WO2021039961A1 - Dérivé de pyrazole à cycle condensé - Google Patents

Dérivé de pyrazole à cycle condensé Download PDF

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WO2021039961A1
WO2021039961A1 PCT/JP2020/032589 JP2020032589W WO2021039961A1 WO 2021039961 A1 WO2021039961 A1 WO 2021039961A1 JP 2020032589 W JP2020032589 W JP 2020032589W WO 2021039961 A1 WO2021039961 A1 WO 2021039961A1
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alkyl
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良雄 中井
浩平 岩本
昌門 岩田
一 柴田
智也 城
亮 深澤
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to pharmaceutically useful fused pyrazole derivatives and pharmaceutically acceptable salts thereof, and diseases involving sodium channels (particularly Nav1.1) containing them as active ingredients and various central nervous system diseases. And / or prophylactic agents.
  • Nav1.1 is one of voltage-gated sodium channels (VGSC) and is expressed in Palvalbmin positive GABA neurons (PV-GABA neurons) and the like. It is known to be important for its nerve firing function. GABAergic expression of Nav1.1 in patients with central nervous system disorders such as schizophrenia, autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) It has been suggested that neuronal function is impaired (Non-Patent Documents 1 and 2). In addition, the heterozygous function deletion mutation of the SCN1A gene is the cause of epilepsy syndrome such as Dravet syndrome (Infant Severe Myoclonic Epilepsy) and Generalized epilepsy with febrile seizure plus (GEFS +). Has been reported (Non-Patent Document 1).
  • Dravet syndrome Infant Severe Myoclonic Epilepsy
  • GEFS + Generalized epilepsy with febrile seizure plus
  • Dravet syndrome is a serious epileptic encephalopathy in children who develops in infancy under 1 year old and presents with various epileptic seizures including febrile convulsions and status epilepticus.
  • Valproic acid has been used as a first-line drug in the drug therapy of Dravet syndrome, but its effectiveness against epileptic seizures is low.
  • clobazam and stiripentol have been used as second-line drugs, they are less effective against seizures and only a limited number of patients are given stiripentol because it can only be used in combination with valproic acid or clobazam.
  • drugs that activate the function of Nav1.1 improve a wide range of central nervous system diseases such as schizophrenia, ASD, ADHD and epilepsy, as well as cognitive dysfunction and epilepsy attacks associated therewith. It is expected to be a therapeutic agent for diseases.
  • Examples of the compound that regulates the function of Nav1.1 include N. N'-(1,3-phenylene) bis (2-methylbenzamide) (Non-Patent Document 3), PF-05661014 (Non-Patent Document 4), AA43279 (Non-Patent Document 5), Lu AE98134 (Non-Patent Document 6) , 4-Phenyl-2- (pyrrolidinyl) nicotine amide derivative (Non-Patent Document 7) and the like are known, but their chemical structures are different from those of the compound of the present invention.
  • Nav1.5 one of the other subtypes of potential-dependent sodium channels, is highly expressed in the heart and contributes to the formation of PR intervals, QRS widths and QT intervals in the electrocardiogram, and conducts electrical conduction between the atria and ventricles. It is known to be involved in the contraction and relaxation of ventricular muscles. Anti-arrhythmic drugs with Nav1.5 inhibitory activity are known to prolong the PR interval and QRS complex in the electrocardiogram, so when Nav1.5 is activated, the PR interval, QRS width and QT interval in the electrocardiogram It is believed that changes, atrial-ventricular electrical conduction, ventricular muscle contraction and relaxation, etc. may occur.
  • One of the problems to be solved by the present invention is a fused pyrazole derivative useful as a therapeutic agent and / or a preventive agent for diseases associated with Nav1.1 and various central nervous system diseases and / or pharmaceuticals thereof. It is to provide an acceptable salt and a drug containing them as an active ingredient.
  • the present inventors may refer to the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as "the compound of the present invention”).
  • the compound of the present invention Has a strong Nav1.1 activating effect and can be a useful drug for the treatment and / or prevention of Nav1.1-related diseases and various central nervous system diseases, and to complete the present invention. I arrived.
  • Equation (1) [In the equation, Y 1 , Y 2 and Y 3 independently represent N or CR 2; R 1 is substituted with a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species, and 1 to 3 halogen atoms of the same or different species. May be C 3-6 cycloalkyl, may be substituted with 1 to 3 halogen atoms of the same or different species, or C 1-6 alkoxy or 1 to 2 C 1 to 6 alkyl of the same or different species.
  • R 2 may be independently substituted with hydrogen atom, halogen atom, cyano, 1 to 3 halogen atoms of the same type or different types, if there are a plurality of C 1-6 alkyl, 1 of the same type or different types.
  • M 1 is (1-1) Saturated or partially unsaturated C 4-12 carbocyclic group (where the group is (A) Halogen atom, (B) Hydroxy, (C) a halogen atom, hydroxy and C 1-6 1 ⁇ 3 amino C 1-6 alkyl optionally substituted with a group of same or different selected from the group consisting of alkoxy, (D) a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, (E) Substituted with 1 to 2 C 1-6 alkyls of the same or different species (where the C 1-6
  • C 1-6 alkyl which may be amino, and (f) the same or different 1-2 C 1-6 alkyl (wherein said C 1-6 alkyl is substituted with one to three halogen atoms the same or different It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of amino-carbonyls which may be substituted with), (1-2) 4- to 12-membered saturated or partially unsaturated heterocyclic group (where the group is (A) Halogen atom, (B) Hydroxy, (C) a halogen atom, hydroxy and C 1-6 1 ⁇ 3 amino C 1-6 alkyl optionally substituted with a group of same or different selected from the group consisting of alkoxy, (D) a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, (E) C 3-6 cycloalkyl, which may be substituted with 1 to 3 halogen
  • a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, (F) the same or different 1-2 C 1-6 alkyl (wherein said C 1-6 alkyl, may be substituted by 1-3 halogen atoms the same or different) substituted with Amino, which may be, and (g) one or two homologous or heterologous C 1-6 alkyls (where the C 1-6 alkyl is substituted with one or three homologous or heterologous halogen atoms.
  • a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, (F) the same or different 1-2 C 1-6 alkyl (wherein said C 1-6 alkyl, may be substituted by 1-3 halogen atoms the same or different) substituted with Amino, which may be, and (g) one or two homologous or heterologous C 1-6 alkyls (where the C 1-6 alkyl is substituted with one or three homologous or heterologous halogen atoms.
  • (D) A 5- to 10-membered heteroaryl optionally substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl and C 1-6 alkoxy. It may be substituted with one or two groups of the same or different species selected from the group consisting of), (1-6) C 6-10 aryloxy (where the group is (A) Halogen atom, (B) Hydroxy, (C) Cyano, (D) C 1-6 alkyl, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy.
  • a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, (F) the same or different 1-2 C 1-6 alkyl (wherein said C 1-6 alkyl, may be substituted by 1-3 halogen atoms the same or different) substituted with Amino, which may be, and (g) one or two homologous or heterologous C 1-6 alkyls (where the C 1-6 alkyl is substituted with one or three homologous or heterologous halogen atoms.
  • C C 6-10 aryl, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl and C 1-6 alkoxy, or (D) A 5- to 10-membered heteroaryl optionally substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl and C 1-6 alkoxy.
  • C C 6-10 aryl, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl and C 1-6 alkoxy, or (D) A 5- to 10-membered heteroaryl optionally substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl and C 1-6 alkoxy.
  • (C) C 6-10 aryl which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl and C 1-6 alkoxy, or (D) A 5- to 10-membered heteroaryl optionally substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl and C 1-6 alkoxy. It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of), or (1-11) -NR e R f. (Here, Re and R f are independent of each other.
  • C 3-10 cycloalkyl May be C 3-10 cycloalkyl, (D) C 3-10 cycloalkyl C 1 which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl.
  • M 2 is (2-1) The following formula (2a) or (2b): [In the equation, X 1a , X 1b , X 1c , X 5 , X 6 , X 7 and X 8 independently represent N or CR 3; X 2 , X 3 and X 4 independently represent CR 3 , O, S, N or NR 4; A 1 and A 2 independently represent N or C; Here, X 1a , X 1b , X 1c , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , A 1 and A 2 have 9 or 10 rings containing them.
  • R 3 is (A) Hydrogen atom, (B) Halogen atom, (C) Cyano, (D) Hydroxy, (E) 4- to 7-membered saturated heterocyclic groups optionally substituted with halogen atoms, hydroxy, saturated or partially unsaturated C 3-7 carbocyclic groups, C 1-6 alkoxy, C 1-6 alkoxy and May be substituted with 1 to 2 C 1-6 alkyl of the same or different species C 1-6 may be substituted with 1 to 3 groups of the same or heterologous selected from the group consisting of aminos.
  • C 1-6 alkoxy which may be substituted with a group of (H) a halogen atom, hydroxy and C 1-6 C 1-6 alkyl optionally substituted with one to three groups the same or different are selected from the group consisting of alkoxy; saturated or partially unsaturated C It consists of a 3-7 carbocyclic group; and a C 2-7 alkylcarbonyl that may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy.
  • Amino which may be substituted with one or two homologous or heterologous groups selected from the group.
  • (I) A 5- or 6-membered heteroaryl, optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano and C 1-6 alkyl.
  • (J) A 4- to 7-membered saturated or optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy, C 1-6 alkyl and C 1-6 alkoxy.
  • R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may be combined with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated heterocyclic group).
  • R 4 is, (A) Hydrogen atom, C 1-6 alkyl, or (c) halogen atom, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of (b) halogen atom, hydroxy and C 1-6 alkoxy, A saturated or partially unsaturated C 3-7 carbocyclic group which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of hydroxy, C 1-6 alkyl and C 1-6 alkoxy.
  • each R 3 and R 4 may be the same or different.
  • C 1-6 alkyl (E) Saturated or partially unsaturated C which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, C 1-6 alkyl and C 1-6 alkoxy. 3-7 Carbocyclic groups, (F) a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, (G) Consists of C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species; saturated or partially unsaturated C 3-7 carbocyclic groups; and C 2-7 alkylcarbonyl.
  • Amino which may be substituted with one or two homologous or heterologous groups selected from the group.
  • H A 5- or 6-membered heteroaryl, optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano and C 1-6 alkyl.
  • I 4- to 7-membered saturation or optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy, C 1-6 alkyl and C 1-6 alkoxy.
  • R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may form a 4- to 7-membered saturated heterocycle together with the nitrogen atom to which they bind).
  • C 2-7 alkylcarbonyl may be substituted with 1 to 3 halogen atoms of the same or different species, or (l) may be substituted with 1 to 3 halogen atoms of the same or different species.
  • C 1-6 alkyl which may be substituted with 1 to 3 groups of the same or different species selected from (E) C 3-6 cycloalkyl, which may be substituted with 1 to 3 halogen atoms of the same or different species.
  • F The same species selected from the group consisting of halogen atoms, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and aminos optionally substituted with one or two C 1-6 alkyls of the same or different species.
  • a saturated or partially unsaturated C 3-7 carbocyclic group which may be substituted with 1 to 4 different groups.
  • G 1 to 3 of the same or different species selected from the group consisting of halogen atoms, hydroxy, C 1-6 alkoxy and aminos optionally substituted with 1 to 2 C 1-6 alkyls of the same or different species.
  • C 1-6 alkoxy which may be substituted with a group of (H) a halogen atom, hydroxy and C 1-6 C 1-6 alkyl optionally substituted with one to three groups the same or different are selected from the group consisting of alkoxy; saturated or partially unsaturated C It consists of a 3-7 carbocyclic group; and a C 2-7 alkylcarbonyl that may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy.
  • Amino which may be substituted with one or two homologous or heterologous groups selected from the group.
  • Substituents may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl, C 1-6 alkoxy and C 2-7 alkoxycarbonyl. 5 or 6 member heteroaryl,
  • a halogen atom, hydroxy and C 1-6 1 ⁇ 3 amino C 1-6 alkyl optionally substituted with a group of same or different selected from the group consisting of alkoxy; C 1-6 alkoxy; 4 ⁇ 7-membered saturated or partially unsaturated heterocyclic group; C 2 which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy and C 1-6 alkoxy.
  • R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may form a 4- to 7-membered saturated heterocycle together with the nitrogen atom to which they bind).
  • R Z stands for C 1-6 alkyl
  • R 8 and R 9 together with the carbon atom to which they are attached, are a 5- to 7-membered saturated or partially unsaturated carbon ring or heterocycle (where the rings are halogen atoms and C. It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkyl)].
  • Bond represents a single bond;
  • X 15 represents NR 17 or O; R 11, when there are a plurality of independently, (A) Hydrogen atom, (B) Halogen atom, (C) A 5- or 6-membered heteroaryl optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl and C 1-6 alkoxy. , (D) A 5- or 6-membered heteroaryl optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyanos, C 1-6 alkyls and C 1-6 alkoxys.
  • R 12 and R 14 or R 13 and R 14 may be combined with the carbon atoms to which they are attached to form a crosslinked structure
  • R 15 is, (A) Phenyl, which may be substituted with one or two homologous or dissimilar groups selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl and C 1-6 alkoxy.
  • R 16 is (A) Phenyl, which may be substituted with one or two homologous or dissimilar groups selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl and C 1-6 alkoxy.
  • B A group consisting of halogen atom, cyano, C 1-6 alkyl optionally substituted with 1 to 3 fluorine atoms and C 1-6 alkoxy optionally substituted with 1 to 3 fluorine atoms.
  • a 5- or 6-membered heteroaryl which may be substituted with one or two homologous or heterologous groups selected from (C) A 5- or 6-membered heteroaryl optionally substituted with one or two homologous or heterologous groups selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl and C 1-6 alkoxy. Methyl, (D) 5- or 6-membered saturated or partially unsaturated carbocyclic groups that may be substituted with 1 to 3 halogen atoms of the same or different species, or (e) 1 to 3 halogens of the same or different species.
  • R 17 is (A) Pyridyl, which may be substituted with one or two groups of the same or different species selected from the group consisting of halogen atoms, cyano, C 1-6 alkyl and C 1-6 alkoxy, or (b) the same.
  • R 18 is, (A) Phenyl, which may be substituted with one or two groups of the same or different species selected from the group consisting of halogen atom, cyano, C 1-6 alkyl and C 1-6 alkoxy, or (b) halogen.
  • a benzyl optionally substituted with one or two homologous or heterologous groups selected from the group consisting of atomic, cyano, C 1-6 alkyl and C 1-6 alkoxy; k 1 and k 2 independently represent 0 or 1;
  • the nitrogen-containing saturated ring in the formula (2p) may be substituted with oxo].
  • Amino which may be substituted with one or two homologous or heterologous groups selected from the group.
  • E A 5- or 6-membered heteroaryl, optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano and C 1-6 alkyl.
  • F 4- to 7-membered saturation or optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy, C 1-6 alkyl and C 1-6 alkoxy.
  • R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may be combined with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated heterocyclic group).
  • R 5 and R 6 together with the carbon atoms to which they are attached, are 5- to 7-membered saturated or partially unsaturated carbon or heterocycles (where the rings are halogens.
  • C 1-6 alkyl optionally substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of alkoxy; saturated or partially unsaturated C 3-7 carbocyclic groups; C 1-6 alkoxy A 4- to 7-membered saturated heterocyclic group optionally substituted with; and 1 to 3 homogeneous or heterologous groups selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy.
  • C 1-6 alkyl May be substituted with one or two homologous or heterologous groups selected from the group consisting of C 2-7 alkylcarbonyl) 1 to 3 homologous or heterologous groups selected from the group consisting of C 1-6 alkyl, which may be substituted with (E) a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, (F) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species; saturated or partially unsaturated C 3-7 carbocyclic groups; and halogen atoms, hydroxy and C 1-.
  • E a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group
  • F C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different
  • (J) -C (O) NR x Ry (Here, R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may form a 4- to 7-membered saturated heterocycle together with the nitrogen atom to which they bind).
  • R 8 and R 9 together with the carbon atom to which they are attached, are a 5- to 7-membered saturated or partially unsaturated carbon ring or heterocycle (where the rings are halogen atoms and C. It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkyl)]. It is a group represented by
  • 2d in the formulas (2d), (2f), (2g) and (2h), one fluorine atom may be further substituted on the substitutable carbon atom on the ring, or (4) the following formula.
  • M 2 is (1) the following formulas (2a-1), (2a-2), (2a-12), (2a-20), (2a-21), (2b-3), (2b-). 4), (2b-7) or (2b-10): [In the formula, X 1a , X 1b and R 3 are synonymous with [1] above] Group represented by, (2) The following formula (2c'): [In the formula, R 5 and R 6 are independent of each other.
  • M 1 From the group consisting of halogen atoms; and C 1-6 alkyl which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy. Saturated or partially unsaturated C 4-12 carbocyclic groups, which may be substituted with 1 to 4 groups of the same or different species of choice.
  • a 4- to 12-membered saturated or partially unsaturated heterocyclic group which may be substituted with 1 to 4 groups of the same or different species selected, or (3) -NR e R f. And Re and R f are independent of each other.
  • C C 3-10 cycloalkyl, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl
  • D C 3-10 cycloalkyl C 1 which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl.
  • Y 1 is N; Y 2 and Y 3 are independently N or CR 2 ; R 1 is substituted with a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species, and 1 to 3 halogen atoms of the same or different species. May be C 3-6 cycloalkyl, may be substituted with 1 to 3 halogen atoms of the same or different species, or C 1-6 alkoxy or 1 to 2 C 1 to 6 alkyl of the same or different species.
  • R 2 may be independently substituted with hydrogen atom, halogen atom, cyano, 1 to 3 halogen atoms of the same type or different types, if there are a plurality of C 1-6 alkyl, 1 of the same type or different types.
  • C 3-6 cycloalkyl optionally substituted with ⁇ 3 halogen atoms, C 1-6 alkoxy optionally substituted with 1-3 halogen atoms of the same or different species or 1 of the same or heterogeneous Amino that may be substituted with two C 1-6 alkyls;
  • M 1 is (1) From the group consisting of halogen atoms; and C 1-6 alkyl which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy.
  • Saturated or partially unsaturated C 4-12 carbocyclic groups which may be substituted with 1 to 4 groups of the same or different species of choice.
  • C C 3-10 cycloalkyl, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl
  • D C 3-10 cycloalkyl C 1 which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl.
  • M 2 is (1) The following equations (2a-1), (2a-2), (2a-12), (2a-20), (2a-21), (2b-3), (2b-4), (2b-) 7) or (2b-10): [In the formula, X 1a , X 1b and R 3 are synonymous with [1] above] Group represented by, (2) The following formula (2c'): [In the formula, it is synonymous with [3] above] It is a group represented by Here, in the formula (2c'), one fluorine atom may be further substituted on the substitutable carbon atom on the ring.
  • M 2 is the following formula (2a-20), (2a-21), (2b-3), (2b-4) or (2b-7):
  • X 1a and X 1b independently represent N or CR 3; R 3, when there are a plurality of independently, (A) Hydrogen atom, (B) Halogen atom, (C) Cyano, (D) Hydroxy, (E) 4- to 7-membered saturated heterocyclic groups optionally substituted with halogen atoms, hydroxy, saturated or partially unsaturated C 3-7 carbocyclic groups, C 1-6 alkoxy, C 1-6 alkoxy and May be substituted with 1 to 2 C 1-6 alkyl of the same or different species C 1-6 may be substituted with 1 to 3 groups of the same or heterologous selected from the group consisting of aminos.
  • C 1-6 alkoxy optionally substituted with 1 to 3 groups of the same or different type selected from the group consisting of (h) halogen atom, hydroxy and C 1-6 alkoxy.
  • M 2 is the following formula (2a'-20), (2a'-21), (2b'-3), (2b'-4) or (2b'-7): Wherein, R 3, when there are a plurality of independently, (A) Hydrogen atom, (B) Halogen atom, (C) Cyano, (D) 4- to 7-membered saturated heterocyclic groups optionally substituted with halogen atoms, hydroxy, saturated or partially unsaturated C 3-7 carbocyclic groups, C 1-6 alkoxy, C 1-6 alkoxy and May be substituted with 1 to 2 C 1-6 alkyl of the same or different species C 1-6 may be substituted with 1 to 3 groups of the same or heterologous selected from the group consisting of aminos.
  • R 3 when there are a plurality of independently, (A) Hydrogen atom, (B) Halogen atom, (C) Cyano, (D) 4- to 7-membered saturated heterocyclic groups optionally substituted with halogen atoms, hydroxy, saturated or partially unsaturated C 3
  • M 2 is the following formula (2d) or (2f): [In the formula, R 8 , R 9 and R 10 are independent of each other.
  • C 1-6 alkyl optionally substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of alkoxy; saturated or partially unsaturated C 3-7 carbocyclic groups; C 1-6 alkoxy A 4- to 7-membered saturated heterocyclic group optionally substituted with; and 1 to 3 homogeneous or heterologous groups selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy.
  • C 1-6 alkyl May be substituted with one or two homologous or heterologous groups selected from the group consisting of C 2-7 alkylcarbonyl) 1 to 3 homologous or heterologous groups selected from the group consisting of C 1-6 alkyl, which may be substituted with (E) a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, (F) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species; saturated or partially unsaturated C 3-7 carbocyclic groups; and halogen atoms, hydroxy and C 1-.
  • E a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group
  • F C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different
  • (J) -C (O) NR x Ry (Here, R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may form a 4- to 7-membered saturated heterocycle together with the nitrogen atom to which they bind).
  • R 8 and R 9 together with the carbon atom to which they are attached, are a 5- to 7-membered saturated or partially unsaturated carbon ring or heterocycle (where the rings are halogen atoms and C. It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkyl)].
  • R 8 , R 9 and R 10 are independent of each other.
  • A Hydrogen atom
  • B Halogen atom
  • C Cyano
  • D a halogen atom, hydroxy, hydroxy or C 1-6 optionally alkoxy substituted C 1-6 alkoxy; and amino (wherein the amino is a halogen atom, hydroxy and C 1-6 alkoxy C 1-6 alkyl optionally substituted with 1 to 3 groups of the same or heterologous selected from the group; and homologous or heterologous selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy.
  • C 2-7 alkylcarbonyls which may be substituted with 1 to 3 groups, may be substituted with 1 to 2 groups of the same or different species).
  • C 1-6 alkyl which may be substituted with 1 to 3 groups of the same or different species.
  • E C 1-6 alkoxy which may be substituted with 1 to 3 groups of the same or different type selected from the group consisting of halogen atom, hydroxy and C 1-6 alkoxy, or (f) the same or different type.
  • M 1 is expressed by the following equation (3): [In the formula, X 16 represents N, C or CH; Bonds containing dashed lines represent single or double bonds; m represents 0, 1, 2 or 3; R a and R b are independent of each other. (1-1) Hydrogen atom, C 1 which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of (1-2) halogen atoms or (1-3) halogen atoms, hydroxy and C 1-6 alkoxy. Does it represent -6 alkyl?
  • Ra and R b together with the carbon atom to which they are attached, are a 3- to 6-membered saturated carbon ring (where the ring is: (A) Halogen atom, (B) Hydroxy, (C) a halogen atom, hydroxy and C 1-6 the same or different one to three C 1-6 alkyl optionally substituted with a group selected from the group consisting of alkoxy, and (d) a halogen atom, 1 to 4 of the same or different species selected from the group consisting of hydroxy and C 1-6 alkoxy, which may be substituted with 1 to 3 groups of the same or different species selected from the group of C 1-6 alkoxy. May be replaced by groups) May form]
  • M 1 is ⁇ NR e R f , and Re and R f are independent of each other.
  • A Hydrogen atom
  • B C 1-6 alkyl, which may be substituted with 1 to 3 halogen atoms of the same or different species.
  • C C 3-10 cycloalkyl, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl
  • C 3-10 cycloalkyl C 1 which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl.
  • M 1 is ⁇ NR e R f , and Re and R f are independent of each other
  • A Hydrogen atom
  • C C 1-6 alkyl, which may be substituted with 1 to 3 halogen atoms of the same or different species.
  • C C 3-10 cycloalkyl, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl, or
  • C 3-10 cycloalkyl C 1 which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl.
  • -4 The compound according to any one of [1] to [10], which is alkyl, or a pharmaceutically acceptable salt thereof.
  • M 1 is ⁇ NR e R f , and Re is methyl
  • R f is (A) C 1-6 alkyl, which may be substituted with 1 to 3 halogen atoms of the same or different species.
  • C C 3-10 cycloalkyl C 1 which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl.
  • M 1 has the following equations (3a-1) to (3a-4): The compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof, which is a group represented by any of the above.
  • M 1 has the following formulas (3c-1) to (3c-6): The compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof, which is a group represented by any of the above.
  • M 1 has the following equations (3d-1) to (3d-12): The compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof, which is a group represented by any of the above.
  • R 2 When there are a plurality of R 2 , they are independently hydrogen atom, halogen atom, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy, [1] to [23].
  • R 2 When there are a plurality of R 2 , they are independently hydrogen atom, halogen atom, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 alkoxy, [1] to [23].
  • R 2 is, when a plurality of each independently a hydrogen atom or a halogen atom, [1] A compound or a pharmaceutically acceptable salt thereof according to any one of - [23] ..
  • a therapeutic and / or prophylactic agent for central nervous system diseases which comprises the compound according to any one of [1] to [30] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Agent
  • a therapeutic agent for a disease associated with a functional decline of Nav1.1 which contains the compound according to any one of [1] to [30] or a pharmaceutically acceptable salt thereof as an active ingredient. / Or a preventive agent.
  • Central nervous system disease is febrile seizure (FS); generalized epilepsy with febrile seizure plus; GEFS +; epilepsy (specifically, localization-related epilepsy) epilepsy), generalized epilepsy); epilepsy syndrome (Dravet syndrome, intractable childhood epilepsy with generalized tonic-clonic seizures; ICE-GTC), Epilepsy with myochrony weakness (Doose syndrome), West syndrome, Lennox-Gastaut syndrome, severe infantile multifocal epilepsy; SIMFE Severe myoclonic epilepsy (borderline; SMEB), benign familial neonatal-infantile epilepsy (BFNIE), etc.); Schizophrenia; autism spectrum disorder (autism spectrum)
  • the therapeutic and / or prophylactic agent according to [33] or [36], which is at least one disease selected from the group consisting of disorder; ASD); and attention deficit hyperactivity disorder (ADHD). ..
  • a therapeutically effective amount of the compound according to any one of [1] to [30] or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment.
  • the compound of the present invention may exhibit a significant Nav1.1 activating effect. Moreover, in some embodiments, it may exhibit a selective effect on Nav1.1 as compared to other subtypes of voltage-gated sodium channels (eg, Nav1.5). Therefore, the compounds of the present invention are expected to be useful as therapeutic and / or prophylactic agents for diseases associated with Nav1.1 and various central nervous system diseases.
  • the number of carbons in the definition of "substituent” may be expressed as, for example, “C 1-6".
  • C 1-6 alkyl is synonymous with an alkyl group having 1 to 6 carbon atoms.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, it is “C 1-4 alkyl”. Specific examples of “C 1-6 alkyl” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, Examples thereof include 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • C 1-10 alkyl means a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms. Preferably, it is “C 1-6 alkyl”. Specific examples of “C 1-10 alkyl” include, for example, heptyl, 2-methyl-3,3-dimethylbutyl, octyl, and 2,4-dimethylhexyl, in addition to the specific examples of "C 1-6 alkyl”. , Nonyl, decyl, 4-ethyl-2-methylheptyl and the like.
  • C 2-7 alkylcarbonyl means a carbonyl group substituted with the “C 1-6 alkyl”.
  • C 2-4 alkylcarbonyl is mentioned.
  • Specific examples of the “C 2-7 alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, normalpropylcarbonyl, isopropylcarbonyl and the like.
  • C 1-6 alkoxy means a substituted oxy group in the "C 1-6 alkyl", “C 1-6 alkyl” moiety of the “C 1-6 alkoxy", the “C 1- It is synonymous with “ 6 alkyl”. Preferably, it is “C 1-4 alkoxy”. Specific examples of “C 1-6 alkoxy” include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • C 1-10 alkoxy refers to a substituted oxy group at the "C 1-10 alkyl", “C 1-10 alkyl” portion of the “C 1-10 alkoxy", the "C 1- It is synonymous with “ 10 alkyl”.
  • it is "C 1-6 alkoxy”.
  • Specific examples of "C 1-10 alkoxy” include, for example, heptyloxy, 2-methyl-3,3-dimethylbutoxy, octyloxy, 2,4-, in addition to the specific example of "C 1-6 alkoxy”. Examples thereof include dimethylhexyloxy, nonyloxy, decyloxy and 4-ethyl-2-methylheptyloxy.
  • C 2-7 alkoxycarbonyl means a carbonyl group substituted with the “C 1-6 alkoxy”.
  • C 2-5 alkoxycarbonyl is mentioned.
  • Specific examples of “C 2-7 alkoxycarbonyl” include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like.
  • C 2-10 alkenyl means a linear or branched unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing 1 to 3 carbon-carbon double bonds. It is preferably “C 2-6 alkenyl”. Specific examples of “C 2-10 alkenyl” include ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
  • C 2-10 alkynyl means a linear or branched unsaturated hydrocarbon group having 2 to 10 carbon atoms and containing 1 to 3 carbon-carbon triple bonds. It is preferably “C 2-6 alkynyl”. Specific examples of “C 2-10 alkynyl” include ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
  • C 3-10 cycloalkyl means a cyclic saturated or partially unsaturated hydrocarbon group having 3 to 10 carbon atoms, and includes crosslinked and partially unsaturated hydrocarbon groups.
  • the "C 3-10 cycloalkyl” is preferably “C 3-6 cycloalkyl”. Specific examples of “C 3-6 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 3-10 cycloalkyl include, for example, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl and the like, in addition to those mentioned as specific examples of "C 3-6 cycloalkyl”. ..
  • “Saturated or partially unsaturated C 3-7 carbocyclic groups” means 3- to 7-membered monocyclic or polycyclic cyclic saturated or partially unsaturated hydrocarbon groups. Preferably, it is a "saturated or partially unsaturated C 5-7 carbocyclic group". Specific examples of the "saturated or partially unsaturated C 3-7 carbocyclic group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and the like.
  • “Saturated or partially unsaturated C 4-12 carbocyclic groups” means 4- to 12-membered monocyclic or polycyclic cyclic saturated or partially unsaturated hydrocarbon groups. Preferably, it is a "saturated or partially unsaturated C 4-6 carbocyclic group". Specific examples of the "saturated or partially unsaturated C 4-12 carbocyclic group” include, for example, cyclo in addition to those mentioned as the specific example of the "saturated or partially unsaturated C 3-7 carbocyclic group”. Examples thereof include octyl, cyclodecyl and cyclododecyl.
  • the "saturated or partially unsaturated C 4-12 carbocyclic group” also includes a condensed or crosslinked saturated or partially unsaturated bicyclo ring and a saturated or partially unsaturated spiro ring. Specific examples include, for example, groups represented by the following groups.
  • “5- or 6-membered saturated or partially unsaturated carbocyclic group” means a 5- to 6-membered monocyclic saturated or partially unsaturated hydrocarbon group.
  • Specific examples of the "5- or 6-membered saturated or partially unsaturated carbocyclic group” include, for example, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and the like.
  • the "5- to 7-membered saturated or partially unsaturated hydrocarbon ring” means a monocyclic or bicyclic saturated or partially unsaturated hydrocarbon ring having 5 to 7 carbon atoms and is partially unsaturated. It also includes those having a saturated bond, those having a fused ring structure, those having a crosslinked structure, and those having a spiro ring.
  • Specific examples of the "5- to 7-membered saturated or partially unsaturated carbocycle” include, for example, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene, cycloheptadiene and the like.
  • the "3- to 6-membered saturated carbocycle” means a saturated hydrocarbon ring having 3 to 6 carbon atoms, including those forming a spiro ring.
  • Specific examples of the "3- to 6-membered saturated carbocycle” include cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.
  • 5- or 6-membered heteroaryl means a 5- or 6-membered aromatic heterocyclic group, which comprises one homologous or heterologous heteroatom selected from nitrogen, sulfur and oxygen atoms.
  • the above (for example, 1 to 4) may be contained and appropriately substituted with oxo.
  • Specific examples of the "5- or 6-membered heteroaryl” include groups represented by the following formulas.
  • it is imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazil, or pyridazole; Pilazil, or pyridadyl.
  • C 6-10 aryl means an aromatic hydrocarbon ring group having 6 to 10 carbon atoms. Specific examples of “C 6-10 aryl” include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like. Preferred is phenyl.
  • the "C 6-10 aryl” also includes a bicyclic one in which the C 6-10 aryl and a C 4-6 cycloalkyl or a 5- to 6-membered saturated heterocycle form a fused ring. Specific examples of the bicyclic "C 6-10 aryl" forming a fused ring include groups represented by the following.
  • C 6-10 aryloxy means an oxy group substituted with the "C 6-10 aryl".
  • Specific examples of “C 6-10 aryl” include, for example, phenyloxy, naphthyloxy and the like, preferably phenyloxy.
  • Examples of the "5- to 10-membered heteroaryl” include a 5- to 10-membered monocyclic or 9- or 10-membered bicyclic aromatic heterocyclic group, and the group includes a nitrogen atom and a sulfur atom. And one or more (for example, 1 to 4) heteroatoms of the same type or different types selected from oxygen atoms may be contained and appropriately substituted with oxo.
  • Bicyclic heteroaryl groups also include those in which the monocyclic heteroaryl group is fused with an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexane, piperidine, etc.).
  • Specific examples of the "5- to 10-membered heteroaryl” include those given as specific examples of the "5- or 6-membered heteroaryl", as well as groups represented by the following formulas.
  • the "5- to 10-membered heteroaryloxy” means an oxy group substituted with the "5- to 10-membered heteroaryl".
  • Specific examples of the "5- to 10-membered heteroaryloxy” include, for example, pyridyloxy, imidazolyloxy, furyloxy and the like, preferably pyridyloxy.
  • Bonding across a ring as used herein means that the "group” is attached at a substitutable position in the ring.
  • the "4- to 7-membered saturated or partially unsaturated heterocyclic group” includes, for example, a 4- to 7-membered single having 1 to 2 homologous or heterologous atoms selected from nitrogen, oxygen and sulfur atoms. Cyclic or polycyclic saturated or partially unsaturated heterocyclic groups and the like can be mentioned. Preferably, it is a "5- to 7-membered saturated or partially unsaturated heterocyclic group".
  • 5- to 7-membered saturated or partially unsaturated heterocyclic groups include pyranyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuryl, dihydropyrrolill, dihydrofuranyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl. , Dioxanyl, azepanyl, morpholinyl, thiomorpholinyl and the like.
  • Specific examples of the "4- to 7-membered saturated or partially unsaturated heterocyclic group” include azetidinyl in addition to those listed as specific examples of the "5- to 7-membered saturated or partially unsaturated heterocyclic group".
  • the "4- to 7-membered saturated heterocyclic group” include azetidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperazinyl, dioxanyl, azepanyl, morpholinyl, thiomorpholinyl and the like.
  • the bond of the group may be either on a carbon atom or a nitrogen atom constituting the ring.
  • the "4- to 12-membered saturated or partially unsaturated heterocyclic group” includes, for example, a 4- to 12-membered single having 1 to 3 homologous or heterologous atoms selected from nitrogen, oxygen and sulfur atoms. Cyclic or polycyclic saturated or partially unsaturated heterocyclic groups and the like can be mentioned. It is preferably a 4- to 10-membered saturated or partially unsaturated heterocyclic group. Specifically, in addition to those listed as specific examples of the "4- to 7-membered saturated or partially unsaturated heterocyclic group", azocanyl, 1,4-oxazocanyl, 1,5-oxazocanyl, 1,4- Examples thereof include diazocanyl and 1,5-diazocanyl.
  • the bond of the group may be either on a carbon atom or a nitrogen atom constituting the ring.
  • “4- to 7-membered saturated or partially unsaturated heterocyclic groups” and “4 to 12-membered saturated or partially unsaturated heterocyclic groups” include condensed or cross-linked saturated or partially unsaturated bicyclocycles and Saturated or partially unsaturated spirocycles are also included.
  • Specific examples of the "4- to 7-membered saturated or partially unsaturated heterocyclic group” include groups represented by the following groups.
  • Specific examples of the "4- to 12-membered saturated or partially unsaturated heterocyclic group” include groups represented by the following groups.
  • the "nitrogen-containing saturated ring” includes a saturated heterocycle containing one or more nitrogen atoms as a ring-constituting atom.
  • Specific examples of the "nitrogen-containing saturated ring” include azetidine, pyrrolidine, piperidine and the like.
  • a "9 or 10-membered bicyclic aromatic heterocycle” is 9 or 10 including 1 to 3 heteroatoms of the same or different species selected from the group consisting of oxygen, nitrogen and sulfur atoms. It means a bicyclic aromatic heterocycle composed of the atoms of the above, and may be appropriately substituted with oxo.
  • the oxygen atoms and sulfur atoms of the carbonyl, sulfinyl, sulfonyl and thiocarbonyl constituting the bicyclic aromatic heterocycle are 9 or 10-membered numbers (ring size) and the heteros constituting the ring. Not included in the atom.
  • 9 or 10-membered bicyclic aromatic heterocycle include, for example, quinoline, isoquinoline, naphthylidine, quinazoline, quinoxalin, benzofuran, benzothiophene, indol, benzoxazole, benzoisoxazole, benzimidazole, benzo.
  • Examples thereof include oxadiazol, benzothiazol, indolidin, benzofuran, indazole, pyrazolopyridine, imidazolepyridine, triazolopyridine, imidazolepyridazine, imidazolepyridazine, thiazolopyridine, pyrazolopyrimidine, triazolopyridazine and flopyridine.
  • a "3- to 6-membered saturated heterocycle” is composed of 3 to 6 atoms, including one or two heteroatoms of the same or different species selected from the group consisting of oxygen, nitrogen and sulfur atoms. It means a monocyclic or bicyclic saturated heterocycle to be used, and includes those forming a spiro ring. Further, the saturated heterocycle may be appropriately substituted with oxo, and may contain one or two carbonyls, thiocarbonyls, sulfinyls or sulfonyls.
  • the oxygen atoms of carbonyl, sulfinyl and sulfonyl are not included in the number of 3 to 6 members (ring size) and the heteroatoms constituting the ring, and the sulfur atom of thiocarbonyl is 3 to 6 members. It is not included in the number (ring size) and the heteroatoms that make up the ring.
  • the "3- to 6-membered saturated heterocycle” is preferably a "5- or 6-membered saturated heterocycle". Specific examples of the "5- or 6-membered saturated heterocycle” include, but are not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, tetrahydropyran and the like.
  • Specific examples of the "3- to 6-membered saturated heterocycle” include aziridine, azetidine, and the like, in addition to those mentioned as specific examples of the "5- or 6-membered saturated heterocycle".
  • specific examples of the "6-membered saturated heterocycle” include piperidine, morpholine, tetrahydropyran and the like.
  • the "4- to 7-membered saturated or partially unsaturated heterocyclic group-oxy" means an oxy group substituted with the above-mentioned "4 to 7-membered saturated or partially unsaturated heterocyclic group”.
  • R 5 and R 6 form a 5- to 7-membered saturated or partially unsaturated carbon ring or heterocycle formed together with the carbon atom to which they are bonded.
  • Specific examples of the above include, for example, a group represented by the following formula.
  • R a and R b form a 3- to 6-membered saturated carbon ring and a 3- to 6-membered saturated heterocycle formed together with the carbon atom to which they are bonded, they are represented by the formula (3).
  • Specific examples of the group include a group represented by the following formula.
  • Y 1 , Y 2 and Y 3 are preferably N or CR 2 independently of each other. More preferably, there is an embodiment in which Y 1 is N and Y 2 and Y 3 are N or CR 2 independently of each other. In another aspect of Y 1 , Y 2 and Y 3 , Y 1 is N and Y 2 and Y 3 are CR 2 . In yet another embodiment, Y 1 and Y 2 are N and Y 3 is CR 2 . In yet another embodiment, Y 1 and Y 3 are N and Y 2 is CR 2 . As yet another aspect of the Y 1, Y 2 and Y 3, Y 1, Y 2 and Y 3 are CR 2. As a further aspect, Y 1, Y 2 and Y 3 are N.
  • R 1 preferably, hydrogen atom, halogen atom, cyano, C 1-6 alkyl which may be substituted with 1 to 3 halogen atoms of the same kind or different kinds, or 1 to 3 halogen atoms of the same kind or different kinds Examples thereof include C 3-6 cycloalkyl which may be substituted with, and more preferably, hydrogen atom, halogen atom, cyano, C 1-6 alkyl or C 3-6 cycloalkyl.
  • R 1 is more preferably a hydrogen atom, a halogen atom or a C 1-3 alkyl, particularly preferably a hydrogen atom or a halogen atom, and most preferably a hydrogen atom.
  • R 2 preferably, hydrogen atom, halogen atom, cyano, C 1-6 alkyl which may be substituted with 1 to 3 halogen atoms of the same kind or different kinds, or 1 to 3 halogen atoms of the same kind or different kinds Examples thereof include C 3-6 cycloalkyl which may be substituted with, and more preferably, hydrogen atom, halogen atom, cyano, C 1-6 alkyl or C 3-6 cycloalkyl.
  • R 2 more preferably a hydrogen atom, halogen atom or C 1-3 alkyl, particularly preferably include hydrogen atom or a halogen atom, and most preference given to a hydrogen atom.
  • M 1 preferably (1) From the group consisting of halogen atoms; and C 1-6 alkyl which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy. Saturated or partially unsaturated C 4-12 carbocyclic groups, which may be substituted with 1 to 4 groups of the same or different species selected. (2) From the group consisting of halogen atoms; and C 1-6 alkyl which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy.
  • a 4- to 12-membered saturated or partially unsaturated heterocyclic group which may be substituted with 1 to 4 groups of the same or different species selected, or (3) -NR e R f.
  • Re and R f are independent of each other.
  • A Hydrogen atom
  • B C 1-6 alkyl, which may be substituted with 1 to 3 halogen atoms of the same or different species.
  • C C 3-10 cycloalkyl, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl
  • D C 3-10 cycloalkyl C 1 which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl.
  • Halogen atoms and substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1 to 3 halogen atoms of the same or different species, which may be substituted with C 1-6 alkyl.
  • Saturated or partially unsaturated C 4-12 carbocyclic groups which may be (2) Halogen atoms; and substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1 to 3 halogen atoms of the same or different species, which may be substituted with C 1-6 alkyl. It may be a 4- to 12-membered saturated or partially unsaturated heterocyclic group, or (3) -NR e R f.
  • Re and R f are independent of each other.
  • -4 Alkyl may be used.
  • X 16 represents N, C or CH; Bonds containing dashed lines represent single or double bonds; m represents 0, 1, 2 or 3; R a , R b , R c and R d are independent of each other.
  • halogen atoms, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy of three may be substituted by C 1-6 alkoxy or (1-6 )
  • Ra and R b together with the carbon atoms to which they are bonded,
  • (2-1) A 3- to 6-membered saturated carbocyclic ring (where, the ring is (A) Halogen atom, (B) Hydroxy, (C) a halogen atom, hydroxy and C 1-6 the same or different one to three C 1-6 alkyl optionally substituted with a group selected from the group consisting of alkoxy, and (d) a halogen atom, 1 to 4 of the same or different species selected from the group consisting of hydroxy and C 1-6 alkoxy, which may be substituted with 1 to 3 groups of the same or
  • X 16 is C or N
  • m is 1 or 2
  • Ra and R b are independently hydrogen atoms and halogens, respectively. It is a C 1-6 alkyl which may be substituted with an atom or 1 to 3 halogen atoms of the same kind or a different kind, and examples thereof include cases where R c and R d are hydrogen atoms.
  • Equation (3a) [In the formula, m represents 0, 1, 2 or 3; R a , R b , R c , and R d are independent of each other. (1-1) Hydrogen atom, (1-2) Halogen atom, (1-3) Hydroxy, (1-4) C 1-6 alkyl, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C 1-6 alkoxy.
  • halogen atoms, hydroxy, and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy of three may be substituted by C 1-6 alkoxy or (1- 6)
  • Ra and R b together with the carbon atoms to which they are bonded,
  • (2-1) A 3- to 6-membered saturated carbocyclic ring (where, the ring is (A) Halogen atom, (B) Hydroxy, (C) a halogen atom, hydroxy, and C 1-6 1 ⁇ 3 amino C 1-6 alkyl optionally substituted with a group of same or different selected from the group consisting of alkoxy, and (d) a halogen atom , hydroxy, and C 1-6 1 the same or different are selected from the group consisting of a C 1-6 alkoxy optionally with one to
  • Equation (3b) [In the formula, m represents 0, 1, 2 or 3; R a , R b , R c , and R d are independent of each other. (1-1) Hydrogen atom, (1-2) Halogen atom, (1-3) Hydroxy, (1-4) C 1-6 alkyl, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C 1-6 alkoxy.
  • halogen atoms, hydroxy, and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy of three may be substituted by C 1-6 alkoxy or (1- 6)
  • Ra and R b together with the carbon atoms to which they are bonded,
  • (2-1) A 3- to 6-membered saturated carbocyclic ring (where, the ring is (A) Halogen atom, (B) Hydroxy, (C) a halogen atom, hydroxy, and C 1-6 1 ⁇ 3 amino C 1-6 alkyl optionally substituted with a group of same or different selected from the group consisting of alkoxy, and (d) a halogen atom , hydroxy, and C 1-6 1 the same or different are selected from the group consisting of a C 1-6 alkoxy optionally with one to
  • Equation (3c) [In the formula, m represents 0, 1, 2 or 3; R a , R b , R c , and R d are independent of each other. (1-1) Hydrogen atom, (1-2) Halogen atom, (1-3) Hydroxy, (1-4) C 1-6 alkyl, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, and C 1-6 alkoxy.
  • halogen atoms, hydroxy, and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy of three may be substituted by C 1-6 alkoxy or (1- 6)
  • Ra and R b together with the carbon atoms to which they are bonded,
  • (2-1) A 3- to 6-membered saturated carbocyclic ring (where, the ring is (A) Halogen atom, (B) Hydroxy, (C) a halogen atom, hydroxy, and C 1-6 1 ⁇ 3 amino C 1-6 alkyl optionally substituted with a group of same or different selected from the group consisting of alkoxy, and (d) a halogen atom , hydroxy, and C 1-6 1 the same or different are selected from the group consisting of a C 1-6 alkoxy optionally with one to
  • M 1 in -NR e R f (wherein, R e and R f each independently, (A) Hydrogen atom, (B) C 1-6 alkyl, which may be substituted with 1 to 3 halogen atoms of the same or different species. (C) C 3-10 cycloalkyl, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl, (D) C 3-10 cycloalkyl C 1 which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, C 1-6 alkyl and C 3-6 cycloalkyl.
  • M 1 As another preferred embodiment of M 1 , the following formulas (3a-1), (3a-2), (3a-3), (3a-4), (3a-5), (3a-6), (3b) -1), (3b-2), (3b-3), (3b-4), (3c-1), (3c-2), (3c-3), (3c-4), (3c-5) ), (3c-6), (3c-7), (3d-1), (3d-2), (3d-3), (3d-4), (3d-5), (3d-6), (3d-7), (3d-8), (3d-9), (3d-10), (3d-11), (3d-12), (3d-13) or (3d-14): It is a group represented by. More preferably, the formulas (3a-1), (3a-2), (3a-3), (3a-4), (3c-2), (3c-3), (3c-4), (3d-). It is a group represented by 1), (3d-2), (3d-3), (3d-4), (3d-5), (3d-6) or (3d-7).
  • C 1-6 alkyl May be C 1-6 alkyl, (F) Saturated or partially unsaturated, optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy.
  • C 3-7 carbocyclic group (G) a halogen atom, hydroxy, and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, (H) Consists of C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species; saturated or partially unsaturated C 3-7 carbocyclic groups; and C 2-7 alkylcarbonyl.
  • Amino which may be substituted with one or two homologous or heterologous groups selected from the group.
  • 5- or 6-membered saturation which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, C 1-6 alkyls, and C 1-6 alkoxys.
  • R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl, or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may be combined with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated heterocyclic group).
  • each R 3 may be the same or different;
  • R 4 is, (A) Hydrogen atom, (B) C 1-6 alkyl, or (c) halogen atom, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy.
  • Saturated or partially unsaturated C 3-7 carbons which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy.
  • (E) A 5- or 6-membered heteroaryl, optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano and C 1-6 alkyl.
  • R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may be combined with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated heterocyclic group).
  • R 5 and R 6 together with the carbon atoms to which they are attached, are 5- to 7-membered saturated or partially unsaturated carbon or heterocycles (where the rings are halogens.
  • C 1-6 alkyl optionally substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of alkoxy; saturated or partially unsaturated C 3-7 carbocyclic groups; C 1-6 alkoxy A 4- to 7-membered saturated heterocyclic group optionally substituted with; and 1 to 3 homogeneous or heterologous groups selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy.
  • C 1-6 alkyl May be substituted with one or two homologous or heterologous groups selected from the group consisting of C 2-7 alkylcarbonyl) 1 to 3 homologous or heterologous groups selected from the group consisting of C 1-6 alkyl, which may be substituted with (E) a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, (F) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species; saturated or partially unsaturated C 3-7 carbocyclic groups; and halogen atoms, hydroxy and C 1-.
  • E a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group
  • F C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different
  • (J) -C (O) NR x Ry (Here, R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may form a 4- to 7-membered saturated heterocycle together with the nitrogen atom to which they bind).
  • R 8 and R 9 together with the carbon atom to which they are attached, are a 5- to 7-membered saturated or partially unsaturated carbon ring or heterocycle (where the rings are halogen atoms and C. It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkyl)].
  • the group represented by (here, in the formulas (2d), (2f), (2g) and (2h), one fluorine atom may be further substituted on the substitutable carbon atom on the ring). Any of the following groups can be mentioned.
  • M 2 the following formula (2a ') or (2b'): [In the equation, X 2 , X 5 , X 6 , X 7 and X 8 independently represent N, CR 21 or O, respectively. A 1 and A 2 independently represent N or C, respectively.
  • X 2 , X 5 , X 6 , X 7 , X 8 , A 1 , and A 2 the ring containing these is formed so that a 9- or 10-membered bicyclic aromatic heterocycle is formed. Selected; R 21 and R 22 are independent of each other.
  • Hydrogen atom (2) Halogen atom, (3) Cyano, (4) Substituentally substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy, saturated or partially unsaturated C 3-7 carbocyclic groups, and C 1-6 alkoxy. May be C 1-6 alkyl, (5) Saturated or partially unsaturated, which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, C 1-6 alkyls, and C 1-6 alkoxys.
  • C 3-7 carbocyclic group (6) a halogen atom, hydroxy, and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy of three may be substituted by C 1-6 alkoxy or (7), the same or Selected from the group consisting of C 1-6 alkyl optionally substituted with 1 to 3 heterologous halogen atoms; saturated or partially unsaturated C 3-7 carbocyclic groups; and C 2-7 alkylcarbonyl.
  • M 2 Another aspect of M 2, the following formula (2a-1) ⁇ (2a -23) and (2b-1) ⁇ (2b -11): [In the equation, X 1a or X 1b independently represent N or CR 3; R 3 is (A) Hydrogen atom, (B) Halogen atom, (C) Cyano, (D) Hydroxy, (E) Substituentally substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of halogen atoms, hydroxy, saturated or partially unsaturated C 3-7 carbocyclic groups, and C 1-6 alkoxy.
  • C 1-6 alkyl May be C 1-6 alkyl, (F) Saturated or partially unsaturated, optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy.
  • C 3-7 carbocyclic group (G) a halogen atom, hydroxy, and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, (H) Consists of C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species; saturated or partially unsaturated C 3-7 carbocyclic groups; and C 2-7 alkylcarbonyl.
  • Amino which may be substituted with one or two homologous or heterologous groups selected from the group.
  • 5- or 6-membered saturation which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, hydroxys, C 1-6 alkyls, and C 1-6 alkoxys.
  • R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl, or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may be combined with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated heterocyclic group).
  • each R 3 may be the same or different;
  • R 4 is, (A) Hydrogen atom, (B) C 1-6 alkyl, or (c) halogen atom, which may be substituted with 1 to 3 groups of the same or different species selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy.
  • R 5 and R 6 are independent of each other.
  • A Hydrogen atom
  • B Halogen atom
  • C Cyano
  • D Consists of C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species; saturated or partially unsaturated C 3-7 carbocyclic groups; and C 2-7 alkylcarbonyl.
  • Amino which may be substituted with one or two homologous or heterologous groups selected from the group.
  • (E) A 5- or 6-membered heteroaryl, optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyano and C 1-6 alkyl.
  • R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may be combined with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated heterocyclic group).
  • R 5 and R 6 together with the carbon atoms to which they are attached, are 5- to 7-membered saturated or partially unsaturated carbon or heterocycles (where the rings are halogens.
  • C 1-6 alkyl optionally substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of alkoxy; saturated or partially unsaturated C 3-7 carbocyclic groups; C 1-6 alkoxy A 4- to 7-membered saturated heterocyclic group optionally substituted with; and 1 to 3 homogeneous or heterologous groups selected from the group consisting of halogen atoms, hydroxy and C 1-6 alkoxy.
  • C 1-6 alkyl May be substituted with one or two homologous or heterologous groups selected from the group consisting of C 2-7 alkylcarbonyl) 1 to 3 homologous or heterologous groups selected from the group consisting of C 1-6 alkyl, which may be substituted with (E) a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, (F) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species; saturated or partially unsaturated C 3-7 carbocyclic groups; and halogen atoms, hydroxy and C 1-.
  • E a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group
  • F C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different
  • (J) -C (O) NR x Ry (Here, R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may form a 4- to 7-membered saturated heterocycle together with the nitrogen atom to which they bind).
  • R 8 and R 9 together with the carbon atom to which they are attached, are a 5- to 7-membered saturated or partially unsaturated carbon ring or heterocycle (where the rings are halogen atoms and C. It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of 1-6 alkyl)]. It is a group represented by Here, in the formulas (2d), (2f), (2g) and (2h), one fluorine atom may be further substituted on the substitutable carbon atom on the ring. The group is mentioned.
  • R 8 , R 9 and R 10 are independent of each other.
  • A Hydrogen atom
  • B Halogen atom
  • C Cyano
  • D Halogen atom
  • hydroxy may be substituted with hydroxy or C 1-6 alkoxy C 1-6 alkoxy; may be substituted with C 1-6 alkyl or C 1-6 alkoxy 4-7 members Saturated or partially unsaturated heterocyclic groups; 5- or 6-membered heteroaryls optionally substituted with C 1-6 alkyl; and aminos (where the aminos are halogen atoms, hydroxy, and C 1-.
  • C 1-6 alkyl optionally substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of 6 alkoxys; saturated or partially unsaturated C 3-7 carbocyclic groups; C 1-6 4- to 7-membered saturated heterocyclic groups optionally substituted with alkoxy; and substituted with 1 to 3 homologous or heterologous groups selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy.
  • 1 to 3 of the same or different species selected from the group consisting of 1 to 2 groups of the same or different species selected from the group consisting of C 2-7 alkylcarbonyl which may be substituted.
  • C 1-6 alkyl which may be substituted with a group of (E) a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three C 1-6 alkoxy optionally substituted by group, C 3-7 carbocyclic group, saturated or partially unsaturated;; (f) halogen substituted with atoms C 1-6 alkyl and halogen atoms, selected from hydroxy, and from the group consisting of C 1-6 alkoxy Amino, which may be substituted with 1 to 2 groups of the same or heterogeneous, selected from the group consisting of C 2-7 alkylcarbonyls which may be substituted with 1 to 3 groups of the same or heterologous.
  • a 4- to 7-membered saturated or partially unsaturated heterocyclic group optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of C 2-7 alkylcarbonyl; and oxo.
  • a 4- to 7-membered saturated or partially unsaturated heterocyclic group-oxy optionally substituted with 1 to 4 C 1-6 alkyls.
  • R x and R y each independently represent a hydrogen atom, a C 1-6 alkyl, or a saturated or partially unsaturated C 3-7 carbocyclic group; Alternatively, R x and R y may form a 4- to 7-membered saturated heterocycle together with the nitrogen atom to which they bind).
  • K -C (O) OR Z (where R Z stands for C 1-6 alkyl), or (l) with ethenyl optionally substituted with one 6-membered saturated heterocyclic group.
  • R 8 and R 9 together with the carbon atom to which they are attached, are a 5- to 7-membered saturated or partially unsaturated carbocycle or heterocycle (where the ring is a halogen atom, and It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of C 1-6 alkyl)].
  • the groups represented by are mentioned.
  • Y 2 and Y 3 are independently N or CR 2 ;
  • R 1 is a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl or a C 3-6 cycloalkyl;
  • R 2 is a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl or a C 3-6 cycloalkyl, respectively, if there is more than one;
  • M 1 is a saturated or partially unsaturated C 4-12 carbocyclic group which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms and C 1-6 alkyl.
  • M 2 is represented by the formulas (2a-1), (2a-2), (2a-12), (2a-20), (2a-21), (2b-3), (2b-4), (2b-). 7) or a group represented by (2b-10);
  • X 1a and X 1b are independently N or CR 3 ;
  • R 3 is a hydrogen atom, a halogen atom, a cyano, a hydroxy, a C 1-6 alkyl or a C 1-6 alkoxy, respectively, if there is more than one;
  • Another embodiment of the compound represented by the formula (1) includes the following (B).
  • (B) Y 2 and Y 3 are independently N or CR 2 ;
  • R 1 is a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl or a C 3-6 cycloalkyl;
  • R 2 is a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl or a C 3-6 cycloalkyl, respectively, if there is more than one;
  • M 1 is a 4- to 12-membered saturated or partially unsaturated heterocyclic group optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms and C 1-6 alkyl.
  • M 2 is represented by the formulas (2a-1), (2a-2), (2a-12), (2a-20), (2a-21), (2b-3), (2b-4), (2b-). 7) or a group represented by (2b-10);
  • X 1a and X 1b are independently N or CR 3 ;
  • R 3 is a hydrogen atom, a halogen atom, a cyano, a hydroxy, a C 1-6 alkyl or a C 1-6 alkoxy, respectively, if there is more than one;
  • Y 2 and Y 3 are independently N or CR 2 ;
  • R 1 is a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl or a C 3-6 cycloalkyl;
  • R 2 is a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl or a C 3-6 cycloalkyl, respectively, if there is more than one;
  • M 1 is -NR e R f ; Re and R f are independent of each other.
  • M 2 is represented by the formulas (2a-1), (2a-2), (2a-12), (2a-20), (2a-21), (2b-3), (2b-4), (2b-). 7) or a group represented by (2b-10);
  • X 1a and X 1b are independently N or CR 3 ;
  • R 3 is a hydrogen atom, a halogen atom, a cyano, a hydroxy, a C 1-6 alkyl or a C 1-6 alkoxy, respectively, if there is more than one;
  • Y 2 and Y 3 are independently N or CR 2 ;
  • R 1 is a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl or a C 3-6 cycloalkyl;
  • R 2 is a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl or a C 3-6 cycloalkyl, respectively, if there is more than one;
  • M 1 is a saturated or partially unsaturated C 4-12 carbocyclic group which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms and C 1-6 alkyl.
  • M 2 is a group represented by the formula (2d) or (2f);
  • R 8 , R 9 and R 10 are independently hydrogen atoms, halogen atoms, cyano, C 1-6 alkyl or C 1-6 alkoxy;
  • Y 2 and Y 3 are independently N or CR 2 ;
  • R 1 is a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl or a C 3-6 cycloalkyl;
  • R 2 is a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl or a C 3-6 cycloalkyl, respectively, if there is more than one;
  • M 1 is a 4- to 12-membered saturated or partially unsaturated heterocyclic group optionally substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms and C 1-6 alkyl.
  • M 2 is a group represented by the formula (2d) or (2f);
  • R 8 , R 9 and R 10 are independently hydrogen atoms, halogen atoms, cyano, C 1-6 alkyl or C 1-6 alkoxy;
  • Y 2 and Y 3 are independently N or CR 2 ;
  • R 1 is a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl or a C 3-6 cycloalkyl;
  • R 2 is a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl or a C 3-6 cycloalkyl, respectively, if there is more than one;
  • M 1 is -NR e R f ; Re and R f are independent of each other.
  • M 2 is a group represented by the formula (2d) or (2f);
  • R 8 , R 9 and R 10 are independently hydrogen atoms, halogen atoms, cyano, C 1-6 alkyl or C 1-6 alkoxy;
  • Specific examples of the compound of the present invention include the compounds shown in Examples described later or pharmaceutically acceptable salts thereof, and among them, the compounds shown in the following compound group can be mentioned as specific examples.
  • Examples of “pharmaceutically acceptable salts” include acid addition salts, base addition salts and amino acid salts.
  • an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, or citrate, oxalate, phthalate, Fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonic acid
  • organic acid salts such as salts and camphor sulfonates.
  • the base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminum salt, or trimethylamine, triethylamine, pyridine, picoline, 2,6-rutidine, ethanolamine, and diethanolamine. , Triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, N, N-dibenzylethylamine and other salts with organic bases.
  • the amino acid salt include amino acid salts with basic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid, or acidic amino acids.
  • the compound of the present invention includes all crystalline forms.
  • the compound represented by the formula (1) may have at least one asymmetric carbon atom. Therefore, the compound of the present invention includes not only the racemate of the compound represented by the formula (1) but also the optical isomers of these compounds. Also included in either one or the compounds represented by more than one 1 deuterium converter converted to H and 2 H (D) be the formula (1) of the compound represented by formula (1) .. Some of the compounds represented by the formula (1) may have metamutants such as keto-enol, positional isomers, geometric isomers or optical isomers. All possible isomers and mixtures of the isomers in any proportion are also included in the invention.
  • the compound represented by the formula (1) may exist in the form of a hydrate or a solvate (for example, an ethanol solvate) with various solvents such as water or ethanol, and hydration thereof. Substances and solvates are also included in the present invention.
  • the compound of the present invention may be synthesized by a method combining the production methods shown below and a known synthesis method.
  • the compounds in the reaction formula include the case where each compound forms a salt, and examples of the salt include the same as the above-mentioned "pharmaceutically acceptable salt". It should be noted that these reactions are merely examples, and the compound of the present invention can be appropriately produced by another method based on the knowledge of a person who is proficient in synthetic organic chemistry.
  • the functional group is protected as necessary.
  • the desired product may be obtained by deprotecting after completion of the reaction or after performing a series of reactions.
  • protecting group examples include literature (TW Greene and PGM Wuts, ⁇ Protective Groups in Organic Synthesis'', 3rd Ed., John Willey and Sons, Inc., 19 (Inc., 19), New. ) And the like, and more specifically, as the protecting group for the amino group, for example, tert-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzene can be used.
  • Sulfonyl, tetrahydropyranyl, etc. as a protecting group for hydroxy groups, for example, trialkylsilyl, acetyl, benzyl, tetrahydropyranyl, methoxymethyl, etc., as protecting groups for aldehyde groups, for example, dialkylacetal, cyclic alkyl
  • protecting group for the carboxyl group, acetal and the like can be mentioned, for example, tert-butyl ester, orthoester, amide and the like.
  • protecting groups are performed by methods commonly used in synthetic organic chemistry (for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley. It can be performed by a method described in and Sons, inc., New York (1999), etc.) or a method similar thereto.
  • Manufacturing method 1 The compound represented by the formula (1) is produced, for example, by the method shown below.
  • R represents C 1-6 alkyl
  • X represents halogen atom
  • LG represents a leaving group (eg, iodine atom, bromine atom, chlorine atom, substituted sulfonyloxy (eg, methanesulfonyloxy, p-toluenesulfonyloxy, etc.), etc.)
  • Z represents boronic acid, boronic acid ester, BF 3 Represents K, BF 3 Na, trialkyltin, zinc halide or hydrogen atom.
  • Step 1-1 Production of compound (1-3) Compound (1-3) reacts compound (1-1) with compound (1-2) in the presence of a base in a suitable inert solvent.
  • Manufactured by Compound (1-1) is synthesized by a known method (for example, the method described in US Patent Publication No. 2005/0277655, International Publication No. 2018/081091, International Publication No. 2017/09798) or a method similar thereto.
  • a product or a commercially available product can be used.
  • As the compound (1-2) a commercially available product, or a compound synthesized by a known method or a method similar thereto can be used.
  • Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, dipotassium hydrogen phosphate, potassium phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, etc.
  • Inorganic bases such as sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide; organic bases such as triethylamine, diisopropylethylamine and pyridine can be mentioned.
  • the inert solvent examples include aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile, acetone and methyl ethyl ketone; ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane; Halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; and mixed solvents thereof and the like can be mentioned.
  • the reaction temperature is not particularly limited, but is usually selected from the range of ⁇ 10 ° C. to 200 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time varies depending on the conditions such as the reaction temperature, the raw materials used, and the solvent, but is usually 10 minutes to 48 hours.
  • Step 1-2 Production step of compound (1-5) Of compound (1-5), a partially unsaturated C 4-12 carbocyclic group in which M 1 may be substituted may be substituted. 4- to 12-membered partially unsaturated heterocyclic groups , optionally substituted C 6-10 aryl, optionally substituted 5-10-membered heteroaryl, or optionally substituted C 2-10.
  • the compound represented by alkenyl is a compound (1-3) in a suitable inert solvent, in the presence of a palladium catalyst and a phosphine ligand, and in some cases in the presence of a base, where Z is boronic acid, boronic acid ester, It is produced by reacting with a compound (1-4) represented by BF 3 K, BF 3 Na, trialkyltin or zinc halide.
  • a compound (1-4) a compound purchased as a commercially available product, a known method, or a compound synthesized by a method similar thereto can be used.
  • the palladium catalyst examples include tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and bis (tri-tert-butylphosphine) palladium.
  • (0) Palladium acetate (0), [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) And so on.
  • phosphine ligand examples include o-tolylphosphine, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl (S-Phos), 2-dicyclohexylphosphino-2', 4', 6'-triisopropyl.
  • DPPF 1,1'-bis (diphenylphosphino) ferrocene
  • DPPE 1,2-bis (diphenylphosphino) ethane
  • DPPP 1,3-bis (diphenyl
  • Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide and the like.
  • Examples of the inert solvent include 1,4-dioxane, THF, 1,2-dimethoxyethane, acetonitrile, water and a mixed solvent thereof.
  • the reaction temperature is not particularly limited, but is usually selected from the range of 50 ° C to 200 ° C, preferably 80 ° C to 150 ° C. This step can also be performed under microwave irradiation, if desired.
  • the reaction time is usually 30 minutes to 48 hours.
  • C 1-10 alkoxy in which M 1 may be substituted C 6-10 aryloxy in which M 1 may be substituted, and 5 to 10 members which may be substituted.
  • heteroaryloxy or -NR e R f (wherein, the R e and R f have the same meanings as the above [1]) compound represented by the basic compound (1-3) in a suitable inert solvent It is produced by reacting Z with a compound (1-4) represented by a hydrogen atom in the presence of.
  • M 1 is -NR e R f compound represented by the compound (1-3) It is also produced by reacting Z with compound (1-4) represented by a hydrogen atom in the presence of a palladium catalyst, a phosphine ligand and a base in a suitable inert solvent.
  • compound (1-4) a compound purchased as a commercially available product, a known method, or a compound synthesized by a method similar thereto can be used.
  • the base examples include organic bases such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, dipotassium hydrogen phosphate, potassium phosphate, disodium hydrogen phosphate, phosphorus.
  • organic bases such as triethylamine, diisopropylethylamine, and pyridine
  • Inorganic bases such as sodium acid, potassium hydroxide, sodium hydroxide and sodium hydride
  • metal alkoxides such as sodium methoxide and potassium tert-butoxide can be mentioned.
  • the inert solvent examples include aprotonic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile, acetone and methyl ethyl ketone; halogenated hydrocarbons such as chloroform and dichloromethane; aromatics such as benzene and toluene. Group hydrocarbons; and mixed solvents thereof and the like.
  • aprotonic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile, acetone and methyl ethyl ketone
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatics such as benzene and toluene.
  • Group hydrocarbons and mixed solvents thereof and the like.
  • the palladium catalyst examples include tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and bis (tri-tert-butylphosphine) palladium.
  • (0) Palladium acetate (0), [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) And so on.
  • phosphine ligand examples include o-tolylphosphine, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl (S-Phos), 2-dicyclohexylphosphino-2', 4', 6'-triisopropyl.
  • DPPF 1,1'-bis (diphenylphosphino) ferrocene
  • DPPE 1,2-bis (diphenylphosphino) ethane
  • DPPP 1,3-bis (diphenyl
  • the reaction temperature is not particularly limited, but is usually selected from the range of 20 ° C. to 200 ° C., preferably 50 ° C. to 170 ° C.
  • This step can also be performed under microwave irradiation, if desired.
  • the reaction time varies depending on the conditions such as the reaction temperature, the raw materials used, and the solvent, but is usually 10 minutes to 48 hours. Further, this step can also be carried out according to a known method, for example, by converting X to another leaving group such as an alkylsulfonyl group and then reacting with compound (1-4).
  • Step 1-3 Preparation process of Compound (1-6) (1-6), the compound (1-5) a known method (for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc .), Comprehensive Organic Transformation, by RC Larock et al., VCH publisher Inc., 1989, etc.), produced by hydrolysis or hydrocracking in the same manner.
  • a known method for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc .), Comprehensive Organic Transformation, by RC Larock et al., VCH publisher Inc., 1989, etc.
  • Step 1-4 Production step of compound (1)
  • the compound represented by the formula (1) is a compound (1-6) in a suitable inert solvent in the presence or absence of a base. It is produced by reacting with -7) using a condensing agent.
  • a compound purchased as a commercially available product, or a compound synthesized by a known method or a method similar thereto can be used.
  • condensing agent examples include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (WSC), and benzotriazole-1-yl-tris (dimethylamino) phosphonium.
  • DCC dicyclohexylcarbodiimide
  • DIPC diisopropylcarbodiimide
  • WSC 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide
  • benzotriazole-1-yl-tris dimethylamino
  • Hexafluorophosphate BOP
  • diphenylphosphonyldiamide DPPA
  • N N-carbonyldiimidazole
  • HBTU benzotriazole-1-yl-N, N, N', N'-tetramethyluronium -Hexafluorophosphate
  • HATU 7-azabenzotriazole-1-yl-N, N, N', N'-tetramethyluronium hexafluorophosphate
  • N-hydroxysuccinimide HOSu
  • 1-hydroxybenzotriazole HOBt
  • 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine HOOBt
  • the reaction can be carried out by adding the additive of.
  • the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4- (dimethylamino) pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, dipotassium hydrogen phosphate, potassium phosphate.
  • Inorganic bases such as disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride and the like; metal alkoxides such as sodium methoxyde and potassium tert-butoxide.
  • the inert solvent include aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile, acetone and methyl ethyl ketone; ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane; Halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; and mixed solvents thereof and the like can be mentioned.
  • the reaction temperature is not particularly limited, but is usually selected from the range of ⁇ 10 ° C. to 200 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time varies depending on the conditions such as the reaction temperature, the raw materials used, and the solvent, but is usually 10 minutes to 48 hours.
  • compound (1-6) is induced into an acid anhydride, a mixed acid anhydride, or an acid halide to activate a carboxy group and react with compound (1-7) according to a known method. It can also be done by.
  • Step 1-5 Production step of compound (1-8) Compound (1-8) is produced from compound (1-3) according to the method described in step (1-3).
  • Step 1-6 Production step of compound (1-9)
  • Compound (1-9) is prepared from compound (1-8) and compound (1-7) according to the method described in step (1-4). Manufactured.
  • Step 1-7 Production Step of Compound (1)
  • Compound (1) is produced from compound (1-9) and compound (1-4) according to the method described in step (1-2).
  • R 1 , Y 1 , Y 2 and Y 3 are synonymous with [1] above;
  • R represents C 1-6 alkyl;
  • X represents a halogen atom;
  • LG represents a leaving group.
  • iodine atom, bromine atom, chlorine atom, substituted sulfonyloxy (for example, methanesulfonyloxy, p-toluenesulfonyloxy, etc.), etc. are represented.
  • sulfonyloxy for example, methanesulfonyloxy, p-toluenesulfonyloxy, etc.
  • Step 2-1 Production of compound (1-3)
  • Compound (1-3) is produced by reacting compound (2-1) with compound (2-2) in a suitable inert solvent.
  • the inert solvent include aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide, acetonitrile, acetone and methyl ethyl ketone; ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane; Aromatic hydrocarbons such as benzene and toluene; alcoholic solvents such as methanol, ethanol, 2-propanol, tert-butanol and 1-butanol; and mixed solvents thereof and the like can be mentioned.
  • aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide, acetonitrile, acetone and methyl ethyl ketone
  • the reaction temperature is not particularly limited, but is usually selected from the range of ⁇ 10 ° C. to 200 ° C., preferably 20 ° C. to 150 ° C.
  • the reaction time varies depending on the conditions such as the reaction temperature, the raw materials used, and the solvent, but is usually 10 minutes to 48 hours.
  • Manufacturing method 3 The compound represented by the formula (1-3) is also produced, for example, by the method shown below.
  • R 1 is cyano , optionally substituted C 1-6 alkyl, or optionally substituted C 3 -6 cycloalkyl
  • R represents C 1-6 alkyl
  • X represents halogen atom
  • X a represents iodine atom or bromine atom
  • Z represents boronic acid, boronic acid ester or BF 3 Represents K, BF 3 Na or zinc cyanide.
  • Step 3-1 Production of Compound (1-3)
  • Compound (1-3) comprises compound (3-1) in a suitable inert solvent in the presence of a palladium catalyst and a phosphine ligand, as the case may be. It is produced by reacting with compound (3-2) in the presence of a base.
  • Compound (3-1) is produced according to the method described in step 1-1.
  • the palladium catalyst examples include tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and bis (tri-tert-butylphosphine) palladium.
  • (0) Palladium acetate (0), [1,1-bis (diphenylphosphino) ferrocene] palladium (II) dichloride, bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) And so on.
  • phosphine ligand examples include o-tolylphosphine, 2-dicyclohexylphosphino-2', 6'-dimethoxybiphenyl (S-Phos), 2-dicyclohexylphosphino-2', 4', 6'-triisopropyl.
  • DPPF 1,1'-bis (diphenylphosphino) ferrocene
  • DPPE 1,2-bis (diphenylphosphino) ethane
  • DPPP 1,3-bis (diphenyl
  • Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide and the like.
  • Examples of the inert solvent include 1,4-dioxane, THF, 1,2-dimethoxyethane, acetonitrile, dimethylformamide, water and a mixed solvent thereof.
  • the reaction temperature is not particularly limited, but is usually selected from the range of 50 ° C to 200 ° C, preferably 80 ° C to 150 ° C. This step can also be performed under microwave irradiation, if desired.
  • the reaction time is usually 30 minutes to 48 hours.
  • the compound represented by the formula (4-2) is produced, for example, by the method shown below.
  • M 2 , R 1 , Y 1 , Y 2 and Y 3 are synonymous with [1] above;
  • Q 1 is a 4- to 12-membered partially unsaturated heterocycle that may be substituted. represents C 4-12 carbon ring group group or partially unsaturated;
  • Q 2 represents a heterocyclic group, or a C 4-12 carbocyclic group, saturated saturated substituted - may also be 4-membered optionally 12-membered .. ]
  • Step 4-1 Production of compound (4-2) Compound (4-2) is subjected to catalytic reduction of compound (4-1) in a suitable inert solvent under a hydrogen atmosphere using a metal catalyst. Manufactured by. Compound (4-1) is produced according to the method described in Step 1-7.
  • the metal catalyst include palladium / carbon, palladium / carbon hydroxide, Raney nickel, platinum oxide / carbon, rhodium / carbon and the like.
  • the amount of the metal catalyst used is usually 0.1% by weight to 1000% by weight, preferably 1% by weight to 100% by weight, based on the compound (4-1).
  • the inert solvent examples include ethers such as tetrahydrofuran; esters such as ethyl acetate; alcohols such as methanol and the like.
  • the hydrogen pressure is usually 1 atm to 100 atm, preferably 1 to 5 atm.
  • the reaction can also be carried out by using a reagent such as ammonium formate instead of in a hydrogen atmosphere.
  • the reaction temperature is not particularly limited, but is usually selected from the range of 0 ° C. to 120 ° C., preferably 20 ° C. to 80 ° C.
  • the reaction time is usually 30 minutes to 72 hours.
  • Manufacturing method 5 The compound represented by the formula (1-9) is also produced, for example, by the method shown below.
  • M 2 , R 1 , Y 1 , Y 2 and Y 3 are synonymous with [1] above;
  • X represents a halogen atom;
  • LG represents a leaving group (eg, iodine atom, bromine atom, Represents a chlorine atom, substituted sulfonyloxy (eg, methanesulfonyloxy, p-toluenesulfonyloxy, etc.), etc. ]
  • Step 5-1 Production step of compound (1-9)
  • Compound (1-9) is produced from compound (1-1) and compound (5-1) according to the method described in step 1-1.
  • the compound (5-1) one purchased as a commercially available product, or one synthesized by a known method or a method similar thereto can be used.
  • the compound represented by the formula (6-4) in which M 1 is ⁇ NR e R f is also produced, for example, by the method shown below.
  • R 1 , Y 1 , Y 2 , Y 3 , Re and R f are synonymous with [1] above;
  • X represents a halogen atom;
  • R represents C 1-6 alkyl;
  • LG represents a leaving group (eg, iodine atom, bromine atom, chlorine atom, substituted sulfonyloxy (eg, methanesulfonyloxy, p-toluenesulfonyloxy, etc.), etc.).
  • X represents a halogen atom
  • R represents C 1-6 alkyl
  • LG represents a leaving group (eg, iodine atom, bromine atom, chlorine atom, substituted sulfonyloxy (eg, methanesulfonyloxy, p-toluenes
  • Step 6-1 Production step of compound (6-2)
  • Compound (6-2) is produced from compound (1-3) and compound (6-1) according to the method described in step 1-2. Will be done.
  • the compound (6-1) a compound purchased as a commercially available product, or a compound synthesized by a known method or a method similar thereto can be used.
  • Step 6-2 Production step of compound (6-4)
  • Compound (6-4) reacts compound (6-2) with compound (6-3) in the presence of a base in a suitable inert solvent.
  • a base include potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, dipotassium hydrogen phosphate, potassium phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, etc.
  • Inorganic bases such as sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide; organic bases such as triethylamine, diisopropylethylamine and pyridine can be mentioned.
  • the inert solvent examples include aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile, acetone and methyl ethyl ketone; ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane; Aromatic hydrocarbons such as benzene and toluene; and mixed solvents thereof and the like can be mentioned.
  • the reaction temperature is not particularly limited, but is usually selected from the range of ⁇ 78 ° C. to 200 ° C., preferably 0 ° C. to 180 ° C. This step can also be performed under microwave irradiation, if desired.
  • the reaction time varies depending on the conditions such as the reaction temperature, the raw materials used, and the solvent, but is usually 10 minutes to 48 hours.
  • Manufacturing method 7 The compound represented by the formula (7-4) is produced, for example, by the method shown below.
  • P represents a protective group of an amino group
  • LG represents a leaving group (eg, iodine atom, bromine atom, chlorine atom, substituted sulfonyloxy (eg, methanesulfonyloxy, p-toluenesulfonyloxy, etc.), etc.)
  • R 8 is a partially unsaturated C 3-7 carbocyclic group which may be substituted, an amino which may be substituted, a 5- or 6-membered heteroaryl or which may be substituted. It represents a optionally 4- to 7-membered partially unsaturated heterocyclic group
  • Z represents a boronic acid, a boronic acid ester, a BF 3 K, a BF 3 Na or a hydrogen atom.
  • Step 7-1 Production step of compound (7-3)
  • Compound (7-3) is produced from compound (7-1) and compound (7-2) according to the method described in step 1-2.
  • the compound (7-1) and the compound (7-2 those purchased as commercial products, those synthesized by a known method, or a method similar thereto can be used.
  • Step 7-2 Preparation process of Compound (7-4) (7-4) from compound (7-3), a known method (for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, RC Lalock et al., VCH publisher Inc., 1989, etc.)), which is produced by removing the protecting group in the same manner as described).
  • a known method for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, RC Lalock et al., VCH publisher Inc., 1989, etc.
  • Manufacturing method 8 The compound represented by the formula (8-7) is produced, for example, by the method shown below.
  • R 3 is synonymous with [1] above;
  • LG is a leaving group (eg, iodine atom, bromine atom, chlorine atom, substituted sulfonyloxy (eg, methanesulfonyloxy, p-toluenesulfonyloxy, etc.) ) Etc.;
  • P represents a protecting group for an amino group.
  • Step 8-1 Production step of compound (8-3)
  • Compound (8-3) is produced by reacting compound (8-1) with compound (8-2) in an inert solvent.
  • the compound (8-1) and the compound (8-2) those purchased as commercially available products, those synthesized by a known method, or a method similar thereto can be used.
  • the inert solvent examples include aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile, acetone and methyl ethyl ketone; ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane; Halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; and mixed solvents thereof and the like can be mentioned.
  • this reaction can be carried out under solvent-free conditions.
  • the reaction temperature is not particularly limited, but is usually selected from the range of 0 ° C. to 200 ° C., preferably 40 ° C. to 150 ° C.
  • the reaction time varies depending on the conditions such as the reaction temperature, the raw materials used, and the solvent, but is usually 10 minutes to 48 hours.
  • Step 8-2 Production step of compound (8-5)
  • Compound (8-5) is produced by reacting compound (8-3) with compound (8-4) in the presence of a base in an inert solvent.
  • a base in an inert solvent.
  • the compound (8-4) a compound purchased as a commercially available product, a known method, or a compound synthesized by a method similar thereto can be used.
  • the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, and 4- (dimethylamino) pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, dipotassium hydrogen phosphate, potassium phosphate.
  • Inorganic bases such as disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride and the like; metal alkoxides such as sodium methoxyde and potassium tert-butoxide.
  • the inert solvent include aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide, acetonitrile, acetone and methyl ethyl ketone; ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane; Halogenized hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; alcohols such as methanol, ethanol, 2-propanol and tert-butanol; and mixed solvents thereof and the like can be mentioned.
  • the reaction temperature is not particularly limited, but is usually selected from the range of ⁇ 10 ° C. to 200 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time varies depending on the conditions such as the reaction temperature, the raw materials used, and the solvent, but is usually 10 minutes to 48 hours.
  • this step can also be performed according to a known method (for example, the method described in European Journal of Organic Chemistry 2005, 3761.).
  • Step 8-3 Production step of compound (8-6)
  • Compound (8-6) is produced from compound (8-5) according to the method described in step 1-2.
  • Step 8-4 Preparation process of Compound (8-7) (8-7) from compound (8-6), a known method (for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, RC Lalock et al., VCH publisher Inc., 1989, etc.)), which is produced by removing the protecting group in the same manner as described).
  • a known method for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, RC Lalock et al., VCH publisher Inc., 1989, etc.
  • the compound of the present invention having a desired substituent at a desired position can be obtained.
  • Isolation and purification of intermediates and products in the above production method shall be carried out by appropriately combining methods used in ordinary synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, crystallization, and various types of chromatography. Can be done. Further, the intermediate can be subjected to the next reaction without any particular purification.
  • the raw material compound or intermediate in the above production method may exist in the form of a salt such as hydrochloride, but can be used as it is or in a free form.
  • the raw material compound or intermediate is obtained in the form of a salt and the raw material compound or intermediate is to be used or obtained in a free form, these are dissolved or suspended in a suitable solvent, for example, a base such as an aqueous sodium hydrogen carbonate solution. It can be converted to a free form by neutralizing with or the like.
  • a suitable solvent for example, a base such as an aqueous sodium hydrogen carbonate solution. It can be converted to a free form by neutralizing with or the like.
  • the optical isomer can be separated by carrying out a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the above-mentioned production method.
  • An optically active substance can also be used as a starting material.
  • the salt of the compound represented by the formula (1) When it is desired to obtain the salt of the compound represented by the formula (1), if the salt of the compound represented by the formula (1) can be obtained, it may be purified as it is, and the compound represented by the formula (1) can be obtained. When obtained in the free form, the compound represented by the formula (1) may be dissolved or suspended in an appropriate solvent, and an acid or base may be added to form a salt.
  • the compound of the present invention may be useful as a Nav1.1 activator. Since the compounds of the present invention also exhibit Nav1.1 activating activity, therapeutic and / or prophylactic agents for diseases associated with Nav1.1, particularly those associated with decreased function of Nav1.1, such as central nervous system diseases (for example, febrile convulsions; generalized epilepsy feverish convulsions plus; epilepsy (specifically, localization-related epilepsy, generalized epilepsy); epilepsy syndrome (drabe syndrome, refractory pediatric epilepsy with systemic tension-interval attacks, myocrony weakness Epilepsy with seizures, West syndrome, Lennox-Gastau syndrome, severe infantile multifocal epilepsy, infantile borderline severe intermuscular epilepsy, benign familial neonatal infantile epilepsy, etc.); schizophrenia; autism spectrum disorder; caution It may also be useful as a therapeutic and / or prophylactic for deficient hyperactivity disorder.
  • central nervous system diseases For example, febrile convulsions; generalized epilepsy feverish con
  • the compounds of the present invention can be used as therapeutic agents and / for the above-mentioned epilepsy syndromes or epilepsy (particularly refractory epilepsy) for which the symptoms cannot be sufficiently suppressed by multiple agents, particularly three or more existing antiepileptic agents. It is also expected as a preventive agent.
  • it exhibits a particularly selective pharmacological effect on Nav1.1 and has a weak effect on other Nav subtypes, such as Nav1.5, thus reducing cardiotoxicity concerns and safety. Can be expected to be high.
  • prevention is an act of administering the compound of the present invention to a healthy person who has not developed a disease, and is intended to prevent the onset of a disease, for example.
  • Treatment is the act of administering the compound of the present invention to a person (patient) who has been diagnosed as having a disease by a doctor.
  • the compound of the present invention can be directly administered by an appropriate route of administration, or can be formulated and administered in an appropriate dosage form.
  • routes of administration it is desirable to use the most effective route for treatment, and oral; or parenteral administration such as intravenous, application, inhalation and eye drops can be mentioned.
  • Oral administration is preferred.
  • the dosage form include tablets, capsules, powders, granules, liquids, suspensions, injections, patches, haptics and the like. It is preferably a tablet.
  • Formulation into dosage forms or pharmaceutical compositions can be carried out according to known methods with pharmaceutically acceptable additives.
  • Pharmaceutically acceptable additives include excipients, disintegrants, binders, fluidizers, lubricants, coatings, solubilizers, solubilizers, thickeners, dispersants, depending on the purpose. , Stabilizers, sweeteners, flavors and the like can be used. Specifically, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, stear. Examples thereof include magnesium acid, stearyl sodium fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.
  • the dose and frequency of administration of these dosage forms or pharmaceutical compositions can be appropriately determined depending on the administration form, the patient's disease and symptoms, the age and weight of the patient, etc., but are usually effective for adults per day.
  • the amount of the component (also referred to herein as a "therapeutically effective amount”) ranges from about 0.0001 to about 5000 mg, preferably from about 0.001 to about 1000 mg, more preferably about 0.
  • the range of 1 to about 500 mg, particularly preferably the range of about 1 to about 300 mg, can be administered several times a day, preferably 1 to 3 times a day.
  • the compound of the present invention can be used in combination with another drug (hereinafter, also referred to as "combination drug") for the purpose of enhancing its effect and / or reducing side effects.
  • Concomitant medications include, for example, antiepileptic drugs, antipsychotics, antidepressants, mood stabilizers, anxiolytics, psychostimulants, antiemetics, sleep inducers, anticonvulsants, antiparkinson drugs, schizophrenia. Examples thereof include therapeutic agents and ADHD therapeutic agents.
  • the compounds of the present invention are GABA signal enhancers such as valproic acid; GABAA receptor positive allosteric modulators such as clobazam; T-type potential-dependent calcium channel inhibitors such as etosuccimid; SV2A ligands such as levetiracetam; carbamazepine.
  • GABA signal enhancers such as valproic acid; GABAA receptor positive allosteric modulators such as clobazam; T-type potential-dependent calcium channel inhibitors such as etosuccimid; SV2A ligands such as levetiracetam; carbamazepine.
  • GABA signal enhancers such as valproic acid
  • GABAA receptor positive allosteric modulators such as clobazam
  • T-type potential-dependent calcium channel inhibitors such as etosuccimid
  • SV2A ligands such as levetiracetam
  • carbamazepine Such as therapeutic agents for partial attacks; calcium channel ⁇
  • the compounds of the present invention are also multi-receptor acting antipsychotics such as clozapine (MARTA); serotonin-nore antagonists such as risperidone (SDA); dopamine receptor partial agonists such as aripiprazole (DPA); selective such as fluvoxamine.
  • MARTA multi-receptor acting antipsychotics
  • SDA serotonin-nore antagonists
  • DPA dopamine receptor partial agonists
  • fluvoxamine selective such as fluvoxamine.
  • Serotonin uptake inhibitor SSRI
  • serotonin / noradrenaline reuptake inhibitor SNRI
  • noradrenalinergic / specific serotoninergic antidepressant NaSSA
  • miltazapine noradrenalinergic / specific serotoninergic antidepressant
  • mood stabilizer such as lithium carbonate
  • tandospirone Serotonin 1A receptor agonists such as; histamine H1 receptor blockers such as hydroxydin; central nervous system stimulants such as methylphenidate; selective noradrenergic reuptake inhibitors such as atomoxetine can also be used in combination.
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or at different times. Further, it may be a mixture of the compound of the present invention and a concomitant drug.
  • the dose or combination ratio of the concomitant drug can be appropriately selected based on the clinically used dose, depending on the administration target, administration route, target disease, symptom, combination thereof, and the like. For example, when the administration target is a human, 0.01 to 100 parts by weight of the concomitant drug may be used with respect to 1 part by weight of the compound of the present invention.
  • CDCl 3 Deuterated chloroform
  • DMSO-d 6 Deuterated dimethyl sulfoxide
  • Rt Retention time min: Minutes
  • HATU O- (7-aza-1H-benzotriazol-1-yl) -N, N, N', N'-tetra Methyluronium Hexafluorophosphate
  • THF Tetrahydrofuran
  • TFA Trifluoroacetic acid Boc: tert-butoxycarbonyl
  • Tf Trifluoromethanesulfonyl
  • Cbz benzyloxycarbonyl Ph: phenyl
  • WSC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
  • s is a single line
  • d is a double line
  • dd is a double double line
  • t is a triple line
  • td is a triple double line
  • dt is a double triple line
  • q Is a quadruple line
  • m is a multiple line
  • br is a wide single line or multiple line
  • J is a coupling constant.
  • Method B Solvent: Solution A; 0.05% TFA / H 2 O, Solution B; Acetonitrile gradient condition: 0.0-1.7 minutes (liner gradation from B 10% to 99%) Flow velocity: 0.5 mL / min; Detection UV: 220 nm; Temperature: 40 ° C
  • Method C Solvent: A liquid; 10mM NH 4 HCO 3 / H 2 O, B solution; acetonitrile gradient conditions: 0.0-0.2 min (5% B) 0.2-1.5 min (linear gradient from B 5% to 95%) 1.5-2.8 minutes (B 95%) Flow velocity: 1.8 mL / min; Detection UV: 214 nm and 254 nm; Temperature: 50 ° C.
  • Method D Solvent A solution; 0.05% Formic Acid / H 2 O, B solution; acetonitrile gradient conditions: 0.0-1.3 min (linear gradient from B 10% to 95%) 1.3-1.5 min ( B 10%) Flow velocity: 0.8 mL / min; Detection UV: 220 nm and 254 nm; Temperature: 40 ° C.
  • Reference example 1 [6- (4,4-Dimethylpiperidine-1-yl) -1H-pyrazolo [3,4-b] pyrazine-1-yl] acetate hydrochloride a) Add cesium carbonate (7.38 g) and tert-butyl bromoacetate (3.08 mL) to a solution of 6-chloro-1H-pyrazolo ⁇ 3,4-b ⁇ pyrazine (2.50 g) in dimethylformamide (65 mL). In addition, the mixture was stirred at room temperature for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Reference example 2 [6- (4-Methylpiperidin-1-yl) -1H-pyrazolo [3,4-b] pyrazine-1-yl] acetate hydrochloride a) In a solution of compound 1A (330 mg) in toluene (5 mL), sodium tert-butoxide (236 mg), 4-methylpiperidin (0.30 mL), [(2-di-tert-butylphosphino-2', 4').
  • Reference example 3 [6- (4-Methylcyclohexa-1-ene-1-yl) -1H-pyrazolo [3,4-b] pyrazine-1-yl] acetic acid a) Compound 3A using 6-chloro-1H-pyrazolo ⁇ 3,4-b ⁇ pyrazine (15.0 g) and ethyl chloroacetate (11.6 mL) according to the method described in step a) of Reference Example 1. (12.5 g) was obtained.
  • Reference example 7 6-Chloro-1H-pyrazolo [3,4-b] pyrazine-1-yl) -N- (4-cyanophenyl) acetamide a) According to the method described in step a) of Reference Example 1, using 6-chloro-1H-pyrazolo ⁇ 3,4-b ⁇ pyrazine (20.0 mg) and the compound of Reference Example 6 (27.7 mg). The title compound (21.0 mg) was obtained.
  • Reference example 8 2- (4,4-difluorocyclohexa-1-en-1-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane a) Add 2-chloropyridine (26.5 g) and trifluoromethanesulfonic anhydride (63.1 g) to a solution of 4,4-difluorocyclohexanone (25.0 g) in 1,2-dichloroethane (373 mL), and add 50 ° C. Was stirred for 6 hours. After cooling to 0 ° C., hexane (750 mL) was added, the precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure to give compound 8A (46.1 g).
  • Reference example 10 8-fluoro [1,2,4] triazolo [1,5-a] pyridine-7-amine a) 2-Chloro-3-fluoro-4-iodopyridine (3.1 g), benzyl carbamate (2.28 g), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (1.74 g) ), Tris (dibenzylideneacetone) dipalladium (1.32 g) in toluene (80 mL) was stirred at 100 ° C. for 8 hours.
  • Reference example 11 2- (Trifluoromethyl) imidazole [1,2-a] pyridine-7-amine Suspension of pyridine-2,4-diamine (300 mg) and sodium hydrogen carbonate (462 mg) in ethanol (9.1 mL), addition of 3-chloro-1,1,1-trifluoropropane-2-one, 4 It was heated under reflux for hours. After cooling to room temperature, water was added to the reaction solution, and the mixture was extracted with a mixed solvent of chloroform and ethanol (3: 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Reference example 12 4- (Morpholine-4-yl) -2,3-dihydro-1H-indole dihydrochloride a) tert-Butyl 4-bromo-2,3-dihydro-1H-indole-1-carboxylate (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), sodium tert-butoxide (0.999 g) toluene (17.3 mL) The solution was stirred at 100 ° C.
  • Reference example 13 4- (Pyridazine-4-yl) -2,3-dihydro-1H-indole hydrochloride a) tert-Butyl 4-bromo-2,3-dihydro-1H-indole-1-carboxylate (2.62 g), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-Indole) pyridazine (2.17 g), bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (0.62 g), 2 mol / L potassium acetate aqueous solution (13 ml) acetonitrile The (35 mL) solution was stirred at 90 ° C.
  • Reference example 15 [6- (4-Methylpiperidin-1-yl) -1H-pyrazolo [3,4-b] pyrimidin-1-yl] acetate hydrochloride a) In accordance with the method described in step a) of Reference Example 1, using 6-chloro-1H-pyrazolo ⁇ 3,4-b ⁇ pyrimidine (1.24 g) and tert-butyl bromoacetate (12.0 mL). Compound 15A (1.25 g) was obtained.
  • Reference example 18 [6- (4-Methylpiperidin-1-yl) -1H-pyrazolo [3,4-b] pyridin-1-yl] acetate hydrochloride a) According to the method described in step a) of Reference Example 1, using 6-chloro-1H-pyrazolo ⁇ 3,4-b ⁇ pyridine (1.0 g) and tert-butyl bromoacetate (1.43 mL). Compound 18A (0.96 g) was obtained.
  • Reference example 21 [6- (4-Methylcyclohexa-1-en-1-yl) -1H-indazole-1-yl] acetate hydrochloride a) Compound 21A (1.1 g) was added to compound 21A (1.1 g) using 6-bromo-1H-indazole (1.0 g) and tert-butyl bromoacetate (0.89 mL) according to the method described in step a) of Reference Example 1. Obtained. LC-MS: [M + H] + / Rt (min) 313.1 / 1.025 (Method A) b) Compound 21B (503 mg) was obtained using Compound 21A (500 mg) according to the method described in Step b) of Reference Example 3.
  • Example 1 2- [6- (4-Methylpiperidin-1-yl) -1H-pyrazolo [3,4-b] pyrazine-1-yl] -N- ([1,2,4] triazolo [1,5-a] ] Pyrazine-7-yl) acetamide Imidazo [1,2-A] pyridine-7-amine hydrochloride (66.4 mg), WSC (61.5 mg) and 4-dimethylamino in a solution of the compound of Reference Example 2 (50.0 mg) in dichloromethane (2 mL). Pyridine (118.0 mg) was added and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Example 2 2- ⁇ 6- [methyl (2-methylpropyl) amino] -1H-pyrazolo [3,4-b] pyrazine-1-yl ⁇ -N-([1,2,4] triazolo [1,5-a] ] Pyrazine-7-yl) acetamide
  • N,2-dimethylpropan-1-amine hydrochloride (6.8 mg) and potassium carbonate (18.9 mg) were added, and the mixture was added at 50 ° C. Stirred for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Example 4 2- [6- (5-Methyl-1,3-thiazole-2-yl) -1H-pyrazolo [3,4-b] pyrazine-1-yl] -N- ([1,2,4] triazolo [ 1,5-a] Pyrazine-7-yl) acetamide
  • 5-methyl-2- (tributylstanyl) thiazole 39.0 mg
  • tetrakis triphenylphosphine) palladium (0)
  • Example 5 6-Cyclobutyl-1H-pyrazolo [3,4-b] pyrazine-1-yl) -N- ([1,2,4] triazolo [1,5-a] pyridin-7-yl) acetamide 0.5 mol / L cyclobutylzinc bromide (0.548 mL), bis (tri-tert-butylphosphine) palladium (0) (18.7 mg) in a solution of the compound (60.0 mg) of Reference Example 4 in tetrahydrofuran (2 mL). Was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Examples 6-69 Compounds of Examples 6 to 69 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 1 to 5, the methods described in Examples 1 to 5, and known reaction conditions.
  • Examples 70-77 Compounds of Examples 70 to 77 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 1 to 5, the methods described in Examples 1 to 5, and known reaction conditions.
  • Examples 78-97 Compounds of Examples 78 to 97 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 1 to 5, the methods described in Examples 1 to 5, and known reaction conditions.
  • Examples 98-113 Compounds of Examples 98 to 113 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 1 to 5, the methods described in Examples 1 to 5, and known reaction conditions.
  • Examples 114-127 Compounds of Examples 114 to 127 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 1 to 5, the methods described in Examples 1 to 5, and known reaction conditions.
  • Examples 128-163 Compounds of Examples 128 to 163 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 1 to 5, the methods described in Examples 1 to 5, and known reaction conditions.
  • Examples 164-190 Compounds of Examples 164 to 190 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 1 to 5, the methods described in Examples 1 to 5, and known reaction conditions.
  • Example 191 2- [6- (2-Cyclopropylethoxy) -1H-pyrazolo [3,4-d] pyrimidin-1-yl] -N- ([1,2,4] triazolo [1,5-a] pyridine- 7-yl) acetamide 55% sodium hydride (11.7 mg) was added to a solution of 2-cyclopropyl ethanol (18.6 mg) in dimethylformamide (0.54 mL), and the mixture was stirred at room temperature for 10 minutes. The compound of Reference Example 14 (20.0 mg) was added to the reaction solution, and the mixture was stirred at 60 ° C. for 2 hours.
  • Examples 192 to 233 Compounds of Examples 192 to 233 were obtained using the methods described in Reference Examples 14 to 17, the methods described in Examples 1 to 5 and 191 and the corresponding raw material compounds according to known reaction conditions.
  • Examples 234-239 Compounds of Examples 234 to 239 were obtained using the methods described in Reference Examples 14 to 17, the methods described in Examples 1 to 5 and 191 and the corresponding raw material compounds according to known reaction conditions.
  • Examples 240-251 Compounds of Examples 240 to 251 were obtained using the methods described in Reference Examples 14 to 17, the methods described in Examples 1 to 5 and 191 and the corresponding raw material compounds according to known reaction conditions.
  • Examples 252 to 259 Compounds of Examples 252 to 259 were obtained using the methods described in Reference Examples 14 to 17, the methods described in Examples 1 to 5 and 191 and the corresponding raw material compounds according to known reaction conditions.
  • Examples 260-280 Compounds of Examples 260 to 280 were obtained using the methods described in Reference Examples 14 to 17, the methods described in Examples 1 to 5 and 191 and the corresponding raw material compounds according to known reaction conditions.
  • Examples 281 to 292 Compounds of Examples 281 to 292 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 18 to 20, the methods described in Examples 1 to 5, and known reaction conditions.
  • Examples 293-299 Compounds of Examples 293 to 299 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 18 to 20, the methods described in Examples 1 to 5, and known reaction conditions.
  • Examples 300-304 Compounds of Examples 300 to 304 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 18 to 20, the methods described in Examples 1 to 5, and known reaction conditions.
  • Examples 305-309 Compounds of Examples 305 to 309 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 18 to 20, the methods described in Examples 1 to 5, and known reaction conditions.
  • Examples 310-323 Compounds of Examples 310 to 323 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 18 to 21, the methods described in Examples 1 to 5, and known reaction conditions.
  • Example 324 and 325 The compound (4.6 mg) obtained in Example 6 was divided by a chiral column to obtain the following optically active substance.
  • Examples 326-342 The compounds of Examples 326 to 342 were prepared using the corresponding raw material compounds according to the methods described in Reference Examples 1, 2, 15 and 17, the methods described in Examples 1 to 2, 191 and known reaction conditions. Obtained.
  • Test Examples The results of pharmacological tests of representative compounds in the present specification will be shown below, and the pharmacological actions of the compounds will be described, but the present invention is not limited to these test examples.
  • Test Example 1 Evaluation of Nav1.1-derived potential-dependent sodium current (Nav1.1 current) enhancing activity using human Nav1.1 stable expression cells (1) Preparation of test compound solution The test compound has a concentration 200 times higher than the evaluation concentration.
  • the solution extracellular fluid NaCl 135mmol / L, KCl 4mmol / L, MgCl 2 1mmol / L, CaCl 2 5mmol / L, Glucose 5mmol / L, HEPES 10mmol / L
  • Nav1.1 current Human Nav1.1 stable expression HEK293 cells (cat # CYL3009, Millipore, USA, Human Embryonic Kidney 293) were purchased and used in this test.
  • the Nav1.1 current was triggered by Ramp wave potential stimulation.
  • the HTS type auto patch clamp system SynchroPatch 768PE, Nanion Technologies GmbH, Germany
  • the current associated with the potential stimulation was detected by the patch clamp potential fixation method.
  • Cells in which the magnitude of the potential-dependent sodium current evoked by the Ramp wave potential stimulus is less than 500 pA may have a higher proportion of the endogenous potential-dependent sodium channel-derived current component, and thus the Nav1.1 current.
  • Nav1.1 current enhancement rate 100 ⁇ [peak value or area of Nav1.1 current after addition of evaluation compound] / [peak value or area of Nav1.1 current before addition of evaluation compound] -100
  • Test result 1 For the representative compounds in the present specification, the Nav1.1 current enhancement rate (%) is shown in the table below.
  • Test Example 2 Evaluation of Nav1.5-derived potential-dependent sodium current (Nav1.5 current) enhancing activity using human Nav1.5 stable expression cells
  • Human Nav1 using the purchased T-Rex System (ThermoFisher Scientific, USA). 5 (Gene Bank Accession No: P_000326.2) Stable expression CHO-K1 cell line (Chinese hamster ovary) is obtained and used in this test.
  • Stable expression CHO-K1 cell line Choinese hamster ovary
  • the Nav1.5 current enhancing effect of the test compound is evaluated by the HTS type auto patch clamp system according to the same method as Nav1.1.
  • DMSO was added to the extracellular fluid to a concentration of 1%, and a test compound was added to a solution to which Tetrodotoxin (TTX) was further added to a concentration of 500 nmol / L, and the peak value and area of the Nav1.5 current were added.
  • Evaluation of antiepileptic drugs includes clinically predictable maximum electric shock convulsant model (MES) evaluation, subcutaneous injection pentetrazole model (minimum convulsant model, scPTZ) evaluation, and 6 Hz psychomotor showing resistance to existing antiepileptic drugs.
  • Seizure model Psychomotor seizure model evaluation can be used.
  • Test Example 3 Evaluation of Maximum Electric Shock Convulsions Model (MES) This test is a test to evaluate the anticonvulsant effect of a drug.
  • the animal model used in this study is a phenotype of generalized tonic-clonic seizures and secondary generalized partial epilepsy.
  • Slc ddY male mice (body weight 20-30 g) were administered the test compound, and 15 minutes to 3 hours later, electrical stimulation (60 Hz, 25 mA, 0.2 seconds) was given from the cornea to induce tonic extensor convulsions in the hind limbs.
  • the anticonvulsant effect can be confirmed by observing the suppression of the expression of.
  • Test Example 4 Subcutaneous injection pentetrazole model (minimum convulsive model, scPTZ) evaluation This test is a test to evaluate the anticonvulsant effect of a drug in the same manner as the MES model.
  • the animal model used in this study is a phenotype of generalized absence seizures and myoclonic seizures.
  • the test compound is administered to Slc: ddY male mice (body weight 20 to 30 g), and pentetrazole 85 mg / kg is subcutaneously administered 15 minutes to 3 hours later. After that, the anticonvulsant effect can be confirmed by observing the presence or absence of the occurrence of clonic convulsions for 30 minutes.
  • Test Example 5 Evaluation of 6 Hz psychomotor seizure model This test is a test for evaluating the anticonvulsant effect of a drug.
  • the animal model used in this study is a seizure phenotype that is refractory to existing antiepileptic drugs.
  • Slc dddy male mice (body weight 20-30 g) were administered the test compound, and 15 minutes to 3 hours later, electrical stimulation (6 Hz, 32 mA, 3 seconds) was given from the cornea to induce clonic convulsions in the fore limbs and raising the tail. Anticonvulsant action can be confirmed by observing the presence or absence of reaction and immobility.
  • Test Example 6 Evaluation of Febrile Seizure Suppression Using SCN1A Mutant This test is a test to evaluate the inhibitory effect of a drug on febrile seizures expressed by a gene mutation lacking SCN1A gene function.
  • the animal model used in this study has a deletion-type gene mutation in the SCN1A gene similar to Dravet syndrome, and is a phenotype of Dravet syndrome that presents with febrile convulsions associated with elevated body temperature, and can be purchased from the RIKEN BioResource Research Center. (System: BALB / c-Scn1a ⁇ +/->, Catalog number: RBRC06422).
  • the test compound is administered to SCN1A gene function-deficient gene mutant mice (18-23 g).
  • the mouse is placed in a plastic chamber whose internal temperature has been raised by keeping it warm using a warm bath at about 43 ° C., and the body temperature is raised by keeping it warm continuously.
  • the rectal body temperature 1 hour after being placed in the chamber was compared with the group not administered with the test compound to show the effect of suppressing the induction of febrile seizures of the test compound. You can check.
  • the compound of the present invention has a Nav1.1 activating effect, it can be a useful drug for the treatment and / or prevention of diseases associated with Nav1.1 and various central nervous system diseases.

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Abstract

L'invention concerne un dérivé de pyrazole à cycle condensé, qui est utile en tant qu'agent thérapeutique et/ou agent prophylactique pour des maladies associées au gène SCN1A et diverses maladies du système nerveux central, et/ou un sel pharmaceutiquement acceptable de celui-ci, et un produit pharmaceutique le comprenant en tant que principe actif.　L'invention concerne également un composé représenté par la formule (1) ou un sel pharmaceutiquement acceptable de celui-ci. [Dans la formule : Y1, Y2 et Y3 représentent indépendamment N ou CR2 ; R1 représente un atome d'hydrogène, etc. ; R2 représente un atome d'hydrogène, etc. ; M1 est un groupe carbocyclique saturé ou partiellement insaturé en C4-12, etc. ; M2 représente un groupe représenté par la formule (2a) ou (2b), etc. ; et X1a, X1b, X1c, X2, X3, X4, X5, X6, X7, X8, A1 et A2 sont tels que définis dans la description.]
PCT/JP2020/032589 2019-08-30 2020-08-28 Dérivé de pyrazole à cycle condensé Ceased WO2021039961A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12054486B2 (en) 2021-09-24 2024-08-06 Xenon Pharmaceuticals Inc. Pyridine derivatives and their use as sodium channel activators

Citations (4)

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JP2006508036A (ja) * 2002-06-12 2006-03-09 ケモセントリックス インコーポレーティッド 炎症および免疫障害治療用ｃｃｒ１アンタゴニストとして使用するための１−アリール−４−置換ピペラジン誘導体
WO2008147822A1 (fr) * 2007-05-22 2008-12-04 Chemocentryx, Inc. Composés d'azaindazole et procédés d'utilisation
JP2016169161A (ja) * 2013-07-19 2016-09-23 大日本住友製薬株式会社 新規イミダゾピリジン化合物
WO2018098499A1 (fr) * 2016-11-28 2018-05-31 Praxis Precision Medicines, Inc. Composés et procédés d'utilisation desdits composés

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JP2006508036A (ja) * 2002-06-12 2006-03-09 ケモセントリックス インコーポレーティッド 炎症および免疫障害治療用ｃｃｒ１アンタゴニストとして使用するための１−アリール−４−置換ピペラジン誘導体
WO2008147822A1 (fr) * 2007-05-22 2008-12-04 Chemocentryx, Inc. Composés d'azaindazole et procédés d'utilisation
JP2016169161A (ja) * 2013-07-19 2016-09-23 大日本住友製薬株式会社 新規イミダゾピリジン化合物
WO2018098499A1 (fr) * 2016-11-28 2018-05-31 Praxis Precision Medicines, Inc. Composés et procédés d'utilisation desdits composés

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FATHY, U. ET AL.: "Ultrasonic assisted synthesis, anticancer and antioxidant activity of some novel pyrazolo[3,4-b]pyridine derivatives", JOURNAL OF CHEMICAL AND PHARMACEUTICAL RESEARCH, vol. 7, no. 9, 2015, pages 4 - 12, XP055797165 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12054486B2 (en) 2021-09-24 2024-08-06 Xenon Pharmaceuticals Inc. Pyridine derivatives and their use as sodium channel activators

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