Pyrimidine compounds and their pharmaceutical uses

Abstract

It is a pyrimidine compound of formula (I). [Formula 1] JPEG2023517205000053.jpg4161 The assignments to the variables in the formula are described herein. Also disclosed are methods of treating cancer with one of the pyrimidine compounds.

Description

Background Art

[0001] Aurora A kinase is a serine / threonine kinase that regulates the progression of mitosis, centrosome maturation, and spindle assembly. This kinase plays an important role in the stabilization of MYC family cancer proteins, and according to The Cancer Genome Atlas (TCGA), its gene amplification is observed in 28% of cancers. Small molecule inhibitors that induce conformational changes in the DFG loop of Aurora A kinase result in the degradation of MYC family cancer proteins and thus present the potential for cancer treatment.

[0002] An Aurora A kinase inhibitor containing compound CD532 has been identified. See International Publication No. 2014 / 190207. However, CD532 has weak in vivo efficacy.

[0003] There is a need to develop novel compounds that effectively inhibit Aurora A kinase activity.

Summary of the Invention

[0004] The present invention is based on the discovery that certain pyrimidine compounds are effective in inhibiting Aurora A kinase activity both in vitro and in vivo.

[0005] In one aspect, the invention relates to a compound of formula (I) shown below.

Chemical formula

[0006] In this formula, A is CH or N, and R 1 is C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, aryl or heteroaryl, and R 2 is H, C 1-6 alkyl, R 5 NDNR 6 R7 or C 1-10 is a heterocycloalkyl, and R 5 , R 6 and R 7 each independently is H or C 1-6 alkyl, D is C 1-6 a divalent aliphatic radical, and R 3 is C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 7-12 aralkyl, C 1-12 heteroaralkyl, -C(O)R 8 or -S(O) 2 R 8 wherein R 8 is aryl or heteroaryl, and R 4 is C 1-6 alkyl or preferably H, and each of m and n independently is 1 or 2.

[0007] C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, C 7-12 aralkyl, C 1-12 heteroaralkyl, aryl and heteroaryl each independently is halo, OH, CN, NH 2 , NO 2 , SO 2 C 1-6 alkyl, C 1-6 haloalkyl, C 3-13 cycloalkyl, C 2-8 heterocycloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 1-6 alkylamino, C 2-6 dialkylamino, C 7-12 aralkyl, C 1-12 heteroaralkyl, aryl, heteroaryl, -C(O)R 9 , -C(O)OR 9 or -C(O)NR 9 R 10 is mono-, di- or trisubstituted, and R 9and R 10 Each of which is independently H, halo, OH, CN, COOH, acetyl, acetamide, dialkylamino, alkylamino, C 1-6 alkyl, C 1-6 multi-haloalkyl, C 1-6 alkoxyl, C 1-6 multi-haloalkoxyl, C 3-8 cycloalkyl, C 1-10 heterocycloalkyl, aryl or heteroaryl.

[0008] The term "alkyl" herein refers to a straight-chain or branched-chain hydrocarbon group containing 1 to 20 (e.g., 1 to 10 and 1 to 6) carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. The term "haloalkyl" refers to an alkyl substituted with one or more halogen (chloro, fluoro, bromo, or iodo) atoms. Examples include trifluoromethyl, bromomethyl, and 4,4,4-trifluorobutyl. The term "alkoxyl" refers to an -O-alkyl group. Examples include methoxy, ethoxy, propoxy, and isopropoxy. The term "haloalkoxy" refers to an alkoxy substituted with one or more halogen atoms. Examples include -O-CH 2 Cl and -O-CHClCH 2 Cl.

[0009] The term "cycloalkyl" refers to a saturated and partially unsaturated monocyclic, bicyclic, tricyclic, or tetracyclic hydrocarbon group having 3 to 12 carbons. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0010] The term "heterocycloalkyl" refers to a non-aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic or 11- to 14-membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples of heterocycloalkyl groups include, without limitation, piperazinyl, imidazolidinyl, azepanyl, pyrrolidinyl, dihydrothiazolyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0011] The term "aryl" refers to a monocyclic aromatic ring system having 6 carbon atoms, a bicyclic aromatic ring system having 10 carbon atoms, or a tricyclic aromatic ring system having 14 carbon atoms, wherein each ring may have 1 to 5 substituents. Examples of aryl groups include phenyl, naphthyl, and anthracenyl. The term "arylene" refers to divalent aryl. The term "aralkyl" refers to alkyl substituted with an aryl group.

[0012] The term "heteroaryl" refers to an aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic or 11- to 14-membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include triazolyl, oxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, thiazolyl, and benzothiazolyl. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group.

[0013] The term "halo" refers to a radical of fluoro, chloro, bromo, or iodo. The term "amino" refers to a radical derived from an amine that is unsubstituted or mono- or di-substituted with alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. The term "alkylamino" refers to alkyl-NH-. The term "dialkylamino" refers to alkyl-N(alkyl)-.

[0014] The term "acyl" refers to -C(O)-alkyl, -C(O)-aryl, -C(O)-cycloalkyl, -C(O)-heterocycloalkyl, or -C(O)-heteroaryl.

[0015] The alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkoxy and aryloxy referred to herein include both substituted and unsubstituted moieties. Examples of substituents include, without limitation, halo, hydroxyl, amino, cyano, nitro, mercapto, alkoxycarbonyl, amide, carboxy, alkanesulfonyl, alkylcarbonyl, carbamide, carbamyl, carboxyl, thioureido, thiocyanate, sulfonamide, alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, and the alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl may be further substituted.

[0016] In another aspect, the invention relates to a method of treating cancer. The method includes administering to a subject in need an effective amount of a compound of formula (I) above.

[0017] When referring to the compounds of formula (I), the term "compound" also includes its salts, solvates and prodrugs. Salts may be formed between an anion and a positively charged group (e.g., amino) in the compound. Examples of suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate and maleate. Salts may also be formed between a cation and a negatively charged group. Examples of suitable cations include ammonium cations such as sodium ion, potassium ion, magnesium ion, calcium ion and tetramethylammonium ion. Salts further include those containing a quaternary nitrogen atom. Solvates refer to complexes formed between the active compound and pharmaceutically acceptable solvents. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid and ethanolamine. Prodrugs refer to pharmaceuticals or compounds that are metabolized into pharmaceutically active agents after administration. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives that can supply active pyrimidine compounds when administered to a subject.

[0018] Details of one or more embodiments of the invention are set forth in the following description. Other features, objects, and advantageous effects of the invention will become apparent from the description and the claims.

Brief Description of the Drawings

[0019]

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0020] The pyrimidine compounds of formula (I) reproduced below, as well as their synthesis and their anti-cancer efficacy, will be described in detail below.

Chemical Formula

[0021] R 1 ~R 4 , m, n and A are defined in the Summary of the Invention section above.

[0022] In a preferred set of compounds of formula (I), the sum of m and n is 3, A is N, R 1 is C 3-10 cycloalkyl or 5-membered heteroaryl, and R 2 is

Chemical Formula

[0023] In another preferred set of compounds encompassed by formula (I), each of m and n is 2, A is N, R 1 is C 3-10 cycloalkyl or 5-membered heteroaryl, and R 2 is H, C 1-6 alkyl,

Chemical Formula

[0024] The compounds of the present invention can be prepared by synthetic methods known in the art. For example, see R. Larock, Comprehensive Organic Transformations (2nd Edition, VCH Publishers, 1999), P.G.M. Wuts and T.W. Greene, Greene’s Protective Groups in Organic Synthesis (4th Edition, John Wiley and Sons, 2007), L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (John Wiley and Sons, 1994) and L. Paquette ed., Encyclopedia of Reagents for Organic Synthesis (2nd Edition, John Wiley and Sons, 2009) and subsequent editions thereof.

[0025] The compounds referred to herein may contain non-aromatic double bonds and one or more asymmetric centers. Accordingly, each compound may occur as a racemate or racemic mixture, a single R enantiomer, a single S enantiomer, individual diastereomers, a mixture of diastereomers or cis or trans isomers. All such isomeric forms of the compounds are within the scope of the present invention.

[0026] The compounds of formula (I) prepared as such can first be screened for their ability in inhibiting aurora A kinase activity using the enzymatic aurora A kinase activity inhibition assay described in Example 2 below. It can then be further evaluated for its effectiveness in inhibiting cancer cell proliferation using in vitro assays such as the MYC- or MYCN-amplified cancer cell line assay described in Example 3 and the cell proliferation inhibition assays described in Examples 4 and 5. The selected compounds can be further tested to verify their effectiveness in the treatment of cancer. For example, as described in Examples 6 and 7, the compounds may be administered to animals (e.g., mice) having xenografted tumors, and their therapeutic effects are evaluated.

[0027] A method for treating cancer is also within the scope of this invention. The method includes the step of administering an effective amount of a compound of formula (I) to a subject in need thereof. Examples of cancer include leukemia, lung cancer, neuroblastoma, pancreatic cancer, colon cancer, prostate cancer, breast cancer, liver cancer, brain cancer, and cholangiocarcinoma.

[0028] This invention also encompasses a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutical carrier. The pharmaceutical composition can be used to treat cancer.

[0029] To practice the methods of the present invention, a composition having one or more of the above pyrimidine compounds can be administered parenterally, orally, nasally, enterally, topically, or transmucosally. The term "parenteral" as used herein refers to subcutaneous, intradermal, intravenous, intraperitoneal, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional, or intracranial injection and any suitable infusion technique.

[0030] Aseptic injectable compositions can be solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, fixed oils (e.g., synthetic mono- or di-glycerides) are conventionally employed as solvents or suspending media. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, particularly in their polyoxyethylated forms, as are natural pharmaceutically acceptable oils such as olive oil and castor oil. These oily solutions or suspensions can also contain long-chain alcohol diluents or dispersants, carboxymethylcellulose, or similar dispersing agents. Surfactants such as other commonly used Tweens and Spans, or other similar emulsifying agents, or bioavailability enhancing substances commonly used in the manufacture of other pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for formulating purposes.

[0031] Compositions for oral administration can be in any orally acceptable dosage form including capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension or emulsion is administered orally, the active ingredient can be suspended or dissolved in an oil phase combined with an emulsifying or suspending agent. Optionally, certain sweetening, flavoring, or coloring agents can be added. Oral solid dosage forms can be prepared by spray drying techniques, hot melt extrusion strategies, micronization, and nanomilling techniques.

[0032] Nasal aerosols or inhalation compositions can be prepared by techniques known in the field of pharmaceutical formulations. For example, such compositions can be prepared as solutions in physiological saline, employing benzyl alcohol or other suitable preservatives, absorption promoters that enhance bioavailability, fluorocarbons and / or other solubilizing or dispersing agents known in the art. Compositions having an active compound can also be administered in the form of suppositories for rectal administration.

[0033] The carrier in a pharmaceutical composition needs to be "acceptable" in the sense that it is compatible with the active ingredient of the composition (preferably, it can stabilize the active ingredient) and is not harmful to the subject being treated. One or more solubilizing agents can be utilized as pharmaceutical excipients for the delivery of the active compound. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

[0034] The term "treating" refers to the application or administration of a compound to a subject for the purpose of curing, alleviating, reducing, modifying, repairing, improving, or affecting a disease, symptom, or predisposition. "Effective amount" refers to the amount of a compound required to give a desired effect to a subject. As will be recognized by those skilled in the art, the effective amount will vary depending on factors such as the route of administration, the use of excipients, and the possibility of combination with other therapeutic treatments such as the use of other active agents.

[0035] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following examples are to be construed as merely illustrative and in no way limit the remainder of the disclosure. All publications cited herein are hereby incorporated by reference in their entirety.

[0036] The structures of 127 exemplary compounds of this invention are described below.

Chemical formula

[0037] Exemplary methods for preparing the above compounds and other compounds of the present invention, as well as exemplary methods for identifying their anti-cancer activity, are provided below. [Examples]

[0038] Example 1 Preparation of Compounds 1 to 127 Compounds 41, 71, and 72 were prepared according to the scheme involving the following six steps. [Chemistry]

[0039] Step 1 Preparation of Compound B (S)-tert-Butyl 3-aminopyrrolidine-1-carboxylate (20 g, 105.7 mmol) was added dropwise to a solution of starting material 4,6-dichloro-2-(methylsulfonyl)pyrimidine (20 g, 88.1 mmol) and triethylamine (25.5 mL, 176.2 mmol) in THF (200 mL) at -70 °C over 1 hour. The reaction mixture was warmed to room temperature, stirred for 6 hours, and quenched with brine (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 200 mL). The combined organic extracts were washed with water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give a crude residue. The residue was purified by flash column chromatography on silica gel using n-hexane / ethyl acetate (4:1) to give compound B (16.4 g, 49.3 mmol, 56% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 6.65 (s, 1H), 5.42 (brs, 1H), 4.60 - 4.47 (m, 1H), 3.69 (dd, J = 11.2, 6.0 Hz, 1H), 3.52 - 3.40 (m, 3H), 3.35 - 3.15 (m, 1H), 2.23 (m, 1H), 1.85 - 1.75 (m, 1H), 1.47 (s, 9H). ESMS m / z: 355.1 (M+23).

[0040] Step 2 Preparation of Compound C A solution of compound B (7 g, 21.0 mmol), 3-amino-5-methylpyrazole (8.1 g, 84.0 mmol), triethylamine (3.5 mL, 25.2 mmol), and NaI (4.7 g, 31.5 mmol) in DMSO (70 mL) was stirred at 90 °C for 16 hours. The solution was cooled to room temperature and poured into water. A precipitate formed, was collected, and purified by flash column chromatography on silica gel using n-hexane / ethyl acetate (1:1) to give compound C (7 g, 17.9 mmol, 85% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3 ) δ 6.32 (s, 1H), 5.93 (s, 1H), 4.48 (brs, 1H), 3.85 - 3.60 (m, 1H), 3.60 - 3.40 (m, 4H), 2.31 (s, 3H), 1.46 (s, 9H). ESMS m / z: 394.1 (M+1).

[0041] Step 3 Preparation of Compound D A solution of Compound C (7 g, 17.8 mmol) and 1 - ethylpiperazine (4.1 g, 35.6 mmol) in 1 - pentanol (14 mL) was heated at 140 °C for 2 h and then quenched with brine (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 200 mL). The combined organic extracts were washed with water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give a crude residue, which was purified by flash column chromatography on silica gel using ethyl acetate / methanol (90:10) to afford Compound D (7 g, 14.9 mmol, 84% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 5.87 (s, 1H), 5.62 (s, 1H), 4.70 - 4.39 (m, 1H), 3.80 - 3.30 (m, 7H), 2.52 - 2.40 (m, 6H), 2.27 (s, 3H), 2.24 - 2.04 (m, 2H), 1.46 (s, 9H), 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 472.1 (M+1).

[0042] Step 4 Preparation of Compound E A solution of 2N hydrochloric acid in ether (52 mL, 104 mmol) was added to a solution of Compound D (9.8 g, 20.8 mmol) in dichloromethane / methanol (2:1, 75 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h and then concentrated in vacuo to afford Compound E (9.9 g, 2.1 mmol, 99% yield) as a yellow oil. 11H NMR (400 MHz, DMSO-d6) δ 6.34 (s, 1H), 5.86 (s, 1H), 4.39 (s, 1H), 3.56 - 2.98 (m, 8H), 2.98 - 2.49 (m, 6H), 2.25 (s, 3H), 2.03 - 1.98 (m, 2H), 1.28 (t, J = 7.6 Hz, 3H). ESMS m / z: 372.66 (M+1).

[0043] Step 5 Preparation of Compound 41 A solution of compound E (9 g, 18.7 mmol), triethylamine (15.7 mL, 112.0 mmol), 4-chloro-2-fluorobenzoic acid (3.6 g, 20.6 mmol), and propanephosphonic anhydride (T3P, 50 wt% or more in ethyl acetate, 17.9 g, 28.1 mmol) was added to a solution of the amine salt in DMF / dichloromethane (1:3, 50 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 h and quenched with brine (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 200 mL). The combined organic extracts were washed with water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give a crude residue, which was purified by flash column chromatography on silica gel using ethyl acetate / methanol (85:15) to give compound 41 (8.4 g, 15.9 mmol, 85% yield) as a white solid. 1 1H NMR (400 MHz, CD 3 OD) δ 7.46 - 7.25 (m, 3H), 5.95 - 5.75 (m, 1H), 5.62 - 5.45 (m, 1H), 4.53 and 4.36 (brs, 1H), 3.98 - 3.64 (m, 3H), 3.63 - 3.56 (m, 2H), 3.54 - 3.40 (m, 4H), 2.60 - 2.40 (m, 6H), 2.36 - 2.29 (m, 1H), 2.23 and 2.22 (s, 3H), 2.10 - 1.90 (m, 1H), 1.15 and 1.14 (t, J = 7.2 Hz, 3H). ESMS m / z: 528.2 (M+1).

[0044] Step 6 Preparation of Compounds 71 and 72 A solution of propionic anhydride (1.7 mL, 13.29 mmol) in 1,4-dioxane (10 mL) was added to a solution of compound 41 (5.4 g, 10.23 mmol) in 1,4-dioxane (100 mL) at 140 °C. The resulting mixture was stirred at 140 °C for 30 minutes, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using n-hexane / ethyl acetate / triethylamine (60:35:5) to give compound 71 (3.34 g, 5.73 mmol, 56% yield) and compound 72 (1.67 g, 2.86 mmol, 28% yield) as pale yellow solids. Compound 71: 1 H NMR (300 MHz, CDCl 3 ) δ 9.88 and 9.84 (brs, 1H), 7.34 and 7.32 (t, J = 7.7 Hz, 1H), 7.12 (q, J = 8.3 Hz, 1H), 7.05 (d, J = 9.3 Hz, 1H), 6.51 and 6.42 (s, 1H), 5.30 and 5.25 (s, 1H), 4.72 (brs, 1H), 4.60 - 4.40 (m, 1H), 4.00 - 3.60 (m, 3H), 3.60 - 3.15 (m, 5H), 3.06 and 3.05 (q, J = 8.3 Hz, 2H), 2.65 - 2.37 (m, 6H), 2.35 - 2.23 (m, 1H), 2.19 and 2.17 (s, 3H), 2.03 - 1.92 (m, 1H), 1.23 - 1.07 (m, 6H). ESMS m / z: 584.3 (M+1). Compound 72: 1 H NMR (400 MHz, CDCl 3) δ 7.35 (q, J = 6.8 Hz, 1H), 7.15 (q, J = 9.7 Hz, 1H), 7.09 (d, J = 9.6 Hz, 1H), 6.35 and 6.30 (s, 1H), 6.04 and 6.00 (s, 1H), 5.03 and 4.93 (brs, 1H), 4.55 and 4.44 (d, J = 5.7 Hz, 1H), 4.03 - 3.34 (m, 7H), 3.30 - 3.16 (m, 1H), 3.04 (t, J = 7.8 Hz, 2H), 2.60 - 2.36 (m, 5H), 2.47 - 2.36 (m, 4H), 2.35 - 2.18 (m, 2H), 1.29 - 1.19 (m, 3H), 1.11 (t, J = 7.0 Hz, 3H). ESMS m / z: 584.3 (M+1).

[0045] Compounds 86, 122 and 123 were prepared according to the scheme involving the following 5 steps.

Chemical Structure

[0046] Step 1 Preparation of Compound F tert-Butyl 4-aminopiperidine-1-carboxylate (20 g, 100 mmol) was added dropwise to a solution of 4,6-dichloro-2-(methylsulfonyl)pyrimidine (20 g, 88.1 mmol) and triethylamine (25.5 mL, 176.2 mmol) in THF (200 mL) at -70 °C over 1 hour. The reaction mixture was warmed to room temperature, stirred for 6 hours, and quenched with brine (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 200 mL). The combined organic extracts were washed with water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give a crude residue. The residue was purified by flash column chromatography on silica gel using n-hexane / ethyl acetate (4:1) to give Compound F (16.4 g, 49.3 mmol, 56% yield) as a white solid. 11H NMR (400 MHz, CDCl 3 ) δ 6.64 (s, 1H), 5.27 (brs, 1H), 4.25 - 3.80 (m, 4H), 2.97 (t, J = 11.9 Hz, 2H), 2.03 (d, J = 9.6 Hz, 2H), 1.49 (s, 9H), 1.46 - 1.34 (m, 1H). ESMS m / z: 369.1 (M+23).

[0047] Step 2 Preparation of Compound G A solution of Compound F (40 g, 115 mmol), 3 - amino - 5 - methylpyrazole (44.7 g, 461 mmol), triethylamine (32 mL, 230 mmol) and NaI (19 g, 115 mmol) in DMSO (60 mL) was stirred at 90 °C for 24 h. The solution was cooled to room temperature and poured into water. A precipitate formed, was collected and purified by flash column chromatography on silica gel using n - hexane / ethyl acetate (1:1) to give Compound G (35 g, 86 mmol, 75% yield) as a yellow solid. 1 1H NMR (400 MHz, CDCl 3 ) δ 6.35 (s, 1H), 6.08 (s, 1H), 4.20 - 3.87 (m, 4H), 2.97 (t, J = 11.6 Hz, 2H), 2.34 (s, 3H), 2.05 (d, J = 13.3 Hz, 2H), 1.49 (s, 9H), 1.46 - 1.34 (m, 1H). ESMS m / z: 408.2 (M+1).

[0048] Step 3 Preparation of Compound H A solution of compound G (20 g, 49.1 mmol) and 1-ethylpiperazine (11.2 g, 98.3 mmol) in 1-pentanol (20 mL) was heated at 140 °C for 3 hours and then quenched with brine (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 200 mL). The combined organic extracts were washed with water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give a crude residue, which was purified by flash column chromatography on silica gel using ethyl acetate / methanol (90:10) to give compound H (17.7 g, 36.3 mmol, 74% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 5.86 (s, 1H), 5.80 (s, 1H), 4.04 (brs, 1H), 3.94 (brs, 1H), 3.68 - 3.52 (m, 4H), 2.97 (t, J = 11.7 Hz, 2H), 2.54 - 2.49 (m, 6H), 2.50 - 2.43 (m, 4H), 2.30 (s, 3H), 2.04 (d, J = 8.0 Hz, 2H), 1.49 (s, 9H), 1.47 - 1.37 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H). ESMS m / z: 486.3 (M+1).

[0049] Step 4 Preparation of Compound 86 A solution of 2N hydrochloric acid in ether (129 mL, 257 mmol) was added to a solution of compound H (25 g, 51.5 mmol) in dichloromethane / methanol (2:1, 129 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours and then concentrated in vacuo to give the HCl salt of compound H without further purification.

[0050] Then, a solution of triethylamine (10.8 mL, 77.3 mmol), 3-chloro-2-fluorobenzoic acid (9.9 g, 56.7 mmol), and propane phosphonic anhydride (T3P) (≥50 wt% in ethyl acetate, 39 g, 61.9 mmol) in dichloromethane (100 mL) was stirred for 2 hours. The mixture was added at room temperature to a solution of the HCl salt of compound H and triethylamine (28.7 mL, 206 mmol) in dichloromethane (250 mL). The resulting mixture was stirred at room temperature for 16 hours and quenched with brine (100 mL). The aqueous phase was extracted with ethyl acetate (3 × 500 mL). The combined organic extracts were washed with water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give a crude residue. The residue was purified by flash column chromatography on silica gel using ethyl acetate / methanol (85:15) to give compound 86 (23 g, 42.5 mmol, 81% yield) as a white solid. Compound 86: 1 H NMR (400 MHz, CDCl 3 ) δ 7.44 (t, J = 7.8 Hz, 1H), 7.29-7.22 (m, 1H), 7.14 (t, J = 7.8 Hz, 1H), 5.86 (s, 1H), 5.66 (s, 1H), 4.58 (d, J = 13.0 Hz, 1H), 4.09-3.98 (m, 1H), 3.57-3.47 (m, 5H), 3.29-3.02 (m, 2H), 2.50-2.38 (m, 6H), 2.28 (s, 3H), 2.16 (d, J = 13.0 Hz, 1H), 2.06 (d, J = 13.0 Hz, 1H), 1.62-1.46 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 542.2 (M+1).

[0051] Step 5 Preparation of Compounds 122 and 123 A solution of propionic anhydride (1.4 g, 10.8 mmol) in dichloromethane (200 mL) was added to a solution of compound 86 (5 g, 9.2 mmol) in dichloromethane (800 mL) at 40 °C. The resulting mixture was stirred at 40 °C for 4 hours, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using n-hexane / ethyl acetate / triethylamine (60:35:5) to give compound 122 (3.1 g, 5.2 mmol, 56% yield) and 123 (1.4 g, 2.4 mmol, 26% yield) as pale yellow solids. Compound 122: 1 H NMR (300 MHz, CDCl 3 ) δ 9.88 (brs, 1H), 7.45 (td, J = 7.8, 1.8 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.16 (t, J = 7.8 Hz, 1H), 6.55 (s, 1H), 5.33 (s, 1H), 4.71 (brs, 1H), 4.64 (d, J = 14.0 Hz, 1H), 4.14 - 3.97 (m, 1H), 3.57 (d, J = 14.0 Hz, 1H), 3.54 (t, J = 5.0 Hz, 4H), 3.47 (q, J = 7.0 Hz, 1H), 3.23 - 3.00 (m, 3H), 2.53 - 2.39 (m, 6H), 2.25 (s, 3H), 2.22 (d, J = 14.0 Hz, 1H), 2.10 (d, J = 14.0 Hz, 1H), 1.58 - 1.47 (m, 2H), 1.24 and 1.21 (t, J = 7.0 Hz, 3H), 1.12 (t, J = 7.0 Hz, 3H). ESMS m / z: 598.3 (M+1). Compound 123: 1 H NMR (300 MHz, CDCl 3) δ 7.45 (t, J = 7.8 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.69 (brs, 1H), 6.22 (s, 1H), 6.09 (s, 1H), 4.66 - 4.54 (m, 2H), 4.11 - 3.95 (m, 1H), 3.59 (t, J = 4.8 Hz, 4H), 3.57 - 3.48 (m, 1H), 3.21 - 2.99 (m, 4H), 2.57 (s, 3H), 2.53 - 2.39 (m, 6H), 2.18 (d, J = 14.0 Hz, 1H), 2.06 (d, J = 14.0 Hz, 1H), 1.59 - 1.49 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H), 1.14 and 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 598.3 (M+1).

[0052] Using the same procedure as described above, Compounds 1 - 40, 42 - 70, 73 - 85, 87 - 121 and 124 - 127 were prepared.

[0053] Compound 1: 1 H NMR (400 MHz, CDCl 3 ) δ 9.49 (brs, 1H), 7.87 and 7.86 (s, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.22 and 7.20 (dd, J = 8.4, 2.0 Hz, 1H), 7.17 and 7.12 (dd, J = 9.2, 2.0 Hz, 1H), 5.38 and 5.34 (s, 1H), 5.04 and 4.98 (brs, 1H), 4.75 - 4.50 (m, 1H), 4.08 - 3.69 (m, 2H), 3.62 - 3.25 (m, 6H), 2.53 - 2.26 (m, 7H), 2.13 - 2.00 (m, 1H), 1.12 and 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 556.2 (M+1).

[0054] Compound 2:1 H NMR (400 MHz, CDCl 3 ) δ 9.30 (broad singlet, 1H), 8.03 (singlet, 1H), 7.45 - 7.37 (multiplet, 1H), 7.29 - 7.08 (multiplet, 2H), 5.39 and 5.35 (singlet, 1H), 5.01 and 4.95 (broad singlet, 1H), 4.84 - 4.54 (multiplet, 1H), 4.34 (quintet, J = 6.8 Hz, 2H), 4.09 - 3.64 (multiplet, 2H), 3.63 - 3.23 (multiplet, 6H), 2.52 - 2.38 (multiplet, 5H), 2.35 and 2.34 (singlet, 3H), 2.13 - 2.00 (multiplet, 1H), 1.38 and 1.36 (triplet, J = 7.2 Hz, 3H). ESMS m / z: 589.2 (M+1).

[0055] Compound 3: 1 H NMR (400 MHz, DMSO-d6) δ 7.95 and 7.93 (singlet, 1H), 7.59 - 7.46 (multiplet, 2H), 7.42 - 7.37 (multiplet, 1H), 5.67 and 5.61 (singlet, 1H), 4.74 - 4.50 (multiplet, 1H), 3.85 - 3.04 (multiplet, 8H), 2.70 - 2.54 (multiplet, 4H), 2.49 - 2.41 (multiplet, 3H), 2.34 - 2.12 (multiplet, 1H), 2.09 - 1.92 (multiplet, 1H). ESMS m / z: 561.2 (M+1).

[0056] Compound 4: 1 H NMR (300 MHz, CDCl 3) δ 7.48 - 7.41 (m, 1H), 7.29 - 7.22 (m, 1H), 7.09 and 7.07 (t, J = 7.8 Hz, 1H), 6.46 and 6.43 (s, 1H), 5.92 and 5.88 (s, 1H), 5.72 (brs, 1H), 5.30 and 5.10 (brs, 1H), 4.58 - 4.40 (m, 1H), 3.87 - 3.22 (m, 8H), 2.45 and 2.37 (t, J = 4.9 Hz, 4H), 2.34 - 2.26 (m, 6H), 2.25 - 2.12 (m, 1H), 2.02 - 1.84 (m, 1H). ESMS m / z: 531.2 (M+1).

[0057] Compound 5: 1 H NMR (300 MHz, CDCl 3 ) δ 7.41 and 7.41 (t, J = 8.9 Hz, 1H), 7.22 and 7.22 (dd, J = 8.9, 6.2 Hz, 1H), 7.16 and 7.15 (t, J = 8.9 Hz, 1H), 6.04 and 5.99 (brs, 1H), 5.98 and 5.94 (s, 1H), 4.76 - 4.55 (m, 1H), 4.15 - 3.32 (m, 9H), 2.75 - 2.50 (m, 6H), 2.29 and 2.28 (s, 3H), 2.24 - 2.01 (m, 2H), 1.21 and 1.19 (t, J = 7.1 Hz, 3H). ESMS m / z: 529.2 (M+1).

[0058] Compound 6: 1 H NMR (300 MHz, CDCl 3) δ 7.41 - 7.31 (m, 2H), 7.23 - 7.08 (m, 2H), 6.93 (d, J = 3.6 Hz, 1H), 6.48 and 6.43 (s, 1H), 4.62 - 4.40 (m, 1H), 4.06 - 3.71 (m, 2H), 3.71 - 3.17 (m, 6H), 2.57 - 2.39 (m, 6H), 2.37 - 1.95 (m, 2H), 1.13 (t, J = 7.4 Hz, 3H). ESMS m / z: 515.2 (M+1).

[0059] Compound 7: 1 H NMR (400 MHz, CDCl 3 ) δ 7.38 and 7.37 (t, J = 8.6 Hz, 1H), 7.19 and 7.18 (t, J = 8.6 Hz, 1H), 7.14 and 7.11 (dd, J = 9.6, 2.0 Hz, 1H), 4.90 and 4.86 (s, 1H), 4.69 (brs, 1H), 4.58 - 4.37 (m, 1H), 4.07 - 3.94 (m, 1H), 3.84 - 3.43 (m, 6H), 3.43 - 3.14 (m, 1H), 2.52 - 2.14 (m, 9H), 1.99 - 1.65 (m, 6H), 1.12 and 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 502.2 (M+1).

[0060] Compound 8: 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 - 7.26 (m, 1H), 7.12 - 7.09 (m, 2H), 5.90 and 5.85 (s, 1H), 5.30 and 5.27 (s, 1H), 4.70 - 4.53 (m, 1H), 4.08 - 3.89 (m, 3H), 3.82 - 3.66 (m, 4H), 3.51 - 3.10 (m, 2H), 2.29 and 2.28 (s, 3H), 2.20 and 2.18 (s, 6H), 2.15 - 2.00 (m, 2H). ESMS m / z: 514.2 (M+1).

[0061] Compound 9: 1 H NMR (300 MHz, CDCl 3 ) δ 7.31 - 7.24 (m, 1H), 7.19 - 7.09 (m, 2H), 5.89 and 5.86 (s, 1H), 5.55 and 5.52 (s, 1H), 4.72 - 4.47 (m, 1H), 4.37 - 4.00 (m, 2H), 3.90 - 3.57 (m, 2H), 3.54 - 3.13 (m, 4H), 2.69 - 2.55 (m, 1H), 2.34 - 2.03 (m, 7H), 1.27 - 1.02 (m, 6H). ESMS m / z: 528.2 (M+1).

[0062] Compound 10: 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 and 7.30 (t, J = 7.7 Hz, 1H), 7.18 - 7.09 (m, 2H), 5.90 and 5.85 (s, 1H), 5.64 and 5.62 (s, 1H), 4.68 - 4.51 (m, 1H), 4.21 - 3.97 (m, 3H), 3.80 - 3.66 (m, 2H), 3.54 - 3.23 (m, 2H), 2.94 - 2.75 (m, 2H), 2.48 - 2.33 (m, 2H), 2.30 and 2.29 (s, 3H), 2.26 - 2.04 (m, 2H), 1.36 (d, J = 6.4 Hz, 3H), 1.14 (d, J = 6.4 Hz, 3H). ESMS m / z: 528.2 (M+1).

[0063] Compound 11: 1 H NMR (300 MHz, CD 3 OD) δ 7.49 (t, J = 8.4 Hz, 1H), 7.40 - 7.31 (m, 2H), 5.80 (m, 1H), 4.71 - 4.51 (m, 2H), 4.06 - 3.34 (m, 7H), 2.44 - 2.30 (m, 5H), 2.23 - 2.02 (m, 2H). ESMS m / z: 512.1 (M+1).

[0064] Compound 12: 1 H NMR (300 MHz, CDCl 3 ) δ 7.32 - 7.24 (m, 1H), 7.18 - 7.09 (m, 2H), 5.91 and 5.86 (s, 1H), 5.64 and 5.62 (s, 1H), 4.74 - 4.50 (m, 1H), 4.17 - 4.02 (m, 1H), 3.83 - 3.22 (m, 11H), 2.31 and 2.30 (s, 3H), 2.26 - 2.14 (m, 2H), 2.13 and 2.12 (s, 3H). ESMS m / z: 542.2 (M+1).

[0065] Compound 13: 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 - 7.25 (m, 1H), 7.17 - 7.09 (m, 2H), 5.91 and 5.86 (s, 1H), 5.61 and 5.59 (s, 1H), 4.72 - 4.52 (m, 1H), 4.16 - 3.98 (m, 1H), 3.80 - 3.64 (m, 2H), 3.62 - 3.41 (m, 7H), 3.40 - 3.22 (m, 5H), 2.60 (q, J = 5.5 Hz, 2H), 2.54 (t, J = 4.8 Hz, 2H), 2.50 (t, J = 4.8 Hz, 2H), 2.30 and 2.29 (s, 3H), 2.26 - 2.17 (m, 1H), 2.15 - 2.04 (m, 1H). ESMS m / z: 558.2 (M+1).

[0066] Compound 14: 1 H NMR (400 MHz, CDCl 3) δ 8.01 (s, 1H), 7.29-7.24 (m, 1H), 7.17-7.09 (m, 2H), 5.92 and 5.86 (s, 1H), 5.61 and 5.58 (s, 1H), 4.74-4.51 (m, 1H), 4.19-4.05 (m, 1H), 3.81-3.23 (m, 7H), 3.04-2.96 (m, 2H), 2.70 (t, J = 4.8 Hz, 2H), 2.66 (t, J = 4.8 Hz, 2H), 2.30 and 2.29 (s, 3H), 2.27-2.03 (m, 2H). ESMS m / z: 582.2 (M+1).

[0067] Compound 15: 1 H NMR (400 MHz, CDCl 3 ) δ 7.30-7.27 (m, 1H), 7.17-7.09 (m, 2H), 5.92 and 5.86 (s, 1H), 5.60 and 5.58 (s, 1H), 4.70-4.51 (m, 1H), 4.16-3.90 (m, 3H), 3.80-3.64 (m, 2H), 3.52-3.24 (m, 2H), 2.69-2.55 (m, 2H), 2.30 and 2.29 (s, 3H), 2.28 and 2.27 (s, 3H), 2.25-2.03 (m, 5H), 1.16-1.07 (m, 6H). ESMS m / z: 542.2 (M+1).

[0068] Compound 16: 1 H NMR (400 MHz, CDCl 3) δ 7.29 - 7.22 (m, 1H), 7.17 - 7.08 (m, 2H), 5.91 and 5.86 (s, 1H), 5.61 and 5.58 (s, 1H), 4.73 - 4.51 (m, 5H), 4.18 - 4.05 (m, 1H), 3.80 - 3.22 (m, 8H), 2.36 (t, J = 5.0 Hz, 2H), 2.32 (t, J = 5.0 Hz, 2H), 2.29 and 2.28 (s, 3H), 2.27 - 2.03 (m, 2H). ESMS m / z: 556.1 (M+1).

[0069] Compound 17: 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 - 7.26 (m, 1H), 7.18 - 7.09 (m, 2H), 5.92 and 5.87 (s, 1H), 5.55 and 5.52 (s, 1H), 4.65 - 4.50 (m, 1H), 4.10 - 3.99 (m, 1H), 3.80 - 3.46 (m, 5H), 3.46 - 3.21 (m, 5H), 3.01 and 2.97 (s, 3H), 2.29 and 2.28 (s, 3H), 2.25 - 2.16 (m, 2H). ESMS m / z: 503.2 (M+1).

[0070] Compound 18: 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 - 7.27 (m, 1H), 7.19 - 7.09 (m, 2H), 5.92 and 5.86 (s, 1H), 5.40 and 5.37 (s, 1H), 4.71 - 4.52 (m, 1H), 4.08 - 3.98 (m, 1H), 3.82 - 3.06 (m, 7H), 2.83 - 2.68 (m, 1H), 2.35 - 2.00 (m, 12H), 1.91 - 1.74 (m, 1H). ESMS m / z: 528.2 (M+1).

[0071] Compound 19: 1 H NMR (300 MHz, CDCl3 ) δ 7.33 (t, J = 7.2 Hz, 1H), 7.20 - 7.08 (m, 2H), 5.87 and 5.83 (s, 1H), 5.36 and 5.33 (s, 1H), 4.64 - 4.50 (m, 1H), 4.34 - 4.02 (m, 2H), 3.91 - 3.61 (m, 5H), 3.57 - 3.35 (m, 1H), 3.32 and 3.31 (s, 3H), 3.28 - 3.16 (m, 1H), 2.28 and 2.27 (s, 3H), 2.26 - 2.10 (m, 2H). ESMS m / z: 501.1 (M+1).

[0072] Compound 20: 1 H NMR (300 MHz, CDCl 3 ) δ 7.42 (t, J = 7.6 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.10 and 7.09 (t, J = 7.6 Hz, 1H), 5.93 and 5.87 (s, 1H), 5.39 and 5.36 (s, 1H), 4.75 - 4.52 (m, 1H), 4.11 - 3.98 (m, 1H), 3.82 - 3.06 (m, 7H), 2.83 - 2.67 (m, 1H), 2.34 - 2.00 (m, 12H), 1.92 - 1.74 (m, 1H). ESMS m / z: 528.2 (M+1).

[0073] Compound 21: 1 H NMR (300 MHz, CDCl 3) δ 7.43 (t, J = 7.2 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.09 (t, J = 7.8 Hz, 1H), 5.92 and 5.86 (s, 1H), 5.66 and 5.63 (s, 1H), 4.75 - 4.52 (m, 1H), 4.41 - 4.20 (m, 2H), 4.15 - 4.00 (m, 1H), 3.84 - 3.21 (m, 3H), 2.83 - 2.64 (m, 2H), 2.53 - 2.36 (m, 1H), 2.35 - 2.26 (m, 9H), 2.25 - 2.02 (m, 2H), 1.92 - 1.75 (m, 2H), 1.54 - 1.32 (m, 2H). ESMS m / z: 542.2 (M+1).

[0074] Compound 22: 1 H NMR (300 MHz, CDCl 3 ) δ 7.47 - 7.40 (m, 1H), 7.33 - 7.27 (m, 1H), 7.16 - 7.08 (m, 1H), 5.90 and 5.85 (s, 1H), 5.46 - 5.36 (m, 2H), 4.59 (brs, 1H), 4.10 - 3.60 (m, 3H), 3.60 - 3.10 (m, 5H), 2.88 - 2.75 (m, 1H), 2.35 - 2.24 (m, 11H), 1.96 - 1.80 (m, 2H). ESMS m / z: 528.2 (M+1).

[0075] Compound 23: 1 H NMR (300 MHz, CDCl 3) δ 7.43 (t, J = 7.5 Hz, 1H), 7.25-7.17 (m, 1H), 7.10 (t, J = 7.8 Hz, 1H), 5.94 and 5.88 (s, 1H), 5.43 and 5.41 (s, 1H), 4.75-4.56 (m, 1H), 4.39-4.00 (m, 2H), 3.84-3.54 (m, 3H), 3.53-3.15 (m, 7H), 2.29 and 2.28 (s, 3H), 2.24-2.08 (m, 2H), 2.07-1.81 (m, 4H). ESMS m / z: 529.2 (M+1).

[0076] Compound 24: 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 (t, J = 7.4 Hz, 1H), 7.21 (t, J = 6.6 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 5.95 and 5.89 (s, 1H), 5.43 and 5.40 (s, 1H), 4.72-4.52 (m, 1H), 4.33-4.07 (m, 2H), 3.83-3.64 (m, 2H), 3.52-3.10 (m, 8H), 2.29 and 2.28 (s, 3H), 2.27-2.06 (m, 2H), 2.06-1.85 (m, 4H). ESMS m / z: 529.2 (M+1).

[0077] Compound 25: 1 H NMR (300 MHz, CDCl 3) δ 7.42 and 7.42 (t, J = 7.2 Hz, 1H), 7.24 - 7.17 (m, 1H), 7.09 (t, J = 7.8 Hz, 1H), 5.91 and 5.85 (s, 1H), 5.29 and 5.26 (s, 1H), 4.71 and 4.58 (brs, 1H), 4.09 - 3.90 (m, 3H), 3.81 - 3.65 (m, 4H), 3.51 - 3.10 (m, 3H), 2.29 and 2.28 (s, 3H), 2.23 - 2.03 (m, 8H). ESMS m / z: 514.2 (M+1).

[0078] Compound 26: 1 H NMR (300 MHz, CD 3 OD) δ 7.59 (q, J = 8.2 Hz, 1H), 7.43 - 7.32 (m, 1H), 7.32 - 7.21 (m, 1H), 5.97 - 5.73 (m, 2H), 4.55 and 4.40 (quin, J = 5.6 Hz, 1H), 4.00 - 3.77 (m, 1H), 3.76 - 3.37 (m, 7H), 3.07 and 2.97 (t, J = 5.3 Hz, 4H), 2.40 - 2.24 (m, 1H), 2.24 and 2.22 (s, 3H), 2.14 - 1.97 (m, 1H). ESMS m / z: 500.1 (M+1).

[0079] Compound 27: 1 H NMR (400 MHz, CDCl 3) δ 7.43 (t, J = 7.6 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.10 (t, J = 7.8 Hz, 1H), 5.93 and 5.88 (s, 1H), 5.51 and 5.49 (s, 1H), 4.69 and 4.60 (brs, 1H), 4.15 - 4.04 (m, 1H), 3.83 - 3.44 (m, 5H), 3.42 - 3.25 (m, 1H), 2.98 and 2.94 (s, 3H), 2.41 - 2.35 (m, 2H), 2.32 - 2.25 (m, 7H), 2.23 (s, 3H), 2.20 - 2.05 (m, 1H). ESMS m / z: 516.2 (M+1).

[0080] Compound 28: 1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (t, J = 7.4 Hz, 1H), 7.24 - 7.18 (m, 1H), 7.09 (t, J = 7.8 Hz, 1H), 5.92 and 5.87 (s, 1H), 5.65 and 5.62 (s, 1H), 4.74 - 4.54 (m, 1H), 4.17 - 4.03 (m, 1H), 3.99 - 3.66 (m, 3H), 3.52 - 3.07 (m, 8H), 2.30 and 2.29 (s, 3H), 2.27 - 2.04 (m, 2H), 1.95 - 1.80 (m, 2H), 1.63 - 1.42 (m, 2H). ESMS m / z: 529.2 (M+1).

[0081] Compound 29: 1 H NMR (400 MHz, CDCl 3) δ 7.42 and 7.42 (d, J = 8.4 Hz, 2H), 7.36 and 7.34 (d, J = 8.4 Hz, 2H), 5.91 and 5.85 (s, 1H), 5.62 and 5.57 (s, 1H), 4.69 and 4.56 (brs, 1H), 4.20-4.14 (m, 1H), 3.77-3.66 (m, 2H), 3.64-3.40 (m, 8H), 2.50-2.40 (m, 6H), 2.29 and 2.28 (s, 3H), 2.26-2.17 (m, 1H), 2.14-2.05 (m, 1H), 1.12 and 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 510.2 (M+1).

[0082] Compound 30: 1 H NMR (300 MHz, CDCl 3 ) δ 7.34-7.26 (m, 2H), 7.04 (t, J = 8.0 Hz, 1H), 5.82 (s, 1H), 5.58 (s, 1H), 4.60-4.46 (m, 1H), 3.71 (s, 2H), 3.54 (t, J = 5.0 Hz, 4H), 2.88-2.77 (m, 2H), 2.70-2.62 (m, 1H), 2.51-2.39 (m, 5H), 2.38-2.27 (m, 4H), 2.26 (s, 3H), 1.75-1.61 (m, 1H). ESMS m / z: 500.2 (M+1).

[0083] Compound 31: 1 H NMR (400 MHz, CDCl 3) δ 7.32 - 7.26 (m, 2H), 7.04 (td, J = 7.8, 1.2 Hz, 1H), 5.83 (s, 1H), 5.57 (s, 1H), 4.60 - 4.48 (m, 1H), 3.70 (s, 2H), 3.54 (t, J = 5.0 Hz, 4H), 2.88 - 2.76 (m, 2H), 2.74 - 2.66 (m, 1H), 2.49 - 2.38 (m, 7H), 2.36 - 2.26 (m, 1H), 2.24 (s, 3H), 1.72 - 1.61 (m, 1H), 1.10 (t, J = 7.2 Hz, 3H). ESMS m / z: 514.2 (M+1).

[0084] Compound 32: 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 and 7.41 (d, J = 11.8 Hz, 1H), 7.25 - 7.23 (m, 1H), 7.22 and 7.20 (t, J = 7.6 Hz, 1H), 5.91 and 5.86 (s, 1H), 5.65 and 5.64 (s, 1H), 4.57 (brs, 1H), 4.11 - 4.00 (m, 1H), 3.80 - 3.68 (m, 1H), 3.63 - 3.47 (m, 5H), 3.45 - 3.14 (m, 2H), 2.51 - 2.40 (m, 6H), 2.29 and 2.28 (s, 3H), 2.27 - 2.02 (m, 2H), 1.12 (t, J = 7.6 Hz, 3H). ESMS m / z: 544.2 (M+1).

[0085] Compound 33: 1 H NMR (400 MHz, CDCl 3) δ 7.36 - 7.30 (m, 2H), 7.23 and 7.23 (d, J = 8.0 Hz, 1H), 5.91 and 5.84 (s, 1H), 5.64 and 5.61 (s, 1H), 4.65 and 4.56 (brs, 1H), 4.12 - 4.00 (m, 1H), 3.80 - 3.70 (m, 2H), 3.65 - 3.40 (m, 6H), 2.53 - 2.40 (m, 6H), 2.36 (s, 3H), 2.29 and 2.28 (s, 3H), 2.25 - 2.16 (m, 1H), 2.15 - 2.03 (m, 1H), 1.12 and 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 524.3 (M+1).

[0086] Compound 34: 1 H NMR (400 MHz, CDCl 3 ) δ 7.22 - 7.07 (m, 3H), 5.91 and 5.86 (s, 1H), 5.66 (s, 1H), 4.55 (brs, 1H), 4.15 - 4.05 (m, 1H), 3.79 - 3.32 (m, 7H), 3.20 - 3.13 (m, 1H), 2.54 - 2.40 (m, 6H), 2.30 - 2.25 (m, 6H), 2.15 - 2.05 (m, 2H), 1.13 and 1.12 (t, J = 7.0 Hz, 3H). ESMS m / z: 524.3 (M+1).

[0087] Compound 35: 1 H NMR (300 MHz, CDCl 3) δ 7.43 (t, J = 6.6 Hz, 1H), 7.24-7.18 (m, 1H), 7.09 (t, J = 7.8 Hz, 1H), 5.93 and 5.87 (s, 1H), 5.63 and 5.60 (s, 1H), 4.72 and 4.78 (brs, 1H), 4.17-4.07 (m, 1H), 3.82-3.24 (m, 8H), 2.46-2.37 (m, 4H), 2.35-2.28 (m, 6H), 2.57-2.04 (m, 2H). ESMS m / z: 514.2 (M+1).

[0088] Compound 36: 1 H NMR (300 MHz, CDCl 3 ) δ 7.31-7.26 (m, 1H), 7.18-7.08 (m, 2H), 5.92 and 5.86 (s, 1H), 5.63 and 5.61 (s, 1H), 4.73-4.51 (m, 1H), 4.16-4.01 (m, 1H), 3.82-3.54 (m, 3H), 3.54-3.23 (m, 4H), 2.49-2.37 (m, 4H), 2.33 and 2.31 (s, 3H), 2.30 and 2.29 (s, 3H), 2.27-2.19 (m, 1H), 2.16-2.03 (m, 1H). ESMS m / z: 514.2 (M+1).

[0089] Compound 37: 1 H NMR (400 MHz, CDCl 3) δ 7.39 - 7.30 (m, 2H), 7.06 and 7.03 (t, J = 8.8 Hz, 1H), 5.89 and 5.85 (s, 1H), 5.73 and 5.71 (s, 1H), 4.56 (brs, 1H), 3.99 - 3.80 (m, 1H), 3.80 - 3.50 (m, 6H), 3.46 - 3.24 (m, 2H), 2.62 - 2.45 (m, 6H), 2.31 and 2.29 (s, 3H), 2.23 - 2.15 (m, 2H), 1.17 and 1.15 (t, J = 7.2 Hz, 3H). ESMS m / z: 528.2 (M+1).

[0090] Compound 38: 1 H NMR (400 MHz, CDCl 3 ) δ 7.43 and 7.43 (t, J = 7.5 Hz, 1H), 7.21 and 7.20 (q, J = 7.5 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 5.93 and 5.87 (s, 1H), 5.62 and 5.59 (s, 1H), 4.72 and 4.58 (brs, 1H), 4.13 (m, 1H), 3.82 - 3.66 (m, 2H), 3.62 - 3.42 (m, 5H), 3.41 - 3.25 (m, 1H), 2.51 - 2.40 (m, 6H), 2.31 and 2.29 (s, 3H), 2.28 - 2.21 (m, 1H), 2.16 - 2.05 (m, 1H), 1.12 and 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 528.3 (M +1).

[0091] Compound 39: 11H NMR (700 MHz, DMSO-d6) δ 8.70 (broad singlet, 1H), 7.68 and 7.64 (triplet, J = 8.1 Hz, 1H), 7.60 and 7.57 (doublet of doublets, J = 9.8, 1.4 Hz, 1H), 6.51 (broad singlet, 1H), 6.06 (broad singlet, 1H), 5.80 (broad singlet, 1H), 4.41 and 4.20 (broad singlet, 1H), 3.85 - 3.73 (multiplet, 1H), 3.67 - 3.62 (multiplet, 1H), 3.61 - 3.50 (multiplet, 1H), 3.50 - 3.40 (multiplet, 3H), 2.49 - 2.22 (multiplet, 6H), 2.16 and 2.13 (singlet, 3H), 2.11 - 2.09 (multiplet, 1H), 2.03 - 1.86 (multiplet, 1H), 1.07 - 0.99 (multiplet, 3H). ESMS m / z: 528.2 (M+1).

[0092] Compound 40: 1 1H NMR (700 MHz, CDCl 3 ) δ 7.18 (triplet, J = 7.0 Hz, 1H), 7.04 (singlet, 1H), 5.93 and 5.87 (singlet, 1H), 5.63 and 5.60 (singlet, 1H), 4.70 and 4.58 (broad singlet, 1H), 4.11 (multiplet, 1H), 3.79 - 3.68 (multiplet, 2H), 3.60 - 3.57 (multiplet, 1H), 3.56 - 3.46 (multiplet, 4H), 3.41 - 3.27 (multiplet, 1H), 2.50 - 2.41 (multiplet, 6H), 2.30 and 2.29 (singlet, 3H), 2.27 - 2.22 (multiplet, 1H), 2.16 - 2.08 (multiplet, 1H), 1.12 and 1.11 (triplet, J = 7.0 Hz, 3H). ESMS m / z: 546.2 (M+1).

[0093] Compound 42: 1 1H NMR (400 MHz, CDCl 3) δ 7.33 - 7.23 (m, 1H), 7.01 - 6.92 (m, 1H), 5.87 and 5.84 (s, 1H), 5.74 and 5.72 (s, 1H), 4.54 (brs, 1H), 3.96 - 3.80 (m, 2H), 3.78 - 3.50 (m, 5H), 3.49 - 3.26 (m, 2H), 2.60 - 2.50 (m, 6H), 2.31 and 2.30 (s, 3H), 2.22 - 2.03 (m, 2H), 1.17 and 1.16 (t, J = 7.0 Hz, 3H). ESMS m / z: 530.3 (M+1).

[0094] Compound 43: 1 H NMR (400 MHz, CDCl 3 ) δ 7.23 - 7.10 (m, 2H), 5.91 and 5.86 (s, 1H), 5.70 and 5.68 (s, 1H), 4.63 and 4.58 (brs, 1H), 4.02 - 3.95 (m, 1H), 3.80 - 3.70 (m, 2H), 3.65 - 3.47 (m, 5H), 3.44 - 3.25 (m, 1H), 2.55 - 2.42 (m, 6H), 2.30 and 2.29 (s, 3H), 2.22 - 2.03 (m, 2H), 1.14 and 1.13 (t, J = 7.2 Hz, 3H). ESMS m / z: 546.2 (M+1).

[0095] Compound 44: 1 H NMR (400 MHz, CDCl 3) δ 7.34 and 7.32 (t, J = 8.0 Hz, 1H), 6.92 - 6.78 (m, 2H), 5.92 and 5.86 (s, 1H), 5.63 and 5.60 (s, 1H), 4.73 - 4.53 (m, 1H), 4.15 - 4.04 (m, 1H), 3.80 - 3.52 (m, 3H), 3.52 - 3.25 (m, 4H), 2.52 - 2.39 (m, 6H), 2.31 and 2.29 (s, 3H), 2.28 - 2.18 (m, 1H), 2.17 - 2.05 (m, 1H), 1.11 and 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 512.3 (M+1).

[0096] Compound 45: 1 H NMR (400 MHz, CDCl 3 ) δ 7.18 and 7.15 (d, J = 7.0 Hz, 2H), 5.88 and 5.84 (s, 1H), 5.76 and 5.73 (s, 1H), 4.57 (brs, 1H), 4.01 - 3.85 (m, 1H), 3.82 - 3.53 (m, 6H), 3.52 - 3.40 (m, 2H), 2.58 - 2.45 (m, 6H), 2.30 and 2.29 (s, 3H), 2.20 - 2.15 (m, 2H), 1.20 - 1.10 (m, 3H). ESMS m / z: 546.2 (M+1).

[0097] Compound 46: 1 H NMR (300 MHz, CD 3OD) δ 7.74 - 7.55 (m, 3H), 5.87 and 5.82 (s, 1H), 4.56 and 4.42 (brs, 1H), 4.01 - 3.77 (m, 1H), 3.77 - 3.62 (m, 4H), 3.62 - 3.57 (m, 3H), 3.57 - 3.40 (m, 1H), 2.83 - 2.57 (m, 6H), 2.40 - 2.30 (m, 1H), 2.24 and 2.22 (s, 3H), 2.15 - 2.02 (m, 1H), 1.27 - 1.14 (m, 3H). ESMS m / z: 562.3 (M+1).

[0098] Compound 47: 1 H NMR (400 MHz, CDCl 3 ) δ 7.10 - 6.95 (m, 2H), 5.88 and 5.85 (s, 1H), 5.76 and 5.74 (s, 1H), 4.58 (brs, 1H), 4.21 - 3.87 (m, 2H), 3.80 - 3.68 (m, 1H), 3.67 - 3.47 (m, 5H), 3.43 - 3.17 (m, 1H), 2.57 - 2.43 (m, 6H), 2.38 - 2.30 (m, 1H), 2.29 and 2.28 (s, 3H), 2.24 - 2.25 (m, 1H), 1.14 and 1.14 (t, J = 7.2 Hz, 3H). ESMS m / z: 546.2 (M+1).

[0099] Compound 48: 1 H NMR (300 MHz, CDCl 3) δ 7.65 (t, J = 7.2 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.31 - 7.21 (m, 1H), 5.91 and 5.86 (s, 1H), 5.71 and 5.68 (s, 1H), 4.72 - 4.53 (m, 1H), 4.12 - 3.98 (m, 1H), 3.85 - 3.44 (m, 6H), 3.44 - 3.24 (m, 1H), 2.57 - 2.38 (m, 6H), 2.28 and 2.27 (s, 3H), 2.25 - 2.06 (m, 2H), 1.12 and 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 562.2 (M+1).

[0100] Compound 49: 1 H NMR (300 MHz, CDCl 3 ) δ 7.82 and 7.78 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 5.91 and 5.85 (s, 1H), 5.66 and 5.62 (s, 1H), 4.74 - 4.53 (m, 1H), 4.20 - 4.02 (m, 1H), 3.82 - 3.47 (m, 6H), 3.47 - 3.37 (m, 1H), 2.55 - 2.39 (m, 6H), 2.28 (s, 3H), 2.26 - 2.18 (m, 1H), 2.18 - 2.00 (m, 1H), 1.12 and 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 578.2 (M+1).

[0101] Compound 50: 1 H NMR (300 MHz, CDCl 3) δ 7.50 (q, J = 8.2 Hz, 1H), 7.43-7.35 (m, 1H), 5.88 and 5.85 (s, 1H), 5.76 and 5.74 (s, 1H), 4.73-4.54 (m, 1H), 3.96-3.74 (m, 2H), 3.74-3.34 (m, 6H), 2.57-2.43 (m, 6H), 2.30 and 2.29 (s, 3H), 2.25-2.05 (m, 2H), 1.14 and 1.13 (t, J = 7.2 Hz, 3H). ESMS m / z: 529.3 (M+1).

[0102] Compound 51: 1 H NMR (300 MHz, CDCl 3 ) δ 8.41 and 8.39 (d, J = 1.2 Hz, 1H), 7.59 and 7.56 (dd, J = 8.4, 1.2 Hz, 1H), 5.89 and 5.86 (s, 1H), 5.65 and 5.63 (s, 1H), 4.76-4.58 (m, 1H), 4.01-3.60 (m, 4H), 3.60-3.39 (m, 4H), 2.59-2.43 (m, 6H), 2.29 (s, 3H), 2.25-2.06 (m, 2H), 1.14 and 1.13 (t, J = 7.2 Hz, 3H). ESMS m / z: 529.2 (M+1).

[0103] Compound 52: 1 H NMR (400 MHz, CDCl 3) δ 8.53 and 8.52 (d, J = 2.8 Hz, 1H), 7.80 - 7.76 (m, 1H), 7.36 and 7.35 (d, J = 8.4 Hz, 1H), 5.90 and 5.84 (s, 1H), 5.65 and 5.63 (s, 1H), 4.71 - 4.55 (m, 1H), 4.16 - 4.01 (m, 1H), 3.84 - 3.58 (m, 3H), 3.58 - 3.40 (m, 4H), 2.53 - 2.42 (m, 6H), 2.29 and 2.28 (s, 3H), 2.26 - 2.05 (m, 2H), 1.12 and 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 511.2 (M+1).

[0104] Compound 53: 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 and 7.82 (t, J = 8.2 Hz, 1H), 7.29 - 7.24 (m, 1H), 5.90 and 5.85 (s, 1H), 5.68 and 5.66 (s, 1H), 4.63 and 4.59 (brs, 1H), 4.04 - 3.93 (m, 1H), 3.83 - 3.72 (m, 2H), 3.63 - 3.26 (m, 6H), 2.53 - 2.42 (m, 6H), 2.31 and 2.30 (s, 3H), 2.22 - 2.04 (m, 2H), 1.13 and 1.13 (t, J = 7.2 Hz, 3H). ESMS m / z: 529.2 (M+1).

[0105] Compound 54: 1 H NMR (400 MHz, CDCl 3) δ 7.60 and 7.55 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 5.93 and 5.87 (s, 1H), 5.63 and 5.62 (s, 1H), 4.68-4.54 (m, 1H), 4.17-4.01 (m, 1H), 3.81-3.45 (m, 5H), 3.45-3.16 (m, 2H), 2.52-2.40 (m, 6H), 2.37-2.22 (m, 4H), 2.18-2.04 (m, 1H), 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 545.2 (M+1).

[0106] Compound 55: 1 H NMR (300 MHz, CDCl 3 ) δ 8.29 and 8.29 (s, 1H), 7.43 and 7.40 (s, 1H), 5.90 and 5.86 (s, 1H), 5.67 and 5.66 (s, 1H), 4.59 (m, 1H), 4.14-3.97 (m, 1H), 3.84-3.61 (m, 3H), 3.61-3.14 (m, 4H), 2.62-2.42 (m, 6H), 2.36-2.20 (m, 4H), 2.20-2.02 (m, 1H), 1.16 and 1.15 (t, J = 7.2 Hz, 3H). ESMS m / z: 545.2 (M+1).

[0107] Compound 56: 1 H NMR (300 MHz, CD 3OD) δ 7.95 and 7.91 (d, J = 7.5 Hz, 1H), 5.87 (s, 1H), 5.82 (s, 1H), 4.63-4.38 (m, 1H), 3.99-3.59 (m, 6H), 3.59-3.36 (m, 2H), 3.04-2.95 (m, 2H), 2.95-2.79 (m, 4H), 2.42-2.28 (m, 1H), 2.25 and 2.24 (s, 3H), 2.17-2.01 (m, 1H), 1.28 and 1.28 (t, J = 7.2 Hz, 3H). ESMS m / z: 563.2 (M+1).

[0108] Compound 57: 1 H NMR (400 MHz, CDCl 3 ) δ 8.42 and 8.41 (d, J = 2.0 Hz, 1H), 7.90 and 7.88 (d, J = 2.0 Hz, 1H), 5.91 and 5.85 (s, 1H), 5.65 and 5.64 (s, 1H), 4.70-4.56 (m, 1H), 4.15-3.99 (m, 1H), 3.84-3.54 (m, 4H), 3.54-3.43 (m, 3H), 2.52-2.39 (m, 6H), 2.30 and 2.29 (s, 3H), 2.28-2.20 (m, 1H), 2.18-2.04 (m, 1H), 1.12 and 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 545.2 (M+1).

[0109] Compound 58: 1 H NMR (300 MHz, CDCl 3) δ 7.43 (t, J = 7.6 Hz, 1H), 7.24 - 7.16 (m, 1H), 7.09 (t, J = 7.6 Hz, 1H), 5.93 and 5.87 (s, 1H), 5.62 and 5.59 (s, 1H), 4.77 - 4.52 (m, 1H), 4.20 - 4.03 (m, 1H), 3.84 - 3.53 (m, 3H), 3.53 - 3.22 (m, 4H), 2.53 - 2.38 (m, 6H), 2.30 and 2.29 (s, 3H), 2.27 - 2.19 (m, 1H), 2.16 - 2.03 (m, 1H), 1.11 and 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 528.2 (M+1).

[0110] Compound 59: 1 H NMR (300 MHz, CDCl 3 ) δ 7.43 (t, J = 7.8 Hz, 1H), 7.24 - 7.17 (m, 1H), 7.09 (t, J = 7.8 Hz, 1H), 5.92 and 5.87 (s, 1H), 5.63 and 5.61 (s, 1H), 4.75 - 4.53 (m, 1H), 4.18 - 4.02 (m, 1H), 3.84 - 3.53 (m, 3H), 3.53 - 3.22 (m, 4H), 2.50 - 2.37 (m, 4H), 2.33 and 2.31 (s, 3H), 2.31 and 2.29 (s, 3H), 2.27 - 2.19 (m, 1H), 2.17 - 2.03 (m, 1H). ESMS m / z: 514.2 (M+1).

[0111] Compound 60: 1 H NMR (400 MHz, CDCl 3) δ 7.42 - 7.33 (m, 1H), 7.23 - 7.08 (m, 2H), 6.84 and 6.78 (brs, 1H), 5.85 and 5.83 (s, 1H), 5.63 and 5.60 (s, 1H), 5.32 - 5.03 (m, 1H), 3.97 - 3.86 (m, 1H), 3.67 - 3.25 (m, 9H), 2.57 - 2.38 (m, 6H), 2.28 - 2.18 (m, 4H), 2.15 - 2.07 (m, 1H), 1.21 - 1.05 (m, 6H). ESMS m / z: 556.3 (M+1).

[0112] Compound 61: 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 8.4, 2.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 5.86 (s, 1H), 5.72 (s, 1H), 4.44 - 4.38 (m, 1H), 3.57 - 3.42 (m, 7H), 3.40 - 3.30 (m, 1H), 2.51 - 2.41 (m, 6H), 2.30 (s, 3H), 2.13 - 1.88 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 580.2 (M+1).

[0113] Compound 62: 1 H NMR (300 MHz, CDCl 3) δ 7.86 (d, J = 8.2 Hz, 1H), 7.32 (s, 1H), 7.29 (d, J = 8.2 Hz, 1H), 5.90 (s, 1H), 5.65 (s, 1H), 4.67 - 4.56 (m, 1H), 3.64 - 3.41 (m, 7H), 3.39 - 3.27 (m, 1H), 2.63 (s, 3H), 2.52 - 2.39 (m, 6H), 2.31 (s, 3H), 2.16 - 2.02 (m, 1H), 1.99 - 1.88 (m, 1H), 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 560.2 (M+1).

[0114] Compound 63: 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.36 (dd, J = 8.4, 2.0 Hz, 1H), 5.88 (s, 1H), 5.68 (s, 1H), 4.61 - 4.53 (m, 1H), 3.69 - 3.59 (m, 2H), 3.57 - 3.42 (m, 6H), 2.50 - 2.40 (m, 6H), 2.30 (s, 3H), 2.21 - 2.10 (m, 1H), 2.08 - 1.99 (m, 1H), 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 580.2 (M+1).

[0115] Compound 64: 1 H NMR (300 MHz, CD 3OD) δ 7.81 and 7.80 (t, J = 7.5 Hz, 1H), 7.34-7.28 (m, 2H), 5.82 (s, 1H), 5.57 (s, 1H), 4.27 (brs, 1H), 3.80-3.66 (m, 4H), 3.63-3.45 (m, 5H), 3.02-2.80 (m, 6H), 2.26 (s, 3H), 2.23-2.15 (m, 1H), 2.04-1.93 (m, 1H), 1.28 and 1.27 (t, J = 7.1 Hz, 3H). ESMS m / z: 564.2 (M+1).

[0116] Compound 65: 1 H NMR (300 MHz, CDCl 3 ) δ 7.81 (ddd, J = 7.8, 6.0, 1.8 Hz, 1H), 7.61 (ddd, J = 7.8, 6.0, 1.8 Hz, 1H), 7.21 (td, J = 7.8, 1.2 Hz, 1H), 5.89 (s, 1H), 5.66 (s, 1H), 4.61-4.49 (m, 1H), 3.71-3.59 (m, 1H), 3.59-3.42 (m, 7H), 2.51-2.39 (m, 6H), 2.31 (s, 3H), 2.15-2.00 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 564.2 (M+1).

[0117] Compound 66: 1 H NMR (400 MHz, CDCl 3) δ 7.61 (d, J = 8.6 Hz, 1H), 7.58 - 7.51 (m, 2H), 5.87 (s, 1H), 5.71 (s, 1H), 4.46 - 4.38 (m, 1H), 3.57 - 3.41 (m, 7H), 3.38 - 3.30 (m, 1H), 2.51 - 2.40 (m, 6H), 2.30 (s, 3H), 2.12 - 2.01 (m, 1H), 2.00 - 1.90 (m, 1H), 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 564.2 (M+1).

[0118] Compound 67: 1 H NMR (300 MHz, CDCl 3 ) δ 7.85 (d, J = 7.2 Hz, 2H), 7.65 - 7.50 (m, 3H), 5.91 (s, 1H), 5.63 (s, 1H), 4.56 - 4.45 (m, 1H), 3.62 - 3.41 (m, 6H), 3.33 - 3.18 (m, 2H), 2.41 (t, J = 4.8 Hz, 4H), 2.32 (s, 3H), 2.31 (s, 3H), 2.06 - 1.84 (m, 2H). ESMS m / z: 498.2 (M+1).

[0119] Compound 68: 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 5.88 (s, 1H), 5.68 (s, 1H), 4.49 - 4.42 (m, 1H), 3.56 - 3.43 (m, 6H), 3.41 - 3.32 (m, 1H), 3.30 - 3.24 (m, 1H), 2.50 - 2.40 (m, 6H), 2.31 (s, 3H), 2.03 - 1.93 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 546.2 (M+1).

[0120] Compound 69: 11H NMR (400 MHz, CDCl 3 ) δ 8.13 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.6, 2.0 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 5.86 (s, 1H), 5.71 (s, 1H), 4.46-4.38 (m, 1H), 3.58-3.42 (m, 7H), 3.41-3.32 (m, 1H), 2.51-2.41 (m, 6H), 2.30 (s, 3H), 2.15-2.03 (m, 1H), 2.01-1.92 (m, 1H), 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 614.2 (M+1).

[0121] Compound 70: 1 1H NMR (300 MHz, CDCl 3 ) δ 9.80 (brs, 1H), 7.43-7.35 (m, 1H), 7.24-7.08 (m, 2H), 6.57 and 6.50 (s, 1H), 5.36 and 5.32 (s, 1H), 4.84 and 4.78 (brs, 1H), 4.65-4.44 (m, 1H), 4.11-3.71 (m, 2H), 3.68-3.32 (m, 6H), 2.66 and 2.65 (s, 3H), 2.57-2.41 (m, 6H), 2.30-2.13 (m, 4H), 2.09-1.97 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H). ESMS m / z: 570.2 (M+1).

[0122] Compound 73: 1 1H NMR (400 MHz, CDCl 3) δ 7.42 - 7.35 (m, 1H), 7.23 - 7.09 (m, 2H), 6.55 and 6.50 (s, 1H), 5.87 and 5.84 (s, 1H), 4.92 and 4.79 (brs, 1H), 4.56 and 4.47 (q, J = 5.7 Hz, 1H), 4.06 - 3.79 (m, 1H), 3.77 - 3.55 (m, 5H), 3.54 - 3.19 (m, 2H), 2.56 - 2.40 (m, 9H), 2.36 - 2.22 (m, 1H), 2.03 - 1.94 (m, 1H), 1.53 and 1.51 (s, 9H), 1.16 - 1.12 (m, 3H). ESMS m / z: 612.3 (M+1).

[0123] Compound 74: 1 H NMR (400 MHz, CDCl 3 ) δ 7.39 and 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 7.21 and 7.18 (dd, J = 8.4, 2.0 Hz, 1H), 7.15 and 7.11 (dd, J = 9.4, 2.0 Hz, 1H), 6.83 and 6.76 (brs, 1H), 6.53 and 6.49 (s, 1H), 5.86 and 5.83 (s, 1H), 4.74 and 4.68 (brs, 1H), 4.60 - 4.42 (m, 1H), 4.08 - 3.70 (m, 2H), 3.68 - 3.45 (m, 5H), 3.45 - 3.18 (m, 1H), 2.58 - 2.48 (m, 5H), 2.48 - 2.40 (m, 4H), 2.37 - 2.18 (m, 1H), 2.03 - 1.91 (m, 1H), 1.53 and 1.51 (s, 9H), 1.13 and 1.13 (t, J = 7.2 Hz, 3H). ESMS m / z: 612.3 (M+1).

[0124] Compound 75: 1 H NMR (400 MHz, CDCl 3) δ 7.39 and 7.37 (dd, J = 8.2, 7.0 Hz, 1H), 7.20 and 7.17 (dd, J = 8.2, 2.0 Hz, 1H), 7.14 and 7.11 (dd, J = 9.4, 2.0 Hz, 1H), 6.95 (brs, 1H), 6.02 and 5.98 (s, 1H), 5.90 and 5.89 (s, 1H), 5.87 (s, 2H), 5.07 and 4.90 (brs, 1H), 4.61-4.41 (m, 1H), 4.04-3.69 (m, 2H), 3.66-3.45 (m, 5H), 3.45-3.18 (m, 1H), 2.55-2.41 (m, 6H), 2.32 and 2.31 (s, 3H), 2.27-2.17 (m, 1H), 2.03-1.92 (m, 1H), 1.18 and 1.17 (s, 9H), 1.13 and 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 642.3 (M+1).

[0125] Compound 76: 1 H NMR (400 MHz, CDCl 3 ) δ 9.35 and 9.31 (brs, 1H), 7.38 (q, J = 7.3 Hz, 1H), 7.22-7.07 (m, 2H), 6.56 and 6.48 (s, 1H), 5.37 and 5.33 (s, 1H), 4.90 and 4.84 (brs, 1H), 4.62-4.44 (m, 3H), 4.04-3.68 (m, 2H), 3.66-3.45 (m, 4H), 3.43-3.21 (m, 2H), 2.57-2.40 (m, 6H), 2.38-2.29 (m, 1H), 2.27 and 2.26 (s, 3H), 2.06-1.95 (m, 1H), 1.47 and 1.46 (t, J = 7.2 Hz, 3H), 1.13 and 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 600.3 (M+1).

[0126] Compound 77:1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (q, J = 7.5 Hz, 1H), 7.17 (q, J = 10.3 Hz, 1H), 7.10 (d, J = 9.6 Hz, 1H), 6.31 and 6.26 (s, 1H), 5.97 and 5.89 (s, 1H), 4.98 and 4.88 (brs, 1H), 4.58 - 4.39 (m, 3H), 4.04 - 3.67 (m, 2H), 3.65 - 3.51 (m, 4H), 3.50 - 3.19 (m, 2H), 2.53 and 2.52 (s, 3H), 2.50 - 2.42 (m, 6H), 2.35 - 2.17 (m, 2H), 1.43 and 1.42 (t, J = 7.0 Hz, 3H), 1.13 and 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 600.3 (M+1).

[0127] Compound 78: 1 H NMR (400 MHz, CDCl 3 ) δ 9.33 (brs, 1H), 7.43 - 7.32 (m, 1H), 7.24 - 7.06 (m, 2H), 6.55 and 6.48 (s, 1H), 5.38 and 5.33 (s, 1H), 4.85 and 4.79 (brs, 1H), 4.65 - 4.44 (m, 1H), 4.23 and 4.22 (d, J = 6.8 Hz, 1H), 4.07 - 3.70 (m, 2H), 3.67 - 3.20 (m, 6H), 2.53 - 2.39 (m, 6H), 2.38 - 2.31 (m, 1H), 2.28 and 2.27 (s, 3H), 2.24 - 2.13 (m, 1H), 2.08 - 1.96 (m, 1H), 1.12 (t, J = 6.8 Hz, 3H), 1.02 and 1.01 (d, J = 6.6 Hz, 6H). ESMS m / z: 628.3 (M+1).

[0128] Compound 79: 1 H NMR (300 MHz, CDCl3 ) δ 7.43 - 7.33 (m, 1H), 7.24 - 7.07 (m, 2H), 6.91 and 6.81 (brs, 1H), 6.22 and 6.17 (s, 1H), 6.13 and 6.06 (s, 1H), 4.84 and 4.75 (brs, 1H), 4.62 - 4.39 (m, 1H), 4.17 and 4.17 (d, J = 6.4 Hz, 1H), 4.08 - 3.68 (m, 2H), 3.68 - 3.17 (m, 6H), 2.59 - 2.38 (m, 9H), 2.36 - 2.19 (m, 1H), 2.18 - 2.05 (m, 1H), 2.05 - 1.92 (m, 1H), 1.12 (t, J = 7.2 Hz, 3H), 1.03 and 1.02 (d, J = 7.0 Hz, 6H). ESMS m / z: 628.3 (M+1).

[0129] Compound 80: 1 H NMR (400 MHz, CDCl 3 ) δ 9.44 and 9.42 (brs, 1H), 7.39 (q, J = 7.7 Hz, 1H), 7.24 - 7.09 (m, 2H), 6.55 and 6.47 (s, 1H), 5.39 and 5.35 (s, 1H), 4.83 and 4.78 (brs, 1H), 4.63 - 4.45 (m, 2H), 4.23 - 4.00 (m, 2H), 3.92 - 3.72 (m, 2H), 3.65 - 3.48 (m, 2H), 3.47 - 3.23 (m, 1H), 2.55 - 2.39 (m, 4H), 2.39 - 2.32 (m, 2H), 2.28 and 2.27 (s, 3H), 2.07 - 1.99 (m, 2H), 1.56 (s, 9H), 1.14 and 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 628.3 (M+1).

[0130] Compound 81: 1 H NMR (400 MHz, CDCl 3) δ 7.38 and 7.37 (dd, J = 8.2, 6.6 Hz, 1H), 7.20 and 7.18 (dd, J = 8.2, 2.0 Hz, 1H), 7.15 and 7.11 (dd, J = 9.4, 2.0 Hz, 1H), 7.00 (brs, 1H), 6.27 and 6.18 (s, 1H), 6.12 and 6.09 (s, 1H), 4.87 and 4.78 (brs, 1H), 4.60-4.41 (m, 1H), 4.05-3.69 (m, 2H), 3.68-3.52 (m, 5H), 3.52-3.19 (m, 1H), 2.54-2.40 (m, 9H), 2.36-2.17 (m, 1H), 2.04-1.92 (m, 1H), 1.63 and 1.62 (s, 9H), 1.12 and 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 628.3 (M+1).

[0131] Compound 82: 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.6, 2.0 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 5.86 (s, 1H), 5.71 (s, 1H), 4.46-4.38 (m, 1H), 3.58-3.42 (m, 7H), 3.41-3.32 (m, 1H), 2.51-2.41 (m, 6H), 2.30 (s, 3H), 2.15-1.92 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 630.2 (M+1).

[0132] Compound 83: 1 H NMR (400 MHz, CDCl 3) δ 7.45 and 7.42 (t, J = 7.8 Hz, 1H), 7.22-7.16 (m, 1H), 7.16-7.10 (m, 1H), 6.65-6.35 (m, 1H), 6.24 and 6.21 (s, 1H), 4.56-4.42 (m, 3H), 4.24-3.53 (m, 9H), 3.47-3.24 (m, 4H), 3.22-2.86 (m, 6H), 2.50 (s, 3H), 2.31-2.18 (m, 1H), 2.13-2.01 (m, 1H), 1.44-1.36 (m, 3H). ESMS m / z: 630.3 (M+1).

[0133] Compound 84: 1 H NMR (300 MHz, CDCl 3 ) δ 7.44 (t, J = 7.8 Hz, 1H), 7.34 (s, 1H), 7.29-7.22 (m, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.93 (s, 1H), 6.48 (s, 1H), 4.57 (d, J = 13.0 Hz, 1H), 4.12-3.97 (m, 1H), 3.67-3.46 (m, 5H), 3.28-3.00 (m, 2H), 2.54-2.38 (m, 6H), 2.14 (d, J = 13.0 Hz, 1H), 2.04 (d, J = 13.0 Hz, 1H), 1.67-1.46 (m, 2H), 1.12 and 1.10 (t, J = 7.2 Hz, 3H). ESMS m / z: 529.2 (M+1).

[0134] Compound 85: 1 H NMR (300 MHz, CDCl 3) δ 7.45 (t, J = 7.8 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.08 (s, 1H), 5.99 (s, 1H), 4.80 (brs, 1H), 4.57 (d, J = 14.0 Hz, 1H), 4.10 - 3.94 (m, 1H), 3.60 (t, J = 5.2 Hz, 4H), 3.58 - 3.48 (m, 1H), 3.27 - 3.02 (m, 2H), 2.52 - 2.39 (m, 6H), 2.37 (s, 3H), 2.16 (d, J = 14.0 Hz, 1H), 2.05 (d, J = 14.0 Hz, 1H), 1.63 - 1.46 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H). ESMS m / z: 543.2 (M+1).

[0135] Compound 87: 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (t, J = 8.0 Hz, 1H), 7.31 - 7.24 (m, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.57 (brs, 1H), 5.82 (s, 1H), 5.49 (s, 1H), 4.91 (d, J = 13.0 Hz, 1H), 4.82 - 4.64 (m, 1H), 3.61 (d, J = 13.0 Hz, 1H), 3.56 (t, J = 4.9 Hz, 4H), 3.48 (q, J = 7.2 Hz, 2H), 3.31 - 3.03 (m, 1H), 2.92 - 2.79 (m, 1H), 2.52 - 2.40 (m, 6H), 2.27 (s, 3H), 1.94 (d, J = 13.0 Hz, 1H), 1.89 - 1.73 (m, 3H), 1.22 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H). ESMS m / z: 570.3 (M+1).

[0136] Compound 88: 1 H NMR (300 MHz, CDCl 3) δ 7.34 - 7.26 (m, 2H), 7.05 (t, J = 8.0 Hz, 1H), 6.65 (brs, 1H), 5.83 (s, 1H), 5.58 (s, 1H), 4.66 (brs, 1H), 3.85 - 3.70 (m, 1H), 3.61 (s, 2H), 3.55 (t, J = 4.8 Hz, 4H), 2.85 (d, J = 13.0 Hz, 2H), 2.51 - 2.38 (m, 6H), 2.27 (s, 3H), 2.23 (d, J = 13.0 Hz, 2H), 2.05 (d, J = 13.0 Hz, 2H), 1.63 - 1.43 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H). ESMS m / z: 528.3 (M+1).

[0137] Compound 89: 1 H NMR (400 MHz, CDCl 3 ) δ 7.44 (t, J = 8.0 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 5.84 (s, 1H), 5.31 (s, 1H), 4.57 (d, J = 13.0 Hz, 1H), 4.10 - 4.01 (m, 1H), 4.00 (t, J = 8.0 Hz, 2H), 3.81 (t, J = 8.0 Hz, 2H), 3.53 (d, J = 13.0 Hz, 1H), 3.28 - 3.02 (m, 3H), 2.27 (s, 3H), 2.22 - 2.12 (m, 7H), 2.09 - 1.96 (m, 1H), 1.68 - 1.48 (m, 2H). ESMS m / z: 528.2 (M+1).

[0138] Compound 90: 11H NMR (400 MHz, CDCl3) δ 7.45 (t, J = 7.5 Hz, 1H), 7.26-7.26 (m, 1H), 7.15 (t, J = 7.5 Hz, 1H), 5.85 (s, 1H), 5.68 (s, 1 H), 4.65-4.38 (m, 1H), 4.16-4.01 (m, 1H), 3.69 (m, 5 H), 3.48-3.05 (m, 2H), 2.47-2.44 (m. 4H), 2.33 (s, 3H), 2.30 (s, 3H), 2.18-2.03 (m, 2H), 1.30-1.26 (m, 2H). ESMS m / z: 528.2 (M+1).

[0139] Compound 91: 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (t, J = 7.4 Hz, 1H), 7.32-7.26 (m, 1H), 7.15 (t, J = 7.4 Hz, 1H), 5.84-5.68 (m. 2H), 4.65-4.40 (m, 2H), 4.08-3.98 (m, 2H), 3.61-3.39 (m, 8H), 3.34-2.98 (m, 2H), 2.27 (s, 3H), 2.16-2.02 (m, 1H), 1.41-1.38 (m, 2H). ESMS m / z: 514.2 (M+1).

[0140] Compound 92: 1 H NMR (400 MHz, CDCl 3) δ 7.44 (t, J = 7.6 Hz, 1H), 7.26 - 7.25 (m, 1H), 7.15 (t, J = 7.6 Hz, 1H), 5.84 (s, 1H), 5.68 (s, 1H), 4.57 (brs, 1H), 4.33 - 7.30 (m, 2H), 4.04 (brs, 1H), 3.56 - 3.52 (m, 2H), 3.27 - 3.17 (m, 4H), 2.77 (t, J = 12 Hz, 2H), 2.53 - 2.38 (m, 2H), 2.32 (s, 6H), 2.28 (s, 3H), 2.18 - 2.05 (m, 2H), 1.58 - 1.25 (m, 4H). ESMS m / z: 556.3 (M+1).

[0141] Compound 93: 1 H NMR (400 MHz, CDCl 3 ) δ 7.46 (t, J = 7.7 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.16 (t, J = 7.7 Hz, 1H), 5.86 (s, 1H), 5.67 (s, 1H), 4.64 - 4.10 (m, 2H), 3.80 - 3.62 (m, 6H), 3.38 - 3.05 (m, 2H), 2.34 (s, 3H), 2.22 - 2.12 (m, 4H), 2.10 (s, 3H), 2.05 - 1.98 (m, 1H), 1.44 - 1.21 (m, 2H). ESMS m / z: 556.3 (M+1).

[0142] Compound 94: 1 H NMR (400 MHz, CDCl 3) δ 7.44 (t, J = 7.6 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.15 (t, J = 7.6 Hz, 1H), 5.86 (s, 1H), 5.37 (s, 1H), 4.19 - 4.11 (m, 2H), 3.66 - 3.58 (m, 2H), 3.48 - 3.10 (m, 4H), 2.86 - 2.77 (m, 2H), 2.69 - 2.39 (m, 2H), 2.33 (s, 3H), 2.30 (s, 6H), 2.24 - 1.90 (m, 2H), 1.35 - 1.20 (m, 2H). ESMS m / z: 542.2 (M+1).

[0143] Compound 95: 1 H NMR (400 MHz, CDCl 3 ) δ 7.44 (t, J = 7.4 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.15 (t, J = 7.4 Hz, 1H), 5.86 (s, 1H), 5.51 (s, 1H), 4.63 - 4.51 (m, 2H), 4.08 - 3.98 (m, 2H), 3.70 - 3.49 (m, 4H), 3.31 - 3.01 (m, 2H), 3.00 (s, 3H), 2.50 - 2.46 (m, 2H), 2.30 (s, 6H), 2.28 (s, 3H), 2.19 - 2.04 (m, 1H). ESMS m / z: 530.3 (M+1).

[0144] Compound 96: 1 H NMR (400 MHz, CDCl 3) δ 7.45 (t, J = 8.0 Hz, 1H), 7.30 - 7.24 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 5.85 (s, 1H), 5.44 (s, 1H), 4.13 - 4.00 (m, 2H), 3.70 - 3.50 (m, 3H), 3.49 - 3.36 (m, 6H), 3.34 - 3.05 (m, 8H), 2.28 (s, 3H), 2.17 - 1.91 (m, 1H), 1.72 - 1.52 (m, 2H). ESMS m / z: 542.2 (M+1).

[0145] Compound 97: 1 H NMR (400 MHz, CD 3 OD) δ 7.60 (t, J = 7.8 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.29 (t, J = 7.8 Hz, 1H), 4.10 - 4.00 (m, 2H), 4.53 - 4.50 (m, 2H), 4.20 - 4.03 (m, 2H), 3.85 - 3.60 (m, 4H), 3.59 - 3.44 (m, 3H), 3.25 - 3.11 (m, 3H), 2.33 (s, 3H), 2.23 (s, 3H), 1.68 - 1.48 (m, 4H). ESMS m / z: 543.2 (M+1).

[0146] Compound 98: 1 H NMR (400 MHz, CD 3 OD) δ 7.59 (t, J = 7.8 Hz, 1H), 7.36 - 7.32 (m, 1H), 7.28 (t, J = 7.8 Hz, 1H), 5.78 (s, 1H), 5.39 (s, 1H), 4.53 - 4.50 (m, 2H), 4.11 - 3.98 (m, 2H), 3.68 (t, J = 8.0 Hz, 2H), 3.57 - 3.54 (m, 2H), 3.34 (s, 3H), 3.00 (s, 3H), 2.98 - 2.95 (m, 1H), 2.23 (s, 3H), 2.19 - 1.98 (m, 2H), 1.68 - 1.49 (m, 2H). ESMS m / z: 517.3 (M+1).

[0147] Compound 99: 1 H NMR (400 MHz, CD 3 OD) δ 7.61 (t, J = 8.0 Hz, 1H), 7.40 - 7.26 (m, 1H), 7.29 (t, J = 8.0 Hz, 1H), 5.76 (s, 1H), 5.12 (s, 1H), 4.59 - 4.55 (m, 1H), 4.39 - 4.28 (m, 3H), 3.96 - 3.93 (m, 2H), 3.59 - 3.55 (m, 2H), 3.34 (s, 3H), 3.24 - 3.16 (m, 2H), 2.29 (s, 3H), 2.19 - 2.04 (m, 2H), 1.67 - 1.57 (m, 2H). ESMS m / z: 515.2 (M+1).

[0148] Compound 100: 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (t, J = 8.0 Hz, 1H), 7.31 - 7.22 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 5.84 (s, 1H), 5.67 (s, 1H), 4.88 - 4.80 (m, 1H), 4.62 - 4.54 (m, 1H), 4.13 - 3.96 (m, 3H), 3.57 - 3.53 (m, 1H), 3.37 - 3.00 (m, 3H), 2.75 - 2.55 (m, 2H), 2.28 (s, 6H), 220 - 2.07 (m, 2H), 1.58 - 1.55 (m, 2H), 1.17 (d, J = 6.2 Hz, 6H). ESMS m / z: 556.2 (M+1).

[0149] Compound 101: 1 H NMR (400 MHz, CDCl 3) δ 7.44 (t, J = 8.0 Hz, 1H), 7.30 - 7.24 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 5.84 (s, 1H), 5.66 (s, 1H), 4.76 (brs, 1H), 4.58 (brs, 1H), 4.08 - 4.01 (m, 1H), 3.57 - 3.52 (m, 8H), 3.36 (s, 3H), 3.29 - 3.02 (m, 2H), 2.60 (t, J = 8.0 Hz, 2H), 2.54 - 2.52 (m, 4H), 2.28 (s, 3H), 2.20 - 2.04 (m, 2H), 1.50 - 1.36 (m, 2H). ESMS m / z: 572.3 (M+1).

[0150] Compound 102: 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (t, J = 8.0, 1H), 7.31 - 7.24 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 5.84 (s, 1H), 5.71 (s, 1H), 4.57 (brs, 1H), 4.13 - 4.04 (m, 3H), 3.57 - 3.49 (m, 1H), 3.32 - 3.07 (m, 2H), 2.92 - 2.80 (m, 2H), 2.38 (t, J = 8.0 Hz, 2H), 2.28 (s, 3H), 2.20 - 2.05 (m, 2H), 2.62 - 2.46 (m, 2H), 1.14 (d, J = 6.3 Hz, 6H). ESMS m / z: 542.2 (M+1).

[0151] Compound 103: 1 H NMR (400 MHz, CDCl 3) δ 7.45 (t, J = 8.0 Hz, 1H), 7.31 - 7.23 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 5.85 (s, 1H), 5.70 (s, 1H), 4.70 - 4.60 (m, 5H), 4.08 - 4.01 (m, 1H), 3.59 - 3.53 (m, 4H), 3.51 - 3.47 (m, 2H), 3.35 - 3.03 (m, 2H), 2.38 - 2.35 (m, 4H), 2.28 (s, 3H), 2.19 - 2.05 (m, 2H), 1.54 - 1.42 (m, 2H). ESMS m / z: 570.3 (M+1).

[0152] Compound 104: 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (t, J = 8.0 Hz, 1H), 7.32 - 7.23 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 5.98 - 5.74 (m, 1H), 5.58 - 5.25 (m, 1H), 4.89 - 4.72 (m, 1H), 4.62 - 4.59 (m, 1H), 4.32 - 4.11 (m, 1H), 4.14 - 3.99 (m, 1H), 3.47 - 3.49 (m, 2H), 3.46 - 3.38 (m, 2H), 3.49 - 3.34 (m, 4H), 3.23 (t, J = 8.0 Hz, 2H), 3.18 - 3.06 (m, 2H), 2.27 (s, 3H), 2.22 - 1.94 (m, 5H). ESMS m / z: 543.2 (M+1).

[0153] Compound 105: 1 H NMR (400 MHz, CD 3OD) δ 7.60 (t, J = 7.2 Hz, 1H), 7.33 - 7.26 (m, 2H), 5.76 (s, 1H), 5.51 (s, 1H), 4.54 - 4.51 (m, 1H), 4.00 - 3.95 (m, 1H), 3.55 - 3.41 (m, 5H), 3.35 - 3.31 (m, 4H), 3.19 - 2.98 (m, 2H), 2.33 (s, 3H), 2.14 - 1.92 (m, 4H), 1.64 - 1.38 (m, 4H). ESMS m / z: 543.2 (M+1).

[0154] Compound 106: 1 H NMR (400 MHz, CD 3 OD) δ 7.60 (t, J = 7.8 Hz, 1H), 7.38 - 7.31 (m, 1H), 7.29 (t, J = 7.8 Hz, 1H), 6.20 - 5.80 (m, 1H), 5.69 - 5.20 (m, 1H), 4.53 - 4.50 (m, 1H), 4.10 - 4.02 (m, 1H), 3.62 - 3.49 (m, 5H), 3.40 - 3.22 (m, 2H), 3.10 (q, J = 9.6 Hz, 2H), 2.71 - 2.69 (m, 4H), 2.23 (s, 3H), 2.17 - 2.01 (m, 2H), 1.60 - 1.58 (m, 2H). ESMS m / z: 596.3 (M+1).

[0155] Compound 107: 1 H NMR (600 MHz, CD 3OD) δ 7.59 (t, J = 8.0 Hz, 1H), 7.38-7.32 (m, 1H), 7.28 (t, J = 8.0 Hz, 1H), 6.25-5.88 (m, 1H) 5.70-5.43 (m, 1H), 4.54-4.48 (m, 1H), 4.08-4.01 (m, 1H), 3.57-3.52 (m, 1H), 3.25-3.19 (m, 4H), 2.91 (d, J = 8.0 Hz, 1H), 2.74-7.68 (m, 1H), 2.59 (d, J = 8.0 Hz, 1H), 2.39 (t, J = 8.0 Hz, 1H), 2.23 (s, 3H), 2.16-2.03 (m, 2H), 1.65-1.47 (m, 2H), 1.29-1.14 (m, 6H). ESMS m / z: 542.2 (M+1).

[0156] Compound 108: 1 H NMR (300 MHz, CD 3 OD) δ 7.78 (d, J = 5.4 Hz, 1H), 6.43-5.97 (m, 2H), 3.78-3.65 (m, 1H), 3.65-3.52 (m, 1H), 2.26 (s, 3H), 2.08 (d, J = 11.4 Hz, 2H), 1.99 (d, J = 11.4 Hz, 2H), 1.51-1.24 (m, 4H). ESMS m / z: 289.2 (M+1).

[0157] Compound 109: 1 H NMR (400 MHz, CD 3OD) δ 7.62 (td, J = 7.2, 1.8 Hz, 1H), 7.50 - 7.35 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 5.83 (s, 1H), 5.68 (s, 1H), 4.74 - 4.50 (m, 2H), 3.75 - 3.60 (m, 5H), 3.48 (t, J = 12.8 Hz, 2H), 3.44 - 3.34 (m, 1H), 3.34 - 3.23 (m, 4H), 3.15 (t, J = 12.8 Hz, 2H), 3.10 - 3.01 (m, 1H), 2.31 (s, 3H), 2.08 - 1.78 (m, 4H), 1.42 (t, J = 7.2 Hz, 3H), 1.41 - 1.33 (m, 3H). ESMS m / z: 570.2 (M+1).

[0158] Compound 110: 1 H NMR (300 MHz, CD 3 OD) δ 8.09 - 7.75 (m, 1H), 7.72 - 7.61 (m, 2H), 7.34 (t, J = 8.0 Hz, 1H), 6.61 - 6.30 (m, 2H), 4.53 (s, 2H), 4.32 - 4.00 (m, 1H), 3.68 (d, J = 12.0 Hz, 2H), 3.58 - 3.47 (m, 1H), 3.36 (d, J = 12.0 Hz, 1H), 2.42 (s, 3H), 2.38 - 2.15 (m, 2H), 2.12 - 1.89 (m, 2H). ESMS m / z: 416.2 (M+1).

[0159] Compound 111: 1 H NMR (300 MHz, CDCl 3) δ 7.39 - 7.27 (m, 2H), 7.06 (t, J = 7.8 Hz, 1H), 6.70 (brs, 1H), 6.04 (s, 1H), 5.94 (s, 1H), 4.70 - 4.55 (m, 1H), 3.65 (s, 2H), 3.05 (s, 3H), 3.01 (d, J = 11.0 Hz, 2H), 2.28 (s, 3H), 2.27 - 2.17 (m, 5H), 1.95 - 1.77 (m, 2H), 1.76 - 1.64 (m, 2H). ESMS m / z: 444.2 (M+1).

[0160] Compound 112: 1 H NMR (300 MHz, CD 3 OD) δ 7.84 - 7.64 (m, 5H), 6.22 - 6.04 (m, 2H), 4.65 - 4.47 (m, 1H), 4.12 - 3.99 (m, 1H), 3.76 - 3.59 (m, 1H), 3.37 - 3.05 (m, 2H), 2.27 (s, 3H), 2.23 - 1.94 (m, 2H), 1.70 - 1.42 (m, 2H). ESMS m / z: 446.2 (M+1).

[0161] Compound 113: 1 H NMR (300 MHz, CD 3 OD) δ 7.81 (d, J = 6.0 Hz, 1H), 7.44 - 7.33 (m, 1H), 7.32 - 7.24 (m, 1H), 7.23 - 7.13 (m, 1H), 6.32 - 5.90 (m, 2H), 4.59 (d, J = 13.5 Hz, 1H), 4.14 - 3.97 (m, 1H), 3.59 (d, J = 13.5 Hz, 1H), 3.30 - 3.09 (m, 2H), 2.26 (s, 3H), 2.17 (d, J = 13.5 Hz, 1H), 2.03 (d, J = 13.5 Hz, 1H), 1.72 - 1.42 (m, 2H). ESMS m / z: 414.2 (M+1).

[0162] Compound 114: 11H NMR (400 MHz, CDCl 3 ) δ 7.25 - 7.09 (m, 3H), 6.12 (s, 1H), 6.05 (s, 1H), 4.57 (d, J = 14.0 Hz, 1H), 4.16 - 4.03 (m, 1H), 3.57 (d, J = 14.0 Hz, 1H), 3.29 - 3.07 (m, 2H), 2.31 (s, 3H), 2.23 (s, 3H), 2.19 (d, J = 11.6 Hz, 1H), 2.06 (d, J = 11.6 Hz, 1H), 1.66 - 1.38 (m, 2H). ESMS m / z: 428.2 (M+1).

[0163] Compound 115: 1 1H NMR (400 MHz, CDCl 3 ) δ 9.97 (brs, 1H), 7.45 (d, J = 3.8 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.08 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 3.8 Hz, 1H), 5.88 (s, 1H), 4.88 - 4.77 (m, 1H), 3.67 (s, 2H), 3.14 (s, 3H), 3.02 (d, J = 11.0 Hz, 2H), 2.35 - 2.24 (m, 5H), 1.96 - 1.83 (m, 2H), 1.80 - 1.70 (m, 2H). ESMS m / z: 447.2 (M+1).

[0164] Compound 116: 11H NMR (400 MHz, DMSO-d6) δ 7.49 (t, J = 7.8 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.22 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 3.6 Hz, 1H), 6.97 (brs, 1H), 6.01 (s, 1H), 3.97 - 3.83 (m, 1H), 3.57 (s, 2H), 2.83 (d, J = 11.6 Hz, 2H), 2.20 - 2.13 (m, 2H), 2.12 (s, 3H), 1.96 - 1.83 (m, 2H), 1.56 - 1.42 (m, 2H). ESMS m / z: 433.2 (M+1).

[0165] Compound 117: 1 H NMR (300 MHz, CD 3 OD) δ 7.79 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 6.41 - 5.88 (m, 2H), 4.16 (d, J = 13.5 Hz, 2H), 4.12 - 3.99 (m, 1H), 3.12 (t, J = 11.7 Hz, 2H), 2.27 (s, 3H), 2.19 (s, 3H), 2.11 (d, J = 13.0 Hz, 1H), 1.61 - 1.45 (m, 2H). ESMS m / z: 475.2 (M+1).

[0166] Compound 118: 1 H NMR (300 MHz, CD 3OD) δ 7.81 (d, J = 6.0 Hz, 1H), 7.63 and 7.62 (dd, J = 7.8, 1.8 Hz, 1H), 7.42 and 7.41 (t, J = 7.8 Hz, 1H), 7.34 and 7.29 (dd, J = 7.8, 1.8 Hz, 1H), 6.39 - 5.83 (m, 2H), 4.66 - 4.52 (m, 1H), 4.11 - 3.95 (m, 1H), 3.52 - 3.37 (m, 1H), 3.29 - 3.06 (m, 2H), 2.26 (s, 3H), 2.17 (d, J = 14.0 Hz, 1H), 2.00 (d, J = 14.0 Hz, 1H), 1.72 - 1.36 (m, 2H). ESMS m / z: 446.1 (M+1).

[0167] Compound 119: 1 H NMR (300 MHz, CD 3 OD) δ 7.47 - 7.31 (m, 2H), 7.15 (td, J = 7.8, 1.2 Hz, 1H), 6.39 - 6.15 (s, 1H), 6.13 - 5.85 (s, 1H), 3.86 - 3.71 (m, 1H), 3.68 (s, 2H), 2.92 (d, J = 11.7 Hz, 2H), 2.38 - 2.25 (m, 2H), 2.24 (s, 3H), 2.16 (s, 3H), 2.04 (d, J = 11.7 Hz, 2H), 1.70 - 1.50 (m, 2H). ESMS m / z: 430.2 (M+1).

[0168] Compound 120: 1 H NMR (400 MHz, CDCl 3) δ 7.45 (t, J = 7.8 Hz, 1H), 7.30 - 7.24 (m, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.12 (s, 1H), 6.04 (s, 1H), 5.15 (brs, 1H), 4.59 (d, J = 14.0 Hz, 1H), 4.15 - 4.04 (m, 1H), 3.54 (d, J = 14.0 Hz, 1H), 3.30 - 3.04 (m, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 2.19 (d, J = 14.0 Hz, 1H), 2.07 (d, J = 14.0 Hz, 1H), 1.63 - 1.49 (m, 2H). ESMS m / z: 444.1 (M+1).

[0169] Compound 121: 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 and 7.47 (dd, J = 7.8, 1.2 Hz, 1H), 7.29 - 7.15 (m, 2H), 6.11 and 6.10 (s, 1H), 6.04 and 6.02 (s, 1H), 5.44 and 5.29 (brs, 1H), 4.65 - 4.51 (m, 1H), 4.15 - 4.01 (m, 1H), 3.50 - 3.37 (m, 1H), 3.27 - 3.06 (m, 2H), 2.30 and 2.29 (s, 3H), 2.26 - 2.15 (m, 4H), 2.09 - 1.97 (m, 1H), 1.67 - 1.29 (m, 2H). ESMS m / z: 460.1 (M+1).

[0170] Compound 124: 1 H NMR (400 MHz, CDCl 3) δ 9.95 (broad singlet, 1H), 7.45 (triplet, J = 7.8 Hz, 1H), 7.31 - 7.25 (multiplet, 1H), 7.15 (triplet, J = 7.8 Hz, 1H), 6.56 (singlet, 1H), 5.32 (singlet, 1H), 4.72 (broad singlet, 1H), 4.58 (doublet, J = 12.8 Hz, 1H), 4.11 - 4.00 (multiplet, 1H), 3.86 (septet, J = 6.8 Hz, 1H), 3.62 - 3.47 (multiplet, 5H), 3.32 - 3.00 (multiplet, 2H), 2.47 (triplet, J = 4.8 Hz, 4H), 2.44 (quartet, J = 7.2 Hz, 2H), 2.25 (singlet, 3H), 2.24 - 2.17 (multiplet, 1H), 2.06 (doublet, J = 12.8 Hz, 1H), 1.64 - 1.48 (multiplet, 2H), 1.26 (doublet, J = 6.8 Hz, 6H), 1.11 (triplet, J = 7.2 Hz, 3H). ESMS m / z: 612.3 (M+1).

[0171] Compound 125: 1 H NMR (400 MHz, CDCl 3 ) δ 9.89 (broad singlet, 1H), 7.45 (triplet, J = 7.8 Hz, 1H), 7.31 - 7.25 (multiplet, 1H), 7.15 (triplet, J = 7.8 Hz, 1H), 6.56 (singlet, 1H), 5.33 (singlet, 1H), 4.73 (broad singlet, 1H), 4.63 (doublet, J = 12.4 Hz, 1H), 4.12 - 4.00 (multiplet, 1H), 3.64 - 3.48 (multiplet, 5H), 3.33 - 3.02 (multiplet, 4H), 2.48 (triplet, J = 4.8 Hz, 4H), 2.44 (quartet, J = 7.2 Hz, 2H), 2.29 - 2.17 (multiplet, 4H), 2.09 (doublet, J = 12.4 Hz, 1H), 1.83 - 1.71 (multiplet, 2H), 1.65 - 1.47 (multiplet, 2H), 1.11 (triplet, J = 7.2 Hz, 3H), 1.02 (triplet, J = 7.4 Hz, 3H). ESMS m / z: 612.3 (M+1).

[0172] Compound 126: 1 H NMR (400 MHz, CDCl 3 ) δ 9.93 (brs, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.59 (s, 1H), 5.30 (s, 1H), 4.72 (brs, 1H), 4.63 (d, J = 12.0 Hz, 1H), 4.12 - 4.00 (m, 1H), 3.62 - 3.47 (m, 5H), 3.19 - 3.03 (m, 2H), 2.51 - 2.40 (m, 6H), 2.28 (s, 3H), 2.22 (d, J = 13.0 Hz, 1H), 2.10 (d, J = 13.0 Hz, 1H), 1.66 - 1.51 (m, 3H), 1.25 - 1.20 (m, 2H), 1.16 - 1.07 (m, 5H). ESMS m / z: 610.3 (M+1).

[0173] Compound 127: 1 H NMR (300 MHz, CDCl 3 ) δ 9.32 (brs, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.30 - 7.22 (m, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.55 (s, 1H), 5.34 (s, 1H), 4.77 (brs, 1H), 4.61 (d, J = 12.3 Hz, 1H), 4.50 (q, J = 7.3 Hz, 2H), 4.12 - 3.97 (m, 1H), 3.62 - 3.41 (m, 5H), 3.32 - 2.99 (m, 2H), 2.47 (t, J = 4.7 Hz, 4H), 2.43 (q, J = 7.1 Hz, 2H), 2.26 (s, 3H), 2.20 (d, J = 15.0 Hz, 1H), 2.08 (d, J = 12.3 Hz, 1H), 1.64 - 1.47 (m, 2H), 1.46 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H). ESMS m / z: 614.3 (M+1).

Example

[0174] Example 2 In Vitro Inhibition of Aurora A Kinase Activity The effectiveness of 75 compounds of formula (I) in the inhibition of Aurora A kinase activity in vitro was evaluated using the Kinase-Glo® Luminescent Kinase assay (Promega, USA) as described below. These 75 compounds are Compound 1, 2, 8, 12-17, 19-41, 43-44, 47-50, 54, 58, 62-63, 65, 86-90, 92-97, 99-104, 106-107, 109-111, 113-116 and 118-123.

[0175] Recombinant glutathione S-transferase (GST) tag N-terminal truncated human Aurora A (amino acids 123-401) was expressed in Sf9 insect cells and purified by glutathione affinity chromatography to obtain recombinant Aurora A. Recombinant Aurora A (150 ng) was added to 50 μL of 50 mM Tris-HCl pH 7.4, 10 mM NaCl, 10 mM MgCl 2 , 0.01% bovine serum albumin, 5.0 μM ATP, 1 mM dithiothreitol, 15 μM tetra(-LRRASLG) peptide, and reacted with each test compound (100 nM) at 37 °C for 120 minutes. Then, 50 μL of Kinase-Glo Plus Reagent was added to the reaction. The resulting mixture was incubated at 25 °C for 20 minutes. A 70 μL aliquot of the mixture was transferred to a black microtiter plate. Luminescence was measured using a Wallac Vector 1420 multilabel counter (PerkinElmer, USA).

[0176] As shown in Table 1, each test compound showed an IC 50 value of less than 100 nM.

[0177] These results indicate that the compounds of formula (I) have high in vitro efficacy in the inhibition of aurora A kinase activity. [Table 1] JPEG0007691991000019.jpg216146JPEG0007691991000020.jpg215144JPEG0007691991000021.jpg135144 [Examples]

[0178] Example 3 Decrease in cMYC and MYCN protein levels in cMYC / MYCN amplified cancer cells Compounds 41 and 86, both encompassed by formula (I), were tested for their efficacy in decreasing the level of cMYC oncoprotein in the human small cell lung cancer ("SCLC") cell line NCI-H82 (ATCC® HTB-175, USA) and the level of MYCN oncoprotein in the human neuroblastoma cell line SK-N-BE(2) (ATCC® CRL-2271, USA) as follows.

[0179] NCI-H82 was maintained in RPMI 1640 medium (ThermoFisher Scientific, USA) supplemented with 10% fetal bovine serum (FBS, HyClone, USA) and antibiotics. SK-N-BE(2) was maintained in minimum essential medium (MEM, ThermoFisher Scientific, USA) supplemented with 10% FBS (HyClone, USA) and antibiotics. Cancer cells from each cell line were treated with each of compounds 41 and 86 at four different compound concentrations, namely 50 nM, 200 nM, 500 nM, and 1000 nM. After 24 hours, each cancer cell solution was washed with 1× phosphate-buffered saline (PBS), lysed in 1× Laemmli protein sample buffer, and boiled at 100 °C for 10 minutes. Each lysate was separated by SDS-PAGE, transferred to a polyvinylidene fluoride (PVDF, Millipore, USA) membrane, and blotted with antibodies. The primary antibodies used for Western blotting were cMYC (Cell Signaling, Cat No. 5605S), MYCN (Cell Signaling, 9405S), PARP-1 (Abcam, ab32378), and GAPDH (Genetex, GTX100118). After blotting with the primary antibody, the membrane was washed with 1× blotting buffer (0.2% casein in 1× PBS), and the corresponding alkaline phosphatase-conjugated secondary antibody (Sigma-Aldrich) was added. The blot was developed by chemiluminescence (PerkinElmer, USA). Cleaved PARP1 (cPARP-1) served as an indicator of cell apoptosis, and GAPDH was used as a control.

[0180] As shown in Figure 1, compounds 41 and 86 significantly decreased the protein levels of cMYC and MYCN in two types of human cancer cells, namely SCLC and neuroblastoma.

[0181] These results indicate that the compounds of formula (I) have high in vitro efficacy in reducing the protein levels of cMYC and MYCN in cancer cells.

Example

[0182] Example 4 Small Cell Lung Cancer Cell Proliferation Inhibition Assay The efficacy of 74 compounds of formula (I) in inhibiting cancer cell proliferation was determined using PrestoBlue™ Cell Viability Reagent (ThermoFisher Scientific, USA). These 74 compounds are Compounds 1-2, 8-10, 12-19, 21-22, 25-27, 31-32, 35-41, 43-44, 47-50, 54, 62-63, 65, 70-75, 78-83, 86, 88-90, 92-107, 122-125 and 127.

[0183] Small cell lung cancer cells NCI-H82 (ATCC® HTB-175, cMYC amplified), NCI-H446 (ATCC® HTB-171, cMYC amplified) and NCI-H69 (ATCC® HTB-119, MYCN amplified) were seeded in 96-well plates at a density of 5000-10000 cells per well. After 24 hours, the cancer cells were treated with each compound at various concentrations (0-10 μM) and further incubated for 72 hours. IC 50 values were calculated based on a double 8-point titration.

[0184] As shown in Table 2, each test compound showed an IC 50 value of less than 1.0 μM in one or more of the three types of small cell lung cancer cells.

[0185] These results indicate that the compounds of formula (I) have high in vitro efficacy in inhibiting the proliferation of small cell lung cancer cells. [Table 2] JPEG0007691991000023.jpg166156 JPEG0007691991000024.jpg183155 JPEG0007691991000025.jpg105155

Example

[0186] Example 5 Assay for Inhibiting Proliferation of Various Cancer Cells The effectiveness of Compounds 41 and 86 of formula (I) in inhibiting the proliferation of 11 types of cancer cells was determined using PrestoBlue™ Cell Viability Reagent (ThermoFisher Scientific, USA). The 11 types of cancer cells were small cell lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, breast cancer, colon cancer, prostate cancer, neuroblastoma, brain cancer, leukemia, and cholangiocarcinoma.

[0187] More specifically, 11 cancer cell lines, namely, NCI-H82 (ATCC® HTB-175), NCI-H446 (ATCC® HTB-171), NCI-H69 (ATCC® HTB-119), NCI-H146 (ATCC® HTB-173), NCI-H1792 (ATCC® CRL-5895), NCI-H1299 (ATCC® CRL-5803), SNU-398 (ATCC® CRL-2233), PSN-1 (ATCC® CRL-3211), MIA PaCa-2 (ATCC® CRL-1420), MDA-MB-231 (ATCC® HTB-26), LOVO (ATCC® CCL-229), COLO205 (ATCC® CCL-222), PC-3 (ATCC® CRL-1435), SK-N-BE(2) (ATCC® CRL-2271), D341 Med (ATCC® HTB-187), K562 (ATCC® CCL-243), MOLM-13 (DSMZ - German Collection of Microorganisms and Cell Cultures, ACC No. 554), and SNU-478 (KCLB 00478) were seeded in 96-well plates at a density of 4000 - 10000 cells per well for 24 hours. Then, the cancer cells were treated with each compound at various concentrations (0 - 10 μM) and subsequently incubated for an additional 72 hours. IC50 The value was calculated based on a double 8-drop titration.

[0188] As shown in Table 3, both Compound 41 and Compound 86 unexpectedly showed IC 50 values of less than 10.0 μM in the inhibition of the growth of all 11 types of cancer cells. More specifically, these two compounds unexpectedly showed (i) IC values of less than 0.2 μM in the inhibition of the growth of cells of small cell lung cancer, liver cancer, neuroblastoma, brain cancer, and leukemia, (ii) IC values of less than 0.3 μM in the inhibition of the growth of breast cancer cells, (iii) IC values of less than 1.0 μM in the inhibition of the growth of cells of non-small cell lung cancer, pancreatic cancer, and colon cancer, (iv) IC values of less than 2.0 μM in the inhibition of the growth of cholangiocarcinoma cells, and (v) IC 50 values of less than 10.0 μM in the inhibition of the growth of prostate cancer cells.

[0189] These results indicate that Compounds 41 and 86 have high in vitro anti-cancer efficacy. [Table 3]

Example

[0190] Example 6 Inhibition of Xenograft Tumor Growth in Mice The efficacy of two compounds of formula (I), namely Compound 71 and Compound 122, in inhibiting tumor growth was determined as follows using an NCI-H446 xenograft tumor-bearing mouse model.

[0191] Six-week-old male athymic nu / nu nude mice (BioLASCO, Taiwan) were housed in a sterile cage maintained at a controlled temperature and humidity with a 12-hour light / dark cycle. Resuspended in physiological saline mixed with 50% Metrigel Matrix (Corning, USA), 1×10 6Individual NCI-H446 cells (ATCC® HTB-171) were subcutaneously inoculated into mice. The size of the xenografted tumors was measured with a digital caliper (GMC-190, Goldsun Electronics), and the tumor volume (mm 3 ) = length × (width) 2 / 2 algorithm was used for calculation. Body weight and tumor size were measured at least twice a week. When the xenografted tumors reached a size of 200 mm 3 or more, compound 71, compound 122, reference compound MLN8237 (structure shown below) and reference compound LY3295668 (also structure shown below) were orally administered to mice at a dose of 100 mg / kg and a dosing regimen of 5 days on and 2 days off over 2 - 4 weeks, together with mice treated with vehicle as a control.

Chem.

Chem.

[0192] As shown in Figures 2A and 2C, unexpectedly, compound 71 at 100 mg / kg substantially reduced the tumor size in mice from approximately 250 mm 3 to less than 50 mm 3 in 10 days and from more than 750 mm 3 to less than 50 mm 3 in 14 days. These results indicate that compound 71 unexpectedly induced a tumor regression of more than 80%.

[0193] As also shown in Figure 2A, unexpectedly, compound 71 showed much higher efficacy than the reference compound MCLN8237. Both compounds at 100 mg / kg reduced the tumor size from approximately 250 mm 3 to less than 50 mm 3 in 10 days, but in mice treated with compound MCLN8237, 700 mm 3Compared to the tumor size that increased extremely, the tumor size in the mice treated with Compound 71 remained less than 50 mm. 3 It remained less than.

[0194] Figure 2B shows that Compound 122 unexpectedly induced tumor regression exceeding 80% and much higher efficacy than the reference compound LY3295668. Specifically, Compound 122 at 100 mg / kg substantially reduced the tumor size from about 250 mm 3 to less than 50 mm, 3 whereas Compound LY3295668 at 100 mg / kg increased the tumor size from about 250 mm 3 to more than 350 mm. 3 It increased beyond.

[0195] The above results indicate that the compounds of formula (I) have unexpectedly high in vivo efficacy in inhibiting tumor growth.

Example

[0196] Example 7 In Vivo Reduction of cMYC Protein Level and Induction of Cell Apoptosis The efficacy of the compounds of formula (I), namely Compound 71, in reducing cMYC protein level and inducing cell apoptosis was evaluated as follows using an NCI-H446 xenograft tumor-bearing mouse model.

[0197] Six-week-old male athymic nu / nu nude mice (BioLASCO, Taiwan) were housed in sterile cages maintained at a controlled temperature and humidity with a 12-hour light / dark cycle. 1×10 6 cells of NCI-H446 resuspended in physiological saline mixed with 50% Metrigel Matrix (Corning, USA) were subcutaneously inoculated into the mice. The size of the xenografted tumors was measured with a digital caliper (GMC-190, Goldsun Electronics), and the tumor volume (mm 3 ) = length × (width) 2Calculations were performed using the algorithm of / 2. Body weight and tumor size were measured at least twice a week. The xenografted NCI-H446 tumors reached 500 mm 3 or more in size, and the xenografted tumor-bearing nude mice were orally (PO) administered Compound 71 at a single dose of 100 mg / kg. Tumors were harvested at 2 hours, 4 hours, 8 hours, and 24 hours after administration. Tumor lysates were subjected to Western blot analysis. The primary antibodies used were cMYC (Cell Signaling, Cat No. 5605S), PARP-1 (Abcam, ab32378), and β-ACTIN (Sigma-Aldrich, A1978).

[0198] As shown in Figure 3 below, Compound 71 significantly induced cell apoptosis, as indicated by an increase in the amount of cleaved PARP-1 (cPARP-1) in more than 80% of the xenografted tumors 24 hours after administration of Compound 71. Furthermore, Compound 71 decreased the cMYC protein level in more than 50% of the xenografted tumors.

[0199] Other embodiments All features disclosed in this specification can be combined in any combination. Each feature disclosed in this specification may be replaced by alternative features that serve the same, equivalent, or similar purpose. Thus, unless otherwise specified, each feature disclosed is only an example of a general series of equivalent or similar features.

[0200] From the above description, those skilled in the art can easily identify the essential features of the present invention and make various changes and modifications to the present invention without departing from its spirit and scope, and adapt it to various uses and conditions. For example, compounds structurally similar to the compounds of this invention can also be prepared and screened for their effectiveness in the treatment of conditions related to cells containing phosphatidylserine with an inverted surface. Thus, other embodiments are also within the scope of the claims.

[0201] REFERENCES 1. Carmena, M., and Earnshaw, W. C. (2003) The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 4, 842-854 2. Lens, S. M., Voest, E. E., and Medema, R. H. (2010) Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer 10, 825-841 3. Fu, J., Bian, M., Jiang, Q., and Zhang, C. (2007) Roles of Aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 5, 1-10 4. Agnese, V., Bazan, V., Fiorentino, F. P., Fanale, D., Badalamenti, G., Colucci, G., Adamo, V., Santini, D., and Russo, A. (2007) The role of Aurora-A inhibitors in cancer therapy. Ann Oncol 18 Suppl 6, vi47-52 5. Tatsuka, M., Katayama, H., Ota, T., Tanaka, T., Odashima, S., Suzuki, F., and Terada, Y. (1998) Multinuclearity and increased ploidy caused by overexpression of the aurora- and Ipl1-like midbody-associated protein mitotic kinase in human cancer cells. Cancer Res 58, 4811-4816 6. Kollareddy, M., Zheleva, D., Dzubak, P., Brahmkshatriya, P. S., Lepsik, M., and Hajduch, M. (2012) Aurora kinase inhibitors: progress towards the clinic. Invest New Drugs 30, 2411-2432 7. Anand, S., Penrhyn-Lowe, S., and Venkitaraman, A. R. (2003) Aurora-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 3, 51-62 8. Glover, D. M., Leibowitz, M. H., McLean, D. A., and Parry, H. (1995) Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 81, 95-105 9. Terada, Y., Uetake, Y., and Kuriyama, R. (2003) Interaction of Aurora-A and centrosomin at the microtubule-nucleating site in Drosophila and mammalian cells. J Cell Biol 162, 757-763 10. Zeitlin, S. G., Shelby, R. D., and Sullivan, K. F. (2001) CENP-A is phosphorylated by Aurora B kinase and plays an unexpected role in completion of cytokinesis. J Cell Biol 155, 1147-1157 11. Uren, A. G., Wong, L., Pakusch, M., Fowler, K. J., Burrows, F. J., Vaux, D. L., and Choo, K. H. (2000) Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype. Curr Biol 10, 1319-1328 12. Hanson, K. K., Kelley, A. C., and Bienz, M. (2005) Loss of Drosophila borealin causes polyploidy, delayed apoptosis and abnormal tissue development. Development 132, 4777-4787 13. Wilkinson, R. W., Odedra, R., Heaton, S. P., Wedge, S. R., Keen, N. J., Crafter, C., Foster, J. R., Brady, M. C., Bigley, A., Brown, E., Byth, K. F., Barrass, N. C., Mundt, K. E., Foote, K. M., Heron, N. M., Jung, F. H., Mortlock, A. A., Boyle, F. T., and Green, S. (2007) AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res 13, 3682-3688 14. Koh, C. M., Sabo, A., and Guccione, E. (2016) Targeting MYC in cancer therapy: RNA processing offers new opportunities. Bioessays 38, 266-275 15. Dang, C. V. (2013) MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb Perspect Med 3 16. Brockmann, M., Poon, E., Berry, T., Carstensen, A., Deubzer, H. E., Rycak, L., Jamin, Y., Thway, K., Robinson, S. P., Roels, F., Witt, O., Fischer, M., Chesler, L., and Eilers, M. (2013) Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma. Cancer Cell 24, 75-89 17. Dauch, D., Rudalska, R., Cossa, G., Nault, J. C., Kang, T. W., Wuestefeld, T., Hohmeyer, A., Imbeaud, S., Yevsa, T., Hoenicke, L., Pantsar, T., Bozko, P., Malek, N. P., Longerich, T., Laufer, S., Poso, A., Zucman-Rossi, J., Eilers, M., and Zender, L. (2016) A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med 22, 744-753 18. Lee, J. K., Phillips, J. W., Smith, B. A., Park, J. W., Stoyanova, T., McCaffrey, E. F., Baertsch, R., Sokolov, A., Meyerowitz, J. G., Mathis, C., Cheng, D., Stuart, J. M., Shokat, K. M., Gustafson, W. C., Huang, J., and Witte, O. N. (2016) N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells. Cancer Cell 29, 536-547

Claims

1. A compound of formula (I), wherein 【Chemical 1】 A is CH or N, R １ is C １－６ alkyl, C １－６ alkoxyl, C ３－１０ cycloalkyl, aryl or heteroaryl, and R ２ is a C １－１０ heterocycloalkyl, and R ３ is C １－６ alkyl, C １－６ alkoxyl, C ３－１０ cycloalkyl, C ７－１２ aralkyl, C １－１２ heteroaralkyl, -C(O)R ８ or -S(O) ２ R ８ where R ８ is aryl or heteroaryl, R ４ is H or C １－６ alkyl, each of m and n is independently 1 or 2, C １－６ alkyl, C １－６ alkoxyl, C ３－１０ cycloalkyl, C １－１０ heterocycloalkyl, C ７－１２ aralkyl, C １－１２ each of heteroaralkyl, aryl and heteroaryl is unsubstituted or independently halo, OH, CN, NH ２ , NO ２ , C １－６ alkyl, C １－６ haloalkyl, C ３－１３ cycloalkyl, C ２－８ heterocycloalkyl, C １－６ alkoxyl, C １－６ haloalkoxyl, C １－６ alkylamino, C ２－６ dialkylamino, C ７－１２ aralkyl, C １－１２ heteroaralkyl, aryl, heteroaryl, -C(O)R ９ , -C(O)OR ９ or -C(O)NR ９ R １０ is mono-, di- or tri-substituted with, R ９ and each of R １０ is independently H, halo, OH, CN, COOH, acetyl, acetamide, dialkylamino, alkylamino, C １－６ alkyl, C １－６ multi-haloalkyl, C １－６ alkoxyl, C １－６ multi-haloalkoxyl, C ３－８ cycloalkyl, C １－１０ heterocycloalkyl, aryl or heteroaryl, a compound.

2. The compound according to claim 1, wherein the sum of m and n is 3 and A is N.

3. R １ is C ３－１０ The compound according to claim 2, which is cycloalkyl or 5-membered heteroaryl.

4. R ２ is [Chemical 2] The compound according to claim 3, wherein

5. R ３ is C ７－１２ alkyl, -C(O)R ８ or -S(O) ２ R ８ The compound according to claim 4, wherein

6. The compound according to claim 5, which is one of the following compounds. [Chemical Formula 3] 【Chemical 4】 【Chemical Formula 5】

7. R ３ is C ７－１２ alkyl, -C(O)R ８ or -S(O) ２ R ８ The compound according to claim 3, wherein

8. R ２ is 【Chemical Formula 6】 The compound according to claim 2, wherein

9. R ３ is C ７－１２ alkyl, -C(O)R ８ or -S(O) ２ R ８ The compound according to claim 2, wherein it is

10. R ２ is 【Chemical Formula 7】 The compound according to claim 9, wherein

11. The compound according to claim 1, wherein each of m and n is 2 and A is N.

12. R １ is C ３－１０ cycloalkyl or 5-membered heteroaryl, the compound according to claim 11.

13. R ２ is [Chemical Formula 8] The compound according to claim 12, wherein

14. R ３ is C ７－１２ alkyl, -C(O)R ８ or -S(O) ２ R ８ The compound according to claim 13, wherein it is

15. The compound according to claim 14, which is one of the following compounds. 【Chemical Formula 9】 【Chemical 10】

16. R ３ is C ７－１２ aralkyl, -C(O)R ８ or -S(O) ２ R ８ The compound according to claim 12, wherein it is

17. R ２ is 【Chemical Formula 11】 The compound according to claim 11, wherein

18. R ３ is C ７－１２ alkyl, -C(O)R ８ or -S(O) ２ R ８ The compound according to claim 11, wherein

19. R ２ is 【Chemical Formula 12】 The compound according to claim 18, wherein

20. R ４ The compound according to claim 1, wherein R is H.

21. The compound according to claim 1, which is one of the following compounds. 【Chemical 13】 【Chemical 14】 【Chemical Formula 15】 【Chemical 16】 【Chemical 17】 【Chemical Formula 18】 【Chemical Formula 19】 【Chemical 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】

22. Use of the compound according to claim 1 in the manufacture of a medicament for treating cancer.

23. The use according to claim 22, wherein the cancer is leukemia, lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer or neuroblastoma.

24. The use according to claim 22, wherein the compound is the compound according to claim 2.

25. The use according to claim 24, wherein the cancer is leukemia, lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer or neuroblastoma.

26. The use according to claim 22, wherein the compound is the compound according to claim 11.

27. The use according to claim 26, wherein the cancer is leukemia, lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer or neuroblastoma.

28. The use according to claim 22, wherein the cancer is liver cancer, brain cancer or bile duct cancer.

29. The use according to claim 24, wherein the cancer is liver cancer, brain cancer or bile duct cancer.

30. The use according to claim 26, wherein the cancer is liver cancer, brain cancer or bile duct cancer.

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