Triazaspiro[5.5]undecane derivatives and pharmaceutical compositions comprising thereof, as an active ingredient

A triazaspiro[5.5]undecane compound of the formula (I):

• wherein R1 is
• (1) hydrogen,
• (2) C1–18alkyl,
• (3) C2–18 alkenyl,
• (4) C2–18 alkynyl,
• (5) —COR6,
• (6) —CONR7R8,
• (7) —COOR9,
• (8) —SO2R10,
• (9) —COCOOR11,
• (10) —CONR12COR13,
• (11) Cyc 1, or
• (12) C1–18 alkyl, C2–18 alkenyl or C2–18 alkynyl substituted by 1–5 substituent(s) selected from (a) halogen, (b) —CONR7R8, (c) —COOR , (d) —OR14, (e) —SR15, (f) —NR16R17, (g) —NR18COR19, (h) —SO2NR20R21, (i) —OCOR22, (j) —NR23SO2R24, (k) —NR25COOR26, (l) —NR27CONR28R29, (m) Cyc 1, (n) keto or (o) —N(SO2R24)2,
• wherein R6–R9, R11–R21, R23, R25 and R27–R29 are each independently,
• (1) hydrogen,
• (2) C1–8 alkyl,
• (3) C2–8 alkenyl,
• (4) C2–8 alkynyl,
• (5) Cyc 1, or
• (6) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by 1–5 substituents(s) selected from (a) Cyc 1, (b) halogen, (c) —OR30, (d) —SR31, (e) —NR32R33, (f) —COOR34, (g) —CONR35R36, (h) —NR37COR38, (i) —NR39SO2R40 or (j) —N(SO2R40)2, or
• R7 and R8, R20 and R21, R28 and R29, taken together, are 1) C2–6 alkylene, 2) —(C2–6 alkylene)-O—(C2–6 alkylene)-, 3) —(C2–6 alkylene)-S—(C2–6 alkylene)- or 4) —(C2–6 alkylene)-NR195—(C2–6 alkylene)-,
• wherein R195 is hydrogen, C1–8 alkyl, phenyl or C1–8alkyl substituted by phenyl,
• R10, R22, R24 and R26 are each independently,
• (1) C1–8 alkyl,
• (2) C2–8 alkenyl,
• (3) C2–8 alkynyl,
• (4) Cyc 1, or
• (5) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by 1–5 substituents(s) selected from (a) Cyc 1, (b) halogen, (c) —OR30, (d) —SR31, (e) —NR32R33, (f) —COOR34, (g) —CONR35R36, (h) —NR37COR38, (i) —NR39SO2R40 or (j) —N(SO2R40)2,
• wherein R30–R37 and R39 are each independently, hydrogen, C1–8 alkyl, Cyc 1 or C1–8 alkyl substituted by Cyc 1, or
• R35 and R36, taken together, are 1) C2–6 alkylene, 2) —(C2–6 alkylene)-O—(C2–6 alkylene)-, 3) —(C2–6 alkylene)-S—(C2–6 alkylene)- or 4) —(C2–6 alkylene)-NR196—(C2–6 alkylene)-,
• wherein R196 is hydrogen, C1–8 alkyl, phenyl or C1–8 alkyl substituted by phenyl,
• R38 and R40 are each independently C1–8 alkyl, Cyc 1 or C1–8 alkyl substituted by Cyc 1,
• Cyc 1 is C3–15 mono-, bi- or tri-(fused or spiro)carbocyclic ring or 3–15 membered mono-, bi- or tri-(fused or spiro)cyclic hetero ring containing 1–4 nitrogen atom(s), 1–3 oxygen atom(s) and/or 1–3 sulfur atom(s),
• wherein Cyc 1 maybe substituted by 1–5 of R51,
• R51 is
• (1) C1–8 alkyl,
• (2) C2–8 alkenyl,
• (3) C2–8 alkynyl,
• (4) halogen,
• (5) nitro,
• (6) trifluoromethyl,
• (7) trifluoromethoxy,
• (8) nitrile,
• (9) keto,
• (10) Cyc 2
• (11) —OR52,
• (12) —SR53,
• (13) —NR54R55,
• (14) —COOR56,
• (15) —CONR57R58,
• (16) —NR59COR60,
• (17) —SO2NR61R62,
• (18) —OCOR63,
• (19) —NR64SO2R65,
• (20) —NR66COOR67,
• (21) —NR68CONR69R70,
• (22) —B(OR71)2,
• (23) —SO2R72,
• (24) —N(SO2R72)2, or
• (25) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by 1–5 substituents(s) selected from (a) halogen, (b) Cyc 2, (c) —OR52, (d) —SR53, (e) —NR54R55, (f) —COOR56, (g) —CONR57R58, (h) —NR59COR60, (i) —SO2NR61R62, (j) —OCOR63, (k) —NR64SO2R65, (l) —NR66COOR67, (m) —NR68CONR69R70, (n) —B(OR71)2, (o) —SO2R72 or (p) —N(SO2R72)2,
• wherein R52–R62, R64, R66 and R68–R71 are each independently 1) hydrogen, 2) C1–8 alkyl, 3) C2–8 alkenyl, 4) C2–8 alkynyl, 5) Cyc 2 or 6) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by Cyc 2, —OR73, —COOR74, —NR75R76, or
• R57 and R58, R61 and R62, R69 and R70, taken together, are 1) C2–6 alkylene, 2) —(C2–6 alkylene)-O—(C2–6 alkylene)-, 3) —(C2–6 alkylene)-S—(C2–6 alkylene)- or 4) —(C2–6 alkylene)-NR197—(C2–6 alkylene)-,
• wherein R197 is hydrogen, C1–8 alkyl, phenyl or C1–8alkyl substituted by phenyl,
• R63, R65, R67 and R72 are each independently 1) C1–8 alkyl, 2) C2–8 alkenyl, 3) C2–8 alkynyl, 4) Cyc 2 or 5) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by Cyc 2, —OR73, —COOR74 or —NR75R76,
• wherein R73–R76 are independently hydrogen, C1–8 alkyl, Cyc 2 or C1–8 alkyl substituted by Cyc 2,
• Cyc 2 has the same meaning as Cyc 1,
• wherein Cyc 2 may be substituted by 1–5 of R77,
• R77 is
• 1) C1–8alkyl,
• 2) halogen,
• 3) nitro,
• 4) trifluoromethyl,
• 5) trifluoromethoxy,
• 6) nitrile,
• 7) —OR78,
• 8) —NR79R80,
• 9) —COOR81,
• 10) —SR82,
• 11) —CONR83R84,
• 12) C2–8 alkenyl,
• 13) C2–8 alkynyl,
• 14) keto,
• 15) Cyc 6,
• 16) —NR161COR162,
• 17) —SO2NR163R164,
• 18) —OCOR165,
• 19) —NR166SO2R167,
• 20) —NR168COOR169,
• 21) —NR170CONR171R172,
• 22) —SO2R173,
• 23) —N(SO2R167)2, or
• 24) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by 1–5 substituents(s) selected from (a) halogen, (b) —OR78, (c) —NR79R80, (d) —COOR81, (e) —SR82, (f) —CONR83R84, (g) keto, (h) Cyc 6, (i) —NR161COR162, (j) —SO2NR163R164, (k) —OCOR165, (l) —NR166SO2R167, (m) —NR168COOR169, (n) —NR170CONR171R172, (o) —SO2R173 or (p) —N(SO2R167)2,
• wherein R78–R84, R161–R164, R166, R168 and R170–R172 are each independently (a) hydrogen, (b) C1–8 alkyl, (c) C2–8 alkenyl, (d) C2–8 alkynyl, (e) Cyc 6 or (f) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by Cyc 6, —OR174, —COOR175, —NR176R177 or —CONR178R179, or
• R83 and R84, R163 and R164, R171 and R172, taken together, are 1) C2–6 alkylene, 2) —(C2–6 alkylene)-O—(C2–6 alkylene)-, 3) —(C2–6 alkylene)-S—(C2–6 alkylene)- or 4) —(C2–6 alkylene)-NR198—(C2–6 alkylene)-,
• wherein R198 is hydrogen, C1–8 alkyl, phenyl or C1–8 alkyl substituted by phenyl,
• R165, R167, R169 and R173 are each independently (a) C1–8 alkyl, (b) C2–8 alkenyl, (c) C2–8 alkynyl, (d) Cyc 6 or (e) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by Cyc 6, —OR174, —COOR175, —NR176R177 or —CONR178R179,
• wherein R174–R177 are each independently 1) hydrogen, 2) C1–8 alkyl, 3) Cyc 6 or 4) C1–8 alkyl substituted by Cyc 6, or
• R178 and R179, taken together, are 1) C2–6 alkylene, 2) —(C2–6 alkylene)-O—(C2–6 alkylene)-, 3) —(C2–6 alkylene)-S—(C2–6 alkylene)- or 4) —(C2–6 alkylene)-NR199—(C2–6 alkylene)-,
• wherein R199 is hydrogen, C1–8 alkyl, phenyl or C1–8 alkyl substituted by phenyl,
• Cyc 6 is C3–8 mono-carbocyclic ring or 3–8 membered mono-cyclic hetero ring containing 1–4 nitrogen atom(s), 1–2 oxygen atom(s) and/or 1–2 sulfur atom(s),
• wherein Cyc 6 may be substituted by 1–5 of R180,
• R180 is,
• (1) C1–8 alkyl,
• (2) halogen,
• (3) nitro,
• (4) trifluoromethyl,
• (5) trifluoromethoxy,
• (6) nitrile,
• (7) —OR181,
• (8) —NR182R183,
• (9) —COOR184,
• (10) —SR185, or
• (11) —CONR186R187,
• wherein R181–R187 are each independently 1) hydrogen, 2) C1–8 alkyl, 3) phenyl or 4) C1–8 alkyl substituted by phenyl,
• R182 and R183, R186 and R187, taken together, are 1) C2–6 alkylene, 2) —(C2–6 alkylene)-O—(C2–6 alkylene)-, 3) —(C2–6 alkylene)-S—(C2–6 alkylene)- or 4) —(C2–6 alkylene)-NR200—(C2–6 alkylene)-,
• wherein R200 is hydrogen, C1–8 alkyl, phenyl or C1–8 alkyl substituted by phenyl,
• R2 is
• (1) hydrogen,
• (2) C1–8 alkyl,
• (3) C2–8 alkenyl,
• (4) C2–8 alkynyl,
• (5) —OR90,
• (6) Cyc 3, or
• (7) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by 1–5 substituents(s) selected from (a) halogen, (b) —OR90, (c) —SR91, (d) —NR92R93, (e) —COOR94, (f) —CONR95R96, (g) —NR97COR98, (h) —SO2NR99R100, (i) —OCOR101, (j) —NR102SO2R103, (k) —NR104COOR105, (l) —NR106CONR107R108, (m) Cyc 3, (n) keto or (o) —N(SO2R103)2,
• wherein R90–R100, R102, R104 and R106–R108 are each independently 1) hydrogen, 2) C1–8 alkyl, 3) C2–8 alkenyl, 4) C2–8 alkynyl, 5) Cyc 3 or 6) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by Cyc 3, or
• R95 and R96, R99 and R100, R107 and R108, taken together, are 1) C2–6 alkylene, 2) —(C2–6 alkylene)-O—(C2–6 alkylene)-, 3) —(C2–6 alkylene)-S—(C2–6 alkylene)- or 4) —(C2–6 alkylene)-NR201—(C2–6 alkylene)-,
• wherein R201 is hydrogen, C1–8 alkyl, phenyl or C1–8 alkyl substituted by phenyl,
• R101, R103 and R105 are each independently 1) C1–8 alkyl, 2) C2–8 alkenyl, 3) C2–8 alkynyl, 4) Cyc 3, or 5) C1–8 alkyl, C2–8alkenyl or C2–8alkynyl substituted by Cyc 3,
• Cyc 3 has the same meaning as Cyc 1,
• wherein Cyc 3 may be substituted by 1–5 of R109,
• R109 has the same meaning as R51,
• R3 and R4 are each independently
• (1) hydrogen,
• (2) C1–8 alkyl,
• (3) C2–8 alkenyl,
• (4) C2–8 alkynyl,
• (5) —COOR120,
• (6) —CONR121R122,
• (7) Cyc 4, or
• (8) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by 1–5 substituents(s) selected from (a) halogen, (b) nitrile, (c) Cyc 4, (d) —COOR120, (e) —CONR121R122, (f) —OR123, (g) —SR124, (h) —NR125R126, (i) —NR127COR128, (j) —SO2NR129R130, (k) —OCOR131, (l) —NR132SO2R133, (m) —NR134COOR135, (n) —NR136CONR137R138, (o) —S—SR139, (p) —NHC(═NH)NHR140, (q) keto, (r) —NR145CONR146COR147 or (s) —N(SO2R133)2,
• wherein R120–R130, R132, R134, R136–R138, R145 and R146 are each independently 1) hydrogen, 2) C1–8 alkyl, 3) C2–8 alkenyl, 4) C2–8 alkynyl, 5) Cyc 4 or 6) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by Cyc 4, halogen, OR148, —SR149, —COOR150 or —NHCOR141, or
• R121 and R122, R129 and R130, R137 and R138, taken together, are 1) C2–6 alkylene, 2) —(C2–6 alkylene)-O—(C2–6 alkylene)-, 3) —(C2–6 alkylene)-S—(C2–6 alkylene)- or 4) —(C2–6 alkylene)-NR202—(C2–6 alkylene)-,
• wherein R202 is hydrogen, C1–8 alkyl, phenyl or C1–8 alkyl substituted by phenyl,
• R131, R133, R135, R139 and R147 are each independently 1) C1–8 alkyl, 2) C2–8 alkenyl, 3) C2–8 alkynyl, 4) Cyc 4 or 5) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by Cyc 4, halogen, —OR148, —SR149, —COOR150 or —NHCOR141,
• R140 is hydrogen, —COOR142 or —SO2R143,
• wherein R141–R143 are each independently 1) C1–8 alkyl, 2) C2–8 alkenyl, 3) C2–8 alkynyl, 4) Cyc 4 or 5) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by Cyc 4,
• R148–R150 are each independently 1) hydrogen, 2) C1–8 alkyl, 3) C2–8 alkenyl, 4) C2–8 alkynyl, 5) Cyc 4 or 6) C1–8 alkyl, C2–8 alkenyl or C2–8 alkynyl substituted by Cyc 4,
• Cyc 4 has the same meaning as Cyc 1,
• wherein Cyc 4 maybe substituted by 1–5 of R144,
• R144 has the same meaning as R51 or
• R3 and R4, taken together, are
• wherein R190 and R191 each has independently the same meaning as R3 or R4,
• R5 is
• (1) hydrogen,
• (2) C1–8 alkyl,
• (3) Cyc5, or
• (4) C1–8alkyl substituted by Cyc 5,
• wherein Cyc 5 have the same meaning as Cyc 1,
• wherein Cyc 5 may be substituted by 1–5 of R160,
• R160 has the same meaning as R51,
• a quaternary ammonium salt thereof, an N-oxide thereof or a non-toxic salt thereof.