Fused bicyclic heteroaromatic derivatives as modulators of TNF activity

Abstract

A series of substituted heteroaromatic compounds containing two fused six-membered rings, tivity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

Claims

1. A compound represented by formula (IIB), or a pharmaceutically acceptable salt thereof: ##STR00036## wherein V represents C—R.sup.22 or N; R.sup.21 represents hydroxy(C.sub.1-6)alkyl or R.sup.21 represents (C.sub.3-7)cycloalkyl, which group is optionally substituted by one, two, or three substituents independently selected from halogen, halo(C.sub.1-6)alkyl, cyano, C.sub.1-6 alkyl, trifluoromethyl, hydroxy, hydroxy(C.sub.1-6)alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulphinyl, C.sub.1-6 alkylsulphonyl, amino, C.sub.1-6 alkylamino, di(C.sub.1-6)alkylamino, C.sub.2-6 alkylcarbonylamino, (C.sub.2-6)alkylcarbonylamino(C.sub.1-6)alkyl, C.sub.2-6 alkoxycarbonylamino, (C.sub.2-6)alkoxycarbonylamino-(C.sub.1-6)alkyl, C.sub.1-6 alkyl sulphonylamino, (C.sub.1-6)alkyl-sulphonylamino(C.sub.1-6)alkyl, formyl, C.sub.2-6 alkylcarbonyl, carboxy, carboxy(C.sub.1-6)alkyl, C.sub.2-6 alkoxycarbonyl, C.sub.2-6 alkoxycarbonyl(C.sub.1-6)alkyl, aminosulphonyl, (C.sub.1-6)alkylsulphoximinyl, [(C.sub.1-6)alkyl][N—(C.sub.1-6)alkyl]sulphoximinyl, (C.sub.1-6)alkylsulphonylaminocarbonyl, (C.sub.2-6)alkylcarbonyl-aminosulphonyl, (C.sub.1-6)alkoxyaminocarbonyl, tetrazolyl and hydroxyoxadiazolyl; R.sup.22 represents hydrogen, halogen or C.sub.1-6 alkyl; R.sup.23 represents hydrogen, C.sub.1-6 alkyl, trifluoromethyl or C.sub.1-6 alkoxy; q is zero or 1; A represents C—R.sup.2 or N; G represents the residue of a six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl; E represents —O—, —CH.sub.2—, or —CH(CH.sub.3); Q represents —CH.sub.2— or —CH.sub.2O; Z represents hydrogen or methyl; R.sup.2 represents hydrogen or halogen; R.sup.15 represents hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or difluoromethoxy; and R.sup.16 represents hydrogen, halogen, cyano, C.sub.1-6 alkyl, trifluoromethyl, difluoromethoxy or amino.

2. The compound as claimed in claim 1 wherein R.sup.21 represents hydroxy(C.sub.1-6)alkyl.

3. The compound as claimed in claim 1 represented by formula (IIF), (IIG), (IIH), or (IIJ), or a pharmaceutically acceptable salt thereof: ##STR00037## wherein W represents C(R.sup.32)(R.sup.33); R.sup.32 represents hydrogen, halogen, cyano, hydroxy, hydroxy(C.sub.1-6)alkyl, C.sub.1-6 alkylsulphonyl, formyl, carboxy, carboxy(C.sub.1-6)alkyl, C.sub.2-6 alkoxycarbonyl, C.sub.2-6 alkoxycarbonyl(C.sub.1-6)alkyl, aminosulphonyl, (C.sub.1-6)alkylsulphoximinyl, [(C.sub.1-6)alkyl][N—(C.sub.1-6)alkyl]sulphoximinyl, (C.sub.1-6)alkylsulphonylaminocarbonyl, (C.sub.2-6)alkylcarbonyl-aminosulphonyl, (C.sub.1-6)alkoxyaminocarbonyl, tetrazolyl or hydroxyoxadiazolyl; R.sup.33 represents hydrogen, halogen, C.sub.1-6 alkyl, trifluoromethyl, hydroxy, hydroxy-(C.sub.1-6)alkyl, C.sub.1-6 alkoxy, amino or carboxy; R.sup.34 represents hydrogen, halogen, halo(C.sub.1-6)alkyl, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulphinyl, C.sub.1-6 alkylsulphonyl, amino, C.sub.1-6 alkylamino, di(C.sub.1-6)alkyl-amino, (C.sub.2-6)alkylcarbonylamino, (C.sub.2-6)alkylcarbonylamino(C.sub.1-6)alkyl, (C.sub.1-6)alkyl-sulphonylamino or (C.sub.1-6)alkylsulphonylamino(C.sub.1-6)alkyl; q is zero or 1.

4. The compound as claimed in claim 3 wherein R.sup.34 represents hydrogen, fluoro or hydroxy.

5. The compound as claimed in claim 1 wherein R.sup.15 represents difluoromethoxy.

6. A compound that is 2-{5-[3-Methyl-4-(1-phenylethyl)cinnolin-6-yl]pyrimidin-2-yl}propan-2-ol, 2-(5-{4-[2-(Difluoromethoxy)benzyl]-3-methylcinnolin-6-yl}pyrimidin-2-yl)propan-2-ol, or 2-{5-[3-Methyl-4-(2-methylphenoxy)cinnolin-6-yl]pyrimidin-2-yl}propan-2-ol.

7. A pharmaceutical composition comprising a compound of formula (IIB) as defined in claim 1 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

8. The pharmaceutical composition as claimed in claim 7 further comprising an additional pharmaceutically active ingredient.

Description

EXAMPLES

Abbreviations

(1) DCM: dichloromethane EtOAc: ethyl acetate

(2) MeOH: methanol DMSO: dimethylsulfoxide

(3) DMF: N,N-dimethylformamide THF: tetrahydrofuran

(4) Pd(dppf)Cl.sub.2: [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

(5) Barluenga's Reagent: bis(pyridine)iodonium(I) tetrafluoroborate

(6) h: hour M: mass

(7) r.t. room temperature RT: retention time

(8) HPLC: High Performance Liquid Chromatography

(9) LCMS: Liquid Chromatography Mass Spectrometry

(10) ES+: Electrospray Positive Ionisation

Nomenclature

(11) Compounds were named with the aid of ACD/Name Batch (Network) version 12.0 and/or Accelrys Draw 4.0.

Analytical Conditions

(12) All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware.

(13) LCMS data were determined by using Method 1 below.

(14) Method 1

(15) Column: Waters Acquity-SQD, Waters Acquity UPLC, BEH C18, 2.1×50 mm, 1.7 μm

(16) Mobile phase A: 10 mM ammonium formate+0.1% ammonia

(17) Mobile phase B: 95% acetonitrile+5% water+0.1% ammonia

(18) Gradient program (flow rate 1.0 mL/minute, column temperature 40° C.):

(19) TABLE-US-00001 Time A % B % 0.00 95.0 5.0 0.50 95.0 5.0 1.75 5.0 95.0 2.00 5.0 95.0 2.25 95.0 5.0

Intermediate 1

1-(2-Aminophenyl)propan-1-one

(20) To a cooled (0° C.) solution of 2-aminobenzonitrile (5 g, 42.3 mmol) in THF (20 mL) was added dropwise ethylmagnesium chloride (2M in THF, 52.9 mL, 105.8 mmol) over 30 minutes via an addition funnel. The reaction mixture was allowed to warm to r.t. and stirred for 6 h. The reaction mixture was cooled to 0° C. and quenched by careful addition of 2M aqueous hydrochloric acid solution (ca. 60 mL). After 10 minutes, the mixture was basified at 0° C. by the slow addition of 2M aqueous sodium hydroxide solution (ca. 60 mL). The mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO.sub.2, 0-25% EtOAc/heptane), yielding the title compound (2.91 g, 46%) as a yellow oil which crystallised upon standing. δ.sub.H (250 MHz, CDCl.sub.3) 7.77 (dd, J 8.5, 1.5 Hz, 1H), 7.42-7.12 (m, 1H), 6.71-6.62 (m, 2H), 6.28 (br s, 2H), 3.00 (q, J 7.5 Hz, 2H), 1.23 (t, J 7.5 Hz, 3H). LCMS (ES.sup.+) 151.0 (M+H).sup.+, RT 1.12 minutes.

Intermediate 2

N-(2-Propanoylphenyl)acetamide

(21) To a solution of Intermediate 1 (2.91 g, 19.5 mmol) in DCM (80 mL) was added triethylamine (2.99 mL, 21.5 mmol), followed by acetyl chloride (1.66 mL, 23.4 mmol). The reaction mixture was stirred at r.t. for 3 h, then washed with water (100 mL). The aqueous layer was back-extracted with DCM (2×50 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in vacuo, yielding the title compound (3.72 g, 99%) as a pale yellow solid, which was used without further purification. δ.sub.H (500 MHz, CDCl.sub.3) 11.75 (s, 1H), 8.74 (dd, J 8.5, 1.0 Hz, 1H), 7.93 (dd, J 8.0, 1.5 Hz, 1H), 7.58-7.51 (m, 1H), 7.15-7.08 (m, 1H), 3.08 (q, J 7.0 Hz, 2H), 2.24 (s, 3H), 1.23 (t, J 7.0 Hz, 3H). LCMS (ES.sup.+) 192.0 (M+H).sup.+, RT 1.11 minutes.

Intermediate 3

N-(4-Bromo-2-propanoylphenyl)acetamide

(22) To a solution of Intermediate 2 (3.72 g, 19.5 mmol) in acetic acid (40 mL) was added bromine (1.61 mL, 31.3 mmol) dropwise. The reaction mixture was stirred at r.t. for 1.5 h, then poured into water (80 mL). The resultant precipitate was collected by filtration, washed with water (50 mL) and heptane (50 mL), then dried in a vacuum oven at 40° C. for 18 h, yielding the title compound (4.82 g, 84%) as a pale yellow solid, which was used without further purification. δ.sub.H (500 MHz, CDCl.sub.3) 11.63 (s, 1H), 8.68 (d, J 9.0 Hz, 1H), 8.02 (d, J 2.5 Hz, 1H), 7.63 (dd, J 9.0, 2.5 Hz, 1H), 3.05 (q, J 7.0 Hz, 2H), 2.24 (s, 3H), 1.23 (t, J 7.0 Hz, 3H). LCMS (ES.sup.+) 270.0/272.0 (M+H).sup.+, RT 1.26 minutes.

Intermediate 4

6-Bromo-3-methyl-1H-cinnolin-4-one

(23) To a solution of Intermediate 3 (4.82 g, 16.3 mmol) in THF (55 mL) were added conc. HCl (12 mL) and water (12 mL) and the resultant slurry was heated at 75° C. for 1.5 h. The reaction mixture was cooled to r.t. and the organic solvent was removed in vacuo. The resultant aqueous suspension was diluted with water (4 mL) and conc. HCl (4 mL), then cooled to −5° C. A solution of sodium nitrite (1.36 g, 19.5 mmol) in water (8 mL) was added in five portions, maintaining a reaction temperature below 0° C. The reaction mixture was warmed slowly to r.t. over 2 h, then stirred at r.t. for 18 h. After this time, the reaction mixture was heated at reflux for 6 h, then cooled to r.t. and filtered. The resultant solid was washed with water (2×20 mL) and diethyl ether (30 mL), then dried in a vacuum oven at 40° C. for 18 h, yielding the title compound (3.23 g, 83%) as a beige solid, which was used without further purification. δ.sub.H (500 MHz, CDCl.sub.3) 13.35 (s, 1H), 8.13 (d, J 2.0 Hz, 1H), 7.88 (dd, J 9.0, 2.0 Hz, 1H), 7.54 (d, J 9.0 Hz, 1H), 2.27 (s, 3H). LCMS (ES.sup.+) 239.0/241.0 (M+H).sup.+, RT 0.99 minutes.

Intermediate 5

3-Methyl-6-[4-(methylsulfonyl)phenyl]-1H-cinnolin-4-one

(24) A mixture of Intermediate 4 (500 mg, 1.97 mmol) and 4-(methylsulfonyl)phenyl-boronic acid (433 mg, 2.16 mmol) in 1,4-dioxane (30 mL) and 2M aqueous potassium carbonate solution (2.95 mL, 5.90 mmol) was degassed for 10 minutes under a stream of nitrogen prior to the addition of Pd(dppf)Cl.sub.2.DCM (161 mg, 0.2 mmol). The reaction mixture was heated at 100° C. for 1 h. The reaction mixture was cooled to r.t, then partitioned between water (100 mL) and EtOAc (100 mL). The resultant precipitate between the layers was collected by filtration and dried in a vacuum oven at 40° C. for 18 h, yielding the title compound (484 mg, 78%) as a grey solid. δ.sub.H (500 MHz, DMSO-d.sub.6) 8.36 (d, J 2.0 Hz, 1H), 8.13 (dd, J 9.0, 2.0 Hz, 1H), 8.04 (s, 4H), 7.71 (d, J 9.0 Hz, 1H), 3.27 (s, 3H), 2.31 (s, 3H). LCMS (ES.sup.+) 315.0 (M+H).sup.+, RT 1.02 minutes.

Intermediate 6

4-Chloro-3-methyl-6-[4-(methylsulfonyl)phenyl]cinnoline

(25) A solution of Intermediate 5 (200 mg, 0.64 mmol) in phosphorus trichloride (1.48 mL, 15.9 mmol) was heated at 100° C. for 2 h. The reaction mixture was poured onto ice (20 mL) and the pH was adjusted to ca. pH 5 by the addition of 6M aqueous sodium hydroxide solution, then the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), then dried (Na.sub.2SO.sub.4) and concentrated in vacuo, yielding the title compound (223 mg, quantitative) as a dark purple solid, which was used without further purification. δ.sub.H (500 MHz, DMSO-d.sub.6) 8.67 (d, J 9.0 Hz, 1H), 8.45 (s, 1H), 8.39 (d, J 9.0 Hz, 1H), 8.27-8.08 (m, 4H), 3.02 (s, 3H). LCMS (ES.sup.+) 332.9/334.8 (M+H).sup.+, RT 1.16 minutes.

Intermediates 7 & 8

6-Bromo-4-chloro-3-methylcinnoline and 4,6-Dichloro-3-methylcinnoline

(26) A solution of Intermediate 4 (400 mg, 1.57 mmol) in phosphorus trichloride (2.49 mL, 26.7 mmol) was heated at 100° C. for 2 h. The reaction mixture was poured onto ice (20 mL) and the pH was adjusted to ca. pH 5 by the addition of 6M aqueous sodium hydroxide solution, then the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), then dried (Na.sub.2SO.sub.4) and concentrated in vacuo, yielding a 65:35 inseparable mixture of the title compounds (366 mg, 59%) as a grey solid, which was used without further purification. δ.sub.H (500 MHz, DMSO-d.sub.6) 8.46 (d, J 9.0 Hz, 1H), 8.37 (d, J 2.0 Hz, 1H), 8.12 (dd, J 9.0, 2.0 Hz, 1H), 2.98 (s, 3H). LCMS (ES.sup.+) 256.8/258.0 (M+H).sup.+, RT 1.28 minutes; and 212.9/214.9 (M+H).sup.+ RT 1.25 minutes.

Intermediate 9

2-[5-(4-Chloro-3-methylcinnolin-6-yl)pyrimidin-2-yl]propan-2-ol

(27) A solution of a 65:35 mixture of Intermediates 7 and 8 (366 mg, 0.92 mmol) and 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (245 mg, 0.93 mmol) in 1,4-dioxane (10 mL) and 2M aqueous potassium carbonate solution (1.39 mL, 2.78 mmol) was degassed for 10 minutes under a stream of nitrogen prior to the addition of Pd(dppf)Cl.sub.2.DCM (38 mg, 0.05 mmol). The reaction mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to r.t, diluted with water (25 mL) and extracted with DCM (3×25 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO.sub.2, 0-100% EtOAc/heptane), yielding the title compound (223 mg, 77%) as a yellow solid. δ.sub.H (500 MHz, DMSO-d.sub.6) 9.37 (s, 2H), 8.67 (d, J 9.0 Hz, 1H), 8.54 (d, J 2.0 Hz, 1H), 8.43 (dd, J 9.0, 2.0 Hz, 1H), 5.19 (s, 1H), 3.01 (s, 3H), 1.58 (s, 6H). LCMS (ES.sup.+) 315.0/317.0 (M+H).sup.+, RT 1.08 minutes.

Intermediate 10

6-Chloro-3-methyl-4-(2-methylphenoxy)cinnoline

(28) To a cooled (0° C.) solution of 2-methylphenol (44 μL, 0.43 mmol) in DMF (3 mL) was added sodium hydride (60% suspension in mineral oil, 20 mg, 0.51 mmol). The reaction mixture was stirred at 0° C. for 15 minutes, prior to the addition of Intermediate 8 (90 mg, 0.39 mmol) in DMF (1 mL). The reaction mixture was stirred at r.t. for 5 h, then quenched by the addition of water (5 mL), further diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (30 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The resultant crude material was purified by flash column chromatography (SiO.sub.2, 0-50% EtOAc/heptane), yielding the title compound (91 mg, 77%) as a pale yellow solid. δ.sub.H (250 MHz, CDCl.sub.3) 8.50 (d, J 9.0 Hz, 1H), 7.88 (d, J 2.0 Hz, 1H), 7.72 (dd, J 9.0, 2.0 Hz, 1H), 7.40-7.30 (m, 1H), 7.10-6.94 (m, 2H), 6.23-6.11 (m, 1H), 2.70 (s, 3H), 2.53 (s, 3H). LCMS (ES.sup.+) 284.9/287.0 (M+H).sup.+, RT 1.45 minutes.

Intermediate 11

2-Chloro-4-[4-(methanesulfonyl)phenyl]benzaldehyde

(29) A mixture of 4-bromo-2-chlorobenzaldehyde (5.00 g, 22.8 mmol) and 4-(methanesulfonylphenyl)boronic acid (4.56 g, 22.8 mmol) in 1,4-dioxane (100 mL) and 2M aqueous sodium carbonate solution (34.6 mL, 69.2 mmol) was degassed for 10 minutes under a stream of nitrogen prior to the addition of Pd(dppf)Cl.sub.2.DCM (930 mg, 1.14 mmol). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to r.t., diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO.sub.4) and concentrated in vacuo. The resulting material was purified by flash column chromatography (SiO.sub.2, 30-100% EtOAc/heptane), yielding the title compound (4.0 g, 58%) as an orange solid. δ.sub.H (500 MHz, CDCl.sub.3) 10.53 (d, J 1.0 Hz, 1H), 8.09-8.02 (m, 3H), 7.82-7.78 (m, 2H), 7.70 (d, J 1.5 Hz, 1H), 7.64-7.61 (m, 1H), 3.11 (s, 3H).

Intermediate 12

4-[4-(Methylsulfonyl)phenyl]-2-(prop-1-ynyl)benzaldehyde

(30) A solution of Intermediate 11 (2.61 g, 8.77 mmol) in toluene (60 mL) was degassed for 10 minutes under a stream of nitrogen prior to the addition of tetrakis-(triphenylphosphine)palladium(0) (486 mg, 0.42 mmol), followed by tributyl(1-propynyl)tin (4.00 mL, 13.2 mmol). The reaction mixture was heated at 110° C. for 5 h. The reaction mixture was cooled to r.t., then poured into saturated aqueous potassium fluoride solution (100 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine (75 mL), dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO.sub.2, 20-100% EtOAc/heptane), yielding the title compound (3.06 g, 52%) as an off-white solid. δ.sub.H (500 MHz, CDCl.sub.3) 10.56 (d, J 1.0 Hz, 1H), 8.07-8.03 (m, 2H), 8.00 (d, J 8.0 Hz, 1H), 7.82-7.78 (m, 2H), 7.75 (d, J 2.0 Hz, 1H), 7.62 (dd, J 8.0, 1.0 Hz, 1H), 3.11 (s, 3H), 2.17 (s, 3H). LCMS (ES.sup.+) 299.0 (M+H).sup.+, RT 1.63 minutes.

Intermediate 13

{4-[4-(Methylsulfonyl)phenyl]-2-(prop-1-ynyl)phenyl}methanol

(31) To a cooled (0° C.) suspension of Intermediate 12 (2.56 g, 8.58 mmol) in THF (30 mL) and MeOH (30 mL) was added sodium borohydride (649 mg, 17.2 mmol) portionwise. The reaction mixture was allowed to warm to r.t. over 1 h, then quenched with water (15 mL). The organic solvents were removed in vacuo. The resultant mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with water (15 mL), then dried (MgSO.sub.4) and concentrated in vacuo, yielding the title compound (2.59 g, 85%) as an off-white solid, which was used without further purification. δ.sub.H (500 MHz, CDCl.sub.3) 8.02-7.98 (m, 2H), 7.77-7.74 (m, 2H), 7.66 (s, 1H), 7.55-7.51 (m, 2H), 4.86 (d, J 6.5 Hz, 2H), 3.09 (s, 3H), 2.13 (s, 3H).

Intermediate 14

1-(Azidomethyl)-4-[4-(methanesulfonyl)phenyl]-2-(prop-1-yn-1-yl)benzene

(32) To a solution of Intermediate 13 (2.59 g, 6.9 mmol) in toluene (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.55 mL, 10.3 mmol), followed by diphenyl phosphoryl azide (1.94 mL, 8.9 mmol). The reaction mixture was stirred at r.t. for 18 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (20 mL), then extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (30 mL), dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO.sub.2, 10-100% EtOAc/heptane), yielding the title compound (1.79 g, 79%) as a yellow solid. δ.sub.H (500 MHz, CDCl.sub.3) 8.03-7.99 (m, 2H), 7.78-7.74 (m, 2H), 7.69 (d, J 2.0 Hz, 1H), 7.55-7.52 (m, 1H), 7.46 (d, J 8.0 Hz, 1H), 4.58 (s, 2H), 3.10 (s, 3H), 2.14 (s, 3H).

Intermediate 15

4-Iodo-3-methyl-6-[4-(methylsulfonyl)phenyl]isoquinoline

(33) To a cooled (−78° C.) solution of Barluenga's Reagent (4.13 g, 10.8 mmol) in DCM (65 mL) was added tetrafluoroboric acid diethyl ether complex (2.93 mL, 10.8 mmol). The resultant solution was added slowly to a cooled (−78° C.) solution of Intermediate 14 (1.79 g, 5.4 mmol) in DCM (5 mL) and the reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was quenched with saturated aqueous sodium thiosulfate solution (50 mL), then extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (30 mL), dried (MgSO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO.sub.2, 20-100% EtOAc/heptane), yielding the title compound (1.48 g, 64%) as a purple-brown solid. δ.sub.H (500 MHz, CDCl.sub.3) 9.09 (s, 1H), 8.30 (s, 1H), 8.13-8.10 (m, 2H), 8.01 (d, J 8.5 Hz, 1H), 7.95-7.92 (m, 2H), 7.83 (dd, J 8.5, 1.5 Hz, 1H), 3.13 (s, 3H), 3.03 (s, 3H). LCMS (ES.sup.+) 424.0 (M+H).sup.+, RT 1.29 minutes.

Example 1 (Method A)

4-(2-Methoxybenzyl)-2-methylquinazoline

(34) To a solution of 4-chloro-2-methylquinazoline (100 mg, 0.56 mmol) and tetrakis-(triphenylphosphine)palladium(0) (32 mg, 0.03 mmol) in THF (7 mL) was added 2-methoxybenzylzinc chloride (0.5M in THF, 2.02 mL, 1.01 mmol) dropwise over 5 minutes. The reaction mixture was heated at 50° C. for 18 h, then cooled to r.t. and quenched with saturated aqueous ammonium chloride solution (2 mL). The organic solvent was removed in vacuo. The residue was taken up in water (30 mL) and extracted with DCM (2×30 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO.sub.2, 0-100% EtOAc/heptane), yielding the title compound (95 mg, 64%) as a yellow solid. δ.sub.H (500 MHz, CDCl.sub.3) 8.13 (d, J 8.0 Hz, 1H), 8.01-7.88 (m, 1H), 7.79 (t, J 7.5 Hz, 1H), 7.47 (t, J 7.5 Hz, 1H), 7.23-7.16 (m, 1H), 7.01 (d, J 7.0 Hz, 1H), 6.90 (d, J 8.0 Hz, 1H), 6.81 (t, J 7.5 Hz, 1H), 4.59 (s, 2H), 3.90 (s, 3H), 2.89 (s, 3H). LCMS (ES.sup.+) 265.0 (M+H).sup.+, RT 1.45 minutes.

Example 2

3-(2-Methoxybenzyl)quinoline

(35) Prepared from 3-bromoquinoline (65 μL, 0.48 mmol), tetrakis(triphenyl-phosphine)palladium(0) (28 mg, 0.02 mmol) and 2-methoxybenzylzinc chloride (0.5M in THF, 1.73 mL, 0.87 mmol) in THF (7 mL) by Method A to give the title compound (29 mg, 24%). δ.sub.H (500 MHz, CDCl.sub.3) 8.88 (s, 1H), 8.09 (d, J 8.5 Hz, 1H), 7.91 (s, 1H), 7.73 (d, J 8.5 Hz, 1H), 7.67-7.63 (m, 1H), 7.53-7.48 (m, 1H), 7.25-7.22 (m, 1H), 7.17 (dd, J 7.5, 1.5 Hz, 1H), 6.94-6.87 (m, 2H), 4.15 (s, 2H), 3.81 (s, 3H). LCMS (ES.sup.+) 250.1 (M+H).sup.+, RT 1.59 minutes.

Example 3

4-(2-Methoxybenzyl)quinazoline

(36) Prepared from 4-chloroquinazoline (100 mg, 0.61 mmol), tetrakis(triphenyl-phosphine)palladium(0) (35 mg, 0.03 mmol) and 2-methoxybenzylzinc chloride (0.5M in THF, 2.19 mL, 1.10 mmol) in THF (7 mL) by Method A to give the title compound (70 mg, 44%). δ.sub.H (500 MHz, CDCl.sub.3) 9.24 (s, 1H), 8.24 (d, J 8.5 Hz, 1H), 8.03 (d, J 8.5 Hz, 1H), 7.86 (ddd, J 8.5, 7.0, 1.5 Hz, 1H), 7.59 (ddd, J 8.5, 7.0, 1.0 Hz, 1H), 7.22 (td, J 8.0, 2.0 Hz, 1H), 7.11 (dd, J 7.5, 1.5 Hz, 1H), 6.93-6.84 (m, 2H), 4.63 (s, 2H), 3.84 (s, 3H). LCMS (ES.sup.+) 251.0 (M+H).sup.+. RT 1.43 minutes.

Example 4

2-(2-Chlorophenoxy)-3-methylquinoxaline

(37) A mixture of 2-chloro-3-methylquinoxaline (100 mg, 0.56 mmol), 2-chlorophenol (144 mg, 1.12 mmol) and potassium carbonate (929 mg, 6.72 mmol) in DMSO (5.6 mL) was heated at 120° C. in a sealed tube for 18 h. The reaction mixture was partitioned between EtOAc (60 mL) and water (60 mL). The organic layer was separated and the aqueous layer was back-extracted with 10% propan-2-ol in chloroform (2×60 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO.sub.2, 0-100% EtOAc/heptane, followed by 1-100% MeOH/EtOAc), then repurified by preparative HPLC, yielding the title compound (37.5 mg, 24%) as an off-white solid. δ.sub.H (500 MHz, DMSO-d.sub.6) 8.03-7.99 (m, 1H), 7.73-7.58 (m, 4H), 7.56-7.45 (m, 2H), 7.44-7.35 (m, 1H), 2.80 (s, 3H). LCMS (ES.sup.+) 271.0/273.0 (M+H).sup.+, RT 1.69 minutes.

Example 5

2-[(2-Methoxyphenyl)methyl]-3-methylquinoxaline

(38) Prepared from 2-chloro-3-methylquinoxaline (100 mg, 0.56 mmol), tetrakis-(triphenylphosphine)palladium(0) (32 mg, 0.03 mmol) and 2-methoxybenzylzinc chloride (0.5M in THF, 2.02 mL, 1.01 mmol) in THF (8 mL) by Method A to give the title compound (52 mg, 35%). δ.sub.H (500 MHz, DMSO-d.sub.6) 8.01-7.92 (m, 2H), 7.78-7.69 (m, 2H), 7.24 (td, J 8.0, 2.0 Hz, 1H), 7.03 (d, J 7.5 Hz, 1H), 6.92 (dd, J 7.5, 2.0 Hz, 1H), 6.85 (td, J 7.5, 1.0 Hz, 1H), 4.31 (s, 2H), 3.78 (s, 3H), 2.64 (s, 3H). LCMS (ES.sup.+) 265.0 (M+H).sup.+ RT 1.55 minutes.

Example 6

3-Methyl-6-[4-(methylsulfonyl)phenyl]-4-(1-phenylethyl)cinnoline

(39) Prepared from Intermediate 6 (117 mg, 0.35 mmol), tetrakis(triphenylphosphine)-palladium(0) (81 mg, 0.07 mmol) and 1-phenylethylzinc chloride (0.5M in THF, 1.27 mL, 0.64 mmol) in THF (10 mL) by Method A to give the title compound (32 mg, 41%). δ.sub.H (500 MHz, CDCl.sub.3) 8.58 (d, J 9.5 Hz, 1H), 8.01-7.95 (m, 2H), 7.91-7.84 (m, 2H), 7.51-7.45 (m, 2H), 7.38-7.34 (m, 2H), 7.31-7.28 (m, 1H), 7.25-7.23 (m, 2H), 4.99 (q, J 7.0 Hz, 1H), 3.10 (s, 3H), 3.04 (s, 3H), 1.87 (d, J 7.0 Hz, 3H). LCMS (ES.sup.+) 403.0 (M+H).sup.+, RT 1.48 minutes.

Example 7

4-[2-(Difluoromethoxy)benzyl]-3-methyl-6-[4-(methylsulfonyl)phenyl]cinnoline

(40) A mixture of Intermediate 6 (50 mg, 0.14 mmol) and 2-{[2-(difluoromethoxy)-phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (64 mg, 0.21 mmol) in 1,4-dioxane (2 mL) and 2M aqueous potassium carbonate solution (214 μL, 0.43 mmol) was degassed for 10 minutes under a stream of nitrogen prior to the addition of Pd(dppf)Cl.sub.2.DCM (12 mg, 0.01 mmol). The reaction mixture was heated in a sealed tube at 100° C. for 24 h. After this time, the reaction had not gone to completion so further 2-{[2-(difluoromethoxy)phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (64 mg, 0.21 mmol), 2M aqueous potassium carbonate solution (100 μL, 0.20 mmol) and Pd(dppf)Cl.sub.2.DCM (12 mg, 0.01 mmol) were added. The reaction mixture was heated at 100° C. for 3 h, then diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (30 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO.sub.2, 0-100% EtOAc/heptane), then repurified by preparative HPLC, yielding the title compound (9 mg, 15%) as a pale yellow solid. δ.sub.H (500 MHz, CDCl.sub.3) 8.64 (d, J 9.0 Hz, 1H), 8.08-8.02 (m, 3H), 7.99 (dd, J 8.5, 1.7 Hz, 1H), 7.79 (d, J 8.5 Hz, 2H), 7.27-7.19 (m, 2H), 7.00 (t, J 7.5 Hz, 1H), 6.69 (t, J 75.0 Hz, 1H), 6.60 (d, J 8.0 Hz, 1H), 4.53 (s, 2H), 3.10 (s, 3H), 2.97 (s, 3H). LCMS (ES.sup.+) 455.0 (M+H).sup.+, RT 1.47 minutes.

Example 8

2-{5-[3-Methyl-4-(1-phenylethyl)cinnolin-6-yl]pyrimidin-2-yl}propan-2-ol

(41) Prepared from Intermediate 9 (93 mg, 0.30 mmol), tetrakis(triphenylphosphine)-palladium(0) (68 mg, 0.06 mmol) and 1-phenylethylzinc chloride (0.5M in THF, 1.06 mL, 0.53 mmol) in THF (10 mL) by Method A to give the title compound (17 mg, 15%). δ.sub.H (500 MHz, CDCl.sub.3) 8.66 (s, 2H), 8.62 (d, J 9.0 Hz, 1H), 7.88-7.82 (m, 2H), 7.38-7.35 (m, 2H), 7.32-7.29 (m, 1H), 7.24-7.22 (m, 2H), 4.99 (q, J 7.5 Hz, 1H), 4.56 (s, 1H), 3.06 (s, 3H), 1.89 (d, J 7.5 Hz, 3H), 1.64 (s, 6H). LCMS (ES.sup.+) 385.0 (M+H).sup.+, RT 1.43 minutes.

Example 9

2-(5-{4-[2-(Difluoromethoxy)benzyl]-3-methylcinnolin-6-yl}pyrimidin-2-yl)propan-2-ol

(42) A mixture of Intermediate 9 (80 mg, 0.25 mmol) and 2-{[2-(difluoromethoxy)-phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (152 mg, 0.51 mmol) in 1,4-dioxane (5 mL) and 2M aqueous potassium carbonate solution (381 pt, 0.76 mmol) was degassed for 10 minutes under a stream of nitrogen prior to the addition of Pd(dppf)Cl.sub.2.DCM (10 mg, 0.01 mmol). The reaction mixture was heated in a sealed tube at 100° C. for 6 h. After this time, the reaction had not gone to completion so further 2-{[2-(difluoromethoxy)phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (152 mg, 0.51 mmol) in 1,4-dioxane (1 mL), 2M aqueous potassium carbonate solution (381 pt, 0.76 mmol) and Pd(dppf)Cl.sub.2.DCM (10 mg, 0.01 mmol) were added. The reaction mixture was heated in a sealed tube at 100° C. for 18 h. The reaction mixture was cooled to r.t., diluted with water (10 mL) and brine (10 mL), then extracted with DCM (3×20 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO.sub.2, 20-100% EtOAc/heptane), then repurified by preparative HPLC, yielding the title compound (24 mg, 24%) as a pale yellow solid. δ.sub.H (500 MHz, CDCl.sub.3) 8.94 (s, 2H), 8.69 (d, J 9.0 Hz, 1H), 8.03 (d, J 1.5 Hz, 1H), 7.96 (dd, J 9.0, 1.5 Hz, 1H), 7.28-7.20 (m, 2H), 7.00 (t, J 7.5 Hz, 1H), 6.69 (t, J 75.0 Hz, 1H), 6.58 (d, J 7.5 Hz, 1H), 4.56 (s, 1H), 4.53 (s, 2H), 2.98 (s, 3H), 1.65 (s, 6H). LCMS (ES.sup.+) 437.0 (M+H).sup.+, RT 1.42 minutes.

Example 10

2-{5-[3-Methyl-4-(2-methylphenoxy)cinnolin-6-yl]pyrimidin-2-yl}propan-2-ol

(43) A mixture of Intermediate 10 (90 mg, 0.32 mmol) and 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (100 mg, 0.38 mmol) in 1,4-dioxane (4 mL) and 2M aqueous potassium carbonate solution (474 μl, 0.95 mmol) was degassed for 10 minutes under a stream of nitrogen prior to the addition of Pd(dppf)Cl.sub.2.DCM (13 mg, 0.02 mmol). The reaction mixture was heated at 100° C. in a sealed tube for 2 h. After this time, the reaction had not gone to completion so further 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (50 mg, 0.19 mmol) was added and the reaction mixture was heated at 100° C. in a sealed tube for 2 h. The reaction mixture was cooled to r.t, then diluted with water (20 mL) and extracted with EtOAc (20 mL). The organic layer was separated and the aqueous layer was back-extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (20 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO.sub.2, 0-100% EtOAc/heptane), then repurified by preparative HPLC, yielding the title compound (56 mg, 46%) as a yellow solid. δ.sub.H (500 MHz, CDCl.sub.3) 8.94 (s, 2H), 8.71 (d, J 9.0 Hz, 1H), 8.04 (d, J 2.0 Hz, 1H), 7.99 (dd, J 9.0, 2.0 Hz, 1H), 7.34 (d, J 7.0 Hz, 1H), 7.07-6.96 (m, 2H), 6.22 (d, J 8.0 Hz, 1H), 4.55 (s, 1H), 2.75 (s, 3H), 2.54 (s, 3H), 1.64 (s, 6H). LCMS (ES.sup.+) 387.0 (M+H).sup.+, RT 1.48 minutes.

Example 11

4-[2-(Difluoromethoxy)benzyl]-3-methyl-6-[4-(methylsulfonyl)phenyl]isoquinoline

(44) A mixture of Intermediate 15 (70 mg, 0.16 mmol) and 2-{[2-(difluoromethoxy)-phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (95 mg, 0.32 mmol) in 1,4-dioxane (5 mL) and 2M aqueous potassium carbonate solution (238 μL, 0.48 mmol) was degassed for 10 minutes under a stream of nitrogen prior to the addition of Pd(dppf)Cl.sub.2.DCM (6 mg, 0.01 mmol). The reaction mixture was heated in a sealed tube at 100° C. for 3 h. After this time, the reaction had not gone to completion so further 2-{[2-(difluoromethoxy)phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (95 mg, 0.32 mmol) was added and the mixture was stirred at 100° C. for 1.5 h. To push the reaction to completion, further 2-{[2-(difluoromethoxy)phenyl]methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (95 mg, 0.32 mmol), 2M aqueous potassium carbonate solution (238 μL, 0.48 mmol) and Pd(dppf)Cl.sub.2.DCM (6 mg, 0.01 mmol) were added and the mixture was stirred at 100° C. for 18 h. Further 2-{[2-(difluoromethoxy)phenyl]-methyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (95 mg, 0.32 mmol), 2M aqueous potassium carbonate solution (238 μL, 0.48 mmol) and Pd(dppf)Cl.sub.2.DCM (6 mg, 0.01 mmol) were added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was cooled to r.t., diluted with water (10 mL) and brine (10 mL), then extracted with DCM (3×20 mL). The combined organic layers were dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography (SiO.sub.2, 30-100% EtOAc/heptane), then repurified by preparative HPLC, yielding the title compound (19 mg, 29%) as an off-white solid. δ.sub.H (500 MHz, CDCl.sub.3) 9.22 (s, 1H), 8.09 (d, J 8.5 Hz, 1H), 8.04-7.98 (m, 3H), 7.78-7.74 (m, 3H), 7.24-7.18 (m, 2H), 7.00-6.95 (m, 1H), 6.70 (t, J 74.0 Hz, 1H), 6.64 (d, J 7.5 Hz, 1H), 4.51 (s, 2H), 3.09 (s, 3H), 2.73 (s, 3H). LCMS (ES.sup.+) 454.0 (M+H).sup.+, RT 1.52 minutes.

Example 12

3-Methyl-6-[4-(methylsulfonyl)phenyl]-4-(1-phenylethyl)isoquinoline

(45) Prepared from Intermediate 15 (200 mg, 0.47 mmol), tetrakis(triphenyl-phosphine)palladium(0) (109 mg, 0.09 mmol) and 1-phenylethylzinc chloride (0.5M in THF, 1.70 mL, 0.85 mmol) in THF (10 mL) by Method A to give the title compound (31 mg, 28%). δ.sub.H (500 MHz, CDCl.sub.3) 9.14 (s, 1H), 8.01 (d, J 8.5 Hz, 1H), 7.97-7.93 (m, 2H), 7.85 (s, 1H), 7.65 (dd, J 8.5, 1.5 Hz, 1H), 7.44-7.41 (m, 2H), 7.36-7.32 (m, 2H), 7.30-7.26 (m, 3H), 5.03 (q, J 7.0 Hz, 1H), 3.09 (s, 3H), 2.82 (s, 3H), 1.86 (d, J 7.0 Hz, 3H). LCMS (ES.sup.+) 402.0 (M+H).sup.+, RT 1.55 minutes.