Fused pentacyclic imidazole derivatives as modulators of TNF activity

Abstract

A compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, being potent modulators of human TNF a activity, 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 of formula (I), or a pharmaceutically acceptable salt thereof: ##STR00025## wherein X represents N or C—F; R.sup.1 represents hydrogen or methyl or an isotopic variant thereof; R.sup.2 represents hydroxy or cyano; R.sup.3 represents hydroxy or cyano; and R.sup.2 is different from R.sup.3.

2. The compound as claimed in claim 1 represented by formula (IIA), or a pharmaceutically acceptable salt thereof: ##STR00026## wherein X and R.sup.1 are as defined in claim 1.

3. The compound as claimed in claim 1 represented by formula (IIB), or a pharmaceutically acceptable salt thereof: ##STR00027## wherein X and R.sup.1 are as defined in claim 1.

4. The compound as claimed in claim 1 represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R.sup.1 represents hydrogen, —CH.sub.3 or —CD.sub.3.

5. The compound as claimed in claim 1 that is 3-[5-[(1R,11R)-18-(difluoromethoxy)-13-oxo-12-(trideuteriomethyl)-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014, 19]icosa-3(8),4,6,9,14(19),15,17-heptaen-5-yl]pyrimidin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile; 3-[5-[(1R,11R)-18-(difluoromethoxy)-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19), 15,17-heptaen-5-yl]pyrimidin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile; 3-[5-[(1R,11R)-18-(difluoromethoxy)-6-fluoro-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19), 15,17-heptaen-5-yl]pyrimidin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile; 3-[5-[(1R,11R)-18-(difluoromethoxy)-12-methyl-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014, 19]icosa-3,5,7,9,14(19), 15,17-heptaen-5-yl]-3-fluoropyridin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile; 3-[5-[(1R,11R)-18-(difluoromethoxy)-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3,5,7,9,14(19),15,17-heptaen-5-yl]-3-fluoropyridin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile; 1-[5-[(1R,11R)-18-(difluoromethoxy)-12-methyl-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-5-yl]pyrimidin-2-yl]-3-hydroxy-3-methylcyclobutane-1-carbonitrile; or 1-[5-[(1R,11R)-18-(difluoromethoxy)-12-methyl-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-5-yl]-3-fluoropyridin-2-yl]-3-hydroxy-3-methylcyclobutane-1-carbonitrile.

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

7. The pharmaceutical composition as claimed in claim 6 further comprising an additional pharmaceutically active ingredient.

8. A method for the treatment of Rheumatoid arthritis or Crohn's disease which comprises administering to a patient in need of such treatment an effective amount of the compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

Abbreviations

(1) TABLE-US-00001 DCM: dichloromethane EtOAc: ethyl acetate MeOH: methanol THF: tetrahydrofuran DMSO: dimethyl sulfoxide EtOH: Ethanol MeCN: acetonitrile h: hour TBME: Methyl tert-butyl ether RT: retention time XPhos: 2-dicyclohexylphosphino-2', 4',6'-triisopropylbiphenyl r.t.: room temperature M: mass HPLC: High Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry ES+: Electrospray Positive Ionisation

Nomenclature

(2) IUPAC names of all the Intermediates and Examples described herein were generated using Pipeline Pilot (version 2018) which uses OEMMetachem software version 1.4.5. provided by OpenEye Scientific.

(3) Analytical Conditions

(4) All NMR spectra were obtained at 250 MHz, 300 MHz, 400 MHz or 500 MHz.

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

(6) LCMS Data Determination

(7) Method 1

(8) Method 1: Performed using an Agilent 1200RR-6140 LC-MS system, with an Agilent binary pump and Agilent DAD (230-400 nm) module. 6140 mass detection (ES) 100-1000 m/z.

(9) Column: XBridge C18, 2.1×20 mm, 2.5 μm

(10) Mobile Phase A: 10 mM Ammonium Formate in water+0.1% Ammonia

(11) Solution

(12) Mobile Phase B: Acetonitrile+5% water+0.1% Ammonia Solution

(13) TABLE-US-00002 Gradient: Time A % B % 0.00 95.10 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00 Flow: 1 mL/min Run Time: 6 min

(14) Method 2

(15) Method 2: Crude system 2 (basic)—Performed using an Agilent 1260-6120 LC-MS system, with an Agilent binary pump and Agilent DAD (240-400 nm) module. 6120 mass detection (ES) 120-1000 m/z.

(16) Column: XBridge C18, 2.1×20 mm, 2.5 μm

(17) Mobile Phase A: 10 mM Ammonium Formate in water+0.1% Ammonia Solution

(18) Mobile Phase B: Acetonitrile+5% water+0.1% Ammonia Solution

(19) TABLE-US-00003 Gradient: Time A % B % 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00 Flow Rate: 1 mL/min Run Time:   3.5 min

(20) Method 3

(21) Method 3: Crude system 2 (basic)—Performed using an Agilent 1260-6120 LC-MS system, with an Agilent binary pump and Agilent DAD (240-400 nm) module. 6120 mass detection (ES) 120-1000 m/z.

(22) Column: XBridge C18, 2.1×20 mm, 2.5 μm

(23) Mobile Phase A: 10 mM Ammonium Formate in water+0.1% Ammonia Solution

(24) Mobile Phase B: Acetonitrile+5% water+0.1% Ammonia Solution

(25) Gradient:

(26) TABLE-US-00004 Time A % B % 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.00 95.00 5.00 Flow Rate: 1 mL/min Run Time:    6 min

(27) Method 4

(28) Waters UPLC-SQD apparatus, ionization: electrospray in positive and/or negative mode (ES+/−), chromatographic conditions: column: Acquity CSH C18 1.7 μm-2.1×50 mm, solvents: A: H2O (0.1% formic acid) B: CH.sub.3CN (0.1% formic acid), column temperature: 45° C., flow rate: 1.0 ml/min, gradient (2.5 min): from 5 to 100% of B.

Intermediate 1

(1R,11R)-5-chloro-18-(difluoromethoxy)-12-methyl-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014.19]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one

(29) ##STR00007##

(30) To a solution of (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(141)-one (WO 2016/050975, Example 11) (10 g, 26.6 mmol) in dry THF (135 mL), cooled to −78° C. under nitrogen, was added potassium bis(trimethylsilyl)amide (1M in THF, 30 mL, 30 mmol) dropwise over 15 minutes. The resulting mixture was stirred at −78° C. for 1 h prior to the addition of iodomethane (2.5 mL, 40 mmol) dropwise over 5 minutes. The reaction mixture was stirred at −78° C. for 1 h, then allowed to warm slowly to ambient temperature overnight. The reaction mixture was poured into saturated aqueous ammonium chloride solution (600 mL) and extracted with EtOAc (2×800 mL). The organic extracts were dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. Purification by flash chromatography on silica (elution with 5% MeOH/DCM) afforded the title compound (9.12 g, 88%) as a beige solid.

(31) δ.sub.H (300 MHz, DMSO-d.sub.6) 8.33-8.21 (m, 1H), 7.87-7.33 (m, 5H), 7.22 (dd, J 8.7, 2.1 Hz, 1H), 6.23 (d, J 7.1 Hz, 1H), 5.22 (d, J 7.1 Hz, 1H), 3.55-3.41 (m, 1H), 3.33 (s, 3H), 2.81 (d, J 13.8 Hz, 1H). LCMS (ES+) [M+H].sup.+ 390.0, RT 1.10 minutes (Method 2).

Intermediate 2

(1R,11R)-18-(difluoromethoxy)-12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one

(32) ##STR00008##

(33) Intermediate 1 (4 g, 10.3 mmol) in 1,4-dioxane (42 mL) was treated with bis(pinacolato)diboron (3.9 g, 15 mmol) and potassium acetate (3 g, 30.6 mmol). The reaction mixture was degassed and flushed with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (484 mg, 0.51 mmol), and tricyclohexylphosphonium tetrafluoroborate (390 mg, 1.03 mmol) was added and the reaction mixture was degassed and nitrogen flushed before heating overnight at 140° C. Further bis(pinacolato)diboron (2.6 g, 10.3 mmol) was added and the reaction mixture was heated at 140° C. for 24 h. The reaction mixture was partitioned between EtOAc and brine, the organic phase was separated, concentrated in vacuo and purified by flash column chromatography on silica (gradient elution with EtOAc/MeOH 0 to 10%) to afford the title compound (2.5 g, 50%) as a white solid.

(34) LCMS (ES+) [M+H].sup.+ 482, RT 2.40 minutes (Method 3).

Intermediate 3

3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile

(35) ##STR00009##

(36) 1-methyl-3-oxo-cyclobutanecarbonitrile (2.0 g, 18.3 mmol) and 5-bromo-2-iodo-pyrimidine (6 g, 21.0 mmol), both available commercially, were dissolved in DCM (100 mL). The mixture was cooled to −78° C. before the dropwise addition of n-butyllithium (8.4 mL, 21 mmol, 2.5 mol/L) The mixture was stirred at −78° C. for one hour before slowly warming up to r.t. and stirred for additional hour. The mixture was filtered through phase separator, washed with DCM, concentrated in vacuo. The crude product was s purified by flash column chromatography on silica (gradient elution with 0-10% EtOAc/hexane) to give the major undesired isomer, 700 mg, and mixed fractions (1.7 g) containing both isomers with rough ratio of 1:1. The mixed fraction were combined and purified by preparative LC to afford title compound as a yellow solid (700 mg, 10%)

(37) LCMS (ES+) [M+H].sup.+ 250/270, RT 0.90 minutes (Method 3).

Intermediate 4

(1R,11R)-18-(difluoromethoxy)-6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-13-one

(38) ##STR00010##

(39) (7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (Example 10 of WO 2016/050975) (150 mg, 0.38 mmol) in 1,4-dioxane (1.3 mL, 15 mmol) was added to bis(pinacolato)diboron (145.1 mg, 0.57 mmol), and potassium acetate (112 mg, 1.14 mmol), tricyclohexylphosphonium tetrafluoroborate (14 mg, 0.038 mmol) and tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.019 mmol) were added. The reaction mixture was degassed for 10 mins before heating up to 140° C. in a seal tube for 3 hours in the microwave. After this time water and EtOAc was added to the reaction mixture. The two phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were filtered through a phase separator and the solvent was evaporated. The residue was purified by flash column chromatography on silica (gradient elution with EtOAc/isohexane from 0 to 100% and then DCM/MeOH from 0 to 15%. The fractions containing the product were combined and the solvent evaporated to afford the title compound as a grey solid (145 mg, 79%).

(40) LCMS (ES+) [M+H].sup.+ 486, RT 1.90 minutes (Method 3).

Intermediate 5

3-(5-bromo-3-fluoropyridin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile

(41) ##STR00011##

(42) A solution of n-butyllithium (2.5 M in hexane, 12.54 mL, 31.3 mmol) was added dropwise to a solution of 2,5-dibromo-3-fluoropyridine (7.99 g, 31.3 mmol) in toluene (200 mL) at −70° C. and after addition the reaction mixture was stirred at −70° C. over 1 h. A solution of 1-methyl-3-oxocyclobutanecarbonitrile (3.00 g, 26.1 mmol) in toluene (50 mL) was added dropwise to the reaction mixture at −70° C. and the resulting solution was then stirred over 2 h at −70° C.

(43) The reaction mixture was then allowed to warm up to 0° C. and a saturated solution of ammonium chloride (50 mL) was added at 0° C. The resulting mixture was extracted with EtOAc (2×100 mL) and the combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica (gradient elution with MeOH/DCM 0-2%) to afford the title compound (857 mg, 11.5%).

(44) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.29 (s, 3H), 2.6 (d, J=13.3 Hz, 1H), 2.89 (dd, J=1.8 & 13.3 Hz, 1H), 6.21 (s, 1H), 8.17 (dd, J=1.8 & 10.2 Hz, 1H), 8.53 (t, J=1.8 Hz, 1H).

Intermediate 6

3-methylidene-1-(morpholine-4-carboximidoylcyclobutane-1-carbonitrile

(45) ##STR00012##

(46) 3-methylenecyclobutanecarbonitrile (8 g, 83.3 mmol, was dissolved in tetrahydrofuran (100 mL) lithium diisopropylamide (46 mL, 92 mmol, 2.0 mol/L) was added dropwise at −78° C. The mixture was stirred at −78° C. for 1 hour before adding the solution of morpholine-4-carbonitrile (9.4 mL, 92 mmol) in THF (20 mL) dropwise. The mixture was stirred at −78° C. for 1 additional hour. The reaction was quenched with saturated NH.sub.4Cl solution and extracted twice with TBME. The organics were combined and concentrated. The crude material was purified by flash column chromatography on silica (gradient elution with 0-20% MeOH/DCM) to give the title compound (8.0 g, 47%).

(47) LCMS (ES+) [M+H].sup.+ 206, RT 0.68 minutes (Method 3).

Intermediate 7

1-(5-bromopyrimidin-2-yl)-3-methylidenecyclobutane-1-carbonitrile

(48) ##STR00013##

(49) 5-bromo-1,2,3-triazine available commercially (1.30 g, 8.13 mmol) was suspended in MeCN (5 mL) and cooled in an ice bath. A solution of Intermediate 6 (1.83 g, 8.92 mmol) in MeCN (10 mL) was then added dropwise. After stirring for 10 min the ice bath was removed and the reaction heated to 45° C. overnight. The mixture was reduced under vacuum and the residue purified by flash column chromatography on silica (gradient elution with 0-25% EtOAc/isohexane). Relevant fractions combined and concentrated to give the title compound as a yellow oil which solidified upon standing (375 mg, 18.5%).

(50) LCMS (ES+) [M+H].sup.+ 250/252, RT 1.99 minutes (Method 3).

Intermediate 8

1-(5-bromopyrimidin-2-yl)-3-hydroxy-3-methylcyclobutane-1-carbonitrile

(51) ##STR00014##

(52) Intermediate 7 (375 mg, 1.50 mmol) in tetrafluoroboric acid (2.5 mL, 19 mmol) was heated to 70° C. for 6 hr before cooling. The reaction was quenched by addition of saturated sodium bicarbonate solution. EtOAc was then added and the layers were separated and the aqueous layer again extracted with EtOAc. The combined organic phase was dried, filtered and reduced under vacuum. The residue was purified flash column chromatography on silica (gradient elution with 20-50% EtOAc/isohexane). The relevant fractions were combined and concentrated under vacuum to afford product as a mixture of isomers. These were then separated by preparative HPLC to afford title compound as a white solid (110 mg, 27%).

(53) LCMS (ES+) [M+H].sup.+ 268/270, RT 0.93 minutes (Method 3).

(54) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.10 (s, 2H), 2.95-2.85 (m, 2H), 2.84-2.75 (m, 2H), 1.21 (s, 3H).

Intermediate 9

1-(5-bromo-3-fluoropyridin-2-yl)-3-methylidenecyclobutane-1-carbonitrile

(55) ##STR00015##

(56) In a 1 litre 3-necked round bottom flask, under nitrogen, were combined 5-bromo-2,3-difluoropyridine (25.0 g, 126 mmol) and 3-methylenecyclobutanecarbonitrile (16 mL, 152 mmol) in anhydrous toluene (250 mL). The solution was cooled to 0° c. (ice/salt bath). Then sodium bis(trimethylsilyl)amide (242 mL, 145 mmol) was added via a dropping funnel. During the addition the temperature rose to 12° C. for a short time. When the addition was complete the reaction was stirred for 45 minutes at 0° C. The reaction mixture was poured into 1 M citric acid (200 mL), layers separated and the aqueous layer extracted with EtOAc (2×250 mL). The combined organics were passed through a phase separator, filtered and concentrated in vacuo to give a brown oil. This was purified with flash column chromatography on silica (gradient elution with 0-20% EtOAc/isohexane to afford title compound as a white solid (25.2 g, 75%)

(57) LCMS (ES+) [M+H].sup.+ 267/269, RT 1.09 minutes (Method 2).

Intermediate 10

5-(5-bromo-3-fluoropyridin-2-yl)-1-oxaspiro[2.3]hexane-5-carbonitrile

(58) ##STR00016##

(59) 3-chloroperoxybenzoic acid (2.69 g, 12.0 mmol) was added to a solution of Intermediate 9 (1.50 g, 5.62 mmol) in DCM (60 mL) and stirred at r.t. overnight. Reaction was quenched with sat. aq. Na.sub.2S.sub.2O.sub.5 solution, diluted with DCM and the layers separated. The organic layer was washed twice with sat. bicarb and then water before concentrating under vacuum. This residue was purified with flash column chromatography on silica (gradient elution with 10-30% EtOAc/isohexane). The relevant fractions were combined and concentrated under vacuum to give an off-white solid (1.10 g, 69%).

(60) LCMS (ES+) [M+H].sup.+ 283/285, 1.53 minutes (Method 3).

Intermediate 11

1-(5-bromo-3-fluoropyridin-2-yl)-3-hydroxy-3-methylcyclobutane-1-carbonitrile

(61) ##STR00017##

(62) Intermediate 10 (900 mg, 3.18 mmol) was dissolved in anhydrous EtOH (30 mL), stirred for 10 min. Anhydrous MeOH (5 mL) was then added to aid solubility followed by sodium borohydride (425 mg, 11.1 mmol). After 6.5 hr, the reaction was quenched by partitioning between sat. aq. ammonium chloride and EtOAc. Layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic phase was washed with brine and then dried, filtered and reduced under vacuum. The crude residue was purified with flash column chromatography on silica (gradient elution with 30-45% EtOAc/isohexane). Relevant fractions were combined and concentrated under vacuum to afford product as a mixture of isomers. These were separated by preparative HPLC to afford Intermediate 11 as a white solid (52 mg, 6%) LCMS (ES+) [M+H].sup.+ 285/287, RT 1.28 minutes. (Method 3).

(63) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.69-8.62 (m, 1H), 8.36 (dd, J=10.0, 1.9 Hz, 1H), 5.54 (s, 1H), 2.97 (d, J=12.7 Hz, 2H), 2.80 (d, J=12.7 Hz, 2H), 1.05 (s, 3H).

Example 1

3-[5-[(1R,11R)-18-(difluoromethoxy)-13-oxo-12-(trideuteriomethyl)-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-5-yl]pyrimidin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile

(64) ##STR00018##

(65) (7R,14R)-11-chloro-1-(difluoromethoxy)-6-(trideutero)methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (Intermediate 159 of WO 2016/050975) (700 mg, 1.44 mmol), Intermediate 3 (461 mg, 1.72 mmol), potassium phosphate tribasic (1252 mg, 5.78 mmol) and tricyclohexylphosphonium tetrafluoroborate (66 mg, 0.174 mmol) were suspended in a mixture of 1,4-dioxane (15 mL, 175 mmol) and water (2 mL). The mixture was degassed/nitrogen-purged 3 times before addition of tris(dibenzylideneacetone)dipalladium(0) (70 mg, 0.074 mmol). The mixture was further degassed/nitrogen-purged and heated in a microwave at 110° C. for 2.5 hours. The mixture was then diluted with water and twice extracted with EtOAc. The organics were combined, dried and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (gradient elution 0-100% EtOAc/isohexane and 0-10% MeOH/DCM to give the title compound (343 mg, 31%).

(66) LCMS (ES+) [M+H].sup.+ 546, RT 1.97 minutes (Method 1).

(67) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.11 (s, 2H), 8.28 (dd, J=6.1, 3.3 Hz, 1H), 7.83-7.74 (m, 2H), 7.69 (t, J=73.0 Hz, 1H), 7.64 (dd, J=8.5, 1.8 Hz, 1H), 7.55-7.46 (m, 2H), 6.32 (d, J=7.1 Hz, 1H), 6.16 (s, 1H), 5.26 (d, J=7.1 Hz, 1H), 3.53 (dt, J=14.1, 7.2 Hz, 1H), 2.96-2.86 (m, 2H), 2.85 (d, J=13.7 Hz, 1H), 2.81-2.72 (m, 2H), 1.45 (s, 3H).

Example 2

3-[5-[(1R,11R)-18-(difluoromethoxy)-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-5-yl]pyrimidin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile

(68) ##STR00019##

(69) A flame-dried three-necked flask under nitrogen was charged with (6R,12R)-2-chloro-11-(difluoromethoxy)-7,12-dihydro-6H-6,12-methanobenzimidazo[2,1-c][1,4]benzodiazepine (Example 11 of WO 2016/050975 (750 mg, 1.996 mmol)), XPhos(PiAllyl) precatalyst (67 mg, 0.099 mmol), potassium acetate (494 mg, 4.98 mmol) and bis(pinacolato)diboron (532 mg, 2.10 mmol) before it was evacuated and backfilled with nitrogen three times. Then, 1,4-dioxane (4 mL) was added and the mixture was stirred at 100° C. After 3.5 hours, a solution of Intermediate 3 (589 mg, 2.20 mmol) in dry 1,4-dioxane (2 mL) was added followed by aqueous solution of potassium phosphate tribasic (1.5 mL, 3.0 mmol). Stirring at 100° C. was continued for 19 hours before the mixture was cooled down to r.t. poured into brine (100 mL), diluted with EtOAc (100 mL) and partitioned. The aqueous washings were re-extracted with EtOAc (100 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification by flash column chromatography on silica (gradient elution with MeOH in DCM (0 to 5%), followed by trituration of the product in Et2O to afford the title compound as a tan solid (511 mg, 49%).

(70) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.16 (d, J=6.8 Hz, 1H), 9.11 (s, 2H), 8.23 (dd, J=5.7, 3.8 Hz, 1H), 7.81-7.73 (m, 2H), 7.70 (t, J=73 Hz, 1H), 7.63 (dd, J=8.5, 1.8 Hz, 1H), 7.55-7.46 (m, 2H), 6.38 (d, J=7.0 Hz, 1H), 6.15 (s, 1H), 4.91 (t, J=6.8 Hz, 1H), 3.50 (dt, J=13.6, 7.1 Hz, 1H), 2.96-2.87 (m, 2H), 2.81-2.72 (m, 3H), 1.45 (s, 3H)

(71) LCMS (ES+) [M+H].sup.+ 529, RT 1.45 minutes (Method 3)

Example 3

3-[5-[(1R,11R)-18-(difluoromethoxy)-6-fluoro-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-5-yl]pyrimidin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile

(72) ##STR00020##

(73) Intermediate 4 (910 mg, 1.69 mmol), Intermediate 3 (500 mg, 1.87 mmol), potassium phosphate tribasic (1.10 g, 5.08 mmol) and tricyclohexylphosphonium tetrafluoroborate (65 mg 0.171 mmol) were suspended in 1,4-dioxane (20 mL) and water (5 mL) added. The reaction was degassed with three cycles of vacuum and nitrogen before the addition of tris(dibenzylideneacetone)dipalladium(0) (80 mg 0.085 mmol). The reaction was again degassed/refilled and heated to 100° C. for 4.5 hr before being allowed to cool to r.t. O/N. The reaction was partitioned between brine and EtOAc and the layers separated. The organic layer was removed and the aqueous further extracted with EtOAc. The combined organic phase was dried, filtered and reduced under vacuum. The residue was triturated in DCM and filtered. Material was purified by flash column chromatography on silica (gradient elution with 0-20% MeOH/DCM) and the relevant fractions combined and concentrated to give the title compound as a pale yellow solid (465 mg, 50%).

(74) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.17 (d, J=6.9 Hz, 1H), 9.01 (d, J=1.7 Hz, 2H), 8.27-8.20 (m, 1H), 7.69 (d, J=11.4 Hz, 1H), 7.62 (t, J=73.0 Hz, 1H), 7.57 (d, J=6.8 Hz, 1H), 7.54-7.48 (m, 2H), 6.36 (d, J=7.1 Hz, 1H), 6.19 (s, 1H), 4.92 (t, J=6.8 Hz, 1H), 3.55-3.45 (m, 1H), 2.92 (d, J=13.5 Hz, 2H), 2.82-2.70 (m, 3H), 1.46 (s, 3H).

(75) LCMS (ES+) [M+H].sup.+ 547, 1.74 minutes (Method 1).

Example 4

3-[5-[(1R,11R)-18-(difluoromethoxy)-12-methyl-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3,5,7,9,14(19),15,17-heptaen-5-yl]-3-fluoropyridin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile

(76) ##STR00021##

(77) A solution of K.sub.3PO.sub.4 (521 mg, 2.38 mmol) in water (3.75 mL) is added to a mixture of Intermediate 5 (226 mg, 794 μmol) and Intermediate 2 (382 mg, 793 μmol) in 1,4-dioxane (15 mL). Once argon was bubbled through this solution, [bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (30 mg, 40 μmol) was added. The resulting reaction mixture was heated at reflux for 4 h, then was cooled down to room temperature and poured into water (50 mL). This solution was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue as purified by flash column chromatography on silica (gradient elution with MeOH/DCM 0-5%) to afford the title compound (192 mg, 43%) as a beige solid.

(78) LCMS (ES+) [M+H].sup.+ 560, RT 1.28 minutes.

(79) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.33 (s, 3H), 2.78 to 2.85 (m, 3H), 2.96 (broad d, J=12.2 Hz, 2H), 3.36 (s, 3H), 3.52 (m, 1H), 5.24 (d, J=7.2 Hz, 1H), 6.16 (s, 1H), 6.30 (d, J=7.2 Hz, 1H), 7.47 to 7.52 (m, 2H), 7.60 (dd, J=1.7 & 8.5 Hz, 1H), 7.68 (t, J=73.3 Hz, 1H), 7.75 (m, 2H), 7.95 (dd, J=2.0 & 12.0 Hz, 1H), 8.27 (m, 1H), 8.65 (t, J=2.0 Hz, 1H).

Example 5

3-[5-[(1R,11R)-18-(difluoromethoxy)-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3,5,7,9,14(19),15,17-heptaen-5-yl]-3-fluoropyridin-2-yl]-3-hydroxy-1-methylcyclobutane-1-carbonitrile

(80) ##STR00022##

(81) A solution of K.sub.3PO.sub.4 (535 mg, 2.45 mmol) in water (2.5 mL) is added to a mixture of intermediate 5 (232.5 mg, 815.4 μmol) and (7R,14R)-1-(difluoromethoxy)-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (Intermediate 171 of WO 2016/050975) (381 mg, 815.4 μmol) in 1,4-dioxane (10 mL). Once argon was bubbled through this solution, [bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (31.4 mg, 40.8 μmol) was added. The resulting reaction mixture was heated at reflux for 4 hr, then was cooled down to room temperature and poured into water (50 mL). This solution was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/DCM 0-5%) to afford the title compound (67 mg, 15%) as a beige solid.

(82) LCMS (ES+)[M+H].sup.+ 546, RT 1.21 minutes (Method 4).

(83) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ: 1.34 (s, 3H), 2.75 (d, J=13.4 Hz, 1H), 2.80 (broad d, J=13.4 Hz, 2H), 2.96 (broad d, J=13.4 Hz, 2H), 3.49 (m, 1H), 4.89 (t, J=6.9 Hz, 1H), 6.16 (s, 1H), 6.36 (d, J=7.2 Hz, 1H), 7.48 to 7.53 (m, 2H), 7.58 (dd, J=1.8 & 8.6 Hz, 1H), 7.68 (t, J=73.3 Hz, 1H), 7.73 (m, 2H), 7.94 (dd, J=1.8 & 11.9 Hz, 1H), 8.23 (m, 1H), 8.65 (t, J=1.8 Hz, 1H), 9.13 (d, J=6.9 Hz, 1H).

Example 6

1-[5-[(1R,11R)-18-(difluoromethoxy)-12-methyl-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-5-yl]pyrimidin-2-yl]-3-hydroxy-3-methylcyclobutane-1-carbonitrile

(84) ##STR00023##

(85) Intermediate 2 (140 mg, 0.29 mmol), Intermediate 8 (85 mg, 0.32 mmol), potassium phosphate tribasic (185 mg, 0.85 mmol) and tricyclohexylphosphonium tetrafluoroborate (11 mg, 0.029 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL) added. The reaction was degassed with three cycles of vacuum and nitrogen before the addition of tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.015 mmol). The reaction was again degassed/refilled with nitrogen and heated to 100° C. for 5 hr before being allowed to cool to r.t. overnight. The reaction mixture was diluted with DCM and water, passed through a phase separator and the organic phase reduced under vacuum. Purified with flash column chromatography on silica (gradient elution with 50-100% EtOAc/isohexane and then 0-10% MeOH/DCM). Desired fractions combined and concentrated under vacuum to afford title compound as a white solid (56 mg, 36%).

(86) LCMS (ES+) [M+H].sup.+ 543, RT 1.67 minutes (Method 1).

(87) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.16 (s, 2H), 8.34-8.21 (m, 1H), 7.83-7.74 (m, 2H), 7.71-7.63 (m, 1H), 7.70 (t, J=73.6 Hz, 1H), 7.54-7.47 (m, 2H), 6.32 (d, J=7.1 Hz, 1H), 5.52 (s, 1H), 5.27 (d, J=7.1 Hz, 1H), 3.61-3.47 (m, 1H), 3.37 (s, 3H), 3.05-2.91 (m, 2H), 2.89-2.79 (m, 3H), 1.24 (s, 3H)

Example 7

1-[5-[(1R,11R)-18-(difluoromethoxy)-12-methyl-13-oxo-2,9,12-triazapentacyclo[9.8.1.02,10.03,8.014,19]icosa-3(8),4,6,9,14(19),15,17-heptaen-5-yl]-3-fluoropyridin-2-yl]-3-hydroxy-3-methylcyclobutane-1-carbonitrile

(88) ##STR00024##

(89) Intermediate 2 (95 mg, 0.16 mmol), Intermediate 11 (50 mg, 0.18 mmol), potassium phosphate tribasic (100 mg, 0.46 mmol) and tricyclohexylphosphonium tetrafluoroborate (10 mg, 0.026 mmol) were dissolved in 1,4-dioxane (2.0 mL) and water (0.5 mL) added. The reaction was degassed with three cycles of vacuum and nitrogen before the addition of tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.011 mmol). The reaction was again degassed/refilled with nitrogen and heated to 100° C. for 5 h before being allowed to cool to r.t. Reaction was diluted with DCM and water, passed through a phase separator and the organic phase reduced under vacuum. Purified with flash column chromatography on silica (gradient elution with 50-100% EtOAc/isohexane t and then 0-15% MeOH/DCM). Desired fractions eluting at approx. 10% MeOH/DCM were combined and concentrated under vacuum to give a pale yellow foam, further purified by preparative HPLC and freeze-dried overnight to afford the title compound as a white powder (20 mg, 23%)

(90) LCMS (ES+) [M+H].sup.+ 560, RT 1.81 minutes (Method 1).

(91) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.75 (t, J=1.7 Hz, 1H), 8.31-8.25 (m, 1H), 8.12 (dd, J=11.8, 1.9 Hz, 1H), 7.90-7.68 (m, 3H), 7.65 (dd, J=8.6, 1.7 Hz, 1H), 7.53-7.49 (m, 2H), 6.31 (d, J=7.1 Hz, 1H), 5.55 (s, 1H), 5.27 (d, J=7.1 Hz, 1H), 3.65-3.44 (m, 1H), 3.37 (s, 3H), 3.04 (d, J=12.2 Hz, 2H), 2.85 (d, J=13.3 Hz, 3H), 1.10 (s, 3H)