WO2021149767A1 - Dérivé hétérocyclique - Google Patents
Dérivé hétérocyclique Download PDFInfo
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- WO2021149767A1 WO2021149767A1 PCT/JP2021/002044 JP2021002044W WO2021149767A1 WO 2021149767 A1 WO2021149767 A1 WO 2021149767A1 JP 2021002044 W JP2021002044 W JP 2021002044W WO 2021149767 A1 WO2021149767 A1 WO 2021149767A1
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- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- JXHZRQHZVYDRGX-UHFFFAOYSA-M sodium;hydrogen sulfate;hydrate Chemical compound [OH-].[Na+].OS(O)(=O)=O JXHZRQHZVYDRGX-UHFFFAOYSA-M 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000005809 status epilepticus Diseases 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- DUZIJTYKDFFQDJ-UHFFFAOYSA-N tert-butyl 4-bromo-2,3-dihydroindole-1-carboxylate Chemical compound C1=CC=C(Br)C2=C1N(C(=O)OC(C)(C)C)CC2 DUZIJTYKDFFQDJ-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- OVCXRBARSPBVMC-UHFFFAOYSA-N triazolopyridine Chemical compound C=1N2C(C(C)C)=NN=C2C=CC=1C=1OC=NC=1C1=CC=C(F)C=C1 OVCXRBARSPBVMC-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 102000038650 voltage-gated calcium channel activity Human genes 0.000 description 1
- 108091023044 voltage-gated calcium channel activity Proteins 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
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- C07D273/04—Six-membered rings
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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
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to pharmaceutically useful heterocyclic derivatives and pharmaceutically acceptable salts thereof, as well as diseases involving sodium channels (Nav; for example, Nav1.1) containing them as active ingredients and various central nervous systems.
- Nav sodium channels
- therapeutic and / or prophylactic agents for diseases and therapeutic and / or prophylactic agents for tauopathy involving Nav.
- 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), attention deficit hyperactivity disorder (ADHD) It has been suggested that neurological 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 seizures 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 epileptic seizures associated therewith. It is expected to be a therapeutic agent for diseases.
- Tauopathy is a general term for diseases in which tau, which is one of the microtubule-binding proteins, becomes insoluble due to phosphorylation and abnormally accumulates in cells, which is considered to be an important pathogenic mechanism.
- Typical tauopathy includes Alzheimer's disease (AD) and frontotemporal lobar degeneration (Pick disease, progressive supranuclear palsy, corticobasal degeneration, etc.).
- AD Alzheimer's disease
- Pick disease progressive supranuclear palsy, corticobasal degeneration, etc.
- tau abnormalities are a sufficient condition for neurodegeneration.
- the details of the neurodegenerative mechanism due to abnormal tau accumulation are not clear.
- Nav1.1 decreased expression of Nav1.1 is observed in AD patients and AD model mice.
- epilepsy-like hyperexcitability is observed in AD patients and model mice, but in AD model mice and epilepsy model mice due to Nav1.1 heterozygous deficiency, tau deficiency reduces hyperexcitability, resulting in a decrease in Nav1.1.
- Tau is thought to play a central role in the damage of interneurons.
- Non-Patent Document 4 it has been reported that an operation to increase the expression level of Nav1.1 in AD model mice improves cognitive function and mortality rate due to seizure. It has not been reported so far that activation of potential-dependent sodium channels such as these reduces aggregation and accumulation of phosphorylated tau and suppresses brain atrophy.
- Examples of the compound that regulates the function of Nav1.1 include N, N'-(1,3-phenylene) bis (2-methylbenzamide) (Non-Patent Document 5) and PF-05661014 (Non-Patent Document 6).
- AA43279 Non-Patent Document 7
- LuAE98134 Non-Patent Document 8
- 4-phenyl-2- (pyrrolidinyl) nicotine amide derivative Non-Patent Document 9) and the like are known. The structure is different.
- 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 heterocyclic derivative and / or a pharmaceutical product useful as a therapeutic and / or prophylactic agent for diseases involving sodium channels, various central nervous system diseases, and / or tauopathy.
- a heterocyclic derivative and / or a pharmaceutical product useful as a therapeutic and / or prophylactic agent for diseases involving sodium channels, various central nervous system diseases, and / or tauopathy.
- physiologically acceptable salts pharmaceuticals containing them as active ingredients, and their pharmaceutical uses.
- 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 Shows a strong sodium channel (eg, Nav1.1) activating effect and can be a useful drug for the treatment and / or prevention of diseases involving sodium channels, various central nervous system diseases, and / or tauopathy. This has led to the completion of the present invention.
- Equation (1) [During the ceremony, Y 1 represents N, O, CR 1a or CR 1a R 2a ; Y 2 represents N, O, CR 1b or CR 1b R 2b ; Y 3 represents N or CR 1c; R 1a, R 1b, R 1c , R 2a and R 2b are each independently hydrogen atom, halogen atom, cyano, optionally substituted by 1-3 halogen atoms same or different C 1- 6 Alkoxy, C 1-6 alkoxy which may be substituted with 1 to 3 halogen atoms of the same or different kind, or amino which may be substituted with 1 to 2 C 1-6 alkyl of the same or different kind.
- Equation (1) is equation (1'): Not the compound indicated by; M 1 is (1-1) Saturated or partially unsaturated C 4-12 carbocyclic group (where the group is (A) a halogen atom, and (b) 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 It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of), (1-2) 4- to 12-membered saturated or partially unsaturated heterocyclic group (where the group is (A) Halogen atom, (B) Hydroxy, (C) Methoxy, (D) 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 (e) the same or (where
- the phenyl group is located at the 2-position, 3-position, 5-position and 6-position.
- (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) A 3- to 6-membered saturated carbocyclic group which may be substituted with 1 to 3 halogen atoms of the same or different species.
- Amino which may be, and (g) 1 to 2 homologous or dissimilar C 1-6 alkyl (where the C 1-6 alkyl is substituted with 1 to 3 halogen atoms of the same or dissimilar). May be substituted with 1 to 4 groups of the same or different species selected from the group consisting of amino-carbonyl), which may be substituted with (1-4) Amino (where, the group is (A) C 1-6 alkyl, which may be substituted with 1 to 3 halogen atoms of the same or different species.
- (B) A 3-membered to 10-membered group that 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 3- to 6-membered saturated carbocyclic groups. Substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of member saturated carbocyclic groups and (c) halogen atoms, C 1-6 alkyl and 3 to 6 membered saturated carbocyclic groups. May be substituted with one or two groups of the same or different species selected from the group consisting of C 3-10 cycloalkyl C 1-4 alkyl), or (1-5) thiophenyl (here).
- the group is (A) Halogen atom, (B) Hydroxy, (C) 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.
- (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 3- to 6-membered saturated carbocyclic groups optionally substituted with 1 to 3 halogen atoms of the same or different species, and (f) 1 to 2 C 1-6 alkyls of the same or different species.
- 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;
- 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.
- (G) A homologous or heterologous 1 to selected from the group consisting of halogen atoms, hydroxys, C 1-6 alkoxys, and aminos optionally substituted with 1 or 2 C 1-6 alkyls of the same or different species.
- C 1-6 alkoxy which may be substituted with 3 groups, (H) a halogen atom, hydroxy, and C 1-6 the same or different are selected from the group consisting of alkoxy one to three C 1-6 alkyl optionally substituted by group; a saturated or partially unsaturated C 3-7 carbocyclic group; and C 2-7 alkylcarbonyl optionally substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy.
- Amino which may be substituted with one or two homologous or heterologous groups selected from the group consisting of (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, cyanos, and C 1-6 alkyls. (J) A 4-membered to 7-membered group that 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 form a 4- to 7-membered saturated heterocyclic group together with the nitrogen atom to which they are attached).
- 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 atoms, hydroxys, 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.
- R 3 and R 4 may be the same or different.
- C 3-7 carbocyclic group (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 a C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species; a saturated or partially unsaturated C 3-7 carbocyclic group; and a 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, cyanos, and C 1-6 alkyls.
- (I) A 4-membered to 7-membered group that 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 form a 4- to 7-membered saturated heterocyclic group together with the nitrogen atom to which they are attached).
- K C 2-7 alkyl carbonyl or (l) C 2-7 alkoxycarbonyl,] 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.
- the amino, halogen, hydroxy, and C 1-6 optionally substituted by one to three groups the same or different are selected from the group consisting of alkoxy C 1-6 alkyl; saturated or partially From the group consisting of unsaturated C 3-7 carbocyclic groups; 4- to 7-membered saturated heterocyclic groups optionally substituted with C 1-6 alkoxy; and halogen atoms, hydroxy, and C 1-6 alkoxy. It may be substituted with 1 to 3 groups of the same or heterologous selected. It may be substituted with 1 to 2 groups of the same or heterologous selected from the group consisting of C 2-7 alkylcarbonyl.
- 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).
- E Selected from the group consisting of halogen atoms, hydroxys, C 1-6 alkyls, C 1-6 alkoxys, and aminos optionally substituted with one or two C 1-6 alkyls of the same or different species. Saturated or partially unsaturated C 3-7 carbocyclic groups, which may be substituted with 1 to 4 cognate or dissimilar groups.
- F 1 to 1 of the same or different species selected from the group consisting of halogen atoms, hydroxys, C 1-6 alkoxy, and aminos optionally substituted with one or two C 1-6 alkyls of the same or different species.
- C 1-6 alkoxy which may be substituted with 3 groups
- a halogen atom, hydroxy, and C 1-6 the same or different are selected from the group consisting of alkoxy one to three C 1-6 alkyl optionally substituted by group; a saturated or partially unsaturated C 3-7 carbocyclic group; and C 2-7 alkylcarbonyl optionally substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy.
- Amino which may be substituted with one or two homologous or heterologous groups selected from the group consisting of (H) Even if substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, and C 2-7 alkoxycarbonyl.
- Good 5 or 6 member heteroaryl (I) a halogen atom, hydroxy, and C 1-6 optionally substituted by one to three groups the same or different are selected from the group consisting of alkoxy C 1-6 alkyl; C 1-6 alkoxy; 4- to 7-membered saturated or partially unsaturated heterocyclic groups; even if substituted with 1 to 3 homologous or heterologous groups selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy.
- a 4- to 7-membered saturated or partially unsaturated heterocyclic group which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of good C 2-7 alkylcarbonyl; and oxo.
- (J) A 4- to 7-membered saturated or partially unsaturated heterocyclic group-oxy, optionally substituted with 1 to 4 C 1-6 alkyls.
- K -C (O) NR x Ry
- 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 heterocyclic group together with the nitrogen atom to which they are attached).
- R 8 and R 9 are 5- to 7-membered saturated or partially unsaturated carbon rings or heterocycles (where the rings are halogen atoms, together with the carbon atoms to which they are attached. And may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of C 1-6 alkyl)]. It is a group represented by Here, in the formula (2d), (2f) or (2g), one fluorine atom may be further substituted on the substitutable carbon atom on the ring.
- R 8 and R 9 are synonymous with (2-3) above in this section;
- R 10 is, (A) Hydrogen atom, (B) Halogen atom, (C) Cyano, (D) Halogen atom; hydroxy; saturated or partially unsaturated C 3-7 carbocyclic group; C 1-6 alkoxy optionally substituted with hydroxy or C 1-6 alkoxy; C 1-6 alkoxy or C 1 4- to 7-membered saturated or partially unsaturated heterocyclic groups optionally substituted with -6 alkyl; 5- or 6-membered heteroaryl optionally substituted with C 1-6 alkyl; and amino (here).
- the amino, halogen, hydroxy, and C 1-6 optionally substituted by one to three groups the same or different are selected from the group consisting of alkoxy C 1-6 alkyl; saturated or partially From the group consisting of unsaturated C 3-7 carbocyclic groups; 4- to 7-membered saturated heterocyclic groups optionally substituted with C 1-6 alkoxy; and halogen atoms, hydroxy, and C 1-6 alkoxy. It may be substituted with 1 to 3 groups of the same or heterologous selected. It may be substituted with 1 to 2 groups of the same or heterologous selected from the group consisting of C 2-7 alkylcarbonyl.
- 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).
- E Selected from the group consisting of halogen atoms, hydroxys, C 1-6 alkyls, C 1-6 alkoxys, and aminos optionally substituted with one or two C 1-6 alkyls of the same or different species. Saturated or partially unsaturated C 3-7 carbocyclic groups, which may be substituted with 1 to 4 cognate or dissimilar groups.
- F 1 to 1 of the same or different species selected from the group consisting of halogen atoms, hydroxys, C 1-6 alkoxy, and aminos optionally substituted with one or two C 1-6 alkyls of the same or different species.
- C 1-6 alkoxy which may be substituted with 3 groups
- a halogen atom, hydroxy, and C 1-6 the same or different are selected from the group consisting of alkoxy one to three C 1-6 alkyl optionally substituted by group; a saturated or partially unsaturated C 3-7 carbocyclic group; and C 2-7 alkylcarbonyl optionally substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy.
- Amino which may be substituted with one or two homologous or heterologous groups selected from the group consisting of (H) Even if substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy, and C 2-7 alkoxycarbonyl.
- Good 5 or 6 member heteroaryl (I) a halogen atom, hydroxy, and C 1-6 optionally substituted by one to three groups the same or different are selected from the group consisting of alkoxy C 1-6 alkyl; C 1-6 alkoxy; 4- to 7-membered saturated or partially unsaturated heterocyclic groups; even if substituted with 1 to 3 homologous or heterologous groups selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy.
- a 4- to 7-membered saturated or partially unsaturated heterocyclic group which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of good C 2-7 alkylcarbonyl; and oxo.
- (J) A 4- to 7-membered saturated or partially unsaturated heterocyclic group-oxy, optionally substituted with 1 to 4 C 1-6 alkyls.
- R x , R y and R Z are synonymous with (2-3) above in this section; n represents 0, 1 or 2; X 9 represents CH 2 or O] It is a group represented by
- one fluorine atom may be further substituted on the substitutable carbon atom on the ring, or (2-5) the following formula (2j):
- X 14 represents CR 15 , CHR 15 , N or NR 16 ;
- R 12 , R 13 and R 14 independently represent a hydrogen atom or methyl, respectively.
- 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 and R 16 are independent of each other.
- Phenyl 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) halogen.
- M 1 (1-1) Saturated or partially unsaturated C 4-12 carbocyclic group (where the group is (A) a halogen atom, and (b) 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 It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of), (1-2) 4- to 12-membered saturated or partially unsaturated heterocyclic group (where the group is (A) Halogen atom, (B) Hydroxy, (C) Methoxy, (D) 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 (e) the same or (wherein said C 1-6 alkyl is the same or may be substituted by 1-3 halogen atoms heterologous) C 1-6 alkyl
- the phenyl group is located at the 2-position, 3-position, 5-position and 6-position.
- (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) A 3- to 6-membered saturated carbocyclic group which may be substituted with 1 to 3 halogen atoms of the same or different species.
- Amino which may be, and (g) 1 to 2 homologous or dissimilar C 1-6 alkyl (where the C 1-6 alkyl is substituted with 1 to 3 halogen atoms of the same or dissimilar). May be substituted with 1 to 4 groups of the same or different species selected from the group consisting of amino-carbonyl), which may be substituted with (1-4) Amino (where, the group is (A) C 1-6 alkyl, which may be substituted with 1 to 3 halogen atoms of the same or different species.
- (B) A 3-membered to 10-membered group that 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 3- to 6-membered saturated carbocyclic groups. Substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of member saturated carbocyclic groups and (c) halogen atoms, C 1-6 alkyl and 3 to 6 membered saturated carbocyclic groups. May be C 3-10 cycloalkyl C 1-4 alkyl substituted with one or two homologous or heterologous groups selected from the group consisting of C 1-4 alkyl), or (1-5) thiophenyl (where, here).
- the group is (A) Halogen atom, (B) Hydroxy, (C) 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. (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) 3- to 6-membered saturated carbocyclic groups optionally substituted with 1 to 3 halogen atoms of the same or different species, and (f) 1 to 2 C 1-6 alkyls of the same or different species.
- the C 1-6 alkyl may be substituted with 1 to 3 halogen atoms of the same or different species
- R 1a , R 1b , R 1c , R 2a and R 2b are independently hydrogen atom, halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy or 1 to 6 of the same kind or different kinds.
- Equation (1) is expressed in equations (1a) to (1e): [In the formula, M 1 and M 2 are synonymous with [1] above] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, which is represented by any of the above.
- Equation (1) is the equation (1a): [In the formula, M 1 and M 2 are synonymous with [1] above] The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
- Equation (1) is the equation (1b): [In the formula, M 1 and M 2 are synonymous with [1] above] The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
- Equation (1) is the equation (1c): [In the formula, M 1 and M 2 are synonymous with [1] above] The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
- Equation (1) is the equation (1d): [In the formula, M 1 and M 2 are synonymous with [1] above] The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
- Equation (1) is the equation (1e): [In the formula, M 1 and M 2 are synonymous with [1] above] The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
- Amino which may be, and (g) 1 to 2 homologous or dissimilar C 1-6 alkyl (where the C 1-6 alkyl is substituted with 1 to 3 halogen atoms of the same or dissimilar). May be substituted with 1 to 4 groups of the same or different species selected from the group consisting of amino-carbonyl), which may be substituted with (1-4) Amino (where, the group is (A) C 1-6 alkyl, which may be substituted with 1 to 3 halogen atoms of the same or different species.
- (B) A 3-membered to 10-membered group that 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 3- to 6-membered saturated carbocyclic groups. Substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of member saturated carbocyclic groups and (c) halogen atoms, C 1-6 alkyl and 3 to 6 membered saturated carbocyclic groups.
- the group is (A) Halogen atom, (B) Hydroxy, (C) 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, (E) 3- to 6-membered saturated carbocyclic groups optionally substituted with 1 to 3 halogen atoms of the same or different species, and (f) 1 to 2 C 1-6 alkyls of the same or different species.
- the C 1-6 alkyl may be substituted with 1 to 3 halogen atoms of the same or different species
- the same or heterogeneous selected from the group consisting of aminos which may be substituted with. May be substituted with 1 to 4 groups)
- 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, cyanos, and C 1-6 alkyls.
- F A 4-membered to 7-membered group that 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 form a 4- to 7-membered saturated heterocyclic group together with the nitrogen atom to which they are attached).
- C 1-6 alkyl optionally substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of -6 alkoxy; saturated or partially unsaturated C 3-7 carbocyclic groups; C 1- 4- to 7-membered saturated heterocyclic groups optionally substituted with 6- alkoxy; and 1 to 3 homologous or heterologous groups selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy.
- 1 to 2 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 optionally substituted with 3 groups
- 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;
- a 4- to 7-membered saturated or partially unsaturated heterocyclic group which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of good C 2-7 alkylcarbonyl; and oxo.
- 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 heterocyclic group together with the nitrogen atom to which they are attached).
- K -C (O) OR Z (where R Z represents C 1-6 alkyl), or (l) with ethenyl optionally substituted with one 6-membered saturated heterocyclic group.
- R 8 and R 9 are 5- to 7-membered saturated or partially unsaturated carbon rings or heterocycles (where the rings are halogen atoms, together with the carbon atoms to which they are attached. And may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of C 1-6 alkyl)]. It is a group represented by Here, in the formula (2d), (2f) or (2g), one fluorine atom may be further substituted on the substitutable carbon atom on the ring.
- R 8 and R 9 are synonymous with (3) above in this section;
- R 10 is, (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 A member saturated or partially unsaturated heterocyclic group; a 5- or 6-membered heteroaryl optionally substituted with a C 1-6 alkyl; and an amino (where the amino is a halogen atom, 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 alkoxy; saturated or partially unsaturated C 3-7 carbocyclic groups; C 1- 4- to 7-membered saturated heterocyclic groups optionally substituted with 6- alkoxy; and 1 to 3 homologous or heterologous groups selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy.
- 1 to 2 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 optionally substituted with 3 groups
- 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;
- a 4- to 7-membered saturated or partially unsaturated heterocyclic group which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of good C 2-7 alkylcarbonyl; and oxo.
- K) -C (O) OR Z or (l) ethenyl optionally substituted with one 6-membered saturated heterocyclic group.
- R x , R y and R Z are synonymous with (3) above in this section].
- R 1a , R 1b , R 1c , R 2a and R 2b are independently hydrogen atom, halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy or 1 to 6 of the same kind or different kinds.
- R 1a , R 1b , R 1c , R 2a and R 2b are independently hydrogen atom, halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxy or the same or different 1 to 1 to Amino that may be substituted with two C 1-6 alkyls;
- M 1 is (1-1) Saturated or partially unsaturated C 4-12 carbocyclic group (where the group is (A) a halogen atom, and (b) 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 It may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of), (1-2) 4- to 12-membered saturated or partially unsaturated heterocyclic group (where the group is (A) Halogen atom, (B) Hydroxy, From C 1-6 alkyl which may be substituted with 1 to 3 groups of the same or different species selected from
- 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) 3- to 6-membered saturated carbocyclic groups optionally substituted with 1 to 3 halogen atoms of the same or different species, and (f) 1 to 2 C 1-6 alkyls of the same or different species.
- the C 1-6 alkyl may be substituted with 1 to 3 halogen atoms of the same or different species
- the same or heterogeneous selected from the group consisting of aminos which may be substituted with.
- (1-4) Amino where, the group is (A) C 1-6 alkyl, which may be substituted with 1 to 3 halogen atoms of the same or different species.
- the group is (A) Halogen atom, (B) 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.
- (C) 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, (D) 3- to 6-membered saturated carbocyclic groups optionally substituted with 1 to 3 halogen atoms of the same or different species, and (e) 1 to 2 C 1-6 alkyls of the same or different species.
- the C 1-6 alkyl may be substituted with 1 to 3 halogen atoms of the same or different species
- the same or heterogeneous selected from the group consisting of aminos which may be substituted with.
- R 6 is synonymous with [1] above;
- R 5 is (A) Hydrogen atom, (B) Halogen atom, (C) cyano, or (d) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or dissimilar; saturated or partially unsaturated C 3-7 carbocyclic groups; and
- C 2 Represents an amino that may be substituted with one or two homologous or heterologous groups selected from the group consisting of -7 alkylcarbonyls] It is a group represented by Here, in the formula (2c'), one fluorine atom may be further substituted on the cyclic substitutable carbon atom.
- C 1-6 alkyl optionally substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of -6 alkoxy; saturated or partially unsaturated C 3-7 carbocyclic groups; C 1- 4- to 7-membered saturated heterocyclic groups optionally substituted with 6- alkoxy; and 1 to 3 homologous or heterologous groups selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy.
- 1 to 2 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 optionally substituted with 3 groups
- a halogen atom, hydroxy and C 1-6 1 ⁇ the same or different are selected from the group consisting of alkoxy three groups optionally substituted by a C 1-6 alkoxy, or
- a halogen atom Substituentally substituted C 1-6 alkyl; saturated or partially unsaturated C 3-7 carbocyclic group; and homologous or heterologous 1 selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy.
- one fluorine atom may be further substituted on the cyclic substitutable carbon atom.
- 1-6 alkyl C 1-6 alkoxy; 4- to 7-membered saturated or partially unsaturated heterocyclic groups; homologous or heterologous 1 selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy.
- C 2-7 alkylcarbonyl optionally substituted with up to 3 groups; and 4-membered to 7 optionally substituted with 1 to 4 homologous or heterologous groups selected from the group consisting of oxo.
- M 1 (1) Halogen atom; and a group consisting of C 1-6 alkyl which may be substituted with 1 to 3 groups of the same kind or different kinds selected from the group consisting of halogen atom, hydroxy, and C 1-6 alkoxy. Saturated or partially unsaturated C 4-12 carbocyclic groups, or (2) halogen atoms; and halogen atoms, hydroxy, and which may be substituted with 1 to 4 groups of the same or different dissimilarity selected from. 1 to 4 homogeneous or heterologous groups selected from the group consisting of C 1-6 alkyl which may be substituted with 1 to 3 groups of the same or heterogeneous selected from the group consisting of C 1-6 alkoxy. It is a 4- to 12-membered saturated or partially unsaturated heterocyclic group that may be substituted with a group.
- 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 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, hydroxys, and C 1-6 alkoxy.
- Ra and R b may be combined with the carbon atoms to which they are attached to form a 3- to 6-membered saturated carbocycle or saturated heterocycle;
- the structure represented by the equation (3) is (A) Halogen atom, From 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 (b) hydroxy and (c) halogen atom, hydroxy, and C 1-6 alkoxy. It may be further substituted with 1 to 4 groups of the same or different species selected from the group.]
- M 1 has the following equations (38) to (52), (61) and (62): The compound according to any one of [1] to [13] or a pharmaceutically acceptable salt thereof, which is a group represented by any of the above.
- R 3 are independent of each other.
- 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.
- C 2-7 alkylcarbonyl optionally substituted with up to 3 groups; and 4-membered to 7 optionally substituted with 1 to 4 homologous or heterologous groups selected from the group consisting of oxo.
- X 14 represents NR 16;
- R 16 is (A) Phenyl which may be substituted with one or two groups of the same or different species selected from the group consisting of fluorine atom and methoxy, or (b) methyl, methoxy, fluorine atom, trifluoromethyl, and difluoro.
- M 1 is expressed by the following equation (38): The compound according to any one of [1] to [13] or [16] to [17], or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 1 is the following formula (39), (40), (41) or (45): The compound according to any one of [1] to [17] or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 1 is expressed by the following equation (39): The compound according to any one of [1] to [17] or [19], or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 1 is expressed by the following equation (40): The compound according to any one of [1] to [17] or [19], or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 1 is expressed by the following equation (41): The compound according to any one of [1] to [17] or [19], or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 1 is expressed by the following equation (45): The compound according to any one of [1] to [17] or [19], or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 1 is the following formula (48), (49), (50), (51), (61) or (62): The compound according to any one of [1] to [13] or [16] to [17], or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 1 is expressed by the following equation (48): The compound according to any one of [1] to [13], [16] to [17] or [24], or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 1 is expressed by the following equation (49): The compound according to any one of [1] to [13], [16] to [17] or [24], or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 1 is expressed by the following equation (50): The compound according to any one of [1] to [13], [16] to [17] or [24], or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 1 is expressed by the following equation (51): The compound according to any one of [1] to [13], [16] to [17] or [24], or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 1 is expressed by the following equation (61): The compound according to any one of [1] to [13], [16] to [17] or [24], or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 1 is expressed by the following equation (62): The compound according to any one of [1] to [13], [16] to [17] or [24], or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 2 is expressed by the following equations (53) to (58):
- R 3 is independently substituted with a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl, a C 1-6 alkoxy, or one or two C 1-6 alkyls of the same or different species.
- M 2 is the following formula (57) or (58): [In the formula, R 3 may be substituted with a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl, a C 1-6 alkoxy, or one or two C 1-6 alkyls of the same or different species. Represents amino] The compound according to any one of [1] to [31] or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 2 is expressed by the following equation (53): [In the formula, R 3 may be substituted with a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl, a C 1-6 alkoxy, or one or two C 1-6 alkyls of the same or different species. Represents amino] The compound according to any one of [1] to [31] or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 2 is expressed by the following equation (54): [In the formula, R 3 may be substituted with a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl, a C 1-6 alkoxy, or one or two C 1-6 alkyls of the same or different species. Represents amino] The compound according to any one of [1] to [31] or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 2 is the following equation (55): [In the formula, R 3 may be substituted with a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl, a C 1-6 alkoxy, or one or two C 1-6 alkyls of the same or different species. Represents amino] The compound according to any one of [1] to [31] or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 2 is expressed by the following equation (56): [In the formula, R 3 may be substituted with a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl, a C 1-6 alkoxy, or one or two C 1-6 alkyls of the same or different species. Represents amino] The compound according to any one of [1] to [31] or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 2 is expressed by the following equation (57):
- R 3 may be substituted with a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl, a C 1-6 alkoxy, or one or two C 1-6 alkyls of the same or different species.
- M 2 is expressed by the following equation (58): [In the formula, R 3 may be substituted with a hydrogen atom, a halogen atom, a cyano, a C 1-6 alkyl, a C 1-6 alkoxy, or one or two C 1-6 alkyls of the same or different species. Represents amino] The compound according to any one of [1] to [31] or a pharmaceutically acceptable salt thereof, which is a group represented by.
- M 2 is the following equation (2h''): [In the formula, R 8 is (A) A 5- or 6-membered heteroaryl, or (b), which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms, cyanos, and C 1-6 alkyls.
- 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 with C 1-6 alkyl; C 1-6 alkoxy; and oxo Represents a 4- to 7-membered saturated or partially unsaturated heterocyclic group which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of.]
- M 2 is the following equation (2j''):
- RA represents a hydrogen atom, methyl, methoxy, fluorine atom, trifluoromethyl or difluoromethoxy
- RA represents a hydrogen atom, methyl, methoxy, fluorine atom, trifluoromethyl or difluoromethoxy
- a therapeutic and / or prophylactic agent for central nervous system diseases which comprises the compound according to any one of [1] to [47] or a pharmaceutically acceptable salt thereof as an active ingredient.
- a therapeutic and / or prophylactic agent for a disease associated with Nav which comprises the compound according to any one of [1] to [47] or a pharmaceutically acceptable salt thereof as an active ingredient.
- Agent
- a therapeutic agent and / or a therapeutic agent for a disease associated with a decrease in Nav function which comprises the compound according to any one of [1] to [47] or a pharmaceutically acceptable salt thereof as an active ingredient.
- Preventive agent Preventive 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 [47] 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, focal epilepsy) , Generalized epilepsy); Epilepsy syndrome (Dravet syndrome, intractable childhood epilepsy with generalized tonic-clonic seizures; ICE-GTC), myoclony weakness Epilepsy with seizures (Doose syndrome), West syndrome, Lennox-Gastaut syndrome (Rasmussens's encephalitis and Lennox-Gastaut syndrome), infantile spasms, severe infantile multifocal epilepsy (sever infantile) SIMFE), infantile borderline severe intermuscular epilepsy (severe myoclonic epilepsy, borderline; SMEB), benign familial neonatal-infantile seizure (BFNIS), etc.); schizophrenia; autism
- the treatment according to [52] or [59] which is at least one disease selected from the group consisting of epilepsy spectrum disorder (ASD
- [67] Nav comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of [1] to [47] or a pharmaceutically acceptable salt thereof.
- a therapeutically effective amount of the compound according to any one of [1] to [47] or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment.
- a therapeutically effective amount of the compound according to any one of [1] to [47] or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment.
- [70] The compound according to any one of [1] to [47] or a pharmaceutically acceptable salt thereof, and an antiepileptic drug, an antidepressant, an antiparkinsonian drug, a therapeutic drug for schizophrenia, or A drug obtained by combining one or more drugs selected from drugs classified as ADHD therapeutic drugs.
- [71] Selected from drugs classified into antiepileptic drugs, antidepressants, antiparkinson drugs, schizophrenia drugs or ADHD drugs for use in the treatment and / or prevention of central nervous system diseases 1
- [72] Selected from drugs classified into antiepileptic drugs, antidepressants, antiparkinson drugs, schizophrenia drugs or ADHD drugs for use in the treatment and / or prevention of central nervous system diseases 1
- a therapeutic and / or prophylactic agent for tauopathy which comprises the compound according to any one of [1] to [47] or a pharmaceutically acceptable salt thereof as an active ingredient.
- Tauopathy is Alzheimer's disease, Alzheimer-type dementia, diffuse neurofibrillary tangle with calcification, muscular atrophic lateral sclerosis on Guam island-Parkinson dementia complex, muscular atrophic lateral cord on Kii Peninsula Sclerosis-Parkinson's dementia complex, frontotemporal lobar degeneration (Pick's disease, progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, silver granule dementia, glial cell globular inclusion tauopathy, chromosome 17 (Including familial frontotemporal dementia Parkinsonism), neurofibrillary tangle senile dementia, Down syndrome, chronic traumatic encephalopathy, muscle tonic dystrophy, Niemann-Pick disease type C, adult nerve Childhood non-progressive encephalopathy with degeneration, PLA2G6-related neurodegeneration, Gerstmann-Stroisler-Scheinker's disease, familial British dementia, familial Danish dementia, post-encephalitis Parkinsonism, subacute
- Tauopathy is Alzheimer's disease, Alzheimer-type dementia, diffuse neurofibrillary tangle with calcification, muscular atrophic lateral sclerosis on Guam island-Parkinson dementia complex, muscular atrophic lateral cord on Kii Peninsula Sclerosis-Parkinson's dementia complex, frontotemporal lobar degeneration (Pick's disease, progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, silver granule dementia, glial cell globular inclusion tauopathy, chromosome 17 (Including familial frontotemporal dementia Parkinsonism), neurofibrillary tangle senile dementia, Down syndrome, chronic traumatic encephalopathy, muscle tonic dystrophy, Niemann-Pick disease type C, adult nerve Childhood non-progressive encephalopathy with degeneration, PLA2G6-related neurodegeneration, Gerstmann-Stroisler-Scheinker's disease, familial British dementia, familial Danish dementia, post-encephalitis Parkinsonism, subacute
- Tauopathy is a diffuse neurofibrillary tangle with calcification, muscular atrophic lateral sclerosis on Guam Island-Parkinson dementia complex, muscular atrophic lateral sclerosis on Kii Peninsula-Parkinson dementia complex, Frontotemporal lobar degeneration (Pick's disease, progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, silver granule dementia, glial cell globular inclusion tauopathy, familial frontotemporal lobe linked to chromosome 17 Type dementia including Parkinsonism), neurofibrillary tangle senile dementia, Down syndrome, chronic traumatic encephalopathy, muscle tonic dystrophy, Niemann-Pick disease type C, childhood nonprogressive with adult neurodegeneration Encephalopathy, PLA2G6-related neurodegeneration, Gerstmann-Stroisler-Scheinker's disease, familial British dementia, familial Danish dementia, post-encephalitis Parkinsonism, subacute sclerosing pan
- Tauopathy is a diffuse neurofibrillary tangle with calcification, muscle atrophic lateral sclerosis on Guam Island-Parkinson dementia complex, muscle atrophic lateral cord sclerosis on Kii Peninsula-Parkinson dementia complex, Frontotemporal lobar degeneration (Pick's disease, progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, silver granule dementia, glial cell globular inclusion tauopathy, familial frontotemporal lobe linked to chromosome 17 Type dementia including Parkinsonism), neurofibrillary tangle senile dementia, Down syndrome, chronic traumatic encephalopathy, muscle tonic dystrophy, Niemann-Pick disease type C, childhood non-progressive with adult neurodegeneration Encephalopathy, PLA2G6-related neurodegeneration, Gerstmann-Stroisler-Scheinker's disease, familial British dementia, familial Danish dementia, post-encephalitis Parkinsonism, subacute scleros
- a therapeutically effective amount of the compound according to any one of [1] to [47] or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment.
- a method for treating and / or preventing tauopathy is provided.
- [86] The compound according to any one of [1] to [47] or a pharmaceutically acceptable salt thereof, and other therapeutic agents for tauopathy, therapeutic agents for Alzheimer's dementia, antiepileptic agents, antipsychotics.
- tauopathy therapeutic agents Alzheimer-type dementia therapeutic agents, antiepileptic agents, antipsychotic agents, antidepressants, anxiolytics, Chinese herbs, sleep-inducing agents, for use in the treatment and / or prevention of tauopathy.
- drugs selected from anti-Parkinson's disease drug, antihypertensive agent, anti-inflammatory agent, diabetes drug, dyslipidemia drug, anti-obesity drug, anti-vomiting drug, swallowing disorder drug, urinary disorder drug and laxative
- drugs selected from anti-Parkinson's disease drug, antihypertensive agent, anti-inflammatory agent, diabetes drug, dyslipidemia drug, anti-obesity drug, anti-vomiting drug, swallowing disorder drug, urinary disorder drug and laxative
- the compound according to any one of [1] to [47], [64] to [66], or [85], which is used in combination, or a pharmaceutically acceptable salt thereof.
- Or the pharmaceutical composition or agent according to any one of [48] to [51], [53] to [
- tauopathy therapeutic agents Alzheimer-type dementia therapeutic agents, antiepileptic agents, antipsychotic agents, antidepressants, anxiolytics, Chinese herbs, sleep-inducing agents, for use in the treatment and / or prevention of tauopathy.
- drugs selected from anti-Parkinson's disease drug, antihypertensive agent, anti-inflammatory agent, diabetes drug, dyslipidemia drug, anti-obesity drug, anti-vomiting drug, swallowing disorder drug, urinary disorder drug and laxative
- drugs selected from anti-Parkinson's disease drug, antihypertensive agent, anti-inflammatory agent, diabetes drug, dyslipidemia drug, anti-obesity drug, anti-vomiting drug, swallowing disorder drug, urinary disorder drug and laxative
- the compound according to any one of [1] to [47], [66], or [85], which is used in combination, or a pharmaceutically acceptable salt thereof, or [48]. , [51], [55], [58], [73], [75], [77], [79], or [
- a therapeutically effective amount of the compound according to any one of [1] to [47], [64] to [66], or [85] or pharmaceutically pharmaceutically effective thereof for patients in need of treatment, a therapeutically effective amount of the compound according to any one of [1] to [47], [64] to [66], or [85] or pharmaceutically pharmaceutically effective thereof.
- Alzheimer's dementia drug Alzheimer's dementia drug, antiepileptic drug, antipsychotic drug, antidepressant drug, anxiety drug, Chinese herbal medicine, sleep inducer, anti-Parkinson disease drug, antihypertensive agent, anti-inflammatory agent, diabetes drug, dyslipidemia treatment
- tauopathy characterized by concomitant administration of one or more agents selected from drugs, antipsychotics, antiemetics, swallowing disorders therapeutic agents, urinary disorders therapeutic agents and laxatives.
- Drugs and other tauopathy treatments Alzheimer's dementia treatments, antiepileptic drugs, antipsychotics, antidepressants, anxiety drugs, Chinese herbs, sleep-inducing agents, anti-Parkinson's disease agents, antihypertensive agents, anti-inflammatory agents, Tauopathy, characterized by co-administration of one or more agents selected from a therapeutic agent for diabetes, a therapeutic agent for dyslipidemia, an anti-obesity agent, an anti-vomiting agent, a therapeutic agent for swallowing disorders, a therapeutic agent for urinary disorders and a lower drug. Methods for treatment and / or prevention.
- the compounds of the present invention may exhibit significant sodium channel (particularly Nav1.1) activating effects. In addition, 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 involving sodium channels (particularly Nav1.1) and various central nervous system diseases.
- the compound of the present invention can cause a decrease in phosphorylation-aggregated tau and / or suppression of brain atrophy by activating voltage-gated sodium channels. This is expected to be useful as an active ingredient of a therapeutic agent and / or a preventive agent for improving tauopathy accompanied by various symptoms including cognitive dysfunction.
- 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, etc. Examples thereof include 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
- C 2-7 alkyl carbonyl 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, normal propylcarbonyl, isopropylcarbonyl and the like.
- “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, cyclos in addition to those listed as specific examples 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 saturated or partially unsaturated bicyclo ring and a saturated or partially unsaturated spiro ring, and may have a crosslinked structure. .. Specific examples include, for example, groups represented by the following groups.
- the "5- to 7-membered saturated or partially unsaturated carbocycle” means a monocyclic or bicyclic saturated or partially unsaturated hydrocarbon ring having 5 to 7 carbon atoms, and is a part thereof. Those having an unsaturated bond, those having a crosslinked structure, and those forming a spiro ring are also included.
- 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 10-membered saturated carbocyclic group” or “C 3-10 cycloalkyl” means a 3- to 10-membered monocyclic or bicyclic saturated hydrocarbon group and has a crosslinked structure. And those with a spiro ring formed.
- Specific examples of the "3- to 10-membered saturated carbocyclic group” or “C 3-10 cycloalkyl” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Be done.
- C 3-10 cycloalkyl C 1-4 alkyl said substituted with “C 3-10 cycloalkyl” means the “C 1-4 alkyl”.
- Specific examples of "C 3-10 cycloalkyl C 1-4 alkyl” include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, and cyclopropylpropyl.
- the "three- to six-membered saturated carbocycle” means a saturated hydrocarbon ring having 3 to 6 carbon atoms, and may also mean one having a crosslinked structure and one having a spiro ring formed as appropriate. good.
- Specific examples of the "3-membered to 6-membered saturated carbocycle” include cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.
- C 1-6 alkyl moiety of the "C 1-6 alkoxy” has the same meaning as the “C 1-6 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 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 methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like.
- 5- or 6-membered heteroaryl means a 5- or 6-membered heteroaromatic group, which is one or more homologous or heterologous heteroatoms selected from nitrogen, sulfur and oxygen atoms. It may be contained (for example, 1 to 4) 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; It is pyrazil or pyridadyl.
- the "6-membered heteroaryl” means a 6-membered heteroaromatic group among the "5- or 6-membered heteroaryl".
- Specific examples of the "6-membered heteroaryl” include, for example, pyridine, pyridazine, pyrimidine, pyrazine and the like.
- a bond across a ring 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 heterocyclic group having 1 to 2 atoms of the same type or different types selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof include monocyclic or polycyclic saturated or partially unsaturated heterocyclic groups. Preferably, it is a "5- to 7-membered saturated or partially unsaturated heterocyclic group".
- the "5- to 7-membered saturated or partially unsaturated heterocyclic group” include pyranyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuryl, dihydropyrrolill, dihydrofuranyl, pyrrolidinyl, imidazolidinyl, piperidinyl, Examples thereof include piperazinyl, dioxanyl, azepanyl, morpholinyl, thiomorpholinyl and the like.
- Specific examples of the "4-membered to 7-membered saturated or partially unsaturated heterocyclic group” include those listed as specific examples of the "5-membered to 7-membered saturated or partially unsaturated heterocyclic group".
- azetidineyl oxetanyl and the like.
- specific examples of the "4- to 7-membered saturated heterocyclic group” include azetidinyl, oxetanyl, tetrahydropyranyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, dioxanyl, azepanyl, morpholinyl, thiomorpholinyl and the like. Be done.
- the "6-membered saturated heterocyclic group” include tetrahydropyranyl, piperazinyl, piperidinyl, dioxanyl, 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, 4- to 12-membered atoms having 1 to 3 homologous or dissimilar atoms selected from nitrogen, oxygen and sulfur atoms. Examples thereof include monocyclic or polycyclic saturated or partially unsaturated heterocyclic groups. 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 -Diazocanyl, 1,5-diazocanyl can be mentioned.
- the bond of the group may be either on a carbon atom or a nitrogen atom constituting the ring.
- “4 to 7 member saturated or partially unsaturated heterocyclic groups” or “4 to 12 member saturated or partially unsaturated heterocyclic groups” include saturated or partially unsaturated bicyclo rings and saturated or partially saturated. 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.
- 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 a group 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 composed. Further, the saturated heterocycle may be appropriately substituted with oxo, and may contain one or two carbonyls, thiocarbonyls, sulfinyls or sulfonyls. Here, oxygen atoms and sulfur atoms of carbonyl, thiocarbonyl, sulfinyl and sulfonyl are not included in the number of 3 to 6 members (ring size) and the heteroatoms constituting the ring.
- the "3-membered 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-membered 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 a and R b contain a 3- to 6-membered saturated carbocycle and a 3- to 6-membered saturated heterocycle formed together with the carbon atoms to which they are bonded.
- Specific examples of the groups include groups represented by the following formulas.
- the preferred embodiments are as follows.
- the technical scope of the invention is not limited to the scope of aspects exemplified below.
- the preferred embodiments in the present specification may be appropriately combined as long as they do not conflict with each other.
- Y 1 is CR 1a
- Y 2 is CR 1b
- Y 3 is CR 1c
- the bond between 1 and Y 2 may be a double bond, more preferably Y 1 , Y 2 and Y 3 are CH, and the bond between Y 1 and Y 2 is a double bond. There are cases.
- Y 1 is N
- Y 2 is CR 1b
- Y 3 is CR 1c
- Y 1 The bond between Y 1 and Y 2 may be a double bond, more preferably Y 1 is N, Y 2 and Y 3 are CH, and the bond between Y 1 and Y 2 is double. In some cases, it is a bond.
- Y 1 is CR 1a
- Y 2 is N
- Y 3 is CR 1c
- Y 1 The bond between Y 1 and Y 2 may be a double bond, more preferably Y 1 and Y 3 are CH, Y 2 is N, and the bond between Y 1 and Y 2 is double. In some cases, it is a bond.
- Y 1 is CR 1a R 2a
- Y 2 is CR 1b R 2b
- Y 3 is N.
- the bond between Y 1 and Y 2 is a single bond, more preferably Y 1 and Y 2 are CH 2 , Y 3 is N, and between Y 1 and Y 2. There is a case where the bond of is a single bond.
- Y 1 is CR 1a R 2a
- Y 2 is O
- Y 3 is N
- Y The bond between 1 and Y 2 may be a single bond, more preferably Y 1 is CH 2 , Y 2 is O, Y 3 is N, and between Y 1 and Y 2. There is a case where the bond of is a single bond.
- R 1a , R 1b , R 1c , R 2a and R 2b preferably hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy or one or two C 1-6 of the same or different species.
- Amino which may be substituted with alkyl, is mentioned, more preferably a hydrogen atom, fluorine, methyl, methoxy, amino, methylamino or dimethylamino, and even more preferably a hydrogen atom.
- 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.
- Hydrogen atom, (1-2) Halogen atom, (1-3) Does it represent a C 1-6 alkyl optionally 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 ;, Alternatively, Ra and R b may be combined with the carbon atoms to which they are attached to form a 3- to 6-membered saturated carbocycle or saturated heterocycle;
- the structure represented by the equation (3) is (A) Halogen atom, From 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 (b) hydroxy and (c) halogen atom, hydroxy, and C 1-6 alkoxy. It may be further substitute
- X 16 is C or N
- m is 1 or 2
- Ra and R b are independently hydrogen atoms and halogen atoms, respectively.
- it is a C 1-6 alkyl which may be substituted with 1 to 3 halogen atoms of the same type or different types.
- M 1 Another preferred embodiment of M 1 is the following formulas (3a), (3b), (3c), (3d), (3e), (3f), (3g), (3h), (3i), (3j). ), (3k), (3m) (3n), (3p), (3q), (3r), (3s), (3t), (3u), (3v), (3w), (3x), ( 3y), (3z), (3a'), (3b'), (3c'), (3d'), (3e') or (3f'): It is a group represented by.
- (1-1) Hydrogen atom, (1-2) Halogen atom, (1-3) Represents a C 1-6 alkyl optionally 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; , Ra and R b may be combined with the carbon atoms to which they are attached to form a 3- to 6-membered saturated carbon ring or saturated heterocycle;
- the structure represented by the equation (3) is (A) Halogen atom, From 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 (b) hydroxy and (c) halogen atom, hydroxy, and C 1-6 alkoxy. It may be further substituted with 1 to 4 groups of the same or different species selected from the group.]
- the group represented by is mentioned
- (1-1) Hydrogen atom, (1-2) Halogen atom, (1-3) Represents a C 1-6 alkyl optionally 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; , Ra and R b may be combined with the carbon atoms to which they are attached to form a 3- to 6-membered saturated carbon ring or saturated heterocycle;
- the structure represented by the equation (3) is (A) Halogen atom, From 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 (b) hydroxy and (c) halogen atom, hydroxy, and C 1-6 alkoxy. It may be further substituted with 1 to 4 groups of the same or different species selected from the group.]
- the group represented by is
- Equation (11) to (37) [In the equation, X 1a or X 1b independently represent N or CR 3; 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 atoms, hydroxys, 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.
- 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. 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, hydroxys, C 1-6 alkyls, and C 1-6 alkoxys.
- 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 a C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species; a saturated or partially unsaturated C 3-7 carbocyclic group; and a 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 form a 4- to 7-membered saturated heterocyclic group together with the nitrogen atom to which they are attached).
- R 3 and R 4 are a plurality, each R 3 and R 4 may be the same or different]
- A Hydrogen atom
- B Halogen atom
- C Cyano
- D C 1-6 alkyl, which may be substituted with 1 to 3 halogen atoms of the same or different species.
- E C 1-6 alkoxy, which may be substituted with 1 to 3 halogen atoms of the same or different species.
- F Amino, which may be substituted with one or two C 1-6 alkyls of the same or different species. 5 or 6 may be substituted with (g) a 6-membered saturated heterocyclic group or (h) 1 to 4 groups of the same or different species selected from the group consisting of halogen atoms and C 1-6 alkyl.
- X 2, X 5, X 6, X 7, X 8, A 1, and A 2 as ring containing them, bicyclic aromatic heterocyclic ring 9 or 10-membered 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.
- X 1a or X 1b independently represent N or CR 3;
- 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 atoms, hydroxys, 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.
- 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. 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, hydroxys, C 1-6 alkyls, and C 1-6 alkoxys.
- 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 a C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms of the same or different species; a saturated or partially unsaturated C 3-7 carbocyclic group; and a C 2-7 alkylcarbonyl. 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, cyanos, and C 1-6 alkyls.
- (J) A 4-membered to 7-membered group that 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 form a 4- to 7-membered saturated heterocyclic group together with the nitrogen atom to which they are attached).
- R 3 and R 4 are a plurality, each R 3 and R 4 may be the same or different] A group represented by any of the above can be mentioned.
- M 2 Another aspect of M 2, is a 4-cyano-phenylamino.
- C 1-6 alkyl optionally substituted with 1 to 3 homologous or dissimilar groups selected from the group consisting of -6 alkoxy; saturated or partially unsaturated C 3-7 carbocyclic groups; C 1- 4- to 7-membered saturated heterocyclic groups optionally substituted with 6- alkoxy; and 1 to 3 homologous or heterologous groups selected from the group consisting of halogen atoms, hydroxy, and C 1-6 alkoxy.
- 1 to 2 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 optionally substituted with 3 groups
- 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;
- a 4- to 7-membered saturated or partially unsaturated heterocyclic group which may be substituted with 1 to 4 groups of the same or different species selected from the group consisting of good C 2-7 alkylcarbonyl; and oxo.
- 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 heterocyclic group together with the nitrogen atom to which they are attached).
- K -C (O) OR Z (where R Z represents C 1-6 alkyl), or (l) with ethenyl optionally substituted with one 6-membered saturated heterocyclic group.
- R 8 and R 9 are 5- to 7-membered saturated or partially unsaturated carbon rings or heterocycles (where the rings are halogen atoms, together with the carbon atoms to which they are attached. And 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 group represented by is mentioned.
- “Pharmaceutically acceptable salts” include, for example, inorganic acid salts such as hydrochlorides, hydrobromates, sulfates, phosphates, nitrates; and acetates, propionates, oxalates, etc.
- Organic acids such as succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate Specific examples include salt and the like.
- 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 racemic compound 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) ..
- 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 also include the case where they form salts, and examples of the salts include those similar to 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 produced by other methods as appropriate 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 methods commonly used in synthetic organic chemistry (eg, 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.
- the compound represented by the formula (1) is produced by forming a bond at the portions a, b, and c, respectively.
- M 1 , M 2 , Y 1 , Y 2 , Y 3 and the bond between Y 1 and Y 2 are synonymous with [1] above. ]
- the bond forming method for the portions a, b, and c can be exemplified as the methods described in the following production methods 1 to 5, but the order of bond forming can be appropriately changed.
- Manufacturing method 1 The compound represented by the formula (1) is produced, for example, by the method shown below.
- R stands for C 1-6 alkyl
- LG represents a leaving group (eg, iodine atom, bromine atom, chlorine atom, substituted sulfonyl (eg, methanesulfonyl, p-toluenesulfonyl, etc.), etc.).
- LG represents a leaving group (eg, iodine atom, bromine atom, chlorine atom, substituted sulfonyl (eg, methanesulfonyl, p-toluenesulfonyl, etc.), etc.).
- Step 1-1 Production step of compound (1)
- the compound represented by the formula (1) reacts with compound (1-1) in the presence of a base in an appropriate inert solvent with compound (1-2).
- a base in an appropriate inert solvent with compound (1-2).
- the compound (1-1) a compound synthesized by the production method 4 or 5 described later, or a commercially available product can be used.
- the compound (1-2) a commercially available product, or a compound synthesized by a known method or a method similar thereto can be used.
- 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 include aprotonic 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 (1-4)
- Compound (1-4) is produced from compound (1-1) and compound (1-3) according to the method described in step 1-1.
- NS As the compound (1-3), a commercially available product, or a compound synthesized by a known method or a method similar thereto can be used.
- Step 1-3 Preparation process of Compound (1-5) (1-5), the compound (1-4) a known method (for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc .), Comprehensive Organic Transformation, by RC Larock, etc., VCH publisher Inc., 1989, etc.) It is produced by hydrolysis 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, etc., VCH publisher Inc., 1989, etc.
- Step 1-4 Production Step of Compound (1)
- the compound represented by the formula (1) is also a compound (1-5) in a suitable inert solvent in the presence or absence of a base. It is also produced by reacting with 1-6) using a condensing agent.
- 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 CDI
- benzotriazole-1-yl-N, N, N', N'-tetramethyluronium Hexafluorophosphate HBTU
- 7-azabenzotriazole-1-yl-N, N, N', N'-tetramethyluronium hexafluorophosphate HATU
- 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, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, dipotassium hydrogen phosphate, potassium phosphate, disodium hydrogen phosphate, phosphorus.
- 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 include aprotonic 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.
- This step can also be carried out according to a known method, for example, by activating the carboxy group with an acid anhydride, a mixed acid anhydride or an acid halide and reacting with the compound (1-6).
- the compound represented by the formula (2-4) is produced, for example, by the method shown below.
- LG is a leaving group (eg, iodine atom, bromine atom, Represents a chlorine atom, a substituted sulfonyl (eg, methanesulfonyl, p-toluenesulfonyl, etc.);
- R 21 and R 22 are independently substituted C 1-6 alkyl, optionally substituted, respectively.
- R 21 and R 22 are the nitrogen atoms to which they are attached. Together with, it may form a 4- to 12-membered saturated heterocycle that may be substituted.
- Step 2-1 Production step of compound (2-2)
- Compound (2-2) is produced from compound (2-1) and compound (1-2) according to the method described in step 1-1.
- NS As the compound (2-1), a compound synthesized according to a known method (for example, Tetrahedron, 2015, 71, 4859., Bioorganic & Medicinal Chemistry Letters, 2015, 25, 1030., Etc.) or a commercially available product is used. be able to.
- Step 2-2 Production step of compound (2-4)
- Compound (2-4) reacts compound (2-2) with compound (2-3) in the presence of a base in a suitable inert solvent.
- a base such as triethylamine, diisopropylethylamine, and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, dipotassium hydrogen phosphate, potassium phosphate, disodium hydrogen phosphate, phosphorus.
- 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 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.
- the reaction temperature is not particularly limited, but is usually selected from the range of 20 ° C.
- Compound (2-4) is also produced by reacting compound (2-2) with compound (2-3) in the presence of a palladium catalyst, phosphine coordination and a base in a suitable inert solvent. NS. Examples of the base and the inert solvent include those described above.
- 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 (diphenylphosphine) 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 (diphen
- Step 2-3 Production step of compound (2-5)
- Compound (2-5) is produced from compound (2-1) and compound (2-3) according to the method described in step 2-2.
- NS As the compound (2-1), a compound synthesized according to a known method (for example, Tetrahedron, 2015, 71, 4859., Bioorganic & Medicinal Chemistry Letters, 2015, 25, 1030., Etc.) or a commercially available product is used. be able to.
- Step 2-4 Production step of compound (2-4)
- Compound (2-4) is produced from compound (2-5) and compound (1-2) according to the method described in step 1-1.
- NS Production step of compound (2-4)
- the compounds represented by the formulas (3-2) and (3-3) are produced, for example, by the methods shown below.
- LG is a leaving group (eg, iodine atom, bromine atom, Represents a chlorine atom, substituted sulfonyl (eg, methanesulfonyl, p-toluenesulfonyl, etc.);
- A represents boronic acid, boronic acid ester, BF 3 K, or BF 3 Na; Q 2 is substituted.
- C 4-12 carbon ring group heterocyclic group or a saturated or partially unsaturated may also be 4-membered to 12-membered partially unsaturated;
- Q 3 may be substituted saturated or partially unsaturated
- Step 3-1 Production of compound (3-2)
- Compound (3-2) is a compound obtained by mixing compound (2-2) with a suitable inert solvent in the presence of a palladium catalyst, a phosphine ligand and a base. It is produced by reacting with (3-1).
- a commercially available product, or a compound synthesized by a known method or 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 (diphenylphosphine) 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 (diphen
- 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, 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.
- Step 3-2 Production step of compound (3-3)
- Compound (3-3) is subjected to catalytic reduction of compound (3-2) in a suitable inert solvent under a hydrogen atmosphere using a metal catalyst.
- a 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 (3-2).
- the inert solvent include ethers such as tetrahydrofuran; esters such as ethyl acetate and the like.
- the hydrogen pressure is usually 1 atm to 100 atm, preferably 1 to 5 atm.
- 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.
- the compound represented by the formula (4-3) is produced, for example, by the method shown below.
- the bonds between Y 1 , Y 2 , Y 3 and Y 1 and Y 2 are synonymous with [1] above;
- LG 1 and LG 2 are independent leaving groups (respectively).
- it represents an iodine atom, a bromine atom, a chlorine atom, a substituted sulfonyl (eg, methanesulfonyl, p-toluenesulfonyl, etc.);
- R 21 and R 22 may be substituted independently of each other.
- Step 4-1 Production step of compound (4-2)
- Compound (4-2) is produced from compound (4-1) and compound (2-3) according to the method described in step 2-2.
- NS As the compound (4-1) and the compound (2-3), commercially available products or those synthesized by a known method (or a method similar thereto) can be used.
- the amount of the compound (2-3) used is , Usually 1.0 to 1.5 equivalents, preferably 1.05 to 1.2 equivalents, relative to compound (4-2).
- Step 4-2 Production of compound (4-3)
- Compound (4-3) is produced by reacting compound (4-2) with a base or acid in a suitable inert solvent.
- the acid include hydrochloric acid, sulfuric acid, nitric acid, acetic acid and the like.
- 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, water and a mixed solvent thereof.
- the reaction temperature is not particularly limited, but is usually selected from the range of 20 ° C. to 200 ° C., preferably 50 ° 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 (5-4) is produced, for example, by the method shown below.
- the bonds between Y 1 , Y 2 , Y 3 and Y 1 and Y 2 are synonymous with [1] above;
- Q 3 is a saturated or partially unsaturated C that may be substituted.
- G represents a metal species such as magnesium, zinc;
- X represents a halogen atom.
- Step 5-1 Production step of compound (5-3)
- the compound (5-3) is a method known for the organometallic compound (5-2) such as Grignard reagent with respect to the compound (5-1). For example, it is produced by reacting in the same manner as Organic Letters, 2015, 17, 5517., Organic & Biomolecular Chemistry, 2014, 12, 2049., Etc.).
- Compound (5-1) and compound (5-2) are commercially available or known methods (eg, Organic Letters, 2008, 10, 4815., Journal of Organic Chemistry, 2015, 80, 12182., Etc.), or Those synthesized by a method similar thereto can be used.
- Step 5-2 Production step of compound (5-4)
- Compound (5-4) is a method known for hydrazine to compound (5-2) (eg, Journal of Medicinal Chemistry, 1993, 36, 4052. , International Publication No. 2007/20343, etc.), and produced by reacting in the same manner.
- the compound represented by the formula (4-3) is also produced, for example, by the method shown below.
- LG 2 is a leaving group (eg, iodine atom, bromine atom, chlorine).
- P represents a protective group for a hydroxy group;
- R 21 and R 22 may be independently substituted, respectively.
- Step 6-1 Production Step of Compound (6-2)
- Compound (6-1) is compound (6-1) in the presence of a base or silver catalyst in a suitable inert solvent.
- a base include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide and the like.
- the silver catalyst include silver carbonate and the like.
- the inert solvent include benzene, toluene, 1,4-dioxane, THF, 1,2-dimethoxyethane, dimethylformamide, and a mixed solvent thereof.
- the reaction temperature is not particularly limited, but is usually selected from the range of 20 ° C. to 200 ° C., preferably 20 ° C. to 80 ° C.
- the reaction time is usually 30 minutes to 48 hours.
- Step 6-2 Production step of compound (6-3)
- Compound (6-3) is produced from compound (6-2) and compound (2-3) according to the method described in step 2-2.
- Step 6-3 Preparation process of Compound (4-3) (4-3) from compound (6-3), a known method (for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, by RC Lalock, etc., 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, by RC Lalock, etc., VCH publisher Inc., 1989, etc.
- the compound represented by the formula (7-5) is produced, for example, by the method shown below.
- M 1 , Y 1 , Y 2 , and Y 3 are synonymous with [1] above;
- X represents a halogen atom.
- Step 7-1 Production Step of Compound (7-2)
- Compound (7-2) is produced from compound (7-1) and hydrazine according to the method described in Step 1-4.
- Step 7-2 Production step of compound (7-4)
- Compound (7-4) is produced from compound (7-2) and compound (7-3) according to the method described in step 1-4. NS.
- Step 7-3 Production of compound (7-5)
- Compound (7-5) is produced by reacting compound (7-4) with a base in a suitable inert solvent.
- 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 methoxydo and potassium tert-butoxide; organic bases such as triethylamine, diisopropylethylamine, pyridine and diazabicycloundecene can be mentioned.
- the inert solvent examples include benzene, toluene, 1,4-dioxane, THF, 1,2-dimethoxyethane, dimethylformamide, and a mixed solvent thereof.
- the reaction temperature is not particularly limited, but is usually selected from the range of 20 ° C. to 200 ° C., preferably 20 ° C. to 80 ° C.
- the reaction time is usually 30 minutes to 48 hours.
- the compound represented by the formula (8-2) is produced, for example, by the method shown below.
- M 1 , M 2 , Y 1 , Y 2 , and Y 3 are synonymous with [1] above]
- Step 8-1 Production step of compound (8-2)
- Compound (8-2) is produced by reacting compound (8-1) with a metal in a suitable inert solvent under an acid catalyst.
- the acid include acetic acid, hydrochloric acid, ammonium chloride and the like.
- the inert solvent include ethanol, methanol, THF, water and a mixed solvent thereof.
- the metal include zinc, iron, tin and the like.
- the reaction temperature is not particularly limited, but is usually selected from the range of 20 ° C. to 200 ° C., preferably 50 ° C. to 120 ° C.
- the reaction time is usually 30 minutes to 48 hours.
- the compound represented by the formula (9-4) 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 which may be substituted or 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 9-1 Production step of compound (9-3) Compound (9-3) is produced from compound (9-1) and compound (9-2) according to the method described in step 2-2.
- NS As the compound (9-1) and the compound (9-2), those purchased as commercial products, those synthesized by a known method, or a method similar thereto can be used.
- Step 9-2 Preparation process of Compound (9-4) (9-4) from compound (9-3), a known method (for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, by RC Lalock, etc., 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, by RC Lalock, etc., VCH publisher Inc., 1989, etc.
- 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 10-1 Production step of compound (10-3)
- Compound (10-3) is produced by reacting compound (10-1) with compound (10-2) in an inert solvent.
- the compound (10-1) and the compound (10-2) those purchased as commercial products, those synthesized by a known method, or a method similar thereto can be used.
- the inert solvent examples include aprotonic 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 10-2 Production step of compound (10-5)
- Compound (10-5) is produced by reacting compound (10-3) with compound (10-4) in the presence of a base in an inert solvent.
- a base in an inert solvent.
- the compound (10-4) 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 aprotonic 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 10-3 Production Step of Compound (10-6)
- the compound (10-6) is produced from the compound (10-5) according to the method described in Step 2-2.
- Step 10-4 preparation process of Compound (10-7) (10-7) may be prepared from compounds (10-6), a known method (for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.), Comprehensive Organic Transformation, by RC Lalock, etc., 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, by RC Lalock, etc., 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 When 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 free form, they 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 compounds represented by the formula (1) or pharmaceutically acceptable salts thereof are tautomers such as keto-enol, positional isomers, geometric isomers or optical isomers. All possible isomers, including these, and mixtures in any proportion of the isomers are also included in the invention.
- 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 a base may be added to form a salt. Further, the compound (1) or a pharmaceutically acceptable salt thereof may exist in the form of a hydrate or a solvate (for example, an ethanol solvate) with various solvents such as water or ethanol. , These hydrates and solvates are also included in the present invention.
- a hydrate or a solvate for example, an ethanol solvate
- the compounds of the present invention may be useful as Nav1.1 activators because they exhibit a Nav1.1 activating effect. 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 diseases associated with decreased function of Nav1.1, such as central nervous system diseases (epilepsy) For example, febrile epilepsy; generalized epilepsy Thermal spasm plus; epilepsy (specifically, localization-related epilepsy, generalized epilepsy); epilepsy syndrome (drabe syndrome, refractory pediatric epilepsy with systemic tension interstitial attacks, myocrony weakness) Epilepsy with seizures, West syndrome, Lennox-Gasteau syndrome, drip epilepsy, severe infantile multifocal epilepsy, infant borderline severe intermuscular epilepsy, benign familial neonatal infantile spasm, etc.); schizophrenia; autism Spectrum disorders; may also be useful as therapeutic and / or prophylactic agents for attention deficit hyperactivity disorder.
- epilepsy central nervous system diseases
- 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 a plurality of agents, particularly three or more existing antiepileptic agents. It is also expected as a preventive agent.
- 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.
- Dosage forms include, for example, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, poultices and the like. It is preferably a tablet.
- the formulation into a dosage form or pharmaceutical composition can be carried out according to a known method using a pharmaceutically acceptable additive.
- 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, stearate. 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”) is in the range of about 0.0001 to about 5000 mg, preferably in the range of 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, anti-Parkinsonian drugs, schizophrenia.
- Therapeutic agents, ADHD therapeutic agents and the like can be mentioned.
- the compounds of the present invention are GABA signal enhancers such as valproic acid; GABAA receptor positive allosteric modulators such as clobazam; T-type voltage-gated 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 voltage-gated 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 voltage-gated calcium channel inhibitors such as etosuccimid
- SV2A ligands such as levetiracetam
- carbamazepine Such as therapeutic agents for partial attacks; calcium
- the compounds of the present invention are also multi-receptor antipsychotics such as clozapine (MARTA); serotonin-nore antagonists such as risperidone (SDA); dopamine receptor partial agonists such as aripiprazole (DPA); selective such as fluboxamine.
- MARTA multi-receptor antipsychotics
- SDA serotonin-nore antagonists
- DPA dopamine receptor partial agonists
- fluboxamine selective such as fluboxamine.
- Serotonin uptake inhibitor SSRI
- serotonin noradrenaline reuptake inhibitor SNRI
- noradrenergic and specific serotoninergic antidepressants NaSSA
- mirtazapine noradrenergic and specific serotoninergic antidepressants
- mood stabilizers 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; and selective noradrenergic reuptake inhibitors such as atomoxetine can also be used in combination.
- tauopathy is a general term for sporadic or familial pathological conditions in which tau protein undergoes abnormal phosphorylation to become insoluble and causes abnormal accumulation in cells.
- tauopathy includes, for example, Alzheimer's disease (AD), Alzheimer type dementia; ATD: dementia of Alzheimer's type; DAT: dementia in Alzheimer disease, disease: majore Diffuse neurofibrillary tangles with calcification; DNTC, Amyotrophic lateral sclerosis / parkinsonism-dementia complex of Guam island; Guam ALS / PDC), Kii Peninsula muscle atrophic lateral sclerosis / parkinsonism-dementia complex of the Kii peninsula; Kii ALS / PDC), frontotemporal lobar degeneration; FTLD; For example, Pick's disease (PiD), progressive supranuclear palsy; PSP, corticobasal degeneration (CBD), argyrophilic grain dementia AGD), glibular glibular gli
- senile dementia of the neurofibrillary tangle type SD-NFT, Down syndrome DS
- CTE chronic traumatic encephalopathy
- DM myotonic dystrophy
- NPC Niemann-Pick disease type C
- SENDA PLA2G6-associated neurodegeneration
- PLAN PLA2G6-associated neurodegeneration
- FDD familial Danish dementia
- PEP post-encephalitic Parkinsonism
- sub Diseases such as acute sclerosing panencephalitis (SSPE) and SLC9A6-related mental retardation are included, but not limited to these diseases, and phosphorylated tau is present in the brain.
- the pathological condition is included in "tauopathy".
- the pathological condition of the patient and the difference in the diagnosis method it may be determined that any two or more of these diseases are simultaneously applicable.
- a pathological condition in which two or more of these diseases coexist that is, a combination of any two or more diseases of the above-mentioned diseases is also included in "tauopathy”.
- Characteristic inclusion bodies may be formed for each disease, and there are differences in the types of cells that accumulate, the isoforms of tau that accumulate, and the phosphorylation sites of tau. In neurodegenerative diseases accompanied by "tauopathy", the accumulation of abnormally phosphorylated tau protein is considered to cause cerebral atrophy and cerebral dysfunction.
- the action of the compound on cognitive dysfunction of tauopathy can be evaluated by the method described in Test Example 7 described later.
- the action of the compound on tauopathy tau accumulation can be evaluated by the method described in Test Example 8 described later, and the action of the compound on tauopathy tau accumulation and brain atrophy can be evaluated by the method described in Test Example 9.
- a compound that is effective in any of Test Examples 7 to 9 can be expected to have a therapeutic and / or preventive effect on tauopathy.
- Nav activator means an agent that activates the function of a potential-dependent sodium channel, and means an agent that acts on the potential-dependent sodium channel and increases the sodium charge resulting from the act. ..
- the "Nav activator” may be any agent that activates any of Nav1.1 to Nav1.9, which are nine subtypes of voltage-gated sodium channels.
- a “Nav activator” is a substance that activates Nav expressed in the brain. For example, Nav1.1 activator, Nav1.2 activator, Nav1.3 activator, Nav1.6 activator and the like are included in "Nav activator”.
- selective Nav activators that selectively activate one Nav subtype (eg, selective Nav1.1 activators, selective Nav1.2 activators, selective Nav1.6 activators, etc.) ), Dual activators that activate two Nav subtypes (eg, Nav1.1 / Nav1.2 activators and Nav1.1 / Nav1.6 activators, etc.), and activate three Nav subtypes.
- Dual activators eg, Nav1.1 / Nav1.2 / Nav1.6 activators, etc.
- agents that multi-activate four or more Nav subtypes are also included in the "Nav activator".
- Examples of the "Nav activator” include agents that increase the amount of sodium current due to any subtype of Nav by 50%, preferably at 10 ⁇ M, and more preferably due to any subtype of Nav at 1 ⁇ M. Examples include agents that increase the amount of sodium current by 50%. The amount of sodium current caused by each subtype can be measured according to the method described in Test Example 1.
- Nav1.1 Activator means an agent that activates Nav1.1, an agent that selectively activates Nav1.1 and activates both Nav1.1 and other Nav subtypes. Contains agents. When activating both Nav1.1 and other Nav subtypes, it is not necessary to activate Nav1.1 most strongly, and agents that more strongly activate other Nav subtypes are also "Nav1.1 activators". "include. Examples of the "Nav1.1 activator” include a selective Nav1.1 activator, a Nav1.1 / Nav1.2 dual activator, a Nav1.1 / Nav1.3 dual activator, and a Nav1.1 /. Examples include, but are not limited to, Nav1.6 dual activators and Nav1.1 / Nav1.2 / Nav1.6 triple activators.
- the "Nav1.1 activator” activates the function of Nav1.1 by acting on Nav1.1 and increases the sodium current due to Nav1.1. As a result, the nerve firing ability of cells expressing Nav1.1 is increased, and the function of GABAergic neurons is enhanced.
- Examples of the "Nav1.1 activator” include agents that increase the amount of sodium current due to Nav1.1 by 50% at 10 ⁇ M, and more preferably 50% of the amount of sodium current due to Nav1.1 at 1 ⁇ M. Examples include agents that increase.
- the amount of sodium current due to Nav1.1 can be measured by the method described in Test Example 1.
- Nav activators and Nav1.1 activators used in the treatment and / or prevention of tauopathy are prescribed for the purpose of enhancing their effects and / or reducing side effects and for various symptoms of various diseases. It can be used in combination with a drug (concomitant drug).
- concomitant drugs include, for example, other tauopathy treatments, Alzheimer's dementia treatments, antiepileptic drugs, antipsychotics, antidepressants, anxiolytics, Chinese herbs, sleep-inducing agents, anti-Parkinson's disease agents, antihypertensive agents.
- Examples thereof include agents, anti-inflammatory agents, therapeutic agents for diabetes, therapeutic agents for dyslipidemia, anti-obesity agents, anti-vomiting agents, therapeutic agents for swallowing disorders, therapeutic agents for urinary disorders, and lower preparations. More preferably, other tauopathy therapeutic agents, Alzheimer's dementia therapeutic agents, antiepileptic agents, antipsychotic agents, antidepressants, anxiolytics, Chinese herbs, sleep-inducing agents, antiparkinsonian agents and the like can be mentioned. "Other tauopathy therapeutic agents” means any tauopathy therapeutic agent that is different from the Nav activator used.
- concomitant drug examples include acetylcholinesterase inhibitors such as donepezil, NMDA inhibitors such as memantine, GABA signal enhancers such as valproic acid, SV2A ligands such as levetiracetam, and drugs for treating partial epilepsy such as carbamazepine.
- acetylcholinesterase inhibitors such as donepezil
- NMDA inhibitors such as memantine
- GABA signal enhancers such as valproic acid
- SV2A ligands such as levetiracetam
- drugs for treating partial epilepsy such as carbamazepine.
- the above-mentioned concomitant drugs are atypical antipsychotics such as quetiapine, risperidone, clozapine and aripiprazole prescribed for behavioral and psychological symptoms of dementis; BPSD; paroxetine, sertraline and citaloplum.
- Selective serotonin uptake inhibitors such as: Serotonin blockade reuptake inhibitors such as trazodone (SARI); Noradrenergic and specific serotoninergic antidepressants (NaSSA) such as mirtazapine; Serotonin 1A acceptance such as tandospirone It may be one or more drugs selected from the group consisting of somatic agents; Chinese herbal medicines such as hepatosan; and Parkinson's disease therapeutic agents such as levodopa.
- Serotonin blockade reuptake inhibitors such as trazodone (SARI); Noradrenergic and specific serotoninergic antidepressants (NaSSA) such as mirtazapine
- Serotonin 1A acceptance such as tandospirone
- the Nav activator is selected for one or more Nav subtypes selected from the group consisting of several Nav subtypes, eg, Nav1.1, Nav1.2, Nav1.3 and Nav1.6. It may exhibit a specific pharmacological effect, or it may have a weak effect on other Nav subtypes such as Nav1.5. In another embodiment, the Nav activator may have a particularly selective pharmacological effect on Nav1.1 and may have a weak effect on other Nav subtypes such as Nav1.5. A Nav activator with reduced action on Nav1.5 can be expected to be highly safe with less concern about cardiotoxicity.
- 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, symptomatology, 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
- DMF N, N-dimethylformamide Boc: tert-butoxycarbonyl
- 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 line double line
- q is a quadruple line
- m is a double line.
- Multiple lines, br means a wide single line or multiple lines
- J means a coupling constant.
- Method B Solvent: Solution A; 0.05% TFA / H 2 O, Solution B; Acetonitrile gradient condition: 0.0-1.7 minutes (linear gradient 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 7 [2- (4-Methylcyclohexa-1-en-1-yl) -5-oxo-5,6-dihydro-4H-1,3,4-oxadiazine-4-yl] acetic acid a) Sodium hydrogensulfate monohydrate (7.39 g) and sodium cyanide (3.28 g) were added to a solution of 4-methylcyclohexanone (5.0 g) in water (125 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. Compound 5A (6.60 g) was obtained by concentration under reduced pressure.
- Reference example 9 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.
- Example 1 5- (4-Methylcyclohexa-1-en-1-yl) -1- ⁇ 2-oxo-2- [4- (pyridin-3-yl) piperazin-1-yl] ethyl ⁇ pyrimidine-2 (1H) )-on Diisopropylethylamine (0.127 mL), 1-pyridin-3-yl-piperazine dihydrogen bromide, and HBTU (92 mg) were added to a solution of the compound (50 mg) of Reference Example 2 in dichloromethane (1.0 mL), and the temperature was changed to room temperature. Was stirred for 16 hours.
- Examples 2 to 6 Compounds of Examples 2 to 6 were obtained using the corresponding raw material compounds according to the method described in Example 1 and known reaction conditions.
- Examples 7-11 Compounds of Examples 7 to 11 were obtained using the corresponding raw material compounds according to the method described in Reference Example 3, the method described in Example 1, and known reaction conditions.
- Examples 12-19 Compounds of Examples 12 to 19 were obtained using the corresponding raw material compounds according to the method described in Reference Example 3, the method described in Example 1, and known reaction conditions.
- Example 20 N- (4-Cyanophenyl) -2- [5- (4-methylpiperidin-1-yl) -2-oxopyrazine-1 (2H) -yl] acetamide Potassium carbonate (71.5 mg) and the compound of Reference Example 1 (50.4 mg) were added to a solution of the compound of Reference Example 5 (50 mg) in acetonitrile (1.0 mL), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
- Examples 21-22 and 24-25 Compounds of Examples 21-22 and 24-25 were prepared using the corresponding raw material compounds according to the methods described in Reference Examples 1, 4 and 5, the methods described in Examples 1 and 20, and known reaction conditions. Obtained.
- Example 26 N- (4-Cyanophenyl) -2- [3- (4-methylpiperidin-1-yl) -6-oxo-5,6-dihydropyridazine-1 (4H) -yl] acetamide Zinc (93 mg) was added to a solution of the compound (94 mg) of Reference Example 8 in acetic acid (1.4 mL), and the mixture was stirred at 90 ° C. for 2 hours. Toluene was added to the reaction solution, and the mixture was concentrated under reduced pressure.
- Examples 27-34 Compounds of Examples 27 to 34 were obtained using the methods described in Reference Example 6, the methods described in Examples 1 and 26, and the corresponding raw material compounds according to known reaction conditions.
- Examples 35-42 Compounds of Examples 35 to 42 were obtained using the compound of Reference Example 7 and the corresponding raw material compound according to the method described in Example 1 and known reaction conditions.
- Examples 43-50 Compounds of Examples 43 to 50 were obtained using the corresponding raw material compounds according to the method described in Reference Example 7, the method described in Example 1, and known reaction conditions.
- Examples 51 and 52 Compounds of Examples 51 and 52 were obtained using the corresponding raw material compounds according to the method described in Reference Example 7, the method described in Example 1, and known reaction conditions.
- Example 53 The compound (19.0 mg) obtained in Example 51 was divided by a chiral column to obtain the following cis and trans isomers. Here, the compound obtained at the post-peak coincided with the compound of Example 52 in the chemical shift of NMR.
- Examples 54-91 The compounds of Examples 54 to 91 can be synthesized using the corresponding raw material compounds according to the methods described in Reference Examples 5, 10 and 11, the methods described in Examples 1 and 20, and known reaction conditions. can.
- Example 92 The compound of Example 92 was synthesized using the corresponding raw material compounds according to the methods described in Reference Examples 5, 10 and 11, the methods described in Examples 1 and 20, and known reaction conditions.
- Examples 105-106 The compounds of Examples 105 to 106 were synthesized using the corresponding raw material compounds according to the methods described in Reference Examples 5, 10 and 11, the methods described in Examples 1 and 20, and known reaction conditions.
- Examples 107-111 The compounds of Examples 107 to 111 were synthesized using the corresponding raw material compounds according to the methods described in Reference Examples 5, 10 and 11, the methods described in Examples 1 and 20, and known reaction conditions.
- 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.
- the compounds of Examples 54 to 91 and 93 to 104 can also be evaluated according to the methods described in the following 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 extension spasm of 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 for evaluating 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 to 30 g) were administered with 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 of the tail. Anticonvulsant action can be confirmed by observing the presence or absence of reaction and immobility.
- Test Example 6 Evaluation of Febrile Convulsions Suppression Using SCN1A Mutant This test is a test to evaluate the inhibitory effect of a drug on febrile convulsions expressed by a gene mutation lacking SCN1A gene function.
- the animal model used in this test is a BALB / c-Scn1a ⁇ +/-> mouse (catalog number: RBRC06422; provided by the RIKEN BioResource Research Center (RIKEN BRC) through the National BioResource Project of the Ministry of Education, Culture, Sports, Science and Technology. Can be done (Yoshibumi Matsushima Ann.Rep.Jpn.Epi.Res.Found. 2015; 26: 69-76).
- This model mouse has a deletion type gene mutation in the SCN1A gene like Dravet syndrome patients, is a phenotype of Dravet syndrome that presents with febrile convulsions associated with elevated body temperature, and is used as a model animal for spontaneous Dravet syndrome. (Reference: Japan Epilepsy Research Foundation Research Annual Report 2015: 26: 69-76).
- the test compound is administered to SCN1A gene function-deficient gene mutant mice (18-23 g). Twenty minutes after administration, 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. In the case of individuals who developed seizures or did not develop seizures, 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.
- Test Example 7 Evaluation of cognitive function by novel object recognition test (hereinafter sometimes referred to as "NORT") This test is a test for evaluating the cognitive function improving effect of a compound.
- NORT using APP-Tg mice, which are AD (Alzheimer's disease) model mice
- memory deterioration for known objects is observed depending on the interval time between the first trial (training) and the second trial (test). For example, when the second trial is performed 3 hours after the first trial, there is no difference in the search time between the novel object and the known object in the APP-Tg mouse as compared with the healthy mouse, and remarkable forgetting is observed. ..
- AD Alzheimerer's disease
- the APP-Tg mouse used in this test was fertilized after constructing an expression cassette in which a human APP 751 isoform in which Swedish (K670N / M671L) and Indiana (V717F) mutations were introduced downstream of the mouse Thy-1 promoter was ligated. It is produced by injecting into an egg and transplanting it into a foster mother. Since the prepared mice exhibit A ⁇ accumulation and cognitive dysfunction in the brain from an early stage, they can be used for cognitive function evaluation and the like. APP-Tg mice are also reported in Non-Patent Document 6. The test compound is administered to the prepared APP-Tg mice, and the first trial is performed 30 to 60 minutes after intraperitoneal administration or after 10 days of mixed diet administration.
- the second trial is performed 3 hours after the first trial, and the search time for the novel object and the known object in the second trial is evaluated respectively.
- the discrimination index is calculated from the search time for the novel object and the known object in the second trial, and the cognitive function improving effect of the test compound is confirmed by comparing this with the test compound-unadministered group as an index of the cognitive function.
- the identification index is calculated by the following formula.
- Discrimination index ⁇ (Search time for novel objects)-(Search time for known objects) ⁇ / ⁇ (Search time for novel objects) + (Search time for known objects) ⁇
- the compound of Example 1 is intraperitoneally administered to APP-Tg mice at doses of 3, 10 and 30 mg / kg 30 minutes before the first trial, and the cognitive function improving effect is evaluated.
- This test can also be performed in combination with Elacridar (available from Tokyo Chemical Industry Co., Ltd.). Eracridal has the effect of inhibiting the excretion transporters P-gp and BCRP expressed at the blood-brain barrier and improving the brain transferability of the test compound.
- Eracridal was orally administered at 100 mg / kg 2 hours before the first trial and administered to APP-Tg mice, and then the test compound was intraperitoneally administered 60 minutes before the first trial according to the above method. It is administered to mice and the cognitive function improving effect is evaluated.
- the significant difference from the vehicle administration group is determined by using the parametric Dunnett multiple comparison test. This test can also be performed in combination with ABT (1-aminobenzotriazole) (available from Tokyo Chemical Industry Co., Ltd.).
- ABT has the effect of improving the blood concentration of the test compound by inhibiting CYP and suppressing metabolism.
- test compound and ABT (1 mg / g-food) are fed to APP-Tg mice for 10 days, and then the cognitive function improving effect is evaluated according to the above method.
- the significant difference from the vehicle administration group is determined by using the parametric Dunnett multiple comparison test.
- Test Example 8 Evaluation of Phosphorylated Tau Oligomer Using APP-Tg Mice This test is a test for quantifying the oligomer of phosphorylated tau in the brain and evaluating the action of the compound.
- APP-Tg mice do not show neurofibrillary tangles or neuronal cell death, but age-dependent increases in brain phosphorylated tau and its oligomers compared to wild-type mice.
- the APP-Tg mouse used in this test was fertilized after constructing an expression cassette in which a human APP 751 isoform in which Swedish (K670N / M671L) and Indiana (V717F) mutations were introduced downstream of the mouse Thy-1 promoter was ligated.
- mice It was prepared by injecting into an egg and transplanting it into a foster mother. Since the prepared mice exhibit A ⁇ accumulation and cognitive dysfunction in the brain from an early stage, they can be used for cognitive function evaluation and the like.
- APP-Tg mice have also been reported in the Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1163-1174, 2019. The test compound is fed to APP-Tg mice for 7 to 10 days. At this time, in order to increase the blood concentration of the test compound, depending on the compound, ABT is used in combination with a mixed diet of 1 mg / g-food.
- the brain is collected, and the protein is extracted from the collected brain using TBS (Tris Buffered Saline) or sarcosyl, and then SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) of the soluble or insoluble fraction is performed. ) Is carried out. Then, Western blotting using an anti-oligomerized tau antibody (Anti-Tau, oligomeric, clone TOMA-1) is performed, and the effect of the test compound is evaluated by quantifying the band amount of the phosphorylated tau oligomer.
- TBS Tris Buffered Saline
- SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis
- Test Example 9 Evaluation of intracerebral tau aggregate accumulation and cerebral atrophy using rTg4510 mice This test is a test for evaluating the action of a compound on intracerebral tau aggregate accumulation and cerebral atrophy. rTg4510 mice overexpress human-type FTDP-17 mutant tau in the forebrain, and age-dependent intracerebral tau aggregate accumulation and brain atrophy are observed.
- the rTg4510 mice used in this test are produced by mating and breeding Tg (tauP301L) 4510 mice (Stock No. 015815) and CaMKII-tTA mice (Stock No. 007004) that can be purchased from The Jackson Laboratory.
- the test compound is fed to rTg4510 mice from the age of 4 months, and PET scans and MRIs are performed at the ages of 4, 6 and 8 months to quantitatively evaluate the amount of tau aggregates accumulated in the brain and brain atrophy.
- PET scans are performed using a Siemens Medical Solutions MicroPET Focus 220 (0.851 mm thick (intercenter) 95 slices, 19.0 cm axial field of view (FOV), and 7.6 cm intra-section FOV).
- Administration of radioactive compound [ 18 F] PM-PBB3 (precursor obtained from Aprinoia) and PET scans were performed under dim light with 1.5% isoflurane anesthesia in mice to avoid photoracemization of the radioactive compound. conduct.
- Emission scan is performed for 60 minutes immediately after intravenous administration of [18 F] PM-PBB3 (1 mCi) (3D list mode, energy window: 350-750 keV). Then, the list mode data sorted into 3D synograms are converted into 2D synograms by Fourier-rebining (frames: 4 ⁇ 1, 8 ⁇ 2 and 8 ⁇ 5 minutes).
- [ 18 F] A dynamic image 60 minutes after administration of PM-PBB3 is reconstructed by a filter-corrected back projection method using a 0.5 mm Hanning filter.
- the region of interest (ROI) is set in a plurality of brain regions using PMOD image analysis software manufactured by PMOD Technology with reference to the MRI template and the PET reconstructed image.
- SUVR Standardized uptake value ratio
- Evaluation of cerebral atrophy is performed using a horizontal superconducting magnet type MRI (7T, inner diameter 400 mm, self-shielding type, zero boil-off type). Imaging is performed under isoflurane anesthesia while maintaining rectal temperature at 36.5 ⁇ 0.5 ° C. After Tripilot acquisition, brain images are acquired by TurboRARE T2 emphasis sequence (TR: 4200 ms, TE: 36 ms, Fat-Sup: on, NA: 4, RARE factor: 8, scan time: 14 min) (FOV read).
- the ROI of each brain region is set in each acquired slice, and the volume of the brain region is calculated by summing the ROI areas of all slices to evaluate the effect of the test compound.
- the compound of the present invention has a sodium channel activating effect, it can be a useful drug for the treatment and / or prevention of diseases involving sodium channels, various central nervous system diseases, and / or tauopathy.
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Abstract
L'invention concerne : un dérivé hétérocyclique, et/ou un sel pharmaceutiquement acceptable de celui-ci, qui peut servir d'agent thérapeutique et/ou prophylactique pour une maladie dans laquelle le canal sodique (Nav) est impliqué et pour divers troubles du système nerveux central ; et un agent pharmaceutique qui inclut le dérivé hétérocyclique et/ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif. L'invention concerne également : un dérivé hétérocyclique, et/ou un sel pharmaceutiquement acceptable de celui-ci, qui peut servir d'agent thérapeutique et/ou d'agent prophylactique pour la tauopathie, les agents agissant par activation de Nav ; et un agent pharmaceutique qui inclut le dérivé hétérocyclique et/ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif. L'invention concerne en outre un dérivé hétérocyclique, et/ou un sel pharmaceutiquement acceptable de celui-ci, qui peut servir d'agent pharmaceutique et qui est représenté par la formule (I) [dans la formule, Y1, Y2, Y3, M1, et M2 sont tels que définis dans la description] ; et un agent thérapeutique et/ou un agent prophylactique qui inclut le dérivé hétérocyclique et/ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif, et qui est destiné à une maladie dans laquelle le canal sodique est impliqué, à divers troubles du système nerveux central, et/ou à une tauopathie.
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WO2017147379A1 (fr) * | 2016-02-26 | 2017-08-31 | The Johns Hopkins University | Modulateurs pharmacologiques des canaux sodiques voltage-dépendants nav1.1 associés à des douleurs mécaniques |
WO2020017587A1 (fr) * | 2018-07-19 | 2020-01-23 | 大日本住友製薬株式会社 | Dérivé de pyridazinone |
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WO2017147379A1 (fr) * | 2016-02-26 | 2017-08-31 | The Johns Hopkins University | Modulateurs pharmacologiques des canaux sodiques voltage-dépendants nav1.1 associés à des douleurs mécaniques |
WO2020017587A1 (fr) * | 2018-07-19 | 2020-01-23 | 大日本住友製薬株式会社 | Dérivé de pyridazinone |
Non-Patent Citations (6)
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DATABASE REGISTRY 21 September 2021 (2021-09-21), XP055843747, retrieved from STN Database accession no. 2197794-08-2 * |
FRANÇOIS CRESTEY; KRISTEN FREDERIKSEN; HENRIK S JENSEN; KIM DEKERMENDJIAN; PETER H LARSEN; JESPER F BASTLUND; DUNGUO LU; HENRY LIU: "Identification and Electrophysiological Evaluation of 2- Methylllenzamide Derivatives as Nav1.1 Modulators", ACS CHEMICAL NEUROSCIENCE, vol. 6, no. 8, 2015, pages 1302 - 1308, XP055677995, DOI: 10.1021/acschemneuro.51100147 * |
FREDERIKSEN KRISTEN, LU DUNGUO, YANG JINHUI, JENSEN HENRIK SINDAL, BASTLUND JESPER FRANK, LARSEN PETER HJØRRINGGAARD, LIU HENRY, C: "A small molecule activator of Nav1.1 channels increases fast-spiking interneuron excitability and GABAergic transmission in vitro and has anti-convulsive effects in vivo", EUROPEAN JOURNAL OF NEUROSCIENCE, vol. 46, no. 3, 2017, pages 1887 - 1896, XP055843494, DOI: 10.1111/ejn.13626 * |
GILCHRIST, J. ET AL.: "Nav1.1 Modulation by a Novel Triazole Compound Attenuates Epileptic Seizures in Rodents", ACS CHEMICAL BIOLOGY, vol. 9, no. 5, 2014, pages 1204 - 1212, XP055362820, DOI: 10.1021/c11500108p * |
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