PYRIDAZINONE DERIVATIVE
Provided are: a pyridazinone derivative and/or a pharmaceutically acceptable salt thereof, which is useful as a therapeutic agent and/or a prophylactic agent for diseases in which Nav1.1 is involved and various central nervous system diseases; and a medicine containing the pyridazinone derivative and/or the pharmaceutically acceptable salt thereof as an active ingredient. A compound represented by formula (1) or a pharmaceutically acceptable salt thereof. [In the formula, M 1 represents a saturated or partially unsaturated C 4-12 carbocyclic group or the like; R 1 and R 2 independently represent a hydrogen atom or the like; M 2 represents a group represented by formula (2a) or the like; X 1a , X 1b and X 1c independently represent N or the like; X 2 , X 3 and X 4 independently represent CR 3 or the like; A 1 and A 2 independently represent N or the like; and R 3 represents a hydrogen atom or the like.]
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein
M 1 is
(1-1) saturated or partially-unsaturated C 4-12 carbocyclyl, wherein the carbocyclyl may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of:
(a) halogen atom, and
(b) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy;
(1-2) saturated or partially-unsaturated 4- to 12-membered heterocyclyl, wherein the heterocyclyl may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of:
(a) halogen atom,
(b) hydroxy,
(c) methoxy,
(d) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy, and
(e) amino-carbonyl optionally substituted with 1 to 2 the same or different C 1-6 alkyl, wherein the C 1-6 alkyl may be optionally substituted with 1 to 3 the same or different halogen atoms;
provided that the heterocyclyl is not morpholinyl;
(1-3) 4-methylphenyl, wherein a phenyl part of the group may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkyl optionally substituted with 1 to 3 the same or different halogen atoms, and C 1-6 alkoxy optionally substituted with 1 to 3 the same or different halogen atoms; and wherein a methyl part of the group may be optionally substituted with 1 to 3 the same or different halogen atoms;
(1-4) amino, wherein the amino may be optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of:
(a) C 1-6 alkyl optionally substituted with 1 to 3 the same or different halogen atoms,
(b) C 3-10 cycloalkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 3-6 cycloalkyl, and
(c) C 3-10 cycloalkyl-C 1-4 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl, and C 3-6 cycloalkyl;
(1-5) 6-methylpyridin-3-yl or 6-trifluoromethylpyridin-3-yl;
(1-6) 4-chlorothiophen-2-yl, 5-methylthiophen-2-yl, or 3-cyanothiophen-2-yl, provided that when M 1 is 5-methylthiophen-2-yl, then M 2 is not a group shown in the following (4-2); or
(1-7) 4-methylphenyloxy;
R 1 and R 2 are each independently
(2-1) hydrogen atom;
(2-2) halogen atom;
(2-3) cyano;
(2-4) C 1-6 alkyl, wherein the C 1-6 alkyl may be optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of:
(a) halogen atom,
(b) hydroxy,
(c) saturated or partially-unsaturated C 3-7 carbocyclyl,
(d) C 1-6 alkoxy, and
(e) amino optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different halogen atoms; saturated or partially-unsaturated C 3-7 carbocyclyl; and C 2-7 alkylcarbonyl;
(2-5) saturated or partially-unsaturated C 3-7 carbocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy;
(2-6) C 2-6 alkenyl optionally substituted with 1 to 4 the same or different halogen atoms;
(2-7) C 1-6 alkoxy optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, saturated or partially-unsaturated C 3-7 carbocyclyl, and C 1-6 alkoxy; or
(2-8) amino optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different halogen atoms and saturated or partially-unsaturated C 3-7 carbocyclyl; or
alternatively, R 1 and R 2 may be combined together with the carbon atoms to which they attach to form
(3-1) a 5- to 7-membered saturated or partially-unsaturated carbocycle, wherein the carbocycle may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of:
(a) halogen atom,
(b) hydroxy,
(c) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy, and
(d) C 1-6 alkoxy optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; or
(3-2) a 5- to 7-membered saturated or partially-unsaturated heterocycle, wherein the heterocycle may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of (a) to (d) in the above (3-1) of the present claim;
M 2 is
(4-1) a group of the following formula (2a) or (2b):
wherein X 1a , X 1b , X 1c , X 5 , X 6 , X 7 , and X 8 are each independently N or CR 3 ;
X 2 , X 3 , and X 4 are each independently CR 3 , O, S, N, or NR 4 ;
A 1 and A 2 are each independently N or C;
wherein X 1a , X 1b , X 1c , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , A 1 , and A 2 are selected such that a ring comprising them forms a 9- or 10-membered bicyclic aromatic heterocycle;
R 3 is
(a) hydrogen atom,
(b) halogen atom,
(c) cyano,
(d) hydroxy,
(e) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, saturated or partially-unsaturated C 3-7 carbocyclyl, C 1-6 alkoxy, 4- to 7-membered saturated heterocyclyl optionally substituted with C 1-6 alkoxy, and amino optionally substituted with 1 to 2 the same or different C 1-6 alkyl,
(f) saturated or partially-unsaturated C 3-7 carbocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and amino optionally substituted with 1 to 2 the same or different C 1-6 alkyl,
(g) C 1-6 alkoxy optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkoxy, and amino optionally substituted with 1 to 2 the same or different C 1-6 alkyl,
(h) amino optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; saturated or partially-unsaturated C 3-7 carbocyclyl; and C 2-7 alkylcarbonyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,
(i) 5- or 6-membered heteroaryl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, cyano, and C 1-6 alkyl,
(j) 4- to 7-membered saturated or partially-unsaturated heterocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, or
(k) —C(O)NR x R y , wherein R x and R y are each independently hydrogen atom, C 1-6 alkyl, or saturated or partially-unsaturated C 3-7 carbocyclyl; or alternatively, R x and R y may be combined together with the nitrogen atom to which they attach to form 4- to 7-membered saturated heterocyclyl,
R 4 is
(a) hydrogen atom,
(b) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy, or
(c) saturated or partially-unsaturated C 3-7 carbocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy;
provided that when R 3 and R 4 exist plurally, each of R 3 and R 4 may be the same or different;
(4-2) a group of the following formula (2c):
wherein R 5 , R 6 , and R 7 are each independently
(a) hydrogen atom,
(b) halogen atom,
(c) cyano,
(d) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, saturated or partially-unsaturated C 3-7 carbocyclyl, and C 1-6 alkoxy,
(e) saturated or partially-unsaturated C 3-7 carbocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy,
(f) C 1-6 alkoxy optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,
(g) amino optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different halogen atoms; saturated or partially-unsaturated C 3-7 carbocyclyl; and C 2-7 alkylcarbonyl,
(h) 5- or 6-membered heteroaryl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, cyano, and C 1-6 alkyl,
(i) 4- to 7-membered saturated or partially-unsaturated heterocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy,
(j) —C(O)NR x R y , wherein R x and R y are each independently hydrogen atom, C 1-6 alkyl, or saturated or partially-unsaturated C 3-7 carbocyclyl; or alternatively, R x and R y may be combined together with the nitrogen atom to which they attach to form 4- to 7-membered saturated heterocyclyl,
(k) C 2-7 alkylcarbonyl, or
(l) C 2-7 alkoxycarbonyl; and
either of the following condition (X) or (Y) is met:
(X) at least one of R 5 , R 6 , and R 7 is cyano, 5- or 6-membered heteroaryl (wherein the heteroaryl may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, cyano, and C 1-6 alkyl), 4- to 7-membered saturated or partially-unsaturated heterocyclyl (wherein the heterocyclyl may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy), or —C(O)NR x R y (wherein R x and R y are each independently hydrogen atom, C 1-6 alkyl, or saturated or partially-unsaturated C 3-7 carbocyclyl; or alternatively, R x and R y are combined together with the nitrogen atom to which they attach to form 4- to 7-membered saturated heterocyclyl); or
(Y) R 5 and R 6 are combined together with the carbon atoms to which they attach to form a 5- to 7-membered saturated or partially-unsaturated carbocycle or heterocycle (wherein the carbocycle and heterocycle may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, oxo, C 1-6 alkyl, C 1-6 alkoxy, and C 2-7 alkoxycarbonyl);
wherein the group of formula (2c) may further be optionally substituted with a fluorine atom at a substitutable carbon atom of the ring;
(4-3) a group of the following formula (2d), (2e), (2f), or (2g):
wherein R 8 , R 9 , and R 10 are each independently
(a) hydrogen atom,
(b) halogen atom,
(c) cyano,
(d) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom; hydroxy; saturated or partially-unsaturated C 3-7 carbocyclyl; C 1-6 alkoxy optionally substituted with hydroxy or C 1-6 alkoxy; 4- to 7-membered saturated or partially-unsaturated heterocyclyl optionally substituted with C 1-6 alkoxy or C 1-6 alkyl; 5- or 6-membered heteroaryl optionally substituted with C 1-6 alkyl; and amino (wherein the amino may be optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; saturated or partially-unsaturated C 3-7 carbocyclyl; 4- to 7-membered saturated heterocyclyl optionally substituted with C 1-6 alkoxy; and C 2-7 alkylcarbonyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy);
(e) saturated or partially-unsaturated C 3-7 carbocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and amino optionally substituted with 1 to 2 the same or different C 1-6 alkyl,
(f) C 1-6 alkoxy optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkoxy, and amino optionally substituted with 1 to 2 the same or different C 1-6 alkyl,
(g) amino optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; saturated or partially-unsaturated C 3-7 carbocyclyl; and C 2-7 alkylcarbonyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,
(h) 5- or 6-membered heteroaryl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, and C 2-7 alkoxycarbonyl,
(i) 4- to 7-membered saturated or partially-unsaturated heterocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; C 1-6 alkoxy; 4- to 7-membered saturated or partially-unsaturated heterocyclyl; C 2-7 alkylcarbonyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; and oxo,
(j) 4- to 7-membered saturated or partially-unsaturated heterocyclyl-oxy optionally substituted with 1 to 4 C 1-6 alkyl,
(k) —C(O)NR x R y , wherein R x and R y are each independently hydrogen atom, C 1-6 alkyl, or saturated or partially-unsaturated C 3-7 carbocyclyl; or
alternatively, R x and R y may be combined together with the nitrogen atom to which they attach to form 4- to 7-membered saturated heterocyclyl,
(l) —C(O)OR z , wherein R z is C 1-6 alkyl, or
(m) ethenyl optionally substituted with one 6-membered saturated heterocyclyl group;
wherein R 8 and R 9 may be combined together with the carbon atoms to which they attach to form a 5- to 7-membered saturated or partially-unsaturated carbocycle or heterocycle, wherein the carbocycle and heterocycle may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, and C 1-6 alkyl,
wherein both R 8 and R 9 of formula (2d) are not hydrogen atoms at the same time, and the group of formula (2e) may further be optionally substituted with a fluorine atom at a substitutable carbon atom of the ring,
(4-4) a group of the following formula (2h):
wherein R 8 , R 9 , and R 10 are the same as those defined in the above (4-3) of the present claim;
n is 0, 1, or 2;
X 9 is CH 2 or O;
wherein the group of formula (2h) may further be optionally substituted with a fluorine atom at a substitutable carbon atom at the ring;
(4-5) a group of the following formula (2i), (2j), or (2k):
wherein X 10 , X 11 , X 12 , and X 13 are each independently N or CR 11 ;
wherein X 10 , X 11 , X 12 , and X 13 are selected such that a 6-membered ring comprising them forms an aromatic heterocycle;
X 14 is CR 15 , CHR 15 , NR 16 or O;
provided that when X 14 is CR 15 , a bond comprising a broken line in formula (2j) denotes a double bond, and that when X 14 is CHR 15 , NR 16 , or O, a bond comprising a broken line in formula (2j) denotes a single bond;
X 15 is NR 17 or O;
R 11 is
(a) hydrogen atom,
(b) halogen atom,
(c) 5- or 6-membered heteroaryl,
(d) 5- or 6-membered heteroaryl-methyl, or
(e) 4- to 7-membered saturated or partially-unsaturated heterocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 2-7 alkylcarbonyl, and C 2-7 alkoxycarbonyl,
provided that when R 11 exists plurally, each R 11 may be the same or different;
R 12 , R 13 , and R 14 are each independently
(a) hydrogen atom, or
(b) methyl,
wherein R 12 and R 14 , or R 13 and R 14 may be combined with the carbon atoms to which they attach to form a bridged structure;
R 15 is
(a) phenyl,
(b) benzyl,
(c) 5- to 10-membered heteroaryl optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of fluorine atom and methoxy,
(d) hydroxy,
(e) phenyloxy, or
phenylamino;
R 16 is
(a) phenyl optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of fluorine atom and methoxy,
(b) 5- or 6-membered heteroaryl optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of methyl, methoxy, fluorine atom, trifluoromethyl, and difluoromethoxy,
(c) 5- or 6-membered heteroarylmethyl optionally substituted with 1 or 2 methyl,
(d) 5- or 6-membered saturated or partially-unsaturated carbocyclyl, or
(e) 6-membered saturated heterocyclyl;
R 17 is
(a) pyridyl,
(b) 6-membered saturated heterocyclyl, or
(c) methoxypropyl;
k is 0, 1, or 2;
j 1 , j 2 , j 3 , and j 4 are each independently 0 or 1;
(4-6) a group of the following formula (2l):
or
(4-7) a group of the following formula (2m) or (2n):
wherein R 18 is
(a) phenyl, or
(b) benzyl;
k 1 and k 2 are each independently 0 or 1;
wherein the nitrogen-containing saturated ring in formula (2m) may be optionally substituted with oxo;
provided that the compound according to Formula (1) is not the following compounds:
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 are each independently
(1) hydrogen atom,
(2) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, saturated or partially-unsaturated C 3-7 carbocyclyl, and C 1-6 alkoxy,
(3) C 1-6 alkoxy optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy, or
(4) amino optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different halogen atoms, and saturated or partially-unsaturated C 3-7 carbocyclyl, or
alternatively, R 1 and R 2 may be combined together with the carbon atoms to which they attach to form a 5- to 7-membered saturated or partially-unsaturated carbocycle.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
M 2 is
(1) a group of any one of the following formulae (11) to (37):
(2) 4-cyanophenylamino,
(3) a group of the following formula (2c′):
wherein R 5 and R 6 are each independently
(a) hydrogen atom,
(b) halogen atom,
(c) cyano,
(d) amino optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different halogen atoms; saturated or partially-unsaturated C 3-7 carbocyclyl; and C 2-7 alkylcarbonyl,
(e) 5- or 6-membered heteroaryl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, cyano, and C 1-6 alkyl,
(f) 4- to 7-membered saturated or partially-unsaturated heterocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, or
(g) —C(O)NR x R y , wherein R x and R y are each independently hydrogen atom, C 1-6 alkyl, or saturated or partially-unsaturated C 3-7 carbocyclyl; or
alternatively, R x and R y may be combined together with the nitrogen atom to which they attach to form 4- to 7-membered saturated heterocyclyl, and
either of the following condition (X′) or (Y′) is met:
(X′) at least one of R 5 and R 6 is cyano, 5- or 6-membered heteroaryl (wherein the heteroaryl may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, cyano, and C 1-6 alkyl), 4- to 7-membered saturated or partially-unsaturated heterocyclyl (wherein the heterocyclyl may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy), or —C(O)NR x R y (wherein R x and R y are each independently hydrogen atom, C 1-6 alkyl, or saturated or partially-unsaturated C 3-7 carbocyclyl; or alternatively, R x and R y may be combined together with the nitrogen atom to which they attach to form 4- to 7-membered saturated heterocyclyl); or
(Y′) R 5 and R 6 may be combined together with the carbon atoms to which they attach to form a 5- to 7-membered saturated or partially-unsaturated carbocycle or heterocycle (wherein the carbocycle and heterocycle may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, oxo, C 1-6 alkyl, C 1-6 alkoxy, and C 2-7 alkoxycarbonyl),
wherein the group of formula (2c′) may further be optionally substituted with a fluorine atom at a substitutable carbon atom of the ring,
(4) a group of the following formula (2d), (2e), (2f), or (2g):
wherein R 8 , R 9 , and R 10 are each independently
(a) hydrogen atom,
(b) halogen atom,
(c) cyano,
(d) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom; hydroxy; C 1-6 alkoxy optionally substituted with hydroxy or C 1-6 alkoxy; 4- to 7-membered saturated or partially-unsaturated heterocyclyl optionally substituted with C 1-6 alkyl or C 1-6 alkoxy; 5- or 6-membered heteroaryl optionally substituted with C 1-6 alkyl; and amino (wherein the amino may be optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; saturated or partially-unsaturated C 3-7 carbocyclyl; 4- to 7-membered saturated heterocyclyl optionally substituted with C 1-6 alkoxy; and C 2-7 alkylcarbonyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy);
(e) C 1-6 alkoxy optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,
(f) amino optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with halogen atom; saturated or partially-unsaturated C 3-7 carbocyclyl; and C 2-7 alkylcarbonyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,
(g) 5- or 6-membered heteroaryl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, and C 2-7 alkoxycarbonyl,
(h) 4- to 7-membered saturated or partially-unsaturated heterocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; C 1-6 alkoxy; 4- to 7-membered saturated or partially-unsaturated heterocyclyl; C 2-7 alkylcarbonyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; and oxo,
(i) 4- to 7-membered saturated or partially-unsaturated heterocyclyl-oxy optionally substituted with 1 to 4 C 1-6 alkyl,
(j) —C(O)NR x R y , wherein R x and R y are each independently hydrogen atom, C 1-6 alkyl, or saturated or partially-unsaturated C 3-7 carbocyclyl; or
alternatively, R x and R y may be combined together with the nitrogen atom to which they attach to form 4- to 7-membered saturated heterocyclyl,
(k) —C(O)OR z , wherein R z is C 1-6 alkyl, or
(l) ethenyl optionally substituted with one 6-membered saturated heterocyclyl group;
wherein R 8 and R 9 may be combined together with the carbon atoms to which they attach to form a 5- to 7-membered saturated or partially-unsaturated carbocycle or heterocycle, wherein the carbocycle and heterocycle may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom and C 1-6 alkyl,
wherein both R 8 and R 9 in formula (2d) are not hydrogen atoms at the same time, and the group of formula (2e) may further be optionally substituted with a fluorine atom at a substitutable carbon atom of the ring, or
(5) a group of the following formula (2h′):
wherein R 8 , R 9 , and R 10 are the same as those defined in the above (4) of the present claim.
4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein
M 2 is
(1) a group of any one of the following formulae (11), (12), (18), (26), (31), and (34):
(2) 4-cyanophenylamino,
(3) a group of the following formula (2h″):
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
M 1 is
(1) saturated or partially-unsaturated C 4-12 carbocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom and C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy, or
(2) 4- to 12-membered saturated or partially-unsaturated heterocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom and C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy.
6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein
M 1 is a group of the following formula (3):
wherein X 16 is N, C, or CH;
a bond comprising a broken line is a single bond or a double bond;
m is 0, 1, 2, or 3;
R a and R b are each independently
(1-1) hydrogen atom,
(1-2) halogen atom, or
(1-3) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; or
alternatively, R a and R b may be combined together with the carbon atom(s) to which they attach to form a 3- to 6-membered saturated carbocycle, wherein the carbocycle may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of:
(a) halogen atom,
(b) hydroxy,
(c) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy, and
(d) C 1-6 alkoxy optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Formula (1) is formula (1″):
wherein M 1′ is any one of the following formulae (38) to (52):
R 1′ and R 2′ are each independently
(2-1) hydrogen atom,
(2-2) halogen atom,
(2-3) cyano,
(2-4) methyl, or
(2-5) methoxy, and
M 2 is
(1) a group of any one of the following formulae (53) to (58):
wherein R 3 , where les are each independent when existing plurally, is
(a) hydrogen atom,
(b) halogen atom,
(c) cyano,
(d) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, saturated or partially-unsaturated C 3-7 carbocyclyl, C 1-6 alkoxy, 4- to 7-membered saturated heterocyclyl optionally substituted with C 1-6 alkoxy, and amino optionally substituted with 1 to 2 the same or different C 1-6 alkyl,
(e) C 1-6 alkoxy optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 1-6 alkoxy, and amino optionally substituted with 1 to 2 the same or different C 1-6 alkyl, or
(f) amino optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; saturated or partially-unsaturated C 3-7 carbocyclyl; and C 2-7 alkylcarbonyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,
(2) 4-cyanophenylamino, or
(3) a group of the following formula (2h″):
wherein R 8 is
(a) C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom; hydroxy; C 1-6 alkoxy optionally substituted with hydroxy or C 1-6 alkoxy; 4- to 7-membered saturated or partially-unsaturated heterocyclyl optionally substituted with C 1-6 alkyl or C 1-6 alkoxy; 5- or 6-membered heteroaryl optionally substituted with C 1-6 alkyl; and amino (wherein the amino may be optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; saturated or partially-unsaturated C 3-7 carbocyclyl; 4- to 7-membered saturated heterocyclyl optionally substituted with C 1-6 alkoxy; and C 2-7 alkylcarbonyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy),
(b) C 1-6 alkoxy optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,
(c) amino optionally substituted with 1 to 2 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with halogen atom; saturated or partially-unsaturated C 3-7 carbocyclyl; and C 2-7 alkylcarbonyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy,
(d) 5- or 6-membered heteroaryl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, and C 2-7 alkoxycarbonyl,
(e) 4- to 7-membered saturated or partially-unsaturated heterocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; C 1-6 alkoxy; 4- to 7-membered saturated or partially-unsaturated heterocyclyl; C 2-7 alkylcarbonyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; and oxo, or
(f) 4- to 7-membered saturated or partially-unsaturated heterocyclyl-oxy optionally substituted with 1 to 4 C 1-6 alkyl.
8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
M 1′ is a group of the following formula (38):
9 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
M 1′ is a group of the following formula (39), (40), (41), or (45):
10 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
M 1′ is a group of the following formula (48), (50), or (51):
11 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
M 2′ is a group of any one of the following formulae (53) to (58):
wherein R 3 is hydrogen atom, halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, or amino optionally substituted with 1 to 2 the same or different C 1-6 alkyl.
12 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
M 2′ is a group of the following formula (57) or (58):
wherein R 3 is hydrogen atom, halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, or amino optionally substituted with 1 to 2 the same or different C 1-6 alkyl.
13 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein M 2 is 4-cyanophenylamino.
14 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein M 2′ is
(3) a group of the following formula (2h″):
wherein R 8 is
(a) 5- or 6-membered heteroaryl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, cyano, and C 1-6 alkyl, or
(b) 4- to 7-membered saturated or partially-unsaturated heterocyclyl optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy; C 1-6 alkoxy; and oxo.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
N-(4-cyanophenyl)-2-[3-(4-methylpiperidin-1-yl)-6-oxopyridazin-1(6H)-yl]acetamide,
N-(1,3-benzooxazol-5-yl)-2-[3-(4-methylpiperidin-1-yl)-6-oxopyridazin-1(6H)-yl]acetamide,
2-[3-(6-azaspiro[3.4]octan-6-yl)-6-oxopyridazin-1(6H)-yl]-N-(quinazolin-7-yl)acetamide,
N-[2-(dimethylamino)-1,3-benzooxazol-5-yl]-2-[3-(4-methylcyclohex-1-en)-6-oxopyridazin-1(6H)-yl]acetamide,
2-[3-(4,4-dimethylcyclohex-1-en-1-yl)-6-oxopyridazin-1(6H)-yl]-N-([1,2,4]triazolo[1,5-a]pyridin-6-yl)acetamide,
2-[3-(4,4-dimethylcyclohex-1-en-1-yl)-6-oxopyridazin-1(6H)-yl]-N-([1,2,4]triazolo[1,5-a]pyridin-7-yl)acetamide,
N-(1,3-benzooxazol-5-yl)-2-[3-(4,4-dimethylcyclohex-1-en-1-yl)-6-oxopyridazin-1(6H)-yl]acetamide,
2-[6-oxo-3-(spiro[2.5]oct-5-en-6-yl)pyridazin-1(6H)-yl]-N-([1,2,4]triazolo[1,5-a]pyridin-7-yl)acetamide,
2-{2-oxo-2-[4-(pyridazin-4-yl)-2.3-dihydro-1H-indol-1-yl]ethyl}-6-(spiro[2.5]oct-5-en-6-yl)pyridazin-3(2H)one,
N-(1,3-benzooxazol-5-yl)-2-[3-(4-methylcyclohex-1-en-1-yl)-6-oxopyridazin-1(6H)-yl]acetamide,
2-{3-[(4S)-4-methylcyclohex-1-en-1-yl]-6-oxopyridazin-1(6H)-yl}-N-([1,2,4]triazolo[1,5-a]pyridin-7-yl)acetamide,
2-{3-[(4R)-4-methylcyclohex-1-en-1-yl]-6-oxopyridazin-1(6H)-yl}-N-([1,2,4]triazolo[1,5-a]pyridin-7-yl)acetamide,
2-{3-[(4S)-4-methylcyclohex-1-en-1-yl]-6-oxopyridazin-1(6H)-yl}-N-([1,2,4]triazolo[1,5-a]pyridin-6-yl)acetamide, and
2-{3-[(4R)-4-methylcyclohex-1-en-1-yl]-6-oxopyridazin-1(6H)-yl}-N-([1,2,4]triazolo[1,5-a]pyridin-6-yl)acetamide.
16 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, as an active ingredient.
17 . (canceled)
18 . (canceled)
19 . A method for treating a disease involving Nav1.1 or a reduced function of Nav. 1, comprising administering to a person in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof, as an active ingredient.
20 . (canceled)
21 . The of claim 19 , wherein the disease involving Nav1.1 is a central nervous system disease.
22 . The, method of claim 25 wherein the central nervous system disease is at least one selected from the group consisting of febrile seizure; generalised epilepsy with febrile seizure plus; epilepsy (specifically, focal epilepsy, generalized epilepsy); epileptic syndrome (such as Dravet syndrome; intractable childhood epilepsy with generalized tonic-clonic seizure; epilepsy with myoclonic-atonic seizure; West syndrome; Lennox-Gastaut syndrome; infantile spasms; sever infantile multifocal epilepsy; severe myoclonic epilepsy, borderline; benign familial neonatal-infantile seizure); schizophrenia; autism spectrum disorder; and attention deficit hyperactivity disorder.
23 . (canceled)
24 . (canceled)
25 . A method for treating and/or preventing a disease involving Nav1.1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
26 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one drug selected from drugs classified as antiepileptic agents, antidepressant agents, antiparkinsonian agents, antischizophrenic agents, or therapeutic agents for ADHD.
27 . (canceled)
28 . A method treating a subject with a central nervous system disease comprising administering at least one compound of claim 1 and one or more drugs selected from the group consisting of drugs selected from drugs classified as antiepileptic agents, antidepressant agents, antiparkinsonian agents, antischizophrenic agents, or therapeutic agents for ADHD.