosuccinimide (236 mg, 1.33 mmol). The mixture was stirred then at room temperature for 1 h and quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x30 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 508 mg. MS-(+)-ion, M+H = 465.90, 467.85. c) 4-(4-Cyano-3-hydroxy-7-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0351] A mixture of 4-(4-Bromo-3-hydroxy-7-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (505 mg, 1.1 mmol), zinc cyanide (257 mg, 2.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (101 mg, 0.11 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 122 mg, 0.22 mmol), and zinc dust (21 mg, 0.33 mmol) in anhydrous dimethylacetamide (10 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 239 mg. MS-(+)-ion, M+H = 413.14. d) 4-(4-Cyano-3-hydroxy-7-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid [0352] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-7-m-tolylethynyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (64 mg, 0.15 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.75 mL, 0.75 mmol). After 20h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (20mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.42 mg. MS-(+)-ion, M+H = 385.04. Example 47 4-[7-(2-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid a) (2-Amino-4-bromo-phenyl)-methanol [0353] To a solution of 2-amino-4-bromo benzoic acid (10 g, 46.2 mmol) in THF (100 ml), LAH (2.5 g, 69.3 mmol) was added at 0 ^o C and stirred at room temperature for 8 h. The reaction was quenched using saturated solution of sodium sulfate and filtered through Celite bed to yield 7 g of the title compound after trituration with hexane. MS: (+) m/z 202, 204 (M+1). b) 2-Amino-4-bromo-benzaldehyde [0354] To a solution of (2-amino-4-bromo-phenyl)-methanol (7 g, 34.65 mmol) in DCM (200 mL) at room temperature was added MnO2 (30.14g, 346 mmol) in portions. Reaction mixture was stirred at room temperature for 10 h. Reaction mixture was filtered through a pad of Celite and washed with DCM. The filtrate was concentrated in vacuo to give the crude product. The obtained crude was purified by column chromatography (10% EtOAc/hexane) to yield 5 g of the title compound. MS: (+) m/z 200, 202 (M+1). c) 3-Amino-7-bromo-quinoline-2-carboxylic acid ethyl ester [0355] A solution of ethyl bromopyruvate (3.57 ml, 27.5 mmol) in ethanol (25 ml) was added dropwise to a mixture of pyridine (2.2ml, 27.5 mmol) and ethanol (20 ml) at room temperature for a period of more than 30 minutes and reaction mixture was stirred at room temperature for 1 h. Then the mixture was stirred at 60 ^o C for 2 h and was cooled to room temperature. To the mixture was added 2- amino-4-bromo-benzaldehyde (5g, 25 mmol) and pyridine (20 ml). The mixture was refluxed at 85 ^o C for 4 hours. Pyrrolidine (5 ml, 62.5 mmol) was added and the mixture was refluxed at 85 ^o C for 4 hours. The reaction mixture was concentrated on rotavapor, mixed with water, and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to yield the crude product. The obtained crude was purified by column chromatography using 0-2% ethyl acetate in DCM as the eluent to give 1 g of the title compound. MS: (+) m/z 295, 297 (M+1). d) 7-Bromo-3-hydroxy-quinoline-2-carboxylic acid ethyl ester [0356] Compound 3-amino-7-bromo-quinoline-2-carboxylic acid ethyl ester (2g, 6.77 mmol) was dissolved in anhydrous THF (20 mL) and placed in an ice bath. With vigorous stirring, concentrated H2SO4 (1.08 mL, 20.33 mmol) was slowly added to give a thick suspension. Butyl nitrite (2.3 mL, 20.33 mmol) was then added dropwise, and the resulting suspension was stirred vigorously in the ice bath for 2 h. The mixture was diluted with 10 mL of cold THF and the solid was isolated by filtration and dried under high vacuum for several hours. In a separate flask, glacial acetic acid (20 mL) was heated to 115 ^o C. The solid from above was suspended in glacial acetic acid (20 mL) and added to the pre-heated acetic acid, and the resulting homogeneous mixture was then stirred at 115-120 ^o C for 16 h. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was re-dissolved in absolute EtOH (30 mL) and placed in ice bath. Thionyl chloride (1 mL) was added, and the mixture was warmed to room temperature and refluxed for 16h. The mixture was concentrated on rotavapor. Ethyl acetate was added to the reaction mixture and washed with water and aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated to yield the crude product. The obtained crude was purified by column chromatography using 5% ethyl acetate in DCM as eluent to yield 415 mg of the title compound. MS: (+) m/z 296, 298 (M+1). e) 3-Benzyloxy-7-bromo-quinoline-2-carboxylic acid ethyl ester [0357] A mixture of 7-bromo-3-hydroxy-quinoline-2-carboxylic acid ethyl ester (0.2 g, 0.56 mmol), Cs ₂ CO ₃ (0.33 g, 1.01 mmol) and benzyl bromide (0.139 g, 0.81 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and evaporated to yield the crude product. The crude was purified by flash column chromatography (using 5-20% EtOAc in heptane) to afford 150 mg of the title compound. MS: (+) m/z 386, 388 (M+1). f) 3-Benzyloxy-7-bromo-quinoline-2-carboxylic acid [0358] To a solution of 3-benzyloxy-7-bromo-quinoline-2-carboxylic acid ethyl ester (150 mg, 0.388 mmol) in THF/H2O (9 mL/0.5 mL) was added lithium hydroxide monohydrate (48 mg, 1.14 mmol, 3.0 eq) and stirred at room temperature for 4 h. The reaction mixture was evaporated in vacuo and diluted in water. The pH of the aqueous layer was adjusted to 4 using 1N HCl, the resulting mixture was filtered, washed with water and dried to obtain the title compound (120 mg). MS: (+) m/z 358, 360 (M+1). g) 4-(3-Benzyloxy-7-bromo-quinolin-2-yl)-3,3-bis-tert-butoxycar bonyl-4-oxo-butyric acid ethyl ester [0359] A solution of 3-benzyloxy-7-bromo-quinoline-2-carboxylic acid (3.5 g, 9.8 mmol, 1 eq.). oxalyl chloride (2 eq.) and catalytic DMF in THF (35 ml) was stirred at 0 ^o C for 1 h then at room temperature for 1 h. THF was distilled off under vacuum to obtain acid chloride. In a separate flask, NaH (3 eq) was added to a solution of 2-tert-butoxycarbonyl-succinic acid 1-tert-butyl ester 4-ethyl ester (1.5 eq) in anhydrous THF at room temperature and stirred at 40 ^o C for 4 h. The above prepared acid chloride in anhydrous THF was added at room temperature and the reaction mixture stirred at room temperature for 2 h. The reaction was quenched with aqueous ammonium chloride, extracted with EtOAc and purified by flash column chromatography to give 3.1 g of the title compound. MS: (+) m/z 642, 644 (M+1). h) 4-(3-Benzyloxy-7-bromo-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0360] A solution of 4-(3-benzyloxy-7-bromo-quinolin-2-yl)-3,3-bis-tert-butoxycar bonyl-4-oxo- butyric acid ethyl ester (3.1 g, 4.8 mmol, 1 eq) and p-toluenesulfonic acid (99 mg, catalytic amount) in toluene (18.6 ml) was stirred at 120 ^o C for 3 h. The reaction mixture was concentrated and partitioned between EtOAc and water. The organic layer was dried over Na2SO4, concentrated and purified by flash column chromatography to obtain 1.6 g of the title compound. MS: (+) m/z 442, 444 (M+1). i) 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0361] A mixture of 4-(3-benzyloxy-7-bromo-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (0.13 g, 0.294 mmol) and thioanisole (0.161 g, 1.47 mmol) in TFA (1.0 mL) was heated at 90 ^o C for 4 h. The reaction mixture was quenched with aqueous sodium bicarbonate solution to pH 8. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was concentrated under reduced pressure and purified by flash column chromatography to yield 60 mg of the title compound. MS: (+) m/z 352, 354 (M+1). j) 4-[7-(2-Chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester [0362] To a solution of 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (179 mg, 0.51 mmol, prepared from 47i) in toluene (3.4 mL) and H2O (18 mg) at room temperature were added 2-chlorophenylboronic acid (119 mg, 0.76 mmol), K ₃ PO ₄ (216 mg, 1.01 mmol), Pd(OAc) ₂ (2.3 mg, 0.01 mmol), and S-Phos (10.4 mg, 0.03 mmol) to give a suspension. The reaction mixture was allowed to stir at 100°C for 18 h. After cooled to room temperature, the mixture was diluted with EtOAc (100 mL), filtered through a Celite plug, and rinsed with EtOAc (100 mL). The organic layers were washed with 0.1 N HCl solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by ISCO over silica gel, eluting with 2-35% EtOAc / hexanes to give the title compound (178 mg). MS (m/z) 383.9 (M+1) ⁺ . k) 4-[4-Bromo-7-(2-chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0363] To a solution of 4-[7-(2-chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester (178 mg, 0.46 mmol) in DMF (4.6 mL) at room temperature was added NBS (86.8 mg, 0.48 mmol) to give a suspension. The reaction mixture was stirred at room temperature for 1 h, and diluted with EtOAc (100 mL). The organic layer was washed with Na ₂ S ₂ O ₃ solution and water, dried over MgSO ₄ , and concentrated in vacuo. The residue was purified by ISCO over silica gel, eluting with 2-35% EtOAc / hexanes to give the product (110 mg). MS (m/z) 461.8, 463.8 (M+1) ⁺ . l) 4-[7-(2-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0364] To a solution of 4-[4-bromo-7-(2-chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester (110 mg, 0.24 mmol) in DMAC (3.4 mL) at room temperature were added Zn(CN) ₂ (56 mg, 0.48 mmol), Pd ₂ (dba) ₃ (22 mg, 0.024 mmol), dppf (26 mg, 0.048 mmol), and Zn dust (4.6 mg, 0.07 mmol) to give a suspension. The reaction mixture was allowed to stir at 100°C for 2 hours. After cooled to room temperature, the mixture was diluted with EtOAc (50 mL), filtered through a Celite plug, and rinsed with EtOAc (50 mL). The organic layers were washed with 0.1 N HCl solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by ISCO over silica gel, eluting with 2-35% EtOAc / hexanes to give the product (32.4 mg). MS (m/z) 406.9 (M-1) ⁺ . m) 4-[7-(2-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid [0365] To a solution of the 4-[7-(2-chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o- butyric acid ethyl ester (32.4 mg, 0.07 mmol) in MeOH (2 mL) and water (0.65 mL) at room temperature was added lithium hydroxide monohydrate (13.3 mg, 0.31 mmol) to give a suspension. The reaction mixture was stirred at room temperature for 24 h, concentrated in vacuo to remove methanol. The residue was dissolved in water (15 mL) and washed with EtOAc(3 x 5 mL). The aqueous solution was acidified by 1N HCl solution, filtered, washed with water, and dried to give the product (20.9 mg). MS (m/z) 378.9 (M-1) ⁺ . Example 48 4-[7-(3-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid a) 4-[7-(3-Chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester [0366] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 47i) and 3-chlorophenylboronic acid in analogy to Example 47j. MS (m/z) 384.0 (M+1) ⁺ . b) 4-[4-Bromo-7-(3-chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0367] The title compound was prepared from 4-[7-(3-chloro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 461.8, 463.8 (M+1) ⁺ . c) 4-[7-(3-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0368] The title compound was prepared from 4-[4-bromo-7-(3-chloro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 408.9 (M+1) ⁺ . d) 4-[7-(3-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid [0369] The title compound was prepared from 4-[7-(3-chloro-phenyl)-4-cyano-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and LiOH.H2O in analogy to Example 47m. MS (m/z) 380.9 (M+1) ⁺ . Example 49 4-[7-(4-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid a) 4-[7-(4-Chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester [0370] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 47i) and 4-chlorophenylboronic acid in analogy to Example 47j. MS (m/z) 384.0 (M+1) ⁺ . b) 4-[4-Bromo-7-(4-chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0371] The title compound was prepared from 4-[7-(4-chloro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 461.8, 463.8 (M+1) ⁺ . c) 4-[7-(4-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0372] The title compound was prepared from 4-[4-bromo-7-(4-chloro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 408.9 (M+1) ⁺ . d) 4-[7-(4-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid [0373] The title compound was prepared from 4-[7-(4-chloro-phenyl)-4-cyano-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and LiOH.H ₂ O in analogy to Example 47m. MS (m/z) 381.0 (M+1) ⁺ . Example 50 4-[4-Cyano-7-(4-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid a) 4-[7-(4-Fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester [0374] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 47i) and 4-fluorophenylboronic acid in analogy to Example 47j. MS (m/z) 368.0 (M+1) ⁺ . b) 4-[4-Bromo-7-(4-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0375] The title compound was prepared from 4-[7-(4-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 445.9, 447.9 (M+1) ⁺ . c) 4-[4-Cyano-7-(4-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0376] The title compound was prepared from 4-[4-bromo-7-(4-fluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 393.0 (M+1) ⁺ . d) 4-[4-Cyano-7-(4-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid [0377] The title compound was prepared from 4-[4-cyano-7-(4-fluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and LiOH.H2O in analogy to 47m. MS (m/z) 363.0 (M-1) ⁺ . Example 51 4-[4-Cyano-7-(3-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid a) 4-[7-(3-Fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester [0378] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 47i) and 3-fluorophenylboronic acid in analogy to Example 47j. MS (m/z) 368.1 (M+1) ⁺ . b) 4-[4-Bromo-7-(3-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0379] The title compound was prepared from 4-[7-(3-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 445.9, 447.8 (M+1) ⁺ . c) 4-[4-Cyano-7-(3-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0380] The title compound was prepared from 4-[4-bromo-7-(3-fluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 393.0 (M+1) ⁺ . d) 4-[4-Cyano-7-(3-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid [0381] The title compound was prepared from 4-[4-cyano-7-(3-fluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and LiOH.H2O in analogy to Example 47m. MS (m/z) 362.9 (M-1) ⁺ . Example 52 4-[4-Cyano-7-(2-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid a) 7-Bromo-3-hydroxy-4-iodo-quinoline-2-carboxylic acid ethyl ester [0382] To a solution of 7-bromo-3-hydroxy-quinoline-2-carboxylic acid ethyl ester (1.31 g, 4.42 mmol, prepared from Example 47d) in CH ₂ Cl ₂ (44 mL) at room temperature was added I(collidine)PF ₆ (2.5 g, 4.86 mmol) to give a suspension. The reaction mixture was stirred at room temperature for 1 h, diluted with EtOAc (100 mL), and washed by Na2S2O3 solution and water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by ISCO over silica gel, eluting with 2- 35% EtOAc / hexanes to give the product (1.79 g). MS (m/z) 421.7, 423.7 (M+1) ⁺ . b) 3-Benzyloxy-7-bromo-4-iodo-quinoline-2-carboxylic acid ethyl ester [0383] To a solution of 7-bromo-3-hydroxy-4-iodo-quinoline-2-carboxylic acid ethyl ester (1.76 g, 4.17 mmol) in DMF (42 mL) at room temperature were added potassium carbonate (1.15 g, 8.34 mmol) and benzyl bromide (1.07 g, 6.25 mmol) to give a suspension. The reaction mixture was stirred at room temperature for 3 h, diluted with EtOAc (100 mL), filtered through a Celite plug, and rinsed with EtOAc (50 mL). The organic layer was washed with 0.1 N HCl solution and water, dried over MgSO4 and concentrated in vacuo. The residue was purified by ISCO over silica gel, eluting with 2-35% EtOAc / hexanes to give the product (1.47 g). MS (m/z) 511.7, 513.7 (M+1) ⁺ . c) 3-Benzyloxy-7-bromo-4-cyano-quinoline-2-carboxylic acid ethyl ester [0384] To a solution of 3-benzyloxy-7-bromo-4-iodo-quinoline-2-carboxylic acid ethyl ester (1.26 g, 2.46 mmol) in DMAC (12.3 mL) at room temperature was added CuCN (660 mg, 7.38 mmol) to give a suspension. The reaction mixture was stirred at 140 ºC for 2 h, cooled to room temperature, diluted with EtOAc (100 mL), filtered through a celite plug, and rinsed with EtOAc (100 mL). The organic layer was washed with 0.1 N HCl solution and water, dried over MgSO4 and concentrated in vacuo. The residue was purified by ISCO over silica gel, eluting with 10-50% EtOAc / hexanes to give the product (398 mg). MS (m/z) 410.9, 412.9 (M+1) ⁺ . d) 3-Benzyloxy-7-bromo-4-cyano-quinoline-2-carboxylic acid [0385] To a solution of the 3-benzyloxy-7-bromo-4-cyano-quinoline-2-carboxylic acid ethyl ester (398 mg, 0.96 mmol) in THF (7.2 mL) and water (2.5 mL) at room temperature was added lithium hydroxide monohydrate (162 mg, 3.87 mmol). The reaction mixture was stirred at room temperature for 24 h, and concentrated in vacuo. The aqueous solution was acidified by 1N HCl solution, filtered, washed with water, dried to give crude product (371 mg). MS (m/z) 382.9, 384.9 (M+1) ⁺ . e) 4-(3-Benzyloxy-7-bromo-4-cyano-quinolin-2-yl)-3,3-bis-tert-b utoxycarbonyl-4-oxo-butyric acid ethyl ester [0386] To a solution of the 3-benzyloxy-7-bromo-4-cyano-quinoline-2-carboxylic acid (371 mg, 0.96 mmol) in THF (4.8 mL) was added oxalyl chloride (245 mg, 1.93 mmol) and 1 drop of DMF at 0 ºC. The mixture was stirred at 0 ºC for 1 h, then allowed to warm to room temperature for another 1 h. Removal of solvent and drying under vacuum gave 3-benzyloxy-7-bromo-4-cyano-quinoline-2-carbonyl chloride as the crude product. It was used in the next step without further purification. [0387] To a suspension of 60% NaH (44 mg, 1.83 mol) in THF (4.8 ml) at 0 °C was slowly added a solution of 2-tert-butoxycarbonyl-succinic acid 1-tert-butyl ester 4-ethyl ester (438 mg, 1.45 mol) in THF. The resulting mixture was stirred at 40 °C for 2 h, after which 3-benzyloxy-7-bromo-4- cyano-quinoline-2-carbonyl chloride in THF (1.5 mL) was added. The solution was allowed to stir for 20 h at room temperature. The reaction mixture was quenched with saturated NH4Cl solution and was extracted with EtOAc. The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by ISCO over silica gel, eluting with 2-50% EtOAc / hexanes, to give the product (451 mg). MS (m/z) 666.9, 669.1 (M+1) ⁺ . f) 4-(7-Bromo-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0388] To a solution of 4-(3-benzyloxy-7-bromo-4-cyano-quinolin-2-yl)-3,3-bis-tert- butoxycarbonyl-4-oxo-butyric acid ethyl ester (451 mg, 0.67 mmol) in toluene (6.7 mL) was added p- toluenesulfonic acid monohydrate (64 mg, 0.34 mmol). The reaction mixture was refluxed for 2 h, cooled to room temperature, and diluted with EtOAc (50 mL). The organic layer was washed with NaHCO3 solution and water, dried over MgSO ₄ , and concentrated in vacuo The residue was purified by ISCO over silica gel, eluting with 10-50% EtOAc / hexanes to give the product (167 mg). MS (m/z) 376.9, 378.9 (M+1) ⁺ . g) 4-[4-Cyano-7-(2-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0389] To a solution of 4-(7-bromo-4-cyano-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (116 mg, 0.31 mmol) in toluene (3.1 mL) and H2O (11 mg) at room temperature were added 2- fluorophenylboronic acid (64.5 mg, 0.46 mmol), K ₃ PO ₄ (131 mg, 1.01 mmol), Pd(OAc) ₂ (3.4 mg, 0.02 mmol), and S-Phos (12.5 mg, 0.03 mmol). The reaction mixture was allowed to stir at 100°C for 48 h, cooled to room temperature, diluted with EtOAc (50 mL), filtered through a Celite plug, and rinsed with EtOAc (50 mL). The organic layers were washed with 0.1 N HCl solution and water, dried over MgSO4 and concentrated in vacuo. The residue was purified by ISCO over silica gel, eluting with 2-35% EtOAc / hexanes to give the product (70.4 mg). MS (m/z) 393.0 (M+1) ⁺ . [0390] The title compound was prepared from 4-[4-cyano-7-(2-fluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and LiOH.H2O in analogy to Example 47m. MS (m/z) 364.9 (M+1) ⁺ . Example 53 4-[4-Cyano-3-hydroxy-7-(2-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid a) 4-[3-Hydroxy-7-(2-methoxy-phenyl)-quinolin-2-yl]-4-oxo-butyr ic acid ethyl ester [0391] The title compound was prepared from 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 2-methoxyphenylboronic acid to give the title compound in analogy to Example 47j. MS (m/z) 380.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-7-(2-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0392] The title compound was prepared from 4-[3-Hydroxy-7-(2-methoxy-phenyl)-quinolin-2- yl]-4-oxo-butyric acid ethyl ester and NBS to give the title compound in analogy to Example 47k. MS (m/z) 457.9, 459.9 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-7-(2-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0393] The title compound was prepared from 4-[4-Bromo-3-hydroxy-7-(2-methoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 to give the title compound in analogy to Example 47l. MS (m/z) 405.0 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-7-(2-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid [0394] The title compound was prepared from 4-[4-Cyano-3-hydroxy-7-(2-methoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and LiOH.H2O to give the title compound in analogy to Example 47m. MS (m/z) 377.0 (M+1) ⁺ . Example 54 4-[4-Cyano-3-hydroxy-7-(4-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid a) 4-[3-Hydroxy-7-(4-methoxy-phenyl)-quinolin-2-yl]-4-oxo-butyr ic acid ethyl ester [0395] The title compound was prepared from 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 4-methoxyphenylboronic acid to give the title compound in analogy to Example 47j. MS (m/z) 380.1 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-7-(4-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0396] The title compound was prepared from 4-[3-Hydroxy-7-(4-methoxy-phenyl)-quinolin-2- yl]-4-oxo-butyric acid ethyl ester and NBS to give the title compound in analogy to Example 47k. MS (m/z) 457.9, 459.9 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-7-(4-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0397] The title compound was prepared from 4-[4-Bromo-3-hydroxy-7-(4-methoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 to give the title compound in analogy to Example 47l. MS (m/z) 405.0 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-7-(4-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid [0398] The title compound was prepared from 4-[4-Cyano-3-hydroxy-7-(4-methoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and LiOH.H ₂ O to give the title compound in analogy to Example 47m. MS (m/z) 377.0 (M+1) ⁺ . Example 55 4-[4-Cyano-8-(4-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid a) (2-Amino-3-bromo-phenyl)-methanol [0399] To a solution of 2-amino-3-bromo benzoic acid (10g, 46.2 mmol) in THF (100ml), LAH (2.5 g, 69.3 mmol) was added at 0 ^o C and stirred at room temperature for 8h. The reaction was quenched using saturated solution of sodium sulfate and filtered through Celite bed to yield 7 g of the title compound after trituration with hexane. MS: (+) m/z 202, 204 (M+1). b) 2-Amino-3-bromo-benzaldehyde [0400] To a solution of (2-Amino-3-bromo-phenyl)-methanol (7 g, 34.65 mmol) in DCM (200 mL) at room temperature was added MnO2 (30.14g, 346 mmol) in portions. Reaction mixture was stirred at room temperature for 10 h. Reaction mixture was filtered through a pad of Celite and washed with DCM. The filtrate was concentrated in vacuo to yield the crude product. The obtained crude was purified by column chromatography (10% EtOAc/hexane) to yield 5 g of the title compound. MS: (+) m/z 200, 202 (M+1). c) 3-Amino-8-bromo-quinoline-2-carboxylic acid ethyl ester [0401] A solution of ethyl bromopyruvate (3.57 ml, 27.5 mmol) in ethanol (25 ml) was added dropwise to a mixture of pyridine (2.2ml, 27.5 mmol) and ethanol (20 ml) at room temperature for a period of more than 30 minutes. The reaction mixture was stirred at room temperature for 1 h, at 60 ^o C for 2 h, and then was cooled to room temperature. To the mixture was added 2-Amino-3-bromo- benzaldehyde (5g, 25 mmol) and pyridine (20 ml). The mixture was refluxed at 85 ^o C for 4 hours. Pyrrolidine (5 ml, 62.5 mmol) was added and the mixture was refluxed at 85 ^o C for 4 hours. The reaction mixture was concentrated on rotavapor, mixed with water and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to yield the crude product. The obtained crude was purified by column chromatography using 0-2% ethyl acetate in DCM as eluent gave 1 g of the title compound. MS: (+) m/z 295, 297 (M+1). d) 8-Bromo-3-hydroxy-quinoline-2-carboxylic acid ethyl ester [0402] 3-Amino-8-bromo-quinoline-2-carboxylic acid ethyl ester (2g, 6.77 mmol) was dissolved in anhydrous THF (20 mL) and placed in an ice bath. With vigorous stirring, concentrated H ₂ SO ₄ (1.08 mL, 20.33 mmol) was slowly added to give a thick suspension. Butyl nitrite (2.3 mL, 20.33 mmol) was then added dropwise, and the resulting suspension was stirred vigorously in the ice bath for 2 h. The mixture was diluted with 10 mL of cold THF and the solid was isolated by filtration and dried under high vacuum for several hours. In a separate flask, glacial acetic acid (20 mL) was heated to 115 ^o C. The solid from above was suspended in glacial acetic acid (20 mL) and added to the pre-heated acetic acid, and the resulting homogeneous mixture was then stirred at 115-120 ^o C for 16 h. The reaction mixture was allowed to come to room temperature and concentrated to dryness. The residue was re-dissolved in absolute EtOH (30 mL) and placed in ice bath. Thionyl chloride (1 mL) was added, and the mixture was warmed to room temperature and refluxed for 16h. The mixture was concentrated on rotavapor. Ethyl acetate was added to the reaction mixture and washed with water and aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated to yield the crude product. The obtained crude was purified by column chromatography using 5% ethyl acetate in DCM as eluent to yield 415mg of the title compound. MS: (+) m/z 296, 298 (M+1). e) 3-Benzyloxy-8-bromo-quinoline-2-carboxylic acid ethyl ester [0403] A mixture of compound 8-bromo-3-hydroxy-quinoline-2-carboxylic acid ethyl ester (0.2 g, 0.56 mmol), Cs2CO3 (0.33 g, 1.01 mmol) and benzyl bromide (0.139 g, 0.81 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and evaporated to yield the crude product. The crude was purified by flash column chromatography (using 5- 20% EtOAc in heptane) to afford 150 mg of the title compound. MS: (+) m/z 386, 388 (M+1). f) 3-Benzyloxy-8-bromo-quinoline-2-carboxylic acid [0404] To a solution of compound 3-benzyloxy-8-bromo-quinoline-2-carboxylic acid ethyl ester (150 mg, 0.388 mmol) in THF/H ₂ O (9 mL/0.5 mL) was added lithium hydroxide monohydrate (48 mg, 1.14 mmol, 3.0 eq) and stirred at room temperature for 4 h. The reaction mixture was evaporated in vacuo and diluted with water. The pH of the aqueous layer was adjusted to 4 using 1N HCl. The resulting mixture was filtered, washed with water and dried to obtain the title compound (120 mg). MS: (+) m/z 358, 360 (M+1). g) 4-(3-Benzyloxy-8-bromo-quinolin-2-yl)-3,3-bis-tert-butoxycar bonyl-4-oxo-butyric acid ethyl ester [0405] A solution of compound 3-benzyloxy-8-bromo-quinoline-2-carboxylic acid (3.5 g, 9.8 mmol, 1 eq.). oxalyl chloride (2 eq.) and catalytic DMF in THF (35 ml) was stirred at 0 ^o C for 1 h, then at room temperature for 1 h. THF was distilled off under vacuum to obtain acid chloride. In a separate flask, NaH (3 eq) was added to a solution of 2-tert-butoxycarbonyl-succinic acid 1-tert-butyl ester 4-ethyl ester (1.5 eq) in anhydrous THF at room temperature and stirred at 40 ^o C for 4 h. The above prepared acid chloride in anhydrous THF was added at room temperature and the reaction mixture stirred at room temperature for 2 h. The reaction was quenched with aqueous ammonium chloride, extracted with EtOAc and purified by flash column chromatography to give 3.1 g of the title compound. MS: (+) m/z 642, 644 (M+1). h) 4-(3-Benzyloxy-8-bromo-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0406] A solution of 4-(3-benzyloxy-8-bromo-quinolin-2-yl)-3,3-bis-tert-butoxycar bonyl-4-oxo- butyric acid ethyl ester (3.1 g, 4.8 mmol, 1 eq) and p-toluenesulfonic acid (99 mg, catalytic amount) in toluene (18.6 ml) was stirred at 120 ^o C for 3 h. The reaction mixture was concentrated and partitioned between EtOAc and water. The organic layer was dried over Na ₂ SO ₄ , concentrated and purified by flash column chromatography to obtain 1.6 g of the title compound. MS: (+) m/z 442, 444 (M+1). i) 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0407] A mixture of 4-(3-benzyloxy-8-bromo-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (0.13 g, 0.294 mmol) and thioanisole (0.161 g, 1.47 mmol) in TFA (1.0 mL) was heated at 90 ^o C for 4 h. The reaction mixture was quenched with aqueous sodium bicarbonate solution to pH 8. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was concentrated under reduced pressure and purified by flash column chromatography to yield 60 mg of the title compound. MS: (+) m/z 352, 354 (M+1). j) 4-[8-(4-Fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester [0408] The title compound was prepared from 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester and 4-fluorophenylboronic acid in analogy to Example 47j. MS (m/z) 368.1 (M+1) ⁺ . k) 4-[4-Bromo-8-(4-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0409] The title compound was prepared from 4-[8-(4-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 445.9, 447.8 (M+1) ⁺ . l) 4-[4-Cyano-8-(4-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0410] The title compound was prepared from 4-[4-bromo-8-(4-fluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 393.1 (M+1) ⁺ . m) 4-[4-Cyano-8-(4-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid [0411] The title compound was prepared from 4-[4-cyano-8-(4-fluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and LiOH.H2O in analogy to Example 47m. MS (m/z) 364.9 (M+1) ⁺ . Example 56 4-[4-Cyano-8-(3-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid a) 4-[8-(3-Fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester [0412] The title compound was prepared from 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 3-fluorophenylboronic acid in analogy to Example 47j. MS (m/z) 368.1 (M+1) ⁺ . b) 4-[4-Bromo-8-(3-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0413] The title compound was prepared from 4-[8-(3-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 445.9, 447.9 (M+1) ⁺ . c) 4-[4-Cyano-8-(3-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0414] The title compound was prepared from 4-[4-bromo-8-(3-fluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 393.0 (M+1) ⁺ . d) 4-[4-Cyano-8-(3-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid [0415] The title compound was prepared from 4-[4-cyano-8-(3-fluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and LiOH.H ₂ O in analogy to Example 47m. MS (m/z) 364.9 (M+1) ⁺ . Example 57 4-[4-Cyano-8-(2-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid a) 4-[8-(2-Fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester [0416] The title compound was prepared from 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 2-fluorophenylboronic acid in analogy to Example 47j. MS (m/z) 368.0 (M+1) ⁺ . b) 4-[4-Bromo-8-(2-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0417] The title compound was prepared from 4-[8-(2-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 445.8, 447.8 (M+1) ⁺ . c) 4-[4-Cyano-8-(2-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0418] The title compound was prepared from 4-[4-bromo-8-(2-fluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 393.0 (M+1) ⁺ . d) 4-[4-Cyano-8-(2-fluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid [0419] The title compound was prepared from 4-[4-cyano-8-(2-fluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and LiOH.H2O in analogy to Example 47m. MS (m/z) 365.0(M+1) ⁺ . Example 58 4-[8-(4-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid a) 4-[8-(4-Chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester [0420] The title compound was prepared from 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 4-chlorophenylboronic acid in analogy to Example 47j. MS (m/z) 384.0 (M+1) ⁺ . b) 4-[4-Bromo-8-(4-chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0421] The title compound was prepared from 4-[8-(4-chloro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 461.8, 463.8 (M+1) ⁺ . c) 4-[8-(4-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0422] The title compound was prepared from 4-[4-bromo-8-(4-chloro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 408.9 (M+1) ⁺ . d) 4-[8-(4-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid [0423] The title compound was prepared from 4-[8-(4-chloro-phenyl)-4-cyano-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and LiOH.H2O in analogy to Example 47m. MS (m/z) 380.9 (M+1) ⁺ . Example 59 4-[8-(3-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid a) 4-[8-(3-Chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester [0424] The title compound was prepared from 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 3-chlorophenylboronic acid in analogy to Example 47j. MS (m/z) 384.0 (M+1) ⁺ . b) 4-[4-Bromo-8-(3-chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0425] The title compound was prepared from 4-[8-(3-chloro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 461.9, 463.8 (M+1) ⁺ . c) 4-[8-(3-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0426] The title compound was prepared from 4-[4-bromo-8-(3-chloro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 408.9 (M+1) ⁺ . d) 4-[8-(3-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid [0427] To a solution of the 4-[8-(3-chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o- butyric acid ethyl ester (64 mg, 0.16 mmol) in MeOH (3.9 mL) and water (1.3 mL) at room temperature, was added sodium hydroxide (25 mg, 0.64 mmol) to give a suspension. The reaction mixture was stirred at room temperature. After 4 h, the mixture was concentrated in vacuo to remove methanol. The residue was dissolved in water (15 mL), extracted with EtOAc(3 x 5 mL). The aqueous solution was acidified by 1N HCl solution. The resulting mixture was filtered, washed with water, and dried to give the product (22.5 mg). MS (m/z) 380.9 (M+1) ⁺ . Example 60 4-[8-(2-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid a) 4-[8-(2-Chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-butyri c acid ethyl ester [0428] The title compound was prepared from 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 2-chlorophenylboronic acid in analogy to Example 47j. MS (m/z) 384.0 (M+1) ⁺ . b) 4-[4-Bromo-8-(2-chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0429] The title compound was prepared 4-[8-(2-chloro-phenyl)-3-hydroxy-quinolin-2-yl]-4- oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 461.8, 463.8 (M+1) ⁺ . c) 4-[8-(2-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0430] The title compound was prepared from 4-[4-bromo-8-(2-chloro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 408.9 (M+1) ⁺ . d) 4-[8-(2-Chloro-phenyl)-4-cyano-3-hydroxy-quinolin-2-yl]-4-ox o-butyric acid [0431] The title compound was prepared from 4-[8-(2-chloro-phenyl)-4-cyano-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 380.9 (M+1) ⁺ . Example 61 4-[4-Cyano-3-hydroxy-8-(4-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid a) 4-[3-Hydroxy-8-(4-methoxy-phenyl)-quinolin-2-yl]-4-oxo-butyr ic acid ethyl ester [0432] The title compound was prepared from 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 4-methoxyphenylboronic acid in analogy to Example 47j. MS (m/z) 380.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-8-(4-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0433] The title compound was prepared from 4-[3-hydroxy-8-(4-methoxy-phenyl)-quinolin-2- yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 457.9, 459.9 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-8-(4-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0434] The title compound was prepared from 4-[4-bromo-3-hydroxy-8-(4-methoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 405.1 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-8-(4-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid [0435] The title compound was prepared from4-[4-cyano-3-hydroxy-8-(4-methoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 377.1 (M+1) ⁺ . Example 62 4-[4-Cyano-3-hydroxy-8-(2-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid a) 4-[3-Hydroxy-8-(2-methoxy-phenyl)-quinolin-2-yl]-4-oxo-butyr ic acid ethyl ester [0436] The title compound was prepared from 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 2-methoxyphenylboronic acid in analogy to Example 47j. MS (m/z) 380.1 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-8-(2-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0437] The title compound was prepared from 4-[3-hydroxy-8-(2-methoxy-phenyl)-quinolin-2- yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 457.9, 459.9 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-8-(2-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0438] The title compound was prepared from 4-[4-bromo-3-hydroxy-8-(2-methoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 405.1 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-8-(2-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid [0439] The title compound was prepared from 4-[4-cyano-3-hydroxy-8-(2-methoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 377.0 (M+1) ⁺ . Example 63 4-[4-Cyano-3-hydroxy-8-(3-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid a) 4-[3-Hydroxy-8-(3-methoxy-phenyl)-quinolin-2-yl]-4-oxo-butyr ic acid ethyl ester [0440] The title compound was prepared from 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 3-methoxyphenylboronic acid in analogy to Example 47j. MS (m/z) 384.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-8-(3-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0441] The title compound was prepared from 4-[3-hydroxy-8-(3-methoxy-phenyl)-quinolin-2- yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 457.9, 459.9 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-8-(3-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0442] The title compound was prepared from 4-[4-bromo-3-hydroxy-8-(3-methoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 405.1 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-8-(3-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid [0443] The title compound was prepared from 4-[4-cyano-3-hydroxy-8-(3-methoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 377.1 (M+1) ⁺ . Example 64 4-[4-Cyano-3-hydroxy-7-(3-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid a) 4-[3-Hydroxy-7-(3-methoxy-phenyl)-quinolin-2-yl]-4-oxo-butyr ic acid ethyl ester [0444] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 3-methoxyphenylboronic acid in analogy to Example 47j. MS (m/z) 380.1 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-7-(3-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0445] The title compound was prepared 4-[3-hydroxy-7-(3-methoxy-phenyl)-quinolin-2-yl]-4- oxo-butyric acid ethyl ester from and NBS in analogy to Example 47k. MS (m/z) 457.9, 459.9 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-7-(3-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0446] The title compound was prepared from 4-[4-bromo-3-hydroxy-7-(3-methoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 405.1 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-7-(3-methoxy-phenyl)-quinolin-2-yl]-4-o xo-butyric acid [0447] The title compound was prepared from 4-[4-cyano-3-hydroxy-7-(3-methoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 377.1 (M+1) ⁺ . Example 65 4-[4-Cyano-3-hydroxy-7-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-7-(4-trifluoromethyl-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0448] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 4-trifluoromethylphenylboronic acid in analogy to Example 47j. MS (m/z) 418.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-7-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0449] The title compound was prepared from 4-[3-hydroxy-7-(4-trifluoromethyl-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 495.8, 497.8 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-7-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0450] The title compound was prepared from 4-[4-bromo-3-hydroxy-7-(4-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 443.0 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-7-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid [0451] The title compound was prepared from 4-[4-cyano-3-hydroxy-7-(4-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 412.9 (M-1) ⁺ . Example 66 4-[4-Cyano-3-hydroxy-7-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-7-(3-trifluoromethyl-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0452] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 3-trifluoromethylphenylboronic acid in analogy to Example 47j. MS (m/z) 418.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-7-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0453] The title compound was prepared from 4-[3-hydroxy-7-(3-trifluoromethyl-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 495.8, 497.8 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-7-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0454] The title compound was prepared from 4-[4-bromo-3-hydroxy-7-(3-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 443.1 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-7-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid [0455] The title compound was prepared from 4-[4-cyano-3-hydroxy-7-(3-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 412.9 (M-1) ⁺ . Example 67 4-[4-Cyano-3-hydroxy-7-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-7-(2-trifluoromethyl-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0456] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 2-trifluoromethylphenylboronic acid in analogy to Example 47j. MS (m/z) 418.1 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-7-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0457] The title compound was prepared from 4-[3-hydroxy-7-(2-trifluoromethyl-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 495.8, 497.8 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-7-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0458] The title compound was prepared from 4-[4-bromo-3-hydroxy-7-(2-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 443.0 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-7-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid [0459] The title compound was prepared from 4-[4-cyano-3-hydroxy-7-(2-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 414.9 (M+1) ⁺ . Example 68 4-[4-Cyano-3-hydroxy-7-(2-m-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid a) 4-(4-Cyano-3-hydroxy-7-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0460] To a solution of 4-(4-Bromo-3-hydroxy-7-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (170 mg, 0.41 mmol) in ethyl acetate (20 mL) was added Pd/C (25 mg, 0.025eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 4 hr at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hexane (0% - 20%) to give the title compound, 116 mg, MS-(+)-ion, M+H = 417.09. b) 4-[4-Cyano-3-hydroxy-7-(2-m-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid [0461] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-7-m-tolylethynyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (110 mg, 0.26 mmol) in methanol(4 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.3 mL, 1.3 mmol). After 8h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.46 mg. MS-(+)-ion, M+H = 389.09. Example 69 4-(4-Cyano-3-hydroxy-7-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid a) 4-(3-Hydroxy-7-p-tolylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0462] To a round-bottom-flask were added 4-(7-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (530 mg, 1.5 mmol), PdCl2(PPh3)2 (53 mg, 0.075 mmol), CuI (29 mg, 015 mmol), Et3N (757 mg, 7.5 mmol), and 1-ethynyl-4-methyl-benzene (348 mg, 3.0 mmol) in anhydrous DMF (8 mL). The mixture was heated at 100 °C under N ₂ atmosphere for 3 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 50 mL H ₂ O, treated with 5 mL 1N HCl, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (50 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 520 mg, MS-(+)-ion, M+H = 388.07. b) 4-(4-Bromo-3-hydroxy-7-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0463] At 0°C, to a solution of 4-(3-Hydroxy-7-p-tolylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (520 mg, 1.34 mmol) in DMF (15 mL) was added N-Bromosuccinimide (249 mg, 1.41 mmol). The mixture was stirred then at room temperature for 1 h and quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x30 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 405 mg. MS-(+)-ion, M+H = 466.01, 467.81. c) 4-(4-Cyano-3-hydroxy-7-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0464] A mixture of 4-(4-Bromo-3-hydroxy-7-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (400 mg, 0.86 mmol), zinc cyanide (201 mg, 1.72 mmol), tris(dibenzylideneacetone)dipalladium(0) (79 mg, 0.086 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 94 mg, 0.17 mmol), and zinc dust (17 mg, 0.26 mmol) in anhydrous dimethylacetamide (10 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 206 mg. MS-(+)-ion, M+H = 413.02. d) 4-(4-Cyano-3-hydroxy-7-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid [0465] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-7-p-tolylethynyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (76 mg, 0.18 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.9 mL, 0.9 mmol). After 20h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (20mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (20mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.48 mg. MS-(+)-ion, M+H = 385.02. Example 70 4-[4-Cyano-3-hydroxy-7-(2-p-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid a) 4-(4-Cyano-3-hydroxy-7-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0466] To a solution of 4-(4-Bromo-3-hydroxy-7-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (125 mg, 0.3 mmol) in ethyl acetate (6 mL) was added Pd/C (32 mg, 0.04eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 1 day at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hexane (0% - 20%) to give the title compound, 39 mg, MS-(+)-ion, M+H = 417.12. b) 4-[4-Cyano-3-hydroxy-7-(2-p-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid [0467] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-7-p-tolylethynyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (38 mg, 0.1 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.45 mL, 0.45 mmol). After 8h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.22 mg. MS-(+)-ion, M+H = 389.07. Example 71 4-(4-Cyano-3-hydroxy-8-phenylethynyl-quinolin-2-yl)-4-oxo-bu tyric acid a) 4-(3-Hydroxy-8-phenylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0468] To a round-bottom-flask were added 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (530 mg, 1.5 mmol), PdCl2(PPh3)2 (53 mg, 0.075 mmol), CuI (29 mg, 015 mmol), Et3N (757 mg, 7.5 mmol), and ethynyl-benzene (306 mg, 3.0 mmol) in anhydrous DMF (8 mL). The mixture was heated at 100 °C under N2 atmosphere for 3 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 50 mL H ₂ O, treated with 5 mL 1N HCl, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (50 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 542 mg, MS- (+)-ion, M+H = 374.07. b) 4-(4-Bromo-3-hydroxy-8-phenylethynyl-quinolin-2-yl)-4-oxo-bu tyric acid ethyl ester [0469] At 0°C, to a solution of 4-(3-Hydroxy-8-phenylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (540 mg, 1.45 mmol) in DMF (15 mL) was added N-Bromosuccinimide (540 mg, 3.1 mmol). The mixture was stirred then at room temperature for 1 h and quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x30 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 320 mg. MS-(+)-ion, M+H = 465.90, 467.85. c) 4-(4-Cyano-3-hydroxy-8-phenylethynyl-quinolin-2-yl)-4-oxo-bu tyric acid ethyl ester [0470] A mixture of 4-(4-Bromo-3-hydroxy-8-phenylethynyl-quinolin-2-yl)-4-oxo-bu tyric acid ethyl ester (320 mg, 0.71 mmol), zinc cyanide (124 mg, 1.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.0355 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 39 mg, 0.071 mmol), and zinc dust (13.8 mg, 0.21 mmol) in anhydrous dimethylacetamide (7 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and ethyl acetate (30 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 112 mg. MS-(+)-ion, M+H = 399.12. d) 4-(4-Cyano-3-hydroxy-8-phenylethynyl-quinolin-2-yl)-4-oxo-bu tyric acid [0471] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-8-phenylethynyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (28 mg, 0.07 mmol) in methanol(1 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.42 mL, 0.42 mmol). After 4h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.5.8 mg. MS-(+)-ion, M+H = 371.07. Example 72 4-(4-Cyano-3-hydroxy-8-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid a) 4-(4-Cyano-3-hydroxy-8-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid ethyl ester [0472] To a solution of 4-(4-Cyano-3-hydroxy-8-phenylethynyl-quinolin-2-yl)-4-oxo-bu tyric acid ethyl ester (82 mg, 0.2 mmol) in ethyl acetate (10 mL) was added Pd/C (21 mg, 0.04eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 3 h at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hexane (0% - 20%) to give the title compound, 38 mg, MS-(+)-ion, M+H = 403.07. b) 4-(4-Cyano-3-hydroxy-8-phenethyl-quinolin-2-yl)-4-oxo-butyri c acid [0473] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-7-p-tolylethynyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (38 mg, 0.1 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.5 mL, 0.5 mmol). After 8h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.26 mg. MS-(+)-ion, M+H = 375.02. Example 73 4-[4-Cyano-3-hydroxy-7-(4-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-7-(4-trifluoromethoxy-phenyl)-quinolin-2-yl]-4- oxo-butyric acid ethyl ester [0474] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 4-trifluoromethoxyphenylboronic acid in analogy to Example 47j. MS (m/z) 434.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-7-(4-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0475] The title compound was prepared from 4-[3-hydroxy-7-(4-trifluoromethoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 511.8, 513.8 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-7-(4-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0476] The title compound was prepared from 4-[4-bromo-3-hydroxy-7-(4-trifluoromethoxy- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 456.9 (M-1) ⁺ . d) 4-[4-Cyano-3-hydroxy-7-(4-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid [0477] The title compound was prepared from 4-[4-cyano-3-hydroxy-7-(4-trifluoromethoxy- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 431.0 (M+1) ⁺ . Example 74 4-[4-Cyano-3-hydroxy-7-(3-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-7-(3-trifluoromethoxy-phenyl)-quinolin-2-yl]-4- oxo-butyric acid ethyl ester [0478] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 3-trifluoromethoxyphenylboronic acid in analogy to Example 47j. MS (m/z) 384.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-7-(3-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0479] The title compound was prepared from 4-[3-hydroxy-7-(3-trifluoromethoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 511.8, 513.8 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-7-(3-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0480] The title compound was prepared from 4-[4-bromo-3-hydroxy-7-(3-trifluoromethoxy- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 459.0 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-7-(3-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid [0481] The title compound was prepared from 4-[4-cyano-3-hydroxy-7-(3-trifluoromethoxy- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 431.0 (M+1) ⁺ . Example 75 4-[4-Cyano-3-hydroxy-7-(2-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-7-(2-trifluoromethoxy-phenyl)-quinolin-2-yl]-4- oxo-butyric acid ethyl ester [0482] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 2-trifluoromethoxyphenylboronic acid in analogy to Example 47j. MS (m/z) 434.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-7-(2-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0483] The title compound was prepared from 4-[3-hydroxy-7-(2-trifluoromethoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 511.8, 513.8 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-7-(2-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0484] The title compound was prepared from 4-[4-bromo-3-hydroxy-7-(2-trifluoromethoxy- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 459.0 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-7-(2-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid [0485] The title compound was prepared from 4-[4-cyano-3-hydroxy-7-(2-trifluoromethoxy- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 431.0 (M+1) ⁺ . Example 76 4-(4-Cyano-3-hydroxy-7-naphthalen-1-yl-quinolin-2-yl)-4-oxo- butyric acid a) 4-(3-Hydroxy-7-naphthalen-1-yl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0486] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 1-naphthaleneboronic acid to give the title compound in analogy to Example 47j. MS (m/z) 400.0 (M+1) ⁺ . b) 4-(4-Bromo-3-hydroxy-7-naphthalen-1-yl-quinolin-2-yl)-4-oxo- butyric acid ethyl ester [0487] The title compound was prepared from 4-(3-hydroxy-7-naphthalen-1-yl-quinolin-2-yl)-4- oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 477.9, 479.9 (M+1) ⁺ . c) 4-(4-Cyano-3-hydroxy-7-naphthalen-1-yl-quinolin-2-yl)-4-oxo- butyric acid ethyl ester [0488] The title compound was prepared from 4-(4-bromo-3-hydroxy-7-naphthalen-1-yl- quinolin-2-yl)-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 423.1 (M-1) ⁺ . d) 4-(4-Cyano-3-hydroxy-7-naphthalen-1-yl-quinolin-2-yl)-4-oxo- butyric acid [0489] The title compound was prepared from 4-(4-cyano-3-hydroxy-7-naphthalen-1-yl- quinolin-2-yl)-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 397.0 (M+1) ⁺ . Example 77 4-(4-Cyano-3-hydroxy-8-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid a) 4-(3-Hydroxy-8-o-tolylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0490] To a round-bottom-flask were added 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (530 mg, 1.5 mmol), PdCl ₂ (PPh ₃ ) ₂ (53 mg, 0.075 mmol), CuI (29 mg, 015 mmol), Et ₃ N (757 mg, 7.5 mmol), and 1-ethynyl-2-methyl-benzene (348 mg, 3.0 mmol) in anhydrous DMF (8 mL). The mixture was heated at 100 °C under N ₂ atmosphere for 3 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 50 mL H2O, treated with 5 mL 1N HCl, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (50 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 551 mg, MS-(+)-ion, M+H = 388.07. b) 4-(4-Bromo-3-hydroxy-8-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0491] At 0°C, to a solution of 4-(3-Hydroxy-8-o-tolylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (550 mg, 1.4 mmol) in DMF (15 mL) was added N-Bromosuccinimide (540 mg, 3.1 mmol). The mixture was stirred then at room temperature for 1 h and quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x30 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 132 mg. MS-(+)-ion, M+H = 465.96. c) 4-(4-Cyano-3-hydroxy-8-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0492] A mixture of 4-(4-Bromo-3-hydroxy-8-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (325 mg, 0.70 mmol), zinc cyanide (124 mg, 1.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.0355 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 39 mg, 0.071 mmol), and zinc dust (13.8 mg, 0.21 mmol) in anhydrous dimethylacetamide (7 mL) was heated at 90 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and ethyl acetate (30 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 162 mg. MS-(+)-ion, M+H = 413.07. d) 4-(4-Cyano-3-hydroxy-8-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid [0493] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-8-o-tolylethynyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (41 mg, 0.1 mmol) in methanol(1 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.5 mL, 0.5 mmol). After 16h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.27 mg. MS-(+)-ion, M+H = 385.07. Example 78 4-[4-Cyano-3-hydroxy-8-(2-o-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid a) 4-[4-Cyano-3-hydroxy-8-(2-o-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0494] To a solution of 4-(4-Cyano-3-hydroxy-8-o-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (120 mg, 0.3 mmol) in ethyl acetate (10 mL) was added Pd/C (16 mg, 0.02eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 6 h at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hexane (0% - 20%) to give the title compound, 67 mg, MS-(+)-ion, M+H = 417.12. b) 4-[4-Cyano-3-hydroxy-8-(2-o-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid [0495] At room temperature, to a solution of 4-[4-Cyano-3-hydroxy-8-(2-o-tolyl-ethyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester (62 mg, 0.15 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.75 mL, 0.75 mmol). After 18h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.46 mg. MS-(+)-ion, M+H = 389.07. Example 79 4-(4-Cyano-3-hydroxy-8-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid a) 4-(3-Hydroxy-8-m-tolylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0496] To a round-bottom-flask were added 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (530 mg, 1.5 mmol), PdCl ₂ (PPh ₃ ) ₂ (53 mg, 0.075 mmol), CuI (29 mg, 015 mmol), Et ₃ N (757 mg, 7.5 mmol), and 1-ethynyl-3-methyl-benzene (348 mg, 3.0 mmol) in anhydrous DMF (8 mL). The mixture was heated at 100 °C under N ₂ atmosphere for 3 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 50 mL H2O, treated with 5 mL 1N HCl, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (50 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 503 mg, MS-(+)-ion, M+H = 388.07. b) 4-(4-Bromo-3-hydroxy-8-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0497] At 0°C, to a solution of 4-(3-Hydroxy-8-m-tolylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (440 mg, 1.15 mmol) and acetic acid (645 mg, 10.75 mmol) in DMF (15 mL) was added N-Bromosuccinimide (463 mg, 2.6 mmol). The mixture was stirred then at [0498] room temperature for 1 h and quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x30 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 220 mg. MS-(+)-ion, M+H = 465.91, 467.96. c) 4-(4-Cyano-3-hydroxy-8-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0499] A mixture of 4-(4-Bromo-3-hydroxy-8-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (295 mg, 0.64 mmol), zinc cyanide (117 mg, 1.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (29 mg, 0.032 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 35 mg, 0.064 mmol), and zinc dust (13 mg, 0.2 mmol) in anhydrous dimethylacetamide (7 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and ethyl acetate (30 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 166 mg. MS-(+)-ion, M+H = 413.07. d) 4-(4-Cyano-3-hydroxy-8-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid [0500] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-8-m-tolylethynyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (41 mg, 0.1 mmol) in methanol(1 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.5 mL, 0.5 mmol). After 16h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.27 mg. MS-(+)-ion, M+H = 385.07. Example 80 4-[4-Cyano-3-hydroxy-8-(2-m-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid a) 4-[4-Cyano-3-hydroxy-8-(2-m-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0501] To a solution of 4-(4-Cyano-3-hydroxy-8-m-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (120 mg, 0.3 mmol) in ethyl acetate (10 mL) was added Pd/C (16 mg, 0.02eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 6 h at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hexane (0% - 20%) to give the title compound, 74 mg, MS-(+)-ion, M+H = 417.12. b) 4-[4-Cyano-3-hydroxy-8-(2-m-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid [0502] At room temperature, to a solution of 4-[4-Cyano-3-hydroxy-8-(2-m-tolyl-ethyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester (70 mg, 0.17 mmol) in methanol(2 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.85 mL, 0.85 mmol). After 18h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.49 mg. MS-(+)-ion, M+H = 389.07. Example 81 4-(4-Cyano-3-hydroxy-8-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid a) 4-(3-Hydroxy-8-p-tolylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester [0503] To a round-bottom-flask were added 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (530 mg, 1.5 mmol), PdCl2(PPh3)2 (53 mg, 0.075 mmol), CuI (29 mg, 015 mmol), Et3N (757 mg, 7.5 mmol), and 1-ethynyl-4-methyl-benzene (348 mg, 3.0 mmol) in anhydrous DMF (8 mL). The mixture was heated at 100 °C under N2 atmosphere for 3 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 50 mL H ₂ O, treated with 5 mL 1N HCl, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (50 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 521 mg, MS-(+)-ion, M+H = 388.12. b) 4-(4-Bromo-3-hydroxy-8-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0504] At 0°C, to a solution of 4-(3-Hydroxy-8-p-tolylethynyl-quinolin-2-yl)-4-oxo-butyric acid ethyl ester (520 mg, 1.35 mmol) and acetic acid (810 mg, 13.5 mmol) in DMF (15 mL) was added N- Bromosuccinimide (505 mg, 2.8 mmol). The mixture was stirred then at room temperature for 1 h and quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x30 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 135 mg. MS-(+)-ion, M+H = 465.92, 467.90. c) 4-(4-Cyano-3-hydroxy-8-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester [0505] A mixture of 4-(4-Bromo-3-hydroxy-8-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (295 mg, 0.64 mmol), zinc cyanide (117 mg, 1.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (29 mg, 0.032 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 35 mg, 0.064 mmol), and zinc dust (13 mg, 0.2 mmol) in anhydrous dimethylacetamide (7 mL) was heated at 90 °C under N ₂ atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and ethyl acetate (30 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 166 mg. MS-(+)-ion, M+H = 413.07. d) 4-(4-Cyano-3-hydroxy-8-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid [0506] At room temperature, to a solution of 4-(4-Cyano-3-hydroxy-8-p-tolylethynyl-quinolin- 2-yl)-4-oxo-butyric acid ethyl ester (20 mg, 0.05 mmol) in methanol(1 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.3 mL, 0.3 mmol). After 16h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.10 mg. MS-(+)-ion, M+H = 385.02. Example 82 4-[4-Cyano-7-(4-fluoro-3-methyl-phenyl)-3-hydroxy-quinolin-2 -yl]-4-oxo-butyric acid a) 4-[7-(4-Fluoro-3-methyl-phenyl)-3-hydroxy-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0507] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 4-fluoro-3-methylphenylboronic acid in analogy to Example 47j. MS (m/z) 382.1 (M+1) ⁺ . b) 4-[4-Bromo-7-(4-fluoro-3-methyl-phenyl)-3-hydroxy-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0508] The title compound was prepared from 4-[7-(4-fluoro-3-methyl-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 459.9, 461.9 (M+1) ⁺ . c) 4-[4-Cyano-7-(4-fluoro-3-methyl-phenyl)-3-hydroxy-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0509] The title compound was prepared from 4-[4-bromo-7-(4-fluoro-3-methyl-phenyl)-3- hydroxy-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analogy to Example 47l. MS (m/z) 407.1 (M+1) ⁺ . d) 4-[4-Cyano-7-(4-fluoro-3-methyl-phenyl)-3-hydroxy-quinolin-2 -yl]-4-oxo-butyric acid [0510] The title compound was prepared from 4-[4-cyano-7-(4-fluoro-3-methyl-phenyl)-3- hydroxy-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 379.0 (M+1) ⁺ . Example 83 4-[4-Cyano-7-(2-fluoro-3-methyl-phenyl)-3-hydroxy-quinolin-2 -yl]-4-oxo-butyric acid a) 4-[7-(2-Fluoro-3-methyl-phenyl)-3-hydroxy-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0511] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 2-fluoro-3-methylphenylboronic acid in analogy to Example 47j. MS (m/z) 382.1 (M+1) ⁺ . b) 4-[4-Bromo-7-(2-fluoro-3-methyl-phenyl)-3-hydroxy-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0512] The title compound was prepared from 4-[7-(2-fluoro-3-methyl-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 459.9, 461.9 (M+1) ⁺ . c) 4-[4-Cyano-7-(2-fluoro-3-methyl-phenyl)-3-hydroxy-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0513] The title compound was prepared from 4-[4-bromo-7-(2-fluoro-3-methyl-phenyl)-3- hydroxy-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 407.0 (M+1) ⁺ . d) 4-[4-Cyano-7-(2-fluoro-3-methyl-phenyl)-3-hydroxy-quinolin-2 -yl]-4-oxo-butyric acid [0514] The title compound was prepared from 4-[4-cyano-7-(2-fluoro-3-methyl-phenyl)-3- hydroxy-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 379.0 (M+1) ⁺ . Example 84 4-[4-Cyano-7-(2-fluoro-5-methyl-phenyl)-3-hydroxy-quinolin-2 -yl]-4-oxo-butyric acid a) 4-[7-(2-Fluoro-5-methyl-phenyl)-3-hydroxy-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0515] The title compound was prepared from 4-(7-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from 47i) and 2-fluoro-5-methylphenylboronic acid in analogy to Example 47j. MS (m/z) 382.1 (M+1) ⁺ . b) 4-[4-Bromo-7-(2-fluoro-5-methyl-phenyl)-3-hydroxy-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0516] The title compound was prepared from 4-[7-(2-fluoro-5-methyl-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 459.9, 461.9 (M+1) ⁺ . c) 4-[4-Cyano-7-(2-fluoro-5-methyl-phenyl)-3-hydroxy-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0517] The title compound was prepared from 4-[4-bromo-7-(2-fluoro-5-methyl-phenyl)-3- hydroxy-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 407.1 (M+1) ⁺ . d) 4-[4-Cyano-7-(2-fluoro-5-methyl-phenyl)-3-hydroxy-quinolin-2 -yl]-4-oxo-butyric acid [0518] The title compound was prepared from 4-[4-cyano-7-(2-fluoro-5-methyl-phenyl)-3- hydroxy-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 379.0 (M+1) ⁺ . Example 85 4-[4-Cyano-3-hydroxy-8-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-8-(4-trifluoromethyl-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0519] The title compound was prepared from 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 4-trifluoromethylphenylboronic acid in analogy to Example 47j. MS (m/z) 418.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-8-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0520] The title compound was prepared from 4-[3-hydroxy-8-(4-trifluoromethyl-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 495.8, 497.8 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-8-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0521] The title compound was prepared from 4-[4-bromo-3-hydroxy-8-(4-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 443.0 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-8-(4-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid [0522] The title compound was prepared from 4-[4-cyano-3-hydroxy-8-(4-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 415.0 (M+1) ⁺ . Example 86 4-[4-Cyano-3-hydroxy-8-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-8-(3-trifluoromethyl-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0523] The title compound was prepared from 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 3-trifluoromethylphenylboronic acid in analogy to Example 47j. MS (m/z) 418.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-8-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0524] The title compound was prepared from 4-[3-hydroxy-8-(3-trifluoromethyl-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 495.8, 497.8 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-8-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0525] The title compound was prepared from 4-[4-bromo-3-hydroxy-8-(3-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 443.1 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-8-(3-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid [0526] The title compound was prepared from 4-[4-cyano-3-hydroxy-8-(3-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 415.0 (M+1) ⁺ . Example 87 4-[4-Cyano-3-hydroxy-8-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-8-(2-trifluoromethyl-phenyl)-quinolin-2-yl]-4-o xo-butyric acid ethyl ester [0527] The title compound was prepared from 4-(8-bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 2-trifluoromethylphenylboronic acid in analogy to Example 47j. MS (m/z) 418.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-8-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0528] The title compound was prepared from 4-[3-hydroxy-8-(2-trifluoromethyl-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analogy to Example 47k. MS (m/z) 495.8, 497.7 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-8-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid ethyl ester [0529] The title compound was prepared from 4-[4-bromo-3-hydroxy-8-(2-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analogy to Example 47l. MS (m/z) 443.0 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-8-(2-trifluoromethyl-phenyl)-quinolin-2 -yl]-4-oxo-butyric acid [0530] The title compound was prepared from 4-[4-cyano-3-hydroxy-8-(2-trifluoromethyl- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analogy to Example 59d: MS (m/z) 415.0 (M+1) ⁺ . Example 88 4-[4-Cyano-3-hydroxy-8-(2-p-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid a) 4-[4-Cyano-3-hydroxy-8-(2-p-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid ethyl ester [0531] To a solution of 4-(4-Cyano-3-hydroxy-8-p-tolylethynyl-quinolin-2-yl)-4-oxo-b utyric acid ethyl ester (40 mg, 0.1 mmol) in ethyl acetate (5 mL) was added Pd/C (5 mg, 0.03eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 6 h at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hexane (0% - 20%) to give the title compound, 21 mg, MS-(+)-ion, M+H = 417.17. b) 4-[4-Cyano-3-hydroxy-8-(2-p-tolyl-ethyl)-quinolin-2-yl]-4-ox o-butyric acid [0532] At room temperature, to a solution of 4-[4-Cyano-3-hydroxy-8-(2-p-tolyl-ethyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester (19 mg, 0.05 mmol) in methanol(1 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.3 mL, 0.3 mmol). After 18h at room temperature, the reaction was diluted in 15 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.11 mg. MS-(+)-ion, M+H = 389.07. Example 89 4-[8-(2-Chloro-phenylethynyl)-4-cyano-3-hydroxy-quinolin-2-y l]-4-oxo-butyric acid a) 4-[8-(2-Chloro-phenylethynyl)-3-hydroxy-quinolin-2-yl]-4-oxo -butyric acid ethyl ester [0533] To a round-bottom-flask were added 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (530 mg, 1.5 mmol), PdCl2(PPh3)2 (53 mg, 0.075 mmol), CuI (29 mg, 015 mmol), Et3N (757 mg, 7.5 mmol), and 1-Chloro-2-ethynyl-benzene (411 mg, 3.0 mmol) in anhydrous DMF (8 mL). The mixture was heated at 100 °C under N2 atmosphere for 3 hours. The reaction mixture was then allowed to reach ambient temperature, diluted in 50 mL H ₂ O, treated with 5 mL 1N HCl, and extracted with ethyl acetate (50 mL x 3). The combined organics were washed with brine (50 mL) and dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 542 mg, MS-(+)-ion, M+H = 408.07. b) 4-[4-Bromo-8-(2-chloro-phenylethynyl)-3-hydroxy-quinolin-2-y l]-4-oxo-butyric acid ethyl ester [0534] At 0°C, to a solution of 4-[8-(2-Chloro-phenylethynyl)-3-hydroxy-quinolin-2-yl]-4-oxo - butyric acid ethyl ester (550 mg, 1.2 mmol) in DMF (20 mL) was added 2-Bromo-isoindole-1,3-dione (380 mg, 1.68 mmol). The mixture was stirred then at room temperature for 18 h and quenched with saturated aqueous sodium sulfite (5 mL) and diluted with 20 mL water. The mixture was extracted with ethyl acetate (3x30 mL). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (0% - 20%) to give the title compound, 486 mg. MS- (+)-ion, M+H = 487.81. c) 4-[8-(2-Chloro-phenylethynyl)-4-cyano-3-hydroxy-quinolin-2-y l]-4-oxo-butyric acid ethyl ester [0535] A mixture of 4-[4-Bromo-8-(2-chloro-phenylethynyl)-3-hydroxy-quinolin-2-y l]-4-oxo- butyric acid ethyl ester (485 mg, 1.0 mmol), zinc cyanide (234 mg, 2.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (92 mg, 0.1 mmol), 1,1'-Bis(diphenylphosphino)ferrocene (dppf, 110 mg, 0.2 mmol), and zinc dust (20 mg, 0.3 mmol) in anhydrous dimethylacetamide (10 mL) was heated at 80 °C under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and ethyl acetate (30 mL).2 mL of 1 N HCl was added to the mixture and it was allowed to stir for 10 min at room temperature. The organic layer was collected. The aqueous layer was further extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with ethyl acetate/hexane (10% - 30%) to give the title compound, 211 mg. MS-(+)-ion, M+H = 432.97. d) 4-[8-(2-Chloro-phenylethynyl)-4-cyano-3-hydroxy-quinolin-2-y l]-4-oxo-butyric acid [0536] At room temperature, to a solution of 4-[8-(2-Chloro-phenylethynyl)-4-cyano-3- hydroxy-quinolin-2-yl]-4-oxo-butyric acid ethyl ester (87 mg, 0.2 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 1.0 mL, 1.0 mmol). After 16h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.56 mg. MS-(+)-ion, M+H = 405.02. Example 90 4-{8-[2-(2-Chloro-phenyl)-ethyl]-4-cyano-3-hydroxy-quinolin- 2-yl}-4-oxo-butyric acid a) 4-{8-[2-(2-Chloro-phenyl)-ethyl]-4-cyano-3-hydroxy-quinolin- 2-yl}-4-oxo-butyric acid ethyl ester [0537] To a solution of 4-[8-(2-Chloro-phenylethynyl)-4-cyano-3-hydroxy-quinolin-2-y l]-4- oxo-butyric acid ethyl ester (130 mg, 0.3 mmol) in ethyl acetate (10 mL) was added Pd/C (24 mg, 0.03eq, 10 wt.%, wet, contains ~51% water). The mixture was vacuumed/refilled with hydrogen gas for three times and attached to a hydrogen gas balloon. After stirring for 6 h at room temperature, the reaction mixture was filtrated off through celite. The filtrate was evaporated in vacuo to afford the crude product. This material was purified by flash chromatography eluting with EtOAc/Hexane (0% - 20%) to give the title compound, 62 mg, MS-(+)-ion, M+H = 437.02. b) 4-{8-[2-(2-Chloro-phenyl)-ethyl]-4-cyano-3-hydroxy-quinolin- 2-yl}-4-oxo-butyric acid [0538] At room temperature, to a solution of 4-{8-[2-(2-Chloro-phenyl)-ethyl]-4-cyano-3- hydroxy-quinolin-2-yl}-4-oxo-butyric acid ethyl ester (56 mg, 0.13 mmol) in methanol(3 mL) was added sodium hydroxide aqueous solution (1.0 M in water, 0.65 mL, 0.65 mmol). After 18h at room temperature, the reaction was diluted in 25 mL water and extracted with ethyl acetate (10mL x 3). The resulting aqueous layer was treated with 1N HCl to pH = 4, followed by extraction with ethyl acetate (10mL x 3). The combined organic layers were washed with brine and dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound.35 mg. MS-(+)-ion, M+H = 409.02. Example 91 4-[4-Cyano-3-hydroxy-8-(4-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-8-(4-trifluoromethoxy-phenyl)-quinolin-2-yl]-4- oxo-butyric acid ethyl ester [0539] The title compound was prepared from 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 4-trifluoromethoxyphenylboronic acid in analog to Example 47j : MS (m/z) 433.9 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-8-(4-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0540] The title compound was prepared from 4-[3-Hydroxy-8-(4-trifluoromethoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analog to Example 47k: MS (m/z) 511.7, 513.8 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-8-(4-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0541] The title compound was prepared from 4-[4-Bromo-3-hydroxy-8-(4-trifluoromethoxy- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analog to Example 47l : MS (m/z) 459.0 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-8-(4-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid [0542] The title compound was prepared from 4-[4-Cyano-3-hydroxy-8-(4-trifluoromethoxy- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide to give the title compound in analog to Example 59d: MS (m/z) 431.0 (M+1) ⁺ . Example 92 4-[4-Cyano-3-hydroxy-8-(3-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-8-(3-trifluoromethoxy-phenyl)-quinolin-2-yl]-4- oxo-butyric acid ethyl ester [0543] The title compound was prepared from 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 3-trifluoromethoxyphenylboronic acid in analog to Example 47j : MS (m/z) 434.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-8-(3-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0544] The title compound was prepared from 4-[3-Hydroxy-8-(3-trifluoromethoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analog to Example 47k: MS (m/z) 511.8, 513.8 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-8-(3-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0545] The title compound was prepared from 4-[4-Bromo-3-hydroxy-8-(3-trifluoromethoxy- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analog to Example 47l : MS (m/z) 458.9 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-8-(3-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid [0546] The title compound was prepared from 4-[4-Cyano-3-hydroxy-8-(3-trifluoromethoxy- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analog to Example 59d: MS (m/z) 431.1 (M+1) ⁺ . Example 93 4-[4-Cyano-3-hydroxy-8-(2-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid a) 4-[3-Hydroxy-8-(2-trifluoromethoxy-phenyl)-quinolin-2-yl]-4- oxo-butyric acid ethyl ester [0547] The title compound was prepared from 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 2-trifluoromethoxyphenylboronic acid in analog to Example 47j : MS (m/z) 434.0 (M+1) ⁺ . b) 4-[4-Bromo-3-hydroxy-8-(2-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0548] The title compound was prepared from 4-[3-Hydroxy-8-(2-trifluoromethoxy-phenyl)- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analog to Example 47k: MS (m/z) 511.8, 513.8 (M+1) ⁺ . c) 4-[4-Cyano-3-hydroxy-8-(2-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0549] The title compound was prepared from 4-[4-Bromo-2-hydroxy-8-(2-trifluoromethoxy- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analog to Example 47l : MS (m/z) 459.0 (M+1) ⁺ . d) 4-[4-Cyano-3-hydroxy-8-(2-trifluoromethoxy-phenyl)-quinolin- 2-yl]-4-oxo-butyric acid [0550] The title compound was prepared from 4-[4-Cyano-3-hydroxy-8-(2-trifluoromethoxy- phenyl)-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analog to Example 59d: MS (m/z) 431.0 (M+1) ⁺ . Example 94 4-[4-Cyano-8-(2-fluoro-4-methoxy-phenyl)-3-hydroxy-quinolin- 2-yl]-4-oxo-butyric acid a) 4-[8-(2-Fluoro-4-methoxy-phenyl)-3-hydroxy-quinolin-2-yl]-4- oxo-butyric acid ethyl ester [0551] The title compound was prepared from 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 2-Fluoro-4-methoxyphenylboronic acid in analog to Example 47j : MS (m/z) 398.1 (M+1) ⁺ . b) 4-[4-Bromo-8-(2-fluoro-4-methoxy-phenyl)-3-hydroxy-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0552] The title compound was prepared from 4-[8-(2-Fluoro-4-methoxy-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and NBS in analog to Example 47k: MS (m/z) 475.9, 477.9 (M+1) ⁺ . c) 4-[4-Cyano-8-(2-fluoro-4-methoxy-phenyl)-3-hydroxy-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester [0553] The title compound was prepared from 4-[4-Bromo-8-(2-fluoro-4-methoxy-phenyl)-3- hydroxy-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analog to Example 47l : MS (m/z) 423.0 (M+1) ⁺ . d) 4-[4-Cyano-8-(2-fluoro-4-methoxy-phenyl)-3-hydroxy-quinolin- 2-yl]-4-oxo-butyric acid [0554] The title compound was prepared from 4-[4-Cyano-8-(2-fluoro-4-methoxy-phenyl)-3- hydroxy-quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analog to Example 59d: MS (m/z) 395.0 (M+1) ⁺ . Example 95 4-[4-Cyano-8-(2,4-difluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid a) 4-[8-(2,4-Difluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-bu tyric acid ethyl ester [0555] The title compound was prepared from 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 2,4-difluorophenylboronic acid in analog to Example 47j : MS (m/z) 386.0 (M+1) ⁺ . b) 4-[4-Bromo-8-(2,4-difluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester [0556] The title compound was prepared from 4-[8-(2,4-Difluoro-phenyl)-3-hydroxy-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester and NBS in analog to Example 47k: MS (m/z) 463.9, 465.9 (M+1) ⁺ . c) 4-[4-Cyano-8-(2,4-difluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester [0557] The title compound was prepared from 4-[4-Bromo-8-(2,4-difluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN)2 in analog to Example 47l : MS (m/z) 411.0 (M+1) ⁺ . d) 4-[4-Cyano-8-(2,4-difluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid [0558] The title compound was prepared from 4-[4-Cyano-8-(2,4-difluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analog to Example 59d: MS (m/z) 383.0 (M+1) ⁺ . Example 96 4-[4-Cyano-8-(2,5-difluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid a) 4-[8-(2,5-Difluoro-phenyl)-3-hydroxy-quinolin-2-yl]-4-oxo-bu tyric acid ethyl ester [0559] The title compound was prepared from 4-(8-Bromo-3-hydroxy-quinolin-2-yl)-4-oxo- butyric acid ethyl ester (prepared from Example 55i) and 2,5-difluorophenylboronic acid in analog to Example 47j: MS (m/z) 386.1 (M+1) ⁺ . b) 4-[4-Bromo-8-(2,5-difluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester [0560] The title compound was prepared from 4-[8-(2,5-Difluoro-phenyl)-3-hydroxy-quinolin- 2-yl]-4-oxo-butyric acid ethyl ester and NBS in analog to Example 47k: MS (m/z) 463.8, 465.8 (M+1) ⁺ . c) 4-[4-Cyano-8-(2,5-difluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid ethyl ester [0561] The title compound was prepared from 4-[4-Bromo-8-(2,5-difluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and Zn(CN) ₂ in analog to Example 47l : MS (m/z) 411.0 (M+1) ⁺ . d) 4-[4-Cyano-8-(2,5-difluoro-phenyl)-3-hydroxy-quinolin-2-yl]- 4-oxo-butyric acid [0562] The title compound was prepared from 4-[4-Cyano-8-(2,5-difluoro-phenyl)-3-hydroxy- quinolin-2-yl]-4-oxo-butyric acid ethyl ester and sodium hydroxide in analog to Example 59d: MS (m/z) 383.0 (M+1) ⁺ . [0563] Each of the following compounds were prepared according to Example 96, described above, using the appropriate starting materials. Example 118 4-(4-cyano-8-(3-fluoropyridin-4-yl)-3-hydroxyquinolin-2-yl)- 4-oxobutanoic acid a) ethyl 4-[3-(benzyloxy)-8-(3-fluoropyridin-4-yl)quinolin-2-yl]-4-ox obutanoate [0564] A mixture of ethyl 4-[3-(benzyloxy)-8-bromoquinolin-2-yl]-4-oxobutanoate (2.40 g, 5.43 mmol, 1 equiv), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyri dine (1.82 g, 8.13 mmol, 1.5 equiv), K3PO4 (3.46 g, 16.3 mmol, 3.0 equiv) and Pd(dppf)Cl2 (0.401 g, 0.541 mmol, 0.1 equiv) in dioxane (20 mL) and H2O (2 mL) was stirred for 3 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ethyl 4-[3-(benzyloxy)-8-(3-fluoropyridin- 4-yl)quinolin-2-yl]-4-oxobutanoate (1 g, 46%). MS (m/z) 459.16 (M+H). ¹ H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 1.8 Hz, 1H), 8.56 (dd, J = 4.8 Hz, 1.1 Hz, 1H), 8.22 (s, 1H), 8.09 (dd, J = 7.7 Hz, 2.0 Hz, 1H), 7.84 – 7.76 (m, 2H), 7.66 (dd, J = 6.2 Hz, 4.8 Hz, 1H), 7.58 – 7.52 (m, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.38 – 7.31 (m, 1H), 5.36 (s, 2H), 4.02 (q, J = 7.1 Hz, 2H), 3.92 (s, 2H), 2.57 (t, J = 6.5 Hz, 2H), 1.20 – 1.12 (m, 4H). b) ethyl 4-[8-(3-fluoropyridin-4-yl)-3-hydroxyquinolin-2-yl]-4-oxobut anoate [0565] A mixture of ethyl 4-[3-(benzyloxy)-8-(3-fluoropyridin-4-yl) quinolin-2-yl]-4- oxobutanoate (1.01 g, 2.18 mmol, 1.0 equiv) and thioanisole (1.35 g, 10.9 mmol, 5.0 equiv) in TFA (11 mL) was stirred for overnight at 90°C. After cooling to room temperature, the mixture was acidified to pH 7 with saturated aqueous NaHCO ₃ and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ethyl 4-[8-(3-fluoropyridin-4-yl)-3-hydroxyquinolin-2-yl]-4- oxobutanoate (450 mg, 56%). MS (m/z) 369.12 (M+H). ¹ H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.70 (d, J = 1.9 Hz, 1H), 8.57 (d, J = 4.9 Hz, 1H), 8.06 (dd, J = 7.0 Hz, 2.8 Hz, 1H), 7.97 (s, 1H), 7.83 – 7.74 (m, 2H), 7.68 (dd, J = 6.3 Hz, 4.8 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 2.62 (t, J = 6.6 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H). c) ethyl 4-(4-bromo-8-(3-fluoropyridin-4-yl)-3-hydroxyquinolin-2-yl)- 4-oxobutanoate [0566] A mixture of ethyl 4-[8-(3-fluoropyridin-4-yl)-3-hydroxyquinolin-2-yl]-4-oxobut anoate (200 mg, 0.181 mmol, 1.0 equiv) and NBS (35.4 mg, 0.199 mmol, 1.1 equiv) in DMF (0.5 mL) was stirred for 2 h at room temperature. The reaction was quenched with ice water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford ethyl 4-(4-bromo-8-(3- fluoropyridin-4-yl)-3-hydroxyquinolin-2-yl)-4-oxobutanoate (160 mg, 74%). MS (m/z) 447.03 (M+H). d) ethyl 4-[4-cyano-8-(3-fluoropyridin-4-yl)-3-hydroxyquinolin-2-yl]- 4-oxobutanoate [0567] A mixture of ethyl 4-[4-bromo-8-(3-fluoropyridin-4-yl)-3-hydroxyquinolin-2-yl]- 4- oxobutanoate (160 mg, 0.358 mmol, 1.0 equiv), Zn(CN) ₂ (126 mg, 1.07 mmol, 3.0 equiv), Pd ₂ (dba) ₃ (32.8 mg, 0.0361 mmol, 0.1 equiv), Zn (46.8 mg, 0.716 mmol, 2.0 equiv) and dppf (39.5 mg, 0.0721 mmol, 0.2 equiv) in DMA (1 mL) was stirred for 1 h at 75°C under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in ethyl 4-[4-cyano-8-(3-fluoropyridin-4-yl)-3- hydroxyquinolin-2-yl] -4-oxobutanoate (80 mg, 26%). MS (m/z) 394.11 (M+H). e) 4-[4-cyano-8-(3-fluoropyridin-4-yl)-3-hydroxyquinolin-2-yl]- 4-oxobutanoic acid [0568] A mixture of ethyl 4-[4-cyano-8-(3-fluoropyridin-4-yl)-3-hydroxyquinolin-2-yl]- 4- oxobutanoate (90.0 mg, 0.229 mmol, 1.0 equiv) and LiOH.H2O (28.8 mg, 0.687 mmol, 3.0 equiv) in THF (0.75 mL) and H2O (0.25 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 6 with HCl (2 M). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with following conditions (2#SHIMADZU (HPLC-01): Column, X Bridge Shield RP18 OBD Column, 19*150 mm, 5µm; mobile phase, water (0.05% FA) and CH ₃ CN (40% CH ₃ CN up to 60% in 8 min); Detector, UV 220 nm to afford 4-[4-cyano-8-(3-fluoropyridin-4-yl)-3-hydroxyquinolin-2-yl]- 4-oxobutanoic acid (5 mg, 7%). MS (m/z) 366.20 (M+H). ¹ H NMR (300 MHz, DMSO-d6) δ 8.80 – 8.51 (m, 2H), 8.20 – 8.02 (m, 2H), 7.95 (d, J = 7.1 Hz, 1H), 7.68 (t, J = 5.6 Hz, 1H), 2.57 (t, J = 6.5 Hz, 2H), 1.24 (s, 1H). Example 119 4-(4-cyano-8-(3,5-difluoropyridin-4-yl)-3-hydroxyquinolin-2- yl)-4-oxobutanoic acid a) 3-(benzyloxy)-2-(4-ethoxy-4-oxobutanoyl)quinolin-8-ylboronic acid [0569] Into a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were added ethyl 4-[3-(benzyloxy)-8-bromoquinolin-2-yl]-4-oxobutanoate (1 g, 2.26 mmol, 1.0 equiv.), Pin ₂ B ₂ (860 mg, 3.390 mmol, 1.5 equiv.) KOAc (670 mg, 6.780 mmol, 3.0 equiv.) and Pd(dppf)Cl ₂ (170 mg, 0.226 mmol, 0.1 equiv.), dioxane (10 mL) at room temperature. The mixture was stirred for overnight at 100°C under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give of 3- (benzyloxy)-2-(4-ethoxy-4-oxobutanoyl)quinolin-8-ylboronic acid (700 mg, 76%). MS (m/z) 408.23 (M+H). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.12 (s, 2H), 8.26 (s, 1H), 8.16 (dd, J = 6.8, 1.5 Hz, 1H), 8.05 (dd, J = 8.3, 1.5 Hz, 1H), 7.71 (dd, J = 8.2, 6.8 Hz, 1H), 7.60 – 7.49 (m, 2H), 7.47 – 7.31 (m, 4H), 5.38 (s, 2H), 4.06 (q, J = 7.1 Hz, 3H), 3.39 (t, J = 7.5, 5.2 Hz, 2H), 2.70 (t, J = 6.3 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H). b) ethyl 4-[3-(benzyloxy)-8-(3,5-difluoropyridin-4-yl)quinolin-2-yl]- 4-oxobutanoate [0570] Into a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were added 3-(benzyloxy)-2-(4-ethoxy-4-oxobutanoyl)quinolin-8-ylboronic acid (800 mg, 1.96 mmol, 1 equiv.), 4-bromo-3,5-difluoropyridine (457 mg, 2.35 mmol, 1.2 equiv.), Pd(dppf)Cl2 (143 mg, 0.19 mmol, 0.1 equiv.), K2CO3 (814 mg, 5.89 mmol, 3.0 equiv.), dioxane (15 mL) and H2O (1.5 mL) at room temperature. The above mixture was stirred for overnight at 100°C under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give ethyl 4-[3-(benzyloxy)-8-(3,5- difluoropyridin-4-yl)quinolin-2-yl]-4-oxobutanoate (200 mg, 21%). MS (m/z) 477.48 (M+H). c) ethyl 4-[8-(3,5-difluoropyridin-4-yl)-3-hydroxyquinolin-2-yl]-4-ox obutanoate [0571] Into a 100 mL round-bottom flask, were added ethyl 4-[3-(benzyloxy)-8-(3,5- difluoropyridin-4-yl)quinolin-2-yl]-4-oxobutanoate (200 mg, 0.42 mmol, 1 equiv.), thioanisole (208 mg, 1.68 mmol, 4 equiv.) and TFA (3 mL) at room temperature. The above mixture was stirred overnight at 90 ^o C. After cooling to room temperature, the mixture neutralized to pH 7 with saturated NaHCO ₃ (aq.). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give ethyl 4-[8-(3,5- difluoropyridin-4-yl)-3-hydroxyquinolin-2-yl]-4-oxobutanoate (130 mg, 80%). MS (m/z) 387.35 (M+H). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.81 (s, 1H), 8.70 (s, 2H), 8.11 (dd, J = 7.4, 2.4 Hz, 1H), 7.99 (s, 1H), 7.87 – 7.77 (m, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.25 (t, J = 6.6 Hz, 2H), 2.60 (t, J = 6.6 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H). d) ethyl 4-[4-bromo-8-(3,5-difluoropyridin-4-yl)-3-hydroxyquinolin-2- yl]-4-oxobutanoate [0572] Into a 100 mL round-bottom flask, were added ethyl 4-[8-(3,5-difluoropyridin-4-yl)-3- hydroxyquinolin-2-yl]-4-oxobutanoate (130 mg, 0.33 mmol, 1 equiv.) and NBS (62 mg, 0.35 mmol, 1.05 equiv.), CH3CN (5 mL). The mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of NH ₄ Cl (aq.) (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give ethyl 4-[4-bromo-8-(3,5-difluoropyridin-4-yl)-3-hydroxyquinolin-2- yl]- 4-oxobutanoate (110 mg 70%). MS (m/z) 465.25 (M+H). ¹ H NMR (300 MHz, Chloroform-d) δ 11.78 (s, 1H), 8.55 (s, 2H), 8.34 (dd, J = 8.6, 1.3 Hz, 1H), 7.86 (dd, J = 8.6, 7.1 Hz, 1H), 7.75 (d, J = 7.1 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.43 (t, J = 6.4 Hz, 2H), 2.70 (t, J = 6.5 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). e) ethyl 4-[4-cyano-8-(3,5-difluoropyridin-4-yl)-3-hydroxyquinolin-2- yl]-4-oxobutanoate [0573] Into a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were added ethyl 4-[4-bromo-8-(3,5-difluoropyridin-4-yl)-3-hydroxyquinolin-2- yl]-4- oxobutanoate (110 mg, 0.236 mmol, 1 equiv.), Zn(CN) ₂ (55 mg, 0.472 mmol, 2 equiv.), Pd ₂ (dba) ₃ (21 mg, 0.024 mmol, 0.1 equiv.), Zn (0.8 mg, 0.012 mmol, 0.05 equiv.) and dppf (13 mg, 0.024 mmol, 0.1 equiv.), DMA (2 mL). The mixture was stirred for 6 h at 75°C under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (0.1% TFA), 30% to 70% gradient in 10 min; detector, UV 254 nm to give ethyl 4-[4-cyano-8-(3,5-difluoropyridin-4-yl)-3- hydroxyquinolin-2-yl]-4-oxobutanoate (20 mg 20 %). MS (m/z) 412.36 (M+H). f) 4-[4-cyano-8-(3,5-difluoropyridin-4-yl)-3-hydroxyquinolin-2- yl]-4-oxobutanoic acid [0574] Into a 100 mL round-bottom flask, were added ethyl 4-[4-cyano-8-(3,5-difluoropyridin- 4-yl)-3-hydroxyquinolin-2-yl]-4-oxobutanoate (20 mg, 0.05 mmol, 1 equiv.), LiOH.H2O (4 mg, 0.19 mmol, 4 equiv.), THF (3 mL), MeOH (3 mL) and H ₂ O (1 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The mixture was neutralized to pH 7 with HCl (2 M) and extracted with EtOAc (3 x 15mL). The resulting mixture was concentrated under reduced pressure. The crude product (15 mg) was purified by Prep-HPLC with the following conditions, C18 silica gel; mobile phase, CH3CN in water (0.1% FA), 30% to 70% gradient in 10 min; detector, UV 254 nm to give of 4-[4-cyano-8-(3,5-difluoropyridin-4-yl)-3-hydroxyquinolin-2- yl]-4-oxobutanoic acid (6 mg 36%). MS (m/z) 383.31 (M+H). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.06 (s, 2H), 8.72 (s, 2H), 8.09 (d, J = 8.3 Hz, 1H), 8.01 (t, J = 7.7 Hz, 1H), 7.92 (d, J = 7.1 Hz, 1H), 3.15 (t, J = 6.6 Hz, 2H), 2.53 (t, 2H). Example 120 4-(4-cyano-3-hydroxy-8-(6-(trifluoromethoxy)pyridin-3-yl)qui nolin-2-yl)-4-oxobutanoic acid a) ethyl 4-[3-(benzyloxy)-8-[6-(trifluoromethoxy)pyridin-3-yl]quinoli n-2-yl]-4-oxobutanoate [0575] Into a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were added 3-(benzyloxy)-2-(4-ethoxy-4-oxobutanoyl)quinolin-8-ylboronic acid (500 mg, 1.22 mmol, 1 equiv.), 5-bromo-2-(trifluoromethoxy)pyridine (356 mg, 1.47 mmol, 1.2 equiv.), K2CO3 (509 mg, 3.68 mmol, 3.0 equiv.), 1,4-dioxane (10 mL) and H2O (1 mL). The mixture was stirred overnight at 100°C under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 15 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give ethyl 4-[3-(benzyloxy)-8-[6-(trifluoromethoxy)pyridin-3-yl]quinoli n-2-yl]-4- oxobutanoate (450 mg 69%). MS (m/z) 525.50 (M+H). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.71 (d, J = 2.4 Hz, 1H), 8.45 (dd, J = 8.5, 2.5 Hz, 1H), 8.22 (s, 1H), 8.04 (dd, J = 8.0, 1.7 Hz, 1H), 7.92 – 7.73 (m, 2H), 7.56 (d, J = 7.3 Hz, 2H), 7.47 – 7.29 (m, 4H), 5.36 (s, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.30 (t, 2H), 2.61 (t, J = 6.5 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H). b) ethyl 4-{3-hydroxy-8-[6-(trifluoromethoxy)pyridin-3-yl]quinolin-2- yl}-4-oxobutanoate [0576] Into a 100 mL round-bottom flask, were added ethyl 4-[3-(benzyloxy)-8-[6- (trifluoromethoxy)pyridin-3-yl]quinolin-2-yl]-4-oxobutanoate (450 mg, 0.85 mmol, 1 equiv.), thioanisole (532 mg, 4.29 mmol, 5 equiv.), TFA (5 mL). The mixture was stirred overnight at 90 ^o C. After cooling to room temperature, the mixture was neutralized to pH 7 with saturated NaHCO ₃ (aq.). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give ethyl 4-{3-hydroxy-8-[6-(trifluoromethoxy)pyridin-3-yl]quinolin-2- yl}-4-oxobutanoate (280 mg 75%). MS (m/z) 435.37 (M+H). ¹ H NMR (400 MHz, Chloroform-d) δ 11.04 (s, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.26 (dd, J = 8.4, 2.4 Hz, 1H), 7.82 (dd, J = 8.0, 1.8 Hz, 1H), 7.76 (s, 1H), 7.73 – 7.61 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.62 – 3.54 (m, 2H), 2.76 (t, J = 6.4 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H), c) ethyl 4-{4-bromo-3-hydroxy-8-[6-(trifluoromethoxy)pyridin-3-yl]qui nolin-2-yl}-4-oxobutanoate [0577] Into a 100 mL round-bottom flask, were added ethyl 4-{3-hydroxy-8-[6- (trifluoromethoxy)pyridin-3-yl]quinolin-2-yl}-4-oxobutanoate (280 mg, 0.64 mmol, 1 equiv.), NBS (120 mg, 0.67 mmol, 1.05 equiv.), CH ₃ CN (5 mL). The mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of NH ₄ Cl (aq.) (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give ethyl 4-{4-bromo-3-hydroxy-8-[6- (trifluoromethoxy)pyridin-3-yl]quinolin-2-yl}-4-oxobutanoate (250 mg 75%). MS (m/z) 514.27 (M+H). ¹ H NMR (300 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.72 (d, J = 2.5 Hz, 1H), 8.47 (dd, J = 8.5, 2.5 Hz, 1H), 8.20 (dd, J = 6.5, 3.4 Hz, 1H), 8.05 – 7.89 (m, 2H), 7.44 (d, J = 8.5 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.47 (t, J = 6.7 Hz, 2H), 2.67 (t, J = 6.7 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H). d) ethyl 4-{4-cyano-3-hydroxy-8-[6-(trifluoromethoxy)pyridin-3-yl]qui nolin-2-yl}-4-oxobutanoate [0578] Into a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were added ethyl 4-{4-bromo-3-hydroxy-8-[6-(trifluoromethoxy)pyridin-3-yl]qui nolin-2-yl}-4- oxobutanoate (250 mg, 0.48 mmol, 1 equiv.), Zn(CN)2 (114 mg, 0.974 mmol, 2 equiv.), Zn (1.5 mg, 0.024 mmol, 0.05 equiv.), Pd2(dba)3 (44 mg, 0.049 mmol, 0.1 equiv.), dppf (26 mg, 0.049 mmol, 0.1 equiv.), DMA (3 mL). The mixture was stirred for 1 h at 75°C under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, CH3CN in water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in ethyl 4-{4-cyano-3- hydroxy-8-[6-(trifluoromethoxy)pyridin-3-yl]quinolin-2-yl}-4 -oxobutanoate (110 mg 49%). MS (m/z) 460.38 (M+H). ¹ H NMR (300 MHz, DMSO-d6) δ 8.72 (d, J = 2.4 Hz, 1H), 8.45 (dd, J = 8.5, 2.5 Hz, 1H), 8.11 – 7.97 (m, 3H), 7.46 (d, J = 8.5 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.43 (t, J = 6.7 Hz, 1H), 2.67 (t, J = 6.6 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H). e) 4-{4-cyano-3-hydroxy-8-[6-(trifluoromethoxy)pyridin-3-yl]qui nolin-2-yl}-4-oxobutanoic acid [0579] Into a 100 mL round-bottom flask, were added ethyl 4-{4-cyano-3-hydroxy-8-[6- (trifluoromethoxy)pyridin-3-yl]quinolin-2-yl}-4-oxobutanoate (100 mg, 0.22 mmol, 1 equiv.), LiOH.H2O (15 mg, 0.6 mmol, 3 equiv.), THF (3 mL) and H2O (1 mL). The resulting mixture was stirred for 1 h at room temperature. The mixture was neutralized to pH 7 with HCl (2 M) and extracted with EtOAc (3 x 15 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions, C18 silica gel; mobile phase, CH ₃ CN in water (0.1% FA), 30% to 70% gradient in 10 min; detector, UV 254 nm to give of 4-{4-cyano-3-hydroxy-8-[6- (trifluoromethoxy)pyridin-3-yl]quinolin-2-yl}-4-oxobutanoic acid (30 mg 31%). MS (m/z) 432.33 (M+H). ¹ H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 2H), 8.72 (d, J = 2.4 Hz, 1H), 8.45 (dd, J = 8.5, 2.5 Hz, 1H), 8.15 – 7.88 (m, 3H), 7.45 (d, J = 8.5 Hz, 1H), 3.39 (t, J = 6.5 Hz, 2H), 2.60 (t, J = 6.5 Hz, 2H). BIOLOGICAL EXAMPLES Biological Example 1 [0580] Enzymatic activity was determined based on the capture of ¹⁴ CO2 released by the decarboxylation of [1- ¹⁴ C] αKG (Zhang et al., Anal. Biochem., 1998, vol.271, pp.137-142). [1- ¹⁴ C] alphaketoglutarate (αKG) was from Perkin-Elmer, H3K4me3 and H3K9me3 peptides were from Mimotopes. All other reagents were from Sigma. Reaction mixtures included the following components: Fe(SO ₄ ), [1- ¹⁴ C] αKG, non-labeled αKG, ascorbate, peptide-substrate (H3K4me3: H- ARTK(me3)QTARKSTGGKAPRKQLA-OH. H3K9me3: H-ARTKQTARK(me3)STGGKAPRKQLA- OH), NaCl, Tween-20 and catalase in 25 mM HEPES buffer, pH 7.4. The enzymatic reactions were initiated by addition of recombinant human KDM5B or KDM4A enzyme (truncated enzyme produced in house by method and using sequence disclosed in Ng et al, Nature 448:87-91, 2007). The reactions were performed in 96-well microtiter plates (20 µL total assay volume) (Greiner #650201). ¹⁴ CO2 was captured on a glass fiber filter paper (Cat. No. IH-201-A, Inotech Biosystems International) soaked with saturated Ba(OH) ₂ that was laid on top of the 96-well plate. A microtiter plate sealer film (Thermal Seal cat# T7961100) was applied to the filter paper. The plate and filter paper were sandwiched between two custom made aluminum plates (Advanced Component Manufacturing, Burlingame, CA) and transferred to a 37 °C oven and allowed to incubate for 1 hour. After incubation, the filter paper was dried in a 103 °C oven for 40-60 minutes. To determine percent turnover, aliquots of the reaction mixture were spotted onto the filter paper and the filter paper was dried again. The dry filter paper was exposed to a storage phosphor screen for 24-72 hours and the images recorded using a Typhoon FLA 7000 Imager (Amersham Biosciences, Piscataway, NJ). Integrated spot intensities corresponding to control reactions lacking the enzyme were subtracted from integration results for enzyme containing reactions and data were converted to enzyme dependent percent ¹⁴ CO2 release. All enzymatic reactions were run in duplicates. [0581] For IC50 determination, a 3-fold dilution series of compound was prepared and added to the reaction mixture (final 1 % DMSO, v/v) prior to enzyme addition. The final reagent concentrations were: 10 µM Fe(SO ₄ ), 10 µM [1- ¹⁴ C] αKG, 90 µM non-labeled αKG, 2 mM ascorbate, 50 µM peptide substrate, 75 mM NaCl, 0.01 % Tween-20 and ~2 units/µL catalase. IC ₅₀ s were determined by non-linear fitting using Grafit version 7.0. Data for compounds disclosed herein is shown in Table 2. TABLE 2

Biological Example 2 a) Cell-Based Assay for KDM5 inhibitors [0582] COS-7 monkey kidney fibroblasts (ATCC, Manassas VA) were seeded into collagen- coated 96-well culture dishes and incubated overnight at 37°C, 5% CO2 in standard culture medium, e.g., Dulbecco's Modified Eagle Medium containing 10% fetal bovine serum. The next day, cells were transfected with an expression plasmid for Myc-His-tagged KDM5B (Origene, Rockville MD) for 3h before replacing the transfection medium with fresh culture medium and treating with vehicle or compound. [0583] After 18h incubation, the cell culture treatment medium was removed and cell layers were fixed using 4% formaldehyde in Dulbecco’s Phosphate Buffered Saline (DPBS), then permeabilized with 0.25% Triton X-100, and then blocked using a suitable blocking agent e.g., Odyssey Blocking Buffer (LICOR, Lincoln NE). Cell layers were then incubated overnight with primary antibodies for detection of MYC (Thermo Fisher Scientific, Waltham MA) and tri-methylated Lysine 4 of Histone 3 (H3K4me3) (Cell Signaling Technology, Danvers MA). The next day cell layers were washed and incubated with appropriate fluorescently labeled secondary antibodies. Finally, nuclei were stained using 4′,6-diamidino-2-phenylindole (DAPI). b) Imaging and Analyses of Cell-Based Assay for KDM5 Inhibitors [0584] In one analysis method, fold increases in H3K4me3 levels per cell were assessed. A suitable cell imaging system e.g., Cytation5 (Biotek, Winooski VT) was used to scan cell layers that had been immunostained for MYC and H3K4me3. Scanned objects were gated using DAPI (cells) and binned according to MYC-KDM5B expression levels (low, medium, or high). H3K4me3 levels were quantified per cell. Mean fold increases in H3K4me3 in compound-treated cells relative to vehicle- treated cells were calculated for each MYC-KDM5B expressing bin (low, medium, or high). [0585] In another analysis method, the percentages of MYC-KDM5B-overexpressing cells with H3K4me3 levels above a pre-determined threshold were calculated. A suitable cell imaging system e.g., Incucyte ZOOM (Sartorius, Germany) was used to scan cell layers that had been immunostained for MYC-KDM5B and H3K4me3. Cells highly overexpressing MYC-KDM5B were gated based on MYC staining levels and then the percentages of cells within vehicle- and compound-treated groups with H3K4me3 levels above a set threshold were determined. Compound-dependent increases in percentages of cells above the pre-determined H3K4me3 threshold were calculated.