triazineoxadiazoles, pharmaceutical composition that comprises them and their use

专利摘要:
TRIAZINAOXADIAZÓIS, PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS THEM AND USE OF THE SAME.The invention relates to new derivatives of formula (I).(I)where the substituents are defined in the report; for processes for the preparation of such derivatives; pharmaceutical compositions comprising such derivatives; such derivatives as a medicine such derivatives for the treatment of chronic pain.
公开号:BR112013005889A2
申请号:R112013005889-7
申请日:2011-09-13
公开日:2020-08-25
发明作者:Oliver BARKER；Alexander Heifetz；Richard Law；Ali Raoof；David WILLOWS；Jonathan Bentley；Mark G. Bock；Thomas Cain；Praful CHOVATIA；Jennifer Ruth DOD；Florence Eustache；Laura GLEAVE；Jonathan HARGRAVE
申请人:Novartis Ag；
IPC主号:

专利说明:

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ITESES IESESTNS o ESSISES EL TorcÃo o ToIeErs CF ToONIESES o o Toe <Soo ui so> XOEXL o> =. gEÉVIADS SESNINE S L26EXNOTIO 2 8EXNÓON & LAW 2Ãors 2 Erection of the ZWT TONS Z = uTroosIT É. = T AND CS. And if So. eo às az = FS T = és Z) & s3 À nO EXo z o Sá yz E TS nº 22 FER O 8 —Z a by a - SED = EE - SS SRE TÃL no. IT'S 833 NO SxT: s = 5 29º 3 3s5E = 2 208 EIS => À 6 Sounds ST zu 2 — Z os 2 2a º x I 2 wu o o
MM MM iu COMFORT 379/490
W -> & Zz o ”o É & Es q & = o <E = 2
FIT SES BSS ORFN -EBS TRY STE 1 ITS URE A n2SoOTFIr + 1nº2oEI NEOTELE IN THIS NTRO TAS ND EMUV- E EE ro E = rNrNo E ENQST 2 E ENT Dn 2 x So 2 So Io23S do SR 2x O To A. FT Ta DTPIEOSA o [CE o I "EBN CEE uBsx o 2 TLOTL troSTTE IFRONTT 1H E = OgS8YIXI = 029 SO LC EN oO “TI Ro NX Usa RT NON D + co OT o = N = = D Oo N 2" 2 / X2ÇQ036 ZIEZgOL x) ONE-Q AXN ONE LL <kaN Ê JEÇSS.-. IES o LISFLSEE 2 ES La 8 IomroftE. IgwIrsBa Fá <CBZITELS mESTES uu SZHQrX IL SZ II & SESQIAINSS BEZJOO Ss LS6XNroanaSO 2 8% XNHQO So 20r 2e-oo, 2cCI Zen Q Z2WTTBSSNT ZWTTOoN = o =) - T. o É s e e | : 2% 22 “a tTE Seo Es 9, 0" | 5 k = Fo DIAS are> 96 Fa Pucca so E to eg = PTC a - LE as to TI - Nu E = E eos TOC ss S 50 o 2 '8 28 = air 2 Ro sc so 25 TSE 25 EE O TN pe So TN TS Zu Oors NOS E. 2: xox ú Ss Ss
ATT SANS SS ARS SS NSi1 TIN “nncãéeMÁNANPNÕÕOS OA NS SA RI RAS ASS SASSAASSSSNSSSÓÕLLC-CC- = CC — CO” -C = O = O = OOO (LOSCCCcCCOOEIO 380/490 de> o Zz ooe Ss = Es 8 s = o Ds <E A o CATA XA O (5 AT XX O EI SSS Ss IES ES FETEE-TOR PE TOS - E nNnººeorIrr.
EESTECO EETECTION c EENTRQa 5 E ET N o Um 2 e “the Sw Log FR ST RIA FO TES
LORI ERS EMPEE +! 3 EE + LZEaCtion IFQCEr Io "X. = -ON TITE [ISCAS TS SEO NÇOSE SON E QT NO Oo QT NTE a gnETOSS EFFECTIVE <N Aa E SESSION. SESSION. S TES TAS. AfoºP%" x4x, & ISSBISEEÉ ISBISEEE ISBISEE <P TT oCrY + o <€ TTTI <> à SZoQEIXOX SZSIEEL a SESSILAN SEZÇNSA 6 2 EEXNMNOTIMO L2EEXN TIO Ss REI QEN = Oo 2cCcr ooo Oo ZzWToTooN— Z = WTTosa + E I ã o 2 3º = Oo 1 = SO | 5S5 to LD TÊE z = 28,. MA ss and 88 RO | E38 424) SF AS = º 2) z com = Es = SS = Le E so | O 285 (OE ooo 2X KA E Ze SxT ES '£ 29 qa 2 = TS x I2 os DN E - = - = EE SEN dz So RA TTE Zzu o = s TIO doe dao 2 - oo
DM MM "ii nGOGSSNSSNSSNÇSNA.“ ZfPRÉÊXMASRTTRII o 381/490 m 7> o Zz o "o o Po o Ps 22 <E 2 o [5
O o o ww o o "o o o 2 L AND
DEE = do
O: s o e
EE o mo Zu) o 2 AND
S uu
Example 269, Example 298, Example 435, Example 485 and Example 511 do not exist.
Intermediate 1: 4-Amino-N-hydroxy-6- (methyl-phenyl-amino) - [1,3,5] triazine-2-carboxamidine A solution of 4-amino-6- (methyl-phenyl-amino) - [1,3,5] triazine-2-carbonitrile (Intermediate 2, 138 mg, 0.6 mmol) in EtoOH (4 mL) was added to a hydroxylamine hydrochloride solution (51 mg, 0.7 mmol) and sodium hydrogencarbonate (61 mg, 0.73 mmol) in water (2 mL). The mixture was heated to 70 ° C for 2 h, allowed to cool to room temperature, and the solvent was evaporated.
The crude solid residue was suspended with water (4 ml) before filtering under reduced pressure to provide Intermediate 1 (95 mg, 60%). HPLC-MS Method C: MH + requires m / z = 260; Found: m / z = 260, Tr = min 0.88 (98%). The following N-hydroxy-carboxamidine intermediates were prepared in a manner analogous to Intermediate 1. 4-Amino-N-hydroxy-6-phenylamino-Method and HPLO-MS: MH + requires 4 [1,3 5] triazine-2- carboxamidine miz = 246; Found: m / z = 248, Is Tr = 0.82 min (98%) 4-Amino-N-hydroxy-6- (methyl-3- Method B HPLC-MS: MH + requires methylphenyl-amino) - [1, 3, S] triazine-2- | m / z = 274; Found: m / z = 274, carboxamidine Tr = 1.31 min (96%) 4-Amino-N-hydroxy-6- (methyl-4- Method B HPLC-MS: MH + requires methylphenyl-amino) - [1, 3.5] triazine-2- | m / z = 274; Found: m / z = 274, carboxamidine Tr = 1.33 min (96%) 4-Amino-N-hydroxy-6- (methyl-3- Method B HPLC-MS: MH + requires 10 | methoxyphenyl-amino) - [ 1,3,5] triazine- | m / z = 290; Found: m / z = 290, 2-carboxamidine Tr = 1.25 min (88%). 4-Amino-N-hydroxy-6- (methyl4- Method B HPLC-MS: MH + requires 12 | methoxyphenyl-amino) - [1,3,5] triazine- | m / z = 290; Found: m / z = 290, 2-carboxamidine Tr = 1.23 min (97%) '4-Amino-N-hydroxy-6- (methyl-3- Method B HPLC-MS: MH + requires 14 | chlorophenyl-amino ) - [1,3,5] triazine-2- | m / z = 294/296; Found: m / z = carboxamidine 294/296, Tr = 1.40 min (60%) 4-Amino-N-hydroxy-6- (methyl-4- Method B HPLC-MS: MH + requires 16 | chlorophenyl-amino) - [1,3,5] triazine-2- | m / z = 294/296; Found: m / z = carboxamidine 294/296, Tr = 1.40 min (87%) 4-Amino-6 - [(2-fluoro-phenyl) -methyl- | HPLC-MS Method B: MH + requires amino] -N-hydroxy- [1,3, S] triazine-2- | m / z = 278; Found: m / z = 278, carboxamidine Tr = 1.23 min (98%) 4-Amino-6 - [(3-fluoro-phenyl) -methyl- | HPLC-MS Method B: MH + requires 24 | amino] -N-hydroxy- [1,3,5] triazine-2- | m / z = 278; Found: m / z = 278, carboxamidine Tr = 1.26 min (95%) 4-Amino-6 - [(4-fluoro-phenyl) -methyl- | HPLC-MS Method B: MH + requires 26 | amino] -N-hydroxy- [1,3,5] triazine-2- | m / z = 278; Found: m / z = 278, carboxamidine Tr = 1.23 min (98%) 4-Amino-6 - [(2-chloro-phenyl) -methyl- Method C HPLC-MS: MH + requires 28 | amino] -N-hydroxy- [1,3,5] triazine-2- | m / z = 294; Found: m / z = 294, carboxamidine Tr = 0.95 min (98%) Also dried by 4-Amino-N-hydroxy-6- (methyl-o-tolyl- | toluene | amino) azeotrope - [1, 3.5] triazine-2-Method B HPLC-MS: MH + requires carboxamidine m / z = 274; Found: m / z = 274, Tr = 1.74 min (100%) 4-Amino-6- (benzyl-methyl-amino) - Method C HPLC-MS: MH + requires 32 | N-hydroxy- [1,3,5] triazine-2-m / z = 274; Found: m / z = 274, carboxamidine Tr = 0.94 min (77%) 4-Amino-6- (ethyl-phenyl-amino) -N- Method C HPLC-MS: MH + requires | hydroxy- [1,3,5] triazine-2-m / z = 274; Found: m / z = 274, carboxamidine Tr = 0.94 min (86%) Also dried by toluene azeotrope 4-Amino-6- (2,3-dihydro-indol-1- 4 38 | inTina O im HPLC-MS Method B: MH + requires iI) - [1,3,5] triazine-2-carboxamidine m / z = 272: Found: m / z = 272, Tr = 1.48 min (75%) 4-Amino -N-hydroxy-6- (isopropyl- Method C HPLC-MS: MH + requires 43 | phenyl-amino) - [1,3,5] triazine-2- m / z = 288; Found: m / z = 288, carboxamidine Tr = 1.10 min (75%) 4-Amino-6- (3-chloro-phenylamino) -N- | HPLC-MS C method: MH + requires hydroxy- [1,3,5] triazine-2-m / z = 280/282; Found: m / z = carboxamidine 280/282, Tr = 0.97 min (80%) 4-Amino-N-hydroxy-6- [methyl- (3- Method C HPLC-MS: MH + requires 49 | trifluoromethyl-phenyl ) -amino] - m / z = 328; Found: m / z = 328, "[1,3, S] triazine-2-carboxamidine Tr = 1.06 min (60%) 4-Amino-N-hydroxy-6- (methyl-2,3- Method B HPLC-MS: MH + requires, 52 | difluorophenyl-amino) - m / z = 296; Found: m / z = 296, [1.3 S] triazine-2-carboxamidine Tr = 1.29 min (93%) 4 -Amino-6- (5-chloro-2-fluoro-phenyl- | Method HPLC-MS: MH + requires 64 | amino) -N-hydroxy- [1,3,5] triazine-2- | m / z = 298; Found: m / z = 298, carboxamidine Tr = 1.18 min (58%) 4-Amino-6- (2,5-difluoro-phenyl- Method B HPLC-MS: MH + requires amino) -N-hydroxy - [1,3,5 Jtriazine-2- | m / z = 282: Found: m / z = 282,
[| eatoamidna TA TE T 2 mn (17%)
4-Amino-6- (2-fluoro-S-methyl-phenyl- | Method B HPLC-MS: MH + requires
70 | amino) -N-hydroxy- [1,3,5] triazine-2- | m / z = 278; Found: m / z = 278, carboxamidine Tr = 1.75 min (94%)
4-Amino-6- (3-chloro-2-fluoro-phenyl- | Method B HPLC-MS: MH + requires
73 | amino) -N-hydroxy- [1,3, S] triazine-2- | m / z = 298; Found: m / z = 298, carboxamidine Tr = 1.18 min (62%)
4-Amino-6- (2-fluoro-3-methyl-phenyl- | Method B HPLC-MS: MH + requires
76 | amino) -N-hydroxy- [1,3,5] triazine-2- | m / z = 278; Found: m / z = 278, carboxamidine Tr = 1.78 min (88%)
4-Amino-6- (2,3-difluoro-phenyl- Method B HPLC-MS: MH + requires
79 | amino) -N-hydroxy- [1,3,5] triazine-2- | m / z = 282; Found: m / z = 282, carboxamidine Tr = 1.51 min (87%)
4-Amino-N-hydroxy-6- (3,4-di- Method C HPLC-MS: MH + requires
82 | hydroquinolin-1-i1) - [1,3,5] triazine- | m / z = 286; Found: m / z = 286, 2-carboxamidine Tr = 0.87 min (76%)
4-Amino-6- (3-fluoro-phenylamino) - | HPLC-MS C method: MH + requires
85 | N-hydroxy- [1,3,5] triazine-2-m / z = 264; Found: m / z = 264, carboxamidine Tr = 0.90 min (53%)
4-Amino-N-hydroxy-6 - [(2-methoxy- Method C HPLC-MS: MH + requires ethyl) -phenyl-amino] - [1,3,5] triazine-2- | m / z = 304; Found: m / z = 304, carboxamidine Tr = 0.94 min (34%)
4-Amino-6- (cyclopropylmethyl-phenyl- | Method C HPLC-MS: MH + requires
91 | amino) -N-hydroxy- [1,3,5] triazine-2- | m / z = 300; Found: m / z = 300, carboxamidine Tr = 1.05 min (33%)
4-Amino-6- (2-fluoro-phenyl-amino) - | HPLC-MS Method B: MH + requires
97 | N-hydroxy- [1,3,5] triazine-2-m / z = 264; Found: m / z = 264, carboxamidine Tr = 1.16 min (96%)
1st Methyl 3- (f (4-amino-6 - [(Z) -N'- | Method B HPLC-MS: MH + requires
7 hydroxycarbamimidoyl] -1,3,5- m / z = 304 Found: m / z = 304, triazin-2-yl) amino) benzoate Tr = 1.35 min (91%)
Batch 1 (precipitated): Method B
(Z) -4-Amino-N'-hydroxy-6 - [(3-HPLC-MS: MHA + requires mi / zz 324 kb - 7. Found: m / z = 324, Tr = 1.15 methanesulfonylphenyl) amino] -1,3,5- o, '
triazine-2-carboximidamide (48%). Batch 2: (conc filtered)
, Found: m / z = 324, Tr = 1.15 min (81%)
7 "4-Amino-6 - [(3-chloro4- Method D HPLC-MS: MH + requires
7 fluorophenyl) amino] -N'-hydroxy-m / z = 312 Found: m / z = 312, 1,3,5-triazine-2-carboxyidamide | Tr = 2.03 min (92%)
4-Amino-6 - [(2,4- HPLC-MS Method B: MH + requires
| difluorophenyl) (methyl) amino] -N'- m / z = 296 Found: m / z = 296, 3 | hydroxy-1,3,5-triazine-2-Tr = 1.37 min (98%)
carboximidamide [15 | 4-Amino-6 - [(6-fluoropyridin-3- Method B HPLC-MS: MH + requires iN (methyl) amino] -N'-hydroxy-1,3,5- m / z = 279 Found: m / z = 279, triazine-2-carboxyimidamide Tr = 1.12 min (83%) 16 | 4-Amino-N'-hydroxy-6 - [(2- Method B HPLC-MS: MH + requires methoxyethyl) (phenyl) amino ] -1,3,5- m / z = 304 Found: m / z = 304, triazine-2-carboximidamide Tr = 1.27 min (95%) 16 4-Amino-6 - [(3,4- Method B HPLC-MS: MH + requires 4 difluorophenyl) amino] -N'-hydroxy-m / z = 282 Found: m / z = 282, 1,3,5-triazine-2-carboxyidamide | Tr = 1.37 min (91% ) Intermediate 2: 4-Amino-6- (methyl-phenyl-amino) - [1,3,5] triazine-2-carbonitrile In 2-amino-4-chloro-6-cyano- [1,3,5] triazine (Intermediate 3, 243 mg, 1.6 mmol) anhydrous DMF (5 mL), diisopropylethylamine (0.54 mL, 3.1 mmol) and N-methylaniline (184 mg, 1.7 mmol) were added ) The mixture was heated to 90 C in a pressure tube for 18 h, before allowing to cool to room temperature.
The reaction mixture was diluted with EtOAc (20 mL), washed with water (2 x 10 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the desired product, which was used directly without further purification (138 ma, 39%). HPLC-MS Method C: MH + requires m / z = 227; Found: m / z = 227, Tr = 1.20 min (93%). The following carbonitriles were prepared according to a procedure similar to Intermediate 2. 4-Amino-6-phenylamino- Method C HPLC-MS: MH + requires S —lns5Htriazine-2-carbonitria - | M / 2 = 213; Found: m / z = 213,> Tr = 1.14 min (79%) 4-Amino-6 - [(2-fluoro-phenyl) - Method C HPLC-MS: MH + requires 23 methyl-amino] - [1 , 3.5] triazine-2- | m / z = 245; Found: m / z = 245, carbonitrile Tr = 1.41 min (73%) 4-Amino-6 - [(3-fluoro-phenyl) - Method C HPLC-MS: MH + requires' - 25 methyl-amino] - [1,3,5] triazine-2-m / z = 245; Found: m / z = 245, carbonitrile Tr = 1.41 min (82%). 4-Amino-6 - [(4-fluoro-phenyl) - Method C HPLC-MS: MH + requires 27 methyl-amino] - [1,3,5] triazine-2- | m / z = 245; Found: m / z = 245, carbonitrile Tr = 1.40 min (82%) 4-Amino-6 - [(2-chloro-phenyl) - Method C HPLC-MS: MH + requires methyl-amino] - [1, 3.5] triazine-2- | m / z = 260; Found: m / z = 261, carbonitrile Tr = 1.31 min (60%)
Ú 386/490> Tr = 1.24 min (94%) Alternatively, 4-amino-6- (methyl-phenyl-amino) - [1,3,5] triazine-2-carbonitrile was prepared according to the method next: In a stirring solution of G6-chloro-N-methyl-N-phenyl- [1,3 5] triazine-2 4-diamine (Intermediate 41, 360 mg, 2.67 mmol) in DMF (25ml) was added potassium cyanide (435 mg, 6.68 mmol). The reaction was stirred at 120 C under nitrogen for 2 h.
The reaction mixture was diluted with EtOAc (80 ml); the solution was then extracted with aq. sodium hydrogen carbonate solution. 5% (2 x 20 ml), and saturated brine (2 x 5 ml). After evaporation of the solvent, the crude residue was purified by FCC on silica gel eluting with heptane: EtOAc 1: 0 to 8: 2 to 6: 4 to provide the desired product (380 mg, 63%). HPLC-MS Method C: MH + requires m / z = 227; Found: m / z = 227, Tr = 1.24 min (95%). The following carbonitriles were prepared according to a procedure similar to Intermediate 2. 4-Amino-N'-hydroxy-6 - [(2- Method B HPLC-MS: MH + requires m / z 160 methoxyethyl) (phenyl)> amino] -1,3,5- / - | = 304 Found: m / z = 304, Tr = Intermediate 3: 2-Amino-4-chloro-6-cyano- [1,3,5] triazine In 2-amino-4-cyano-6-0x0-1, 3,5-triazine (J.
Am.
Chem.
Soc, 1961, 83, 1261-2, 2.30 g, 16.8 mmol), phosphoryl trichloride (50 mL, 547 mmol) was added, and the mixture heated to 90 ° C for 2 h.
The reaction mixture was cooled to room temperature before pouring over ice-water (250 ml) and basifying to pH 8 with solid sodium carbonate.
The mixture went on se-. extracted in DCM (3 x 250 mL), and the combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. to provide the desired compound, which was used crude without further purification (343 mg, 13%). HPLC-MS Method C: 2MH + requires m / z = 311; Found m / z = 311, Tr = 0.74 min (100%). Intermediate 7: 4-Cyano-N-methyl-N-3-methylphenyl- [1,3,5] triazine-2,6-diamine In 2-amino4-chloro-6-cyano- [1,3,5] triazine (Prepared in an analogous manner to Intermediate 3, 468 mg, 296 umol) 1 ml of anhydrous DMSO, diisopropylethylamine (77 µl, 444 pmol) and N-methyl-m-toluidine (40 mg, 326 umol) were added. The mixture was heated to 90 ° C for 2 h, allowed to cool and diluted with 10 ml of ethyl acetate. The mixture was then extracted with water (10 ml), 0.5 M HCl (3 x 10 ml), water (10 ml) and saturated brine (10 ml). The organic layer was also dried over anhydrous sodium sulfate and evaporated to produce the desired product, which was directly used without further purification or characterization (42 mg, 59%). The following carbonitriles were prepared according to a procedure similar to Intermediate 7.
4-Cyano-N-methyl-N-4-methylphenyl- Used directly without other purification- [1,3,5] triazine-2,6-diamine or characterization (69 mg, 91%) [1,3 5] triazine-2,6-diamine or characterization (56 mg, 73%) [1,3,5] triazine-2,6-diamine or characterization (60 mg, 78%) 11,3,5] Jtriazine-2 , 6-diamination or characterization (72 mg, 94%) Intermediate 18: Pyridine-2-carbonyl chloride Commercially available. Intermediate 19: 5-chloro-thiophene-2-carbonyl chloride Commercially available. Intermediate 20: 6-cyclopentoxynicotinoyl chloride In 6-cyclopentoxynicotinic acid (Intermediate 21, 74 mg, 358 umol), 2 ml of DCE and oxalyl chloride (63 µL, 716 umol) were added - under an atmosphere of nitrogen. The mixture was heated to 80 ° C for 1 h, and after cooling to room temperature, evaporated to produce a “20 clear oil (81mg, 100%). HPLC-MS Method B (in MeOH, identifying methyl ester): MH + requires m / z = 222; Found: m / z = 222, Tr = 2.19 min (94%). The following acid chlorides were prepared in a manner analogous to Intermediate 20.
HPLC-MS method C (in MeOH, ident; identifying methyl ester): MH + requires 56 | 1H-pyrazol-3-carbonyl chloride m / z = 127; Found: m / z = 127, Tr = 0.65 min (96%) Method C HPLC-MS (in MeOH, identifying 59-3-bromo-pyridine-2- | chloride methyl ester): MH + requires carbonyl m / z = 217; Found: m / z = 218, Tr | = 1.08 min (100%) Method C HPLC-MS (in MeOH, id 88 S5-methoxy-pyridine-2- | chloride methyl ester): MH + requires carbonyl m / z = 168; Found: m / z = 168, Tr = 0.95 min (100%); ; -. .; | Method B HPLC-MS: MH + requires m / z 170 6-cyclopropylmethoxy- chloride | 208 (methyl ester); Found: m / z = 208, Tr = 2.06 min (97%): Method B HPLC-MS: Methyl ester MH + 172 to mid-furan-S- requires m / z = 224; Found: m / z = 224, Tr = 1.69 min (97%) Intermediate 21: Commercially available 6-cyclopentoxynicotinic acid. Intermediate 33: 4-Amino-6- (benzyl-methyl-amino) - [1,3,5] triazine-2-carbonitrile In N-benzyl-6-chloro-N-methyl- [1,3,5] triazine -2 4-diamine (Intermediate 34, 350 mg, 1.40 mmol) n-butylammonium tetra cyanide (1.15 g, 4.28 mmol) and anhydrous acetonitrile (15 mL) were added. The reaction mixture was stirred at 50 C for 1 h, diluted with EtOAc (20 ml), extracted with water (2x 10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the desired product, which was used directly without further purification (327 mg, 97%). HPLC-MS C method: MH + requires m / z = 241; Found: m / z = 241, Tr = 1.29 min (86%). 7 The following carbonitriles were prepared in a manner similar to Intermediate 33.
4-Amino-6 - [(3-chloro-4- Method D HPLC-MS: MH + requires m / z 118 | fluorophenyl) amino] -1,3,5-triazine-2- | = 265 Found: m / z = 265, Tr = carbonitrile 2.75 min (90%) Intermediate 34: N-Benzyl-6-chloro-N-methyl- [1,3,5] triazine-2 4-diamine In cyanuric chloride (250 mg, 1.4 mmol) anhydrous THF (10 mL), diisopropylethylamine (0.38 mL, 2.0 mmol) and N-methylbenzylamine (164 mg, 1.4 mmol) were added. The mixture was stirred at 0 ° C for 0.5 h, and then allowed to stir and warm to room temperature for an additional 1.5 h. The reaction mixture was treated with concentrated ammonia (d = 0.88.04 mL, 6.2 mmol) and allowed to stir at room temperature for 18 h. The solvent was evaporated, and the reaction mixture was diluted with EtOAc (10 ml) and washed with aq. 1M (5 ml) and saturated sodium chloride (5 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the desired product, which was used directly without further purification (350 mg, 103%). Method C H- PLC-MS: MH + requires m / z = 250; Found: m / z = 250, Tr = 1.25 min (95%).
The following triazine-diamines were prepared in a manner analogous to Intermediate 34., Method C HPLC-MS: MH + requires m / z 37 ÀS line 2 4 dismina = 250; Found: m / z = 250, Tr =. 1.24 min (99%) acids - Method B HPLC-MS: MH + requires m / z 40 3 Sia to buffer TD: = 248; Found: m / z = 248, Tr = = 2.01 min (100%),:, Method C HPLC-MS: MH + requires m / z 45 IS Mrs. A branch = 264; Found: m / z = 264, Tr = => 1.29 min (98%). HPLC-MS C method: MH + requires m / z 48 [13 Blazins 4 diambha = 256/258; Found: m / z = 256/258, = 'Tr = 1.25 min (85%) 6-Chlorine-N-methyl-N- (3- Method C HPLC-MS: MH + requires m / z 51 | trifluoromethyl- phenyl) - [1,3,5] triazine- | = 304; Found: m / z = 304, Tr = 24-diamine 1.34 min (97%); HPLC-MS Method B: MH + requires m / z 'Ss ainuorotenitamiho) A to sltriazine = 258; Found: m / z = 268, Tr = = 1.61 min (65%) "6-Chlorine-N- (5-chlorine-2-fluoro-phenyl) - ERES VAI method Eos [1,3 5] triazine- 2 A4-diamine 1.86 min (51%) 6-Chlorine-N- (2,5-difluoro-phenin- - | Method B HPLOAMS: MH requires m / z [1,3,5] triazine-2,4 -diamine 1.75 min (70%) '72 6-Chloro-N- (2-fluoro-S-methyl-phenyl) - | Method HPLC-MS: MH + requires m / z [1,3 5] triazine- 2 4-diamine = 254: Found: m / z = 254, Tr =
Lo [177 miner%); HPLC-MS Method B: MH + requires m / z 75 SENIONE SAE ia = 274; Found: m / z = 274, Tr = ”EDF 1.72 min (55%); - Method B HPLC-MS: MH + requires m / z 78 E Chlorine N- (2 fluoro-a-meryl-phenyl- = 254; Found: m / z = 254, Tr = [1,3,5] triazine-2, 4-diamin: 1.67 min (97%) ii Method B HPLC-MS: MH + requires m / z 81 E Sono Na, 3 difluoro-phenyl) - = 258; Found: m / z = 258, Tr = [1,3, S] triazine-2 4-diamine 1.61 min (65%) 1 o Method C HPLC-MS: MH + requires m / z 84 1 a Basa guaiquinolin- t- = 262; Found: m / z = 262, Tr = AP lnazine- & 1.29 min (100%) P Method C HPLC-MS: MH + requires m / z 87 to Olioetna at 4 Meniia = 240; Found: m / z = 240, Tr = De '1.18 min (60%): Method B HPLC-MS: MH + requires m / z Cd Bliasna o A diana = 240; Found: m / z = 240, Tr = '1.61 min (97%) 6-Chlorine-2-N- (3- Method B HPLC-MS: MH + requires m / z 112 | methanesulfonylphenyl) -1.3, 5- = 300/302 Found: m / z = 300/302, triazine-2,4-diamine Tr = 1.45 min (90%) 6-Chlorine-2-N- (3-chlorine-4- Method D HPLC-MS: MH + requires m / z 119 | fluorophenyl) -1,3,5-triazine-2,4- = 289 Found: m / z = 289, Tr = diamine 1.79 min (97%) B: Method B HPLC-MS: MH + requires m / z 155 Roloro-aN and aa = 272 Found: m / z = 272, Tr = met 5.5-nazine-2, 1.84 min (99%) Ni a Method B HPLC-MS: MH + requires m / z 159 | Chlorine at NS fuoropyridin & l- | = 241 Found: m / z = 241, Tr => '1.40 min (100%) e ”Method B HPLC-MS: MH + requires m / z 162 | Core AN (Ameloxeti AN = 280 Found: m / z = 280, Tr = - '1.76 min (99%) Intermediate 36: 4-Amino-6- (ethyl-phenyl-amino) - [1,3,5 ] triazine-2-carbonitrile - 6-Chloro-N-ethyl-N-phenyl- [1,3,5] triazine-2,4-diamine —— (Intermediate 37, 400 mg, 1.60 mmol) was dissolved in Anhydrous DMSO (5 mL) before: addition of potassium cyanide (200 mg, 3.07 mmol) The reaction mixture was stirred at 120 ° C in a pressure tube for 2 h before allowing to cool to room temperature.
The product mixture was diluted with EtOAc (20 ml), extracted with water (2 x 10 ml), saturated sodium chloride (5 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The pro-
The desired product was obtained and used directly without further purification (300 mg, 78%). HPLC-MS C method: MH + requires m / z = 241; Found: m / z = 241, Tr = 1.27 min (89%). The following nitriles were prepared in a manner analogous to intermediate 36.,; - at 5; Method C HPLC-MS: MH + requires m / z 44 ds Skirts now nO = 255; Found: m / z = 255, Tr = = 1.33 min (93%) z Aa Method C HPLC-MS: MH + requires m / z 47 EA E a = 247/249; Found: m / z = 247/249, asia Tr = 1.38 min (68%) 4-Amino-6- [methyl- (3-trifluoromethyl- Method C HPLC-MS: MH + requires m / z 50 | phenyl) -amino] - [1,3,5] triazine-2- = 295; Found: m / z = 295, Tr = carbonitrile 1.43 min (55%) 4-Amino-6- (3-fluoro-phenylamino) - Used immediately without another ca- [1,3 5] triazine-2-carbonitrile characterization or purification; ; ; Method B HPLC-MS: MH + requires m / zon on-2- MN OlaSnÇDÃt 1,8,5- | = 271 Found: m / z = 271, Tr = 1.74 min (97%) n 4-Amino-6 - [(3- Method B HPLC-MS: MH + requires m / z 1 methanesulfonylphenyl)> amino] -1 , 3,5- | = 291 Found: m / z = 291, Tr = triazine-2-carbonitrile 1.55 min (81%) 15 4-Amino-6 - [(2,4-. Method B HPLC-MS : MH + requires m / z 4 difluorophenyl) (methyl) amino] -1,3,5- = 262 Found: m / z = 262, Tr = triazine-2-carbonitrile 1.84 min (92%) 15 4-Amino -6 - [(6-fluoropyridin-3- Method B HPLC-MS: MH + requires m / z 7 iN (methyl) amino] -1,3,5-triazine-2- = 246 Found: m / z = 246, Tr = carbonitrile 1.58 min (74%) 16 4-Amino-6 - [(2- Method B HPLC-MS: MH + requires m / z 1 methoxyethyl) (phenyl) amino] -1,3,5- = 271 Found: m / z = 271, Tr = triazine-2-carbonitrile 1.81 min (97%) Intermediate 39: 4-Amino-6- (2,3-dihydro-indole-1-i1) - [1 , 3,5] triazine-2-B carbonitrile 4-Chloro-6- (2,3-dihydro-indol-1-yl) - [1,3,5] triazin-2-ylamine - (Intermediate 40, 680 mg, 2.48 mmol), potassium cyanide (323 mg, 4.98 mmol) and 18-crown-6 (328 mg, 1.24 mmol) were loaded into a flask with b rounded beaker then seized in DMF (12 mL). The resulting mixture was reduced in a heating block preheated to 110 C and stirred under nitrogen for 2 h, and then at room temperature for
56 h.
The reaction was then diluted with EtOAc (60 ml) and extracted with aq. 5% (2 x 10 ml), brine (10 ml) and also dried over anhydrous magnesium sulfate.
The crude residue was purified by FCC on silica gel eluting with heptane: EtOAc 1: 0 to 8: 2a 1: 1 to 0: 1, and the column stimulated with THF to produce the title compound after evaporation solvent (155 mg, 26%). HPLC-MS Method B: MH + requires m / z = 239; Found: m / z = 239, Tr = 1.36 min (75%). Intermediate 41: 6-Chloro-N-methyl-N-phenyl- [1,3,5] triazine-2,4-diamine In a stirred solution of (4,6-dichloro- [1,3,5] triazin- 2-yl) -methyl-phenyl-amine (Intermediate 42, 2.7 g, 10.58 mmol) in THF (45 ml) was added. A conc. (3 ml, 52.91 mmol). The reaction was allowed to stir at room temperature for 1 h, the reaction was then diluted with THF (50 ml), treated with conc. (1 ml, 17.64 mmol) and stirred for 18 h.
The reaction was concentrated in vacuo and taken up in DCM (150 ml); the solution was then extracted with aq. at 2M (2 x 50 mL), and saturated brine (20 mL) and dried also on anhydrous sodium sulfate.
The organic phase was evaporated to dryness to provide the product as an off-white solid (2.743 9, 110%). HPLC-MS Method B: MH + requires m / z = 236; Found: m / z = 236, Tr = 1.76 min (88%). 1H NMR (500 MHz, CDCl3) δ ppm 7.09-7.44 (5H, m), 5.21-5.65 (2H, m), 3.40 (3H, s). Intermediate 42: (4,6-Dichloro- [1,3,5] triazin-2-yl) -methyl-phenyl-amine In a stirred solution of cyanuric chloride (2 9, 10.84 mmol) in DCM (40 ml ) at 0 - 5ºC, a solution of N- methylaniline (1.416 ml, 10.84 mmol) and DIPEA (2.08 ml, 12.26 mmol) in DCM: (30 ml) was added dropwise. The resulting mixture was allowed to warm to room temperature: and stirred for 48 h.
The reaction mixture was diluted with DCM (40 ml), and the solution was then extracted with aq. 2M (2 x 40 mL) and saturated brine (30 mL) and dried also on anhydrous sodium sulfate.
The organic phase was evaporated to dryness to provide the title compound as an off-white solid (2.726 g, 99%). HPLC-MS Method C: MH + requires m / z = 255; Found: m / z = 255, Tr = 1.48 min (100%). 1H NMR (500
MHz, CDCl3) 5 ppm 7.35-7.42 (2H, m), 7.29 (1H, d), 7.15-7.21 (SH, m), 3.48 (3H, s). Intermediate 53: 2-Amino-4-cyano-6- (2,3-difluorophenyl-N-methylamino) - 7 [1,3 5] triazine 25 In 2-amino-4-cyano-6- (2,3-difluorophenylamino) - [1,3,5] triazine (Intermediate 54, 332 mg, 1.34 mmol) were potassium carbonate (203 mg, 1.46 mmol), methyl iodide (83 µl, 1.34 mmol) and anhydrous DMF (3 mL) were added. The mixture was stirred at room temperature for 1 h, and then diluted with 1% aq. 1M (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 10 ml), and the combined extracts washed with water (4 x 10 ml), saturated brine (10 ml) and dried also in anhydrous sodium sulfate.
Evaporation of the solvent produced a gum, which was loaded onto a silica column and eluted with heptane-30% ethyl acetate to produce the desired compound (320 mg, 91%). BHPLC-MS method: MH + requires m / z = 262; Found: m / z = 262, Tr = 1.76 min (98%). Intermediate 54: 2-Amino-4 cyano-6- (2,3-difluorophenylamino) - [1,3,5] triazine In 2-amino-4-chloro-6- (2,3-difluorophenylamino) - [1, 3.5] triazine (Intermediate 55, 1.0 g, 3.89 mmol) DABCO (540 mg, 4.67 mmol), n-butylammonium tetra cyanide (1.15 g, 4.28 mmol) were added ) and anhydrous acetonitrile (15 mL). The reaction mixture was stirred at 50 ° C for 1 h, diluted with 50 ml of ethyl acetate, with aq. 1M (2 x 50 ml), water (2 x 50 ml), saturated brine (50 ml) and dried also on anhydrous sodium sulfate.
Evaporation of the solvent produced a red gum, which was purified by column chromatography on silica eluting with DCM-2% ethyl acetate to produce the desired compound (429 mg, 69%). Method 'B HPLC-MS: MH + requires m / z = 249; Found: m / z = 249, Tr = 1.64 min (91%). The following nitriles were prepared in an analogous way to intermediate 54.
4-Amino-6- (5-chloro-2-fluoro-phenyl- | Method B HPLC-MS: MH + requires m / z 65 | amino- [1,3,5] triazine-2- = 265; Found: m / z = 265, Tr = carbonitrile 1.84 min (55%) 4-Amino-6- (2,5-difluoro-phenyl- Method B HPLC-MS: MH + requires m / z amino- [1,3, S] triazine-2- = 249; Found: m / z = 249, Tr = - carbonitrile 2.04 min (67%) 4-Amino-6- (2-fluoro-5-methyl-phenyl- | Method B HPLC -MS: MH + requires m / z 71 amino) - [1,3,5] triazine-2- = 249; Found: m / z = 249, Tr = carbonitrile 2.08 min (97%) 4-Amino-6 - (3-chloro-2-fluoro-phenyl- | Method B HPLC-MS: MH + requires m / z 74 amino) - [1,3,5] triazine-2- = 265; Found: m / z = 265, Tr = carbonitrile 1.82 min (56%) 4-Amino-6- (2-fluoro-3-methyl-phenyl- | Method B HPLC-MS: MH + requires m / z 77 | amino) - [1,3, S] triazine-2- = 245; Found: m / z = 245, Tr = carbonitrile 2.03 min (84%) Purified using DCM-1% MeOH 4-Amino-6- (2,3-difluoro-phenyl - on silica (778 mg, 53%). Method B amino) - [1,3,5] triazine-2-HPLC-MS: MH + requires m / z = 249; Contracted carbonitrile: m / z = 249, Tr = 1.63 min (96%) 4-Amino-N-hydroxy-6- (3,4-di- Method C HPLC-MS: MH + requires m / z 83 | hydroquinolin-1-11) - [1,3, S5] triazine- | = 253; Found: m / z = 253, Tr = 2-carbonitrile 1.58 min (100%); :; HPLC-MS Method B: MH + requires m / z to love the menu | = 234: Found: mz = 231, Tr = 1.66 min (97%) The following oxadiazoles were prepared according to Method 2. N-Methyl-N-phenyl-6- [5- (3- Method HPLC-MS: MH + requires m / z 58 hydroxypyridin-2-yl) - = 363; Found: m / z = 363, Tr = [1.2 A] oxadiazol-3-yl] - 3.75 min (100%) [1.35] triazine-2,4-diamine. 3- (3- [4-Amino-6- (methyl-phenyl- Method B HPLC-MS: MH + requires m / z 63 | amino) - [1,3,5] triazin-2-yl] - = 363; Found: m / z = 363, Tr = [1,2, A4] oxadiazol-5-yl) -pyridin-2-0] 1.51 min (64%) 3-13- [tert-butyl acid ester] 4- | HPLC-MS Method B: MH + requires amino-6- (methyl-phenyl-amino) m / z - = 479; Found: m / z = 479, Tr = 102 | [1,3, S] triazin-2il] - [1,2 4Joxadiazole- | 2.11 min (91%) 5-i1) -8-aza-bicyclo [3.2.1] octane-8-carboxylic tert-Butyl-4- (3-f4-amino-6- Method B HPLC-MS: MH + requires m / z 106 | [methyl (phenyl)) amino] -1,3,5-triazin-2- | = 452 Found: m / z = 453, Tr = yl) -1,2,4-0xadiazol-5-yl) piperidine- | 2.04 min (100%)
[FL sodium tert-Butyl 3- (3- (4-amino-6- | Method B HPLC-MS: MH + requires m / z 114 [methyl (phenyl) amino] -1,3,5-triazin-2- | = 439 Found: m / z = 439, Tr = yl) -1,2,4-0xadiazol-5-yl) pyrrolidine- | 2.02 min (95%) - 1-carboxylate 1- [6- (3- (4-Amino-6- Method C HPLC-MS: MH + requires m / z. 141 [methyl (phenyl) amino] -1, 3,5-triazin-2- | = 389 Found: m / z = 389, Tr = iN-1,2,4-0xadiazol-5-yl) pyridin-3- 1.26 min (78%) illetan-1 -one Methyl mixture 2- (3-f (4-amino-6- | Used without further purification [methyl (phenyl) amino] -1,3,5-triazin-2-yl-1,2 4-0xadiazole- 5-yl) pyridine-3- 147 | carboxylate and methyl 3- (3- (4-amino- 6- [methyl (phenyl) amino] -1,3,5-triazin-2-i11) -1,2, 4-0xadiazol-S-yl) pyridine-2-carboxylate tert-Butyl 3- (3- (4-amino-6- | Method HPLC-MS: MH + requires m / z 150 [methyl (phenyl) amino] -1 , 3,5-triazin-2- | = 425; Found: m / z = 425, Tr = yl) -1,2,4-0xadiazol-5-yl) azetidine- | 4.24 min (99%) 1 -carboxylate Intermediate 57: 6- (2,2,2-trifluoro-ethoxy) -nicotinoyl chloride In 6- (2,2,2-trifluoro-ethoxy) -nicotinic acid (100 mg, 0.45 mmol) were added DCE (5 mL) and oxalyl chloride (60 ul, 0.58 mmol) under an atmosphere of nitrogen.
The mixture was then stirred at rt for 1.5 h, heated to 80 ° C for 2 h, and after cooling to room temperature, evaporated to produce the title compound as a pale yellow oil (110 mg, 100%). HPLC-MS method C (in MeOH, identifying the methyl ester): MH + requires m / z = 236; Found: m / z = 236, Tr = 1.41 min (95%). Intermediate 60: N-Methyl-N-phenyl-6- (5-trichloromethyl- [1,2,4] oxadiaz | -3-11) - [1,3,5] triazine-2,4-diamine] In 4 -amino-N-hydroxy-6- (methyl-3-methylphenyl-amino) - [1,3,5] triazine- '2-carboxamidine (prepared according to a method analogous to Intermediate 1, 1 g, 3,868 mmol) in anhydrous toluene (2.5 mL) under nitrogen, trichloroacetic anhydride (845 ul, 4.63 mmol) was added. The mixture was stirred at room temperature for 1 h, at which point anhydrous pyridine (2.5 ml) was added, and the mixture stirred for 45 min.
Anhydrous pyridine (10 mL) and trichloroacetic anhydride (300 ul, 1.684 mmol) were then added
| and the mixture stirred at room temperature for 30 min in | then heated to 85 ° C for 35 min. The reaction mixture was diluted with EtOAc (100 ml), and the solution was extracted with sat. Aq. Sodium hydrogen carbonate solution (3 x 50 ml), brine (50 ml) and dried over sulfate.
2. 5 anhydrous sodium. The title compound was obtained as a brown solid (1.22 g, 82%). HPLC-MS Method B: MH + requires m / z = 386; Found: m / z = 386, Tr = 2.20 min (77%). Intermediate 61: 6-Methoxy-nicotinic acid: Potassium tert-butoxide (323 mg, 2.88 mmol) and methanol (64 µL, 1.58 mmol) was seized in anhydrous THF (6 mL) in an RBF under trogen, the mixture was stirred for 10 min, at which time a solution of 6-chloropyridine-3-carbonitrile (200 mg, 1.44 mmol) in anhydrous THF (2 mL) was added slowly. The mixture was stirred at room temperature for 18h. The reaction was treated with methanol (6 μl, 0.148 mmol), stirred for 2 h, then treated with methanol (20 μl, 0.494 mmol), stirred for 2 h, then treated with potassium tert-butoxide (50 mg, 0.446 mmol) and stirred for 18 h. The mixture was then concentrated in vacuo, suspended in aq. Sodium hydrogen carbonate solution. sat. and extracted with EtOAc (5 x 10 mL). The combined extracts were washed with brine (10 mL) and concentrated in vacuo to produce the title compound (80 mg, 36%). 1H NMR (500 MHz, CDCl3) at ppm 8.94 (1 H, s), 8.22 (1 H, dd, J = 8.4, 1.8 Hz), 6.82 (1 H, d, J = 8.7 Hz), 4.03 (SH, s). Intermediate 62: 5- (3- [4-Amino-6- (methyl-phenyl-amino) - [1,3,5] triazin-2- i1,24]) oxadiazol-S-yl) -thiophene-2 acid -carboxylic 'In a stirred 543- [4-amino-6- * (methyl-phenyl-amino) - [1,3,5] triazin-2-i1] - [1,2,4 ] Joxadiazol-5-yl) -thiophene-2-carboxylic (Example 82, 1.02 g, 245 mmol) in methane! (5 ml) aqueous sodium hydroxide solution (2M, 5 ml) was added. The mixture was stirred for 18h, and then acidified with hydrochloric acid (IM, 10 ml). The formed precipitate was filtered and dried in vacuo at 50 ° C for 2 h to produce the title compound (450 mg, 46%). HPLC-MS Method B: MH + re-
or m / z = 396; Found: m / z = 396, Tr = 1.84 min (68%). Intermediate 90: 4-Amino-6 - [(2-methoxy-ethyl) -phenyl-amino] - [1,3,5] triazine-2-carbonitrile 'A mixture' of 4-amino-6-phenylamino- [1 , 3,5] triazine-2- - S carbonitrile (prepared in a manner analogous to Intermediate 5, 100 mg, 470 pmol), 1-bromo-2-methoxyethane (50 ul, 0.52 mmol) and potassium carbonate sodium 130 mg, 0.94 mmol) in DMF (5 ml) was heated to 100 ° C and stirred for 3 h.
The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated - under vacuum to produce the crude product, which was used without further purification (400 mg,> 100%, contains DMF). HPLC-MS Method C: MH + requires m / z = 271; Found: m / z = 271, Tr = 1.23 min (52%). Intermediate 92: 4-Amino-6- (cyclopropylmethyl-phenyl-amino) - [1,3,5] triazine-2-carbonitrile In a solution of 4-amino-6-phenylamino- [1,3,5] triazine- 2-carbonitrile (prepared in a manner analogous to Intermediate 5, 160 mg, 0.75 mmol) in DMF (6 mL) was added potassium carbonate (207 mg, 150 pmol) followed by bromomethyl-cyclopropane (111 mg, 830 umol ). The mixture was heated to 120 C for 3 h, allowed to cool to room temperature before extracting in ethyl acetate (10 mL) and washing with water (3 x 10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound, which was used without further purification (300 mg,> 100%). HPLC-MS Method C: MH + requires m / z = 267; Found: m / z = 267, Tr = 1.38 min (43%). Intermediate 93: 3-Methoxypyridine-2-carbonyl chloride Ú In a stirred suspension of 4 sodium 3-methoxypyridine-2-carboxylate (Intermediate 94, -3.3 mmol) in dichloromethane (10 ml) and pyridine (5 ml) to the OC (ice bath) oxalyl chloride was added dropwise (0.58 ml, 6.6 mmol). The mixture was stirred 10 minutes, then DMF (1 drop) was added.
The mixture was warmed to room temperature and stirred for 2 h, then concentrated in vacuo.
The residue was dissolved in dichloromethane (10 ml) and filtered through a cotton wool plug.
The filtrate was concentrated in vacuo to produce the title compound as a brown oil (0.16 g), which was used without further purification or characterization.
Intermediate 94: Sodium 3-Methoxypyridine-2-carboxylate T In a stirred solution of methyl 3-methoxypyridine-2-carboxylate 2 S (Intermediate 95, 0.55 9, 3.3 mmol) in methanol (10 ml) was added dropwise aqueous sodium hydroxide solution (1M, 4 ml, 4 mmol). The mixture was left to stand overnight.
The mixture was concentrated in vacuo to produce a white solid, which was used without further purification or characterization.
Intermediate 95: Methyl 3-methoxypyridine-2-carboxylate A mixture of methyl 3-hydroxypyridine-2-carboxylate (Intermediate 96, 1.2 g, 7.8 mmol), potassium carbonate (1.2 g, 8, 7 mmol), iodomethane (0.63 ml, 1.0 mmol) and DMF (10 ml) was stirred overnight.
The mixture was diluted with water (20 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were washed with water and concentrated in vacuo. The residue (0.82 g) was purified by flash column chromatography (5 g silica; heptane-ethyl acetate, 1: 0 - 5: 1 - 2: 1) to produce the title compound as a clear oil (0.58 g, 45%). HPLC-MS Method C: MH + requires m / z = 168; Found: m / z = 168, Tr = 0.76 min (100%). Intermediate 96: Methyl 3-hydroxypyridine-2-carboxylate A mixture of 3-hydroxypyridine-2-carboxylic acid (2.0 g, 14.4 mmol), conc. (0.5 ml) and methane! (100 ml) was heated to reflux and stirred for 48 hours.
The mixture was cooled to room temperature and stirred for 60 hours, then concentrated in vacuo.
The residue was dissolved in water (20 ml), basified at pH 8 using solid sodium carbonate (caution: evolution of gas!) And extracted with ethyl acetate (3 x 20 ml). The combined organic extracts were washed with water and concentrated in vacuo to yield the title compound as a white solid (1.22 g, 55%). HPLC-MS Method C: MH + requires m / z = 154; Found: m / z = 154, Tr = 0.78 min (100%). Intermediate 100: 6- [5- (6-N-toluenesulfonyl-hydrazonomethyl-pyridin-3-yl) - [1,2 A] oxadiazo | -3-yl] -N-methyl-N-phenyl- [1,3 , 5] triazine-2,4-diamine
In (5- (3- [4-amino-6- (methyl-phenyl-amino) - [1,3,5] triazin-2-yl] - [1,2 A] Joxadiazol-5-yl) -pyridin -2-yl) -netanol (prepared analogously to Example 297, 150 mg, 0.40 mmol) in DCM (5 mL) Dess-Martin periodinane (185 mg, 0.44 mmol) was added ), and the mixture stirred at room temperature for 1 h.
The reaction mixture was evaporated, and to the crude residue p-toluenesulfonylhydrazide (74 mg, 0.40 mmol) and glacial acetic acid (4 mL) were added. The mixture was heated to 50 ° C for 2 h, and then evaporated.
The residue was taken up in DCM (5 ml), extracted with aq. to 1M sodium bicarbonate solution (5 mL) and dried over anhydrous sodium sulfate to produce 268 mg of raw solid.
The solid was then triturated with EtOH (4 x 3 mL) to produce the title compound (104 mg, 535) Method B HPLC-MS: MH + requires m / z = 543; Found: m / z = 543, Tr = 1.99 min (64%). Intermediate 101: 6 - [(1R, 3R, 58) -5- (8-Aza-bicyclo [3.2.1] oct-3-yl) - [1,24] oxadiazol-3-yl] -N-methyl- Racemic N-phenyl- [1,3,5] triazine-2,4-diamine In 3- (3- [4-amino-6- (methyl-phenyl-amino) acid tert-butyl ester) - [1,3 S] triazin-2i1] - [1,2, A4] oxadiazol-5-i1) -8-aza-bicyclo [3.2.1] octane-8-carboxylic (Intermediate 102, 125 mg, 0.37 mmol) were added DCM (3 ml) and trifluoroacetic acid (3 ml). The mixture was stirred at room temperature for 1 h, and then evaporated.
The residue was taken up in DCM (5 ml) and washed with 1M sodium bicarbonate solution (5 ml), saturated brine (5 ml) and dried over sodium sulfate.
Evaporation gave the title compound, which was used directly for the next stage (74 mg, 53%). HPLC-MS Method B: MH + requires m / z = 379; Found: m / z = 379, Tr = 1.37 min (95%). "Intermediate 103: 8-tert-Butyl ester 8-aza-bicyclo [3.2.1] octane-3,8- 4 dicarboxylic acid In tert-butyl ester 3-cyano-8-aza-bicyclo [3.2.1 ] octane-8-carboxylic (Intermediate 104, 190 ma, 0.81 mmol) potassium hydroxide (270 mg, 4.83 mmol), EtOH (3 mL) and water (1 mL) were added. heated to 95 ° C for 4 h, allowed to cool and acidified to pH = 2 | with a 1M aq solution of citric acid.
The mixture was then extracted
with EtOAc (2 x 5 ml), and the combined extracts washed with saturated brine (10 ml) and dried over anhydrous sodium sulfate. Evaporation produced the crude title compound, which was directly used without further purification (190 mg, 94%). Method B HPLC-MS: MH + requires m / z = 255; Find: S / m: z / = 200 (MHBu), Tr = 1.68 min (76%) Intermediate - 104: tertButyl ester of 3-cyano-B-aza-bicyclo [3.2.1] octane-8-carboxylic In tert-butyl ester of 3-0x0-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid (300 ma, 1.33 mmol) DME (9 mL) and EtoH (0.2 mL) were added. The mixture was cooled to OC, when TOSMIC (530 mg, 2.65 mmol) and potassium tert-butoxide (609 mg, 5.2 mmol) were added in. The mixture was stirred at room temperature, and then heated at 50 ° C for 18 h. After this time, the reaction was evaporated and loaded onto a silica column and eluted with 10% to 30% ethyl acetate heptane to produce the title compound (216 mg, 69%). Method B HPLC-MS : MH + requires m / z = 237; Found: m / z = 237, Tr = 1.35 min (86%).
Intermediate 105: 2-N-methyl-2-N-phenyl-6- [5- (piperidin-4-yl) - 1,2,4-0xadiazole-3-11]) - 1,3,5- hydrochloride triazine-2,4-diamine tert-Butyl-4- (3-f4-amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-1) - 1,2,4-oxadiazole -S-yl) piperidine-1-carboxylate (Intermediate 106, 934 mg, 2.06 mmol) and 4M hydrogen chloride in 1,4-dioxane (5 mL) were combined in DCM (5 mL) at O C. The reaction was heated at RT and allowed to stir for 18 h. The mixture was concentrated under reduced pressure to produce the title compound as a yellow solid (832 mg). HPLC-MS Method B: MH + requires / z = 352 Found: m / z = 353, Tr = 1.23 min (100%).
Intermediate 109: Methyl 3 - [(4-amino-6-chloro-1,3,5-triazin-2- «iNamino] benzoate Methyl 3-aminobenzoate (0.69 g, 4.55 mmol) and a solution 1N aqueous NaOH (0.91 mL, 0.91 mmol) was added to a 46-dichloro-1,3,5-triazin-2-amine solution (0.75 g, 4.55 mmol) in a 1: 1 mixture of MeCN / water (40 mL) at O C. The mixture was stirred at OC for 1 h at room temperature for 3 days. Acetonitrile was removed in vacuo,
and the resulting white solid in water was filtered and dried in vacuo to provide the title compound (1.1 g, 87%). HPLC-MS Method B: MH + requires m / z = 280/282 Found: m / z = 280/282, Tr = 1.69 min (95%). 'Intermediate 113: 2-N-Methyl-2-N-phenyl-6- [5- (pyrrolidin-3- 2 SS 1iN) -1,24-oxadiazole-3-11) -1,3 hydrochloride salt, 5-triazine-2 4-diamine A 4N solution of HCl in dioxane (7mL, 28.2 mmol) was added slowly to a solution of tert-butyl 3- (3-f4-amino-6- [methyl ( phenyl) amino] -1,3,5-triazin-2-i1) -1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxylate (Intermediate 114, 1.24 g, 2.82 mmol) in dioxane (15 mL) at room temperature.
The reaction mixture was stirred at room temperature for 18h.
The reaction mixture was concentrated in vacuo to provide the title compound as a yellow solid (1.05 g, 100%). Method B HPLC-MS: MH + (with free base) requires m / z = 339 Found: m / z = 339, Tr = 1.20 min (96%). Intermediate 115: Ethyl 3- (4-amino-6 - [(3-fluorophenyl) amino] -1,3,5-triazin-2-yl) - 1,2,4-oxadiazol-5-carboxylate Ethyl chlorooxoacetate ( 0.12 g, 0.84 mmol) was added to a mixture of (4-amino-6 - [(3-fluorophenyl) amino] -N-hydroxy-1,3,5-triazine-2-carboximidamide (prepared from in a manner analogous to Intermediate 97, 0.209g, 0.76mmol) in pyridine (0.12ml) and toluene (4ml) at room temperature.
The reaction mixture was stirred at room temperature for 1 h, and at 110 ° C for 3 h.
The mixture was then cooled to room temperature; DCM (20 mL) and HC! aq. 1M (50 mL) were added.
The phases were separated, and the aqueous phase was extracted with DCM (2 x 20 ml). The organic extracts were combined, dried over sodium sulfate and concentrated.
The crude residue was washed with diethyl ether.
The organic filtrate was concentrated and purified by flash chromatography to provide the title compound as a yellow solid (45 mg, 17%). HPLC-MS Method D: MH + requires m / z = 346 Found: m / z = 346, Tr = 2.70 (40%). Intermediate 116: 2-N- (3-Fluorophenyl) -6- [5- (trichloromethyl) -1,2,4-oxadiazol-3-yl) -1,3,5-triazine-2,4-diamine Trichloroacetic anhydride (2.61 mL, 14.3 mmol) was added to a solution of 4-amino-6 - [(3-fluorophenyl) amino] -N-hydroxy-1,3,5-triazine-2-carboxyidamide (prepared from in a manner analogous to Intermediate 97, 3.13 g, 11.9 mmol) in dioxane (60 mL) containing molecular sieves (3: spoons) at O C.
The reaction mixture was stirred at room temperature .- 5 ° C for 3.5h, at 100 ° C for 30 min and at 110 ° C for 30 min.
The reaction mixture was concentrated; the resulting residue was dissolved in EtOAc (100 ml) and washed successively with aq. to 1M and aq. sodium bicarbonate. saturated.
The organic phase was concentrated to provide the title compound (4.2 g, 91%), which was used in the subsequent step without further purification.
The following amino oxadiazoles were prepared according to Method 4. tert-Butyl N- [1- (3- (4-amino-6- | Method C HPLC-MS: MH + requires m / z 121 Imethyl (phenyl) amino ] -1,3,5-triazin- | = 468 Found: m / z = 468, Tr = 2-i1) -1,2,4-oxadiazole-S- 1.33 min (98%) il) piperidin- 4-yl | carbamate 1- (3- (4-Amino-6- Method C HPLC-MS: MH + requires m / z 132 [methyl (phenyl) amino] -1,3,5-triazin- | = 369; Found : m / z = 369, Tr = 2-i1) -1,2,4-0xadiazole-5- 1,14 min (69%) ilpiperidin-4-ol tert-Butyl 4- (3-f4-amino-6 - | TH NMR (500 MHZ, CDCl3) 5 ppm 138 [methyl (phenyl) amino] -1,3,5-triazin- | 7.45 (2H, +), 7.32 (SH, m), 5, 13 (2H, br 2-i1) -1,2,4-0xadiazole-5-s), 3.72 (4H, br s), 3.61 (3H, s), 3.57 il) piperazine-1 -carboxylate (4H, m) and 1.50 (9H, s) tert-Butyl 4- (3-f4-amino-6- | Method B HPLC-MS: MH + requires m / z 152 [methyl (phenyl) amino] -1,3,5-triazin- | = 454; Found: m / z = 454, Tr = 2-11) -1,2,4-0xadiazole-5- 2.00 min (96%) il) piperazine- 1-carboxylate 143- [4-Amino-6- (methyl-phenyl- Method C HPLC-MS: MH + requires m / z 166 amin o) - [1,3,5] triazin-2-yl] - = 341; Found: m / z = 341, Tr = [1,2, A4] oxadiaz | -5-yl) -azetidin- | 1.10 min (92%) 3-ol Intermediate 122: 3- (4-fluorophenoxy) azetidine hydrochloride In a stirred solution of 1- (diphenylmethyl) -3- (4-fluorophenoxy) azetidine (Intermediate 123, 3.2 g, 9.6 mmol) in DCE (20 ml) 1-chloroethylchloroformate (1.6 ml, 1.5 eq) was added dropwise. The mixture was stirred for 10 min, then heated to reflux for 6 h.
More 1-chloroethylchloroformate (1.6 ml) was added and heating was continued
continued for 3 h.
The mixture was cooled to room temperature and concentrated in vacuo.
The residue was dissolved in MeOH (20 ml) and left to stand overnight.
The mixture was heated to reflux and stirred for 1 h, then cooled to room temperature and concentrated under. 5 vacuum.
The residue was crystallized from diethyl ether; the solid was broken with a spatula, filtered - washed with diethyl ether - and dried in vacuo to produce the title compound as a cream solid (1.78 g, 91%). HPLC-MS Method B: MH + requires m / z = 168 Found: m / z = 168, Tr = 0.69 min (92%). 1H NMR (250 MHZ, DMSO-d6) δ ppm 9.50 (2H, br s), 7.15 (2H, 4), 6.89 (2H, dd), 5.03 (1H, m), 4 , 39 (2H, m), e3.93 (2H, m). Intermediate 123: 1- (Diphenylmethyl) -3- (4-fluorophenoxy) azetidine In a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.80 g, 20 mmol) in anhydrous DMF (10 ml ) under drop-wise nitrogen, a solution of 1-benzhydryl azetidin-3-o01l was added (359.15 mmol) in DMF (10 ml) - Caution: evolution of hydrogen gas! The mixture was stirred for 30 min after the gas evolution ceased, then 1,4-difluorobenzene (1.8 ml, 18 mmol) was added dropwise.
The mixture was heated to 100 ° C and stirred for 12 h, then cooled to room temperature and poured into aqueous sodium bicarbonate solution (50 ml) and extracted twice with EtOAc (2 x 50 ml). The combined organic layers were washed with water, concentrated in vacuo and purified by flash column chromatography (25 g silica gel; heptan - EtOAc: 1: 0 - 9: 1). The product-containing fractions were combined, concentrated in vacuo, washed with heptane and dried in vacuo to produce the title compound (3.256 g, 67%). HPLC-MS Method B: MH + requires m / z = 334 Found: m / z = 334, Tr = 1.69 min (89%). 1H NMR (250 MHz, CDCl3) at ppm 7.48-7.39 (4H, m), 7.39-7.12 (6H, m), 6.94 (2H, t +), 6.71 (2H , dd), 4.75 (1H, m), 4.46 (1H, s), 3.78-3.65 (2H, m), and 3.20-3.07 (2H, m). Intermediate 124: 5- (3- (4-Amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2- in-1,2,4-oxadiazol-S-yl) -pyridine- 2-carboxylic In a solution of (methyl 5- (3- (4-amino-6- [methyl (phenyl) amino] - 1,3,5-triazin-2-i1) -1,2,4-oxadiazole- 5-yl) pyridine-2-carboxylate) (prepared in a manner analogous to Example 279, 500 mg, 1.23 mmol) in MeOH (20 mL) was added a 1M aqueous solution of sodium hydroxide (1.85 mL, 1.85 mmol). The solution was stirred overnight at room temperature and evaporated to dryness. The resulting solid was dissolved in water (20 mL), and the solution acidified to pH 3 with a 1M HCl aqueous solution The resulting solid was filtered and dried to provide the desired product as a beige solid (418 mg, 87%). Method HPLC-MS C: MH + requires m / z = 391; Found: m / z = 390.9, Tr = 1.16 min (95%) Intermediate 126: [2- (3- (4-amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2 -1) - 1,24-oxadiazol-S-yl) pyridin-3-yl) methyl - methanesulfonate, - [3- (3- (4-amino-6- [Imethyl (phenyl) amino ] -1,3,5-triazin-2-i1) -1,2,4-oxadiazol-S-yl) pyridin-2-yl) methyl methanesulfonate and [2- (3- (4-amino-6 - [methyl (phenyl) amino] -1,3,5-triazin-2-11) -1,2,4- oxadiazol-S5-yl) pyridin-3-yl) methyl methanesulfonate, [3- (3- ( 4-amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-11) -1,2,4-0xadiazol-5-yl) pyridin-2-yl) methyl - methanesulfonate (mixture of regioisomers) In a solution of [2- (3- (4-amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-11) -1,2,4-oxadiazole -S5-yl) pyridin-3-yl] methane! and [3- (3-f4-amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-i1) -1,2,4-oxadiazol-5-yl) pyridin-2- il) methane !; (Intermediate 127-mixture of regioisomers, 300 mg, 0.797 mmol) in DCM (25 mL) under nitrogen, methanesulfonyl chloride (93 UL, 1.419 mmol) and triethylamine (177 µl, 1.27 mmol) were added. The reaction mixture was stirred at room temperature for 4 h, and then washed with water (3 x 25 ml). The organic phase was dried over magnesium sulfate and evaporated to dryness to provide the title compound, which was used without further purification (312 mg, 86%). HPLC-MS Method C: MH + requires m / z = 455; Found: m / z = 455, Tr = 1.25 min (70%).
The following mesylates were prepared according to the procedure described for Intermediate 126.
5- (3- [4-Amino-6- (methyl-phenyl- Used immediately on the next stage)
EEA O 128 | [1,2, A] oxadiazol-5-yl) -pyridin-2-ylmethyl methanesulfonic acid ester
[(methanesulfonyló- = 294 Found: m / z = 237 (MH + - xi) methyl | piperidine-1-carboxylate tBu), Tr = 1.38 min (100%) Methyl 6- | HPLC-MS Method B: MH + requires m / z 189 | [(methanesulfonyló- = 246 Found: m / z = 246, Tr = BR xi) mMethyl | pyridine-3-carboxylate 1.39 min (78%); 14, | HPLC-MS Method B: MH + requires m / z 193 Si idi ST (methanesulfonitoxy) = 260 Found: m / z = 260, Tr = - illpiridine-3-carboxy 1.67 min (85%) at 1 H NMR (500 MHZ , CDCI3) 5 ppm 239 rastanesulionilivhpiperdina- 4.02 (2H, br s), 3.14 (2H, q), 2.98 (3H.; M), 1.97 (2H, d), 1.52 (2H, m) and 1.48 carboxylate (9H, s) [(1R, 5S, 6S) -3-benzyl-3- Method B HPLC-MS: MH + requires m / z 258 | azabicyclo [3.1.0] hexan-6-yl] methyl = 282; Found: m / z = 282, Tr = methanesulfonate 1.01 min (65%) tert-Butyl acid ester 3- | / Method C HPLC-MS: MNa + requires 288 | methanesulfonyloxymethyl-azetidine- | m / z = 288; Found: m / z = 288, Tr 1-carboxylic = 1.25 min (100%) Intermediate 127: [2- (3- (4-amino-6- [methyl (phenyl) amino] -1,3,5 -triazin-2-yl) - 1,2,4-oxadiazol-S-yl) pyridin-3-yl)] methanol and [3- (3- [4-amino-6- [methyl (phenyl) amino] - 1,3,5-triazin-2-i1) -1,2,4-oxadiazol-5-yl) pyridin-2-yl) methanol (mixture of regioisomers)
In a solution of methyl ester of 3-13- [4-amino-6- (methyl-phenyl-amino) - [1,3,5] triazin-2-i1] - [1,2,4] Joxadiaz! -S-yl) -pyridine-2-carboxylic acid and 2-3- [4-amino-6- (methyl-phenyl-amino) - [1,3,5] triazin-2-yl] - [ 1,2,4] oxadiazol-5-yl) -nicotinic (Intermediate 147-mixture of regioisomers, 800 mg, 1.98 mmol) in anhydrous THF (75 mL) sodium borohydride (187 mg, 4.95 mmol) was added ) portion by portion under nitrogen at O C.
The solution was allowed to warm to room temperature and stirred for an additional 16 h.
The reaction mixture was quenched with water (10 ml) and extracted in EtOAc (3 x 50 ml). The combined organics were washed with brine, dried over magnesium sulphate, evaporated to dryness and crushed.
with diethyl ether.
The isolated light yellow solid was dried in vacuo to provide the title compound (540 mg, 73%). Method HPLC-MS: MH + requires m / z = 377; Found: m / z = 377, Tr = 3.40 min (64%). Intermediate 130: [5- (344-Amino-6 - [(2-methoxyethyl) (phenyl) amino] -1,3,5-triazin-2-i1) -1,2,4-oxadiazol-5-yl) pyridin-2-yl) | methane!
In a solution of methyl 5- (3-f4-amino-6 - [(2-
methoxyethyl) (phenyl) amino] -1,3,5-triazin-2-yl) -1,2,4-0xadiazol-S-yl) pyridine-2-carboxylate (Example 311, 212 mg, 0.472 mmol) in THF anhydrous (50 mL) at OC, under nitrogen, sodium borohydride (45 mg, 1.48 mmol) was added
'portion by portion.
The resulting reaction mixture was stirred at room temperature for 16 h, and then quenched with aq. of saturated ammonium chloride (10 mL). The solution was extracted in EtOAc (3 x 25 ml), and combined organics washed with brine, dried over magnesium sulfate and evaporated to dryness to provide the title compound as a yellow solid (186 mg, 94%). HPLC-MS Method C: MH + requires m / z = 421; Found: m / z = 421, Tr = 1.19 min (73%). Intermediate - 131: 1- (344-amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-yl) - 1,2 A-oxadiazol-5S-yl) piperidin-4-o0na In a solution of 1- (3-f4-amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-i1) -1,2,4-oxadiazol-5-yl) piperidine- 4-01 (Intermediate 132, 120 mg, 0.325 mmol) in DCM (20 mL) to OC was added Dess-Martin Periodinane (138 mg, 0.325 mmol). The resulting reaction mixture was stirred at room temperature for 2 h, and then more Dess-Martin Periodinane (138 mg, 0.325 mmol) was added.
The reaction mixture was stirred for an additional 16 h at room temperature, and then quenched with aq. of saturated sodium bicarbonate (10 mL). The resulting bilayer was separated, and the organics were also washed with aq. 1M (10 mL). The organics were dried over magnesium sulfate, evaporated to dryness and purified by silica chromatography (0 to 3% MeOH in DCM) to provide the title compound as an off-white solid (Dess-Martin Periodinane impurities (17 %) likewise present) (179 mg, 150%). HPLC-MS Method C: MH + requires m / z = 367; Found: m / z = 367, Tr = 1.14 min (74%). Intermediate 133: Ethyl 3- [4-amino-6- (phenylamino) -1,3,5-triazin-2-i1] -1,2,4-oxadiazol-5-carboxylate Ethyl oxalyl chloride (0.396 mL, 3 , 55 mmol) was added to a solution of (2Z2) 4-amino-N'-hydroxy-6- (phenylamino) -1,3,5-triazine-2-carboximidamide (prepared in a manner analogous to Intermediate 4,
0.792 g, 3.23 mmol) in a 1: 1 mixture of toluene and pyridine (40 mL) at O C.
The mixture was warmed to room temperature and heated to 50 ° C for 2 h.
The mixture was cooled to room temperature and concentrated in vacuo.
The residue was diluted with water, and the resulting solid was collected by filtration and dried in vacuo to provide the title compound as a yellow solid (0.923 g) without further purification.
HPLC-MS Method B: MH + requires m / z = 328; Found: m / z = 328, Tr = 1.77 min (42%). Intermediate 134: 2-N-Phenyl-6- [5- (trichloromethyl) -1,2,4-oxadiazole-3-11] -1,3,5-triazine-2,4-diamine 2,2,2- Trichloroacetyl trichloroacetate (0.875 mL, 4.90 mmol) was added slowly to a suspension of (2Z) -4-amino-N'-hydroxy-6- (phenylamino) -1,3,5-triazine-2-carboxyidamide ( prepared in a manner analogous to Intermediate 4, 1.00 g, 4.08 mmol) in toluene (20 mL) at O C.
Pyridine (0.62 mL) was added to O C, and the mixture was stirred at room temperature for 45 min before being heated to 65 C for 45 min.
The mixture was then cooled to room temperature, and an additional 0.6 equivalent of trichloroacetyl 2,2,2-trichloroacetate was added.
The reaction mixture was stirred at room temperature for 10 min and 65 ° C for 40 min.
The mixture was concentrated in vacuo.
The resulting residue was dissolved in EtOAc (60 ml), washed with a saturated aqueous solution of sodium bicarbonate (3 x 20 ml), dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a solid. light brown (1.445 g, 95%). HPLC-MS Method B: MH + requires m / z = 372/374; Found: m / z = 372/374, Tr = 1.41 min (72%). Intermediate 135: 6- [5- (6-Chloropyridin-3-yl) -1,2,4-0xadiazol-3-yl) -2-N-methyl-2-N-phenyl-1,3,5-triazine -2 4-diamine 6-chloropyridine-3-carboxylic acid (1g, 6.35 mmol) and thionyl chloride (10 mL, 138 mmol) were heated to reflux for 2 hours.
The mixture was concentrated in vacuo, and the residue was azeotroped with diethyl ether and evaporated.
A portion of this acid chloride (0.75 g, 4.26 mmol) was then added to a solution of 4-amino-N-hydroxy-6- [methyl (phenyl) amino] -1,3,5-triazine- 2-carboximidamide (prepared from a
analogous to Intermediate 1, 0.920 g, 3.55 mmol) in pyridine (12 mL), and the mixture was stirred overnight at room temperature, before being heated to 70 ° C for 3 h.
The mixture was cooled to room temperature and concentrated in vacuo.
Water was added, and the mixture was stirred for 30 minutes.
The solids were filtered and washed with more water.
The solid was then azeotroped with toluene and dried under vacuum to provide the title compound, which was used without purification in the next step.
HPLC-MS Method B: MH + requires m / z = 381 Found: m / z = 381, Tr = 1.99 min (35%). Intermediate 136: 5- (3 (4-Amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-yl) - 1,2 4-0xadiazol-5-yl) pyridin-2- o1 Prepared according to the method described for Intermediate 135 above from 6-hydroxypyridine-3-carboxylic acid (0.556 g, 4 mmol, thionyl chloride (1.2 mL, 16 mmol) and 4-amino- N-hydroxy-6- [methyl (pheni) amino] -1,3,5-triazine-2-carboximidamide (prepared in a manner analogous to Intermediate 1, 0.52 g, 2 mmol). Method B HPLC- MS: MH + requires m / z = 363 Found: m / z = 363, Tr = 1.52 min (87%) Intermediate 139: 1- [6- (344-Amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2- 11) -1,2,4-0xadiazol-5-yl) pyridin-3-ylJetyl 2,2,2-trichloroethanecarboximidate 1- [6- (314-Amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-11) -1,2,4-oxadiazol-5-yl) pyridin-3-ylJetan-1-0! (Intermediate 140, 0.400 g, 1.02 mmol) was suspended in DCM.
Trichloroacetonitrile (0.123 ml, 1.22 mmol) and 1,8-diazabicycloundec-7-ene (a few drops) were added, and the mixture was stirred at room temperature for 19 h.
DCM (30 ml) and water (30 ml) were added, the organic layer was separated and washed with brine (30 ml), before being dried over sodium sulfate and concentrated in vacuo to provide the title compound as a golden brown solid (0.497 g, 91%), which was used in the next step without further purification.
HPLC-MS Method C: MH + requires m / z = 534 Found: m / z = 534, Tr = 1.55 min (57%). Intermediate 140: 1- [6- (3- (4-Amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-i1) - 1,2,4-0xadiazol-S-yl ) pyridin-3-ylJetan-1-01
1- [8- (344-Amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-11) -1,2,4-0xadiazol-5-yl) pyridin-3-ylJetan -1-01
1- [6- (3- (4-Amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-i1) -1,2,4- Ú oxadiazol-5-yl) pyridin -3-ylJetan-1-one (Intermediate 141, 0.934 g, 2.40 mmol) .- 5 was suspended in THF (60 mL), sodium borohydride (0.227 g, 6.01 mmol) was added, and the mixture stirred under room temperature for 2 h.
EtO-Ac (50 ml) and water (100 ml) were added, and the organic layer separated.
The aqueous layer was neutralized using aq. to 1M and extracted with EtOAc (3 x 30 mL). The combined organic layers were
- dried over sodium sulfate and concentrated in vacuo to provide the title compound as a pale yellow solid (1.0 g), which was used in the next step without further purification.
HPLC-MS Method C: MH + requires m / z = 391 Found: m / z = 391, Tr = 1.18 min (84%). Intermediate 142: 2- (3- (4-amino-6- [methyl (phenyl) amino] - 1: 1 acid mixture -
1,3,5-triazin-2-11) -1,2,4-oxadiazol-S-yl) pyridine-3-carboxylic acid and 3- (3-44-amino-6- [methyl (phenyl) amino]] -1,3,5-triazin-2-i1) -1,2,4-oxadiazol-S-yl) pyridine-2-carboxylic
4-Amino-N'-hydroxy-6- [methyl (phenyl) amino] -1,3,5-triazine-2-
carboximidamide (prepared in a manner analogous to Intermediate 1,
500 mg, 1.93 mmol) and 2,3-pyridinedicarboxylic anhydride (290 mg, 1.92 mmol) in pyridine (10 mL) was stirred at 80 ° C for 18 h, and then an additional 1 equivalent of 2,3-pyridinedicarboxylic anhydride was added, and the mixture was also heated to 80 ° C for 12 h.
The reaction mixture was cooled to room temperature, concentrated under reduced pressure and purified by preparative HPLC, Method C to provide a 1: 1 mixture of the title compounds (135 mg, 18%). HPLC-MS Method B: MH + requires m / z = 392; Found: m / z = 392, Tr = 1.52 and 1.58 min (45 and 53%). Intermediate 143: 2- (3- (4-Amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2- in-1,2,4-0xadiazol-5-yl) -pyridine- 3-carboxylic |
The aqueous layer of the preparation of Intermediate 147 was acidified with aq. 1N and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure to provide a crude mixture of acidic isomers, which were purified by preparative HPLC, Method C, to provide the title compound. (120 mg, 3%). Method of B HPLC-MS: MH + requires m / z = 391; Found: m / z = 391, Tr = 1.62 - 5 min (100%). Intermediate 144: 3- (3- (4-Amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2- i1-1,2,4-oxadiazol-5-yl) -pyridine- 2-carboxylic acid 3- (3-f4-amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-i1) -1,2,4-oxadiazol-S-yl) pyridine- 2-carboxylic was prepared from the same mixture as described in Intermediate 143 and purified by preparative HPLC, Method C, to provide the title compound (160 ma, 4%). HPLC-MS Method B: MH + requires m / z = 391; Found: m / z = 391 1.55 min (100%). Intermediate 145: (3: 1) Mixture of 3- (methoxycarbonyl) pyridine-2-carboxylic acid and 2- (methoxycarbonyl) pyridine-3-carboxylic acid 2,3-pyridinedicarboxylic anhydride (5 9, 33.11 mmol) was dissolved in MeOH (25 ml), and the mixture was heated to 80 ° C for 4 h.
The reaction mixture was cooled to room temperature, concentrated under reduced pressure to provide the title mixture as a white solid (6 g, quant.). HPLC-MS Method B: MH + requires m / z = 182; Found: m / z = 182, Tr = 0.75min (94%). Intermediate 146: (1: 1.25) 2- (3- (4-Amino-6-Imethyl (phenyl) amino] -1,3,5-triazin-2-yl) -1,2,4 -oxadiazol-5-yl) pyridine-3-carboxylic acid and 3- (3- (4-amino-6- [methyl (phenyl) amino] -1,3,5-triazin-2-yl) -1,2 , 4-oxadiazol-S-yl) pyridine-2-carboxylic A 3: 1 mixture of methyl 2- (3- (4-amino-6- [methyl (phenyl) amino] - 1,3,5-triazin-2 -i1) -1,2,4-0xadiazol-5-yl) pyridine-3-carboxylate and methyl 3- (3- (4- amino-6- [methyl (phenyl) amino] -1,3,5-triazin -2-11) -1,2,4-oxadiazol-5-yl) pyridine-2-carboxylate (Intermediate 147, 1.4 g, 3.46 mmol) was dissolved in a 1: 1 MeOH mixture: THF (40 mL), and then aq. 2M (14 mL) was added, and the mixture was stirred for 14 h.
The reaction mixture was concentrated under reduced pressure and acidified with HC! aq. to 1N (pH 1-2) and extracted with EtOAc (4 x 50 mL). Combined organic layers
were washed with water (50 ml), then brine (50 ml) and concentrated under reduced pressure.
The residue was purified by preparative HPLC, Method C, to provide the title mixture (135 mg). Method B HPLC- 'MS: MH + requires m / z = 391; Found: m / z = 391, Tr = 1.51 and 1.56 min (59 2 5 e41%. Intermediate 158: 6-Chlorine-2-N- (6-fluoropyridin-3-yl) -2-N- methyl-1,3,5-triazine-2 A-diamine In a solution of G6-chloro-2-N- (6-fluoropyridin-3-yl) -1,3,5-triazine-2,4-diamine ( Intermediate 159, 0.52 g, 2.17 mmol) in DMF (1 mL) at OC under nitrogen was added portion by portion to sodium hydride (60% dispersion in mineral oil, 0.0869 g, 2.17 mmol) The mixture was stirred for 5 min, then iodomethane (0.3 g, 2.17 mmol) was added, and the mixture was heated to 50 ° C for 16 h.
EtOAc was added, and the organic layer was washed with aq. saturated, dried over sodium sulfate and concentrated.
The residue was purified by FCC, eluting with 10-50% EtOAc in heptane to provide the title compound (0.089 g, 16% yield). HPLC-MS Method B: MH + requires m / z = 255 Found: m / z = 255, Tr = 1.52 min (74%). Intermediate 163: N- (2-Methoxyethyl) aniline In phenylboronic acid (5 g, 41.0 mmol) in DCM (50 mL), copper (ll) acetate (0.78 9, 4.1 mmol) was added , and the mixture was stirred for 5 min at room temperature. 2-Methoxyethanamine (3.08 g, 41.0 mmol) was added, and the mixture was stirred at 40 ° C for 19 h.
The mixture was then passed through a plug of silica, and then purified — by FCC, eluting with 10% EtOAc in heptane to provide the title compound (1.065 g, 17% yield). HPLC-MS Method B: MH + requires m / z = 152 Found: m / z = 152, Tr = 1.08 min (87%). Intermediate 168: Methyl 5-aminopyridine-2-carboxylate 5-Aminopyridine-2-carboxylic acid (1.60 9, 11.6 mmol) was dissolved in MeOH (100 mL) and concentrated sulfuric acid (1.7 mL , 12.8 mmol) was added, and the mixture was heated to 80 ° C for 5 hours.
The reaction mixture was concentrated in vacuo, neutralized by adding aq. at 1M and extracted with EtOAc.
The organic layer was dried over sodium sulfate and concentrated in vacuo to provide the title compound as a pale yellow solid (1.813 g, quant). Method 'B HPLC-MS: MH + requires m / z = 153 Found: m / z = 153, Tr = 0.35 (per .- 5 MS). Intermediate 169: 5- (Trifluoromethoxy) pyridine-2-carbonyl chloride A mixture of methyl 5- (trifluoromethoxy) pyridine-2-carboxylate (0.313 g, 1.41 mmol), potassium hydroxide (0.076 9, 1.35 mmol ) in a 5: 1 mixture of MeOH: water (3 mL) was stirred at room temperature for 1 h.
Additional potassium hydroxide (0.015 g, 0.267 mmol) in water (0.2 ml) was added, and the mixture was stirred at room temperature for 1 h.
The reaction mixture was evaporated to dryness twice and azeotroped with toluene to produce the potassium 5- (trifluoromethoxy) pyridine-2-carboxylate intermediate (404 mg 100%). A fraction of this intermediate (0.173 g, 0.706 mmol) was dissolved in oxalyl chloride (4 mL), and the mixture was stirred at room temperature for 2 h, before being evaporated to dryness and used without further purification in the product. - the next step.
Intermediate 171: 6- (tetrahydro-furan-3-yloxy) -nicotinic acid In 6-chloro-nicotinic acid (415 mg, 2.59 mmol), 3-hydroxytetrahydrofuran (468 mg, 5 , 16 mmol), potassium hydroxide (579 mg, 10.3 mmol) and DMSO (5 mL). The mixture was heated to 120 ° C for 24 h.
More potassium hydroxide (579 mg) and 3-hydroxytetrahydrofuran (468 mg) was added, and the mixture heated to 120 ° C for 24 h.
The reaction was allowed to cool to room temperature, acidified to pH = 1-2 with aq. 2M HCI (13 ml) and extracted in EtOAc (3 x 5 ml). The combined extracts were washed with water (5 x 20 ml), saturated brine (2 x 20 ml) and dried over anhydrous sodium sulfate.
Evaporation of the solvent gave the title compound as an orange solid, which was dried under high vacuum to remove traces of solvent (209 mg, 39%). Method B HPLC-MS: MH + requires m / z = 210; Found: m / z = 210, Tr = 1.32 min (100%).
Intermediate 173: 6- (cyclopropylmethoxy) pyridine-3-carboxylic acid 6-chloropyridine-3-carboxylic acid (1.00 g, 6.347 mmol), cyclopropylmethanol (0.759 mL, 9.520 mmol) and potassium hydroxide (1.424 9, : 25.39 mmol) were dissolved in DMSO (25 mL) and heated to 100 ° C for 18 hours. The reaction mixture was cooled to room temperature; water was added and acidified to pH 4-5 with 1M hydrochloric acid.
The resulting precipitate was filtered under vacuum to provide the title compound (1.079 g, 88%). HPLC-MS Method B: MH + requires m / z = 193 Found: m / z = 194, Tr = 1.95 min (968%). Intermediate 174: 6- (2,2,2-trifluoroethoxy) pyridine-2-carboxylic acid 6-chloropyridine-2-carboxylic acid (1.00 g, 6.347 mmol), 2,2,2-trifluoroetan-1-01l ( 0.683 ml, 9.520 mmol) and potassium hydroxide (1.424 g, 25.387 mmol) were dissolved in DMSO (25 ml) and heated at 100 ° C for 18 h.
The reaction mixture was quenched with potassium hydroxide (0.356 g, 6.347 mmol) and heated at 100 ° C for 18 h.
The reaction mixture was then quenched with 2,2,2-trifluoroethane-1-0l (1,367 ml, 19,040 mmol) and potassium hydroxide (0.356 9, 6.347 mmol) and heated at 110 ° C for 18 h.
The reaction mixture was then again quenched with potassium hydroxide (0.356 g, 6.347 mmol) and 2,2,2-trifluoroethane-1-01 (0.683 mL, 9.520 mmol), and the mixture was stirred at room temperature for 72 hours. H.
Water (10 mL) was added and acidified to pH 1 with 1M hydrochloric acid.
The aqueous was extracted with EtOAc (3 x 15 ml), and the organic layer was washed with brine (15 ml). This was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to produce a brown gum. The raw material was purified by FCC (DCM: MeOH, 90:10) to provide the title compound as a solid. yellow (1.26 g, 90%). HPLC-MS Method B: MH + requires m / z = 222 Found: m / z = 222, Tr = 1.71 min (79%). Intermediate 175: 4- (Methoxymethyl) piperidine hydrochloride A solution of 4M hydrogen chloride in 1,4-dioxane (807 HL, 3.23 mmol) was added a tert-butyl 4- (methoxymethyl) piperidine-1-carboxylate (Intermediate 176, 74 mg, 0.323 mmol), and the mixture was stirred at room temperature for 18h, before being evaporated to dryness to provide the title compound (47.7 mg, 89%). HPLC-MS Method B: MH + requires m / z = 130 Found: m / z = 130, Tr = 0.24 min. : The following Intermediates were prepared according to the .- 5 method described for Intermediate 175, 6- [5- (4- | Method C HPLC-MS: MH + hydrochloride requires 120 aminopiperidin-1-11) -1,2 , 4- m / z = 368 Found: m / z = 368, oxadiazole-3-i1) -2-N-methyl-2-N-phenyl- | Tr = 0.99 min (98%) 1,3,5-triazine-2 A4-diamine 6- [5- (Azetidin-3-yl) hydrochloride - | HPLC-MS C method: MH + requires 129 | 1,2,4-0xadiazol-3-yl) -2-N-methyl-2- | m / z = 325; Found: m / z = 325, N-phenyl-1,3,5-triazine-2 A-diamine | Tr = 0.94 min (66%) 2-N-methyl-2-N-phenyl- hydrochloride | Method HPLC-MS: MH + requires 137 6- [5- (piperazin-1-11) -1,2,4- m / z = 354 Found: m / z = 354, oxadiazol-3-yl) -1, 3,5-triazine-2,4- | Tr = 2.61 min (99%) diamine 6- [5- (Azetidin-3-i) -1,2,4- Method B HPLC-MS: MH + requires 149 oxadiazol-3-yl] -2-N- methyl-2-N-phenyl- | m / z = 325; Found: m / z = 325, 1,3,5-triazine-2 A-diamine Tr = 1.04 min (93%) (DCM / bicarb division) 2-N-methyl-2-N-phenyl hydrochloride - | HPLC-MS Method B: MH + requires 151 6- [5- (piperazin-1-11) -1,2,4- m / z = 354; Found: m / z = 354, oxadiazole-3-11) -1,3,5-triazine-2,4- | Tr = 1.24 min (98%) diamine Hydrochloride. N-phenyl-6- (5- | C HPLC-MS method: MH + requires 167 | piperidin-4-yl- [1,2 A4Joxadiaz | -3- m / z = 339; Found: m / z = 339, iN) - [1,3,5] triazine-2 4-diamine Tr = 0.96 min (96%); HPLC-MS Method B: MH + requires 17 eia iperidins | m / z = 192 Found: m / z = 192, PP Tr = 1.24 min 4-4 [(2,2,2- | Method B HPLC-MS Method: MH + requires 182 | trifluoroe- m / z = 213 Found: m / z = 213, ti) sulfanyl] methylpiperidine Tr = 1.13 min; Method B HPLC-MS: MH + requires 4- 184 Hydrochloride; 1 M iris, m / z = 207 Found: m / z = 207, and [(phenylsulfanyl) methyl] piperidine Tr = 1.32 min ã Method B HPLC-MS: MH + requires 186 Ferra rig [(Propan-2 "| mz = 174 Found: m / z = 174, PP Tr = 1.11 min; Method B HPLC-MS: MH + (with 200 CielobutoximetiDpiperidine - | free base) requires m / z = 170 Found: m / z = 170, Tr = 0.96 min 4- (3,3,3-Trifluoropropylidene) - pi- | 1H NMR (500 MHz, CDCl3) 5 ppm
CN Nr 9ºOOoi "*" “º“ ééwi ') ”'” ”. 1 => "0“ “º“. “. ɺ! Ií" SS “Ôéijíjoe> PÔÚÚÍáAh 415/490 peridine 5.09 (1H, t), 2.81 (4H, m), 2.73 (division DCM / bicarb) (2H, m), 2.30 (1H, br. s) and 2.14 (4H, dd) 220 1R, 4R hydrochloride -4- (22.2- | used in the subsequent step without - trifluoroethoxy) cyclohexan-1-amine | other purification 1H NMR (500 MHZ, DMSO-d6) à - 232 4-Methoxy-4- hydrochloride | ppm 8.97 (2H, br s), 7.40 (SH, m), phenylpiperidine 3.18 (2H, m), 3.06 (2H, m), 2.89 (3H, s) and 2, 14 (4H, m) 1H NMR (500 MHZ, MeOH-d4) ô 237 4 - [(2,2,2-trifluoroe- | ppm 3.42 (4H, q), 3.19 (1H, m ), tilsulfanil | piperidine 3.10 (2H, t), 2.28 (2H, dd) and 1.76 (2H, m) 1H NMR (500 MHZ, MeOH-d4) 244 4- (Propan-2 hydrochloride) - | ppm 3.40 (2H, m), 3.09 (4H, m), ylsulfanyl) piperidine 2.21 (2H, m), 1.74 (2H, m) and 1.29 (6H) 1H NMR (500 MHZ, MeOH-d4) to 246 Chloridate - 4- (propane-2- | ppm 3.33 (2H, m), 2.98 (4H, m), sulfinyl) piperidine 2.11 (2H, m), 1.86 (1H, m), 1.63 (1H, m) and 1.21 (6H, m) 4-11 Hydrochloride (2,2,2- | Method B HPLC-MS: MH + requires 267 | trifluoroe- m / z = 214 Found: m / z = 214, tyl) sulfanyl] methyl) piperidine Tr = 1.09 min (100%); HPLC-MS method B: MH + requires 269 (68S) -3- dynordrate | m / z = 164 Found: m / z = 164, Pp Tr = 0.82 min (95%); HPLC-MS Method B: MH + requires 271 | aa SR) 3 "| m / z = 164 Found: m / z = 164, enoxip Tr = 0.72 min (100%) 273 (3R) -3- Hydrochloride (2,2,2- | Used without another purification or trifluoroethoxy) pyrrolidine characterization 1H NMR (500 MHz, MeOD) at ppm; 3.69 (1H, m), 3.34 (2H, +), 3.10 217 Ciolopropylmetoxypiperidine * | (2H, m), 2, 00 (2H, dd), 1.84 (2H, ddd), 1.05 (1H, m), 0.53 (2H, m) and 0.22 (2H, m) Intermediate 176: tert-Butyl 4- (methoxymethyl) piperidine-1-carboxylate A solution of tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (0.300 g, 1.395 mmol) in DMF (2.5 mL) was added dropwise to a suspension of hydride sodium (60% dispersion in mineral oil, 0.067 9, 1.674 mmol) in anhydrous DMF (2.5 mL) at O C.
The reaction mixture was stirred at 0 ° C for 10 min, followed by dropwise addition of iodomethane (86
HL, 1.395 mmol). The mixture was warmed to room temperature and stirred for 18 h.
The reaction mixture was quenched with sodium hydride (60% dispersion in mineral oil, 0.067 g, 1.674 mmol) and iodomethane (86 µL, '1.395 mmol) and stirred at room temperature for 18 h.
The reaction-S mixture was evaporated under reduced pressure, dissolved in DCM and washed with a saturated aqueous solution of sodium bicarbonate.
The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
The crude material was purified by FCC (E-tOAc: heptane, 1: 1) to provide the title compound (0.074 g, 23%). HPLC-MS Method B: MH + requires m / z = 229 Found: m / z = 174 (MH + - tBu) Tr = 1.98 min (99%). The following ethers were prepared in a manner analogous to Intermediate 176. terc-Butyl 4- | HPLC-MS Method B: MH + requires m / z = [(cyclopropylmetho- 270 Found: m / z = 214 (MH + - tBu), | - 199 xi) methyl | piperidine-1- Tr = 2.33 min (83% ) carboxylate (Heated to 80 ° C). tert-Butyl 4-methoxy-4- | 1H NMR (500 MHZ, CDCl3) 5 ppm 7.39 233 phenylpiperidine-1- (4H, m), 7.31 (1H, m), 4.04 (2H, br d), carboxylate 3.17 (2H, br s), 3.00 (3H, s), 2.02 (2H, (Heated to 80 C) br s), 1.87 (2H, br s) and 1.49 (9H, s) Aut - | 1H NMR (500 MHz, CDCI3) 5 ppm 3.81 and opradimets- 4 | (2H, s), 3.44 (1H, m), 3.29 (2H, d), 301 278 xi) piperidine-1-carboxylate (2H, m), 1.83 (2H, d), 1, 50 (11H, m); 1.04 (1H, m), 0.53 (2H, m) and 0.19 (2H, (Heated to 80 C) m) Intermediate 178: tert-Butyl 4- (phenoxymethyl) piperidine-1-carboxylate tert- Butyl 4- (hydroxymethyl) piperidine-1-carboxylate (0.300 g, 1.393 mmol), hay! (0.122 ml, 1.393 mmol), triphenylphosphine (0.440 g, 1.682 mmol) and Nltterc-butoxy) carbonilliminoXterc-butoxy) formamide (0.390 g, 1.682 mmol) were combined in THF (4 ml) and stirred at room temperature 18 H.
The reaction mixture was concentrated under reduced pressure and purified by FCC (EtOAc: heptane, 1: 1) to provide a white solid.
This was also purified by trituration with diethyl ether to provide the title compound (0.289 g, 71%). HPLC-MS Method B: MH + requires m / z =
292 Found: m / z = 235 (MH + - tBu), Tr = 2.44 min (71%). Intermediate 179: 4 - [(2,2,2-trifluoroethoxy) methylpiperidine hydrochloride A solution of 4M hydrogen chloride in 1,4-dioxane '(248 mL, 993 mmol) was added to tert-butyl 4 [(22 , 2- - 5 trifluoroethoxy9metillpiperidine-1-carboxylate (Intermediate 180, 0.289 g, 0.993 mmol), and the mixture was stirred at room temperature for 18 h, before being evaporated to dryness to provide the title compound (0.136 g, 59%) Method B HPLC-MS: MH + (HCI salt) requires m / z = 198 Found: m / z = 198, Tr = 0.72 min.
Intermediate 180: tert-Butyl 4 - [(2,2,2-trifluoroethoxy) mMetillpiperidine-1-carboxylate tert-Butyl 4- (hydroxymethyl) piperidine-1-carboxylate (0.300 g, 1.393 mmol), 2,2,2- trifluoroetan-1-01l (1.00 mL, 13.935 mmol), triphenylphosphine (0.440 9, 1672 mmol) and NXl (tero-butoxy) carbonilliminoWKterc-butoxy) formamiide (0.390 g, 1.672 mmol) were combined in THF (10 mL) and stirred at room temperature for 36 h, before being heated to 75 ° C for 18 h.
The reaction mixture was concentrated under reduced pressure and purified by FCC (EtOAc: heptane, 1: 1) to provide the title compound (0.1992, 50%). HPLC-MS Method B: MH + requires m / z = 297 Found: m / z = 242 (MH + -tBu), Tr = 2.25 min (100%). The following trifluoroethoxy ethers were prepared in a manner analogous to Intermediate 180. tero-Buti 4122.2315, RUN (900 MIECDO) 6 203 thiuoroelenipiperidine-1- m), 315 (2H, m), 1.81 2H, m). 1.58 (2H, m) and 1.45 (9H, s) tert-Butyl N - [(1R, 4R) -4- (2,2,2- | Method B HPLC-MS: MH + requires hexyl | carbamate (MH + -56), Tr = 2.09 min (100%) Intermediate 183: tert-Butyl 4 - ([((2,2,2-trifluoroethyl) sulfanyl | methyl) piperidine-1-carboxylate 2,2,2- Trifluoroethane-1-thiol (0.151 ml, 1.636 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.065 g, 1.636 mmol) in anhydrous DMF (3 ml) at 0 ° C.
Only one-
solution of tert-butyl 4 - [(methanesulfonyloxy) methyl] piperidine-1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) in DMF (4 mL) was then added dropwise, and the reaction mixture it was stirred at room temperature for 4 h.
The mixture was diluted with EtOAc (30 ml) and washed with a saturated aqueous solution of sodium bicarbonate (10 ml) followed by brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure.
The crude material was purified by FCC (EtOAc: heptane, 20:80) to provide the title compound as a colorless oil (0.288 g, 82%). HPLC-MS Method B: MH + requires m / z = 313 Found - found: m / z = 257 (M minus tert-butyl), Tr = 2.28 min (97%). Intermediate 185: tert-Butyl 4 - [(phenylsulfanyl) netylpiperidine-1-carboxylate tert-Butyl 4 - [(phenylsulfanyl) methyl] piperidine-1-carboxylate was prepared from tert-butyl 4- (hydroxymethyl) piperidine- 1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) and thiophenol (0.117 mL, 1.145 mmol) according to the method described for Intermediate 183 to provide the title compound (0.483 9). 1H NMR (250 MHz, CDCl3) 5 ppm 7.22 (5H, m), 4.10 (2H, m), 2.83 (2H d), 2.64 (2H, t), 1.84 (2H , d), 1.63 (1H, m), 1.44 (9H, s) and 1.17 (2H, m). Intermediate 187: tert-Butyl 4 - [(propan-2-ylsulfanyl)] Mmetillpiperidine-1-carboxylate tert-Butyl 4 - [(propan-2-ylsulfanyl)] methyl] piperidine-1-carboxylate was prepared from tert- butyl 4- (hydroxymethyl) piperidine-1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) and sodium propanethiolate (0.161 g, 1.636 mmol) according to the method described for Intermediate 183 to provide the title compound (0.180 g, 60%). HPLC-MS Method B: MH + requires m / z = 274 Found: m / z = 218 (M - tert-Bu), Tr = 2.51 min.
Intermediate 188: 6 ([(1,1,1-trifluoropropan-2-yl) oxylmethyl | pyridine-3-carboxylic acid 1,1 1-Trifluoropropan-2-ol (0.406 mL, 4.483 mmol) was added dropwise to a suspension of sodium hydride (60% in mineral oil) (0.239 g, 5.977 mmol) in dry THF (20 mL) at O C.
The mixture was stirred at O Cc for 15 minutes.
A solution of —methyl 6-
(methanesulfonyloxy) methyl] pyridine-3-carboxylate (Intermediate 189, 0.733 9, 2.989 mmol) in THF (10 mL) was added dropwise.
The reaction mixture was stirred at 0 ºC for 30 minutes and at room temperature for 3
] at.
The reaction mixture was quenched with water (10 ml) and diluted with EtOAc - 5 (30 ml). The phases were separated, and the organic phase was extracted with a saturated aqueous solution of sodium bicarbonate (3 x 15 ml). The aqueous extracts were combined, washed with EtOAc (1 x 10 ml). The organic phase was discarded, and the aqueous phase was acidified to pH 4 using 2N HCI and extracted with EtOAc (3 x 30 mL). The organic extracts were combined, dried over sodium sulphate, filtered and evaporated to provide a brown raw residue.
The crude material was purified by flash chromatography (DCM: MeOH 98: 2) to provide the title compound as a beige solid (0.345 g, 46%). HPLC-MS Method B: MH + requires m / z = 250 Found: m / z = 250, Tr = 1.61 min (89%). The following ethers were prepared in a manner analogous to Intermediate 188, with heating to 80 ° C as appropriate.
Acid 6- | HPLC-MS Method B: MH + requires 191 [(cyclopropylmethoxy) methyl | pyridine- | m / z = 208 Found: m / z = 208, 3-carboxylic Tr = 1.33 min (85%) (hydrolyzed ester in the reaction) 6- [1- (2,2,2- | Acid B HPLC- MS: MH + requires 192 trifluoroethoxy) ethyl | pyridine-3- m / z = 250 Found: m / z = 250, carboxylic Tr = 1.77 min (65%) (hydrolyzed ester in the reaction) 6 - [(2, 2,2- | Method B HPLC-MS: MH + requires trifluoroethoxy) methyl | pyridine-3- m / z = 236 Found: m / z = 236, carboxylic (hydrolyzed ester in | Tr = 1.44 min (65%) reaction) A; Bile ds Method B HPLC-MS: MH + requires 197 of that obutoxyelylpyridine-m / z = 208 Found: m / z = 208, Tr = 1.38 min (68%) tert-Butyl 4- | HPLC-MS Method B: MH + requires 201 | (cyclobutoxymethyl) piperidine-1- m / z = 270 Found: m / z = 214 carboxylate (MH + - tBu), Tr = 2.28 min (35%) (1R, 58.6S) -3-Benzyl-6- HPLC-MS Method B: MH + requires 257 | (phenoxymethyl) m / z = 280; Found: m / z = 280, azabicycle [3.1.0) hexane Tr = 1.49 min (100%) (1R, 58.6S) -3-Benzyl-6- Method B HPLC-MS: MH + requires
[(cyclopropylmethoxy) methyl] -3-m / z = 258; Found: m / z = 258, Ú azabiciclo [3.1.0Jhexane Tr = 1.29 min (94%) (1R, 58.6S) -3-Benzyl-6 - [(3,3,3- Method B HPLC- MS: MH + requires 262 | trifluoropropoxy) methyl] -3- m / z = 300; Found: m / z = 300, BR azabicycle [3.1.0] hexane Tr = 1.12 min (92%) (1R, 58.6S) -3-Benzyl-6 - [(propan- = | Method B HPLC- MS: MH + requires 264 | 2-yloxy)] Methyl] -3-m / z = 246; Found: m / z = 246, "azabicycle [3.1.0) Jhexane Tr = 1.27 min (81%) (1R, 58.6S) -3-Benzyl-6- Method B HPLC-MS: MH + requires 266 | [(cyclopentyloxy) | netyl] -3- mi / z = 272; Found: m / z = 272, azabicycle [3.1.0] Jhexane Tr = 1.40 min (17%) Method C HPLC-MS: ((MH + ) -tert- 287 tert-Butyl acid 3- (butyl) ester requires m / z = 208; Found-phenoxymethylazetidine-1-carboxylic | do: m / z = 208, Tr = 1.51 min (100%) tert -Butyl acid ester 3- (3,3,3. | Method C HPLC-MS: ((289 butyl | trifluoro-propoxymethyl) -azetidine-1- | MH +) - tert) requires m / z = 208; En - contracted carboxylic: m / z = 208, Tr = 1.51 min (100%) 4- tert-Butyl ester (3,3,3- | Method C HPLC-MS: ((291 butyl | trifluoropropoxymethyl) -piperidine-1-MrH +) - tert) requires m / z = 256; Contracted carboxylic: m / z = 256, Tr = 1.57 min (100%) Intermediate 190: Methyl 6- (hydroxymethyl) pyridine-3 -carboxylate Calcium chloride (22.7 g, 204.9 mmol) was added to a suspension of dimethyl pyridine-2,5-dicarboxylate (10.0 g, 51.2 mmol) in a 1: 2 mixture of THF: MeOH (300 mL). The mixture was cooled to O C, sodium borohydride (4.85g, 128.1mmol) was added portion by portion.
The reaction mixture is slowly warmed to room temperature and stirred for 18 h.
An additional 2.5 equivalents of sodium borohydride was added, and the reaction mixture was stirred at room temperature for 2 days.
Additional THF (100 ml) and MeOH (100 ml) were added, and the mixture was stirred for - = 15 h.
An additional 2.5 equivalents of sodium borohydride (newest batch) was added, and the reaction mixture was stirred at room temperature for 15 h.
The mixture was poured slowly over ice-water and diluted with EtOAc (-200 mL). The white solid was filtered and discarded.
The filtrate phases were separated, the organic phase was washed with water (3 x 100 ml). The aqueous washes were combined and re-extracted with EtOAc (2 x 100 mL). The organic extracts were combined
dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as an off-white solid (5.8 g, 73%). HPLC-MS Method B: MH + requires m / z = 168 Found: m / z = 168, 'Tr = 0.91 min (100%). - 5 Intermediate 194: Methyl 6- (1-hydroxyethyl) pyridine-3-carboxylate A solution of methyl magnesium bromide (1M in THF) (3.03 mL, 3.03 mmol) was added dropwise to a solution of methyl 6-formylpyridine-3-carboxylate (Intermediate 195, 0.50 g, 3.03 mmol) in THF (20 mL) at -78 C. The reaction mixture was stirred at -78 C for 1 h and water (20 mL) was added. The mixture was warmed to room temperature and extracted with EtOAc (3 x 20 ml). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as an off-white solid (0.407 g, 74%). Method B HPLC-MS: MH + requires m / z = 182 Found: m / z = 182, Tr = 1.1
15. min (98%) Intermediate 195: Dess-Martin methyl 6-formylpyridine-3-carboxylate Periodinane (2.54 g, 5.98 mmol) was added to a solution of methyl 6- (hydroxymethyl) pyridine-3- carboxylate (Intermediate 190, 1.00 g, 5.98 mmol) in DCM (75 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 hrs, before being diluted with DCM (50 mL), washed with a 1: 1 mixture of saturated aqueous sodium bicarbonate solution and sodium thiosulfate (3 x 75 mL). The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to provide the title compound (1.02 g, 105%). HPLC-MS Method B: MH + requires / z = 166 Found: m / z = 166, Tr = 1.44 min (62%). Intermediate 198: Hydrochloride salt 4 - [(cyclopropylmethoxy) methyl] piperidine A solution of 4N HCl in dioxane (5 mL, 20.0 mmol) was added to a solution of tert-butyl 4 - [(cyclopropylmethoxy) methylpiperidine -1- carboxylate (Intermediate 199, 0.75 g, 2.77 mmol) in dioxane (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h before being evaporated to dryness to provide the title compound as a pale pink sticky solid (0.7 g, 125%). Method B
HPLC-MS: MH + (with free base) requires m / z = 170 Found: m / z = 170, Tr = 0.87 min.
Intermediate - 199: tert-Butyl 4 (cyclopropylmethoxy) methylpiperidine-1- 'carboxylate A solution of N-boc-4-piperidinamethanol (0.500 g, 2.322 mmol) in DMF (10 mL) was added dropwise to a suspension of hi - sodium dreto (60% in mineral oil) (0.186 g, 4.645 mmol) in dry DMF (15 mL) at O C.
The mixture was stirred at 0 ° C for 15 minutes and at room temperature for 10 minutes, before being cooled again, and (bro-mormethyl) cyclopropane (0.227 ml, 2.322 mmol) was added dropwise.
The reaction mixture was stirred at 0 ° C for 10 minutes, room temperature for 1 h and 80 ° C for 4 h.
The reaction mixture was diluted with EtOAc (60 ml) and washed with water (3 x 20 ml). The aqueous washes were combined and re-extracted with EtOAc (3 x 20 mL). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated to provide the title compound as a colorless oil (0.614 g, 98%). HPLC-MS Method B: MH + requires m / z = 270 Found: m / z = 214 (MH + - tBu), Tr = 2.33 min (83%). Intermediate 202: 4- (2,2,2-Trifluoroethoxy) piperidine Trifluoroacetic acid (1.15 mL) was added dropwise to a solution of tert-butyl 4- (2,2,2-trifluoroethoxy) piperidine-1- carboxylate (prepared in a manner analogous to Intermediate 203, 1.14 9, 4.0 mmol) in DCM (10 mL) at room temperature, The reaction mixture was stirred at room temperature for 16 h.
The mixture was then concentrated in vacuo, the crude residue was dissolved in water, and the product was extracted with diethyl ether (2 times). The aqueous phase was basified to pH 10 using solid potassium carbonate and extracted with DCM (4 times). The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo to provide the title compound (610 mg, 83%). 1H NMR (300 - “MHz, CDCl3) δ ppm 3.84 (2H, q), 3.53 (1H, m), 3.10 (2H, m), 2.61 (2H, m), 1, 76 (2H, m) and 1.54 (2H, s). Intermediate 204: Methyl 1- (2,2,2-trifluoroethyl) -1 H-pyrazol-3-carboxylate
Methyl 1H-pyrazol-3-carboxylate (1.0 g, 7.94 mmol) was dissolved in DMF (25 mL), and cesium carbonate (12.9 g, 39.7 mmol) was added.
The mixture was cooled to O C, and 2,2,2-trifluoroethyl methanesulfonate (2.4 mL, 19.8 mmol) was added gradually.
The mixture was warmed to room temperature and stirred for 16 h.
Water was added, and the mixture was extracted with EtOAc (3 x 25 ml). The combined organic extracts were washed with brine (3 x 10 ml) and concentrated in vacuo.
The residue was: purified by FCC, eluting with hexane, followed by 0.5% MeOH in DCM to provide the title compound as a yellow oil (0.312 g, 19%). HPLC-MS Method D: MH + requires m / z = 209 Found: m / z = 209, Tr = 2.08 min (98%). Intermediate 205: Methyl 1- (2,2,2-trifluoroethyl) - 1 H-pyrazol-S-carboxylate Methyl 1- (2,2,2-trifluoroethyl) -1H-pyrazol-S-carboxylate was prepared from the same mix as described for Intermediate 204 to provide the title compound as a yellow oil (0.063 g, 4%). HPLC-MS Method D: MH + requires m / z = 209 Found: m / z = 209, Tr = 1.26 min (96%). Intermediate 206: 6- (2,2,2-trifluoroethoxy) pyridine-3-carboxylic acid A mixture of 6-chloropyridine-3-carboxylic acid (6.0 g, 38.1 mmol), 2,2,2-trifluoroethanol (8.2 ml, 114.2 mmol) and potassium hydroxide (10.7 g, 190.4 mmol) in DMSO (50 ml) was stirred at 120 ° C for 18 h and allowed to stand at room temperature 2 days.
An additional 2 equivalents of potassium hydroxide and 1.5 equivalents of 2,2,2-trifluoroethane! were added, and the reaction mixture was stirred at 120 ° C for 18h.
The mixture was acidified with a concentrated aqueous solution of HCl, until a cream precipitate appeared.
The precipitate was collected by filtration, washed with a 1N aqueous solution of HCl, before being dissolved in EtOAc, washed 3 times with a 1N aqueous solution of HCI and 3 times with brine.
The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a cream solid (6.9 g, 82%). HPLC-MS C method: MH + requires m / z = 222 Found: m / z = 222, Tr = 1.24 min (98%).
Intermediate 207: 6- (3,3,3-trifluoropropyl) pyridine-3-carboxylic acid In a solution of 6- (3,3,3-trifluoropropyl) pyridine-3-carbonitrile (Intermediate 208, 189 mg, 0.945 mmol) in EtoH (20 ml) potassium hydroxide (265 mg, 4.72 mmol) was added. The solution was heated to 100 ° C for 6h, and then additional potassium hydroxide (53 mg, 0.94 mmol) was added.
After stirring for an additional 3h at 105 ° C, the reaction mixture was cooled to room temperature, evaporated to dryness and redissolved in water (20 ml). The solution was acidified to pH 3 with aq. to 1M and extracted with EtOAc (3 x 25 mL). The combined organics were dried over magnesium sulfate and evaporated to dryness to provide the title compound as a light brown solid (183 mg, 89%). HPLC-MS Method C: MH + requires m / z = 220; Found: m / z = 220, Tr = 1.12 min (91%). Intermediate 208: 6- (3,3,3-Trifluoropropyl) pyridine-3-carbonitrile In a solution of 6-methyl-nicotinonitrile (118 mg, 1.0 mmol) in anhydrous THF (20 mL) at -78 C under nitrogen lithium diisopropylamine (2M solution in THF / heptane / ethylbenzene, 550 µl, 1.1 mmol) was added dropwise.
The resulting solution was allowed to warm to room temperature for 5 min, and then cooled again to -78 ° C. 1.1 1-Trifluoro-2-iodo-ethane (524 mg, 2.5 mmol) was then added to the solution dropwise, and the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 2 h.
The reaction mixture was cooled to O C and quenched with water; the resulting solution was extracted with EtOAc (3 x ml). The combined organics were washed with brine (25 ml), 25 dried over magnesium sulfate and purified by silica chromatography (25% EtOAc in heptane) to provide the title compound as a pale yellow oil (191 mg, 95%) . HPLC-MS C method: MH + requires m / z = 201; Found: m / z = 201, Tr = 1.22 min (86%). Intermediate 209: 6 - [(2,2,2-trifluoroethyl) sulfanylpyridine-3-carboxylic acid In a solution of methyl 6 - [(2,2,2-trifluoroethyl) sulfanyl | pyridine-3-carboxylate (Intermediate 210, 345 mg, 1.37 mmol) in MeOH (10 mL) was added aq. 2M (1.37 mL, 2.74 mmol).
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The remaining residue was dissolved in water (20 ml), acidified to pH 4.5 with a solution of aq. the IM is extracted with DCM (3 x 25 mL). The combined organics were dried over magnesium sulfate and evaporated to dryness to provide the title compound as a white solid (300 mg, 93%). HPLC-MS Method C: MH + requires m / z = 238; Found: m / z = 238, Tr = 1.35 min (98%). Intermediate 210: Methyl 6 - [(2,2,2-trifluoroethyl) sulfanyl | pyridine-3-carboxylate In a solution of sodium hydride (60% dispersion in mineral oil, 90 mg, 2.25 mmol) in anhydrous THF (40 ml) to the OC 2,2,2-trifluoro-ethanethiol (200 µl, 2.25 mmol) was added dropwise under nitrogen.
The resulting solution was stirred for 15 min and added to a solution of 6-chloro-nicotinic acid methyl ester (257 mg, 1.5 mmol) in anhydrous THF (40 mL) at 0 ° C dropwise.
The reaction mixture was allowed to warm to room temperature, and stirring was continued for an additional 3 h.
The solution was quenched with water at O C and extracted in EtOAc (3 x 50 mL). The combined organics were washed with brine (20 mL), dried over magnesium sulfate, evaporated to dryness and purified by chromatography on silica (25% EtOAc in heptane) to provide the title compound as a colorless oil (370 mg, 98%). HPLC-MS Method C: MH + requires m / z = 252; Found: m / z = 252, Tr = 1.41 min (94%). Intermediate 212: tert-butyl 4- (3,3,3-trifluoropropylidene) piperidine-1-carboxylate In a solution of triphenyl (3,3,3-trifluoropropyl) phosphonium bromide (Intermediate 213, 972 mg, 2 mmol) in THF (20 mL) at OC under nitrogen potassium tert-butoxide (235 mg, 2.1 mmol) was added. The resulting reaction mixture was stirred at 0 ° C for 15 min, and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (398 mg, 2 mmol) in THF (5 ml) was added.
The solution was stirred for an additional 1 h at 0 ° C, and then evaporated to dryness.
The resulting residue was dissolved in EtOAc (25 ml) and washed with water (2 x 25 ml). The combined organics were washed with brine,
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The crude solid was dissolved in diethyl ether (50 ml), and then filtered to remove insoluble impurities.
The filtrate was evaporated to dryness to provide "tert-butyl / 4- (3,3,3-trifluoropropylidene) piperidine-1-carboxylate (Intermediate 212.0.99g, triphenylphosphine detected as an impurity), which was used without or- purification.
Intermediate 213: Triphenyl bromide (3,3,3-trifluoropropyl) phosphonium In a solution of 1,1,1-trifluoro-3-iodo-propane (3 g, 0.0133 mol) in toluene (20 mL) was added triphenylphosphine (3.51 g, 0.0133 mol). The resulting suspension was heated to 90 ° C for 28 h, and then cooled to rt.
The reaction mixture was evaporated to dryness and sonicated in diethyl ether (100 ml) for 5 min.
The resulting white precipitate was filtered, washed with additional diethyl ether and dried in vacuo to provide the title compound as a white crystalline solid (3.89 g, 60%). HPLC-MS Method C: MH + requires m / z = 359 (free salt); Found: m / z = 359, Tr = 1.06 min (100%). Intermediate 214: 5- (Cyclopropylmethoxy) pyridine-2-carboxylic acid S- (Cyclopropylmethoxy) pyridine-2-carbonitrile (Intermediate 215, 0.12 g, 0.622 mmol) was dissolved in EtoOH (2 mL), and an aqueous solution of sodium hydroxide (35% w / w) (2 ml) was added.
The mixture was stirred at 90 ° C for 3 h and allowed to stand at room temperature for 2 days.
EtOH was removed in vacuo.
The resulting white precipitate was collected by filtration, dried under vacuum and azeotroped with toluene and dried under high vacuum for 6 h to provide the title compound (120 mg, 90%). HPLC-MS Method B: MH + requires m / z = 193; Found: m / z = 193, Tr = 1.21 min (98%). Intermediate 215: 5- (Cyclopropylmethoxy) pyridine-2-carbonitrile Cyclopropylmethane! (0.120 mL, 1.504 mmol) was added to a suspension of sodium hydride (60% in mineral oil) (0.072 g, 1.805 mmol) in bDMF (4 mL) at room temperature.
The mixture was stirred at room temperature for 30 min, 4-chlorobenzonitrile (0.139 g, 1.002 mmol) was added.
The reaction mixture was stirred at room temperature for
18 h.
The mixture was diluted with water and extracted with EtOAc (3 times). The organic extracts were combined, washed with water (2 times), brine (2 times), dried and evaporated in vacuo.
The crude residue was purified: by flash chromatography (hexane: EtOAc 9: 1 to 85:15) to provide the title compound.-8 (0.120 g, 69%). HPLC-MS Method B: MH + requires m / z = 175; Found: m / z = 175, Tr = 1.73 min (100%). Intermediate 216: 6-Ethoxypyridine-3-carboxylic acid Potassium hydroxide powder (0.373 g, 12.005 mmol) and EtoH (0.3 mL, 6.002 mmol) were added to a solution of 6-chloropyridine-3-carboxylic acid ( 0.473 g, 3.001 mmol) in DMSO (12 mL) at room temperature.
The reaction mixture was heated to 100 ° C for 21 h, and cooled to room temperature.
A 1M aqueous solution of HCl was added.
The resulting precipitate was collected by filtration, washed with water and dried in vacuo to provide the title compound (356 mg, 71%). HPLC-MS Method B: MH + requires m / z = 168; Found: m / z = 168, Tr = 1.50 min (95%). : The following alkoxypyridines were prepared in a manner analogous to Intermediate 216. Tr = 1.57 min (100%) 6- (2-Methoxyethoxy) pyridine-3- acid | Method B HPLC-MS: MH + requires after acidification) Tr = 1.28 min (100%) Tr = 1.76 min (96%) Intermediate 222: 5- (2,2,2-Trifluoroethoxy) pyridine-2 acid -Methyl carboxylic / 5- (2,2,2-trifluoroethoxy) pyridine-2-carboxylate (Intermediate 223, 0.650 g, 2.77 mmol) was dissolved in MeOH (10 mL), aq. 2M (3.46 mL, 6.93 mmol) was added, and the mixture stirred at room temperature for 2 h.
MeOH was removed in vacuo, and the aqueous suspension neutralized by adding aq. 2M (3.5 mL) The resulting precipitate was filtered, washed with diethyl ether and dried in vacuo to provide the title compound as a white solid (0.179)
NEN ma, 29%). 1H NMR (500 MHZ, MeOH-d4) 5 ppm 8.41 (1H, d), 8.15 (1H, d), 7.59 (1H, dd) and 4.77 (2H, q). Intermediate 223: Methyl 5- (2,2,2-trifluoroethoxy) pyridine-2-carboxylate: Methyl S-hydroxypyridine-2-carboxylate (Intermediate 224, 0.610 g, -— 5 3.59 mmol) was dissolved in DMF (5 mL) , cesium carbonate (1.40 9, 4.31 mmol) and 2.2, 2-trifluoroethyl trifluoromethanesulfonate (1.0 9, 4.31 mmol) were added, and the mixture stirred at room temperature for 18 h.
The mixture was partitioned between EtOAc (50 ml) and water (15 ml), and the aqueous layer extracted with additional EtOAc (2 x 20 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo.
The raw material was purified by FCC, eluting with a gradient of 0-50% EtOAc in heptane to provide the title compound as a white solid (0.652 g, 77%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.40 (1H, d), 8.09 (1H, d), 7.27 (1H, dd), 4.41 (2H, q) and 3.93 ( 3H, s). Intermediate 224: Methyl 5-hydroxypyridine-2-carboxylate 6-Hydroxypolyolinic acid (0.500 g, 3.59 mmol) was dissolved in MeOH (20 mL) and cooled to O C under nitrogen.
Thionyl chloride (0.651 ml, 8.98 mmol) was added dropwise, the mixture was warmed to room temperature and stirred for 2 h.
TLC did not indicate any reaction, so more thionyl chloride (0.781 mL, 10.77 mmol) was added, and the mixture heated to 75 C for 8 h.
The mixture was concentrated in vacuo to provide the title compound as a white solid (0.685 g), which was used in the next step without further purification.
NMR shows approximately 25% unreacted S-hydroxypicolinic acid. 1 H NMR (500 MHZ, MeOH-d4) δ ppm 38.44 (1H, d), 8.39 (1H, d), 8.02 (1H, dd) and 4.09 (3H, s). Intermediate 225: 5 - [(2,2,2-trifluoroethoxy) methyl] pyridine-2-carboxylic acid Powdered potassium hydroxide (0.331 g, 5.90 mmol) was dissolved in EtoOH (2 mL) and added to 5- [(2,2,2-trifluoroethoxy) methyl | pyridine-2-carbonitrile (Intermediate 226, 0.255 g, 1.418 mmol). The mixture was heated to 110 ° C for 16 h.
After cooling, the residue was dissolved in water (3 ml), acidified to pH 1 by adding aq. 10% and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried
in sodium sulfate and concentrated to provide the title compound as a brown gum (0.252 g, 91%), which was used in the next step without further purification, Method C HPLC-MS: MH + requires m / z = 236 'Found : m / z = 236, Tr = 0.83 min (82%). . 5 Intermediate 226: 5 - [(2,2,2-Trifluoroethoxy) methyl | pyridine-2-carbonitrile 2-Chlorine-5 - [((2,2,2-trifluoroethoxy) methyl] pyridine (Intermediate 227, 0.537 g, 2 , 38 mmol) was dissolved in DMF (6 mL) and zinc cyanide (0.279 9, 2.38 mmol) was added.
The mixture was degassed by stirring under a stream of nitrogen for 10 min.
Tetracis (triphenylphosphine) palladium (0) (0.2759g, 0.24 mmol) and more DMF (2 mL) were added, and the mixture heated to 100 ° C in a sealed tube for 6 h.
The mixture was partitioned between EtOAc (50 ml) and water (50 ml), and the organic layer washed with more water (2 x 50 ml). The organic layer was dried over sodium sulfate and concentrated to produce an orange oil.
This was purified by FCC, eluting with a gradient of 0-30% EtOAc in heptane to provide the title compound as a colorless oil (0.255 g, 50%). 1H NMR (500 MHZ, CDCl3) at ppm 8.62 (1H, d), 7.79 (1H, dd), 7.66 (1H, d), 4.72 (2H, s) and 3.89 ( 2H, q). Intermediate 227: 2-Chlorine-5 - [(2,2,2-trifluoroethoxy) methyl] pyridine (6-Chloropyridin-3-yl) netane! (1.09, 6.97 mmol) was dissolved in THF (20 mL), potassium tert-butoxide (0.860 g, 7.668 mmol) was added, and the mixture stirred at room temperature. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (1.78 g, 7.66 mmol) was added dropwise with ice cooling, and then the mixture stirred at room temperature for 2 h.
EtOAc (50 mL) and water (50 mL) were added, the organic layer was separated, and the aqueous layer neutralized to pH 6. The aqueous layer was then also extracted with EtOAc (3 x 20 mL), the organic layers combined were dried over sodium sulfate and concentrated to produce a yellow solid.
This was purified by FCC, eluting with a gradient of 0-50% EtOAc in heptane to provide the title compound as a colorless oil (0.537 g, 34%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.30 (1H, d), 7.61 (1H, dd), 7.30 (1H, d), 4.61 (2H, s) and 3.82 ( 2H, q).
Intermediate 228: 6- (cyclohexyloxy) pyridine-3-carboxylic acid 6-chloronicotinic acid (0.500 g, 3.17 mmol), powdered potassium hydroxide (0.712 g, 12.69 mmol) and cyclohexanol (0.636 g, 6.35 mmol) were combined in DMSO (12 mL) and heated in a sealed tube at 100 ° C - 5 ° C for 18h, and then at 120 ° C for 21 h.
The mixture was acidified to pH 1 by adding 2M hydrochloric acid.
The mixture was then left to stand overnight at room temperature, and the resulting precipitate filtered, washed with water and dried in vacuo to provide the title compound as a cream solid (0.389 g, 55%). 1H NMR (500 MHZ, MeOH-d4) δ ppm 8.76 (1H, d), 8.19 (1H, dd), 6.79 (1H, d), 5.11 (1H, m), 2, 03 (2H, m), 1.83 (2H, m), 1.64 (1H, m), 1.56 (2H, m), 1.47 (2H, m) and 1.38 (1H, m) ). Intermediate - 229: 6-1,1-trifluoropropan-2-yl) oxylpyridine-3-carboxylic acid 6-chloronicotinic acid (0.500 g, 3.17 mmol), powdered potassium hydroxide (0.712 9, 12.69 mmol ) and 1,1,1-trifluoropropan-2-ol (0.724 g, 6.35 mmol) were combined in DMSO (12 mL) and heated in a sealed tube at 100 ° C for 18 h.
The mixture was acidified to PH 1 by adding 2M hydrochloric acid.
The mixture was then left to stand overnight at room temperature, and the resulting precipitate filtered, washed with water and dried in vacuo to provide the title compound as a cream solid (0.527 g, 71%). 1H NMR (500 MHZ, MeOH-d4) 5 ppm 8.82 (1H, d), 8.29 (1H, dd), 6.94 (1H, d), 5.96 (1H, m) and 1, 52 (3H, d). Intermediate 230; 6- (3,3,3-trifluoropropoxy) pyridine-3-carboxylic acid Methyl 6- (3,3,3-trifluoropropoxy) pyridine-3-carboxylate (Intermediate 231, 0.240 g, 0.91 mmol) was dissolved in EtoH (7.5 mL) and aq. 2M (1.37 mL, 2.74 mmol) was added.
The mixture was stirred at room temperature for 3 h.
The mixture was then concentrated to a minimum volume and acidified by adding 2M hydrochloric acid.
The mixture was extracted with DCM, the organic layer separated and concentrated in vacuo to provide the title compound as a white solid (0.102 9, 48%). 1H NMR (250 MHZ, MeOH-d4) 5 ppm 8.76 (1H, d), 8.20 (1H, dd),
6.80 (1H, d), 4.61 (2H, t) and 2.71 (2H, m). Intermediate 231: Ethyl 6- (3,3,3-trifluoropropoxy) pyridine-3-carboxylate 3,3,3-Trifluoropropanol (0.338 g, 2.968 mmol) was dissolved in 'THF (5 mL) and cooled to O ºC under nitrogen .
Potassium tert-butoxide. 5 (0.332g, 2.96mmol) was added, and the mixture stirred for 5 min.
Ethyl 6-chloronicotinate (0.500 g, 2.69 mmol) was added, the mixture was warmed to room temperature and stirred for 3 h.
Brine (10 ml) was added, and the mixture extracted with EtOAc (3 x 10 ml). The combined organic layers were dried over sodium sulfate and concentrated to produce a yellow oil.
This was purified by FCC, eluting with a gradient of 0-10% EtOAc in heptane to provide the title compound as a colorless oil (0.240 g, 34%), which was used in the next step without further purification. .
NMR shows approximately 15% unreacted ethyl 6-chloronicotinate. 1H NMR (500 MHZ, MeOH-d4) at ppm 8.75 (1H, d), 8.11 (1H, dd), 6.71 (1H, d), 4.55 (2H, t), 4, 31 (2H, q), 2.57 (2H, m) and 1.33 (3H, t). Intermediate 234: tert-Butyl 4-hydroxy-4-phenylpiperidine-1-carboxylate 4-Hydroxy-4-phenylpiperidine (1.0 g, 5.64 mmol) and dithercobutyldicarbonate (1.35 g, 6.21 mmol) were combined in DCM (30 ml) and stirred at room temperature for 3 h.
The mixture was diluted with DCM (100 ml) and washed with aq. saturated (3 x 30 mL). The organic layer was dried over sodium sulfate and concentrated to provide the title compound as a pale yellow oil (1.759 g), which was used in the next step without further purification. 1H NMR (500 MHZ, CD-CI3): 7.50 (2H, d), 7.40 (2H, t), 7.31 (1H, t), 4.06 (2H, br s), 3, 27 (2H, brs), 2.03 (2H, brs), 1.73 (2H, d) and 1.51 (9H, s). Intermediate 235: 6- (Oxan-4-yloxy) pyridine-3-carboxylic acid Ethyl 6- (oxan-4-yloxy) pyridine-3-carboxylate - (Intermediate 236, 0.239 g, 0.95 mmol) was dissolved in EtOH (5 mL), aq. 2M (1.43 mL, 2.85 mmol) was added, and the mixture was stirred at room temperature for 4 h.
The mixture was concentrated in vacuo, and the residue acidified to pH 6 by adding aq. to 2M.
The mixture was then extracted with DCM, followed by chloroform / isopropanol.
A CA-
organic layer was separated using a hydrophobic frit and concentrated in vacuo to provide the title compound as a white solid (0.162 9, 47%), which was directly used in the next step without further purification. HPLC-MS method C: MH + requires m / z = 224 Found: m / z = 224, Tr = .- 5 1.06min (91%). Intermediate 236: Ethyl 6- (oxan-4-yloxy) pyridine-3-carboxylate Oxan-4-ol (0.302 g, 2.96 mmol) was dissolved in THF (5 mL) and cooled to O C under nitrogen.
Potassium tert-butoxide (0.332 g, 2.96 mmol) was added, and the mixture stirred for 5 min.
Ethyl 6-chloronicotinate (0.500 g, 2.69 mmol) was added, the mixture was warmed to room temperature and stirred for 3 h.
Water (5 ml) was added, and the mixture extracted with EtOAc (2 x 10 ml). The organic layers were dried over sodium sulfate and concentrated in vacuo.
The residue was purified by FCC, eluting with a gradient of 5-20% EtOAc in heptane to provide the title compound as a colorless oil (0.239 g, 35%). 1H NMR (250 MHZ, CDCl3) δ ppm 8.80 (1H, dd), 8.14 (1H, m), 6.73 (1H, dd), 5.25 (1H, m), 4.39 ( 2H, dq), 3.96 (2H, m), 3.60 (2H, m), 2.05 (2H, m), 1.81 (2H, m) and 1.40 (3H, dt). Intermediate 238: tert-Butyl 4 - [(2,2,2-trifluoroethyl) sulfanyl | piperidine-1-carboxylate 2,2,2-Trifluoroethanol (0.133 mL, 1.49 mmol) was dissolved in DMF and cooled to OC under nitrogen.
Sodium hydride (60% dispersion in mineral oil, 0.060 g, 1.49 mmol) was added, and the mixture stirred for 10 min. tert-Butyl 4- (methanesulfonyloxy) piperidine-1-carboxylate (Intermediate 239, 0.320 g, 1.15 mmol) was added, and the mixture was stirred at room temperature for 18 h.
The mixture was then diluted with EtOAc (30 ml) and washed with water (10 ml), followed by aq. saturated (10 ml) and brine (10 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo to produce a pale yellow oil.
This was purified by FCC, eluting with a 0-20% gradient of EtOAc in heptane to provide the title compound as a colorless oil (0.197 g, 57%). 1H NMR (500 MHZ, CDCl3) 5 ppm 4.02 (2H, br s),
3.14 (2H, q), 2.98 (3H, m), 1.97 (2H, d), 1.52 (2H, m) and 1.48 (9H, s). Intermediate 240: 6 - [(1-Methylpyrrolidin-3-yl) oxylpyridine-3-carboxylic acid Ethyl 6 - [(1-methylpyrrolidin-3-yl) oxylpyridine-3-carboxylate (Intermediate 241, 0.089 g, 0 , 36 mmol) was dissolved in EtOH (2 mL), 2M sodium hydroxide (0.53mL, 1.07 mmol) was added, and the mixture was stirred at room temperature for 4 h.
The mixture was concentrated in vacuo, and the residue acidified to pH 6 by adding 2M hydrochloric acid.
The mixture was then concentrated and dried in vacuo to provide the title compound as a cream solid (0.136 g), which was used directly in the next step without further purification.
HPLC-MS Method C: MH + requires m / z = 223 Found: m / z = 223, Tr = 0.38 (17% by ELS). Intermediate 241: Ethyl 6 - [(1-methylpyrrolidin-3-yl) oxylpyridine-3-carboxylate Ethyl 6 - [(1-methylpyrrolidin-3-yl) oxylpyridine-3-carboxylate was prepared from 1-methylpyrrolidin- 3-0l (0.161 g, 1.59 mmol) and ethyl 6- — chloronicotinate (0.269 g, 1.45 mmol) according to the method described for Intermediate 236. The crude material was purified by FCC, eluting with a gradient 0-20% MeOH in EtOAc to provide the title compound as a colorless oil (0.089 g, 25%). 1H NMR (250 MHZ, CDCl3) 5 ppm 8.82 (1H, m), 8.13 (1H, dt), 6.74 (1H, m), 5.43 (1H, m), 4.39 ( 2H, dq), 2.82 (3H, m), 2.40 (3H, s), 2.39 (2H, m), 2.04 (1H, m) and 1.40 (3H, dt). Intermediate 242: 6- [2- (2,2, 2-trifluoroethoxy) ethoxy] pyridine-3-carboxylic acid Methyl 6- [2- (2,2,2-trifluoroethoxy) ethoxy] pyridine-3-carboxylate (Inter- medium 243, 0.453 g, 1.62 mmol) was dissolved in MeOH (5 mL), aq. 2M (1.62 mL, 3.24 mmol) was added, and the mixture was stirred at room temperature for 1 h.
The mixture was then concentrated in vacuo and acidified with 2M hydrochloric acid.
The resulting precipitate was filtered and dried in vacuo to provide the title compound as a white solid (0.245 g, 57%). 1H NMR (500 MHZ, MeOH-d4) 5 ppm 8.79 (1H, d), 8.23 (1H, dd), 6.90 (1H, d), 4.55 (2H, dd), 4, 03 (2H, q) and 4.01 (2H, dd) Intermediate 243: Methyl 6- [2- (2,2,2-trifluoroethoxy) ethoxy] pyridine-3-carboxylate 2- (2,2,2-Trifluoroethoxy ) ethanol (0.462 g, 3.21 mmol) was dissolved in THF (5 mL) and cooled to potassium C. tert-Butoxide (0.360 g, 3.21 mmol) was added, the mixture was stirred for 5 min and methyl 6-chloronicotinate (0.500 g, 2.91 mmol) was added.
The mixture was warmed to room temperature and stirred for 3 h.
Brine (10 mL) was added. 5, the sample was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated to produce a yellow oil, which was purified by FCC to provide the title compound as a colorless oil (0.453 g, 56%). 1H NMR (500 MHZ, CDCl3) 5 ppm 8.73 (1H, d), 8.10 (1H, dd), 6.74 (1H, d), 4.50 (2H, t), 3.93 ( 2H, t), 3.87 (2H, q9) and 3.84 (3H, s). Intermediate 245: tert-Butyl 4- (propan-2-ylsulfanyl) piperidine-1-carboxylate tert-Butyl 4- (methanesulfonyloxy) piperidine-1-carboxylate (Intermediate 239, 0.320 g, 1.15 mmol) and 2- Sodium propanethiolate (0.147 g, 1.50 mmol) was combined in DMF (3 mL) and stirred at room temperature for 18 h.
The mixture was then diluted with EtOAc (30 ml) and washed with water (3 x 10 ml). The organic layer was dried over sodium sulfate and concentrated to produce a yellow oil.
This was purified by FCC, eluting with a gradient of 0-20% EtOAc in heptane to provide the title compound as a colorless oil (0.179 g, 60%). 1H NMR (500 MHZ, CDCl3) δ ppm 3.88 (2H, br s), 2.94 (1H, m), 2.86 (2H, m), 2.77 (1H, m), 1.83 (2H, d), 1.42 (2H, m), 1.38 (9H, s) and 1.20 (6H, d). Intermediate 247: tert-Butyl 4- (propane-2-sulfinyl) piperidine-1-carboxylate tert-Butyl 4- (propan-2-ylsulfanyl) piperidine-1-carboxylate (prepared in a manner analogous to Intermediate 245, 0.160 g, 0.62 mmol) was dissolved in DCM (3 mL) and cooled to O C.
M-chloroperbenzoic acid (0.138 g, 0.62 mmol) was added, the mixture was warmed to room temperature and stirred for 17 h.
More m-chloroperbenzoic acid (0.0409, 0.18 mmol) was added, and the mixture was stirred at room temperature for 3 h.
The mixture was then diluted with DCM (10 ml) and washed with aq. Sodium thiosulfate. saturated (10 mL). The organic layer was separated and purified by FCC, eluting with 50-100% EtOAc in heptane, followed by 10% MeOH in EtOAc to provide the title compound as a colorless oil (0.124 g, 73%) . HPLC-MS Method C: MH + requires m / z = 276 Found: m / z = 298 (M + Na), Tr = 1.14 min (100%). Intermediate 248: 4 - [(2,2,2-trifluoroethoxy) methyl | benzoic acid Methyl 4 - [(2,2,2-trifluoroethoxy) methyl | lbenzoate (Intermediate 249, «S 1,059.4,23 mmol) was dissolved in MeOH (10 mL), aq. 2M (6.4 mL, 12.69 mmol) was added, and the mixture was stirred at room temperature for 3 h.
THF (2 ml) was then added, and the mixture stirred at room temperature over the weekend.
The mixture was then concentrated in vacuo, and the residue acidified by adding 2M hydrochloric acid.
The mixture was diluted with a little water and extracted with DCM (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide the title compound as a white solid (0.974 g, 98%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.14 (2H, d), 7.49 (2H, d), 4.79 (2H, s) and 3.91 (2H, q). Intermediate 249: Methyl 4 - [(2,2,2-trifluoroethoxy) methyl | benzoate 2,2,2-Trifluoroethane! (0.35 mL, 4.80 mmol) was dissolved in THF (2 mL) and cooled to O C under nitrogen.
Sodium hydride (60% dispersion in mineral oil, 0.192 g, 4.80 mmol) was added portion by portion, and the mixture stirred for 10 min. A solution of methyl 4 (bromomethyl) benzoate in THF (3 mL) was added. , the mixture was warmed to room temperature, and then heated to 50 ° C for 3 h.
The mixture was then diluted with water (15 ml) and EtOAc (20 ml). The organic layer was separated, and the aqueous neutralized with 1M hydrochloric acid.
The aqueous layer was also extracted with EtOAc (2 x 20 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide the title compound as a colorless oily residue (1.05 g, 97%). 1H NMR (500 MHZ, CDCl3) 5 ppm 7.95 (2H, d), 7.33 (2H, d), 4.64 (2H, s), 3.83 (3H, s) and 3.77 ( 2H, q9). Intermediate 250: 6- (2,2-difluoroethoxy) pyridine-3-carboxylic acid Powdered potassium hydroxide (712 mg, 12.7 mmol) was added to a mixture of 6-chloronicotinic acid (500 mg, 3.17 mmol ) and 2,2-difluoroethane! (520 mg, 6.35 mmol) in DMSO (15 mL), and the mixture was stirred
at 120 ° C for 14 h.
An additional two equivalents of 2,2-difluoroethanol and potassium hydroxide were added, and the mixture was heated for 24 h.
The mixture was cooled to room temperature, diluted with water (5 ml), acidified with aq. to 1N (at pH 1) and extracted. 5 with EtOAc (3x50 mL). The combined organic layers were washed with water (2 x 25 ml) then brine (50 ml) and concentrated under reduced pressure to provide the title compound as a beige solid (620 mg, 96%). HPLC-MS Method B: MH + requires m / z = 204; Found: m / z = 204, Tr = 1.54 min (90%). Intermediate 251: (1R, 58.6S) -6 - [(2,2,2-Trifluoroethoxy) methyl] -3-azabicyclo [3: 1.0] hexane (1R, 58.6S) -3-benzyl-6- [ (2,2,2-trifluoroethoxy) methyl] -3-azabicyclo [3.1.0] hexane (Intermediate 252, 360 mg, 1.26 mmol) and palladium hydroxide on carbon (20% by weight, 108 mg, 0, 15 mmol) were combined in EtOH (95 mL), and the mixture was heated to 50 C under a 4 bar hydrogen atmosphere for 18 h.
The mixture was filtered through celite, fresh catalyst was added to the filtrate, and the mixture was heated to 60 ° C under a 4 bar hydrogen atmosphere for 14 h.
The mixture was filtered through celite and concentrated under reduced pressure to provide the title compound as an oil (203 mg, 82%). HPLC-MS Method B: MH + requires m / z = 196; Found: m / z = 196, Tr = 0.23 min (by MS). The following intermediates were prepared in a manner analogous to Intermediate 251. ds Method B HPLC-MS: MH + requires m / z 256 abieietaa 1 onenan = 190; Found: m / z = 190, Tr = 1.09 min (92%) (1R, 5S8.6S) -6- Method B HPLC-MS: MH + requires m / z 259 | [(Cyclopropylmethoxy) methyl] -3- = 168; Found: m / z = 168, Tr = azabicycle [3.1.0] hexane 0.87 min (by MS) (1R, 58.6S) -6 - [(3,3,3- Method B HPLC-MS: MH + requires m / z 261 | Trifluoropropoxy) methyl] -3- = 210; Found: m / z = 210, Tr = azabicycle [3.1.0] hexane 0.87 min (by MS) (1R, 58.6S) -6 - [(Propan-2- Method B HPLC-MS: MH + requires m / z 263 (yloxy) methyl] -3- = 156; Found: m / z = 156, Tr = azabicycle [3.1.0) hexane 0.65 min (by MS)
265 | [(Cyclopentyloxy) methyl) -3- = 182; Found: m / z = 182, Tr = azabicycle [3.1.0] hexane 1.08 min (by MS) Intermediate - 252: (1R, 58.6S) -3-benzyl-6 - [(2,2,2 -trifluoroethoxy) methyl] -3-: azabicyclo [3.1.0] Jhexane - Methanesulfonyl chloride (320 ul, 4.13 mmol) was added to a solution of [(1R, 5S, 6S) -3-benzyl-3- azabicycle [3.1.0] hexan-6-ylmethane! (Intermediate 253, 600 mg, 2.95 mmol) and triethylamine (620 µL, 4.43 mmol) in DCM (20 mL) at room temperature.
The mixture was stirred for 3 h, and then aq. saturated (20 mL) was added.
The mixture was extracted with DCM (3 x 20 ml). The combined organic layers were washed with water (20 ml) then brine (20 ml) and concentrated under reduced pressure to provide the desired mesylate intermediate.
A 2,2,2-trifluoroethane mixture! (255 μl, 3.54 mmol) and sodium hydride (60% dispersion in mineral oil, 141 mg, 3.54 mmol) in DMF (3 mL) was stirred at OC for 30 minutes, and then added to a solution of the mesylate intermediate in DMF (5 mL) at O C.
The resulting mixture was stirred at room temperature for 14 h.
Aq. Ammonium chloride saturated (20 ml) was added, and the mixture was extracted with E-tOAc (4 x 50 ml). The combined organic layers were washed with water (3 x 20 ml), then brine (20 ml), concentrated under reduced pressure and purified by flash chromatography (40% EtOAc: heptane) to provide the title compound as a light yellow solid. (360 mg, 42%). HPLC-MS Method B: MH + requires m / z = 286; Found: m / z = 286, Tr = 1.24 min (73%). Intermediate 253: I1R, 58.6S) -3-benzyl-3-azabicyclic [3.1.0] hexan-6-illmethane! L A solution of lithium aluminum hydride (5.6 g, 147.5 mmol) in THF (50 mL) was added dropwise to a solution of ethyl (1R, 58.6S) -3-benzyl-2,4-dioxo-3-azabicyclo [3.1.0] hexane-6-carboxylate - (In- termediate 254, 10 9, 36.6 mmol) at OC, the mixture was warmed to room temperature and heated to 70 ° C for 18 h.
The mixture was cooled to room temperature and quenched with aq. saturated (5 ml), followed by water (1 ml) and stirred for 1 h.
The residue was filtered and washed with EtOAc.
The filtrate was dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound as "yellow oil (7.79, quant). Method B HPLC-MS: MH + requires m / z = 204;.: 5 Found: m / z = 204, Tr = 0.67 min (60%) Intermediate 254: Ethyl (1R, 58.6S) -3-benzyl-2 4-dioxo-3-azabicyclo [3.1 .O] hexane -6-carboxylate Ethyl S-benzyl-4,6-dioxo-1H, 3aH, 4H, 5H, 6H, 6aH-pyrrolo [3,4-clpyazol-3-carboxylate (Intermediate 255, 40 g, 132.9 mmol) was heated in a 500 mL flask to 190 C.
After the evolution of nitrogen, additional ethyl 5-benzyl-4,6-dioxide-1H, 3aH, 4H, 5H, 6H, 6aH-pyrrolo [3,4-c] pyrazol-3-carboxylate (3 x 10 g) portion by portion was added, and the mixture was heated for 30 min, until gas evolution stopped.
The mixture was cooled to room temperature and diluted with diethyl ether and stirred at room temperature for 1 h.
The mixture was cooled to -30 ° C and stirred for 30 min.
The mixture was filtered and washed with cold diethyl ether to provide the title compound as an off-white solid (26.1 g, 40%). Method B H- PLC-MS: MH + requires m / z = 274; Found: m / z = 274, Tr = 1.968 min (82%). Intermediate 255: Ethyl 5-benzyl-4,6-dioxo-1H, 3aH, 4H, 5H, 6H, 6aH-pyrrolo [3,4-clpyazol-3-carboxylate Ethyl diazoacetate (30.3 mL, 288.5 mmol ) was added dropwise over a period of 30 min to a solution of N-benzylmaleimide (49.5 g, 264.7 mmol) in diethyl ether (300 ml), and the mixture was stirred for 4 days at room temperature.
The resulting precipitate was filtered, washed with diethyl ether (100 ml) and dried in vacuo to provide the title compound as a white solid (72 g, 90%). HPLC-MS Method B: MH + requires m / z = 302; Found: m / z = 302, Tr = 1.74 min (83%). Intermediate 268: tert-Butyl 4 - ([(2,2,2-trifluoroethyl) sulfanylmethyl) piperidine-1-carboxylate 2,2,2-Trifluoroethane-1-thiol (471 ul, 3.41 mmol) was added drop to a suspension of sodium hydride (60% dispersion in mineral oil, 0.065 g, 1.636 mmol) in dry DMF (10 mL) at OC, and the mixture was stirred “for 15 min. A solution of tert-butyl | 4 [(methanesulfonyloxy) methyl] piperidine-1-carboxylate (prepared in a manner analogous to Intermediate 181, 1 g, 3.41 mmol) in DMF (5 mL) was added. 5 nadagotaagota, and the mixture was stirred at room temperature for 5 h.
The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with aq. saturated (25 ml) then brine (25 ml), dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound as a light yellow oil (1.13 g, quant.). HPLC-MS Method B: MH + requires m / z = 314 Found: m / z = 258 (MH + - tBu), Tr = 2.39 min (98%). Intermediate 270: tert-Butyl (38) -3-phenoxypyrrolidine-1-carboxylate Diisopropylazodicarboxylate (1.19 g, 5.87 mmol) was added to an ice-cooled mixture of tert-butyl (3R) -3-hydroxypyrrolidine -1- carboxylate (1 g, 5.34 mmol), phenol (0.5 g, 5.34 mmol) and triphenylphosphine (1.5 9, 5.8 mmol) in THF (14 mL). The mixture was stirred at room temperature for 20 h.
The mixture was then concentrated in vacuo, and the residue was triturated twice with diethyl ether.
The resulting solid was filtered and discarded.
The filtrate was washed with aq. at 1M, dried over sodium sulfate and concentrated.
The residue was purified by FCC, eluting with 10% EtOAc in heptane to provide the title compound (0.893 g, 63%). HPLC-MS Method B: MH + requires m / z = 208 Found: m / z = 208, Tr = 2.20 min (91%). Intermediate 272: tert-Butyl (3R) -3-phenoxypyrrolidine-1-carboxylate tert-Butyl (3R) -3-phenoxypyrrolidine-1-carboxylate was prepared from tert-butyl (3S) -3-hydroxypyrrolidine-1-carboxylate (0.43 g, 2.286 mmol) according to the method described for Intermediate 270 to provide. the title compound (0.312 g, 51% yield). HPLC-MS Method B: MH + requires / z = 208 Found: m / z = 208, Tr = 2.20 min (100%). Intermediate = 274: tercButil (3R) -3- (2,2,2-trifluoroethoxy) pyrrolidine-1-carboxylate:
Di-tert-butylazodicarboxylate (2.96 g, 12.83 mmol) was added to an ice-cooled mixture of tert-butyl (3S) -3-hydroxypyrrolidine-1-carboxylate (2 g, 10.70 mmol), 2 , 2,2-trifluroethanol (10.70 g, 106.95 mmol) and 1 triphenylphosphine (3.37 g, 12.83 mmol) in THF (24 mL). The mixture was stirred at
2. SS T7O0C for 16h The mixture was concentrated in vacuo, and the residue was purified by FCC, eluting with a gradient of EtOAc in heptane. The collected white solid was washed with heptane, and the filtrate was concentrated to provide the title compound (1.263 g, 44%), which was used without further purification. HPLC-MS Method B: MH + requires m / z = 270 Found: m / z = 214 (M minus tert-butyl), Tr = 2.02 min (82%). Intermediate 275: 6 - [(cyclopropylmethyl) sulfanyl] pyridine-3-carboxylic acid 6 - [(cyclopropylmethyl) sulfanyl] pyridine-3-carboxylic acid was prepared from 6-sulfanylpyridine-3-carboxylic acid (0.5 9, 3.22 mmol) and (bromomethyl) cyclopropane (0.44 g, 3.22 mmol) according to the method described for Intermediate 276 to provide the title compound (0.521 9, 61%). HPLC-MS Method B: MH + requires m / z = 210 Found: m / z = 210, Tr = 1.77 min (79%). Intermediate 276: 6 - [(3,3,3-trifluoropropyl) sulfanyl] pyridine-3-carboxylic acid - In a stirred solution of 6-sulfanylpyridine-3-carboxylic acid (0.5 g, 3.22 mmol) in EtOH (50 mL) to OC was added sodium acetate (0.26 g, 3.22 mmol) and 1,1,1-trifluoro-3-iodopropane (0.72 g, 3.22 mmol), and the mixture was heated to 80 C for 24 h. The mixture was concentrated in vacuo, water was added, and the mixture was acidified to pH 4 using acetic acid. The resulting yellow precipitate was collected by filtration and purified by FCC, eluting with 2% MeOH in DCM to provide the title compound (0.459 g, 57%). HPLC-MS Method B: MH + requires m / z = 252. Found: m / z = 252, Tr = 1.84 min (91%). . Intermediate 279: 5- (2,2,2-Trifluoroethylamino) -pyridine-2-carboxylic acid 5- (2,2,2-trifluoroethylamino) -pyridine-2-carboxylic acid ester (Intermediate 280, 75 mg, 0.320 mmol) was dissolved in a mixture of THF (0.75 mL) and water (0.25 mL) and hydroxide monohydrate | | and ... P M]] $ is cc ss ”To mo 441/490 lithium (27 mg, 0.640 mmol) was added.
The mixture was stirred at room temperature for 18h.
The mixture was diluted with water (5 ml), brought to approximately pH 4 by adding 1M HCl, then extracted with 'DCM (4 x 9 ml). The combined organic extracts were washed with salt. 5 moorish (5 ml), dried over sodium sulfate and evaporated in vacuo to provide the title compound as a white solid (51 mg, 72%). Method B HPLC-MS: MH + requires m / z = 221; Found: m / z = 221, Tr = 1.30 min (100%). Intermediate 280: 5- (2,2,2-Trifluoro-ethylamino) -pyridine-2-carboxylic acid methyl ester Methyl 5-aminopyridine-2-carboxylate (Intermediate 168, 200 mg, 1.31 mmol) and cesium carbonate (642 mg, 1.97 mmol) were dissolved in anhydrous DMF (2 mL) and stirred under nitrogen for 10 min. 2,2,2- Trifluoroethyl trifluoromethanesulfonate (246 µl, 1.70 mmol) was added, and the mixture was stirred at room temperature for 18 h.
More cesium carbonate (642 mg, 1.97 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (246 µL, 1.70 mmol) was added, and the mixture was stirred at 85 ° C for 6 h.
The mixture was diluted with EtOAc (50 ml) and washed with water (3 x 20 ml), then brine (20 ml), and then dried over sodium sulfate and evaporated in vacuo.
The crude residue was purified by flash chromatography (0-10%, EtOAc in heptane) to provide the title compound as a white solid (75 mg, 24%). HPLC-MS Method B: MH + requires m / z = 235; Found: m / z = 235, Tr = 1.76 min (84%). Intermediate 281: 2- (2,2,2-Trifluoroethoxy) pyridine-4-carboxylic acid 2-chloropyridine4-carboxylic acid (200 mg, 1.27 mmol), potassium tert-butoxide (381 mg, 3.81 mmol) and 2,2,2-trifluoroethanol (2.6 mL) were loaded into a tube sealed under nitrogen and stirred at 170 C for 3 h. 2,2,2-Trifluoroethanol (1 mL) was added, and the reaction stirred at. 170 C for 17 h.
The mixture was evaporated in vacuo, and the residue was dissolved in water (5 ml). 2M HCl was added to bring the solution to pH 5, and the mixture was extracted with DCM (3 x 10 ml). 2M HCl was then added to the aqueous layer to bring the solution to pH 3, and the mixture was extracted with DCM (4 x 6 ml). The combined organic extractions were washed with brine (5 ml), dried over sodium sulfate and evaporated in vacuo to provide the title compound as a white solid 7 (210 mg, 75%). HPLC-MS Method C: MH + requires m / z = 222; Found:
2. SS m / z = 222, Tr = 1.26min (95%). Intermediate 282: 2- (2,2,2-trifluoroethoxy) nicotinic acid 2-fluoropyridine-3-carboxylic acid (200 mg, 1.42 mmol) was dissolved in 2,2,2-trifluoroethanol (2 mL) and potassium tert-butoxide (477 mg, 4.25 mmol) was added. The mixture was then heated to 90 ° C for 4h. The mixture was diluted with water (4 ml), 2M HCl was added to bring the solution to pH 4, and the mixture was extracted with DCM (3 x 4 ml) . 2M HCl was added to the aqueous layer to bring the solution to pH 3, and the mixture was extracted with DCM (4 x 5 mL). The combined organic extractions were dried over sodium sulfate and evaporated in vacuo to provide the title compound (100 mg, 32%). HPLC-MS Method C: MH + requires m / z = 222; Found: m / z = 222, Tr = 1.17 min (100%). Intermediate 283: 3- (2-methoxyethoxy) -pyridine-2-carboxylic acid 3-fluoropyridine-2-carboxylic acid (150 mg, 1.06 mol), 2-methoxyethane! (1.5 mL) and potassium tert-butoxide (356 mg, 3.18 mmol) were loaded into a sealed tube under nitrogen, then stirred at 100 C for 18 h. The mixture was then diluted with water (3 ml), 1M HCl was added to bring the solution to pH 5, and the mixture was extracted with DCM (2 x 5 ml). 1M HCI was added to the aqueous layer to bring the solution to pH 3, and the mixture was extracted with DCM (2 x 5 ml). The combined organic extractions were dried over sodium sulfate and evaporated in vacuo to provide the title compound as a brown gum (54 mg, 26%). HPLC-MS Method C: MH + requires m / z = 198; Found: m / z = - 198, Tr = 0.29 min. Intermediate 285: 3- (2,2,2-Trifluoroethoxy) -pyridine-2-carboxylic acid Potassium tert-butoxide (954 mg, 8.51 mmol) was loaded into a sealed tube with 2,2,2-trifluoroethanol (4 mL) and 3-fluoropyridine-2-carboxylic acid (400 mg, 2.84 mmol), and the mixture was heated at 130 C for mm 443/490 26 h, then at 150 C for 4 h, and then then at 120 ° C for approximately 18 h.
The mixture was diluted with water (6 ml) and washed with DCM (2 x 4 ml), which was then discarded.
1M HCl was added to bring the solution to pH 7, and the aqueous was extracted with DCM (2 x 4 ml). The 2nd extraction process was repeated as above at pH 5, 4 and 3. The combined organic extractions were dried over sodium sulfate and evaporated in vacuo to provide the title compound as a white solid (305 mg, 49 %). HPLC-MS Method B: MH + requires m / z = 222; Found: m / z = 222, Tr = 0.73 min (100%). Intermediate 286: 3-Cyclobutoxy-pyridine-2-carboxylic acid Potassium terc-butoxide (358 mg, 3.19 mmol) was suspended in cyclobutanol (0.5 mL), 3-fluoropyridine-2-carboxylic acid (150 mg, 1.06 mmol) was added, and the reaction was stirred at 100 ° C for 18 h.
The mixture was evaporated in vacuo to provide the title compound (assumed 100% conversion), which was used in the next step without further purification.
HPLC-MS Method C: MH + requires m / z = 194; Found: m / z = 194, Tr = 0.83 min (100%). Intermediate 290: 5- (2,2,2-Trifluoroetoxymethyl) -furan-2-carboxylic acid Sodium hydride (60% dispersion in mineral oil, 60 mg, 1.50 mmol) was added to 2.2.2- trifluoroethane! (99 ul, 1.38 mmol) in anhydrous DMF (1 mL), and the mixture was stirred under nitrogen for 20 min.
5-Chloromethylfuran-2-carboxylic acid methyl ester (200 mg, 1.45 mmol) was then added, and the mixture was stirred at room temperature for 18 h, then at 60 C for 3 h, then at 100 ° C for 3 h.
Sodium hydride (60% dispersion in mineral oil, 30 mg, 0.75 mmol) was added under nitrogen, and the reaction mixture was stirred at room temperature for 18 h.
Sodium hydride (60% dispersion in mineral oil, - 30 mg, 0.75 mmol) was added, and the mixture was stirred at room temperature for 3 h.
The reaction mixture was diluted with EtOAc (30 ml), then washed with aq. saturated (4 x 6 mL), aq. saturated (2 x 6 ml), and then brine (6 ml). The aqueous extractions were combined and brought to pH 1 by the addition of HCI
> 444/490 at 2M, and then extracted with DCM (5 mL). The combined organic extractions were washed with water (3 x 6 ml), then brine (6 ml), and then dried over sodium sulfate and evaporated in vacuo Ú to provide the title compound (123 mg, 48%), which was used without further purification.
HPLC-MS Method C: (MH +) requires m / z = 225; Found: m / z = 252, Tr = 1.15 min (97%). Intermediate 125, Intermediate 148, Intermediate 165 and Intermediate 284 do not exist.
Biological data Total cell voltage clamp electrophysiology test Plaster clamp electrophysiology is considered the technique | gold standard for investigation of ion channel function and pharmacol- | gia.
Using this method, sodium channel currents can be measured in cells, which stably (or transiently) express the sodium channel subtype of interest.
The application of compounds during such experiments provides a functional measure of the activity and potency of compounds that affect the ion channel of interest.
Electrophysiological studies can be performed using automated or manual plaster clamp techniques.
Automated gram-plaster instruments suitable for this job include lon Works HT (MDS), lon Works Quattro (MDS), PatchLiner (Nanion technologies), Port-A-Patch (Nanion technologies), QPatch (Sophion) or any another suitable platform.
For recording on automated plaster clamp instruments, cells expressing the voltage-controlled sodium channel subtype of interest are dispensed into appropriate fragments (plates with more than one recording chamber, each containing one or more openings to generate full cell patches), as provided by the manufacturer.
Typically, the perforated plaster per cell configuration is used “30 to probe the pharmacology of compounds in automated plaster clamp electrophysiology in sodium channels.
Extracellular and intracellular plugs for such experiments are composed according to the literature.
or according to the instructions provided by the instrument manufacturer.
Test solutions, which contain the compounds to be tested, are applied to cells that express the sodium channel of interest by a 2-pipetting system, typically integrated in robots. 2 o Electrophysiological studies can also be performed using | the full cell configuration of the standard manual plaster clamp technique as described in the literature (for example, Pflugers Arch., 1981, | 391 (2), 85-100). In this assay, cells expressing the channel protein | voltage-controlled sodium hydroxides are exposed to drugs by conventional microperfusion systems, or by a nationally manufactured perfusion system *.
A suitable voltage stimulus protocol is + used to activate voltage-controlled sodium channels.
A suitable voltage stimulus protocol is used to activate voltage-controlled sodium channel proteins of interest.
A typical stimulus protocol may consist of sequential pulse voltage scans from a containment potential (ie, -65 mV), to a depolarization test pulse potential and more positive (ie, -10 mV) and finally for a hyperpolarization and more negative potential (ie, -100 mV). According to the ion channel biophysics controlled by voltage of interest and the interest in channel configuration, pulse voltages and durations as well as the total frequency of scans applied, could vary.
Consequently, a stimulus protocol was designed to evaluate compounds due to their potential to block NaV1.7 channels, mainly in the inactivated state.
Selectivity in other voltage-controlled sodium channel members was assessed by protocols that reflect the native function of the channels (ie, heart rate or neuron burn). 7 Electrophysiotological studies can also be performed using - the full cell configuration of the standard manual plaster clamp technique as described in the literature (for example Pflugers Arch., 1981, 391 (2), 85-100). In this assay, cells expressing the human voltage-controlled sodium channel protein of interest are exposed to drugs | by conventional microperfusion systems, or by a nationally manufactured perfusion system.
An appropriate voltage stimulation protocol is used to activate voltage-controlled sodium channels. - DZ A suitable voltage stimulation protocol may consist of sequential voltage g 5 pulses from a containment potential, each of which first hyperpolarizes the cell, then depolarizes the channels for a brief period.
A particularly suitable containment potential may be a voltage that allows a fraction of channels to remain in an inactivated state, such as -80 mV.
An adequate hyperpolarization voltage and duration can be -120 mV for 100 ms, and the voltages depolarization and duration can be -20 mV for 25 ms, and a fre- | the appropriate pulse frequency can be 0.1 Hz, but it can also have other parameters.
Consequently, a stimulus protocol was designated | to evaluate compounds due to their potential to block channels | 15 NaV1.7 mainly in the inactivated state.
The selectivity in other mem-! voltage-controlled sodium channel bridges were evaluated by protocols that reflect the native function of the channels (ie, heart rate or neuron burning). inhibition of Nav1.5 by Compounds of formula (1) when measured using QPatch Example - | ICSO / nM IC50 / nM 39 Ea 7060 3020 1031 5964 6889 1672 Inhibition of Nav1.5 by Compounds of formula (1) when measured using manual plaster clamp IC50 / nM IC50 / nM: 2426 3695. 1050 2055 3340 [68 = 10000 86 300 127 2602
SS MAs 447/490 Pharmacological model The compounds of formula (|) may show analgesic activity. 'ca in the FCA test (Freund's Complete Adjuvant) in the rat, a model of inflammatory pain, which is induced by intraplantar injection of Complete Freund's - Adjuvant (Stein et al., Pharmac.
Biochem.
Behav., 1988, 31, 445-451). The analgesic effects in the model can be obtained in doses that do not produce concentrations of tissue that lead to the conduction block in nerve fibers.
Thus, the local anesthetic effect may not mask the analgesic properties of the compounds (Scott et al., British Journal of Anaesthesia, 1988, 61, 165-8). Examples 125 and 130 were shown to be effective at a dose of 1 mg / kg (p.o.) and Example 67 was shown to be effective at a dose of 3 mg / kg (p.o.). All compounds were tested 72 h after the injection of FCA.
Modalities: Modality 1: A compound of formula (1) or a pharmaceutically acceptable salt thereof, R ”HO N Ns 2NRº'Rº dA o. (1) where R 'is selected from hydrogen-halogen- -C1-C; 7-alkyl-halo-C, -C7-alkyl-; W R is selected from hydrogen- C1-Cr-alkyl-
halo-C2-C; -alkyl-amino-C2-C; -alkyl-N-C1-C7-alkyl-amino-C2-C7-alkyl-N, N-di-C, -C; -alkyl-amino- C2-C; -alkyl-hydroxy-C2-C; -alkyl-Cyr-Cr-alkoxy-C2-C7-alkyl-C3-Capo-cycloalkyl-C1-C; -alkyl-cyano-C7-C; -alkyl- ; i or,
R 'and R', together with the atoms to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic ring, which is unsubstituted or substituted by 1-3 substituents selected from
C1-C; -alkyl-halo-C1-C; -alkyl-amino-C1-C; -alkyl-N-C1-C7-alkyl-amino-C1-C; -alkyl-N, N-di-C; -C; -alkyl-amino-C1-C; -alkyl-hydroxy-C1-C; -alkyl-C1-C; 7-alkoxy-C1-C; -alkyl-C3-Ciao-cycloalkyl-C1-C; z -Calkyl-C; -C; -alkyl-; R is selected from halogen-C1-C; -alkyl-halo-C1-C; -alkyl-C1-C; -alkoxy- = cyano-halo-C1-C; -alkoxy-3rd nitro; -C (0) -O-R ', where R' is selected from hydrogen, C1- C; -alkyl; C3a-Cio-cycloalkyl; C1-C7-alkoxy; halo-Cy-C; -alkyl aryl; aryl-Cy-
C7-alkyl-; heteroaryl and C1-C heteroaryl; -alkyl-; heterocyclyl; -S (= 0) 2-C1-C; -S (= 0) 2-C3-Cao-cycloalkyl; -S (= 0) 2-C, -C-alkoxy; R is selected from (a) -L-Y, where -L- is selected from a direct link; - (CH2), y-, -C (O) -, NR ”-, NR / -C (O) - or -C (O) -NR'-, where p is selected from 1, 2 or 3, R 'is selected from hydrogen and C1-C; -alkyl Y is selected from cycloalkyl, aryl, heteroraryl, heterocyclyl, spirocyclyl, which are unsubstituted or substituted by 1-3 substitutes selected from from halogen-; C1-C7-alkyl-; halo-C, -C; -alkyl-; halo-C1-C; -alkyloxy-C1-C; z-alkyl; - halo-C1-C; -alkyl-oxy-C1-C7-alkyl-oxy; Cr-C7-alkoxy-; Cy7-C; 7-C1-C1-alkoxy; NOC-C1-C7-alkoxy-; C1-C7-alkoxy-C; -C; -alkyl-; C3a-Cio-cycloalkyl-oxy-C1-C; z-alkyl-; C3-Cao-cycloalkyl-C, -C; -alkyl-oxy-; C3-Cio-cycloalkyl-oxy-; C3-Cryo-cycloalkyl-NR "-C1-C; z-alkyl-, where R” is selected from hydrogen and C1-C; -alkyl; C3-Cro-cycloalkyl-C1-C; 7-alkoxy- C, -C; -alkyl-; C7-C7-alkenyl; halo-C2-C; -alkenyl; hydroxy-; - hydroxy-C1-C; -alkyl-; halo-C1-C; -alkyl-oxy; 3rd amino-; N-C1-C; -alkyl-amino-; N-halo-C; -C; -alkyl-amino-;
N-heterocyclyl-amino-, N-C3-Co-cycloalkyl-amino-, wherein the heterocyclyl and cycloalkyl are optionally substituted by halo-C1-C; -alkyloxy, C1-C7-alkyl; Ca-Cao-cycloalkyl and C + -C; -alkoxy;
N-C3-Cao-cycloalkyl-C; -C; 7-alkyl-amino-;
N, N-di-C1-C; -alkyl-amino-; N, N-dihalo-C1-C; -alkyl-amino-;
N N-di-heterocyclyl-amino-, N, N-di-C3-Cio-cycloalkyl-amino-, where the heterocyclic and cycloalkyl are optionally substituted by halo-C1-C; 7-alkyl-oxy, C, - C7-alkyl; C3-Cio-cycloalkyl and C1-C; -alkoxy;
cyan-; oxo;
C1-Cr-alkoxy-carbonyl-;
C1-C7-alkoxy-C1-C7-alkoxy-C1-C; -alkyl-;
aryl; aryl-C1-C; -alkyl-; aryloxy;
heterocyclyl;
heterocyclyl-C1-C; -alkyl-; heterocyclyl-oxi-;
heterocyclyl-Oxy-C1-C7-alkyl-; aryl-oxy-C1-C; -alkyl-; heteroaryl-oxy-C1-C7-alkyl-;
hydroxy-carbonyl-;
-S- halo-C1-C; -alkyl; -S-C1-C; -alkyl; -S- aryl;
halo-C1-C; -alkyl-S-C1-C; -alkyl; C7-C7-alkyl-S-C1-C7-alkyl;
-S (= 0) 2-C1-C7-alkyl; -S (= O) 3-halo-C1-C; -alkyl; -S (= O) z-aryl; - S (= O), - heteroaryl; -S (= O) .- NR $ R $; -S (= O)> - heterocyclyl; halo-C1-C7-alkyl-S (= 0) 2-C1-C7-alkyl; - C1-C7-alkyl-S (= 0) 2-C1- C; -alkyl; -S (= 0) -C; -C; -alkyl; -S (= O) -halo-C, -C; -alkyl; -S (= 0) -C1-C7-alkoxy; -S (= O) -C3-Cio-cycloalkyl;
-C (0) -C1-C; z-alkyl; - -C (O) -halo-Cy-C; - -C (0) -C, -C; - alkoxy; - C (O0) -C3-C10 cycloalkyl;
- -C (0) O-C1-C; -alkyl; -C (0) O-C3-Co-cycloalkyl; -C (0) O-halo-C1-C; 7-alkyl; -C (0) O-C1-C; -alkoxy; 3rd -C (O) -NR * Rº or - NHC (O) -Rº, where
Rº is selected from hydrogen, C1-Cz-alkyl, halo-C, -
C7-alkyl, C3-Co-cycloalkyl, C3-C, o-cycloalkyl-C1-C7-alkyl and C7-Cz-alkoxy;
R * 'is selected from hydrogen; or Rº and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional heteroatom selected from N, O or S, and wherein said heterocyclic ring is optionally substituted with aryl, aryloxy-, C; -C; -alkyl, halo-C1- C; -alkyl or C, -C7-alkoxy, and said aryl is optionally substituted with halogen, C1-C; -alkyl, halo-C1-C; -alkyl or Cy-C; 7-alkoxy. or (b) -C (O) -NR $ 'Ró or -C (0) -O-Rº, where Rº and Rº are selected from hydrogen, C1-Cz-alkyl; C3-Cao-cycloalkyl; Cy-C7-alkoxy; halo-C1-C; -alkyl aryl; aryl-C7-C; -alkyl-; aryl; heteroaryl; heteroaryl C, -C; -alkyl-; heterocyclyl; indane; or ReR together with the nitrogen atom to which they are attached, form a 4-9 membered saturated or partially saturated monocyclic or bicyclic 4-9 membered ring, optionally containing an additional heteroatom selected from N, O or S; wherein said C3-Cio-cycloalkyl; aryl, heteroaryl, heterocyclyl and indane are optionally substituted with 1 to 3 substituents selected from C; -C; -alkyl, halo-C1-C; -alkyl, C1-C7z-alkoxy, halo-C1- C; -alkyl-oxy-, - halo-C; -C; -alkyl-oxy-C, -C; -alkyl, - Cyi-C7-alkyl-oxy-C1-C7-alkyl and hydroxy-C, -C ; -alkyl; or (c) -NRÉ'Rô, where R $ is selected from hydrogen, C, 1-C; -alkyl, Rº 'is selected from hydrogen, C; -C; -alkyl, C1-C7- alkyl carbonyl-; C3-Cio-cycloalkyl; or Rô and R $ together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated monocyclic ring or 7-12 membered saturated or partially saturated heterocyclic ring, optionally containing an additional selected heteroatom from N, O or S;
whose monocyclic and bicyclic heterocyclic ring is unsubstituted or substituted by 1-3 substituents selected from C1-C7-alkyl-, halo-C1-C7-alkyl-, C1-C; 7-alkoxy-, halo-C1-C ; -alkoxy-, halo-C; -C; -C1-C-alkoxy; -alkyl-, hydroxy- and C1-C7-alkoxy-carbonyl-; (d) -NR $ -C (O) -R $, where Rº is selected from hydrogen, C, -C; -alkyl; Ca-C10-cycloalkyl; C1-C: z-alkoxy; halo-C; -C; -alkyl; aryl; aryl-C, -C; 7-alkyl-; heteroaryl; heteroaryl-C, 1-C; -alkyl-; heterocyclyl; Rº is selected from hydrogen, C1-C; -alkyl; method n is 0-2; Rº is hydrogen and Rº is selected from hydrogen, C1-C7-alkoxy-C, -C; -alkyl-, C1-C; -alkyl, C1-C7-alkoxy and halo-C1-C; -alkyl; wherein C, 1-C; -alkyl, C1-C; 7-alkoxy, heterocyclic, aryl, heteroaryl are optionally substituted by aryl, heteroaryl, heterocyclyl, C1 + -C7-. alkyl, C1-C; -alkoxy, halo-C, -C; -alkyl; OH; with the proviso that 6- [5- (2-furanyl) -1,2,4-0xadiazol-3-yl] -N2-methyl-N2-phenyl-1,3,5-triazine-2 A4-diamine and 6 - [5- (2-furanyl) -1,2,4-oxadiazole-3- II-N, N, N'-methyl-N'-phenyl-1,3,5-triazine-2,4-diamine are excluded.
Mode 2: A compound according to mode 1, where R 'Re FO N N NH, dA & o. R O where 'R' is selected from hydrogen-halogen-
Cy -C; -alkyl-halo-C1-C; -alkyl-; 'R is selected from hydrogen-C1-C; -alkyl-halo-C2-C; -alkyl-amino-C2-C; -alkyl- N-C1-C7-alkyl-amino-C2-C; -alkyl- N N-di-C 1-C; 7-alkyl-amino-C2-C7; -alkyl-hydroxy-C2-C; -alkyl-C1-C7-alkoxy-C2-C7-alkyl-C3-Chao-cycloalkyl-C , -C7-alkyl-cyano-C2-C; -alkyl-; or R 'and R', together with the atoms to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic ring, which is unsubstituted or substituted by 1-3 substituents selected from C1- C; -alkyl-halo-C1-C; -alkyl-amino-C1-C; -alkyl-NC, 1-C; -alkyl-amino-C1-C; -alkyl- N, N-di-C1-C ; -alkyl-amino-C, -C; -alkyl-hydroxy-C, -C; -alkyl-C1-C; 7-alkoxy-C1-C; -alkyl-C3-Cao-cycloalkyl-C1-C; - alkyl-cyano-C1-C; -alkyl-; - R is selected from halogen- C1-C7-alkyl-halo-C; -C; -alkyl- C1-C7-alkoxy-
cyano-halo-C1-C; -alkoxy-nitro; Rº is selected from (a) -L-Y, where -L- is selected from a direct link; - (CH2) y-, -C (O) -, NR ”-, NR / -C (O) - or -C (O) -NR” -, where p is selected from 1,2 or 3 , R ”is selected from hydrogen, C; -C; -alkyl,
Y is selected from cycloalkyl, aryl, heteroaryl, heterocyclyl, which are unsubstituted or substituted by 1-3 substituents selected from halogen-C1-C; z-alkyl-halo-C1-C; - alkyl-C1r-C; -alkoxy-C3-Cao-cycloalkyl-oxyhydroxy-halo-C1-C; -alkyl-oxy-amino-N-C1-C; 7-alkyl-amino-N, N-di- C1-C; -alkyl-amino-cyano-C1-C; -alkoxy-carbonyl-hydroxy-carbonyl- -C (O) -NRº 'Rô, where Rº is selected from hydrogen, C1-C; -alkyl ; - R * 'is selected from hydrogen, or Rº and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional heteroatom selected from NO or S;
or (b) -C (O) -NRé'RÉ or -C (0) -O-Ró, where Rº and Rº are selected from hydrogen, C1-C; -alkyl; or (oc) -NR Rô, where Rº is selected from hydrogen, C, -C; -alkyl, Rô is selected from hydrogen, C, -C; -alkyl, C1-C; - alkyl carbonyl- , middle right 0-2; with the proviso that G6- [5- (2-furanyl) -1,2,4-0xadiazol-3-yl) -N2-methyl-N2-phenyl-1,3,5-triazine-2,4-diamine is excluded. Mode 3: A compound according to mode 1 or 2, where R Re
HA UN dA o E O) where R 'is selected from hydrogen-halogen-C1-C; -alkyl-halo-C, -C; -alkyl-; . R is selected from hydrogen- 'C1-C; -alkyl- halo-C2-C7; -alkyl-amino-C2-C7; -alkyl-
N-C1-C; -alkyl-amino-C2-C; -alkyl- N N-di-Cy-C; -alkyl-amino-C2-C; -alkyl-hydroxy-C2-C; -alkyl-C1- C7-alkoxy-C2-C; -alkyl-Ca-Capo-cycloalkyl-C1-C; -alkyl-cyano-C2-C; -alkyl-; or R 'and R', together with the atoms to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic ring, which is unsubstituted or substituted by 1-3 substituents selected from C1- C; 7-alkyl-halo-C; yC; -alkyl-amino-C; -C; -alkyl-N-C1-C7-alkyl-amino-Cy-C; -alkyl-N, N-di-C, -C; -alkyl-amino-C, -C; -alkyl-hydroxy-C1-C; -alkyl-C1-Cr-alkoxy-C, -C; -alkyl-C3-Cao-cycloalkyl-C, -C7- alkyl-cyano-C, -C; -alkyl-; R is selected from halogen-C1-C; -alkyl-halo-C, -C; -alkyl-C1-Cr-alkoxy-cyano-halo-C, -C; -alkoxy-. nitro; Rº is selected from (a) - (CH2), - Y, where p is selected from 0, 1, 20u3, and Y is selected from aryl, heteroraryl, heterocyclic, which are unsubstituted or substituted by 1-3 substituents selected from halogen-C1-C; -alkyl-halo-C; -C; -alkyl-C1-C; -alkoxy-C3-Cio-cycloalkyl-oxyhydroxy-halo-C, - C; -alkyl-oxy-amino-N-C1-C; -alkyl-amino-N, N-di-C1-C; -alkyl-amino-cyano-C1-C7-alkoxy-carbonyl-hydroxy-carbonyl- - C (O) -NRÉ'Rº, where Rº is selected from hydrogen, C, -C; -alkyl; R ”'is selected from hydrogen, or Rº and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional selected heteroatom from NO or S; or (b) -C (O) -NRÍÓ'Rº or -C (0) -O-Ró, where Rº is selected from hydrogen, benzyl, indanyl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, C3- Ciao-cycloalkyl, C1-C; -alkyl; Rº ”is selected from hydrogen, C1-C; -alkyl, - or Rº and Rº together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated monocyclic or bicyclic heterocyclic ring, optionally containing an additional heteroatom selected from N, O or S; or
(oc) -N RE R $, where Rº is selected from hydrogen, benzyl, C3-C1-cycloalkyl, C; -C; -alkyl, Rº is selected from hydrogen, C1-C; -alkyl, C1-C7- alkylcarbonyl-, i or Rº and Rº together with the nitrogen atom to which they are attached, form a saturated or partially saturated 4-7 membered monocyclic ring or saturated or partially saturated 7-12 membered heterocyclic ring, optionally containing an additional heteroatom selected from N, OousS; which are unsubstituted or substituted by 1-3 substituents selected from C1-C; -C1-C7-alkyl hydroxy-C1-C7-alkoxy-carbonyl- or (d) -NRÍ $ -C (O) -R $, where Rº is selected from C3-Cao-cycloalkyl; R * 'is selected from hydrogen, C1-C; -alkyl; méli, and right the + 1; with the proviso that G6- [5- (2-furanyl) -1,2,4-0xadiazole-3-11) -N2- methyl-N2-phenyl-1,3,5-triazine-2 4-diamine are excluded . Mode 4: A compound according to any of modalities 1a3, where R 2 FOR o o and Px ã Oo R O
R 'is selected from hydrogen- halogen- C1-C; -alkyl-
halo-C1-C; -alkyl-; R is selected from hydrogen-C1-C; -alkyl-halo-C> -C; -alkyl-
amino-C7-C; -alkyl-N-C1-C; 7-alkyl-amino-C2-C7-alkyl-
N, N = -di-C; -C; -alkyl-amino-C2-C7-alkyl-hydroxy-C2-C; -alkyl-C1-C7-alkoxy-C2-C7-alkyl-
C3-Cao-cycloalkyl-C1-C7-alkyl-cyano-C2-C; -alkyl-; or R'eR , along with the atoms to which they are attached,
form a 4-7 membered saturated or partially saturated heterocyclic ring, which is unsubstituted or substituted by 1-3 substituents selected from C1-C; -alkyl-halo-C1-C; -alkyl-amino-C1 -C; -alkyl-
NC, 1-C; 7-alkyl-amino-C, -C; -alkyl-N, N-di-C; -C; -alkyl-amino-C, 1-C; -alkyl-hydroxy-C, - C; 7-alkyl-
. C1-C7-alkoxy-C, -C; -alkyl-C3-Cro-cycloalkyl-C1-C; -alkyl-
cyano-C1-C; -alkyl-;
R is selected from halogen-
C1-C; -alkyl-halo-C; -C; -alkyl-C1-C; -alkoxy-cyano-halo-C1-C; -alkoxy-nitro; Rº is selected from (a) - (CH2), - Y, where p is selected from 0, 1.20u3, and Y is selected from aryl, heteroaryl, heterocyclyl, which are unsubstituted or substituted by 1-3 selected substituents halogen- 'C1-C; -alkyl-halo-C1-C; -alkyl-C1-C; -alkoxy-C3-Cao-cycloalkyl-oxyhydroxy-halo-C1-C; -alkyl- oxy-amino-N-C1-C; -alkyl-amino-N, N-di-C, -C; -alkyl-amino-cyano- Cy-C7-alkoxy-carbonyl-hydroxy-carbonyl--C (O) -NRºRº, where Rº is selected from hydrogen, C1-C; -alkyl; Rº * 'is selected from hydrogen, - or Rº * and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing a heteroatom additional selected from N, O or S; or
(b) -C (O) -NRº'Rº or -C (0) -OR $, where Rº is selected from hydrogen, benzyl, indanyl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, Ca-Co- cycloalkyl, C1-C7-alkyl; Rº is selected from hydrogen, C1-C; -alkyl, or Rº and R * 'together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated monocyclic or bicyclic heterocyclic ring, optionally containing an additional heteroatom selected from NO or S; .
or (oc) -N RºR $ ô, where Rº is selected from hydrogen, benzyl, C3-Cio-cycloalkyl, C, -C; -alkyl, Rº is selected from hydrogen, C1-C; z- alkyl, C1-C7- alkyl carbonyl-, or Rº and Rº 'together with the nitrogen atom to which they are attached, form a saturated or partially saturated 4-7 membered monocyclic or 7- saturated or partially saturated heterocyclic bicyclic ring 12 members, optionally containing an additional heteroatom selected from N, O or S; which are unsubstituted or substituted by 1-3 substituents selected from C1-C; -alkylhydroxy-C1-C; -alkoxycarbonyl- or (d) -NRÍ-C (O) -R $, where R $ is selected from C3-Cio-cycloalkyl; * Ró 'is selected from hydrogen, C; -C; -alkyl; mébõlie néo; with the proviso that 6- [5- (2-furanyl) -1,2,4-0xadiazol-3-yl] -N2-methyl-N2-phenyl-1,3,5-triazine-2,4-diamine are excluded.
Mode 5: A compound according to any of modalities 1-3, where R 'is selected from hydrogen-halogen-C1-Ca-alkyl-halo-C1-C, -alkyl-. Mode 6: A compound according to any of modalities 1-5, in which R 'is selected from hydrogen-, chloro-, fluoro-emethyl-. Mode 7: A compound according to any of modalities 1-6, where R 'is selected from hydrogen- and fluoro-. Mode 8: A compound according to any one of modalities 1-7, in which R is selected from hydrogen-C1-Ca-alkyl-halo-C2-C, -alkyl-N, N-di-C; -C2-alkyl-amino-C2-Ca-alkyl-hydroxy-C2-Ca-alkyl - Cy -Ca-alkoxy-Ca-Ca-alkyl-C3-Ce-cycloalkyl-C1-C7-alkyl-. Mode 9: A compound according to any one of modalities 1-8, in which R is selected from hydrogen- methyl-. ethyl-isopropyl- 2,2,2-trifluoro-ethyl- N, N-di-methyl-amino-ethyl-hydroxy-ethyl-
methoxy-ethyl-cyclopropyl-methyl-. Mode 10: A compound according to any one of modalities 1-9, in which R is selected from hydrogen-methyl-ethyl-2,2,2-trifluoro-ethyl-. Mode 11: A compound according to any of modalities 1-4, in which R 'and R', together are selected from -CH2-CH7z-, -CH2-CH27-CH2-, -CH = CH-, -CH = CH-CH7- or -CH3- CcH = CH-. Mode 12: A compound according to any of the modalities 11, in which R 'and R', together are selected from -CH2- CH7- or -CH23-CH27-CH;> -. Mode 13: A compound according to any of modalities 1-4, in which R 'is selected from hydrogen-chloro-fluoro-methyl-; R is selected from hydrogen-C1-Ca-alkyl-halo-C2-C, -alkyl-. N, N-di-C1-C> 2-alkyl-amino-C2-Ca-alkyl-hydroxy-C2-Ca-alkyl-C1-Ca-alkoxy-Ca-Ca-alkyl- 'C3-Ce-cycloalkyl-C1 -C; -alkyl-. Mode 14: A compound according to any one of modalities 1-13, wherein R is selected from halogen-C1-Ca-alkyl-halo-C1-C, -alkyl-Ci-Ca-alkoxy-. Mode 15: A compound according to any of modalities 1-14, where R is selected from chloro-fluoro-methyl-trifluoromethyl-methoxy-. Mode 16: A compound according to any one of modalities 1-15, in which R is selected from - (CH2), - Y, where p is selected from 0, 1, 20u3, and Y is selected from aryl, heteroaryl, heterocyclyl, which are unsubstituted or substituted by 1-3 substituents selected from halogen-C1-C; -alkyl-halo-C1-C; -alkyl- "Cr-C; -alkoxy-C3-Cho-cycloalkyl-oxyhydroxy-halo-C1-C; -alkyl- oxy- amino-
N-C1-C; -alkyl-amino-N, N-di-C17-C; -alkyl-amino-S (= 0) 2-C, -C; -alkyl; -S (= O)> - halo-C1-C; -alkyl; -S (= 0) -C1-C; -alkyl; -S (= O) -halo-C, -C; -alkyl; C3-Cao-cycloalkyl-C1-C7-alkoxy-C1-C; -alkyl-; cyano-C1-C; -alkoxy-carbonyl-hydroxy-carbonyl--C (O) -NRÉ'Rº, where Rº is selected from hydrogen, C1-C; -alkyl; R ”is selected from hydrogen, or Rº and R” together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional selected heteroatom at from NO or S.
Mode 17: A compound according to any one of modalities 1-16, in which R is selected from -Y, where Y is selected from aryl, heteroaryl, heterocyclic, which are unsubstituted or substituted by 1-2 substituents selected from halogen- C1r-Ca-alkyl-. halo-C1-Ca-alkyl-C1r-Ca-alkoxy-C3-C; -cycloalkyl-oxy-hydroxy-halo-C1-Ca-alkyl-oxy-amino-cyano-C1-Ca-alkoxy-carbonyl-hydroxy-carbonyl -
-S (= 0) 2-C 1-C; -alkyl; -S (= O)> - halo-C, -C; -alkyl; -S (= 0) -C1-C; -alkyl; -S (= O) -halo-C1-C; -C3 alkyl-Cao-cycloalkyl-C, -C; 7-alkoxy-C1-C; -alkyl-; -C (O) -NR * Rô, where Rº is selected from hydrogen, C1-Ca-alkyl; R * 'is selected from hydrogen, or Rº * and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional heteroatom selected from NO or S.
Mode 18: A compound according to any one of modalities 1-17, in which R is selected from -Y, where Y is selected from aryl, heteroaryl, heterocyclyl, which are unsubstituted or substituted by 1-2 substituents selected from halogen-C1-Ca-alkyl-halo-C1-Ca-alkyl- C1-Ca-alkoxy-C3-C; -cycloalkyl-oxy-hydroxy-halo-C1-Ca-alkyl-oxy-amino-cyano-C1-Ca-alkoxy-carbonyl-hydroxy-carbonyl-. -C (O) -NRÁ R $, in which Rº is selected from hydrogen, C, -C, -alkyl; R * is selected from hydrogen, or Rº and R * together with the nitrogen atom to which they are attached, form a saturated or partially-heterocyclic monocyclic ring
saturated 4-7 member, optionally containing an additional heteroatom selected from N O or S.
Mode 19: A compound according to any of modalities 1-17, in which Rº is selected from phenyl, furanyl, thiophenyl, pyridyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, pyrrolyl, benzofuranyl, pyrimidinyl, oxazolyl, morpholinyl, piperidine, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, dihydrobenzofuranyl that are unsubstituted or substituted by 1-2 substituents selected from halogen-C1-Ca-alkyl-halo-C1-Ca-alkyl-Cr-Ca- C3-C7-cycloalkyl-oxy-hydroxy-halo-C1-Ca-alkyl-oxy-amino-cyano-C1-Ca-alkoxy-carbonyl-S (= 0) 2-C1-C; -alkyl; -S (= O)> - halo-C1-C; -alkyl; -S (= 0) -C, -C; -alkyl; -S (= O) -halo-C; -C; z-C3-Cao-cycloalkyl-C1-C; 7-alkoxy-C1-Cz-alkyl-; -C (O) -NR * Rº, where Rº is selected from hydrogen, C1-Ca-alkyl; R * 'is selected from hydrogen, or Rº and R * together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, pyrrolidinyl.
Mode 20: A compound according to any one of modalities 1-18, in which R is selected from phenyl, furanyl, thiophenyl, pyridyl, thiazolyl, pyrazolyl, isoxazolyl,
imidazolyl, pyrrolyl, benzofuranyl, pyrimidiyl, oxazolyl, morpholinyl, piperidine, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, dihydrobenzofuranyl that are unsubstituted or substituted by 1-2 substituents selected from chlorine-bromine-bromine methyl-trifluoromethyl-2,2,2-trifluoro-ethyl-2,2,2-trifluoro-ethyl-oxy-methyl-cyclopropyl-methoxy-methyl-S (= 0), - 2,2,2-trifluoro- ethyl-; -S (= O)> - propyl; -S (= 0) -3,3,3-trifluoro-propyl; 3,3,3-trifluoro-propyl-oxy-methyl-; methoxy-cyclopentyl-oxy-trifluoromethyl-oxy-2,2,2-trifluoro-ethyl-o6x-amino-cyano-methoxy-carbonyl- -C (O) -NR * Rº, where Rº is selected from hydrogen, methyl; R * is selected from hydrogen, or Rº and R * together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, pyrrolidinyl.
Mode 21: A compound according to any of modalities 1-18, in which 'Rº is selected from phenyl, furanyl, thiophenyl, pyridyl, thiazolyl, pyrazolyl, isoxazolyl,
imidazolyl, pyrrolyl, benzofuranyl, pyrimidinyl, oxazolyl, morpholinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, dihydrobenzofuranyl that are unsubstituted or substituted by 1-2 substituents selected from chlorine-bromine-fluorine methyl-trifluoromethyl-2,2,2-trifluoro-ethyl-cyclopropyl-methoxy-methyl-methoxy-cyclopentyl-oxy-trifluoromethyl-oxy-2,2,2-trifluoro-ethyl-oxy-amino-cyano-methoxy-carbonyl- - “C (O) -NRºRº, where Rº is selected from hydrogen, methyl; R * 'is selected from hydrogen, or Rº and R * together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, pyrrolidinyl.
Mode 22: A compound according to any of the modalities 11-21, in which R is selected from -C (O) -NRÉ'Rº or -C (0) -O-R $ ó, where 'Rº is selected from hydrogen, benzyl, indanyl, tetra-. hydrofuranoyl, tetrahydropyranyl, oxiranyl, C3-Co-cycloalkyl, C7-C; -alkyl; Rº 'is selected from hydrogen, C1-C; -alkyl, or Rº and Rº' together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated monocyclic or bicyclic heterocyclic ring, optionally containing an additional heteroatom selected from N, O or S.
Mode 23: A compound according to any of modalities 1-22, in which Rº is selected from -N Rº R $, in which Rº is selected from hydrogen, benzyl, C3-C1o- cycloalkyl, C, -C; -alkyl, R $ is selected from hydrogen, C, -C; -alkyl, C; -C7- —alkyl carbonyl-, or Rô and Rº 'together with the nitrogen atom to which they are attached, form a saturated or partially saturated 4-7 membered monocyclic or saturated or partially saturated 7-12 membered bicyclic ring, optionally containing an additional heteroatom selected from N OouS; which are unsubstituted or substituted by 1-3 substituents selected from C1-C; -alkylhydroxy-C1-C; -alkoxy-carbonyl-. Mode 24: A compound according to any one of modalities 1-23, in which R is selected from -NR $ Í-C (O) -R $, where Rº is selected from C3-Co-cycloalkyl; R ”'is selected from hydrogen, C1-C; -alkyl.
Mode 25: A compound according to any of the 'modalities 1-24, in which' means.
Modality 26: A compound according to any one of modalities 1-25, in which O or 1, particularly O.
Mode 27: A compound according to mode 1, where R 'is selected from hydrogen-fluoro-; R is selected from hydrogen-C1-Ca-alkyl-halo-C2-Ca-alkyl-
N, N-di-C1-C> -alkyl-amino-C2-Ca-alkyl-hydroxy-C2-Ca-alkyl-C1-Ca-alkoxy-Ca2-Ca-alkyl-C3-Ce-Ccycloalkyl-C, - C; -alkyl-; or
R 'and R', together are selected from -CH2-CH72- or -CH27-CH2-CHa-;
R is selected from halogen- C1-Ca-alkyl-
halo-C1-C, -alkyl-C1-Ca-alkoxy-; and Rº is selected from - (CH2) pY, where p is selected from 0, 1.20u3, and Y is selected from aryl, heteroaryl, heterocyclyl, which are unsubstituted or substituted by 1-3 selected substituents 'halogen-' C1-C; -alkyl-halo-C1-C; -alkyl-C1-C; -alkoxy-C3-Cao-cycloalkyl-oxi-
hydroxy-halo-C; -C7-alkyl-oxy-amino-NC, -C; -alkyl-amino-N, N-di-C1-C; -alkyl-amino-cyano-C1-C; 7-alkoxy- carbonyl-S (= 0)> - C1-C7-alkyl; -S (= O)> - halo-C1-C; -alkyl; -S (= 0) -C1-C; -alkyl; -S (= O) -halo-C, -C; -C3 alkyl-Cao-cycloalkyl-C; -C7-alkoxy-C1-C; -alkyl-; -C (O) -NRÁRº, where Rº is selected from hydrogen, C1-C; -alkyl; R * 'is selected from hydrogen, or Rº and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional selected heteroatom from NO or S, mobile neo-41. Mode 28: A compound according to mode 1, where R 'is selected from hydrogen-fluoro-; R is selected from hydrogen-C1-Ca-alkyl- * halo-C2-C, -alkyl-N, N-di-C1-C; 7-alkyl-amino-C2-Ca-alkyl-hydroxy-Ca-C , -C1-C2-alkoxy-C2-Ca-alkyl- alkyl. C3-Ce-cycloalkyl-C1-C; -alkyl-;
or R 'and R', together are selected from -CH3-CH2- or -CH2-CH7-CHa-; R is selected from halogen-C1-Ca-alkyl-halo-C1-C, -alkyl-C1-Ca-alkoxy-; and R is selected from phenyl, furanyl, thiophenyl, pyridyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, pyrrolyl, benzofuranyl, pyrimidinyl, oxazolyl, morpholinyl, piperidinyl, tetrahydrofuranyl, tetrahydrofuranyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridine unsubstituted or substituted by 1-2 substituents selected from halogen-C1-Ca-alkyl-halo-C1-C, -alkyl-C1-Ca-alkoxy-C3-C; -cycloalkyl-oxy-hydroxy-. halo-C1-Ca-alkyl-oxy-amino-cyano-C1-Ca-alkoxy-carbonyl-S (= O0) 2-C1-C; -alkyl; -S (= O)> - halo-C; -C7-alkyl; -S (= 0) -C1-C; -alkyl; -S (= O) -halo-C1-C; -C3-Cao-cycloalkyl-C1-C; 7-alkoxy-C1-C; -alkyl-; . -C (O) -NR * 'Rô, where Rº is selected from hydrogen, C1-Ca-alkyl; R * is selected from hydrogen, or Rº and R * together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, pyrrolidinyl, methods 41. Mode 29: A compound of formula (1) or a pharmaceutically acceptable salt thereof, for use in medicine, R Rn FO N Ns NRºRº
CARD dA (1) where R 'is selected from hydrogen-halogen-C1-C7-alkyl-halo-C1-C; -alkyl-; R is selected from hydrogen-C1-C; -alkyl-halo-C2-C7-alkyl-amino-C2-C; -alkyl- N-C1-C; -alkyl-amino-C2-C; -alkyl- N N-di-C1-C; -alkyl-amino-C2-Cr; -alkyl-hydroxy-C2-C; -alkyl-C1-C; 7-alkoxy-C2-C; 7-alkyl-. C3a-Cao-cycloalkyl-C1-C7-alkyl-cyano-C2-C7; -alkyl-; Ú or R 'and R', together with the atoms to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic ring, which is unsubstituted or substituted by 1-3 substituents selected from
C1-C; -alkyl-halo-C1-C; -alkyl-
amino-C, -C; -alkyl-N-C1-C; -alkyl-amino-C; -C7-alkyl-N, N-di-C, -C; -alkyl-amino-C, -C; - alkyl-hydroxy-C, -C; -alkyl-C1-C7-alkoxy-Cy-C; -alkyl-
C3-Cio-cycloalkyl-C; -C; 7-alkyl-
cyano-C, -C; -alkyl-; R is selected from halogen-C1-C; -alkyl-halo-C, -C; -alkyl-C1-C; -alkoxy-cyano-halo-C1-C7-alkoxy-nitro;
-C (0) -O-R ', where R' is selected from hydrogen, C; - Cr-alkyl; C3-Cio-cycloalkyl; C1-C; -alkoxy; halo-C, -C; -alkyl aryl; aryl-C1- Cr-alkyl-; heteroaryl; heteroaryl C1-C; -alkyl-; heterocyclic;
-S (= O0) 2-C1-C; -alkyl; -S (= O0) 2-Ca-Chio-cycloalkyl; -S (= 0) 2-C1- Cr-alkoxy; Rº is selected from (a) -L-Y, where -L- is selected from a direct link; - (CH> 2), -, -C (O) -,
'NR ”-, NR / -C (O) - or -C (O) -NR'-,
. where p is selected from 1, 2 or 3,
R 'is selected from hydrogen and C1-C; -alkyl
Y is selected from cycloalkyl, aryl, heteroraryl, heterocyclyl, spirocyclyl, which are unsubstituted or substituted by 1-3 subs-
tituents selected from halogen-;
C1-C; -alkyl-;
halo-C1-C; -alkyl-;
halo-C1-C; -alkyl-6xi-C, -C; -alkyl; - halo-C, -C7-alkyl-oxy-C1-C7-alkyl-oxy;
C1-Cz-alkoxy-; C1-C7-alkoxy-C 1-C; NOC-C1-C7-alkoxy-;
C1-C; 7-C1-alkoxy, -C7-alkyl-;
C3-Cao-cycloalkyl-oxy-C; -C; z-alkyl-;
C3-Cao-cycloalkyl-C1-C7-alkyl-oxy-;
C3-Cao-cycloalkyl-oxy-;
C3-Cao-cycloalkyl-NR ”-C1-C7-alkyl-, where R” is selected from R 'is selected from hydrogen and C1-C; -alkyl;
C3-Cao-cycloalkyl-C1-C7-alkoxy-C; -C7-alkyl-;
C7> -C; 7-alkenyl; halo-C2-C7; -alkenyl;
hydroxy-;
hydroxy-C1-C; -alkyl-;
halo-C1-C; -alkyloxy;
amino-;
N-C1-C; -alkyl-amino-;
N-halo-C; -C; -alkyl-amino-;
N-heterocyclyl-amino-, N-C3-Cio-cycloalkyl-amino-, wherein the heterocyclyl and cycloalkyl are optionally substituted by halo-C, -C; -alkyl-oxy, C1-C; -alkyl; C3-C 1o9-cycloalkyl and C1-C7-alkoxy;
N-C3-C 1st-cycloalkyl-C1-C7-alkyl-amino-; N, N-di-C, -C; -alkyl-amino-; N, N-dihalo-C; -C7-alkyl-amino-; : N N-di-heterocyclyl-amino-, N, N-di-C3-Cip-cycloalkyl-amino-, in which heterocyclyl and cycloalkyl are optionally substituted by halo-. C1-Cz-alkyl-oxy, C; -C; z-alkyl; C3-Cio-cycloalkyl and C, -C; -alkoxy; cyan-; oxo;
C1-C; -alkoxy-carbonyl-;
C1-C7-alkoxy-C1-C7-alkoxy-C1-C7-alkyl-;
aryl; aryl-C17-C; -alkyl-; aryloxy; : heterocyclic; heterocyclic-C, -C; -alkyl-; heterocyclyl-oxi-; heterocyclyl-6xy-C1-C; -alkyl-; aryl-oxy-C, -C; -alkyl-; heteroaryl-6X-CrC; alkyl-; hydroxy-carbonyl-; -S- halo-C, -C; -alkyl; -S-C1-C; -alkyl; -S- aryl; halo-C1-C7-alkyl-S-C; -C7-alkyl; C1-C; -alkyl-S-C, -C; -alkyl; -S (= 0) 3-C1-C; z-alkyl; -S (= O0), - halo-C1-C; -alkyl; -S (= O), - aryl; - S (= O) xheteroaryl; -S (= O0) .- NR $ Ri; -S (= O) -heterocyclyl; halo-C 1-C7-alkyl-S (= 0) 2-C1-C; - C1-C; 7-alkyl-S (= 0), - C1- C; -alkyl; -S (= 0) -C, 1-C; -alkyl; -S (= O) -halo-C -C; -alkyl; -S (= 0) -C, -C; - alkoxy; -S (= O) -C3-C, o-cycloalkyl; -C (0) -C1-C; z-alkyl; - -C (O) -halo-C, -C; -alguyl; - -C (0) -C1-C; 7-alkoxy; - C (O0) -C3-C1o cycloalkyl; -C (0) O-C, -C; -alkyl; -C (0) O-C3-Cio-cycloalkyl; -C (O) O-halo-C1-C; 7-alkyl; -C (0) O-C-C7-alkoxy; -C (O) -NR * 'Rº or -NHC (O) -RÍ, where Rº is selected from hydrogen, C1-Cz-alkyl, halo-C,; - C7-alkyl, C3-Cap-cycloalkyl , C3-Cio-cycloalkyl-C, -C7-alkyl and C1-C; 7-alkoxy; R * is selected from hydrogen; or Rº 'and Rº together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional heteroatom selected from N, O or S, and wherein said heterocyclic ring is optionally substituted with aryl, aryl-oxy-, C1-C7-alkyl, halo-Cy- 'Cr-alkyd or C; -C; 7-alkoxy, and said aryl is optionally substituted with . halogen, C1-C; z-alkyl, halo-C, -C; -alkyl or C1-C; 7-alkoxy. or (b) -C (O) -NR $ 'Rº or -C (0) -O-R , where Rº and R *' are selected from hydrogen, C1-C; -alkyl;
C3-Cio-cycloalkyl; C1-C: z-alkoxy; halo-C1-C; -alkyl aryl; aryl-Cy-C; -alkyl-; aryl; heteroaryl; heteroaryl C1-C; -alkyl-; heterocyclyl; indane; or Rº and Rº together with the nitrogen atom to which they are attached, form a saturated or partially saturated 4--9 membered monocyclic or bicyclic heterocyclic ring, optionally containing an additional heteroatom selected from N, O or S; wherein said C3-C, i, -cycloalkyl; aryl, heteroaryl, heterocyclyl and indane are optionally substituted with 1 to 3 substituents selected from C, 1-C; z-alkyl, halo-C, -C; -alkyl, C1-C; -alkoxy, halo-C; -C; alkyloxy- and hydroxy-Cy-C; -alkyl; or (c) -NR $ Rô, where Rº is selected from hydrogen, C, -C; -alkyl, R * 'is selected from hydrogen, C1-C; -alkyl, C1r-C; - alkyl carbonyl-; C3-Cio-cycloalkyl; or R $ and Rô together with the nitrogen atom to which they are attached, form a saturated or partially saturated 4-7 membered monocyclic or 7-12 membered saturated or partially saturated bicyclic ring, optionally containing an additional selected heteroatom. cited from N, OousS; whose monocyclic and bicyclic heterocyclic ring is unsubstituted or substituted by 1-3 substituents selected from C1-C7-alkyl-, halo-C, -C7-alkyl-, C1-C7-alkoxy-, hydroxy- and C1-Cr -alkoxy-carbonyl-; (d) -NRÉ-C (O) -R $, where Rº is selected from hydrogen, C1-C; -alkyl; C3-C1-cycloalkyl; C1-C; -alkoxy; halo-C1-C; -alkyl; aryl; aryl-C, -C; -alkyl-, heteroa-: rila; heteroaryl-Cy-C; z-alkyl-; heterocyclyl; . Rº 'is selected from hydrogen, C1-C; -alkyl; mêébl-i and n is 0-2; Rº is hydrogen and Rº is selected from hydrogen, .halo-
C1-C; -alkyl-, C1-C7-alkoxy-C1-C; -alkyl-, C1-Cz-alkyl, Cr-C7-alkoxy and halo-C1-C; -alkyl; wherein C, -C; -alkyl, C1-C; -heterocyclyl, aryl, heteroaryl are optionally substituted by aryl, heteroaryl, heterocyclyl, C, -C; 7-alkyl, Cy-C; -alkoxy, halo-C1 -C; -alkyl; OH. Modality 30: A compound according to modality 29, in which Rº Re HO N N NH, eh
NAN o - ”O) where R 'is selected from hydrogen-halogen-C1-C7-alkyl-halo-C1-C; -alkyl-; R is selected from hydrogen-C1-C; -alkyl-halo-C2-C; -alkyl-amino-C2-C; -alkyl- N-C1-C; -alkyl-amino-C2-C; -alkyl- N, N-di-C7-C; -alkyl-amino-C2-C; -alkyl-. hydroxy-C2-C7-alkyl-C1-C7-alkoxy-C2-C7-alkyl-C3-Cao-cycloalkyl-C1-C7-alkyl-cyano-C2-C; -alkyl-; or
R 'and R', together with the atoms to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic ring, which is unsubstituted or substituted by 1-3 substituents selected from C1-C ; -alkyl-halo-C, -C; -alkyl-amino-C, -C; -alkyl- N-C1-C; -alkyl-amino-C, -C; -alkyl-N N-di-C1- C; -alkyl-amino-C1-C; -alkyl-hydroxy-C1-C; -alkyl-C1-C7-alkoxy-C, -C; z-alkyl-C3-Co-cycloalkyl-C1-C7-alkyl- cyano-C, -C; -alkyl-; R is selected from halogen-C1-C; -alkyl-halo-C, -C; -alkyl-C1-C; -alkoxy-cyano-halo-C1-C; -alkoxy-nitro; R is selected from (a) -L-Y, where -L- is selected from a direct link; - (CH2), -, -C (O) -, NR ”, NR / -C (O) - or -C (O) -NR'-, where p is selected from 1,2 or 3, R ”is selected from hydrogen, C, -C; -alkyl," Y is selected from cycloalkyl, aryl, heteroaryl, hetero-. Cyclyl, which are unsubstituted or substituted by 1-3 substituents selected from from halogen- C1-C7-alkyl-
halo-C1-C; -alkyl-Cr -C; -alkoxy-C3a-Cycloalkylalkyl-oxyhydroxy-halo-C, -C; -alkyl-oxy-amino-N-C1-C7; -alkyl-amino - N, N-di-C1-C; -alkyl-amino-cyano-C, -C; -alkoxy-carbonyl-hydroxy-carbonyl- -C (O) -NRÉ'R $, where Rº is selected from hydrogen, C, 1-C; -alkyl; Rº * is selected from hydrogen, or Rº and Rº together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional heteroatom selected from NO or S; or (b) -C (O) -NRº'RÉ or -C (0) -O-R $ ó, where R $ and Rº 'are selected from hydrogen, C1-C; -alkyl; or (oc) -NRERÔ, where R $ is selected from hydrogen, C, -C; -alkyl, RÔ is selected from hydrogen, C1-C; -alkyl, C1-C; 7- alkyl carbonyl- , méõ-i; e 'néo2.
'Mode 31: A compound according to mode 29 or 30, where
Rº R FOX a, dA o, (1) where R 'is selected from hydrogen-halogen-C1-C; -alkyl-halo-C1-C; -alkyl-; R is selected from hydrogen- C1-C; -alkyl-
halo-C2-C7-alkyl-amino-C2-C; -alkyl-N-C; -C; -alkyl-amino-C2-C7-alkyl-
N, N-di-C1-C; -alkyl-amino-C2-C; -alkylhydroxy-C2-C; -alkyl-
C1-C7-alkoxy-C2-C; -alkyl-C3-Chao-cycloalkyl-C1-C; z-alkyl-cyano-C72-C; -alkyl-; or R 'and R , together with the atoms to which they are attached,
form a 4-7 saturated or partially saturated heterocyclic ring
. members, which is unsubstituted or substituted by 1-3 substituents selected
from
C1-C; -alkyl-halo-C1-C; -alkyl-
amino-C1-C; -alkyl-
N-C1-C7-alkyl-amino-C, -C; -alkyl- N, N-di-C1-C; -alkyl-amino-C, -C; -alkyl-hydroxy-C1-C; -alkyl- C1-C7-alkoxy-C1-C7-alkyl-C3-Cro-cycloalkyl-C, -C; -alkyl-cyano-C1-C; -alkyl-; R is selected from halogen-C1-C; -alkyl-halo-C1-C; -alkyl-C1-C; 7-alkoxy cyano-halo-C1-C; -alkoxy nitro; R is selected from (a) (CH2), - Y, where p is selected from 0, 1.20uU3, and Y is selected from aryl, heteroaryl, heterocyclyl, which are unsubstituted or substituted by 1 -3 selected substituents halogen-C1-C; z-alkyl-halo-C, -C; -alkyl-C1-C; 7-alkoxy- Ca-Cao-cycloalkyl-oxy-hydroxy-halo-C1-C; 7- alkyl-oxy-amino- "NC, 1-C; -alkyl-amino-. N N-di-C1-C; -alkyl-amino-cyano-C1-C7-alkoxy-carbonyl-hydroxy-carbonyl-
gu ONLY ÓMML UMAA A.),. “.“ “º2º“ “º“ P “ºO“ OOOOO “OOAS DDD O000000U 484/490 -C (O) -NRÉ'Rº, where Rº is selected from hydrogen, C1-C; -alkyl; R * 'is selected from hydrogen, or Rº and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional selected heteroatom from NO or S; or (b) -C (O) -NR $ 'RÍ or -C (0) -O-Rº, where Rº is selected from hydrogen, benzyl, indanyl, tetrahydrofuranoyl, tetrahydropyranyl, oxiranite, C3 -Co-cycloalkyl, C1-C; -alkyl; Ró is selected from hydrogen, C, -C; -alkyl, or Rº and Rº together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated monocyclic or bicyclic heterocyclic ring, optionally containing an additional heteroatom selected from NO or S; or (e) -N R6Rô, where Rº is selected from hydrogen, benzyl, C3-Cio-cycloalkyl, C; -C; -alkyl, Rº 'is selected from hydrogen, C1-C; -alkyl, C1-C7- alkyl carbonyl-, or Rô and Rº 'together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated monocyclic or partially saturated 7-12 membered heterocyclic bicyclic ring, optionally containing an additional heteroatom selected from N, O or S; 'which are unsubstituted or substituted by 1-3 substituents, selected from C1-C; -alkylhydroxy-C1-C; -alkoxy-carbonyl-
or (d) -NR $ -C (O) -R $, where R $ is selected from C3-Cao-cycloalkyl; R5 'is selected from hydrogen, C1-C; -alkyl; mélcli and néo1i. Modality 32: A compound according to any of modalities 29 to 31, in which R Rn FO no, dA 9
R R 'is selected from hydrogen-halogen-C1-C7-alkyl-halo-C1-C; -alkyl-; R is selected from hydrogen- C1-C7-alkyl-halo-C2-C; -alkyl-amino-C2-C; -alkyl- N-C1-C; -alkyl-amino-C2-C; -alkyl- N , N-di-Cy-C; -alkyl-amino-C2-C; -alkyl- 'hydroxy-C2-C; -alkyl-. C1-C7-alkoxy-C2-C7-alkyl-C3-Cro-cycloalkyl-C1-C7-alkyl-cyano-C2-C; -alkyl-; or
R 'and R', together with the atoms to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic ring, which is unsubstituted or substituted by 1-3 substituents selected from Ss C1- C; -alkyl-halo-C1-C; -alkyl-amino-C1-C; -alkyl-N-C1-C; -alkyl-amino-C1-C; -alkyl-N, N-di-C1-C ; -alkyl-amino-C, -C; 7-alkyl-hydroxy-C1-C; -alkyl-C1-C7-alkoxy-C1-C; z-alkyl-Ca-Cao-cycloalkyl-C, -C7-alkyl - cyano-Cy-C; -alkyl-; R is selected from. halogen-C1-C7-alkyl-halo-C, -C; -alkyl-C1-C; -alkoxy-cyano-halo-C, -C7-alkoxy-nitro; R is selected from (a) (CH2), - Y, where p is selected from 0, 1, 20u3, and Y is selected from aryl, heteroaryl, heterocyclyl, which are unsubstituted or substituted by 1 -3 selected halogen- substituents: C1-C; -alkyl-. halo-C; -C; -alkyl-C1-C; 7-alkoxy-C3-Cao-cycloalkyl-oxyhydroxy-
halo-C1-C; -alkyl-oxy-amino-N-C1-C; -alkyl-amino-N N-di-C, -C; -alkyl-amino-cyano-C1-C; z-alkoxy-carbonyl - hydroxy-carbonyl- -C (O) -NRºRº, where Rº is selected from hydrogen, C1-C; -alkyl; R * is selected from hydrogen, or Rº and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional heteroatom selected at starting from N, O or S; or (b) -C (O) -NRÉ'Rº or -C (0) -OR $, where Rº is selected from hydrogen, benzyl, indanyl, tetrahydrofuranoyl, tetrahydropyranyl, oxiranyl, C3-Cio -cycloalkyl, C1-C7-alquita; R * 'is selected from hydrogen, C; -C; -alkyl,
or Rº and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated monocyclic or bicyclic heterocyclic ring, optionally containing an additional heteroatom selected from N, O or S ;
or (o) -N R $ RÔ, where Rº is selected from hydrogen, benzyl, C3a-Cio-cycloalkyl, C, -C; -alkyl,
'R $ is selected from hydrogen, C1-C; -alkyl, C1-C; 7-
- alkyl carbonyl-,
or Rô and R $ together with the nitrogen atom to which they are attached, form a saturated or partially saturated monocyclic 4-7 membered ring or saturated or partially saturated 7-12 membered heterocyclic ring, optionally containing an additional selected heteroatom. selected from N, O or S; which are unsubstituted or substituted by 1-3 substituents selected from C1-C; -alkylhydroxy-C1-C; -alkoxy-carbonyl- or (d) -NR $ -C (O) -R $, in that Rº is selected from C3-Co-cycloalkyl; R * 'is selected from hydrogen, C; -C; -alkyl; méliie right + 1. Mode 33: A pharmaceutical composition, comprising a therapeutically effective amount of a compound of formula (1) according to any one of modalities 1 to 28 and one or more pharmaceutically acceptable vehicles / excipients.
Mode 34: A combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound of formula (1) according to any of modalities 1 to 28, and one or more therapeutically active agents, particularly pain relief.
Mode 35: Use of a compound of formula (1) according to any of modalities 1 to 28, for the manufacture of a medication for the treatment of chronic pain.
Mode 36: Use of a compound of formula (1) according to any of modalities 1 to 28, for the manufacture of a medication for the treatment of one or more disorders or diseases mediated - by Nav 1.7. Mode 37: Use of a compound of formula (|) according to any of modalities 1 to 28, for the treatment of one or more disorders or diseases mediated by Nav 1.7.
Mode 38: Use of a compound of formula (1) according to any of modalities 1 to 28, for the treatment of chronic pain.
Mode 39: Use according to mode 37, for the treatment of a disorder or disease selected from chronic pain, such as positive symptoms of chronic pain, for example paresthesias, dysesthesias, hyperalgesia, allodynia and spontaneous pain as well as negative symptoms eg loss of sensation.
Mode 40: A method for the treatment of chronic pain, comprising the step of administering to an individual a therapeutically effective amount of a compound of formula (1) according to any one of modalities 1 to 28.
Modality 41: A method according to modality 40, where the disorder or disease is selected from chronic pain, such as positive symptoms of chronic pain eg paresthesias, dysesthesias, hyperalgesia, allodynia and spontaneous pain, as well as negative symptoms eg loss of sensation.
Mode 42: A method of modulating the activity of Nav 1.7 in an individual, comprising the step of administering to an individual, a therapeutically effective amount of a compound of formula (1) according to any of modalities 1 to 28.
Mode 43: A compound according to mode 1, selected from Examples 1 to 517, or a pharmaceutically acceptable salt thereof.
Modality 44: A compound according to modality 43, in which the compound is selected from 2-N-methyl-2-N-phenyl-6- (5- (4 - [(2,2,2-trifluoroethoxy ) mMethyl | piperidin-1- 11-1,2,4-0xadiazole-3-i) -1,3,5-triazine-2,4-diamine; 2-N-methyl-2-N-phenyl-6 - (5- [1- (propane-2-sulfonyl) iperidin-4-i1] -1,2,4-oxadiazol-3-yl) -1,3,5-triazine-2,4-diamine; 6- (5-f4 - [(cyclopropylmethoxy) methyl] piperidin-1-i1) -1,2,4-0xadiazole-3-iN) -2-N-methyl-2-N-phenyl-1,3,5-triazine -2,4-diamine;
2-N- (3-fluorophenyl) -6- [5- (3-fluoropyridin-2-i1) -1,2,4-0xadiazole-3-i1] - 1,3,5-triazine-2 A-diamine ; 2-N-methyl-2-N-phenyl-6- (5- (6- [2- (2,2,2-trifluoroethoxy) ethoxy] pyridin-3-yl-1,2 4-oxadiazole-3-i1 ) -1,3,5-triazine-2,4-diamine; 2-N-methyl-2-N-phenyl-6- (5 - [(2R) -1 - [(2,2,2-trifluoroethane) sulfonyl] pyrrolidin-2-yl] -1,2,4-0xadiazole-3-11) -1,3,5-triazine-2,4-diamine; 2-N-methyl-2-N-phenyl-6- (5-f6 - [(3,3,3-trifluoropropane) sulfinyl] pyridin-3-i1) -1,2,4-0xadiazol-3-yl) -1,3,5-triazine-2,4-diamine ; 2-N-methyl-2-N-phenyl-6- (5- (4 - [(3,3,3-trifluoropropoxy) methyl] piperidin-1-i1) -1,2,4-0xadiazole-3-i1 ) -1,3,5-triazine-2,4-diamine; 2-N-methyl-2-N-phenyl-6- (5- [1- (propane-2-sulfonyl) iperidin-4-i1] -1,2,4-oxadiazol-3-yl) -1,3 , 5-triazine-2, A4-diamine; and N-methyl-N-phenyl-6- [5- [6- (2,2,2-trifluoroethoxy) -pyridin-3-yl] -
15. [1.24] oxadiazol-3-yl) - [1,3,5] triazine-2 A-diamine; or a pharmaceutically acceptable salt thereof.

权利要求:
Claims (16)
[1]
It's 1/21
CLAIMS p 1. Compound, characterized by the fact that it has the formula - (1) or a pharmaceutically acceptable salt thereof, - Ro; FO NON ONRRº
PO 9d 0 where R 'is selected from hydrogen-halogen-C1-C; -alkyl-halo-C, -C; -alkyl-; R is selected from hydrogen-C1-C; -alkyl-halo-C2-C; -alkyl-amino-C2-C; -alkyl- N-C1-C; 7-alkyl-amino-C2-C; -alkyl - N, N-di-C1-C; -alkyl-amino-C2-C; -alkyl-hydroxy-C2-C; -alkyl-C1-C7-alkoxy-C2-C; -alkyl-C3-Cio-cycloalkyl -C, -C7-alkyl-cyano-C2-C; -alkyl-; or R 'and R', together with the atoms to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic ring, which is unsubstituted or substituted by 1-3 substituents selected from
- 2/21 Í C1-C; -alkyl-. halo-C, -C; -alkyl- - amino-C, -C; -alkyl-f N-C1-C; -alkyl-amino-C1-C; -alkyl-hi 5 N, N-di-C1- C; -alkyl-amino-C1-C7-alkyl-hydroxy-C, -C; -alkyl-C1-C7-alkoxy-C, -C; -alkyl-N C3-Cao-cycloalkyl-C 1-C7-alkyl - - cyano-C; -C; -alkyl-; R is selected from C1-C7-alkyl-halo-C1-C; -alkyl-C1-C; 7-alkoxy-cyano-halo-C1-C7-alkoxy-nitro; -C (0) -O-R ', where R' is selected from hydrogen, C; 1- Cr-alkyl; C3-Cio-cycloalkyl; C1-C7-alkoxy; halo-C1-C; -alkyl aryl; aryl-C, - Cr; -alkyl-; heteroaryl; heteroaryl C, -C; -alkyl-; heterocyclyl; -S (= 0), -C1-C; -alkyl; -S (= O0) 2-C3-Cao-cycloalkyl; -S (= 0) 2-C, 1-Cp-alkoxy; Rº is selected from (a) -L-Y, where -L- is selected from a direct link; - (CH> 2), -, -C (O) -, NR ”-, NR / -C (O) - or C (O) -NR'-, where p is selected from 1.2 or 3, R ”is selected from hydrogen and C1-C; -Alkyl Y is selected from cycloalkyl, aryl, heteroraryl, heterocyclic, spirocyclyl, which are unsubstituted or substituted by 1-3 selected substitutes from halogen-;
C1-C; -alkyl-; | . halo-C1-C; -alkyl-;
- halo-C1-C; -alkyl-oxy-C1-C7-alkyl; - halo-C1-C7-alkyl-oxy-C1-C7-
And alkyloxy;
A 5 C1-C7-alkoxy-; C1-C; 7-alkoxy-C1-C7-alkoxy-; NO-C1-C7-alkoxy-; C1-C7-alkoxy-C1-C7-alkyl-; C3-Cio-cycloalkyl-oxy-C; -C7-alkyl-;
Ê C3-Cio-cycloalkyl-C1-C7-alkyloxy-; 7
C3-Cio-cycloalkyl-oxy-;
C3-Cao-cycloalkyl-NR ”-C1-C; -alkyl-, where R” is selected from R ”is selected from hydrogen and C1-C; -alkyl;
C3-Cio-cycloalkyl-C1-C7-alkoxy-C1-C7-alkyl-; C2-C7-alkenyl; halo-C2-C; -alkenyl; hydroxy-;
hydroxy-C1-C7-alkyl-; halo-C1-C7-alkyloxy-; amino-; N-C1-C; -alkyl-amino-; N-halo-C1-C7-alkyl-amino-; |
N-heterocyclyl-amino-, N-C3-Cio-cycloalkyl-amino-, wherein the heterocyclyl and cycloalkyl are optionally substituted by halo-C, -C; -alkyl-oxy, C1-C; -alkyl; C3-C19-cycloalkyl and C7-C7-alkoxy;
N-C3-C; o-cycloalkyl-C1-C; -alkyl-amino-; N, N-di-C1-C; 7-alkyl-amino-; N, N-dihalo-C, -C7-alkyl-amino-;
N N-di-heterocycli-amino-, N, N-di-C3-Cio-cycloalkyl-amino-, where heterocyclyl and cycloalkyl are optionally substituted by halo-C1-C7-alkyl-oxy, C1-C7-alkyl ; C3-C1o-cycloalkyl and C1-C7-alkoxy;
cyan-; oxo; Cy -C; -alkoxy-carbonyl-;
C1-C7-alkoxy-C1-C7-alkoxy-C, -C; -alkyl-;
aryl; aryl-C17-C; -alkyl-; aryloxy; heterocyclyl;
CCC —-- = mmmm —-—- are i 4/21 heterocyclyl-C1-C; z-alkyl-; heterocyclyl-oxi-; ; heterocyclyl-oxy-C1-C; -alkyl-; aryl-oxy-C1-C; -alkyl-; heteroaryl-oxy- -C1-C; -alkyl-; Hydroxy-carbonyl-; f 5 -S-halo-C, -C; -alkyl; -S-C1-C; -alkyl; -S- aryl; halo-C; -C; -alkyl-S-C1-C7-alkyl; C1-C; -alkyl-S-C1-C; -alkyl; -S (= O), 2 -C1-C; -alkyl; -S (= O) 2-halo-C1-C; -alkyl; -S (= O), - aryl; 1 -S (= O) -heteroaryl; -S (= O)> - NR “Rº; -S (= O), - heterocyclyl; halo-C, -C; -alkyl-S (= 0) 2-C1-C; 7-alkyl; C1-C7-alkyl-S (= 0) 2-C1- C: alkyl; -S (= O0) -C1-C; -alkyl; -S (= O) -halo-C; -C; -alkyl; -S (= 0) -C1-C7-alkoxy; -S (= 0) -C3-Cuo-cycloalkyl; -C (0) -C1-C; -alkyl; - -C (O) -halo-C1-C; z-alkyl; - -C (0) -C1-C7-alkoxy; - C (0) -C3-C10 cycloalkyl; -C (0) O-C1-C; -alkyl; -C (0) O-C3-Ciao-cycloalkyl; -C (0) O-halo-Cy1-C; -alkyl; -C (0) O-C1-C; -alkoxy; -C (O) -NR * Rº or -NHC (O) -R $, where Rº is selected from hydrogen, C1-C; -alkyl, halo-C, 1- Cr-alkyl, C3-Cio- cycloalkyl, Ca-Cao-cycloalkyl-C1-C; 7-alkyl and C1-C7-alkoxy; Rº * 'is selected from hydrogen; or Rº and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional heteroatom selected from N, O or S, and wherein said hetero-cyclic ring is optionally substituted with aryl, aryl-oxi-, C; -C7-alkyl, halo-C, 1- C; -alkyl or C, -C7-alkoxy, and said aryl is optionally substituted with halogen, C1-C; -alkyl, halo-C1-C; -alkyl or C1-C7-alkoxy, or (b) -C (O) -NRÍ'Rô or -C (0) -OR $, in that Rº and Rº are selected from hydrogen, C1-C-alkyl; C3-Cio-cycloalkyl; Cy-C; -alkoxy; halo-C1-C; -alkyl aryl; aryl-C1-C; -alkyl-; aryl; heteroaryl; heteroaryl C, -C; 7-alkyl-; heterocyclic; indane; or Rº and Rº together with the nitrogen atom to which they are attached, form one. saturated or partially saturated heterocyclic monocyclic or bicyclic ring
- of 4-9 members, optionally containing an additional heteroatom
'taught from N O or S;
to 5 wherein said C3-Co-cycloalkyl; aryl, heteroaryl, heterocyclyl and indane are optionally substituted with 1 to 3 substituents selected from C, -C; -alkyl, halo-C1-C; -alkyl, C1-C; -alkoxy, halo-C ; -
C; -alkyl-oxy-, - halo-C; -C; -alkyl-oxy-C, -C; -alkyl, - C1-C7-alkyl-oxy-C1-C7- It is alkyl and hydroxy-C1-Cz -alkyl;
or Ô
(c) -NRE Rô, where
R $ is selected from hydrogen, C, -C; -alkyl,
R $ is selected from hydrogen, C1-C; -alkyl, C1-C7- alkyl carbonyl-; C3-C, o-cycloalkyl;
or R $ and Rº together with the nitrogen atom to which they are attached, form a saturated or partially saturated 4-7 membered monocyclic or 7-12 membered saturated or partially saturated heterocyclic ring, optionally containing an additional selected heteroatom. operated from NO or S;
whose monocyclic and bicyclic heterocyclic ring is unsubstituted or substituted by 1-3 substituents selected from
C1-C7-alkyl-, halo-C1-C; z-alkyl-, C7-C7-alkoxy-, halo-C1-C7-alkoxy-, halo-C1-C7-alkoxy-C; -C7-alkyl-, hydroxy- and C1-C; -alkoxy-carbonyl-; (d) -NRÍ-C (O) -R $, where
Rº is selected from hydrogen, Cy-C; -alkyl; C3-C10-cycloalkyl; C, -C; -alkoxy; halo-C, -C; -alkyl; aryl; aryl-C7-C; -alkyl-; heteroaryl; heteroaryl-C1-C; -alkyl-; heterocyclic;
R * 'is selected from hydrogen, C1-C; -alkyl; méolie, right 0-2;
Rº is hydrogen and Rº is selected from hydrogen, C1-C7-alkoxy-C, -C; -alkyl-, C1-C; -alkyl, C1-C7-alkoxy and halo-C1-C; -alkyl;
| 6121 where C; -C; -alkyl, C, -C7-alkoxy heterocyclyl, aryl, heteroaryl: are optionally substituted by aryl, heteroaryl, heterocyclic, C, -C; - - alkyl, C1-C; -alkoxy, halo -C, -C; -alkyl; OH; 'with the proviso that 6- [5- (2-furanyl) -1,2,4-0xadiaz | -3-yl] -N2- f 5 - methyl-N2-phenyl-1,3,5-triazine-2 4-diamine and 6- [5- (2-furanyl) -1,2,4-0xadiazole-3- II-N, N, N'-methyl-N'-phenyl-1,3,5-triazine-2 , 4-diamine are excluded.
[2]
2. Composed according to claim 1, characterized by the fact that it presents the formula (1) 'Ú Rº nº ars
E oe - ”O) where R 'is selected from hydrogen- halogen- C1-C; -alkyl- halo-C1-C; -alkyl-; R is selected from hydrogen-C1-C; -alkyl-halo-C2-C7; -alkyl-amino-C2-C; -alkyl- N-C1-C; -alkyl-amino-C2-C; -alkyl- N, N-di-C1-C; -alkyl-amino-C2-C; -alkyl-hydroxy-C2-C; -alkyl-C1-C7-alkoxy-C2-C; 7-alkyl-C3-Cao-cycloalkyl -C1-C7-alkyl-cyano-C2-C; -alkyl-;
It is 7/21 or FR 'and R', together with the atoms to which they are attached, Ú form a 4-7-membered saturated or partially saturated heterocyclic ring, which is unsubstituted or substituted by 1-3 selected substituents. fi 5 —nothing from C1-C; 7-alkyl-halo-C1-C; -alkyl-7 N "N amino-C1-C; -alkyl-i to N-C1-C; -alkyl-amino-C1-C ; -alkyl- N, N-di-C1-C; -alkyl-amino-C, -C7-alkyl-hydroxy-C, -C; -alkyl-C1-C7-alkoxy-C1-C; -alkyl-C3a -Cryo-cycloalkyl-C1-C7-alkyl-cyano-C, -C; -alkyl-; R is selected from halogen-C1-C; -alkyl-halo-C, -C; -alkyl- C1-C7 -alkoxy-cyano-halo-C, -C; -alkoxy-nitro; Rº is selected from (a) - (CH2), - Y, where Pp is selected from 0, 1,2 or3, and Y is selected from aryl, heteroaryl, heterocyclyl, which are unsubstituted or substituted by 1-3 substituents selected from halogen-C1-C; -alkyl-halo-C, -C; -alkyl-C1-C7-alkoxy- C3-Cao-cycloalkyl-oxi-
i 8/21 hydroxy-: halo-C1-C; -alkyl-oxy- -amino-. NC, -C; -alkyl-amino- at 5 N, N-di-C, -C; -alkyl-amino-cyano-C1-C; -alkoxy-carbonyl-aa hydroxy-carbonyl- '7 -C (O ) -NR * Rº, where | Rº is selected from hydrogen, C1-C; -alkyl; Rº * 'is selected from hydrogen, or Rº * and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional heteroatom selected from N, O or S; or (b) -C (O) -NR $ 'Rº or -C (0) -OR $, where Rº is selected from hydrogen, benzyl, indanyl, tetrahydrofuranyl, tetrahydropyranyl, oxiranyl, Ca- Co-cycloalkyl, C; -C7-alkyl; R $ 'is selected from hydrogen, C, -C; -alkyl, or Rº and R * together with the nitrogen atom to which they are attached, form a 4-7 saturated or partially saturated heterocyclic or bicyclic ring members, optionally containing an additional heteroatom selected from N, O or S; or (o) -N RE RÔ, where Rº is selected from hydrogen, benzyl, C3-C1o- cycloalkyl, C1-C; -alkyl, R $ is selected from hydrogen, C, -C; z- alquita, C1-C7- —alkyl carbonyl-, or Rº and Rº 'together with the nitrogen atom to which they are attached, form a saturated or partially saturated 4-7 membered monocyclic ring or saturated or partially saturated heterocyclic bicyclic. of 7-12 members, optionally containing an additional selected heteroatom. operated from N O or S; f which are unsubstituted or substituted by 1-3 substituents à 5 - selected from C1-C; -C1-C-alkyl hydroxy; -C-alkoxy-carbonyl- 'or (d) -NRÉ-C (O) -R $, where R $ is selected from C3-Cio-cycloalkyl; R5 'is selected from hydrogen, C1-C; -alkyl; méõl-i, and right o-1; with the proviso that 6- [5- (2-Furanyl) -1,2,4-oxadiazol-3-yl) -N2-methyl-N2-phenyl-1,3,5-triazine-2,4-diamine is excluded.
[3]
3. Compound according to claim 1, characterized by the fact that R 'is selected from hydrogen-chloro-fluoro-methyl-; R is selected from hydrogen-C1-Ca-alkyl-halo-C2-Ca-alkyl-N, N-di-C1-C> 7-alkyl-amino-C2-Ca-alkyl-hydroxy-C2-C, - alkyl-C1-C2-alkoxy-Ca-C, α-alkyl-C3-Ce-cycloalkyl-C; -C7-alkyl-.
[4]
A compound according to claim 1 or 2, characterized
by the fact that. Rº is selected from EN - (CH2)] yY, where: p is selected from 0, 1.20u3, and í 5 Y is selected from aryl, heteroaryl, heterocyclyl, which --—- are unsubstituted or substituted by 1-3 substituents selected halogen- RT C1-C; -alkyl-C1-C halo; -C1-C7-alkoxy-C3-Co-cycloalkyl-oxyhydroxy-halo-C1- C; -alkyl-oxy-amino-N-C1-C; 7-alkyl-amino-N, N-di-C1-C; -alkyl-amino-S (= O) 2 -C1-C; -alkyl ; -S (= O)> - halo-C, -C; -alkyl; -S (= 0) -C1-C; -alkyl; -S (= O) -halo-C; -C; 7-C3-Cio-cycloalkyl-C1-C7-alkoxy-C1-C; 7-alkyl-; cyano- C1-C7-alkoxy-carbonyl-hydroxy-carbonyl- -C (O) -NR * R $ º, where Rº is selected from hydrogen, C1-C; -alkyl; R “* 'is selected from hydrogen, or Rº and R *' together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing a heteroatom additional selected from N, O or S.
[5]
5. Composed according to claim 1 or 2, characterized by the fact that R is selected from
CSN | 11/21 | - (CH2), - Y, where Ê Pp is selected from 0, 1.20u3, and 'b Y is selected from aryl, heteorary, heterocyclyl, what are unsubstituted or substituted by 1-3 selected substituents] 5 halogen-C1-C; -alkyl- 'halo-C1-C; -alkyl-C1-Cr-alkoxy- - C3-Cao-cycloalkyl-oxy-hydroxy-halo -C1-C; -alkyl-oxy-amino- N-C1-C; -alkyl-amino-N, N-di-C1-C; -alkyl-amino-cyano-C1-C; -alkoxy-carbonyl-hydroxy -carbonyl- -C (O) -NR * 'Rº, where Rº is selected from hydrogen, C1-C; -alkyl; R * is selected from hydrogen, or Rº and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional heteroatom selected at from NO or S.
[6]
A compound according to any one of claims 1 to 5, characterized by the fact that hand.
[7]
7. Compound according to claim 1, characterized by the fact that: R 'is selected from hydrogen-fluoro-;
"E 12/21 R 'is selected from M- hydrogen. C1-Ca-alkyl- n halo-C2-C, -N-alkyl-ii 5 N, N-di-C7-C> 2-alkyl-amino- C2-C, -Cylalkyl-hydroxy-C2-Ca-alkyl-C1-C2-alkoxy-C2-C, -alkyl- IS Ê C3-Ce-cycloalkyl-C1-C7-alkyl-; "or R 'and R together are selected from -CH2-CH> 2- or -CH2-CH2-CH7-; R is selected from halogen-C1-Ca-alkyl-halo-C1-Ca-alkyl-C1-Ca-alkoxy-; and . R is selected from - (CH2), yY, where p is selected from 0, 1,2 0u3, and Y is selected from aryl, heteroaryl, heterocyclyl, which are unsubstituted or substituted by 1-3 selected substituents halogen-C1-C; -alkyl-halo-C, -C; -alkyl-C1-C; 7-alkoxy-C3-Cycloalkyl-oxyhydroxy-halo-C1-C; 7-alkyl-oxy - Á amino- NC, -C; -alkyl-amino- N, N-di-C1-C; -alkyl-amino-
MMS ns | 13/21 | . cyan- | C1-Cr-alkoxy-carbonyl- - -C (O) -NRÉ'Rº, where 'Rº is selected from hydrogen, C1-C; -alkyl; '5 R *' is selected from hydrogen, or Rº and R * together with the nitrogen atom to which they are attached, form a saturated or partial heterocyclic monocyclic ring | saturated 4-7 membered, optionally containing a heteroatom; additional selected from N O or S, mébe néo1.
[8]
8. Composed according to claim 1, characterized by the fact that Rº is selected from phenyl, furanyl, thiophenyl, pyridyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, pyrrolyl, benzofuranyl, pyrimidinyl, oxazolyl, morpholinyl, piperidinyl, tetrahydrofuranyl, tetrahydrofuranyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridine unsubstituted or substituted by 1-2 substituents selected from chloro-bromo-fluoro-methyl-trifluoromethyl-2,2,2-trifluoro-ethyl-2,2,2-trifluoro-ethyl-oxy-methyl-cyclopropyl-methoxy -methyl- -S (= 0) 2-2,2,2-trifluoro-ethyl-; -S (= O) -propyl; ] -S (= 0) -3,3,3-trifluoro-propyl; 3,3,3-trifluoro-propyl-oxy-methyl-; methoxy-
At 14/21 cyclopentyl-oxy-. trifluoromethyl-oxy- - 2,2,2-trifluoro-ethyl-oxy- 'amino- 5 cyano-methoxy-carbonyl- -C (O) -NR *' R $, where Rº is selected from hydrogen, methyl; To R * is selected from hydrogen, or Rº * and R ** together with the nitrogen atom to which they are attached, form morpholinyl, piperidinyl, pyrrolidinyl.
[9]
A compound according to claim 1, characterized by the fact that it is selected from Examples 1 to 517, or a pharmaceutically acceptable salt thereof.
[10]
10. Compound according to claim 1, characterized by the fact that the compound is selected from 2-N-methyl-2-N-phenyl-6- (5- (4 - [(2,2,2- trifluoroethoxy) mMethylpiperidin-1-i1) -1,2,4-0xadiazole-3-i1) -1,3,5-triazine-2,4-diamine; 2-N-methyl-2-N-phenyl-6-f5- [1- (propane-2-sulfonyl) iperidin-4-11] -1,2,4-oxadiazol-3-yl) -1,3, 5-triazine-2,4-diamine; 6- (5-f4 - [(cyclopropylmethoxy) methyl] piperidin-1-iI) -1,2,4-0xadiazole-3- i1) -2-N-methyl-2-N-phenyl-1,3,5 -triazine-2,4-diamine; 2-N- (3-fluorophenyl! 1) -6- [5- (3-fluoropyridin-2-yl) -1,2,4-0xadiaz | -3-yl] - 1,3,5-triazine-2 , 4-diamine; 2-N-methyl-2-N-phenyl-6- (5- (6- [2- (2,2,2-trifluoroethoxy) ethoxy] pyridin-3-yl-1,2,4-0xadiazole-3- i1) -1,3,5-triazine-2,4-diamine; 2-N-methyl-2-N-phenyl-6-f5 - [(2R) -1 - [(2,2,2-trifluoroethane) sulfonyl] pyrrolidin-2-yl] -1,2,4-oxadiazole-3-i1) -1,3,5-triazine-2,4-diamine; 2-N-methyl-2-N-phenyl-6- (546 - [(3,3,3-trifluoropropane) sulfinyl] pyridin- 3-11) -1,2,4-0xadiazole-3-i1) -1 , 3,5-triazine-2,4-diamine; 2-N-methyl-2-N-phenyl-6- (5- (4 - [(3,3,3-trifluoropropoxy) methyl] piperidin-
15/21] 1-i1-1,2,4-0xadiazol-3-yl) -1,3,5-triazine-2,4-diamine; . 2-N-methyl-2-N-phenyl-6- (5- [1- (propane-2-sulfonyl) iperidin-4-yl) -1,2,4- ooo oxadiaz! -3-yl) -1 , 3,5-triazine-2 4-diamine; e 'N-methyl-N-phenyl-6- [5- [6- (2,2,2-trifluoroethoxy) -pyridin-3-yl] - Ô 5 [1,24] oxadiazol-3-yl) [1 , 3.5] triazine-2,4-diamine; or a pharmaceutically acceptable salt thereof.
[11]
11. Compound, characterized by the fact that it presents the form | mule (1), or a pharmaceutically acceptable salt thereof, 7
R R FO NON, ONRR
And * O) | where R 'is selected from hydrogen-halogen-C1-C; -alkyl-halo-C, -C; -alkyl-; R is selected from hydrogen-C1-C; -alkyl-halo-C2-C7; -alkyl-amino-C2-C; -alkyl- N-C1-C7-alkyl-amino-C2-C7-alkyl-N, N-di-C1-C; -alkyl-amino-C2-C7-alkyl-hydroxy-C2-C; -alkyl- "C1-C7-alkoxy-C2-C7-alkyl-C3-C1o-cycloalkyl-C, - C7-alkyl-cyano-C2-C; -alkyl-;
or. R 'and R', together with the atoms to which they are attached,. form a 4-7 'membered saturated or partially saturated heterocyclic ring, which is unsubstituted or substituted by 1-3 substituents selected- It is 5 from C1-C; -alkyl-halo-C1-C; -alkyl-amino- C, 1-C; -alkyl-ã NC, 1-C; -alkyl-amino-C, -C; -alkyl-N N-di-C, -C7-alkyl-amino-C1-C7; -alkyl- hydroxy-C, -C; -alkyl-C1-C7-alkoxy-C, -C; -alkyl-C3-Cao-cycloalkyl-C 1-C7-alkyl-cyano-C1-C; -alkyl-; R is selected from C1-C halogen; 7-C1-C-alkyl-halo; C1-C-alkyl; 7-alkoxy-cyano- 'C1-C7-alkoxy-nitro; -C (0) -O-R ', where R' is selected from hydrogen, C; - C-alkyl; C3a-Chao-cycloalkyl; C, -C7-alkoxy; halo-C, -C; -alkyl aryl; aryl-C; - —Cr; -alkyl-; heteroaryl; heteroaryl C, -C; -alkyl-; heterocyclyl; -S (= 0) 2-C1-C; z-alkyl; -S (= O) 2-C3-Co-cycloalkyl; -S (= 0) 2-C, 1-C7-alkoxy; Rº is selected from (a) -L-Y, where -L- is selected from a direct link; - (CH2), -, -C (O) -, NR ”-, NR / -C (O) - or C (O) -NR” -, where p is selected from 1, 20u3,
Í 17/21 R ”is selected from hydrogen and C1-C; -alkyl Y is selected from cycloalkyl, aryl, heteroraryl, hetero-
4 rocyclyl, spirocyclyl, which are unsubstituted or replaced by 1-3 subs-
: tituents selected from ã 5 halogen-; C1-C; 7-alkyl-; halo-C1-C; -alkyl-; halo-C1-C7-alkyloxy-C1-C; -alkyl; - halo-Cy-C7-alkyl-oxy-C1-C7- = alkyl-oxy;
C1-C7-alkoxy-; C1-C7-alkoxy-C1-C7-alkoxy-; NO-C1-C7-alkoxy-;
C1-C7-alkoxy-Cy-C7-alkyl-; C3-Cro-cycloalkyl-oxy-C, -C7-alkyl-; C3-Cao-cycloalkyl-C1-C7-alkyl-oxy-; C3-Cio-cycloalkyl-oxy-;
C3-Cio-cycloalkyl-NR -C1-C7-alkyl-, where R ”is selected from R is selected from hydrogen and C1-C; -alkyl;
C3-Cio-cycloalkyl-C1-C7-alkoxy-C1-C7-alkyl-; C2-C7-alkenyl; halo-C2-C; -alkenyl; hydroxy-;
hydroxy-C, -C; -alkyl-; halo-C; 1-C; -alkyloxy; 'amino-; N-C, -C; -alkyl-amino-; N-halo-C, -C; -alkyl-amino-;
N-heterocyclyl-amino-, N-C3-C, io-cycloalkyl-amino-, in which the heterocyclyl and cycloalkyl are optionally substituted by halo-C, -C; -alkyl-oxy, C1-C; -alkyl ; Ca-Cao-cycloalkyl and C1-C7-alkoxy;
N-C3-Co-cycloalkyl-C 1-C7-alkyl-amino-; N N-di-C1-C7-alkyl-amino-; N, N-dihalo-C1-C; 7-alkyl-amino-;
N N-di-heterocycli-amino-, N, N-di-C3-C, 15-cycloalkyl-amino-, where heterocyclyl and cycloalkyl are optionally substituted by halo-C1-C7-alkyl-oxy, C1-C7 -alkyl; C3-Cio-cycloalkyl and C1-C7-alkoxy;
i 18/21 Cyano-; oxo; ! C1-C7-alkoxy-carbonyl-; - C1-C7-alkoxy-C1-C7-alkoxy-C1-C; -alkyl-; Tr aryl; aryl-C1-C; -alkyl-; aryloxy; '5 heterocyclyl; heterocyclyl-C 1-C7-alkyl-; heterocyclyl-oxi-; heterocyclyl-oxy-C1-C; -alkyl-; aryl-oxy-C, -C; -alkyl-, heteroaryl-oxy- | C1-C; -alkyl-; = hydroxy-carbonyl-; -S- halo-C1-C; -alkyl; -S-C, -C; -alkyl; -S- aryl; halo-C1-C7-alkyl-S-C1-C7-alkyl; C1-C7-alkyl-S-C1-C7-alkyl; -S (= O) 2 -C1-C; -alkyl; -S (= O) 2-halo-C1-C; 7-alkyl; -S (= O), - aryl; -S (= O), -heteroaryl; -S (= O) .- NR * R $; -S (= O), - heterocyclyl; halo-C1-C7-alkyl-S (= 0) 2-C1-C; -alkyl; It is C1-C; 7-alkyl-S (= 0) 2-C1- Cy; alkyl; -S (= 0) -C1-C; -alkyl; -S (= O) -halo-C; -C7-alkyl; -S (= 0) -C1-C7-alkoxy; -S (= O0) -C3-C 19-cycloalkyl; -C (O0) -C1-C; -alkyl; -C (O) -halo-C, -C; -alguyl; - -C (0) -C, -C7-alkoxy; - C (0) -C3-C10 cycloalkyl; -C (0) O-C, -C; -alkyl; -C (0) O-C3-Cio-cycloalkyl; -C (0) O-halo-C1-C7-alquita; -C (0) O-C1-C7-alkoxy; -C (O) -NR * Rº or -NHC (O) -R $, where Rº is selected from hydrogen, C1-C; -alkyl, halo-C, - Cz-alkyl, Ca-Cio-cycloalkyl , C3-Cio-cycloalkyl-C, -C7-alkyl and C1-C7-alkoxy; R * is selected from hydrogen; or Rº and R * together with the nitrogen atom to which they are attached, form a 4-7 membered saturated or partially saturated heterocyclic monocyclic ring, optionally containing an additional heteroatom selected from N, O or S, and wherein said hetero-cyclic ring is optionally substituted with aryl, aryl-oxy-, C1-C; -alkyl, halo-C, - Cr-alkyl or C; -C7-alkoxy, and said aryl is optionally substituted with halogen, C, -C; -alkyl, halo-C1-C; 7-alkyl or C1-C; 7-alkoxy.
or: (b) -C (O) -NRÍ'Rº or -C (0) -O-R $, where
: Ró and Rº are selected from hydrogen, C1-Cz-alkyl;
Á C3a-Cao-cycloalkyl; C1-C7-alkoxy; halo-C1-C; -alkyl aryl; aryl-C1-C; z-alkyl-;
5 aryl; heteroaryl; heteroaryl C; -C; -alkyl-; heterocyclyl; indane; or Rº and Ré together with the nitrogen atom to which they are attached, form a saturated or partially saturated monocyclic or bicyclic ring
4-9 member nos, optionally containing an additional hetero atom if- "
taught from N, O or S;
wherein said C3-Ci, -cycloalkyl; aryl, heteroaryl, heterocyclyl and indane are optionally substituted with 1 to 3 substituents selected from C; -C; -alkyl, halo-C, -C; -alkyl, Cy7-C7-alkoxy, halo-C , - C; -alkyloxy- and hydroxy-C, -C; -alkyl;
or (o) -NR6 Rô, where R $ is selected from hydrogen, C1-C; z-alkyl, R $ is selected from hydrogen, C; -C; -alkyl, C1-C7-: alkyl carbonyl-; Ca-C, o-cycloalkyl; or Rô and Rº together with the nitrogen atom to which they are attached, form a saturated or partially saturated 4-7 membered monocyclic or 7-12 membered saturated or partially saturated heterocyclic ring, optionally containing an additional selected heteroatom from N, O or S;
whose monocyclic and bicyclic heterocyclic ring is unsubstituted - or substituted by 1-3 substituents selected from
C1-C; -alkyl-, halo-C1-C; -alkyl-, C1-C7-alkoxy-, hydroxy- and
C1-C; -alkoxy-carbonyl-;
(d) -NRÍ-C (O) -R $, where
Rº is selected from hydrogen, C1-C; -alkyl; C3-C1o-
cycloalkyl; Cy-C; -alkoxy; halo-C1-C; -alkyl; aryl; aryl-C, -C; -alkyl-; heteroaryl; heteroaryl-C1-C7-alkyl-; heterocyclyl;
Rº 'is selected from hydrogen, C, -C; -alkyl;
i 20/21 mébõl-ie right 0-2; fa Rº is hydrogen and Rº is selected from hydrogen, C1-C; - 'C1-C alkoxy; -alkyl-, C1-C7-alkyl, C1-C; 7-alkoxy and halo-C; -C; -alkyl; 5 where C; -C; -alkyl, C, 1-C; 7-alkoxy heterocyclyl, aryl, heteroaryl are optionally substituted by aryl, heteroaryl, heterocyclyl, C1-C; - alkyl, Cy-C; 7-alkoxy , halo-C1-C; 7-alkyl; OH; h for use as a medicine. f
[12]
Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound of formula (1), as defined in any one of claims 1 to 11, and one or more pharmaceutically acceptable vehicles / excipients.
[13]
13. Combination, in particular a pharmaceutical combination, characterized by the fact that it comprises a therapeutically effective amount of a compound of formula (1), as defined in any one of claims 1 to 11, and one or more therapeutically active agents, particularly pain-relieving agents.
[14]
Compound of formula (1) according to any one of claims 1 to 11, characterized in that it is for use in the treatment of chronic pain; and / or for use in the treatment of one or more disorders or diseases mediated by Nav 1.7; and / or for the treatment of a disorder or disease selected from chronic pain, such as positive symptoms of chronic pain, for example, paraesthesias, dysesthesias, hyperalgesia, allodynia and spontaneous pain, as well as negative symptoms for example, loss of sen - sation.
[15]
15. Use of a compound of formula (1), as defined in any one of claims 1 to 11, characterized by the fact that it is to prepare a medication for the treatment of chronic pain; and / or for use in the treatment of one or more disorders or diseases mediated by Nav 1.7; and / or for the treatment of a disorder or disease selected from chronic pain, such as positive symptoms of chronic pain, for example, paraesthesias, dysesthesias, hyperalgesia, allodynia and spontaneous pain, as well as
Mr 21/21 but negative for example, loss of sensation. '
[16]
16. Invention, characterized by any of its embodiments. claims or categories of claim encompassed by the material initially 'disclosed in the patent application or its examples presented here.

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法律状态:
2020-09-01| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-09-08| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-10-20| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 9A ANUIDADE. |

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2020-12-08| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-02-09| B08K| Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette]|Free format text: EM VIRTUDE DO ARQUIVAMENTO PUBLICADO NA RPI 2598 DE 20-10-2020 E CONSIDERANDO AUSENCIA DE MANIFESTACAO DENTRO DOS PRAZOS LEGAIS, INFORMO QUE CABE SER MANTIDO O ARQUIVAMENTO DO PEDIDO DE PATENTE, CONFORME O DISPOSTO NO ARTIGO 12, DA RESOLUCAO 113/2013. |

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2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US38215810P| true| 2010-09-13|2010-09-13|

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US61/382,158|2010-09-13|

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PCT/EP2011/065868|WO2012035023A1|2010-09-13|2011-09-13|Triazine-oxadiazoles|

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