Pyridazinone derivatives

文档序号：722776 发布日期：2021-04-16 浏览：32次中文

阅读说明：本技术 哒嗪酮衍生物 (Pyridazinone derivatives ) 是由西田友明上町昊岩田昌门柴田一西卷拓也清重沙织于 2019-07-18 设计创作，主要内容包括：提供了：哒嗪酮衍生物和/或其药学上可接受的盐,其可用作在其中涉及Nav1.1的疾病和多种中枢神经系统疾病的治疗剂和/或预防剂；和药物,其含有所述哒嗪酮衍生物和/或其药学上可接受的盐作为活性成分。由式(1)表示的化合物或其药学上可接受的盐。[在式中,M～1代表饱和的或部分不饱和的C-(4-12)碳环基团等；R～1和R～2独立地代表氢原子等；M～2代表由式(2a)表示的基团等；X～(1a)、X～(1b)和X～(1c)独立地代表N等；X～2、X～3和X～4独立地代表CR～3等；A～1和A～2独立地代表N等；且R～3代表氢原子等。](Provided is a method for producing: a pyridazinone derivative and/or a pharmaceutically acceptable salt thereof, which is useful as a therapeutic and/or prophylactic agent for diseases in which nav1.1 is involved and various central nervous system diseases; and a medicament containing the pyridazinone derivativeAs an active ingredient, a compound and/or a pharmaceutically acceptable salt thereof. A compound represented by formula (1) or a pharmaceutically acceptable salt thereof. [ in the formula, M 1 Represents saturated or partially unsaturated C 4‑12 Carbocyclic groups, and the like; r 1 And R 2 Independently represent a hydrogen atom or the like; m 2 Represents a group represented by the formula (2a), etc.; x 1a 、X 1b And X 1c Independently represent N, etc.; x 2 、X 3 And X 4 Independently represent CR 3 Etc.; a. the 1 And A 2 Independently represent N, etc.; and R is 3 Represents a hydrogen atom or the like.])

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

M¹Is that

(1-1) saturated or partially unsaturatedC_4-12Carbocyclyl, wherein said carbocyclyl may be optionally substituted with 1 to 4 substituents which may be the same or different, selected from the group consisting of:

(a) a halogen atom, and

(b) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy;

(1-2) a saturated or partially unsaturated 4-12 membered heterocyclic group, wherein said heterocyclic group may be optionally substituted with 1-4 same or different substituents selected from the group consisting of:

(a) a halogen atom,

(b) a hydroxyl group(s),

(d) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy, and

(e) amino-carbonyl optionally substituted by 1 to 2 identical or different C_1-6Alkyl substitution, wherein said C_1-6Alkyl groups may be optionally substituted with 1 to 3 halogen atoms which may be the same or different;

provided that said heterocyclyl is not morpholinyl;

(1-3) 4-methylphenyl, wherein the phenyl moiety of said group may be optionally substituted with 1 to 4 identical or different substituents selected from: halogen atom, hydroxy group, C optionally substituted by 1 to 3 same or different halogen atoms_1-6Alkyl and C optionally substituted by 1 to 3 identical or different halogen atoms_1-6An alkoxy group; and wherein the methyl portion of said group may be optionally substituted with 1 to 3 identical or different halogen atoms;

(1-4) an amino group, wherein the amino group may be optionally substituted with 1 to 2 same or different substituents selected from the group consisting of:

(a) c optionally substituted by 1 to 3 identical or different halogen atoms_1-6An alkyl group, a carboxyl group,

(b) C_3-10cycloalkyl optionally interrupted by 1-3 phasesSame or different from halogen atom, C_1-6Alkyl and C_3-6Substituent substitution of cycloalkyl, and

(c) C_3-10cycloalkyl-C_1-4Alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, C_1-6Alkyl and C_3-6Cycloalkyl substituents;

(1-5) 6-methylpyridin-3-yl or 6-trifluoromethylpyridin-3-yl;

(1-6) 4-chlorothien-2-yl, 5-methylthiophene-2-yl or 3-cyanothien-2-yl, with the proviso that when M is¹When it is 5-methylthiophen-2-yl, then M²A group other than those shown in the following (4-2); or

(1-7) a 4-methylphenoxy group;

R¹and R²Each independently is

(2-1) a hydrogen atom;

(2-2) a halogen atom;

(2-3) cyano;

(2-4)C_1-6alkyl radical, wherein said C_1-6Alkyl groups may be optionally substituted with 1 to 3 substituents which may be the same or different, selected from:

(a) a halogen atom,

(b) a hydroxyl group(s),

(d) C_1-6alkoxy, and

(e) amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: c optionally substituted by 1 to 3 identical or different halogen atoms_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and C_2-7An alkylcarbonyl group;

(2-5) saturated or partially unsaturated C_3-7Carbocyclyl optionally substituted with 1-4 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, C_1-6Alkyl and C_1-6An alkoxy group;

(2-6)C_2-6alkenyl, optionally substituted by 1-4Identical or different halogen atoms;

(2-7)C_1-6alkoxy optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of: halogen atom, hydroxy group, saturated or partially unsaturated C_3-7Carbocyclyl and C_1-6An alkoxy group; or

(2-8) an amino group, which is optionally substituted with 1-2 same or different substituents selected from the group consisting of: c optionally substituted by 1 to 3 identical or different halogen atoms_1-6Alkyl and saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R¹And R²Can be combined with the carbon atoms to which they are attached to form

(3-1) a 5-7 membered saturated or partially unsaturated carbocyclic ring, wherein said carbocyclic ring may be optionally substituted with 1-4 identical or different substituents selected from:

(a) a halogen atom,

(b) a hydroxyl group(s),

(c) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy, and

(d) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent substitution of alkoxy; or

(3-2) a 5-7 membered saturated or partially unsaturated heterocyclic ring, wherein the heterocyclic ring may be optionally substituted with 1 to 4 same or different substituents selected from (a) to (d) in the above (3-1) of the present claim;

M²is that

(4-1) a group of the following formula (2a) or (2 b):

wherein X^1a、X^1b、X^1c、X⁵、X⁶、X⁷And X⁸Each independently is N or CR³；

X²、X³And X⁴Each independently is CR³O, S, N or NR⁴；

A¹And A²Each independently is N or C;

wherein X^1a、X^1b、X^1c、X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸、A¹And A²Selected such that the ring containing them forms a 9 or 10 membered bicyclic aromatic heterocycle;

R³is that

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) a hydroxyl group(s),

(e) C_1-6alkyl, optionally substituted with 1-3 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, saturated or partially unsaturated C_3-7Carbocyclyl, C_1-6Alkoxy, optionally substituted by C_1-6Alkoxy-substituted 4-7 membered saturated heterocyclyl and optionally substituted by 1-2 identical or different C' s_1-6An amino group substituted with an alkyl group,

(f) saturated or partially unsaturated C_3-7Carbocyclyl optionally substituted with 1-4 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, C_1-6Alkyl radical, C_1-6Alkoxy and optionally substituted by 1 to 2 identical or different C_1-6An amino group substituted with an alkyl group,

(g) C_1-6alkoxy optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of: halogen atom, hydroxy group, C_1-6Alkoxy and optionally substituted by 1 to 2 identical or different C_1-6An amino group substituted with an alkyl group,

(h) amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: optionally 1-3 identicalOr different from halogen atom, hydroxy group and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkyl-carbonyl group, a carboxyl group,

(i) 5-or 6-membered heteroaryl, optionally substituted by 1 to 4 identical or different substituents selected from the group consisting of halogen atoms, cyano and C_1-6The substituent of the alkyl group is substituted,

(j) 4-7 membered saturated or partially unsaturated heterocyclyl, optionally substituted by 1-4 same or different substituents selected from halogen atom, hydroxy, C_1-6Alkyl and C_1-6Substituent of alkoxy, or

(k) -C(O)NR^xR^yWherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or alternatively, R^xAnd R^yMay combine together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group,

R⁴is that

(a) A hydrogen atom, and a nitrogen atom,

(b) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent of alkoxy, or

(c) Saturated or partially unsaturated C_3-7Carbocyclyl optionally substituted with 1-4 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, C_1-6Alkyl and C_1-6An alkoxy group;

provided that when R is³And R⁴When there are more than two, R³And R⁴Each of which may be the same or different;

(4-2) a group of the following formula (2 c):

wherein R is⁵、R⁶And R⁷Each independently is

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(f) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6The substituent of the alkoxy group is substituted,

(g) amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: c optionally substituted by 1 to 3 identical or different halogen atoms_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and C_2-7An alkyl-carbonyl group, a carboxyl group,

(h) 5-or 6-membered heteroaryl, optionally substituted by 1 to 4 identical or different substituents selected from the group consisting of halogen atoms, cyano and C_1-6The substituent of the alkyl group is substituted,

(i) 4-7 membered saturated or partially unsaturated heterocyclyl, optionally substituted by 1-4 same or different substituents selected from halogen atom, hydroxy, C_1-6Alkyl and C_1-6The substituent of the alkoxy group is substituted,

(j) -C(O)NR^xR^ywherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or alternatively, R^xAnd R^yMay combine together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group,

(k) C_2-7alkylcarbonyl, or

(l) C_2-7An alkoxycarbonyl group; and

satisfying any one of the following conditions (X) or (Y):

(X)R⁵、R⁶and R⁷Is cyano, 5-or 6-membered heteroaryl (wherein the heteroaryl group may optionally be substituted by 1 to 4 identical or different substituents selected from the group consisting of halogen atoms, cyano and C_1-6Alkyl substituents), 4-to 7-membered saturated or partially unsaturated heterocyclyl (wherein the heterocyclyl may optionally be substituted by 1 to 4 identical or different substituents selected from halogen atoms, hydroxy, C_1-6Alkyl and C_1-6Substituent of alkoxy) or-C (O) NR^xR^y(wherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or alternatively, R^xAnd R^yTaken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group); or

(Y) R⁵And R⁶Combine together with the carbon atom to which they are attached to form a 5-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (wherein the carbocyclic and heterocyclic rings may be optionally substituted with 1-4 identical or different substituents selected from the group consisting of halogen atom, oxo, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-7Alkoxycarbonyl groups);

wherein the group of formula (2c) may be further optionally substituted at the substitutable carbon atom of the ring by a fluorine atom;

(4-3) a group of the following formula (2d), (2e), (2f) or (2 g):

wherein R is⁸、R⁹And R¹⁰Each independently is

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) C_1-6alkyl, optionally substituted with 1-3 substituents, which may be the same or different, selected from: a halogen atom; a hydroxyl group; saturated or partially unsaturated C_3-7A carbocyclic group; optionally substituted by hydroxy or C_1-6Alkoxy-substituted C_1-6An alkoxy group; optionally is covered with C_1-6Alkoxy or C_1-6An alkyl-substituted 4-7 membered saturated or partially unsaturated heterocyclyl; optionally is covered with C_1-6An alkyl-substituted 5 or 6 membered heteroaryl; and amino (wherein the amino group may be optionally substituted with 1 to 2 same or different substituents selected from the group consisting of 1 to 3 same or different substituents selected from the group consisting of halogen atom, hydroxyl group and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; optionally is covered with C_1-6An alkoxy-substituted 4-7 membered saturated heterocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7Alkylcarbonyl);

(e) saturated or partially unsaturated C_3-7Carbocyclyl optionally substituted with 1-4 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, C_1-6Alkyl radical, C_1-6Alkoxy and optionally substituted by 1 to 2 identical or different C_1-6An amino group substituted with an alkyl group,

(f) C_1-6alkoxy optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of: halogen atom, hydroxy group, C_1-6Alkoxy and optionally substituted by 1 to 2 identical or different C_1-6An amino group substituted with an alkyl group,

(g) amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and optionally 1-3 of the same orDifferent from halogen atom, hydroxy group and C_1-6C substituted by substituents of alkoxy_2-7An alkyl-carbonyl group, a carboxyl group,

(h) 5-or 6-membered heteroaryl, optionally substituted with 1-4 identical or different substituents selected from: halogen atom, cyano group, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-7An alkoxycarbonyl group, a carbonyl group,

(i) a 4-7 membered saturated or partially unsaturated heterocyclyl, optionally substituted with 1-4 identical or different substituents selected from: c_1-6Alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy; c_1-6An alkoxy group; a 4-7 membered saturated or partially unsaturated heterocyclyl; optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkylcarbonyl group; and an oxo group, and a salt thereof,

(j) optionally substituted by 1-4C_1-6An alkyl-substituted 4-7 membered saturated or partially unsaturated heterocyclyloxy,

(k) -C(O)NR^xR^ywherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R^xAnd R^yMay combine together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group,

(l) -C(O)OR^Zwherein R is^ZIs C_1-6Alkyl, or

(m) vinyl optionally substituted with a 6-membered saturated heterocyclyl;

wherein R is⁸And R⁹May be combined together with the carbon atom to which they are attached to form a 5-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, wherein the carbocyclic and heterocyclic rings may be optionally substituted with 1-4 identical or different substituents selected from halogen atoms and C_1-6An alkyl group, a carboxyl group,

wherein R of formula (2d)⁸And R⁹Both are not simultaneously hydrogen atoms, and the group of formula (2e) may be further optionally substituted at the substitutable carbon atom of the ring by a fluorine atom,

(4-4) a group of the following formula (2 h):

wherein R is⁸、R⁹And R¹⁰The same as those defined in (4-3) above of the present claim;

n is 0, 1 or 2;

X⁹is CH₂Or O;

wherein the group of formula (2h) may be further optionally substituted at the substitutable carbon atom of the ring by a fluorine atom;

(4-5) a group of the following formula (2i), (2j) or (2 k):

wherein X¹⁰、X¹¹、X¹²And X¹³Each independently is N or CR¹¹；

Wherein X¹⁰、X¹¹、X¹²And X¹³Selected such that the 6-membered rings containing them form an aromatic heterocycle;

X¹⁴is CR¹⁵、CHR¹⁵、NR¹⁶Or O;

with the proviso that when X¹⁴Is CR¹⁵When the bond containing the dotted line in formula (2j) represents a double bond, and when X¹⁴Is CHR¹⁵、NR¹⁶Or O, the bond in formula (2j) containing the dotted line represents a single bond;

X¹⁵is NR¹⁷Or O;

R¹¹is that

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) 5-or 6-membered heteroarylmethyl, or

(e) A 4-7 membered saturated or partially unsaturated heterocyclyl, optionally substituted with 1-4 identical or different substituents selected from: c_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-7Alkylcarbonyl and C_2-7An alkoxycarbonyl group, a carbonyl group,

provided that when R is¹¹When there are more than two, each R¹¹May be the same or different;

R¹²、R¹³and R¹⁴Each independently is

(a) A hydrogen atom, or

(b) The methyl group is a group selected from the group consisting of,

wherein R is¹²And R¹⁴Or R¹³And R¹⁴May combine with the carbon atoms to which they are attached to form a bridging structure;

R¹⁵is that

(a) A phenyl group,

(b) a benzyl group, a phenyl group,

(c) 5-10 membered heteroaryl, optionally substituted with 1-2 identical or different substituents selected from fluorine atom and methoxy group,

(d) a hydroxyl group(s),

(e) phenoxy group, or

(f) A phenylamino group;

R¹⁶is that

(a) Phenyl optionally substituted with 1 to 2 identical or different substituents selected from fluorine atoms and methoxy groups,

(b) 5-or 6-membered heteroaryl, which is optionally substituted by 1 to 2 identical or different substituents selected from the group consisting of methyl, methoxy, fluorine atom, trifluoromethyl and difluoromethoxy,

(d) a 5-or 6-membered saturated or partially unsaturated carbocyclic group, or

(e) A 6-membered saturated heterocyclic group;

R¹⁷is that

(a) A pyridyl group, a carboxyl group,

(b) a 6-membered saturated heterocyclic group, or

k is 0, 1 or 2;

j¹、j²、j³and j⁴Each independently is 0 or 1;

(4-6) a group of the following formula (2 l):

(4-7) a group of the following formula (2m) or (2 n):

wherein R is¹⁸Is that

(a) Phenyl, or

(b) A benzyl group;

k¹and k²Each independently is 0 or 1;

wherein the nitrogen-containing saturated ring in formula (2m) may be optionally substituted by oxo;

with the proviso that the compound according to formula (1) is not:

。

2. a compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

R¹And R²Each independently is

(1) A hydrogen atom, and a nitrogen atom,

(2) C_1-6alkyl radicalOptionally substituted with 1-3 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, saturated or partially unsaturated C_3-7Carbocyclyl and C_1-6An alkoxy group,

(3) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy, or

(4) Amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: c optionally substituted by 1 to 3 identical or different halogen atoms_1-6Alkyl and saturated or partially unsaturated C_3-7Carbocyclyl, or

Alternatively, R¹And R²May combine together with the carbon atoms to which they are attached to form a 5-7 membered saturated or partially unsaturated carbocyclic ring.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein

M²Is that

(1) A group of any one of the following formulae (11) to (37):

wherein X^1a、X^1b、R³And R⁴As well as those defined in claim 1,

(2) 4-cyanophenylamino group, which is a general amino group,

(3) a group of the following formula (2 c'):

wherein R is⁵And R⁶Each independently is

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: c optionally substituted by 1 to 3 identical or different halogen atoms_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and C_2-7An alkyl-carbonyl group, a carboxyl group,

(e) 5-or 6-membered heteroaryl, optionally substituted by 1 to 4 identical or different substituents selected from the group consisting of halogen atoms, cyano and C_1-6The substituent of the alkyl group is substituted,

(f) 4-7 membered saturated or partially unsaturated heterocyclyl, optionally substituted by 1-4 same or different substituents selected from halogen atom, hydroxy, C_1-6Alkyl and C_1-6Substituent of alkoxy, or

(g) -C(O)NR^xR^yWherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R^xAnd R^yMay be combined together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group, an

Satisfying any one of the following conditions (X ') or (Y'):

(X') R⁵and R⁶Is cyano, 5-or 6-membered heteroaryl (wherein the heteroaryl group may optionally be substituted by 1 to 4 identical or different substituents selected from the group consisting of halogen atoms, cyano and C_1-6Alkyl substituents), 4-to 7-membered saturated or partially unsaturated heterocyclyl (wherein the heterocyclyl may optionally be substituted by 1 to 4 identical or different substituents selected from halogen atoms, hydroxy, C_1-6Alkyl and C_1-6Substituent of alkoxy) or-C (O) NR^xR^y(wherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or alternatively, R^xAnd R^yMay combine together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group); or

(Y') R⁵And R⁶May be combined together with the carbon atom to which they are attached to form a 5-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (wherein the carbocyclic and heterocyclic rings may be optionally substituted with 1-4 identical or different substituents selected from the group consisting of halogen atom, oxo, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-7An alkoxycarbonyl group),

wherein the group of formula (2c') may be further optionally substituted at the substitutable carbon atom of the ring by a fluorine atom,

(4) a group of the following formula (2d), (2e), (2f) or (2 g):

wherein R is⁸、R⁹And R¹⁰Each independently is

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) C_1-6alkyl, optionally substituted with 1-3 substituents, which may be the same or different, selected from: a halogen atom; a hydroxyl group; optionally substituted by hydroxy or C_1-6Alkoxy-substituted C_1-6An alkoxy group; optionally is covered with C_1-6Alkyl or C_1-6An alkoxy-substituted 4-7 membered saturated or partially unsaturated heterocyclyl; optionally is covered with C_1-6An alkyl-substituted 5 or 6 membered heteroaryl; and amino (wherein the amino group may be optionally substituted with 1 to 2 same or different substituents selected from the group consisting of 1 to 3 same or different substituents selected from the group consisting of halogen atom, hydroxyl group and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; optionally is covered with C_1-6An alkoxy-substituted 4-7 membered saturated heterocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7Alkylcarbonyl);

(e) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6The substituent of the alkoxy group is substituted,

(f) amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: c optionally substituted by halogen atoms_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkyl-carbonyl group, a carboxyl group,

(g) 5-or 6-membered heteroaryl, optionally substituted with 1-4 identical or different substituents selected from: halogen atom, cyano group, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-7An alkoxycarbonyl group, a carbonyl group,

(h) a 4-7 membered saturated or partially unsaturated heterocyclyl, optionally substituted with 1-4 identical or different substituents selected from: optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; c_1-6An alkoxy group; a 4-7 membered saturated or partially unsaturated heterocyclyl; optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkylcarbonyl group; and an oxo group, and a salt thereof,

(i) 4-7 membered saturated or partially unsaturated heterocyclyloxy, optionally substituted by 1-4C_1-6The substitution of the alkyl group is carried out,

(j) -C(O)NR^xR^ywherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R^xAnd R^yMay combine together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group,

(k) -C(O)OR^Zwherein R is^ZIs C_1-6Alkyl, or

(l) Vinyl optionally substituted with a 6-membered saturated heterocyclyl;

wherein R in formula (2d)⁸And R⁹Both are not both hydrogen atoms, and the group of formula (2e) may be further optionally substituted at the substitutable carbon atom of the ring by a fluorine atom, or

(5) A group of the following formula (2 h'):

wherein R is⁸、R⁹And R¹⁰The same as those defined in (4) above of the present claim.

4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein

M²Is that

(1) A group of any one of the following formulae (11), (12), (18), (26), (31), and (34):

wherein X^1a、X^1bAnd R³As well as those defined in claim 1,

(2) 4-cyanophenylamino group, which is a general amino group,

(3) a group of the following formula (2h ''):

wherein R is⁸And R⁹Is as claimed in3 are the same as those defined in 3.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein

M¹Is that

(1) Saturated or partially unsaturated C_4-12Carbocyclyl optionally substituted with 1-4 identical or different substituents selected from halogen atoms and C_1-6Alkyl radical, said C_1-6Alkyl is optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy, or

(2) A 4-12 membered saturated or partially unsaturated heterocyclic group, which is optionally substituted with 1-4 same or different substituents selected from the group consisting of a halogen atom and C_1-6Alkyl radical, said C_1-6Alkyl is optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy.

6. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein

M¹Is a group of the following formula (3):

wherein X¹⁶Is N, C or CH;

the bond comprising the dotted line is a single or double bond;

m is 0, 1,2 or 3;

R^aand R^bEach independently is

(1-1) a hydrogen atom,

(1-2) a halogen atom, or

(1-3) C_1-6Alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy; or

Alternatively, R^aAnd R^bMay be combined together with the carbon atom to which they are attached to form a 3-6 membered saturated carbocyclic ring, wherein the carbocyclic ring may optionally be substituted with 1-4 identical or different substituents selected from:

(a) a halogen atom,

(b) a hydroxyl group(s),

(c) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy, and

(d) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein

The formula (1) is formula (1'):

wherein M is^1'Is any one of the following formulas (38) to (52):

R^1'and R^2'Each independently is

(2-1) a hydrogen atom,

(2-2) a halogen atom,

(2-3) a cyano group,

(2-4) methyl, or

(2-5) methoxy group, and

M^2'is that

(1) A group of any one of the following formulae (53) to (58):

wherein R is³When more than two are present, each independently, wherein R³Is that

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) C_1-6alkyl, optionally substituted with 1-3 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, saturated or partially unsaturated C_3-7Carbocyclyl, C_1-6Alkoxy, optionally substituted by C_1-6Alkoxy-substituted 4-7 membered saturated heterocyclyl and optionally substituted by 1-2 identical or different C' s_1-6An amino group substituted with an alkyl group,

(e) C_1-6alkoxy optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of: halogen atom, hydroxy group, C_1-6Alkoxy and optionally substituted by 1 to 2 identical or different C_1-6Alkyl-substituted amino, or

(f) Amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkyl-carbonyl group, a carboxyl group,

(2) 4-cyanophenylamino, or

(3) A group of the formula (2h ' ' '):

wherein R is⁸Is that

(a) C_1-6Alkyl, optionally substituted with 1-3 substituents, which may be the same or different, selected from: a halogen atom; a hydroxyl group; optionally substituted by hydroxy or C_1-6Alkoxy-substituted C_1-6An alkoxy group; optionally is covered with C_1-6Alkyl or C_1-6An alkoxy-substituted 4-7 membered saturated or partially unsaturated heterocyclyl; optionally is covered with C_1-6An alkyl-substituted 5 or 6 membered heteroaryl; and amino (wherein the amino group may be optionally substituted with 1 to 2 same or different substituents selected from the group consisting of 1 to 3 same or different substituents selected from the group consisting of halogen atom, hydroxyl group and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; optionally is covered with C_1-6An alkoxy-substituted 4-7 membered saturated heterocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkylcarbonyl group),

(b) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6The substituent of the alkoxy group is substituted,

(c) amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: c optionally substituted by halogen atoms_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkyl-carbonyl group, a carboxyl group,

(d) 5-or 6-membered heteroaryl, optionally substituted with 1-4 identical or different substituents selected from: halogen atom, cyano group, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-7An alkoxycarbonyl group, a carbonyl group,

(e) a 4-7 membered saturated or partially unsaturated heterocyclyl, optionally substituted with 1-4 identical or different substituents selected from: optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; c_1-6An alkoxy group; a 4-7 membered saturated or partially unsaturated heterocyclyl; optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups andC_1-6c substituted by substituents of alkoxy_2-7An alkylcarbonyl group; and oxo, or

(f) 4-7 membered saturated or partially unsaturated heterocyclyloxy, optionally substituted by 1-4C_1-6Alkyl substitution.

8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein

M^1'Is a group of the following formula (38):

。

9. the compound according to 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 according to 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 according to any one of claims 7-10, or a pharmaceutically acceptable salt thereof, wherein

M^2'Is a group of any one of the following formulae (53) to (58):

wherein R is³Is a hydrogen atom, a halogen atom, a cyano group, C_1-6Alkyl radical, C_1-6Alkoxy or optionally substituted by 1 to 2 identical or different C_1-6Alkyl-substituted amino groups.

12. The compound according to any one of claims 7-10, or a pharmaceutically acceptable salt thereof, wherein

M^2'Is a group of the following formula (57) or (58):

wherein R is³Is a hydrogen atom, a halogen atom, a cyano group, C_1-6Alkyl radical, C_1-6Alkoxy or optionally substituted by 1 to 2 identical or different C_1-6Alkyl-substituted amino groups.

13. The compound according to any one of claims 7-10, or a pharmaceutically acceptable salt thereof, wherein M is^2'Is a 4-cyanophenylamino group.

14. The compound according to any one of claims 7-10, or a pharmaceutically acceptable salt thereof, wherein M is^2'Is that

(3) A group of the formula (2h ' ' '):

wherein R is⁸Is that

(a) 5-or 6-membered heteroaryl, optionally substituted by 1 to 4 identical or different substituents selected from the group consisting of halogen atoms, cyano and C_1-6Substituent of alkyl, or

(b) A 4-7 membered saturated or partially unsaturated heterocyclyl, optionally substituted with 1-4 identical or different substituents selected from: optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms,Hydroxy and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; c_1-6An alkoxy group; and oxo.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

n- (4-cyanophenyl) -2- [3- (4-methylpiperidin-1-yl) -6-oxopyridazin-1 (6H) -yl ] acetamide,

n- (1, 3-benzoxazol-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-ene) -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-benzoxazol-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-benzoxazol-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 according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, as an active ingredient.

17. A medicament for activating nav1.1, comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, as an active ingredient.

18. A medicament for treating and/or preventing central nervous system diseases, which comprises the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient.

19. A medicament for treating and/or preventing a disease in which nav1.1 is involved, which comprises a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient.

20. A medicament for treating and/or preventing a disease involving diminished nav1.1 function, which comprises a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient.

21. The medicament according to claim 19 or 20, wherein the disease in which nav1.1 is involved is a central nervous system disease.

22. The medicament according to claim 18 or 21, wherein the central nervous system disease is at least one selected from the group consisting of: febrile seizures; generalized epilepsy with febrile seizure adjunctive symptoms; epilepsy (in particular, focal epilepsy, generalized epilepsy); epileptic syndromes (such as Dravet syndrome; intractable childhood epilepsy with generalized tonic clonic seizures; epilepsy with myoclonic-dystonic seizures; wester syndrome; Lennox-Gastaut syndrome; infantile spasms; severe infantile multifocal epilepsy; critical severe myoclonic epilepsy; benign familial neonatal-infantile epileptic seizures); schizophrenia; autistic spectrum disorders; and attention deficit with hyperactivity disorder.

23. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment and/or prevention of a disease in which nav1.1 is involved.

24. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of a disease in which nav1.1 is implicated.

25. A method for the treatment and/or prevention of a disease in which nav1.1 is implicated, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

26. A combination comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and one or more agents selected from agents classified as therapeutic agents for antiepileptics, antidepressants, anti-parkinson's disease agents, anti-schizophrenia agents or ADHD.

27. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or medicament according to any one of claims 16 to 22 for use in the treatment and/or prevention of a central nervous system disorder, in combination with one or more drugs selected from the group of therapeutic agents classified as antiepileptics, antidepressants, anti-parkinson's disease drugs, anti-schizophrenia drugs or ADHD.

Technical Field

The present invention relates to a pyridazinone derivative or a pharmaceutically acceptable salt thereof which is useful as an agent for the treatment and/or prevention of diseases involving sodium channels (particularly, Nav1.1) and various central nervous system diseases, and a medicament comprising the same as an active ingredient.

Background

Nav1.1 is one of the voltage-gated sodium channels (VGSC) and is expressed in e.g. parvalbumin (palvalbmin) -positive GABA neurons (PV-GABA neurons). It is known that Nav1.1 is important for the function of neuronal firing in neurons.

It has been proposed that patients suffering from central nervous system diseases such as schizophrenia, Autism Spectrum Disorder (ASD), and Attention Deficit Hyperactivity Disorder (ADHD) have dysfunction in GABA-ergic neurons expressing nav1.1 (non-patent documents 1 and 2).

It has also been reported that heterozygous loss-of-function mutations in SCN1A gene lead to epilepsy syndromes such as Dravet syndrome (severe myoclonic epilepsy in infancy) and generalized epilepsy with febrile seizure adjunctive symptoms (GEFS +) (non-patent document 1).

Dravet syndrome occurs in infancy at less than 1 year of age and it is a severe epileptic encephalopathy in children, which causes, for example, various epileptic seizures such as febrile seizures and status epilepticus. As a first-line drug, valproic acid has been used in pharmacotherapy of Dravet syndrome, but it is less effective for epileptic seizures. As second line drugs, clobazam and stiripentol have been used, but they are less effective for epileptic seizures. Stiripentol is only available in combination therapy with valproic acid or clobazam, which limits the number of patients receiving the drug.

Thus, drugs that activate Nav1.1 function are expected to improve diseases such as schizophrenia, ASD, ADHD and epilepsy, and their associated pathological conditions such as cognitive dysfunction and epileptic seizures, as well as to treat a variety of central nervous system disorders.

N, N' - (1, 3-phenylene) bis (2-methylbenzamide) (non-patent document 3) and PF-05661014 (non-patent document 4) are known as exemplary compounds for regulating Nav1.1 function, but these compounds are different from the compounds of the present invention in their chemical structures.

Nav1.5 (which is another subtype of voltage-dependent sodium channel) is expressed predominantly in the heart, and Nav1.5 is known to promote the formation of PR intervals, QRS widths, and QT intervals in electrocardiograms, and to be involved in electrical conduction between the atria and ventricles, as well as contraction and relaxation of the ventricular myocardium. It is also known that antiarrhythmic drugs with inhibitory effect of Nav1.5 prolong PR interval and QRS width in electrocardiograms. Thus, it is believed that activation of Nav1.5 may affect the PR interval, QRS width and QT interval in the electrocardiogram, electrical conduction between the atria and ventricles, and contraction and relaxation of the ventricular myocardium.

CITATION LIST

Non-patent document

[ Nonpatent document 1] Trends in pharmaceutical Sciences 2014, 35, 113.

[ non-patent document 2] curr. med. chem.2015, 22, 1850.

[ non-patent document 3] ACS Chemical Neuroscience 2015, 6, 1302.

[ non-patent document 4] British Journal of Pharmacology 2015, 172, 4905.

Summary of The Invention

Problems to be solved by the invention

One of the problems to be solved by the present invention is to provide a pyridazinone derivative and/or a pharmaceutically acceptable salt thereof which is useful as an agent for the treatment and/or prevention of diseases involving nav1.1 and various central nervous system diseases, and an agent comprising the same as an active ingredient.

Means for solving the problems

The present inventors have extensively studied to find that a compound of the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter, referred to as "the present compound") has an effective activating effect of Nav1.1, and that it can be a drug effective for the treatment and/or prevention of diseases in which Nav1.1 is involved and various central nervous system diseases, and thus, they have completed the present invention.

Thus, the invention is described as follows:

[1] a compound according to formula (1) or a pharmaceutically acceptable salt thereof:

wherein

M¹Is that

(1-1) saturated or partially unsaturated C_4-12Carbocyclyl, wherein said carbocyclyl may be optionally substituted with 1 to 4 substituents which may be the same or different, selected from the group consisting of:

(a) a halogen atom, and

(b) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atomsHydroxy and C_1-6The substituent of the alkoxy group is substituted,

(1-2) a 4-12 membered saturated or partially unsaturated heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-4 same or different substituents selected from the group consisting of:

(a) a halogen atom,

(b) a hydroxyl group(s),

(d) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy, and

(e) amino-carbonyl optionally substituted by 1 to 2 identical or different C_1-6Alkyl substitution, wherein said C_1-6Alkyl groups may optionally be substituted with 1 to 3 identical or different halogen atoms,

with the proviso that said heterocyclyl is not morpholinyl,

(1-4) an amino group, wherein the amino group may be optionally substituted with 1 to 2 same or different substituents selected from the group consisting of:

(a) C_1-6alkyl, which is optionally substituted by 1 to 3 identical or different halogen atoms,

(b) C_3-10cycloalkyl optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, C_1-6Alkyl and C_3-6Substituent substitution of cycloalkyl, and

(c) C_3-10cycloalkyl-C_1-4Alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, C_1-6Alkyl and C_3-6The substituent of the naphthenic base is substituted,

(1-5) 6-methylpyridin-3-yl or 6-trifluoromethylpyridin-3-yl,

(1-6) 4-chlorothien-2-yl, 5-methylthiophene-2-yl or 3-cyanothien-2-yl, with the proviso that when M is¹When it is 5-methylthiophen-2-yl, M²Is not a group represented by the following formula (4-2), or

(1-7) a 4-methylphenoxy group,

R¹and R²Each independently is

(2-1) a hydrogen atom,

(2-2) a halogen atom,

(2-3) a cyano group,

(2-4) C_1-6alkyl radical, wherein said C_1-6Alkyl groups may be optionally substituted with 1 to 3 substituents which may be the same or different, selected from:

(a) a halogen atom,

(b) a hydroxyl group(s),

(d) C_1-6alkoxy, and

(2-6) C_2-6alkenyl, which is optionally substituted by 1 to 4 identical or different halogen atoms,

(2-7) C_1-6alkoxy optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of: halogen atom, hydroxy group, saturated or partially unsaturated C_3-7Carbocyclyl and C_1-6Alkoxy radical, or

(2-8) amino optionally substituted by 1-2 of the same orDifferent substituents are substituted, said substituents being selected from: c optionally substituted by 1 to 3 identical or different halogen atoms_1-6Alkyl and saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R¹And R²Can be combined with the carbon atoms to which they are attached to form

(3-1) a 5-7 membered saturated or partially unsaturated carbocyclic ring, wherein said carbocyclic ring may be optionally substituted with 1-4 identical or different substituents selected from:

(a) a halogen atom,

(b) a hydroxyl group(s),

(c) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy, and

(d) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy, or

(3-2) a 5-7 membered saturated or partially unsaturated heterocyclic ring, wherein the heterocyclic ring may be optionally substituted with 1-4 same or different substituents selected from (a) to (d) in (3-1) above in this clause;

M²is that

(4-1) a group of the following formula (2a) or (2 b):

wherein X^1a、X^1b、X^1c、X⁵、X⁶、X⁷And X⁸Each independently is N or CR³；

X²、X³And X⁴Each independently is CR³O, S, N or NR⁴；

A¹And A²Each independently is N or C;

wherein X^1a、X^1b、X^1c、X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸、A¹And A²Selected such that the ring containing them forms a 9 or 10 membered bicyclic aromatic heterocycle;

R³is that

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) a hydroxyl group(s),

(e) C_1-6alkyl, optionally substituted with 1-3 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, saturated or partially unsaturated C_3-7Carbocyclyl, C_1-6Alkoxy, optionally substituted by C_1-6A 4-7 membered saturated heterocyclic group substituted with alkyl, and C optionally 1-2 same or different_1-6An amino group substituted with an alkyl group,

(h) amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkyl-carbonyl group, a carboxyl group,

(k) -C(O)NR^xR^yWherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R^xAnd R^yMay be combined together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group;

R⁴is that

(a) A hydrogen atom, and a nitrogen atom,

(b) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent of alkoxy, or

(c) Saturated or partially unsaturated C_3-7Carbocyclyl, optionally substituted by 1 to 4 identical or different atoms selected from halogen, hydroxy, C_1-6Alkyl and C_1-6The substituent of the alkoxy group is substituted,

provided that when R is³And R⁴When there are more than two, each R³And R⁴Which may be the same or different and may,

(4-2) a group of the following formula (2 c):

wherein R is⁵、R⁶And R⁷Each independently is

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(f) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6The substituent of the alkoxy group is substituted,

(j) -C(O)NR^xR^ywherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R^xAnd R^yMay combine together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group,

(k) C_2-7alkylcarbonyl, or

(l) C_2-7Alkoxycarbonyl group, and

satisfying any one of the following conditions (X) or (Y):

(X) R⁵、R⁶and R⁷Is cyano, 5-or 6-membered heteroaryl (wherein the heteroaryl group may optionally be substituted by 1 to 4 identical or different substituents selected from the group consisting of halogen atoms, cyano and C_1-6Alkyl substituted with substituents), 4-7 membered saturatedOr a partially unsaturated heterocyclic group (wherein the heterocyclic group may be optionally substituted by 1 to 4 same or different groups selected from halogen atom, hydroxyl group, C_1-6Alkyl and C_1-6Substituent of alkoxy) or-C (O) NR^xR^y(wherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or alternatively, R^xAnd R^yMay combine together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group); or

(Y) R⁵And R⁶May be combined together with the carbon atom to which they are attached to form a 5-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (wherein the carbocyclic and heterocyclic rings may be optionally substituted with 1-4 identical or different substituents selected from the group consisting of halogen atom, oxo, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-7An alkoxycarbonyl group),

wherein the group of formula (2c) may be further optionally substituted at the substitutable carbon atom of the ring by a fluorine atom,

(4-3) a group of the following formula (2d), (2e), (2f) or (2 g):

wherein R is⁸、R⁹And R¹⁰Each independently is

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) C_1-6alkyl, optionally substituted with 1-3 substituents, which may be the same or different, selected from: a halogen atom; a hydroxyl group; saturated or partially unsaturated C_3-7A carbocyclic group; optionally substituted by hydroxy or C_1-6Alkoxy-substituted C_1-6An alkoxy group; optionally is covered with C_1-6Alkoxy or C_1-6An alkyl-substituted 4-7 membered saturated or partially unsaturated heterocyclyl; optionally is covered with C_1-6Alkyl-substituted 5 or 6 membered heteroAn aryl group; and amino (wherein the amino group may be optionally substituted with 1 to 2 same or different substituents selected from the group consisting of 1 to 3 same or different substituents selected from the group consisting of halogen atom, hydroxyl group and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; optionally is covered with C_1-6An alkoxy-substituted 4-7 membered saturated heterocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7Alkylcarbonyl);

(g) amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkyl-carbonyl group, a carboxyl group,

(i) a 4-7 membered saturated or partially unsaturated heterocyclyl, optionally substituted with 1-4 identical or different substituents selected from: optionally, optionallyIs substituted by 1 to 3 same or different groups selected from halogen atoms, hydroxy groups and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; c_1-6An alkoxy group; a 4-7 membered saturated or partially unsaturated heterocyclyl; optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkylcarbonyl group; and an oxo group, and a salt thereof,

(j) optionally substituted by 1-4C_1-6An alkyl-substituted 4-7 membered saturated or partially unsaturated heterocyclyloxy,

(k) -C(O)NR^xR^ywherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R^xAnd R^yMay combine with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group,

(l) -C(O)OR^Zwherein R is^ZIs C_1-6Alkyl, or

(m) vinyl optionally substituted with a 6-membered saturated heterocyclyl;

wherein R in formula (2d)⁸And R⁹Both are not simultaneously hydrogen atoms, and the group of formula (2e) may be further optionally substituted at the substitutable carbon atom of the ring by a fluorine atom,

(4-4) a group of the following formula (2 h):

wherein R is⁸、R⁹And R¹⁰The same as those defined in (4-3) above;

n is 0, 1 or 2;

X⁹is CH₂Or O;

wherein the group of formula (2h) may be further optionally substituted at the substitutable carbon atom of the ring by a fluorine atom,

(4-5) a group of the following formula (2i), (2j) or (2 k):

wherein X¹⁰、X¹¹、X¹²And X¹³Each independently is N or CR¹¹；

Wherein X¹⁰、X¹¹、X¹²And X¹³Selected such that the 6-membered rings containing them form an aromatic heterocycle;

X¹⁴is CR¹⁵、CHR¹⁵、NR¹⁶Or O;

X¹⁵is NR¹⁷Or O;

R¹¹is that

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) 5-or 6-membered heteroarylmethyl, or

provided that when R is¹¹When there are more than two, each R¹¹May be the same or different;

R¹²、R¹³and R¹⁴Each independently is

(a) A hydrogen atom, or

(b) The methyl group is a group selected from the group consisting of,

wherein R is¹²And R¹⁴Or R¹³And R¹⁴Can be combined together with the carbon atoms to which they are attached to form a bridging structure;

R¹⁵is that

(a) A phenyl group,

(b) a benzyl group, a phenyl group,

(c) 5-10 membered heteroaryl, optionally substituted with 1-2 identical or different substituents selected from fluorine atom and methoxy group,

(d) a hydroxyl group(s),

(e) phenoxy group, or

(f) A phenylamino group;

R¹⁶is that

(a) Phenyl optionally substituted with 1 to 2 identical or different substituents selected from fluorine atoms and methoxy groups,

(d) a 5-or 6-membered saturated or partially unsaturated carbocyclic group, or

(e) A 6-membered saturated heterocyclic group,

R¹⁷is that

(a) A pyridyl group, a carboxyl group,

(b) a 6-membered saturated heterocyclic group, or

k is 0, 1 or 2;

j¹、j²、j³and j⁴Each independently being 0 or 1,

(4-6) a group of the following formula (2 l):

(4-7) a group of the following formula (2m) or (2 n):

wherein R is¹⁸Is that

(a) Phenyl, or

(b) A benzyl group;

k¹and k²Each independently is 0 or 1;

wherein the nitrogen-containing saturated ring in formula (2m) may be optionally substituted by oxo,

with the proviso that the compound according to formula (1) is not:

[2] the compound according to [1] or a pharmaceutically acceptable salt thereof, wherein

R¹And R²Each independently is

(1) A hydrogen atom, and a nitrogen atom,

(2) C_1-6alkyl, optionally substituted with 1-3 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, saturated or partially unsaturated C_3-7Carbocyclyl and C_1-6An alkoxy group,

(3) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy, or

Alternatively, R¹And R²May combine together with the carbon atoms to which they are attached to form a 5-7 membered saturated or partially unsaturated carbocyclic ring.

[3] The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein

M²Is that

(1) A group of any one of the following formulae (11) to (37):

wherein X^1a、X^1b、R³And R⁴To above [1]Those defined in (1) are the same as,

(2) 4-cyanophenylamino group, which is a general amino group,

(3) a group of the following formula (2 c'):

wherein R is⁵And R⁶Each independently is

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(g) -C(O)NR^xR^yWherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R^xAnd R^yMay be combined together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group, an

Satisfying any one of the following conditions (X ') or (Y'):

wherein the group of formula (2c') may be further optionally substituted at the substitutable carbon atom of the ring by a fluorine atom,

(4) a group of the following formula (2d), (2e), (2f) or (2 g):

wherein R is⁸、R⁹And R¹⁰Each independently is

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) C_1-6alkyl, optionally substituted with 1-3 substituents, which may be the same or different, selected from: a halogen atom; a hydroxyl group; optionally substituted by hydroxy or C_1-6Alkoxy-substituted C_1-6An alkoxy group; optionally is covered with C_1-6Alkyl or C_1-6An alkoxy-substituted 4-7 membered saturated or partially unsaturated heterocyclyl; optionally is covered with C_1-6An alkyl-substituted 5 or 6 membered heteroaryl; and an amino group, wherein the amino group may be optionally substituted with 1 to 2 substituents which may be the same or different, selected from: optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; optionally is covered with C_1-6An alkoxy-substituted 4-7 membered saturated heterocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkyl-carbonyl group, a carboxyl group,

(e) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6The substituent of the alkoxy group is substituted,

(i) 4-7 membered saturated or partially unsaturated heterocyclyloxy, optionally substituted by 1-4C_1-6The substitution of the alkyl group is carried out,

(j) -C(O)NR^xR^ywherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R^xAnd R^yMay combine together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group,

(k) -C(O)OR^Zwherein R is^ZIs C_1-6Alkyl, or

(l) Vinyl optionally substituted with a 6-membered saturated heterocyclyl;

wherein R of formula (2d)⁸And R⁹Both are not both hydrogen atoms, and the group of formula (2e) may be further optionally substituted at the substitutable carbon atom of the ring by a fluorine atom, or

(5) A group of the following formula (2 h'):

wherein R is⁸、R⁹And R¹⁰The same as those defined in (4) above in the present clause.

[4] A compound according to [3] or a pharmaceutically acceptable salt thereof, wherein

M²Is that

(1) A group of any one of the following formulae (11), (12), (18), (26), (31), and (34):

wherein X^1a、X^1bAnd R³To above [1]Those defined in (1) are the same as,

(2) 4-cyanophenylamino group, which is a general amino group,

(3) a group of the following formula (2h ''):

wherein R is⁸And R⁹To above [3]Those defined in (1) are the same.

[5] The compound according to any one of [1] to [4], or a pharmaceutically acceptable salt thereof, wherein

M¹Is that

[6] The compound according to [5] or a pharmaceutically acceptable salt thereof, wherein

M¹Is a group of the following formula (3):

wherein X¹⁶Is N, C or CH;

the bond comprising the dotted line represents a single or double bond;

m is 0, 1,2 or 3;

R^aand R^bEach independently is

(1-1) a hydrogen atom,

(1-2) a halogen atom, or

(1-3) C_1-6Alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy; or

(a) a halogen atom,

(b) a hydroxyl group(s),

(c) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy, and

(d) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy.

[7] The compound according to any one of [1] to [6], or a pharmaceutically acceptable salt thereof, wherein

The formula (1) is formula (1'):

wherein M is^1'Is a group of any one of the following formulae (38) to (52):

R^1'and R^2'Each independently is

(2-1) a hydrogen atom,

(2-2) a halogen atom,

(2-3) a cyano group,

(2-4) methyl, or

(2-5) methoxy group, and

M^2'is that

(1) A group of any one of the following formulae (53) to (58):

wherein R is³When more than two are present, each independently, wherein R³Is that

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(2) 4-cyanophenylamino, or

(3) A group of the formula (2h ' ' '):

wherein R is⁸Is that

(a) C_1-6Alkyl, optionally substituted with 1-3 substituents, which may be the same or different, selected from: a halogen atom; a hydroxyl group; optionally substituted by hydroxy or C_1-6Alkoxy-substituted C_1-6An alkoxy group; optionally is covered with C_1-6Alkyl or C_1-6An alkoxy-substituted 4-7 membered saturated or partially unsaturated heterocyclyl; optionally is covered with C_1-6An alkyl-substituted 5 or 6 membered heteroaryl; and an amino group, wherein the amino group may be optionally substituted with 1 to 2 substituents which may be the same or different, selected from: optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; optionally is covered with C_1-6An alkoxy-substituted 4-7 membered saturated heterocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkyl-carbonyl group, a carboxyl group,

(b) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6The substituent of the alkoxy group is substituted,

(e) a 4-7 membered saturated or partially unsaturated heterocyclyl, optionally substituted with 1-4 identical or different substituents selected from: optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; c_1-6An alkoxy group; a 4-7 membered saturated or partially unsaturated heterocyclyl; optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkylcarbonyl group; and oxo; or

(f) 4-7 membered saturated or partially unsaturated heterocyclyloxy, optionally substituted by 1-4C_1-6Alkyl substitution.

[8] The compound according to [7] or a pharmaceutically acceptable salt thereof, wherein

M^1'Is a group of the following formula (38):

。

[9] the compound according to [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 according to [7] or a pharmaceutically acceptable salt thereof, wherein

M^1'Is a group of the following formula (48), (50) or (51):

。

[11] the compound according to any one of [7] to [10], or a pharmaceutically acceptable salt thereof, wherein

M^2'Is a group of any one of the following formulae (53) to (58):

wherein R is³Is a hydrogen atom, a halogen atom, a cyano group, C_1-6Alkyl radical, C_1-6Alkoxy or optionally substituted by 1 to 2 identical or different C_1-6Alkyl-substituted amino groups.

[12] The compound according to any one of [7] to [10], or a pharmaceutically acceptable salt thereof, wherein

M^2'Is the following formula (57) or (58):

wherein R is³Is a hydrogen atom, a halogen atom, a cyano group, C_1-6Alkyl radical, C_1-6Alkoxy or optionally substituted by 1 to 2 identical or different C_1-6Alkyl-substituted amino groups.

[13] The compound according to any one of [7] to [10], or a pharmaceutically acceptable salt thereof, wherein

M^2'Is a 4-cyanophenylamino group.

[14] The compound according to any one of [7] to [10], or a pharmaceutically acceptable salt thereof, wherein

M^2'Is that

(3) A group of the formula (2h ' ' '):

wherein R is⁸Is that

(a) 5-or 6-membered heteroaryl, optionally substituted by 1 to 4 identical or different substituents selected from the group consisting of halogen atoms, cyano and C_1-6Substituent of alkyl, or

(b) A 4-7 membered saturated or partially unsaturated heterocyclyl, optionally substituted with 1-4 identical or different substituents selected from: optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6Alkoxy radicalC substituted by a substituent of_1-6An alkyl group; c_1-6An alkoxy group; and oxo.

[15] A compound according to [1], or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

n- (4-cyanophenyl) -2- [3- (4-methylpiperidin-1-yl) -6-oxopyridazin-1 (6H) -yl ] acetamide (example 1),

n- (1, 3-Benzooxazol-5-yl) -2- [3- (4-methylpiperidin-1-yl) -6-oxopyridazin-1 (6H) -yl ] acetamide (example 50),

2- [3- (6-Azaspiro [3.4] oct-6-yl) -6-oxopyridazin-1 (6H) -yl ] -N- (quinazolin-7-yl) acetamide (example 236),

n- [2- (dimethylamino) -1, 3-benzooxazol-5-yl ] -2- [3- (4-methylcyclohex-1-ene) -6-oxopyridazin-1 (6H) -yl ] acetamide (example 244),

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 (example 428),

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 (example 429),

n- (1, 3-Benzooxazol-5-yl) -2- [3- (4, 4-dimethylcyclohex-1-en-1-yl) -6-oxopyridazin-1 (6H) -yl ] acetamide (example 445),

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 (example 512),

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 (example 526),

n- (1, 3-Benzooxazol-5-yl) -2- [3- (4-methylcyclohex-1-en-1-yl) -6-oxopyridazin-1 (6H) -yl ] acetamide (example 531),

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 (example 537),

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 (example 538),

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 (example 539), 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 (example 540).

[16] A pharmaceutical composition comprising a compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof as an active ingredient.

[17] A medicament for activating Nav1.1, comprising a compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof as an active ingredient.

[18] A medicament for treating and/or preventing a central nervous system disease, which comprises the compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof as an active ingredient.

[19] A medicament for treating and/or preventing a disease in which Nav1.1 is involved, which comprises a compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof as an active ingredient.

[20] A medicament for treating and/or preventing a disease involving a decrease in Nav1.1 function, which comprises a compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof as an active ingredient.

[21] The medicament according to claim 19 or 20, wherein the disease in which nav1.1 is implicated is a disease of the central nervous system.

[22] The medicament according to [18] or [21], wherein the central nervous system disease is at least one selected from the group consisting of: febrile Seizures (FS); generalized epilepsy with febrile seizure adjunctive disorder (GEFS +); epilepsy (in particular, focal epilepsy, generalized epilepsy); epilepsy syndromes (such as Dravet syndrome, refractory childhood epilepsy with generalized tonic clonic seizures (ICE-GTC), epilepsy with myoclonic-dystonic seizures (Doose syndrome), wester syndrome, Lennox-Gastaut syndrome (Rasmussen's encephalitis and Lennox-Gastaut syndrome), infantile spasms, severe infantile multifocal epilepsy (SIMFE), critical Severe Myoclonic Epilepsy (SMEB), and benign familial neonatal-infant seizures (BFNIS)); schizophrenia; autism Spectrum Disorder (ASD); and Attention Deficit Hyperactivity Disorder (ADHD).

[23] Use of a compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prevention of a disease in which Nav1.1 is involved.

[24] A compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of a disease in which Nav1.1 is involved.

[25] A method for treating and/or preventing a disease in which Nav1.1 is involved, which comprises administering a therapeutically effective amount of a compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[26] A combination medicament comprising a compound according to any one of [1] to [15], or a pharmaceutically acceptable salt thereof, and one or more medicaments selected from medicaments classified as anti-epileptic agents, anti-depressant agents, anti-parkinson agents, anti-schizophrenia agents or ADHD therapeutic agents.

[27] A compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or medicament according to any one of [16] to [22], for use in the treatment and/or prevention of a central nervous system disease, which is for use in combination with one or more medicaments selected from medicaments classified as anti-epileptic, anti-depressant, anti-Parkinson's disease, anti-schizophrenia or ADHD therapeutics.

Effects of the invention

The compounds of the invention can have a significant effect on the activation of Nav1.1. Furthermore, in one embodiment, the compounds of the invention may have selective activity against Nav1.1 as compared to the activity against a different subset of voltage-dependent sodium channels, such as Nav1.5. Thus, it is expected that the compounds of the present invention may be useful as drugs for the treatment and/or prevention of diseases in which Nav1.1 is involved and various central nervous system diseases.

Description of the embodiments

Hereinafter, the present invention is explained in detail. The specification canThe number of carbon atoms can be indicated in the definition of "substituent", e.g., "C_1-6". Specifically, the term "C_1-6Alkyl "is synonymous with alkyl having 1-6 carbon atoms.

Examples of the term "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The term "C_1-6Alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. It is preferably "C_1-4Alkyl groups ". The term "C_1-6Examples of the alkyl group "include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1-dimethylbutyl, 2-dimethylbutyl, 3-dimethylbutyl and 2-ethylbutyl.

The term "C_2-7Alkylcarbonyl "means" C "as defined above_1-6Alkyl "substituted carbonyl. For example, it is preferably "C_2-4An alkylcarbonyl group ". The term "C_2-7Examples of alkylcarbonyl "include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl and isopropylcarbonyl.

The term "C_2-6Alkenyl "means a straight or branched chain unsaturated hydrocarbon group having 1-3 carbon-carbon double bonds and 2-6 carbon atoms. It is preferably "C_2-4Alkenyl ". The term "C_2-6Examples of alkenyl groups "include ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term "saturated or partially unsaturated C_3-7Carbocyclyl "refers to a 3-7 membered monocyclic or polycyclic saturated or partially unsaturated hydrocarbon group. It is preferably "saturated or partially unsaturated C_5-7Carbocyclyl ". The term "saturated or partially unsaturated C_3-7Examples of carbocyclyl "include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl.

The term "saturated or partially unsaturated C_4-12Carbocyclyl "refers to a 4-12 membered monocyclic or polycyclic saturated or partially unsaturated hydrocarbon group. It is preferably "saturated or partially unsaturated C_4-6Carbocyclyl ". Except as above "saturated or partially unsaturated C_3-7Examples of carbocyclyl "are those listed above, the term" saturated or partially unsaturated C_4-12Examples of carbocyclyl "include cyclooctyl, cyclodecyl and cyclododecyl.

Above "saturated or partially unsaturated C_4-12Carbocyclyl "includes saturated or partially unsaturated bicyclic groups and saturated or partially unsaturated spiro groups. Examples include groups of the formula:

the term "5-or 6-membered saturated or partially unsaturated carbocyclyl" refers to a 5-or 6-membered monocyclic saturated or partially unsaturated hydrocarbon group. Examples of the term "5-or 6-membered saturated or partially unsaturated carbocyclic group" include cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl.

The term "5-7 membered saturated or partially unsaturated carbocyclic ring" refers to monocyclic or bicyclic saturated or partially unsaturated hydrocarbon groups having 5-7 carbon atoms and includes structures having partially unsaturated bonds, structures having bridged structures, and structures forming spiro rings. Examples of the term "5-to 7-membered saturated or partially unsaturated carbocyclic ring" include cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene, and cycloheptadiene.

The term "3-6 membered saturated carbocyclic ring" refers to a saturated hydrocarbon ring having 3-6 carbon atoms and includes structures that form a spiro ring. Examples of the term "3-6 membered saturated carbocyclic ring" include cyclopropane, cyclobutane, cyclopentane and cyclohexane.

The term "C_1-6Of alkoxy "C_1-6Alkyl "moieties with" C "above_1-6Alkyl "is synonymous. The term is preferably "C_1-4Alkoxy ". The term "C_1-6Examples of "alkoxy" include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxyButoxy and tert-butoxy.

The term "C_2-7Alkoxycarbonyl "means a group" C "as defined above_1-6Alkoxy "substituted carbonyl. For example, it is preferably "C_2-5Alkoxycarbonyl groups ". The term "C_2-7Examples of the alkoxycarbonyl group "include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group and a tert-butoxycarbonyl group.

The term "5-or 6-membered heteroaryl" refers to a 5-or 6-membered aromatic group comprising one or more (e.g., 1-4) identical or different heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms, and which may be optionally substituted by oxo. Examples of the term "5-or 6-membered heteroaryl" include groups of the formula:

。

it is preferably imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; and it is more preferably imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl.

The term "5-10 membered heteroaryl" includes, for example, 5-10 membered monocyclic or 9-or 10-membered bicyclic aromatic heterocyclic groups. The "5-to 10-membered heteroaryl group" contains one or more (e.g., 1 to 4) same or different heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, and may be optionally substituted by oxo. Bicyclic heteroaryls also include fused structures of the above monocyclic heteroaryls with aromatic rings (such as benzene and pyridine) or non-aromatic rings (such as cyclohexane and piperidine). Examples of the term "5-to 10-membered heteroaryl" include groups of the formula:

。

in the present specification, a bond through a ring means that a "group" having the bond is attached to the group at a substitutable position of the ring. For example, heteroaryl groups of the formula:

represents a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group.

The term "4-7 membered saturated or partially unsaturated heterocyclic group" includes, for example, a 4-7 membered monocyclic or polycyclic saturated or partially unsaturated heterocyclic group containing 1 to 2 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. It is preferably a "5-7 membered saturated or partially unsaturated heterocyclyl". Examples of the term "5-7 membered saturated or partially unsaturated heterocyclic group" include pyranyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, dihydropyrrolyl, dihydrofuranyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, dioxanyl, azepanyl, morpholinyl, and thiomorpholinyl. Examples of the term "4-7 membered saturated or partially unsaturated heterocyclic group" include azetidinyl and oxetanyl, in addition to those listed as examples of the above "5-7 membered saturated or partially unsaturated heterocyclic group". Among them, examples of the term "4-7 membered saturated heterocyclic group" include azetidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, piperazinyl, dioxanyl, azepanyl, morpholinyl, and thiomorpholinyl. Each group may be attached to the group via any of the carbon and nitrogen atoms that make up the ring.

The term "4-12 membered saturated or partially unsaturated heterocyclic group" includes, for example, a 4-12 membered monocyclic or polycyclic saturated or partially unsaturated heterocyclic group containing 1 to 3 identical or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. It is preferably a 4-to 10-membered saturated or partially unsaturated heterocyclyl group. Examples of the groups include azocinyl, 1, 4-oxaazacinyl, 1, 5-oxaazacinyl, 1, 4-diazacyclocinyl, 1, 5-diazacyclocinyl, and 1, 5-diazacyclocinyl, in addition to those listed as examples of the above "4-to 7-membered saturated or partially unsaturated heterocyclic group". Each group may be attached to the group via any of the carbon and nitrogen atoms that make up the ring.

The term "4-7 membered saturated or partially unsaturated heterocyclyl" or "4-12 membered saturated or partially unsaturated heterocyclyl" includes saturated or partially unsaturated bicyclic groups and saturated or partially unsaturated spiro groups. Examples of the term "4-7 membered saturated or partially unsaturated heterocyclic group" include groups of the formula:

。

examples of the term "4-12 membered saturated or partially unsaturated heterocyclic group" include groups of the formula:

the term "nitrogen-containing saturated ring" includes saturated heterocyclic rings containing one or more nitrogen atoms as a ring component. Examples of the term "nitrogen-containing saturated ring" include azetidine, pyrrolidine and piperidine.

The term "9-or 10-membered bicyclic aromatic heterocycle" refers to a bicyclic aromatic heterocycle: which consists of 9 or 10 atoms and comprises 1 to 3 identical or different heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms, and which may optionally be substituted by oxo. The oxygen atoms and sulfur atoms of the carbonyl group, sulfinyl group, sulfonyl group and thiocarbonyl group constituting the bicyclic aromatic heterocycle are not counted as ring members (i.e., ring size) of the 9-or 10-membered ring, nor are the heteroatoms constituting the ring. Examples of the term "9-or 10-membered bicyclic aromatic heterocycle" include quinoline, isoquinoline, naphthyridine, quinazoline, quinoxaline, benzofuran, benzothiophene, indole, benzoxazole, benzisoxazole, benzimidazole, benzooxadiazole, benzothiadiazole, indolizine, benzofuran, indazole, pyrazolopyridine, imidazopyridine, triazolopyridine, imidazopyrimidine, imidazopyridazine, thiazolopyridine, pyrazolopyrimidine, triazolopyridazine, and furopyridine.

The term "3-6 membered saturated heterocyclic ring" refers to a monocyclic or bicyclic saturated heterocyclic ring consisting of 3 to 6 atoms and containing 1 or 2 identical or different heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms. Saturated heterocycles include structures that form spiro rings. The saturated heterocycle may be optionally substituted by oxo, and may contain 1 or 2 carbonyl, thiocarbonyl, sulfinyl or sulfonyl groups. The oxygen and sulfur atoms of the carbonyl, thiocarbonyl, sulfinyl and sulfonyl groups are not counted as ring members (i.e., ring size) of the 3-6 membered ring, nor are the heteroatoms making up the ring. Preferably, "3-6 membered saturated heterocyclic ring" includes "5 or 6 membered saturated heterocyclic ring". Examples of "5 or 6 membered saturated heterocyclic" include, but are not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran and tetrahydropyran. Examples of the "3-6 membered saturated heterocyclic ring" include aziridine and azetidine, in addition to those listed as examples of the "5-or 6-membered saturated heterocyclic ring" above. Examples of "6-membered saturated heterocyclic ring" include piperidine, morpholine and tetrahydropyran.

The term "4-7 membered saturated or partially unsaturated heterocyclyloxy" refers to an oxy group substituted with the above "4-7 membered saturated or partially unsaturated heterocyclyl".

Comprising a 5-7 membered saturated or partially unsaturated carbocyclic ring (wherein the carbocyclic ring is represented by R¹And R²Combinations of (b) together with the carbon atom to which they are attached) includeA ring of the formula:

。

comprising a 5-7 membered saturated or partially unsaturated heterocyclic ring (wherein the heterocyclic ring is represented by R¹And R²Combinations of (a) and the carbon atom to which they are attached together) include a ring of the formula:

comprising a 5-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring (wherein the carbocyclic and heterocyclic rings are represented by R⁵And R⁶Combinations of (a) and the carbon atom to which they are attached) include groups of the formula:

comprising a 3-6 membered saturated carbocyclic ring or a 3-6 membered saturated heterocyclic ring (wherein the carbocyclic and heterocyclic rings are represented by R^aAnd R^bCombinations of (b) together with the carbon atom to which they are attached) include groups of the formula:

examples of the group of formula (2a) or (2b) containing a 9-or 10-membered bicyclic aromatic heterocycle include groups of the formula:

。

the compounds of the invention in the formula (1)In, below is shown R¹、R²、M¹And M²But the technical scope of the present invention should not be limited to the scope of the following exemplary embodiments. The preferred embodiments shown below may optionally be combined with each other as long as they are not contradictory.

R¹And R²Preferably each of which is independently comprised of,

(1) a hydrogen atom, and a nitrogen atom,

(3) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy, or

(4) Amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: c optionally substituted by 1 to 3 identical or different halogen atoms_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and C_2-7An alkylcarbonyl group.

R¹And R²Another preferred embodiment of (a) includes the case: they combine together with the carbon atom to which they are attached to form a 5-or 7-membered saturated or partially unsaturated carbocyclic ring.

M¹Preferably comprises

(1) Saturated or partially unsaturated C_4-12Carbocyclyl optionally substituted with 1-4 identical or different substituents selected from halogen atoms and C_1-6Alkyl, or

M¹Further preferred are groups of the following formula (3'):

wherein X¹⁶Is N, C or CH;

the bond comprising the dotted line represents a single or double bond;

m is 0, 1,2 or 3;

R^a、R^b、R^cand R^dEach independently is

(1-1) a hydrogen atom,

(1-2) a halogen atom,

(1-3) a hydroxyl group,

(1-4) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6The substituent of the alkoxy group is substituted,

(1-5) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy, or

(1-6) amino-carbonyl optionally substituted by C_1-6Alkyl substitution, said C_1-6Alkyl groups may be optionally substituted with 1 to 3 halogen atoms which may be the same or different;

wherein R is^aAnd R^bCan be combined with the carbon atoms to which they are attached to form

(2-1) a 3-6 membered saturated carbocyclic ring, wherein said carbocyclic ring may be optionally substituted with 1-4 substituents which may be the same or different, selected from:

(a) a halogen atom,

(b) a hydroxyl group(s),

(c) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy, and

(d) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy, or

(2-2) a 3-6 membered saturated heterocyclic ring, wherein the heterocyclic ring may be optionally substituted with 1 to 4 same or different substituents selected from (a) to (d) of (2-1) above in this clause.

M¹More preferably a radical of formula (3'), wherein X¹⁶Is C or N, m is 1 or 2, R^aAnd R^bEach independently is a hydrogen atom, a halogen atom or C optionally substituted by 1 to 3 identical or different halogen atoms_1-6Alkyl, and R^cAnd R^dIs a hydrogen atom.

M¹Another preferred embodiment of (a) includes groups of formulae (3a), (3b), (3c), (3d), (3e), (3f), (3g), (3h), (3i), (3j), (3k), (3m), (3n), (3p), (3q), (3r), (3s), (3t), (3u), (3v), (3w), (3x), (3y), (3z), (3a '), (3b'), (3c '), (3d'), (3e ') and (3 f'):

。

more preferably, M¹Are radicals of the formulae (3a), (3b), (3c), (3d), (3e), (3f), (3g), (3h), (3i), (3j), (3k), (3m), (3n), (3w), (3x), (3y), (3z), (3a '), (3b'), (3c '), (3d'), (3e ') or (3 f').

M¹An embodiment of (1) includes a group of the following formula (3 "):

wherein m is 0, 1,2 or 3;

R^a、R^b、R^cand R^dEach independently is

(1-1) a hydrogen atom,

(1-2) a halogen atom,

(1-3) a hydroxyl group,

(1-4) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Alkoxy radicalThe substituent (b) of (a) is substituted,

(1-5) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy, or

(1-6) amino-carbonyl optionally substituted by C_1-6Alkyl substitution, said C_1-6Alkyl groups may be optionally substituted with 1 to 3 halogen atoms which may be the same or different;

wherein R is^aAnd R^bCan be combined with the carbon atoms to which they are attached to form

(2-1) a 3-6 membered saturated carbocyclic ring, wherein said carbocyclic ring may be optionally substituted with 1-4 substituents which may be the same or different, selected from:

(a) a halogen atom,

(b) a hydroxyl group(s),

(c) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy, and

(d) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy, or

M¹Another embodiment of (a) includes a group of the formula (3' ' '):

wherein m is 0, 1,2 or 3;

R^a、R^b、R^cand R^dEach independently is

(1-1) a hydrogen atom,

(1-2) a halogen atom,

(1-3) a hydroxyl group,

(1-4) C_1-6alkyl, optionally substituted by 1 to 3 of the same or differentAnd is selected from halogen atom, hydroxy and C_1-6The substituent of the alkoxy group is substituted,

(1-5) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy, or

(1-6) amino-carbonyl optionally substituted by C_1-6Alkyl substitution, said C_1-6Alkyl groups may be optionally substituted with 1 to 3 halogen atoms which may be the same or different;

wherein R is^aAnd R^bCan be combined with the carbon atoms to which they are attached to form

(2-1) a 3-6 membered saturated carbocyclic ring, wherein said carbocyclic ring may be optionally substituted with 1-4 substituents which may be the same or different, selected from:

(a) a halogen atom,

(b) a hydroxyl group(s),

(c) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent substitution of alkoxy, and

(d) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy, or

Preferably, M²Comprising the following groups:

(1) a group of any one of the following formulae (11) to (37):

wherein X^1aAnd X^1bEach independently is N or CR³；

R⁴Is that

(a) A hydrogen atom, and a nitrogen atom,

(b) C_1-6alkyl, optionally substituted by 1 to 3 of the sameOr different from halogen atom, hydroxy group and C_1-6Substituent of alkoxy, or

R³is that

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) a hydroxyl group(s),

(g) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6The substituent of the alkoxy group is substituted,

(h) amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: c optionally substituted by 1 to 3 identical or different halogen atoms_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and C_2-7An alkyl-carbonyl group, a carboxyl group,

(i) 5-6 membered heteroaryl, optionally substituted with 1-4 identical or different substituents selected from halogen atom, cyano and C_1-6An alkyl group, a carboxyl group,

(j) a 5-6 membered saturated heterocyclyl, optionally substituted with 1-4 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, C_1-6Alkyl and C_1-6Alkoxy radical, or

(k) -C(O)NR^xR^yWherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R^xAnd R^yMay combine together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group,

provided that when R is³When there are more than two, each R³May be the same as or different from each other,

(2) 4-cyanophenylamino group, which is a general amino group,

(3) a group of the following formula (2 c'):

wherein R is⁵Is optionally substituted by 1 to 2 identical or different atoms selected from halogen atoms and C_1-6A 5-membered heteroaryl group substituted with a substituent for an alkyl group,

(4) a group of the formula (2c ' ' '):

wherein X¹⁷Is O or CH₂(ii) a And

R¹⁹is a hydrogen atom or C_1-6Alkyl, or

(5) A group of the following formula (2d), (2e) or (2 j'):

wherein R is⁸、R⁹And R¹⁰Each independently is

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) C_1-6alkyl, which is optionally substituted by 1 to 3 identical or different halogen atoms,

(e) optionally substituted by 1 to 3 identical or different halogen atomsSubstituted C_1-6An alkoxy group,

(f) optionally substituted by 1-2 identical or different C_1-6An amino group substituted with an alkyl group,

(g) a 6-membered saturated heterocyclic group, or

(h) 5-or 6-membered heteroaryl, optionally substituted with 1 to 4 identical or different substituents selected from halogen atoms and C_1-6An alkyl group;

X¹⁴is CR²⁰；

R¹²、R¹³And R¹⁴Each independently is

(a) A hydrogen atom, or

(b) A methyl group;

R²⁰is that

(a) Phenyl optionally substituted with 1 to 2 identical or different substituents selected from fluorine atoms and methoxy groups, or

More preferably, M²Is a group of the following formula (2a ') or (2 b'):

wherein X²、X⁵、X⁶、X⁷And X⁸Each independently is N, CR²¹Or an oxygen-containing gas,

A¹and A²Each of which is independently N or C,

wherein X²、X⁵、X⁶、X⁷、X⁸、A¹And A²Selected such that the ring containing them forms a 9 or 10 membered bicyclic aromatic heterocycle; and

R²¹and R²²Each independently is

(1) A hydrogen atom, and a nitrogen atom,

(2) a halogen atom,

(3) the cyano group(s),

(4) C_1-6alkyl, optionally substituted with 1-3 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, saturated or partially unsaturated C_3-7Carbocyclyl and C_1-6An alkoxy group,

(5) saturated or partially unsaturated C_3-7Carbocyclyl optionally substituted with 1-4 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, C_1-6Alkyl and C_1-6An alkoxy group,

(6) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6Substituent of alkoxy, or

(7) Amino optionally substituted with 1-2 substituents, which may be the same or different, selected from: c optionally substituted by 1 to 3 identical or different halogen atoms_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; and C_2-7An alkylcarbonyl group.

M²An embodiment of (b) includes a group of any one of the following formulae (11) to (37):

wherein X^1aAnd X^1bEach independently is N or CR³；

R⁴Is that

(a) A hydrogen atom, and a nitrogen atom,

(b) C_1-6alkyl, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl and C_1-6Substituent of alkoxy, or

R³is that

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) a hydroxyl group(s),

(g) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6The substituent of the alkoxy group is substituted,

(j) a 5 or 6 membered saturated heterocyclyl group, optionally substituted with 1 to 4 substituents, which may be the same or different, selected from: halogen atom, hydroxy group, C_1-6Alkyl and C_1-6Alkoxy radical, or

(k) -C(O)NR^xR^yWherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R^xAnd R^yMay combine together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group,

provided that when R is³When there are more than two, each R³May be the same as or different from each other.

M²Another embodiment of (a) is 4-cyanophenylamino.

M²Another embodiment of (d) includes a group of the following formula (2 h'):

wherein R is⁸、R⁹And R¹⁰Each independently is

(a) A hydrogen atom, and a nitrogen atom,

(b) a halogen atom,

(d) C_1-6alkyl, optionally substituted with 1-3 substituents, which may be the same or different, selected from: a halogen atom; a hydroxyl group; optionally substituted by hydroxy or C_1-6Alkoxy-substituted C_1-6An alkoxy group; optionally is covered with C_1-6Alkyl or C_1-6An alkoxy-substituted 4-7 membered saturated or partially unsaturated heterocyclyl; optionally is covered with C_1-6An alkyl-substituted 5 or 6 membered heteroaryl; and an amino group, wherein the amino group may be optionally substituted with 1 to 2 substituents which may be the same or different, selected from: optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_1-6An alkyl group; saturated or partially unsaturated C_3-7A carbocyclic group; optionally is covered with C_1-6An alkoxy-substituted 4-7 membered saturated heterocyclic group; and optionally substituted by 1 to 3 identical or different groups selected from halogen atoms, hydroxyl groups and C_1-6C substituted by substituents of alkoxy_2-7An alkyl-carbonyl group, a carboxyl group,

(e) C_1-6alkoxy, optionally substituted by 1 to 3 identical or different atoms selected from halogen atoms, hydroxy and C_1-6The substituent of the alkoxy group is substituted,

(i) 4-7 membered saturated or partially unsaturated heterocyclyloxy, optionally substituted by 1-4C_1-6The substitution of the alkyl group is carried out,

(j) -C(O)NR^xR^ywherein R is^xAnd R^yEach independently is a hydrogen atom, C_1-6Alkyl or saturated or partially unsaturated C_3-7A carbocyclic group; or

Alternatively, R^xAnd R^yMay combine together with the nitrogen atom to which they are attached to form a 4-7 membered saturated heterocyclic group,

(k) -C(O)OR^Zwherein R is^ZIs C_1-6Alkyl, or

(l) Vinyl optionally substituted with a 6-membered saturated heterocyclyl;

Examples of the term "pharmaceutically acceptable salts" include: inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate; and organic acid salts such as acetate, propionate, oxalate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate and ascorbate.

The compounds of the present invention encompass any crystal form thereof.

The compound of formula (1) may have at least one asymmetric carbon atom. Thus, the compound of the present invention encompasses racemates of the compounds of formula (1) as well as optical isomers thereof. The compounds of formula (1) encompass deuterated compounds, wherein any one or more of the compounds¹H quilt²H, (D) substitution.

Hereinafter, a method for preparing the compound of formula (1) of the present invention is exemplified, but the present invention is not limited to such an example.

Preparation method

The compounds of the present invention can be prepared by the following procedures and methods in combination with ordinary synthetic methods.

The compounds in the reaction schemes include those in salt form, and such salts include, for example, those described in "pharmaceutically acceptable salts" above. It should be noted that these reactions are merely exemplary, and that other methods may optionally be applied to prepare the compounds of the present invention, based on the knowledge of one skilled in the art of synthetic organic chemistry.

In each of the preparation methods described below, when a functional group to be protected is present, the functional group may be protected as necessary, and deprotected after completion of a reaction or a series of reactions to provide the target product, even if the use of a protecting group is not specifically indicated.

As the protecting group herein, general protecting Groups such as those described in the literature can be used (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 3 rd edition, John Wiley and Sons, inc., New York (1999), etc.). More specifically, the protecting group of amino group includes, for example, tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl and tetrahydropyranyl. Protecting groups for hydroxyl groups include, for example, trialkylsilyl, acetyl, benzyl, tetrahydropyranyl and methoxymethyl groups. The protecting group for the aldehyde group includes, for example, dialkyl acetals and cycloalkyl acetals. The protecting group of the carboxyl group includes, for example, tert-butyl esters, orthoesters and amides.

Introduction and deprotection of protecting Groups can be accomplished by methods commonly used in Organic synthetic chemistry (e.g., the methods described in t.w. Greene and p.g.m. Wuts, "Protective Groups in Organic Synthesis", 3 rd edition, John Wiley and Sons, inc., New York (1999), etc.) or their corresponding methods.

Preparing a compound of formula (1) by forming a bond at the positions a, b and c:

wherein M is¹、M²、R¹And R²To above [1]Those defined in (1) are the same.

The method of forming bonds at positions a, b and c is exemplified in the following production methods 1 to 5, but the order of bonding may be optionally changed.

Preparation method 1

For example, the compound of formula (1) can be prepared by the following method:

wherein M is¹、M²、R¹And R²To above [1]Those defined in (1) are the same; r is C_1-6An alkyl group; and LG is a leaving group (e.g., an iodine atom, a bromine atom, a chlorine atom, and a substituted sulfonyl group such as methanesulfonyl and p-toluenesulfonyl).

Step 1-1 preparation step of Compound (1)

The compound of formula (1) is prepared by reacting compound (1-1) with compound (1-2) in an appropriate inert solvent in the presence of a base. As the compound (1-1), a product synthesized in the preparation method 4 or 5 described below or a commercially available product can be used. As the compound (1-2), a commercially available product or a product synthesized by an ordinary method or a method corresponding thereto can be used.

Examples of the base herein include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, dipotassium hydrogen phosphate, potassium phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide and sodium hydride; metal alkoxide such as sodium methoxide and potassium tert-butoxide; and organic bases such as triethylamine, diisopropylethylamine, and pyridine.

Examples of the inert solvent herein include aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, acetone and methyl ethyl ketone; ether solvents such as diethyl ether, tetrahydrofuran and 1, 4-dioxane; halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; and mixed solvents thereof.

The reaction temperature herein is selected from, but not limited to, the range of usually-10 ℃ to 200 ℃, preferably 0 ℃ to 40 ℃. The reaction time herein is usually 10 minutes to 48 hours, but it depends on the conditions including the reaction temperature, materials and solvent used.

Step 1-2 preparation of Compound (1-4)

Compound (1-4) is prepared by reacting compound (1-1) with compound (1-3) according to the method described in step 1-1. For the compounds (1-3), commercial products or products synthesized by ordinary methods or methods corresponding thereto can be used.

Step 1-3 preparation of Compound (1-5)

Compounds (1-5) can be prepared by hydrolyzing compounds (1-4) by a common method (e.g., Protective Groups in Organic Synthesis 3 rd edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, R.C. Laroque et al, VCH publishers Inc., 1989, etc.) or a corresponding method thereof.

Step 1-4 preparation step of Compound (1)

The compound of formula (1) is also prepared by reacting compound (1-5) with compound (1-6) in a suitable inert solvent with or without a base using a condensing agent. For the compounds (1-6), commercial products or products synthesized by ordinary methods or methods corresponding thereto can be used.

Examples of condensing agents include Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (WSC), benzotriazol-1-yl-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), Diphenylphosphorylazide (DPPA), N-Carbonyldiimidazole (CDI), benzotriazol-1-yl-N, N '-tetramethyluronium Hexafluorophosphate (HBTU), and 7-azabenzotriazol-1-yl-N, N' -tetramethyluronium Hexafluorophosphate (HATU). Additives such as N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt) and 3-hydroxy-4-oxo-3, 4-dihydro-1, 2, 3-benzotriazine (HOOBt) may be added to the reaction, if necessary.

Examples of the base herein include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, dipotassium hydrogen phosphate, potassium phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxide salts such as sodium methoxide and potassium tert-butoxide.

The reaction temperature herein is selected from, but not limited to, the range of usually-10 ℃ to 200 ℃, preferably 0 ℃ to 40 ℃. The reaction time is usually 10 minutes to 48 hours, but it depends on the conditions including the reaction temperature, materials and solvent used.

This step may also be carried out, for example, by activating the carbonyl group with an acid anhydride, mixed acid anhydride or acid halide, and then reacting with the compound (1-6).

Preparation method 2

In the compound of formula (1), for example, a compound of formula (2-4) is prepared by the following method:

wherein R is¹、R²And M²To above [1]Those defined in (1) are the same; LG is a leaving group (e.g., an iodine atom, a bromine atom, a chlorine atom, and a substituted sulfonyl group such as methanesulfonyl and p-toluenesulfonyl); r²¹And R²²Each independently is optionally substituted C_1-6An alkyl group; or alternatively, R²¹And R²²May be combined together with the nitrogen atom to which they are attached to form an optionally substituted 4-12 membered saturated heterocyclic ring.

Step 2-1 preparation step of Compound (2-2)

Compound (2-2) is prepared from compound (2-1) and compound (1-2) according to the method described in step 1-1. For the compound (2-1), products synthesized by ordinary methods (for example, those described in Tetrahedron, 2015, 71, 4859, Bioorganic & Medicinal Chemistry Letters, 2015, 25, 1030, etc.) or their corresponding methods or commercial products can be used.

Step 2-2 preparation of Compound (2-4)

Compound (2-4) can be produced by reacting compound (2-2) with compound (2-3) in an appropriate inert solvent in the presence of a base. For the compound (2-3), a commercial product or a product synthesized by a common method or a method corresponding thereto can be used.

Examples of the inert solvent herein include aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, acetone and methyl ethyl ketone; halogenated hydrocarbon solvents such as chloroform and dichloromethane; aromatic hydrocarbon solvents such as benzene and toluene; and mixed solvents thereof.

The reaction temperature herein is selected from, but not limited to, the range of generally 20 ℃ to 200 ℃, preferably 50 ℃ to 170 ℃. This step can be carried out under microwave irradiation, if necessary. The reaction time herein is usually 10 minutes to 48 hours, but it depends on the conditions including the reaction temperature, materials and solvent used.

Preparation method 3

In the compound of formula (1), for example, the compounds of formulae (3-2) and (3-3) are prepared by the following method:

wherein R is¹、R²And M²To above [1]Those described in (1) are the same; LG is a leaving group (e.g., an iodine atom, a bromine atom, a chlorine atom, and a substituted sulfonyl group such as methanesulfonyl and p-toluenesulfonyl); a is borate, BF₃K or BF₃Na； Q²Is an optionally substituted 4-12 membered partially unsaturated heterocyclyl or saturated or partially unsaturated C_4-12A carbocyclic group; and Q³Is optionally substituted saturated or partially unsaturated C_4-12Carbocyclyl or an optionally substituted 4-12 membered saturated heterocyclyl.

Step 3-1 preparation step of Compound (3-2)

Compound (3-2) is prepared by reacting compound (2-2) with compound (3-1) in the presence of a palladium catalyst, a phosphine ligand and a base in an appropriate inert solvent. For the compound (3-1), a commercial product or a product synthesized by a common method or a corresponding method can be used.

Examples of the palladium catalyst herein include tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0), palladium (0) acetate, [1, 1-bis (diphenylphosphino) ferrocene ] dichloropalladium (II), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II).

Phosphine ligands include, for example, o-tolylphosphine, 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl (S-Phos), 2- (dicyclohexylphosphino) -2',4',6 '-triisopropylbiphenyl (X-Phos), 1' -bis (diphenylphosphino) ferrocene (DPPF), 1, 2-bis (diphenylphosphino) ethane (DPPE), 1, 3-bis (diphenylphosphino) propane (DPPP), 1, 4-bis (diphenylphosphino) butane (DPPB), 2 '-bis (diphenylphosphino) -1,1' -Binaphthyl (BINAP), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (XANT-Phos) and bis (2- (diphenylphosphino) phenyl) ether (DPE-Phos).

Examples of the base herein include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide and potassium hydroxide.

Examples of the inert solvent herein include 1, 4-dioxane, THF, 1, 2-dimethoxyethane, water and a mixed solvent thereof.

The reaction temperature herein is selected from, but not limited to, the range of usually 50 ℃ to 200 ℃, preferably 80 ℃ to 150 ℃. This step can be carried out under microwave irradiation, if necessary. The reaction time is usually 30 minutes to 48 hours.

Step 3-2 preparation of Compound (3-3)

Compound (3-3) is produced by catalytic reduction of compound (3-2) with a metal catalyst in an appropriate inert solvent under a hydrogen atmosphere.

Examples of the metal catalyst herein include palladium/carbon, palladium hydroxide/carbon, raney nickel, platinum oxide/carbon and rhodium/carbon. The amount of the metal catalyst is usually 0.1 to 1000% by weight, and preferably 1 to 100% by weight, of the compound (3-2).

Examples of the inert solvent herein include ethers such as tetrahydrofuran; and esters such as ethyl acetate.

The hydrogen pressure herein is usually 1 to 100 atmospheres, and preferably 1 to 5 atmospheres.

The reaction temperature herein is selected from, but not limited to, the range of usually 0 ℃ to 120 ℃, preferably 20 ℃ to 80 ℃. The reaction time is usually 30 minutes to 72 hours.

Preparation method 4

In the compound of formula (1-1), for example, a compound of formula (4-3) is prepared by the following method:

wherein R is¹And R²To above [1]Those defined in (1) are the same; LG (Ligno-lead-acid)¹And LG²Each independently is a leaving group (e.g., an iodine atom, a bromine atom, a chlorine atom, and a substituted sulfonyl group such as a methanesulfonyl group and a p-toluenesulfonyl group); r²¹And R²²Each independently is optionally substituted C_1-6Alkyl, optionally substituted C_3-10Cycloalkyl or optionally substituted C_3-10cycloalkyl-C_1-4An alkyl group; or alternatively, R²¹And R²²May be combined together with the nitrogen atom to which they are attached to form an optionally substituted 4-12 membered saturated heterocyclic ring.

Step 4-1 preparation step of Compound (4-2)

Compound (4-2) is prepared from compound (4-1) and compound (2-3) according to the method described in step 2-2. As the compound (4-1) and the compound (2-3), commercial products or products synthesized by ordinary methods (e.g., WO 2004/006922, ACS Medicinal Chemistry Letters, 2012, 3, 903. and the like) or their corresponding methods can be used. The amount of compound (2-3) used herein is usually 1.0 equivalent to 1.5 equivalents, and preferably 1.05 equivalents to 1.2 equivalents, relative to the amount of compound (4-2).

Step 4-2 preparation of Compound (4-3)

Compound (4-3) is prepared from compound (4-2) according to a common method (e.g., Bioorganic & Medicinal Chemistry Letters, 2013, 23, 2007, WO 2012/114268, etc.) or a method corresponding thereto.

Preparation method 5

In the compound of formula (1-1), for example, a compound of formula (5-4) is prepared by the following method:

wherein R is¹And R²To above [1]Those defined in (1) are the same; q³Is optionally substituted saturated or partially unsaturated C_4-12Carbocyclyl or an optionally substituted 4-12 membered saturated heterocyclyl; g is a metal substance such as magnesium and zinc; and X is a halogen atom.

Step 5-1 preparation step of Compound (5-3)

Compound (5-3) is prepared by reacting compound (5-1) with an organometallic compound (5-2) such as a grignard reagent according to a common method (e.g., Organic Letters, 2015, 17, 5517, Organic & Biomolecular Chemistry, 2014, 12, 2049, etc.) or a corresponding method thereof. As the compound (5-1) and the compound (5-2), commercially available products or products synthesized by a common method (for example, Organic Letters, 2008, 10, 4815, Journal of Organic Chemistry, 2015, 80, 12182, etc.) or a corresponding method thereof can be used.

Step 5-2 preparation step of Compound (5-4)

Compound (5-4) is prepared by reacting compound (5-2) with hydrazine according to a conventional method (for example, Journal of Medicinal Chemistry, 1993, 36, 4052, WO 2007/020343, etc.) or a method corresponding thereto.

The above preparation methods may optionally be combined to provide the compounds of the present invention having a desired substituent at a desired position. Isolation and purification of the intermediates or products in the above preparation methods can be achieved by an optional combination of methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, crystallization, and different types of chromatography. It is also possible to subject the intermediate to subsequent reactions without any particular purification.

Some of the material compounds or intermediates in the above production methods may be present in a salt form such as a hydrochloride salt depending on, for example, reaction conditions, and they may be used as they are or in a free form. When the material compounds or intermediates are obtained in the form of salts and are desired to be used in free form or are obtained, they can be converted into free forms as follows: they are dissolved or suspended in a suitable solvent and subsequently neutralized with a base such as sodium bicarbonate solution.

Some of the compounds of formula (1) or pharmaceutically acceptable salts thereof may have isomers, including tautomers such as keto-enol forms, positional isomers, geometric isomers, or optical isomers. Including all possible isomers thereof and mixtures of such isomers in any proportion are also encompassed by the present invention.

Optical isomers can also be separated by a common separation method such as a method using an optically active column or fractional crystallization at an appropriate step of the above production method. Optically active materials may be used as starting materials.

In the case where a salt of the compound of formula (1) is desired, when the compound of formula (1) is obtained in the form of a salt, the salt can be obtained by purification of the obtained salt, and when the compound of formula (1) is obtained in the free form, the salt can be formed as follows: the compound of formula (1) is dissolved or suspended in a suitable solvent, followed by addition of an acid or base. Compound (1) or a pharmaceutically acceptable salt thereof may exist in the form of a hydrate or solvate (e.g., ethanolate) with various types of solvents such as water and ethanol, and such hydrates and solvents are also encompassed in the present invention.

The compound of the present invention can be used as a drug for activating Nav1.1 because it exhibits the activation effect of Nav1.1.

The compounds of the invention have an activating effect on Nav1.1 and can therefore be used as medicaments for the treatment and/or prevention of diseases in which Nav1.1 is involved, in particular of diseases in which Nav1.1 function is impaired, for example as medicaments for the treatment and/or prevention of the following disorders: central nervous system diseases (e.g., febrile seizures, generalized epilepsy with febrile seizure adjunctive disorders; epilepsy (particularly, localized epilepsy, generalized epilepsy), epilepsy syndromes (such as Dravet syndrome, refractory childhood epilepsy with generalized tonic clonic seizures, epilepsy with myoclonic-dystonic seizures, wester syndrome, Lennox-Gastaut syndrome, infantile spasms, severe infantile multifocal epilepsy, critical severe myoclonic epilepsy, and benign familial neonatal-infantile seizures), schizophrenia, autistic spectrum disorders, and attention deficit with hyperactivity disorder).

In addition, the compounds of the present invention are expected to be useful as agents for the treatment and/or prevention of the above epileptic syndromes or epilepsy (particularly intractable epilepsy), wherein the symptoms are not adequately suppressible with multiple drugs, particularly three or more existing antiepileptic drugs.

One embodiment of the invention has selective pharmacological activity particularly against Nav1.1 and is less active against other subtypes of Nav (such as Nav1.5), and thus, would be expected to reduce the potential for cardiotoxicity to provide high safety.

The term "prevention" as used herein refers to the act of administering a compound of the invention to a healthy person who has not yet developed a disease, and is intended to, for example, prevent the onset of the disease. The term "treatment" as used herein refers to the act of administering a compound of the present invention to a person (i.e., patient) who has been diagnosed by a physician as being affected by a disease.

The compounds of the present invention may be administered directly via the appropriate route of administration, or may be formulated for administration in an appropriate dosage form.

As the administration route, it is preferable to use the most effective therapeutic route, and examples of the administration route include oral administration; and parenteral administration such as intravenous administration, application (application), inhalation, and eye drop. The route of administration is preferably oral administration.

Examples of dosage forms herein include tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. The dosage form is preferably a tablet.

The formulation into a dosage form or pharmaceutical composition can be accomplished according to conventional methods using pharmaceutically acceptable additives.

As the pharmaceutically acceptable additives, excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizing aids, thickeners, dispersants, stabilizers, sweeteners, flavoring agents, and the like may be used depending on the purpose. Specifically, examples of pharmaceutically acceptable additives herein include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, calcium carboxymethylcellulose, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

The amount and frequency of administration of these dosage forms or pharmaceutical compositions may optionally be determined according to the mode of administration, the disease or symptoms thereof of the patient, the age or weight of the patient, and the like. The amount of active ingredient per day (also referred to herein as a "therapeutically effective amount") may generally be administered to an adult human in several parts per day, preferably 1-3 parts per day, wherein the amount ranges from about 0.0001 to about 5000 mg, more preferably from about 0.001 to about 1000 mg, further preferably from about 0.1 to about 500 mg, particularly preferably from about 1 to about 300 mg.

The compound of the present invention may be used in combination with another agent (hereinafter, also referred to as "agent for combined use") in order to enhance the effect of the compound of the present invention and/or reduce side effects. Examples of such agents include anti-epileptics, antipsychotics, antidepressants, mood stabilizers, anxiolytics, psychostimulants, antiemetics, sleep-inducing agents, anticonvulsants, anti-parkinson's disease agents, anti-schizophrenia agents, and therapeutic agents for ADHD. In particular, the compounds of the invention may also be combined with agents such as: signal enhancers of GABA, including valproic acid; positive allosteric modulators of the GABAA receptor, including clobazam; t-type voltage-dependent calcium channel inhibitors including ethosuximide; SV2A ligands, including levetiracetam; partial seizure medications, including carbamazepine; calcium channel α 2 δ (α 2 δ) ligands, including pregabalin; voltage-dependent potassium channel activators including retigabine; and AMPA receptor antagonists including perampanel. The compounds of the present invention may also be used in combination with: antipsychotic agents targeting Multiple Acting Receptors (MARTA), including clozapine; serotonin-dopamine antagonists (SDA), including risperidone; dopamine receptor partial agonists (DPAs), including aripiprazole; selective Serotonin Reuptake Inhibitors (SSRIs), including fluvoxamine; serotonin Norepinephrine Reuptake Inhibitors (SNRIs) including duloxetine; noradrenergic and specific 5-hydroxytryptamine antidepressants (NaSSA), including mirtazapine; mood stabilizers including lithium carbonate; serotonin 1A receptor agonists including tandospirone; histamine H1-receptor antagonists including hydroxyzine; central nervous system stimulants including methylphenidate; and selective norepinephrine reuptake inhibitors including atomoxetine.

The timing of administering the compound of the present invention and the agent for combined use is not limited, and they may be administered to the subject of treatment concurrently or with a time delay. The compounds of the present invention may be formulated as a combination drug with agents for combined use. The dosage or mixing ratio of such agents may optionally be selected based on the dosage in the clinical application, depending on the subject to be administered, the route of administration, the targeted disease, condition, and combinations thereof. For example, when the subject to be administered is a human, the agents for combined use may be used in an amount of 0.01 to 100 parts by weight relative to 1 part by weight of the compound of the present invention.

Examples

The invention is explained in more detail below by reference to reference examples, examples and tests; however, the present invention is not limited thereto. The names of the compounds in the following reference examples and examples do not necessarily conform to the IUPAC nomenclature.

In the present specification, abbreviations shown below may be used.

CDCl₃Deuterated chloroform

DMSO-d₆Deuterated dimethyl sulfoxide

Rt Retention time

min is minute

HATU O- (7-aza-1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

THF tetrahydrofuran

TFA trifluoroacetic acid

DMF N, N-dimethylformamide

Boc tert-butoxycarbonyl

The physicochemical data of each compound in the examples and the reference examples were obtained with the following equipment:

¹H-NMR, JEOL JNM-AL 400; JEOL JNM-ECS 400; brucker AVANCE 400 spectrometer

The symbols used in NMR are defined as follows: s represents a singlet, d represents a doublet, dd represents a doublet, t represents a triplet, td represents a triplet, q represents a quartet, m represents a multiplet, br represents a broad singlet or multiplet, and J represents a coupling constant.

LC/MS data for each compound in the examples and reference examples were obtained using any of the following equipment:

method A

Detection apparatus ACQUITY (registered trademark) SQ detector (Waters Corporation)

HPLC, ACQUITY UPLC (registered trade Mark) SYSTEM

Column: waters ACQUITY UPLC (registered trademark) BEH C18(1.7 um, 2.1 mm. times.30 mm)

Method B

Detection equipment Shimadzu LCMS-2020

Column: phenomenex Kinetex (C18, 1.7 um, 2.1 mm x 50 mm)

Method C

Detection equipment Agilent 6110 Quadropole LC/MS

HPLC Agilent 1200 series

Column: xbridge C18 (3.5 um, 4.6 mm x 50 mm)

Method D

Detection apparatus ACQUITY (registered trademark) SQ detector (Waters Corporation)

HPLC, ACQUITY UPLC (registered trade Mark) SYSTEM

Column: waters ACQUITY UPLC (registered trademark) BEH C18(1.7 um, 2.1 mm. times.30 mm)

High performance liquid chromatograph-mass spectrometer; the measurement conditions for LC/MS, the mass spectrometry observed [ MS (m/z) ]are shown below]Value of (1) is MH⁺Shown, and retention times are shown as Rt (minutes). In each observed value, the measurement condition for measurement is described as any one of a to D.

Method A

Solvent: solution A; 0.06% formic acid/H₂O, solution B; 0.06% formic acid/acetonitrile

Gradient conditions 0.0-1.3 min (linear gradient of B from 2% to 96%)

The flow rate is 0.8 mL/min; detecting ultraviolet rays at 220 nm and 254 nm; the temperature is 40 DEG C

Method B

Solvent: solution A; 0.05% TFA/H₂O, solution B; acetonitrile

Gradient conditions 0.0-1.7 min (linear gradient of B from 10% to 99%)

The flow rate is 0.5 mL/min; detecting ultraviolet rays at 220 nm; the temperature is 40 DEG C

Method C

Solvent: solution A; 10 mM NH₄HCO₃/H₂O, solution B; acetonitrile

Gradient conditions 0.0-0.2 min (5% B), 0.2-1.5 min (linear gradient of B from 5% to 95%), 1.5-2.8 min (95% B)

The flow rate is 1.8 mL/min; detecting ultraviolet rays at 214 nm and 254 nm; the temperature is 50 DEG C

Method D

Solvent: solution A; 0.05% formic acid/H₂O, solution B; acetonitrile

Gradient conditions 0.0-1.3 min (linear gradient from 10% to 95% B), 1.3-1.5 min (10% B)

The flow rate is 0.8 mL/min; detecting ultraviolet rays at 220 nm and 254 nm; the temperature is 40 DEG C

Reference example 1

2-chloro-N- (4-cyanophenyl) acetamide

To a suspension of 4-aminobenzonitrile (25.2 g) and potassium carbonate (35.4 g) in acetone (200 ml) was added 2-chloroacetyl chloride (28.9 g) dropwise at 0 ℃, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, the reaction mixture was slowly poured into water (400 ml), resulting in precipitation of a solid. The precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (35.0 g).

¹H-NMR (400 MHz, DMSO-d₆) δ : 10.71 (s, 1H), 7.80 (d, J = 9.2 Hz, 2H), 7.76 (d, J = 9.2 Hz, 2H), 4.30 (s, 2H)。

Reference example 2

6- (4-methylpiperidin-1-yl) pyridazin-3 (2H) -ones

To a solution of 3, 6-dichloropyridazine (34.3 g) in dimethylformamide (288 mL) were added 4-methylpiperidine (27.4 g) and triethylamine (48.1 mL). The reaction mixture was stirred at 80 ℃ for 8 hours and concentrated under reduced pressure. After a saturated aqueous sodium bicarbonate solution (200 mL) and water (200 mL) were added thereto, the mixture was extracted 2 times with ethyl acetate. The resulting organic layers were combined, dried over sodium sulfate, and concentrated. The residue was dissolved in acetic acid (460 mL) and the mixture was heated at reflux for 37 hours. The reaction mixture was cooled to room temperature, and then the solvent was concentrated under reduced pressure. To the residue were added 10% aqueous sodium hydroxide (300 mL) and diethyl ether (150 mL), resulting in precipitation of a solid. The precipitated solid was filtered, washed successively with water, diethyl ether and ethyl acetate, and dried under reduced pressure to give the title compound (31.6 g).

¹H-NMR (400 MHz, CDCl₃) δ : 7.17 (d, J = 10.5 Hz, 1H), 6.83 (d, J = 10.1 Hz, 1H), 3.73 (dt, J = 12.9, 2.4 Hz, 2H), 2.71 (td, J = 12.6, 2.6 Hz, 2H), 1.72-1.65 (m, 2H), 1.59-1.47 (m, 1H), 1.25 (dd, J = 12.3, 4.1 Hz, 1H), 1.19 (dd, J = 12.1, 4.3 Hz, 1H), 0.95 (d, J = 6.4 Hz, 3H)。

Reference example 3

2- (3-chloro-6-oxopyridazin-1 (6H) -yl) -N- (4-cyanophenyl) acetamide

To a solution of the compound of reference example 1 (16.7 g) in dimethylformamide (240 mL) were added potassium carbonate (23.7 g) and 6-chloropyridazin-3 (2H) -one (14.8 g). After stirring at room temperature for 6 hours, water (360 mL) was added to the mixture, resulting in precipitation of a solid, and the precipitated solid was filtered. After washing with water, the solid was dried under reduced pressure to give the title compound (18.4 g).

¹H-NMR (400 MHz, DMSO-d₆) δ : 10.78 (s, 1H), 7.79 (dt, J = 8.8, 2.1 Hz, 2H), 7.73 (dt, J = 9.0, 2.1 Hz, 2H), 7.64 (d, J = 9.6 Hz, 1H), 7.11 (d, J = 10.1 Hz, 1H), 4.90 (s, 2H)。

Reference example 4

2- (4, 4-Difluorocyclohex-1-en-1-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan

a) To a solution of 4, 4-difluorocyclohexanone (25.0 g) in 1, 2-dichloroethane (373 mL) were added 2-chloropyridine (26.5 g) and trifluoromethanesulfonic anhydride (63.1 g), and the mixture was stirred at 50 ℃ for 6 hours. After cooling to 0 ℃, hexane (750 mL) was added thereto, resulting in precipitation of a solid, and the precipitated solid was filtered. The eluate was concentrated under reduced pressure to give compound 1A (46.1 g).

¹H-NMR (400 MHz, CDCl₃) δ : 5.67-5.63 (m, 1H), 2.69 (td, J = 13.5, 2.9 Hz, 2H), 2.60-2.55 (m, 2H), 2.24-2.14 (m, 2H)。

b) To a solution of compound 1A (46.1 g) and bis (pinacolato) diboron (52.8 g) in 1, 4-dioxane (577 mL) were added potassium acetate (42.5 g) and 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (6.34 g), and the mixture was heated at reflux for 2 hours. After cooling to room temperature, the mixture was filtered through celite and the eluent was concentrated under reduced pressure. After addition of ethyl acetate (1.5L), the organic layer was washed with water (300 mL) and brine (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (solvent; hexane: ethyl acetate = 100:0, then 90:10) to give the title compound (39.8 g).

¹H-NMR (400 MHz, CDCl₃) δ : 6.37-6.35 (m, 1H), 2.60-2.50 (m, 2H), 2.41-2.36 (m, 2H), 2.00-1.89 (m, 2H), 1.24 (s, 12H)。

Reference example 5

6- (4, 4-dimethylcyclohexyl) pyridazin-3 (2H) -ones

a) 6-chloropyridazin-3 (2H) -one (497 mg), 2- (4, 4-dimethylcyclohex-1-en-1-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (900 mg) and 2 mol/L aqueous sodium carbonate (4.76 mL) were suspended in 1, 2-dimethoxyethane (17 mL). To the mixture was added 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (279 mg). The mixture was stirred at 80 ℃ for 6 hours under nitrogen atmosphere. After cooling to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 99:1, then 93:7) to give compound 2A (88 mg).

¹H-NMR (400 MHz, DMSO-d₆) δ : 7.80 (d, J = 10.1 Hz, 1H), 6.80 (d, J = 9.6 Hz, 1H), 6.43-6.40 (m, 1H), 2.35-2.30 (m, 2H), 1.98 (dt, J = 4.1, 1.8 Hz, 2H), 1.42 (t, J = 6.4 Hz, 2H), 0.91 (s, 6H)。

b) A suspension of Compound 2A (88 mg) and 10% palladium on carbon (20 mg) in methanol (20 mL) was stirred under a hydrogen atmosphere at room temperature for 10 hours. The Pd/C was filtered through celite and washed with methanol. The eluate was concentrated to give the title compound (89 mg).

¹H-NMR (400MHz, CDCl₃) δ : 10.66 (s, 1H), 7.19 (d, J = 10.1 Hz, 1H), 6.89 (d, J = 9.6 Hz, 1H), 2.42 (tt, J = 11.8, 4.0 Hz, 1H), 1.71-1.67 (m, 2H), 1.63-1.55 (m, 2H), 1.52-1.45 (m, 2H), 1.27 (td, J = 12.3, 4.0 Hz, 2H), 0.93 (s, 3H), 0.92 (s, 3H)。

Reference example 6

[3- (4-Methylpiperidin-1-yl) -6-oxopyridazin-1 (6H) -yl ] acetic acid

a) The compound of reference example 2 (2.5 g), methyl bromoacetate (2.8 g) and potassium carbonate (3.6 g) in dimethylformamide (26 mL) were stirred at room temperature for 2.5 hours. After addition of saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 30:70) to obtain compound 3A (3.2 g).

¹H-NMR (400 MHz, CDCl₃) δ : 7.16 (d, J = 10.1 Hz, 1H), 6.84 (d, J = 10.1 Hz, 1H), 4.75 (s, 2H), 3.77-3.74 (m, 2H), 3.76 (s, 3H), 2.71 (td, J = 12.5, 2.4 Hz, 2H), 1.69 (d, J = 12.5 Hz, 2H), 1.59-1.48 (m, 1H), 1.28-1.18 (m, 2H), 0.96 (d, J = 6.4 Hz, 3H)。

b) Compound 3A (3.2 g) was dissolved in a mixed solvent of methanol (20 mL) and THF (20 mL), and a 2 mol/L aqueous solution of sodium hydroxide (30 mL) was added thereto under ice-cooling. Then, the mixture was stirred at room temperature for 30 minutes. The organic solvent of the reaction mixture was removed under reduced pressure, and 1 mol/L hydrochloric acid was added to the resulting aqueous layer to adjust the pH to 3, resulting in precipitation of a solid. The precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (3.0 g).

¹H-NMR (400 MHz, CD₃OD) δ : 7.50 (d, J = 10.1 Hz, 1H), 6.86 (d, J = 10.1 Hz, 1H), 4.72 (s, 2H), 3.92-3.88 (br, 2H), 2.76 (td, J = 12.7, 2.6 Hz, 2H), 1.73-1.68 (br, 2H), 1.64-1.51 (m, 1H), 1.23 (ddd, J = 24.4, 12.7, 3.9 Hz, 2H), 0.97 (d, J = 6.4 Hz, 3H)。

Reference example 7

4- (4-methylphenyl) -5,6,7, 8-tetrahydrophthalazin-1 (2H) -one

a) To a solution of 4,5,6, 7-tetrahydroisobenzofuran-1, 3-dione (5.0 g) in tetrahydrofuran (329 mL) was added a solution of p-tolylmagnesium bromide in tetrahydrofuran (32.9 mL) dropwise, and the mixture was stirred at room temperature for 23 hours. 1 mol/L hydrochloric acid was added to the reaction mixture to cause precipitation of a solid, and the precipitated solid was filtered and washed with water. The obtained solid was purified by silica gel column chromatography (solvent; chloroform: methanol = 9:1) to obtain compound 4A (10.7 g).

¹H-NMR (400 MHz, CDCl₃) δ : 7.40-7.31 (m, 2H), 7.15 (d, J = 8.5 Hz, 2H), 2.42-2.20 (m, 6H), 1.98-1.43 (m, 5H)。

b) To a solution of compound 4A (7.61 g) in ethanol (156 mL) was added hydrazine monohydrate (3.03 mL), and the mixture was heated under reflux for 5 hours. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution was added thereto, and ethanol was removed by concentration under reduced pressure, resulting in precipitation of a solid. The precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (6.22 g).

¹H-NMR (400 MHz, CDCl₃) δ : 10.42 (s, 1H), 7.26-7.25 (m, 2H), 7.23-7.21 (m, 2H), 2.64-2.62 (m, 2H), 2.40-2.37 (m, 5H), 1.79-1.77 (m, 2H), 1.68-1.65 (m, 2H)。

Reference example 8

6- (2-azaspiro [4.4] non-2-yl) -4-methylpyridazin-3 (2H) -one

Reference example 9

6- (2-azaspiro [4.4] non-2-yl) -5-methylpyridazin-3 (2H) -one

a) To a solution of 3, 6-dichloro-4-methylpyridazine (0.40 g) in dimethylformamide (4 mL) were added 2-azaspiro [4.4] nonane (0.31 g) and triethylamine (1.03 mL). The reaction mixture was stirred at 80 ℃ for 6 hours. After addition of saturated aqueous sodium bicarbonate (20 mL) and water (20 mL), the mixture was extracted 2 times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 90:10, then 30:70) to give compound 5A (250 mg) and compound 5B (260 mg).

b) Compound 5A was dissolved in acetic acid (3 mL), and the reaction mixture was subjected to microwave irradiation and stirred at 200 ℃ for 2 hours. The reaction mixture was cooled to room temperature, and toluene was added thereto. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (solvent; chloroform: methanol = 100:0, then 98:2) to give 6- (2-azaspiro [4.4] non-2-yl) -4-methylpyridazin-3 (2H) -one (220 mg).

LC-MS: [M+H]⁺Rt (min) 234.2/0.832 (method A)

Similarly, 6- (2-azaspiro [4.4] non-2-yl) -5-methylpyridazin-3 (2H) -one (195 mg) was obtained from compound 5B.

LC-MS: [M+H]⁺Rt (min) 234.2/0.839 (method A)

Reference example 10

6- (6-azaspiro [3.4] octan-6-yl) -4-methoxypyridazin-3 (2H) -one

a) To a solution of 6-chloro-3, 4-dimethoxypyridazine (0.25 g) in toluene (2.5 mL) were added 6-azaspiro [3.4] octane (0.23 g), potassium tert-butoxide (0.14 g) and 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl (6.4 mg). The reaction mixture was subjected to microwave irradiation and stirred at 80 ℃ for 1 hour. After the reaction mixture was cooled to room temperature, water (20 mL) was added thereto, and the mixture was extracted 2 times with ethyl acetate. The combined organic layers were dried over sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 90:10, then 15:85) to give compound 6A (44 mg).

LC-MS: [M+H]⁺Rt (min) 250.2/0.506 (method A)

b) Compound 6A (80 mg) was dissolved in dioxane (500. mu.L) and concentrated hydrochloric acid (2 mL). The reaction mixture was subjected to microwave irradiation and stirred at 100 ℃ for 2 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was poured into water, resulting in precipitation of a solid, and the precipitated solid was filtered to give the title compound (53 mg).

LC-MS: [M+H]⁺Rt (min) 236.2/0.527 (method A)

Reference example 11

1, 1-difluoro-4, 4-dimethyl-6-azaspiro [2.5] octane hydrochloride

a) To a solution of tert-butyl 3, 3-dimethyl-4-methylenepiperidine-1-carboxylate (4.6 g) in tetrahydrofuran (29.2 mL) were added (trifluoromethyl) trimethylsilane (10.54 mL) and sodium iodide (1.53 g), and the mixture was heated under reflux for 33 hours. Heptane (10 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The organic layer was washed with water, saturated aqueous sodium thiosulfate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 95:5, and then 75:25) to give compound 7A (4.2 g).

¹H-NMR (400 MHz, CDCl₃) δ : 3.87 (br s, 1H), 3.43 (br s, 1H), 3.06-2.99 (m, 1H), 2.87-2.83 (m, 1H), 1.97-1.90 (m, 1H), 1.46 (s, 9H), 1.44-1.40 (m, 1H), 1.31-1.23 (m, 1H), 1.06 (s, 3H), 0.92-0.86 (m, 4H)。

b) Compound 7A (4.2 g) was dissolved in cyclopentyl methyl ether (10 ml). To the mixture was added a solution of hydrogen chloride in cyclopentyl methyl ether (18.5 mL) and the mixture was stirred for 5 hours, resulting in precipitation of a solid. The precipitated solid was filtered and dried to give the title compound (3.71 g).

¹H-NMR (400 MHz, DMSO-d₆) δ : 9.59 (s, 1H), 8.96 (s, 1H), 3.16-3.12 (m, 1H), 2.94-2.91 (m, 1H), 2.88-2.70 (m, 2H), 2.09-2.02 (m, 1H), 1.70-1.64 (m, 1H), 1.46-1.40 (m, 1H), 1.32-1.26 (m, 1H), 1.17 (s, 3H), 0.89 (s, 3H)。

Reference example 12

7-chloro-2-methyl-1, 3-benzoxazol-5-amine

a) To a solution of 2-amino-6-chloro-4-nitrophenol (0.5 g) in DMF (15 mL) were added triethyl orthoacetate (1.72 g) and p-toluenesulfonic acid (0.23 g), and the mixture was stirred at 70 ℃ for 4 hours. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 80:20) to give compound 8A (0.37 g).

¹H-NMR (400 MHz, CDCl₃) δ : 8.46 (d, J = 1.8 Hz, 1H), 8.30 (d, J = 2.4 Hz, 1H), 2.75 (s, 3H)。

b) Compound 8A (62.5 mg) was dissolved in a mixed solvent of methanol (4 ml) and water (1 ml), and reduced iron (164 mg) and ammonium chloride (157 mg) were added thereto. The mixture was stirred at 70 ℃ for 2 hours. Insoluble material was filtered off through celite and the organic layer was concentrated. The residue was redissolved in ethyl acetate. The mixture was washed with water and brine, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (43.7 mg).

¹H-NMR (400 MHz, CDCl₃) δ : 6.81 (d, J = 2.1 Hz, 1H), 6.66 (d, J = 1.8 Hz, 1H), 3.69 (br s, 2H), 2.61 (s, 3H)。

Reference example 13

[1,2,4] triazolo [1,5-a ] pyridin-7-amine 2 hydrochloride

a) A solution of 7-bromo [1,2,4] triazolo [1,5-a ] pyridine (975 mg), tert-butyl carbamate (865 mg), sodium tert-butoxide (710 mg), [ (2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl) -2- (2' -amino-1, 1' -biphenyl) ] palladium (II) methanesulfonate (196 mg) in toluene (33 mL) was stirred at 100 ℃ for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent (3:1) of chloroform and ethanol. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (solvent; hexane: ethyl acetate = 75:25, and then ethyl acetate) to give the title compound 9A (780 mg).

¹H-NMR (400 MHz, CDCl₃) δ : 8.43 (d, J = 7.3 Hz, 1H), 8.23 (s, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.18 (dd, J = 7.3, 2.4 Hz, 1H), 6.79 (s, 1H), 1.52 (s, 9H)。

b) Compound 9A (780 mg) was suspended in ethyl acetate (3 ml), and a solution of hydrogen chloride in dioxane (16 ml) was added thereto. The mixture was stirred at 40 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure and the following steps were repeated 2 times: toluene was added thereto, and the mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was stirred, and then filtered to obtain the title compound (499 mg).

¹H-NMR (400 MHz, CD₃OD) δ : 8.71 (s, 1H), 8.54 (d, J = 7.3 Hz, 1H), 6.90 (dd, J = 7.3, 2.1 Hz, 1H), 6.71 (d, J = 2.1 Hz, 1H)。

Reference example 14

4- (morpholin-4-yl) -2, 3-dihydro-1H-indole 2 hydrochloride

a) A solution of 4-bromo-2, 3-dihydro-1H-indole-1-carboxylic acid tert-butyl ester (1.55 g), morpholine (1.81 g), tris (dibenzylideneacetone) dipalladium (0) (0.48 g), (R) - (+) -2,2' -bis (diphenylphosphino) -1, 1-binaphthyl (0.324 g) and sodium tert-butoxide (0.999 g) in toluene (17.3 mL) was stirred at 100 ℃ for 2 hours. Insoluble material was filtered off through celite and the organic layer was concentrated. To the residue was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 80:20) to give compound 10A (1.07 g).

LC-MS: [M+H]⁺Rt (min) 305.2/1.984 (method B)

b) Compound 10A (1.07 g) was dissolved in ethyl acetate (15 ml), and a solution of hydrogen chloride in ethyl acetate (15 ml) was added thereto. The mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was filtered to give the title compound (0.92 g).

¹H-NMR (400 MHz, CD₃OD) δ : 7.48 (t, J = 8.2 Hz, 1H), 7.27 (t, J = 7.9 Hz, 2H), 3.94-3.92 (m, 4H), 3.87 (t, J = 7.6 Hz, 2H), 3.41 (t, J = 7.3 Hz, 2H), 3.26-3.24 (m, 4H)。

Reference example 15

4- (pyridazin-4-yl) -2, 3-dihydro-1H-indole hydrochloride

a) A solution of tert-butyl 4-bromo-2, 3-dihydro-1H-indole-1-carboxylate (2.62 g), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridazine (2.17 g), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (0.62 g), 2M aqueous potassium acetate (13 mL) in acetonitrile (35 mL) was stirred at 90 ℃ for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; ethyl acetate, and then ethyl acetate: methanol = 95:5) to give compound 11A (2.30 g).

LC-MS: [M+H]⁺Rt (min) 298.2/0.891 (method A)

b) Compound 11A (2.30 g) was dissolved in chloroform (35 ml). After addition of a solution of hydrogen chloride in ethyl acetate (35 ml), the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the following steps were repeated 2 times: toluene was added to the mixture, and the mixture was concentrated under reduced pressure. 1.8 g of the title compound are obtained.

LC-MS: [M+H]⁺Rt (min) 198.2/0.333 (method A)

Reference example 16

[3- (4-methylcyclohex-1-en-1-yl) -6-oxopyridazin-1 (6H) -yl ] acetic acid

a) The procedure of a) in reference example 6 was followed using 6-chloropyridazin-3 (2H) -one (44.0 g) to give compound 12A (49.4 g).

¹H-NMR (400 MHz, DMSO-d₆) δ : 7.64 (d, J = 9.8 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.85 (s, 2H), 3.69 (s, 3H)。

b) A solution of compound 12A (2.15 g), 4,5, 5-tetramethyl-2- (4-methylcyclohex-1-en-1-yl) -1,3, 2-dioxaborolan (3.06 g) and 2 mol/L aqueous potassium acetate (15.92 mL) was suspended in acetonitrile (140 mL), and bis (di-t-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (301 mg) was added thereto. The mixture was stirred at 90 ℃ for 5 hours under nitrogen atmosphere. After cooling to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 90:10, and then 70:30) to give compound 12B (2.40 g).

LC-MS: [M+H]⁺Rt (min) 263.2/0.935 (method A)

c) The title compound (1.5 g) was obtained according to the method of B) in reference example 6 using compound 12B (2.40 g).

LC-MS: [M+H]⁺/Rt (min) 249.2/0.835 (method A)

Reference example 17

2- (trifluoromethyl) imidazo [1,2-a ] pyridin-7-amine

Pyridine-2, 4-diamine (300 mg) and sodium hydrogencarbonate (462 mg) were suspended in ethanol (9.1 mL), and 3-chloro-1, 1,1, trifluoropropan-2-one was added thereto. The mixture was heated at reflux for 4 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with a mixed solvent (3:1) of chloroform and ethanol. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (solvent; hexane: ethyl acetate = 50:50, and then ethyl acetate) to obtain the title compound (250 mg).

LC-MS: [M+H]⁺Rt (min) 202.1/0.344 (method A)

Reference example 18

7-fluoro-1, 3-benzoxazol-5-amines

a) 2-amino-6-fluoro-4-nitrophenol (507 mg) and triethoxymethane (0.98 mL) were dissolved in chloroform (14.7 mL) and acetic acid (0.68 mL). The mixture was heated at reflux for 5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 83:17, and then 75:25) to give compound 13A (330 mg).

LC-MS: [M+H]⁺Rt (min) 183.0/0.749 (method A)

b) Compound 13A (330 mg) was dissolved in methanol (9.0 mL) and palladium on carbon (96 mg) was added thereto. The mixture was stirred at room temperature for 3 hours. The insoluble material was filtered through celite, and the organic layer was concentrated to give the title compound (268 mg).

LC-MS: [M+H]⁺Rt (min) 153.0/0.445 (method A)

Reference example 19

2- (difluoromethyl) -1, 3-benzoxazol-5-amines

a) 2-amino-4-nitrophenol (300 mg), triethylamine (1.36 mL), triphenylphosphine (1.28 g) and difluoroacetic acid (0.12 mL) were dissolved in carbon tetrachloride (6.5 mL), and the mixture was heated under reflux for 3 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with a mixed solvent (10:1) of chloroform and methanol. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvate; hexane: ethyl acetate = 75:25, and then ethyl acetate) to give compound 14A (331 mg).

LC-MS: [M+H]⁺Per Rt (min) 215.1/0.850 (method A)

b) The title compound was obtained according to the method of b) in reference example 18, using compound 14A (330 mg).

LC-MS: [M+H]⁺/Rt (min) 185.1/0.505 (method A)

Reference example 20

7-fluoro-2-methoxy-1, 3-benzoxazol-5-amines

a) Following the procedure of a) in reference example 18, using 2-amino-6-fluoro-4-nitrophenol (303 mg) and tetramethyl orthocarbonate (0.47 mL) gave compound 15A (318 mg).

LC-MS: [M+H]⁺Rt (min) 213.1/0.843 (method A)

b) The title compound (248 mg) was obtained according to the method of b) in reference example 18 using compound 120A (318 mg).

LC-MS: [M+H]⁺Rt (min) 183.0/0.517 (method A)

Reference example 21

2-methyl [1,3] thiazolo [5,4-b ] pyridin-6-amine

a) 2-chloro-3, 5-dinitropyridine (300 mg) was dissolved in sulfolane (9.8 mL), and thioacetamide (1.48 g) was added thereto. The mixture was heated at reflux at 110 ℃ for 3 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 90:10, and then 75:25) to give compound 16A (0.23 g).

LC-MS: [M+H]⁺Rt (min) 196.1/0.667 (method A)

b) Compound 16A (177 mg) was dissolved in ethanol (3.8 mL), and water (1.3 mL), ammonium chloride (485 mg) and reduced iron (253 mg) were added thereto. The mixture was heated at reflux for 3 hours. The insoluble material was filtered through celite, and the organic layer was concentrated under reduced pressure. Saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (97 mg).

LC-MS: [M+H]⁺/Rt (min) 166.0/0.423 (method A)

Reference example 22

2- (5-amino-1, 3-benzoxazol-2-yl) propan-2-ol

Methyl 5-amino-1, 3-benzoxazole-2-carboxylate (200 mg) and cerium (III) chloride (1.03 g) were dissolved in tetrahydrofuran (6.9 mL). To this was added 3 mol/L methylmagnesium bromide (1.39 ml) with stirring at 0 ℃ and the mixture was stirred at 0 ℃ for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvate; ethyl acetate, and then ethyl acetate: methanol = 96:4) to obtain the title compound (10.0 mg).

LC-MS: [M+H]⁺Rt (min) 193.1/0.317 (method A)

Reference example 23

1- (5-methoxy-2-methylpyridin-3-yl) piperazine 3 hydrochloride

a) 1-Boc-piperazine (277 mg), tris (dibenzylideneacetone) dipalladium (0) (91 mg), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (172 mg) and sodium tert-butoxide (190 mg) were suspended in toluene (10 ml). 3-bromo-5-methoxy-2-methylpyridine (200 mg) was added thereto, and the mixture was stirred at 70 ℃ for 1 hour. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The insoluble material was filtered through celite, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 70:30, and then 50:50) to give compound 17A (296 g).

¹H-NMR (400 MHz, CDCl₃) δ : 7.94 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 3.84 (s, 3H), 3.60-3.57 (m, 4H), 2.86-2.84 (m, 4H), 2.48 (s, 3H), 1.49 (s, 9H)

b) Compound 17A (296 mg) was dissolved in methanol (5 mL), and a 2 mol/L solution of hydrogen chloride in methanol (9.6 mL) was added thereto with stirring at 0 ℃. The mixture was stirred at 50 ℃ for 3 hours. After cooling to room temperature, the precipitated solid was filtered, and the obtained solid was dried under reduced pressure to obtain the title compound (271.7 mg).

¹H-NMR (400 MHz, CD₃OD) δ : 8.16 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 4.03 (s, 3H), 3.47-3.45 (m, 4H), 3.37-3.35 (m, 4H), 2.68 (s, 3H)。

Reference example 24

(2R,6S) -2, 6-dimethyl-1- (pyridin-3-yl) piperazine 3 hydrochloride

a) 0.5 mol/L potassium hexamethyldisilazane (2.57 ml), tert-butyl (3R, 5S) -3, 5-dimethylpiperazine-1-carboxylate (250 mg) and 3-bromopyridine (184 mg) were suspended in 1, 4-dioxane (10 ml), and the mixture was stirred at 100 ℃ for 8 hours. After cooling to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 80:20, and then 40:60) to give compound 18A (114 mg).

LC-MS: [M+H]⁺Rt (min) 292.0/0.689 (method A)

b) The title compound (75 mg) was obtained according to the method of b) in reference example 15 using compound 18A (114 mg).

LC-MS: [M+H]⁺Rt (min) 192.2/0.149 (method A)

Reference example 25

4- [ (morpholin-4-yl) methyl ] -2, 3-dihydro-1H-indole

a) 2, 3-dihydro-1H-indole-4-carbaldehyde (147 mg) was dissolved in methylene chloride (2 ml), and morpholine (88 mg) and sodium triacetoxyborohydride (322 mg) were added thereto. The mixture was stirred at room temperature for 4 hours. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give compound 19A (209 mg).

LC-MS: [M+H]⁺Rt (min) 217.2/0.292 (method A)

b) Compound 19A (209 mg) was dissolved in acetic acid (3 ml), and sodium cyanoborohydride (182 mg) was added thereto, and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the following steps were repeated 2 times: toluene was added thereto, and the mixture was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to give the title compound (256 mg).

LC-MS: [M+H]⁺Per Rt (min) 219.2/0.131 (method A)

Reference example 26

4- [ (1H-imidazol-1-yl) methyl ] -2, 3-dihydro-1H-indole hydrochloride

a) (2, 3-dihydro-1H-indol-4-yl) methanol (0.92 g) was dissolved in tetrahydrofuran (2 ml), and di-tert-butyl dicarbonate (1.48 g) was added thereto. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, resulting in precipitation of a solid, and the resulting residue was purified by silica gel column chromatography (solvent; hexane, and then hexane: ethyl acetate = 70:30) to obtain compound 20A (1.54 g).

LC-MS: [M+H-tBu]⁺Rt (min) 194.1/0.866 (method A)

b) Compound 20A (1.54 g) was dissolved in methylene chloride (20 ml), and thionyl chloride (0.57 ml) was added thereto at 0 ℃ with stirring. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the following steps were repeated 2 times: toluene was added thereto, and the mixture was concentrated under reduced pressure to give compound 20B (1.65 g).

LC-MS: [M+H-tBu]⁺Rt (min) 212.1/1.169 (method A)

c) Compound 20B (200 mg) was dissolved in dimethylformamide (3 ml), and imidazole (2.5 g) was added thereto. The mixture was stirred at 80 ℃ for 2 hours. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; ethyl acetate, and then ethyl acetate: methanol = 95:5) to give compound 20C (80 mg).

LC-MS: [M+H]⁺Rt (min) 300.3/0.683 (method A)

d) Compound 20C (80 mg) was dissolved in chloroform (3 mL), and a solution of hydrogen chloride in ethyl acetate (0.54 mL) was added thereto. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The following procedure was repeated 2 times, toluene was added to the residue, and the mixture was concentrated to give the title compound (53 mg).

LC-MS: [M+H]⁺Rt (min) 200.1/0.115 (method A)

Reference example 27

(3-chloro-5-methyl-6-oxopyridazin-1 (6H) -yl) acetic acid methyl ester

Reference example 28

(3-chloro-4-methyl-6-oxopyridazin-1 (6H) -yl) acetic acid methyl ester

3, 6-dichloro-4-methylpyridazine (650 mg) was dissolved in acetic acid (6 mL), and the reaction mixture was subjected to microwave irradiation and stirred at 200 ℃ for 2 hours. After cooling to room temperature, the following procedure was repeated 3 times by adding toluene thereto and concentrating the mixture under reduced pressure. The residue was dissolved in dimethylformamide (3 mL), and methyl bromoacetate (855 mg) and potassium carbonate (1.10 g) were added thereto. The mixture was stirred at room temperature overnight. After addition of saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 90:10, and then 25:75) to give the compound of reference example 27 (374 mg) and the compound of reference example 28 (190 mg), respectively.

Reference example 27 LC-MS: [ M + H]⁺Rt (min) 217.1/0.610 (method A)

Reference example 28 LC-MS: [ M + H]⁺Rt (min) 217.1/0.598 (method A)

Reference example 29

4,4,5, 5-tetramethyl-2- (4-methylcyclopent-1-en-1-yl) -1,3, 2-dioxaborolane

a) A solution of 4, 4-dimethyl-2-cyclopenten-1-one (750 mg) in tetrahydrofuran (40 mL) was stirred at-78 deg.C, and 1 mol/L of a solution of lithium tri-sec-butylborohydride in tetrahydrofuran (7.8 mL) was added thereto. The mixture was stirred at-78 ℃ for 1 hour. To the reaction mixture was added a solution of 2- [ N, N-bis (trifluoromethylsulfonyl) amino ] pyridine (2.80 g) in tetrahydrofuran (10 ml), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2 mol/L aqueous sodium hydroxide solution (30 mL) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 99:1) to give compound 21A (310 mg).

¹H-NMR (400 MHz, CDCl₃) δ : 5.57-5.55 (m, 1H), 2.78-2.70 (m, 1H), 2.63-2.49 (m, 2H), 2.22-2.15 (m, 1H), 2.02-1.95 (m, 1H), 1.11 (d, J = 6.8 Hz, 3H)。

b) The title compound (150 mg) was obtained according to the method of b) in reference example 4 using compound 21A (300 mg).

¹H-NMR (400 MHz, CDCl₃) δ : 6.48-6.43 (1H, m), 2.67-2.52 (2H, m), 2.42-2.28 (1H, m), 2.08-1.95 (2H, m), 1.33-1.21 (12H, m), 1.04-0.99 (3H, m)。

Reference example 30

2- (1, 1-Difluorospiro [2.5] oct-5-en-6-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane

a) To a suspension of methyltriphenylphosphonium bromide (121.0 g) in toluene (570 mL) was added potassium tert-butoxide (37.9 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a solution of 1, 4-dioxaspiro [4.5] decan-8-one (24.0 g) in toluene (1000 ml), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added magnesium chloride (64.4 g) in the form of sand, and the mixture was stirred at 60 ℃ for 2 hours. Acetone (13.54 ml) was added to the reaction mixture, and the mixture was stirred at 60 ℃ for 2 hours, and then stirred at room temperature overnight. The reaction mixture was filtered and the solid was washed with heptane (400 ml). The eluate was concentrated under reduced pressure. Hexane was added to the residue, and the mixture was stirred for a while. Insoluble material was filtered, and the eluate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvate; hexane, and then hexane: ethyl acetate = 85:15) to give compound 22A (20.8 g).

¹H-NMR (400 MHz, CDCl₃) δ : 4.65 (s, 2H), 3.96 (s, 4H), 2.27 (t, J = 6.5 Hz, 4H), 1.69 (t, J = 6.5 Hz, 4H)。

b) Compound 22B (24.0 g) was obtained according to the procedure of a) in reference example 11, using compound 22A (20.8 g).

¹H-NMR (400 MHz, CDCl₃) δ : 3.96 (s, 4H), 1.74-1.66 (m, 8H), 1.05 (t, J = 8.2 Hz, 2H)。

c) Compound 22B (23.8 g) was dissolved in a mixed solvent of acetone (180 ml) and water (120 ml). P-toluenesulfonic acid monohydrate (2.22 g) was added thereto, and the mixture was heated under reflux for 4 hours. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution was added thereto, and the acetone layer was removed under reduced pressure. The aqueous layer was extracted 2 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 90:10, and then hexane: ethyl acetate = 75:25) to give compound 22C (15.2 g).

¹H-NMR (400 MHz, CDCl₃) δ : 2.48-2.37 (m, 4H), 1.98-1.89 (m, 4H), 1.25-1.21 (m, 2H)。

d) A solution of compound 22C (4.77 g) and 2, 6-lutidine in methylene chloride (48 ml) was stirred at 0 ℃ and trifluoromethanesulfonic anhydride (10.57 ml) was added thereto. The mixture was warmed and heated at reflux for 3 hours. After cooling to room temperature, a saturated aqueous sodium hydrogencarbonate solution was added thereto, and the dichloromethane layer was removed under reduced pressure. The aqueous layer was extracted 2 times with ethyl acetate. The combined organic layers were washed successively with 1 mol/l aqueous hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 95:5, and then hexane: ethyl acetate = 77:23) to give compound 22D (6.61 g).

¹H-NMR (400 MHz, CDCl₃) δ : 5.78 (t, J = 3.7 Hz, 1H), 2.45-2.35 (m, 3H), 2.19-2.14 (m, 1H), 1.86-1.81 (m, 2H), 1.21-1.11 (m, 2H)。

e) To a solution of compound 22D (6.61 g), triphenylphosphine (593 mg), potassium phenoxide (2.99 g), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (6.03 g) in toluene (113 ml) was added bis (triphenylphosphine) palladium (II) dichloride (794 mg), and the mixture was stirred at 50 ℃ for 4 hours. To the reaction mixture were added potassium phenoxide (1.14 g) and tetrakis (triphenylphosphine) palladium (0) (784 mg), and the mixture was stirred at 50 ℃ for 1.5 hours. After cooling to room temperature, water and ethyl acetate were added thereto, and the mixture was filtered through celite. The organic layer was washed with 1M aqueous sodium carbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane, and then hexane: ethyl acetate = 80:20) and again purified by silica gel column chromatography (solvent; hexane: toluene = 50:50, and then hexane: toluene: ethyl acetate = 45:50:5) to obtain the title compound (3.72 g).

¹H-NMR (400 MHz, CDCl₃) δ : 6.53-6.50 (m, 1H), 2.36-2.14 (m, 3H), 2.05-2.00 (m, 1H), 1.67-1.55 (m, 2H), 1.25 (s, 12H), 1.09-0.97 (m, 2H)。

Reference example 31

8-fluoro- [1,2,4] triazolo [1,5-a ] pyridin-7-amine

a) A solution of 2-chloro-3-fluoro-4-iodopyridine (3.1 g), benzyl carbamate (2.28 g), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (1.74 g), and tris (dibenzylideneacetone) dipalladium (0) (1.32 g) in toluene (80 mL) was stirred at 100 ℃ for 8 hours. After cooling to room temperature, water and ethyl acetate were added thereto, and the mixture was filtered through celite. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 87:13, and then hexane: ethyl acetate = 67:33) to give compound 23A (1.8 g).

LC-MS: [M+H]⁺Rt (min) 281.1/0.948 (method A)

b) A solution of compound 23A (1.25 g), benzophenone imine (1.12 mL), sodium tert-butoxide (642 mg), and palladium (II) [ (2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl) -2- (2' -amino-1, 1' -biphenyl) ] methanesulfonate (354 mg) in toluene (18 mL) was stirred under microwave irradiation at 150 ℃ for 5 hours. After cooling to room temperature, water and ethyl acetate were added thereto, and the mixture was filtered through celite. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (solvent; hexane: ethyl acetate = 87:13, and then hexane: ethyl acetate = 67:33) to give compound 23B (490 mg).

LC-MS: [M+H]⁺Rt (min) 426.3/1.117 (method A)

c) Compound 23B (780 mg) was dissolved in tetrahydrofuran (5.3 ml), and 1 mol/L aqueous hydrochloric acid solution (5.3 ml) was added thereto. The mixture was stirred at room temperature for 4 hours. Saturated sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with a mixed solvent (3:1) of chloroform and ethanol. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (solvent; hexane: ethyl acetate = 87:13, and then ethyl acetate) to give compound 23C (179 mg).

LC-MS: [M+H]⁺Rt (min) 262.1/0.542 (method A)

d) Compound 23C (179 mg) was dissolved in 2-propanol (2.7 ml), and N, N-dimethylformamide dimethyl acetal (0.119 ml) was added thereto. The mixture was stirred at 100 ℃ for 3 hours. Toluene (2.7 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to give compound 23D (212 mg).

LC-MS: [M+H]⁺Rt (min) 317.2/0.598 (method A)

e) Compound 23D (178 mg) was dissolved in 2-propanol (2.7 ml), to which was added 50% aqueous hydroxylamine solution (0.05 ml). The mixture was stirred at 60 ℃ for 6 hours. Water was then added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 67:33, and then hexane: ethyl acetate = 30:70) to give compound 23E (146 mg).

LC-MS: [M+H]⁺Rt (min) 305.2/0.782 (method A)

f) Compound 23E (171 mg) was dissolved in tetrahydrofuran (5.6 ml), and trifluoroacetic anhydride (0.119 ml) was added thereto. The mixture was stirred at room temperature for 21 hours. Saturated sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 83:17, and then hexane: ethyl acetate = 50:50) to give compound 23F (82 mg).

LC-MS: [M+H]⁺Rt (min) 287.2/0.742 (method A)

g) Compound 23F (90 mg) was dissolved in methanol (1.6 ml), and 10% palladium on carbon (17 mg) was added thereto. The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The palladium/carbon was filtered through celite and the eluent was washed with methanol. The eluate was concentrated to give the title compound (47 mg).

LC-MS: [M+H]⁺Rt (min) 153.0/0.294 (method A)

Example 1

N- (4-cyanophenyl) -2- [3- (4-methylpiperidin-1-yl) -6-oxopyridazin-1 (6H) -yl ] acetamide

To a solution of the compound of reference example 2 (1.0 g) in dimethylformamide (14 mL) were added potassium carbonate (1.43 g) and the compound of reference example 1 (1.0 g). After stirring at room temperature for 24 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 2:3, and then ethyl acetate) to obtain the title compound (1.21 g).

¹H-NMR (400 MHz, CDCl₃) δ : 9.79 (s, 1H), 7.63 (dt, J = 9.0, 2.0 Hz, 2H), 7.55 (dt, J = 8.5, 1.8 Hz, 2H), 7.24 (d, J = 9.8 Hz, 1H), 6.93 (d, J = 10.4 Hz, 1H), 4.84 (s, 2H), 3.84 (d, J = 13.4 Hz, 2H), 2.77 (td, J = 12.8, 2.4 Hz, 2H), 1.75-1.68 (m, 2H), 1.58-1.53 (m, 1H), 1.25 (dd, J = 12.5, 4.0 Hz, 1H), 1.19 (dd, J = 12.2, 4.3 Hz, 1H), 0.97 (d, J = 6.7 Hz, 3H)。

Example 2

N- (4-cyanophenyl) -2- [3- (4, 4-dimethylpiperidin-1-yl) -6-oxopyridazin-1 (6H) -yl ] acetamide

A solution of the compound of reference example 3 (60 mg), 4-dimethylpiperidine hydrochloride (93 mg) and diisopropylethylamine (1 mL) in dimethylacetamide (0.5 mL) was stirred at 150 ℃ for 11 hours. After the reaction was completed, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (eluent; 0.035% trifluoroacetic acid in acetonitrile/water) and then by amino silica gel column chromatography (solvent; chloroform: methanol = 99:1, and then 93:7) to give the title compound (22 mg).

¹H-NMR (400 MHz, CDCl₃) δ : 9.78 (s, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 9.8 Hz, 1H), 6.94 (d, J = 10.4 Hz, 1H), 4.84 (s, 2H), 3.32-3.28 (m, 4H), 1.46-1.42 (m, 4H), 0.98 (s, 6H)。

Examples 3 to 36

The compounds of examples 3 to 36 were obtained according to the method of example 1 or 2 and the usual reaction conditions using the corresponding material compounds.

Example 37

N- (4-cyanophenyl) -2- [3- (4, 4-difluorocyclohex-1-en-1-yl) -6-oxopyridazin-1 (6H) -yl ] acetamide

The compound of reference example 3 (1.58 g), the compound of reference example 4 (1.74 g) and 2 mol/L aqueous sodium carbonate solution (6.85 mL) were suspended in 1, 2-dimethoxyethane (25 mL), and 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (401 mg) was added thereto. The mixture was stirred at 80 ℃ for 4 hours under nitrogen atmosphere. After cooling to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol = 99:1, and then 93:7), and recrystallized from ethanol (60 mL) -acetonitrile (20 mL) to give the title compound (1.64 g).

¹H-NMR (400 MHz, CDCl₃) δ : 9.37 (s, 1H), 7.65-7.58 (m, 3H), 7.54 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 9.6 Hz, 1H), 6.22 (s, 1H), 4.99 (s, 2H), 2.82-2.71 (m, 4H), 2.20-2.10 (m, 2H)。

Example 38

N- (4-cyanophenyl) -2- [3- (4, 4-dimethylcyclohexyl) -6-oxopyridazin-1 (6H) -yl ] acetamide

To a solution of the compound of reference example 5 (40 mg) in dimethylformamide (2 mL), potassium carbonate (54 mg) and the compound of reference example 1 (45 mg) were added. After cooling to room temperature for 6 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 1:1, and then 1:4) to obtain the title compound (60 mg).

¹H-NMR (400 MHz, CDCl₃) δ : 9.54 (s, 1H), 7.62 (dt, J = 9.0, 2.2 Hz, 2H), 7.54 (dt, J = 9.1, 2.0 Hz, 2H), 7.27 (d, J = 9.5 Hz, 1H), 7.00 (d, J = 9.6 Hz, 1H), 4.95 (s, 2H), 2.48 (tt, J = 11.9, 3.7 Hz, 1H), 1.73-1.69 (m, 2H), 1.64-1.57 (td, J = 12.8, 3.63 Hz, 2H), 1.55-1.46 (m, 2H), 1.28 (td, J = 13.2, 4.1 Hz, 2H), 0.94 (s, 3H), 0.93 (s, 3H)。

Examples 39 to 49

The compounds of examples 39 to 49 were obtained according to the methods and general reaction conditions of examples 37 and 38 using the corresponding material compounds.

Example 50

N- (1, 3-benzoxazol-5-yl) -2- [3- (methylpiperidin-1-yl) -6-oxopyridazin-1 (6H) -yl ] acetamide

To a suspension of the compound of reference example 6 (50 mg), 1, 3-benzoxazol-5-amine (32 mg) and HATU (91 mg) in acetonitrile (1.5 mL) was added N, N-diisopropylethylamine (0.34 mL), and the mixture was stirred at room temperature for 2 hours. After addition of saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; ethyl acetate: methanol = 100:0, and then 92: 8) to give the title compound (38 mg).

¹H-NMR (400 MHz, CDCl₃) δ : 9.35 (s, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.48 (s, 2H), 7.23 (d, J = 9.8 Hz, 1H), 6.94 (d, J = 9.8 Hz, 1H), 4.86 (s, 2H), 3.86-3.83 (m, 2H), 2.80-2.74 (m, 2H), 1.73-1.70 (m, 2H), 1.61-1.53 (m, 1H), 1.28-1.18 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H)。

Examples 51 to 99

The compounds of examples 51 to 99 were obtained according to the procedure of example 50 and the usual reaction conditions using the corresponding material compounds.

Example 100-

The compounds of example 100-135 were obtained using the corresponding material compounds according to the methods of examples 2, 37, 38 and 50 and the corresponding reaction conditions.

Example 136-

The compounds of example 136-159 were obtained using the corresponding material compounds according to the methods and general reaction conditions of example 37 or 50.

Example 160-

The compounds of example 160-192 were obtained using the corresponding material compounds according to the methods and general reaction conditions of example 1,2 or 50.

Example 193-

The compounds of examples 193-238 were obtained using the corresponding material compounds according to the methods and general reaction conditions of examples 1,2 or 50.

Example 239-

The compounds of examples 239-243 were obtained using the corresponding material compounds according to the methods and general reaction conditions of examples 1, 37 or 50.

Example 244

N- [2- (dimethylamino) -1, 3-benzooxazol-5-yl ] -2- [3- (4-methylcyclohex-1-en-1-yl) -6-oxopyridazin-1 (6H) -yl ] acetamide

To the compound of reference example 16 (45 mg), N²,N²To a suspension of-dimethyl-1, 3-benzoxazole-2, 5-diamine (39 mg) and HATU (90 mg) in acetonitrile (1.8 mL) was added N, N-diisopropylethylamine (0.13 mL), and the mixture was stirred at room temperature for 2 hours. After addition of saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; ethyl acetate: methanol = 100:0, and then 96:4) to obtain the title compound (75 mg).

¹H-NMR (400 MHz, CDCl₃) δ : 8.68 (s, 1H), 7.60 (d, J = 9.8 Hz, 1H), 7.50 (s, 1H), 7.21-7.14 (m, 2H), 6.98 (d, J = 9.8 Hz, 1H), 6.38 (s, 1H), 4.97 (s, 2H), 3.20 (s, 6H), 2.70-2.60 (m, 1H), 2.41-2.30 (m, 2H), 1.92-1.82 (m, 2H), 1.80-1.67 (m, 1H), 1.35-1.25 (m, 1H), 1.03 (d, J = 6.1 Hz, 3H)。

Example 245-

The compounds of examples 245-424 were obtained using the corresponding material compounds according to the methods and general reaction conditions of examples 1, 37 or 50.

Example 425-

The compounds of example 425-445 were obtained using the corresponding material compounds according to the methods and general reaction conditions of example 1, 37 or 50.

Example 446-

The compounds of examples 446-455 were obtained using the corresponding material compounds according to the methods and general reaction conditions of examples 1, 37 or 50.

Example 456-

The compounds of example 456-467 were obtained using the corresponding material compounds according to the methods and general reaction conditions of example 1, 37 or 50.

Example 468-

The compound of example 468-481 was obtained using the corresponding material compound according to the procedures and general reaction conditions of example 1, 37, 38 or 50.

Example 482-

The compounds of examples 482-490 were obtained using the corresponding material compounds according to the methods and general reaction conditions of examples 1, 37 or 50.

Example 491-

The compound of example 491-534 was obtained using the corresponding material compound according to the method of example 1, 37 or 50 and the ordinary reaction conditions.

Examples 535 and 536

The cis-trans isomer (35.5 mg) of the compound obtained in example 472 was resolved by chiral column chromatography to give the following compound (examples 535 and 536):

[ resolution conditions ]

Detection equipment SPD-M20A (Shimadzu Corporation)

HPLC: LC-20AT (Shimadzu Corporation)

Column: waters ACQUITY UPLC (trademark) BEH C18(1.7 um, 2.1 mm x 30 mm)

Column: CHIRALPAK IA (Daicel Corporation) (S-5 μm, 20X 250 mm)

Elution conditions 0.0-60.0 (min): A/B = 55:45

Solvent A hexane containing 0.1% diethylamine

Solvent B-containing 0.1% diethylamine (isopropanol: methanol = 2:1)

Flow rate of 10 ml/min

UV: 220 nm

The column temperature was 40 deg.C

	Examples	Retention time (min.)	Yield (mg)	Purity of
					Front peak	535	31.5	13.5	99.9%
End peak	536	41.5	14.0	99.8%

Examples 537 and 538

The optical isomers of the compound obtained in example 330 were resolved by chiral column chromatography to obtain the following compounds (examples 537 and 538):

[ resolution conditions ]

Detection equipment SPD-M20A (Shimadzu Corporation)

HPLC: LC-20AT(Shimadzu Corporation)

Column: CHIRALPAK AY-H (Daicel corporation) (S-5 μm, 20X 250 mm)

Elution conditions 0.0-80.0 (min): A/B = 65:35

Solvent A hexane

Solvent B isopropanol

Flow rate of 10 ml/min

UV: 220 nm

The column temperature was 40 deg.C

	Examples	Retention time (min.)	Yield (mg)	Optical purity
					Front peak	537	43.5	4.5	87.8%ee
End peak	538	56	4.8	98.6%ee

Examples 539 and 540

An optical isomer (13.7 mg) of the compound obtained in example 339 was resolved by chiral column chromatography to obtain the following compound (examples 539 and 540):

[ resolution conditions ]

Detection equipment SPD-M20A (Shimadzu Corporation)

HPLC: LC-20AT (Shimadzu Corporation)

Column: CHIRALPAK AY-H (Daicel corporation) (S-5 μm, 20X 250 mm)

Elution conditions 0.0-80.0 (min): A/B = 50:50

Solvent A hexane

Solvent B isopropanol

Flow rate of 10 ml/min

UV: 220 nm

The column temperature was 40 deg.C

	Examples	Retention time (min.)	Yield (mg)	Optical purity
					Front peak	539	39.8	4.5	99%ee
End peak	540	52.5	7.6	98.2%ee

Example 541-

The compounds of examples 541-571 were obtained using the corresponding material compounds according to the procedure and general reaction conditions of example 50.

Test of

Hereinafter, the results of pharmacological tests of representative compounds herein are described, and the pharmacological effects of each compound are explained, but the present invention is not limited to the following tests.

Test 1 evaluation of Nav1.1-derived Voltage-dependent sodium Using cell lines stably expressing human Nav1.1 Amplification of the Current (Nav1.1 Current)

(1) Preparation of test Compounds

Test compounds were prepared as follows: was dissolved in DMSO at 200 times the concentration at the time of evaluation, and the resulting solution was applied to an extracellular fluid (135 mmol/L NaCl, 4 mmol/L KCl, 1 mmol/L MgCl)₂, 5 mmol/L CaCl₂5 mmol/L glucose, 10 mmol/L HEPES) to 2-fold the concentration at the time of evaluation.

(2) Induction and measurement of Nav1.1 Current

HEK293 cell line stably expressing human Nav1.1 (Cat. CYL3009, Millipore, USA, human embryonic kidney 293) was purchased and used in this experiment. By stimulating the Ramp wave voltage, Nav1.1 current is induced. The detection of the current with the voltage stimulus was performed by a patch clamp voltage clamping method using an HTS automated patch clamp system (SynchroPatch 768PE, Nanion Technologies GmbH, germany). Only cells with voltage-dependent sodium channel currents in excess of 500 pA were used to evaluate the activity of compounds on Nav1.1 currents, since the following possibilities existed: the current derived from endogenous voltage-dependent sodium channels is a large proportion of cells with voltage-dependent sodium channel currents of less than 500 pA, which are induced by stimulation of Ramp wave voltage.

(3) Pharmacological Effect on Nav1.1 Current

The effect of test compounds on the amplification of Nav1.1-derived voltage-dependent sodium current was evaluated using a cell line stably expressing human Nav1.1 and an HTS automated patch clamp system. In other words, test compounds were added to an extracellular fluid containing 1% DMSO and evaluated as the change in the peak of the nav1.1 current and the area under the curve (AUC).

(4) Pharmacological evaluation method

The Nav1.1 current amplification of the test compound was calculated by the following formula:

nav1.1 Current amplification (%) = 100 x [ Peak value of Nav1.1 Current or area under Curve after test Compound addition ]/[ Peak value of Nav1.1 Current or area under Curve before test Compound addition ]/[ 100

Test 2 evaluation of Nav1.5-derived Voltage-dependent sodium Using cell lines stably expressing human Nav1.5 Amplification of the Current (Nav1.5 Current)

A CHO-K1 cell line (Chinese hamster ovary) stably expressing human Nav1.5 was obtained using the purchased T-Rex System (ThermoFisher Scientific, USA) (Gene Bank Accession No: P-000326.2) and used in the present experiment. Similar to the method using Nav1.1, the effect of test compounds on the amplification of Nav1.5 current was evaluated using a cell line stably expressing human Nav1.5 and an HTS automated patch clamp system. In other words, test compounds were added to extracellular fluid containing 1% DMSO and 500 nmol/L tetrodotoxin (TTX) and evaluated as the change in the peak of Nav1.5 current and the area under the curve (AUC). The method of inducing and measuring Nav1.5 current, pharmacological effect on Nav1.5 current and pharmacological evaluation was accomplished by the same method as in Nav1.1.

Test results 1

Based on the change in area under the curve of Nav1.1 current, the effect of representative compounds herein on the activation of Nav1.1 (Nav1.1 current amplification) was evaluated and found to have an effect on the amplification of Nav1.1 current. Also based on the Nav1.5 current curve under the area change, evaluation on Nav1.5 activation effect (Nav1.5 current amplification rate). When each compound concentration is 10 u mol/L, Nav1.1 current amplification (%) and Nav1.5 current amplification (%) are shown in the table below.

Test results 2

When the concentration of each compound is 3. mu. mol/L, Nav1.1 current amplification (%) and Nav1.5 current amplification (%) of the representative compounds herein are shown in the following table.

Test results 3

When the concentration of each compound is 1. mu. mol/L, Nav1.1 current amplification (%) and Nav1.5 current amplification (%) of the representative compounds herein are shown in the following table.

Test results 4

When each compound concentration is 50 u mol/L, representative compounds of the Nav1.1 current amplification (%) shown in the table below.

Test results 5

When each compound concentration is 10 u mol/L, representative compounds of the Nav1.1 current amplification (%) shown in the table below.

Test results 6

When each compound concentration is 1 u mol/L, representative compounds of the Nav1.1Current amplification (%) shown in the table below.

Test results 7

The Nav1.1 current amplification (%) of representative compounds herein is shown in the following table.

For evaluation of antiepileptics, evaluation in the Maximal Electroshock Seizure (MES) model (which has high clinical predictability), evaluation in the subcutaneous pentaazan model (minimal convulsion model, scPTZ), and evaluation in the 6 Hz psychomotor seizure model (which is resistant to existing antiepileptics) can be used.

Test 3 evaluation in the model of maximal electroshock epileptic seizure (MES)

This test was performed to evaluate the anticonvulsant effect of the drug. The animal models used in this trial were phenotypes of generalized tonic clonic seizures and secondary generalized partial seizures. ddY male mice (20-30 g body weight) were administered test compound and electrically stimulated through the cornea (60 Hz, 25 mA, 0.2 sec) 15 minutes to 3 hours after administration. Anticonvulsant effects can be demonstrated by observing the inhibition of induced tonic stretch seizures in the hind limbs.

Test 4 evaluation in the subcutaneous pentaazan model (minimal convulsions model, scPTZ)

This test was performed similarly to the MES model to evaluate the anticonvulsant effect of the drug. The animal models used in this experiment are the phenotypes of generalized absence seizures and myoclonic seizures. ddY male mice (20-30 g body weight) were administered with the test compound and 15 minutes to 3 hours after administration, the mice were subcutaneously administered with 85 mg/kg pentaerythrite. Anticonvulsant effects can be confirmed by observing the onset or absence of clonic seizures within 30 minutes.

Test 5 evaluation in a 6 Hz psychomotor seizure model

This test was performed to evaluate the anticonvulsant effect of the drug. The animal model used in this experiment is a phenotype of seizures resistant to existing antiepileptic drugs. Ddy male mice (20-30 g body weight) were administered test compound and electrically stimulated through the cornea (6 Hz, 32 mA, 3 seconds) 15 minutes to 3 hours after administration. Anticonvulsant effects can be demonstrated by observing the onset or absence of induced clonic seizures in the forelimbs, Straub tail response and akinesia.

Test 6 rotating rod Performance test

This test was performed to evaluate the inhibition of coordinated movement by the drug. Ddy male mice (20-30 g body weight) were trained to walk without falling on a rotating rod device (which rotated a cylindrical rod with a diameter of 4 cm at 13 revolutions per minute) for 3 minutes one day before or on the day of the experiment. The test compounds were administered to the trained mice, 1 hour after administration, placed on the upper rotating bar apparatus, and subjected to movement observation at 15 rpm for up to 180 seconds. When the mice dropped within 180 seconds, they were walked again (re-testing was performed a maximum of 2 times). Inhibition of coordinated locomotion can be demonstrated by evaluating the longest walking time among the largest of 3 trials.

Test 7 evaluation of inhibition of febrile seizures Using SCN 1A-mutated animals

This experiment was performed to evaluate the inhibitory effect of drugs on febrile seizures expressed due to loss of function mutations in SCN1A gene. The animal model used in this experiment had a deletion mutation in the SCN1A gene (similar to Dravet syndrome) and is a phenotype of Dravet syndrome, which shows febrile seizures by elevation of body temperature. This animal model can be purchased from RIKEN BioResource Research Center (line: BALB/c-Scn1a < + >, catalog number: RBRC 06422).

Mice (18-23 g) with loss-of-function mutations in the SCN1A gene were administered test compounds. The plastic chamber was heated with a 43 ℃ warm bath to raise the internal temperature, and within 20 minutes after application, the mice were placed in the chamber. Heating was continued to raise their body temperature. The inhibitory effect of the test compound on the induction of febrile seizures can be confirmed by comparing the rectal temperature of the test group with that of the untreated group (in which the test compound was not administered) within 1 hour after the placement in the room at the onset of seizures, or when the mice did not express seizures.

INDUSTRIAL APPLICABILITY

The compound of the present invention has a significant Nav1.1 activating effect and can be a drug effective in the treatment and/or prevention of Nav1.1-related diseases and various central nervous system diseases.

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Pyridazinone derivatives

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