MILVEXIAN

ミルベクシアン;

Molecular Formula,C28-H23-Cl2-F2-N9-O2

Molecular Weight, 626.4441

BMS-986177, JNJ-70033093; JNJ-3093, WHO 11401

CAS 1802425-99-5

(5R,9S)-9-(4-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-21-(difluoromethyl)-5-methyl-21H-3-aza-1(4,2)-pyridina-2(5,4)-pyrazolacyclonaphan-4-one

Prevention and Treatment of Thromboembolic Disorders

Milvexian, also known as BMS-986177, is a blood coagulation factor XIa inhibitor.Bristol-Myers Squibb , in collaboration with  Janssen , is developing milvexian (BMS-986177, JNJ-70033093; JNJ-3093), an antithrombotic factor XIa (FXIa) inhibitor, for the oral prevention and treatment of thrombosis.

PATENT

WO-2020210629

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020210629&tab=PCTDESCRIPTION&_cid=P11-KGN1SB-37057-1

Process for preparing milvexian as FXIa and/or plasma kallikrein inhibitors useful for treating deep vein thrombosis, stroke, and atherosclerosis.

(9i?,13ri)-13-{4-[5-chloro-2-(4-chloro- 1 //- 1 2.3-triazol- 1 -yl)phenyl |-6-o\o- 1 6-dihydropyri midin- 1 -yl }-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^{2 (5}]octadeca-l(18),2(6),4,14,16-pentaen-8-one, has the structure of Formula (I):

PATENT

WO2020210613

PATENT

WO2016053455

PATENT

product case WO2016053455 novel macrocyclic compounds are FXIa and/or plasma kallikrein inhibitors.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016053455

Scheme 1

4M HCI or TFA

1c 1a

Scheme 2

2d

Scheme 3

EXAMPLES

Example 1. Preparation of (9i?,135)-13-{4-[5-chloro-2-(4-chloro-lH-l,2,3-triazol-l-yl)phenyl]-6-oxo- 1 ,6-dihydropyrimidin- 1 -yl} -3-(difluoromethyl)-9-methyl-3,4,7, 15-tetraazatricyclo[ 12.3.1.0²‘⁶] -8-one trifluoroacetate

1A. Preparation of l-(difluoromethyl)-4-nitro-lH-pyrazole

CS₂CO₃ (14.41 g, 44.2 mmol) was suspended in a solution of 4-nitro-lH-pyrazole (5.00 g, 44.2 mmol) and DMF (40 mL). After heating to 120 °C for 5 min, solid sodium 2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was added in 10 equal portions over 20 min. The reaction was complete after 10 min of additional heating. The mixture was added to a separatory funnel containing 100 mL water and extracted with Et₂0 (2 x 50 mL). The combined organic layers were concentrated. Purification by normal-phase chromatography eluting with a gradient of hexanes/EtOAc yielded l-(difluoromethyl)-4-nitro-lH-pyrazole (6.99 g, 42.9 mmol, 97% yield) as a clear, colorless oil. 1H NMR (500MHz, CDCI₃) δ 8.58 (s, 1H), 8.22 (s, 1H), 7.39 – 7.05 (t, J= 60 Hz, 1H).

IB. Preparation of (S)-tert-butyl (l-(4-(l-(difluoromethyl)-4-nitro-lH-pyrazol-5-yl)pyridin-2-yl)but-3 -en- 1 -yl)carbamate

To a N₂ flushed, 500 mL RBF was added {S)-tert-bvXy\ (l-(4-chloropyridin-2-yl)but-3-en-l-yl)carbamate, prepared as described in Example 3, (10 g, 35.4 mmol), 1-(difluoromethyl)-4-nitro-lH-pyrazol (6.34 g, 38.9 mmol) and dioxane (100 mL). The solution was bubbled with N₂ for 5 min. Then Pd(OAc)₂ (0.40 g, 1.7 mmol),

di(adamantan-l-yl)(butyl)phosphine (1.27 g, 3.5 mmol), K₂CO₃ (14.7 g, 106 mmol) and PvOH (1.08 g, 10.61 mmol) were added. The reaction mixture was bubbled with N₂ for 5 min then the reaction mixture was heated to 100 °C for 3 h. After this time, the solution was cooled to rt and water (200 mL) was added. The reaction mixture was then extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over Na₂S0₄, filtered and concentrated in vacuo. Purification by normal phase chromatography eluting with a gradient of hexanes/EtOAc afforded (S)-tert-butyl ( 1 -(4-( 1 -(difluoromethyl)-4-nitro- lH-pyrazol-5 -yl)pyridin-2-yl)but-3 -en- 1 -yl)carbamate (12.91 g, 31.5 mmol, 89% yield) as a slightly yellow oil. MS(ESI) m/z: 410.4 [M+H]⁺. 1H NMR (400MHz, CDC1₃) δ 8.80 (dd, J=5.1, 0.7 Hz, 1H), 8.36 (s, 1H), 7.34 (s, 1H), 7.31 (dd, J=5.1, 1.5 Hz, 1H), 7.27 – 6.91 (t, J=58 Hz, 1H), 5.79 – 5.63 (m, 1H), 5.16 – 5.03 (m, 2H), 4.92 (d, J=5.9 Hz, 1H), 2.67 (t, J=6.4 Hz, 2H), 1.46 (br. s., 9H).

1C. Preparation of 
(l-(4-(4-amino-l -(difluoromethyl)- lH-pyrazol-5-yl)pyridin-2-yl)but-3 -en- 1 -yl)carbamate

To a 100 mL, 3-necked RBF was added a solution of (S)-tert-butyl (l-(4-(l-(difluoromethyl)-4-nitro-lH-pyrazol-5-yl)pyridin-2-yl)but-3-en-l-yl)carbamate (0.78 g, 1.90 mmol) in MeOH (12 mL) and a solution of NH₄C1 (1.02 g, 19 mmol) in water (3 mL). To the solution was added Fe (0.53 g, 9.49 mmol). The reaction mixture was heated to 65 °C for 3 h. Water (50 mL) was added. After cooling to rt, the mixture was filtered through a CELITE® pad and rinsed with MeOH (200 mL). The filtrate was concentrated in vacuo. The residue was partitioned between EtOAC (100 mL) and water (100 mL). The organic phase was separated, washed with water (100 mL), brine (100 mL), dried over Na₂S0₄, filtered and concentrated in vacuo. Purification by normal phase chromatography eluting with a gradient of DCM/MeOH yielded (S)-tert-butyl (l-(4-(4-amino- 1 -(difluoromethyl)- lH-pyrazol-5 -yl)pyridin-2-yl)but-3 -en- 1 -yl)carbamate (0.585 g, 1.54 mmol, 81% yield) as an oil. MS(ESI) m/z: 380.1 [M+H]⁺. 1H NMR (400MHz,

CDC1₃) δ 8.70 (dd, J=5.0, 0.7 Hz, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.32 (dd, J=5.1, 1.5 Hz, 1H), 7.28 – 6.97 (t, J=58 Hz, 1H), 5.80 – 5.66 (m, 1H), 5.65 – 5.53 (m, 1H), 5.13 – 5.03 (m, 2H), 4.87 (br. s., 1H), 3.22 (br. s., 2H), 2.65 (t, J=6.5 Hz, 2H), 1.52 – 1.37 (m, 9H).

ID. Preparation of tert-butyl ((5)-l-(4-(l-(difiuoromethyl)-4-((i?)-2-methylbut-3-enamido)- lH-pyrazol-5-yl)pyridin-2-yl)but-3-en- 1 -yl)carbamate

To a N₂ flushed, 3 -necked, 250 mL RBF was added a solution of {S)-tert-bvXy\ (1-(4-(4-amino-l-(difluoromethyl)-lH-pyrazol-5-yl)pyridin-2-yl)but-3-en-l-yl)carbamate (5 g, 13.18 mmol) and EtOAc (50 ml). The solution was cooled to -10 °C and (R)-2-methylbut-3-enoic acid, as prepared in Example 2, (1.72 g, 17.13 mmol), pyridine (4.26 ml, 52.7 mmol). and T3P® (23.54 ml, 39.5 mmol) were added. The cooling bath was removed and the solution was allowed to warm to rt and then stir over a period of 20 h. Water (30 mL) and EtOAc (30 mL) were added and the mixture was stirred for 30 min. The organic phase was separated and the aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were washed with brine (50 mL), dried over

Na₂SC”4, filtered and concentrated in vacuo. Purification by normal phase

chromatography eluting with a gradient of hexanes/EtOAc gave tert-butyl ((5)-l-(4-(l-(difluoromethyl)-4-((i?)-2-methylbut-3-enamido)-lH-pyrazol-5-yl)pyridin-2-yl)but-3-en-l-yl)carbamate (5.69 g, 12.33 mmol, 94% yield). MS(ESI) m/z: 462.2 [M+H]⁺. 1H NMR (400MHz, CDC1₃) δ 8.75 (dd, J=5.0, 0.6 Hz, 1H), 8.37 (s, 1H), 7.32 (t, J=59 Hz, 1H), 7.28 (br. s., 1H), 7.20 (s, 1H), 5.97 – 5.85 (m, 1H), 5.78 – 5.65 (m, 1H), 5.56 – 5.44 (m, 1H), 5.28 – 5.19 (m, 2H), 5.12 (d, J=2.0 Hz, 2H), 4.91 – 4.82 (m, 1H), 3.20 – 3.11 (m, 1H), 2.72 – 2.62 (m, 2H), 1.48 – 1.43 (s, 9H), 1.33 (d, J=6.8 Hz, 3H).

IE. Preparation of tert-butyl N-[(9i?,10E,135)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0²‘⁶]octadeca-l(18),2(6),4,10,14,16-hexaen-13-yl] carbamate

To a N₂ flushed, 2 L, 3 -necked, RBF was added a solution of tert-butyl ((S)-l-(4-(1 -(difluoromethyl)-4-((i?)-2-methylbut-3 -enamido)- lH-pyrazol-5 -yl)pyridin-2-yl)but-3 -en-l-yl)carbamate (3 g, 6.50 mmol) in EtOAc (1300 ml). The solution was sparged with argon for 15 min. Grubbs II (1.38 g, 1.63 mmol) was added in one portion. The reaction mixture was heated to reflux for 24 h. After cooling to rt, the solvent was removed and the residue was purified by normal phase chromatography eluting with a gradient of DCM/MeOH to yield tert-butyl N-[(9R, 10E, 135)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0²‘⁶]octadeca-l(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (2.13 g, 4.91 mmol, 76% yield) as a tan solid. MS(ESI) m/z: 434.4 [M+H]⁺. 1H NMR (400MHz, CDC1₃) δ 8.71 (d, J=5.1 Hz, 1H), 7.78 (s, 1H), 7.44 – 7.40 (m, 1H), 7.36 (br. s., 1H), 7.27 (t, J=58 Hz, 1H), 6.87 (s, 1H), 6.49 – 6.39 (m, 1H), 5.78 (s, 1H), 4.80 (br. s., 2H), 3.18 – 3.08 (m, 1H), 3.08 – 2.98 (m, 1H), 2.06 – 1.93 (m, 1H), 1.51 (s, 9H), 1.19 (d, J=6.6 Hz, 3H).

IF. Preparation of tert-butyl N-[(9i?,135)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0²‘⁶]octadeca-l(18),2(6),4,14,16-pentaen-13-yl]carbamate

Pd/C (0.60 g, 0.570 mmol) was added to a 250 mL Parr hydrogenation flask containing a solution of tert-butyl N-[(9i?,10E,135)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0²‘⁶]octadeca-l(18),2(6),4,10,14,16-hexaen-13-yljcarbamate (2.46 g, 5.68 mmol) in EtOH (100 mL). The flask was purged with N₂ and pressurized to 55 psi of H₂ allowed to stir for 18 h. The reaction was filtered through CELITE® and concentrated to yield tert-butyl N-[(9i?,135)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0²‘⁶]octadeca-l(18),2(6),4,14,16-pentaen-13-yl]carbamate (2.17 g, 88% yield) as a tan solid. MS(ESI) m/z: 436.3 [M+H]⁺. 1H NMR (400MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 7.96 (t, J=58 Hz, 1H), 7.43 (s, 1H), 7.32 (d, J=4.8 Hz, 1H), 7.22 (d, J=7.3 Hz, 1H), 4.66 (d, J=8.3 Hz, 1H), 2.62 (br. s., 1H), 1.88 (d, J=12.8 Hz, 1H), 1.77 – 1.59 (m, 2H), 1.42 – 1.28 (m, 9H), 1.15 (d, J=18.2 Hz, 2H), 0.83 (d, J=7.0 Hz, 3H).

I G. Preparation of (9R, 13S)-l 3-amino-3-(difiuoromethyl)-9-methyl-3,4,7, 15-tetraazatricyclo[ 12.3.1.0²‘⁶]octadeca- 1(18),2(6),4, 14,16-pentaen-8-one

4 N HC1 in dioxane (3.88 mL, 15.5 mmol) was added to a solution of tert-butyl N-[(9R, 13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7, 15-tetraazatricyclo[12.3.1.0²‘⁶] octadeca-l(18),2(6),4,14,16-pentaen-13-yl]carbamate (2.25 g, 5.2 mmol) in MeOH (10 mL). The reaction was allowed to stir at rt for 2 h. The reaction was cooled in an ice bath, and 7 N NH₃ in MeOH (13.3 mL, 93.0 mmol) was added. After 5 min, the reaction was diluted with CH₂C1₂ (80 mL) and the solid that formed was filtered. The filtrate was concentrated to yield (9i?,135)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0²‘⁶]octadeca-l(18),2(6),4,14,16-pentaen-8-one (1.3 g, 3.88 mmol, 75% yield). MS(ESI) m/z: 336.3 [M+H]⁺. 1H NMR (400MHz, DMSO-d₆) δ 9.33 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 7.94 (t, J=58 Hz, 1H), 7.85 (s, 1H), 7.40 (s, 1H), 7.32 (d, J=5.0 Hz, 1H), 4.01 (dd, J=10.2, 5.1 Hz, 1H), 2.63 – 2.53 (m, 1H), 1.90 – 1.69 (m, 2H), 1.53 -1.36 (m, 2H), 1.16 – 1.00 (m, 1H), 0.85 (d, J=7.0 Hz, 3H).

1H. Preparation of (9i?,135)-13-{4-[5-chloro-2-(4-chloro-lH-l,2,3-triazol-l-yl)phenyl]-6-oxo- 1 ,6-dihydropyrimidin- 1 -yl} -3-(difluoromethyl)-9-methyl-3 ,4,7, 15-tetraazatricyclo [12.3.1.0²‘⁶]octadeca- 1 ( 18),2(6),4, 14,16-pentaen-8-one.

To a 100 mL flask containing a white suspension of 6-(5-chloro-2-(4-chloro-lH-l,2,3-triazol-l-yl)phenyl)pyrimidin-4-ol (0.83 g, 2.7 mmol), as prepared in Example 4 in ACN (36 mL) was added HATU (1.12 g, 3.0 mmol) and DBU (0.53 mL, 3.5 mmol). The resulting clear, yellow solution was stirred at rt. After 5 min, (9i?,135)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0²‘⁶]octadeca-l(18),2(6),4,14,16-pentaen-8-one (0.9 g, 2.68 mmol) was added and the resulting suspension was stirred at rt for 3 h. The reaction was then concentrated and purified by normal phase silica gel chromatography, eluting with a gradient of 0% to 100% EtOAc in hexanes to yield (9i?,135)-13-{4-[5-chloro-2-(4-chloro-lH-l,2,3-triazol-l-yl)phenyl]-6-oxo- 1 ,6-dihydropyrimidin- 1 -yl} -3-(difluoromethyl)-9-methyl-3 ,4,7, 15-tetraazatricyclo [12.3.1.0²‘⁶]octadeca-l(18),2(6),4,14,16-pentaen-8-one (0.87 g, 50% yield) as a white solid. MS(ESI) m/z: 626.2 [M+H]⁺. 1H NMR (500MHz, CD₃OD) δ 8.91 – 8.83 (m, 1H), 8.78 – 8.71 (m, 1H), 8.33 (s, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.74 (s, 2H), 7.69 – 7.67 (m, 1H), 7.65 (s, 1H), 7.63 (t, J=58 Hz, 1H), 7.52 – 7.50 (m, 1H), 6.36 (d, J=0.8 Hz, 1H),

6.06 – 5.95 (m, 1H), 2.76 – 2.65 (m, 1H), 2.36 – 2.21 (m, 1H), 2.08 – 1.93 (m, 2H), 1.63 -1.53 (m, 1H), 1.53 – 1.42 (m, 1H), 0.99 (d, J=6.9 Hz, 3H). Analytical HPLC (Method A): RT = 8.87 min, purity = 99.7%.

///////////MILVEXIAN, BMS 986177, JNJ 70033093,  JNJ 3093, WHO 11401, ミルベクシアン ,

C[C@@H]1CCC[C@H](N2C=NC(=CC2=O)c3cc(Cl)ccc3n4cc(Cl)nn4)c5cc(ccn5)c6c(NC1=O)cnn6C(F)F