Phenyl Linked Quinolinyl Modulators Of Ror-Gamma-T

[0545] Example 1a: 1-(4-((4-Chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinolin-6-yl)(hydroxy)(1- Methyl-1H-imidazol-5-yl)methyl)piperidin-1-yl)ethanone

[0546]

[0547] At -78°C, add n-butyllithium (1.6M hexane solution, 0.585mL, 0.937mmol) to 6-bromo-4-chloro-2-methoxy-3-(3-(tri Fluoromethyl)phenyl)quinoline (409.8 mg, 0.984 mmol, Intermediate 5: Step e) in THF (3 mL). After 1 minute, 1-(4-(1-methyl-1H-imidazole-5-carbonyl)piperidin-1-yl)ethanone (231.4 mg, 0.984 mmol, Intermediate 1: step c) was added via a cannula THF (5mL) solution. The mixture was stirred at -78°C for 10 minutes, then transferred to an ice bath and stirred for another 45 minutes. Add saturated NH 4 The reaction mixture was quenched with aqueous Cl, diluted with water and extracted with EtOAc (3x). Dry (Na 2 SO 4 ) Organic phase, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 0-8% MeOH-DCM) to obtain the target compound as a white solid. MSm/e573.3[M+H] +.

[0548] Purification of 1-(4-((4-chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinolin-6-yl) by chiral HPLC (ChiralcelOD-H, EtOH) (Hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)piperidin-1-yl)ethanone, two enantiomers are obtained. Example 1b: (The first enantiomer eluted from the chiral column) 1 HNMR(400MHz, CDCl 3 , A 1.2:1 mixture of rotamers, the minor rotamer peaks are marked with *)δ8.21(s,1H), 8.16*(br.s.,1H), 7.85*(d,J= 2.53Hz,1H),7.83(d,J=2.53Hz,1H),7.72*(s,1H),7.70(s,1H),7.59-7.66(m,4H),7.54-7.58(m,2H) ,7.41-7.51(m,2H),7.34(s,2H),7.23(s,2H),4.78(d,J=12.63Hz,1H), 4.61*(d,J=12.63Hz,1H),4.01 (s,6H),3.95(d,J=13.14Hz,1H), 3.76*(d,J=11.12Hz,1H), 3.28(s,3H), 3.27*(s,3H),3.11-3.24* (m,1H),2.94-3.04(m,1H),2.56-2.70(m,3H),2.40-2.56(m,3H),2.25-2.38(m,2H),2.05(s,3H)*, 2.03(s,3H),1.13-1.44(m,6H); MSm/e573.2[M+H] + , And Example 1c: (the second enantiomer eluted from the chiral column) 1 HNMR(400MHz, CDCl 3 , A 1.2:1 mixture of rotamers, the minor rotamer peaks are marked with *)δ8.21(s,1H), 8.16*(br.s.,1H),7.84*(d,J= 3.03Hz,1H),7.82(d,J=2.53Hz,1H),7.71*(s,1H),7.69(s,1H),7.58-7.65(m,4H),7.52-7.58(m,2H) ,7.40-7.51(m,2H),7.29-7.35(m,2H),7.22(s,2H),4.77(d,J=13.1Hz,1H), 4.60(d,J=13.6Hz,1H), 4.00(s,6H),3.93(d,J=12.63Hz,1H), 3.74*(d,J=13.14Hz,1H), 3.27(s,3H), 3.26*(s,3H), 3.12-3.22 (m,1H),2.92-3.05(m,1H),2.80(s,1H),2.57-2.74(m,2H),2.39-2.55(m,3H),2.22-2.39(m,2H),2.04 *(s,3H),2.02(s,3H),1.12–1.46(m,6H); MSm/e573.2[M+H] +.

[0664] Through saturated NaHCO 3 Partitioning between aqueous solution and DCM neutralizes the racemate. Dry (Na 2 SO 4 ) The organic layer was filtered, concentrated to dryness, and purified by chiral HPLC (ChiralcelOD, 100% EtOH) to obtain two pure enantiomers. Example 34b: (The first enantiomer eluted from the chiral column) 1 HNMR(400MHz, CDCl 3 , About 1.5:1 mixture of rotamers) δ8.45 (d, J = 13.64 Hz, 1H), 8.20 (dd, J = 4.04, 8.59 Hz, 1H), 7.68 (t, J = 10.11 Hz, 1H) ),7.48-7.53(m,3H),7.24-7.34(m,2H),7.10-7.24(m,2H), 4.65(d,J=12.63Hz,0.6H),4.56(d,J=13.14Hz ,0.4H), 3.91(d,J=13.14Hz,0.4H),3.66-3.79(m,0.6H),3.31(s,1.8H), 3.29(s,1.2H), 3.18(t,J= 12.38Hz, 0.4H), 2.97 (t, J = 12.13 Hz, 0.6H), 2.38-2.69 (m, 2H), 2.34 (d, J = 13.14 Hz, 0.4H), 2.22 (d, J = 12.63 Hz ,0.6H),2.01(s,1.8H),1.95(s,1.2H),1.13-1.55(m,2.4H),1.09(d,J=12.63Hz,0.6H); MSm/e543.2[ M+H] +. Example 34c: (the second enantiomer eluted from the chiral column) 1 HNMR(400MHz, CDCl 3 , About 1.5:1 mixture of rotamers) δ8.46 (d, J = 12.63 Hz, 1H), 8.20 (dd, J = 3.79, 8.84 Hz, 1H), 7.68 (t, J = 10.11 Hz, 1H) ),7.46-7.53(m,3H),7.24-7.35(m,2H),7.10-7.23(m,2H), 4.64(d,J=13.14Hz,0.6H),4.55(d,J=12.63Hz ,0.4H), 3.90(d,J=13.14Hz,0.4H), 3.72(d,J=13.14Hz,0.6H), 3.31(s,1.8H), 3.29(s,1.2H), 3.18(t ,J=12.38Hz,0.4H),2.97(t,J=12.38Hz,0.6H),2.38-2.68(m,2H),2.34(d,J=12.63Hz,0.4H),2.21(d,J =13.14Hz,0.6H),2.01(s,1.8H),1.94(s,1.2H),1.12-1.58(m,2.4H),1.08(d,J=12.63Hz,0.6H); MSm/e543 .2[M+H] +.

[0549] Example 2a: 6-((1-Acetylpiperidin-4-yl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-2-methyl Oxy-3-(3-(trifluoromethyl)phenyl)quinoline-4-carbonitrile

[0550]

[0551] Fill a round-bottom flask with 1-(4-((4-chloro-2-methoxy-3-(3-(trifluoromethyl)phenyl)quinolin-6-yl)(hydroxy)(1 -Methyl-1H-imidazol-5-yl)methyl)piperidin-1-yl)ethanone (158mg, 0.276mmol, Example 1a), Zn(CN) 2 (58.3mg, 0.496mmol), Pd 2 (dba) 3 (37.9mg, 0.041mmol), nano zinc powder (5.4mg, 0.083mmol) and dicyclohexyl (2',4',6'-triisopropyl-[1,1'-diphenyl]-2- Yl)phosphine (X-Phos, 27.1 mg, 0.055 mmol). The flask was evacuated and filled with argon (three cycles). Then dimethylacetamide (1.4 mL, filled with argon for 30 minutes) was added, and the mixture was heated at 120°C for 4 hours. The mixture was cooled to room temperature and filtered Wash with EtOAc. Use 2MNH sequentially 4 The filtrate was washed with OH aqueous solution, water and saturated NaCl aqueous solution. Dry (Na 2 SO 4 ) Organic phase, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 1-8% MeOH-DCM) to obtain the title compound. MSm/e564.3[M+H] +.

[0552] Purification of 6-((1-acetylpiperidin-4-yl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-2- by chiral HPLC (ChiralcelOD-H, EtOH) Methoxy-3-(3-(trifluoromethyl)phenyl)quinoline-4-carbonitrile gives 2 enantiomers. Example 2b: (The first enantiomer eluted from the chiral column) 1 HNMR(400MHz, CDCl 3 , A 1.1:1 mixture of rotamers, the minor rotamer peaks are marked with *)δ8.28(s,1H), 8.24*(s,1H),7.84-7.91(m,2H), 7.71 -7.84(m,6H),7.63-7.71(m,2H),7.43-7.50(m,2H),7.29-7.33(m,2H),7.21(s,2H),4.76(d,J=14.65Hz ,1H),4.59*(d,J=11.12Hz,1H),4.06*(s,6H),3.94(d,J=12.63Hz,1H),3.68-3.80(m,1H), 3.29(s, 3H), 3.27*(s,3H),3.22(s,1H),3.13-3.22*(m,1H),3.10*(s,1H),2.93-3.04(m,1H),2.58-2.71(m ,1H),2.23-2.57(m,5H),2.04(s,3H),2.03(s,3H),1.12-1.47(m,6H); MSm/e564.2[M+H] + , And Example 2c: (the second enantiomer eluted from the chiral column) 1 HNMR(400MHz, CDCl 3 , 1.1:1 mixture of rotamers, the minor rotamer peaks are marked with *)δ8.28(s,1H),8.24*(s,1H),7.88-7.90*(m,1H), 7.85-7.87(m,1H),7.71-7.83(m,6H),7.64-7.71(m,2H),7.42-7.50(m,2H),7.31-7.34(m,2H),7.22(s,2H) ), 4.77(d,J=13.14Hz,1H), 4.60*(d,J=14.15Hz,1H), 4.07(s,6H), 3.94*(d,J=14.15Hz,1H), 3.68-3.80 (m, 1H), 3.28(s, 3H), 3.27*(s, 3H), 3.13-3.23(m, 1H), 2.96-3.05*(m, 1H), 2.95(s, 1H), 2.84*( s,1H),2.58-2.70(m,1H),2.22-2.57(m,5H),2.05*(s,3H),2.03(s,3H),1.17-1.45(m,6H); MSm/e564 .2[M+H] +.