WO2011021645A1 - Dérivé d'urée bicyclique ou sel pharmaceutiquement acceptable correspondant - Google Patents

Dérivé d'urée bicyclique ou sel pharmaceutiquement acceptable correspondant Download PDF

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WO2011021645A1
WO2011021645A1 PCT/JP2010/063945 JP2010063945W WO2011021645A1 WO 2011021645 A1 WO2011021645 A1 WO 2011021645A1 JP 2010063945 W JP2010063945 W JP 2010063945W WO 2011021645 A1 WO2011021645 A1 WO 2011021645A1
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group
substituted
alkyl
alkoxy
optionally substituted
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Japanese (ja)
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俊彦 曽根
友子 中嶋
健太郎 ▲高▼井
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大日本住友製薬株式会社
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    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
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    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Definitions

  • the present invention relates to a novel bicyclic urea derivative that inhibits soluble epoxide hydrolase (sEH), or a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a circulatory system including hypertension, a peripheral vascular system, an endocrine metabolic system, a respiratory system, and an autoimmune disease therapeutic agent containing a tropine urea derivative effective as an sEH inhibitor as an active ingredient.
  • sEH soluble epoxide hydrolase
  • EH epoxide hydrolase
  • sEH is also expressed in all organs (Non-patent Document 2) and blood (lymphocytes, monocytes, erythrocytes, platelets, plasma, etc.), and most of them are present in lymphocytes.
  • Non-patent Document 3 Epoxide hydrolase (EH) converts cis-epoxyeicosatrienoic acids (EETs) that are physiologically produced from arachidonic acid by the P450 metabolic pathway into dihydroeicosatrienoic acids (DHETs), which are inactive substances. It is responsible for the conversion reaction (Non-Patent Document 4).
  • EETs cis-epoxyeicosatrienoic acids
  • DHETs dihydroeicosatrienoic acids
  • EETs that increase due to sEH inhibition activate Ca 2+ -activated K + -channels in blood vessels and act as vascular endothelium-derived hyperpolarization factor (EDHF).
  • EDHF vascular endothelium-derived hyperpolarization factor
  • sEH inhibitors such as 1-adamantyl-3-dodecyl urea (ADU) and 1-adamantan-3- (5- (2-ethylethoxy) ethoxy) pentyl) urea (AEPU) are deoxycorticosterone acetate (DOCA) and physiological salt Reported to improve vascular endothelial function of water-loading vascular endothelial disorder model (Non-patent Document 8) and markedly improve cardiac hypertrophy due to renal organ disorder and aortic arch stenosis (Non-patent Documents 9 and 10) Has been.
  • DOTA deoxycorticosterone acetate
  • Non-patent Document 8 markedly improve cardiac hypertrophy due to renal organ disorder and aortic arch stenosis
  • EETs are cardiac hypertrophy, angina pectoris, myocardial infarction, cerebral infarction, diabetes, chronic nephropathy, diabetic nephropathy, obstructive arteriosclerosis, obesity, lipid metabolism abnormality, fatty liver, etc. It is expected to show efficacy in sex diseases and endocrine metabolic diseases. Since some of the DHETs produced by sEH are causative substances of adult respiratory distress syndrome, sEH inhibitors have been reported to improve their mortality (Non-patent Document 11). From these facts, sEH inhibitors are expected to prevent or improve respiratory diseases.
  • R 1 represents optionally substituted C 1-6 alkyl or the like
  • R 2 represents optionally substituted phenyl or the like
  • Q represents N Or CH
  • M 1 and M 2 each independently represent a hydrogen atom or the like
  • M 3 and M 4 each independently represent a hydrogen atom or the like
  • M 4 represents M 2 or Together with M 3 shall form —CH 2 — or —CH 2 —CH 2 —.
  • the 4-sulfonyl piperidine derivative represented by this is known (patent document 1). Although this document describes several compounds having bicyclic properties, the structure is different from the present invention in that all of them have a sulfonyl group as a structural feature.
  • Patent Documents 2 to 4 several compounds have been reported as sEH inhibitors. However, any compound differs in structure from the present invention. Therefore, it has not been known so far that a compound having a structural characteristic of bicyclic urea has sEH inhibitory activity.
  • an object of the present invention is to provide a novel bicyclic urea derivative having strong sEH inhibitory activity.
  • Item 1 A compound represented by formula (I), or a pharmaceutically acceptable salt thereof.
  • R 1 represents an optionally substituted C 3-9 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted C 6-10 aryl group, an optionally substituted Good 5- to 10-membered monocyclic or polycyclic heteroaryl group, optionally substituted C 3-9 cycloalkyl C 1-4 alkyl group, optionally substituted heterocyclic-C 1-4 An alkyl group, an optionally substituted C 7-14 aralkyl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl C 1-4 alkyl group;
  • R 2a and R 2b are (I) each independently, a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted C 1-6 alkyl group, optionally substituted C 1-6 alkoxy group, an optionally substituted C 6 A -10 aryl group, or an optionally substituted amino group, or (ii) taken together to form a C 3-6 cycloalky
  • R 3a , R 3b and R 3c are each independently the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 1- 6 an alkoxy group, an optionally substituted C 1-4 alkylcarbonyl group, an optionally substituted aminocarbonyl group, or
  • R 4 is an optionally substituted C 3-9 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted C 6-10 aryl group, Or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group
  • R 5a and R 5b are (I) each independently a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group, or (ii) Together, they form a C 3-6 cycloalkyl ring, or a 4-membered to 6-membered saturated heterocyclic ring (the C 3-6 cycloalkyl ring and 4-membered to 6-membered saturated heterocyclic ring are each a halogen atom, a hydroxy , C 1-6 alkyl, C 1-6 alkoxy, mono-C 1-6 alkylamino, or di-C 1-6 alkylamino).
  • n 0, 1, 2, or 3;
  • X is a single bond, an oxygen atom, a sulfur atom, —SO 2 —, or —NR 6 —;
  • R 6 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-4 alkylcarbonyl group, an optionally substituted C 3-6 cycloalkyl group, or a substituted, C 3-6 cycloalkylcarbonyl group which may be substituted . ).
  • R 4 is an optionally substituted C 6-10 aryl group, or an optionally substituted 5- to 10-membered monocyclic or polycyclic heteroaryl group
  • X is —SO 4 A compound which is 2- N- (2-fluorophenyl) -3- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazolo-3-yl-]-8-azabicyclo [3.2.1] octane -8-carboxamide, 3- (3,4-dichlorophenoxy) -N-phenyl-8-azabicyclo [3.2.1] octane-8-carboxamide; 3-phenyl-N- [2- [4- (1-pyrrolidinylmethyl) phenyl] ethyl] -8-azabicyclo [3.2.1] octane-8-carboxamide; N- (2,4-dimethoxyphenyl) -3- [5- (4-fluorophenyl)
  • R 1 is (1) an optionally substituted C 3-9 cycloalkyl group, (2) an optionally substituted heterocyclic group, Item 3.
  • Item 3 An optionally substituted C 3-6 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted C 6-10 aryl group, and an optionally substituted group in R 1 A substituent of a 5- to 10-membered monocyclic or polycyclic heteroaryl group, (A) a halogen atom, (B) C 1-4 alkyl (which may be substituted with 1 to 3 fluorine atoms, hydroxy, C 1-4 alkoxy, 4 to 7 membered cyclic amino, or carboxy), (C) C 1-4 alkoxy (the alkyl may be substituted with 1 to 3 fluorine atoms, C 1-4 alkoxy, 4 to 7 membered cyclic amino, or carboxy), (D) C 1-4 alkylthio (the alkyl may be substituted with 1 to 3 fluorine atoms, 4 to 7 membered cyclic amino, or carboxy), (E) carboxy, (F) cyano, (G) C 1-4
  • (T) C 3-6 cycloalkyl It may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of (u) C 3-6 cycloalkyloxy and (v) C 1-4 alkoxycarbonyl. Or a pharmaceutically acceptable salt thereof.
  • R 1 is (1) C 3-6 cycloalkyl group (the group is (A) 1-2 fluorine atoms, (B) C 3-6 cycloalkyl, (C) C 6-10 aryl (the group is Halogen atoms, C 1-4 alkyl ( optionally substituted with 1 to 3 fluorine atoms), C 1-4 alkoxy (optionally substituted with 1 to 3 fluorine atoms), or C 1-4 alkylsulfonyl may be substituted. And d) a C 6-10 aryloxy (the group may be substituted with a halogen atom, C 1-4 alkyl, or C 1-4 alkoxy), or It may be substituted with 1 to 3 different groups.
  • a C 6-10 aryl group (the group is (A) a halogen atom, (B) a 4-7 membered cyclic amino, (C) C 1-4 alkyl (the group may be substituted with 1 to 3 fluorine atoms, hydroxy, or C 1-4 alkoxy), (D) C 1-4 alkoxy (the group may be substituted with 1 to 3 fluorine atoms, or C 1-4 alkoxy), (E) C 1-6 alkylsulfonyl, (F) C 3-6 cycloalkylsulfonyl, (G) C 6-10 arylsulfonyl (the aryl may be substituted with C 1-4 alkoxy), (H) aminosulfonyl, (I) 5- to 10-membered monocyclic or polycyclic heteroaryl (the group may be substituted with a halogen atom, C 1-4 alkyl, or C 1-4 alkoxy), (J) a 5- or 6-membered saturated
  • a 5- to 10-membered monocyclic or polycyclic heteroaryl group (the group includes (A) a halogen atom, and (b) the same or different 1-2 selected from the group consisting of C 1-4 alkyl (the group may be substituted with 1 to 3 fluorine atoms). It may be substituted with groups. ), Or (4) a heterocyclic group (the ring is (A) C 1-4 alkoxycarbonyl, or (b) C 6-10 arylsulfonyl (wherein the aryl may be substituted with C 1-4 alkyl) may be substituted.
  • R 2a and R 2b are each independently (1) hydrogen atom, (2) a halogen atom, (3) hydroxyl group, (4) C 1-6 alkyl group (the group is (A) optionally substituted with 1 to 5 fluorine atoms, or (b) C 1-4 alkoxy. ), (5) C 1-6 alkoxy group (the group is (A) optionally substituted with 1 to 5 fluorine atoms, or (b) C 1-4 alkoxy.
  • (6) a C 6-10 aryl group (the group is (A) a halogen atom, (B) C 1-4 alkyl (which may be substituted with 1 to 3 fluorine atoms, C 1-4 alkoxy, 4 to 7 membered cyclic amino, or carboxy), (C) C 1-4 alkoxy (wherein the alkyl may be substituted with 1 to 3 fluorine atoms, 4 to 7 membered cyclic amino, or carboxy), (D) C 1-4 alkylthio (the alkyl may be substituted with 1 to 3 fluorine atoms, 4 to 7 membered cyclic amino, or carboxy), (E) carboxy, (F) cyano, (G) C 1-4 alkylcarbonyl, (H) C 1-6 alkylsulfonyl, (I) C 3-6 cycloalkylsulfonyl, (J) amino (the amino is C 1-6 alkyl, C 1-6 alkylcarbonyl, C
  • R 2a and R 2b each independently represent a hydrogen atom, a C 1-6 alkyl group, or a C 6-10 aryl group (the group is represented by 1 to 3 halogen atoms, C 1-4 alkyl Or a pharmaceutically acceptable salt thereof. 6.
  • Item 7 The compound according to Item 6, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are both hydrogen atoms.
  • Item 8 The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3, or 4.
  • Item 9 The compound according to Item 8, wherein m is 0, or a pharmaceutically acceptable salt thereof.
  • Item 10 The compound according to Item 8, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.
  • R 3a , R 3b and R 3c are each independently the same or different, (1) a hydrogen atom, (2) a halogen atom, (3) hydroxyl group, (4) C 1-6 alkyl group (the group is (A) 1 to 3 halogen atoms, (B) hydroxy, (C) amino, or (d) C 1-4 alkoxy (the group may be substituted with 1 to 3 halogen atoms). ), (5) C 1-6 alkoxy group (the group is (A) 1 to 3 halogen atoms, (B) hydroxy, (C) amino, or (d) C 1-4 alkoxy (the group may be substituted with 1 to 3 halogen atoms).
  • C 1-4 alkylcarbonyl group (the C 1-4 alkyl is (A) 1 to 3 halogen atoms, (B) hydroxy, or (c) C 1-4 alkoxy (wherein the alkoxy may be substituted with 1 to 3 halogen atoms).
  • C 3-6 cycloalkyl C 1-4 alkylcarbonyl group (the C 3-6 cycloalkyl is (A) a halogen atom, (B) hydroxy, or (c) C 1-4 alkoxy (the group may be substituted with 1 to 3 halogen atoms).
  • Aminocarbonyl group (the amino is (A) C 1-6 alkyl, and (b) C 3-6 cycloalkyl (the alkyl and cycloalkyl are 1 to 3 halogen atoms, It may be substituted with hydroxy and C 1-4 alkoxy optionally substituted with 1 to 3 halogen atoms. ) May be substituted with one or two groups selected from the group consisting of the same or different species. ) Or (9)
  • Item 11 The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof, which is a group represented by:
  • Item 12 The compound according to Item 11, which is a group represented by: or a pharmaceutically acceptable salt thereof.
  • Item 13 To an optionally substituted heterocyclic group in R 4, an optionally substituted C 6-10 aryl group, and an optionally substituted 5- to 10-membered monocyclic or polycyclic
  • the substituent of the teloaryl group is (1) a halogen atom, (2) C 1-4 alkyl (the group is (A) 1 to 3 halogen atoms, (B) C 1-4 alkoxy, (C) amino (the amino is (I) C 1-6 alkyl (the alkyl is C 1-4 alkoxy, 5- or 6-membered heterocycle, It may be substituted with 4- to 7-membered cyclic amino or C 3-6 cycloalkyl.
  • (Viii) a 5- to 10-membered monocyclic or polycyclic heteroaryl C 1-4 alkyl, and (ix) a 5- or 6-membered heterocycle (the ring is substituted with a C 1-4 alkylsulfonyl) It may be substituted with one or two groups of the same or different types selected from the group consisting of: ), (D) a 4- to 7-membered cyclic amino (the amino is Hydroxy, C 1-4 alkyl, It may be substituted with C 6-10 aryl, or C 7-14 aralkyl.
  • (E) Aminocarbonyl (The amino may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of (i) to (ix) which are substituents of the amino.) , (F) C 1-4 alkoxycarbonyl, (G) carboxy, (H) C 6-10 aryloxy, (I) C 7-14 aralkyloxy, (J) a 5- to 10-membered monocyclic or polycyclic heteroaryloxy, (K) 5- to 10-membered monocyclic or polycyclic heteroaryl C 1-4 alkoxy, (L) C 6-10 arylthio, (M) C 7-14 aralkylthio, (N) 5- to 10-membered monocyclic or polycyclic heteroarylthio, (O) optionally substituted with 5- to 10-membered monocyclic or polycyclic heteroaryl C 1-4 alkylthio, or (p) cyano.
  • C 3-6 cycloalkyl the group may be substituted with carboxy
  • C 2-6 alkenyl the group may be substituted with carboxy or C 1-4 alkoxycarbonyl
  • C 1-4 alkoxy the group is (A) 1 to 3 fluorine atoms
  • B) amino the amino may be substituted with C 1-6 alkyl optionally substituted with C 1-4 alkoxy
  • C a 4- to 7-membered cyclic amino
  • D carboxy
  • e optionally substituted with 5 or 6 membered monocyclic heteroaryl.
  • C 3-6 cycloalkoxy (the group may be substituted with carboxy) (7) 5-membered or 6-membered saturated heterocyclic oxy (the group may be substituted with carboxy), (8) C 1-4 alkylthio (the alkyl may be substituted with 1 to 3 fluorine atoms, 4 to 7 membered cyclic amino, or carboxy), (9) C 6-10 arylthio, (10) C 7-14 aralkylthio, (11) 5- to 10-membered monocyclic or polycyclic heteroarylthio, (12) 5- to 10-membered monocyclic or polycyclic heteroaryl C 1-4 alkylthio, (13) Carboxy, (14) cyano, (15) C 1-4 alkylcarbonyl, (16) C 1-6 alkylsulfonyl, (17) C 3-6 cycloalkylsulfonyl, (18) C 6-10 arylsulfonyl, (19) C 7-14 aralkylsulfon
  • R 4 is (1) a C 6-10 aryl group (the group is (A) a halogen atom, (B) carboxyl, (C) cyano, (D) C 1-4 alkyl (the group is 1 to 3 halogen atoms, Carboxyl, Amino (the amino is (I) C 1-6 alkyl (the alkyl is C 1-4 alkoxy, 5- or 6-membered heterocycle, It may be substituted with 4- to 7-membered cyclic amino or C 3-6 cycloalkyl.
  • Item 14 The compound according to Item 13, or a pharmaceutically acceptable salt thereof.
  • R 5a and R 5b are each independently (1) a hydrogen atom, (2) a halogen atom, (3) hydroxyl group, (3) a C 1-6 alkyl group (the group is (A) 1 to 3 halogen atoms, It may be substituted with (b) a hydroxyl group, or (c) a C 1-4 alkoxy group. ), Or (4) a C 1-6 alkoxy group (the group is (A) 1 to 3 halogen atoms, It may be substituted with (b) a hydroxyl group, or (c) a C 1-4 alkoxy group. 14.
  • Item 16 The compound according to Item 15, or a pharmaceutically acceptable salt thereof, wherein R 5a and R 5b are each independently a hydrogen atom or a C 1-6 alkyl group.
  • Item 17 The compound according to any one of Items 1 to 16, wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof.
  • Item 18 The compound according to Item 17, or a pharmaceutically acceptable salt thereof, wherein n is 0.
  • Item 19 The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom or a sulfur atom.
  • Item 20 The compound according to Item 19, or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom.
  • Ring A is represented by the following formula (a):
  • Item 21 The compound according to any one of Items 1 to 20, or a pharmaceutically acceptable salt thereof, which is a group represented by:
  • Ring A is represented by the following formula (a ′)
  • Item 22 The compound according to Item 21, or a pharmaceutically acceptable salt thereof, which is a group represented by:
  • Item 23 A compound represented by formula (II), or a pharmaceutically acceptable salt thereof.
  • R 12 is (1) C 3-6 cycloalkyl group (the group is (A) 1-2 fluorine atoms, (B) C 3-6 cycloalkyl, (C) C 6-10 aryl (the group is Halogen atoms, C 1-4 alkyl ( optionally substituted with 1 to 3 fluorine atoms), C 1-4 alkoxy (optionally substituted with 1 to 3 fluorine atoms), or C 1-4 alkylsulfonyl may be substituted. And d) a C 6-10 aryloxy (the group may be substituted with a halogen atom, C 1-4 alkyl, or C 1-4 alkoxy), or It may be substituted with 1 to 3 different groups.
  • a C 6-10 aryl group (the group is (A) a halogen atom, (B) a 4-7 membered cyclic amino, (C) C 1-4 alkyl (the group may be substituted with 1 to 3 fluorine atoms, hydroxy, or C 1-4 alkoxy), (D) C 1-4 alkoxy (the group may be substituted with 1 to 3 fluorine atoms, or C 1-4 alkoxy), (E) C 1-6 alkylsulfonyl, (F) C 3-6 cycloalkylsulfonyl, (G) C 6-10 arylsulfonyl (the aryl may be substituted with C 1-4 alkoxy), (H) aminosulfonyl, (I) 5- to 10-membered monocyclic or polycyclic heteroaryl (the group may be substituted with a halogen atom, C 1-4 alkyl, or C 1-4 alkoxy), (J) a 5- or 6-membered saturated
  • a 5- to 10-membered monocyclic or polycyclic heteroaryl group (the group includes (A) a halogen atom, and (b) the same or different 1-2 selected from the group consisting of C 1-4 alkyl (the group may be substituted with 1 to 3 fluorine atoms). It may be substituted with groups. ), Or (4) a heterocyclic group (the ring is (A) C 1-4 alkoxycarbonyl, or (b) C 6-10 arylsulfonyl (wherein the aryl may be substituted with C 1-4 alkyl) may be substituted.
  • R 42 is (1) a C 6-10 aryl group (the group is (A) a halogen atom, (B) carboxyl, (C) cyano, (D) C 1-4 alkyl (the group is 1 to 3 halogen atoms, Carboxyl, amino, 5- or 6-membered monocyclic heteroaryl, C 1-6 alkylcarbonylamino, It may be substituted with C 1-6 alkylsulfonylamino or C 1-4 alkoxycarbonyl. ), (E) C 2-6 alkenyl (the group is It may be substituted with carboxyl or C 1-4 alkoxycarbonyl.
  • C 1-4 alkoxy (the group is 1 to 3 halogen atoms, It may be substituted with carboxyl, or a 5- or 6-membered monocyclic heteroaryl group.
  • C 1-4 alkoxycarbonyl (g) 1 to 3 groups of the same or different types selected from the group consisting of C 1-4 alkoxycarbonyl may be substituted.
  • a 5- to 10-membered monocyclic or polycyclic heteroaryl group (the group is the above (a) to (g) (1) a C 6-10 aryl group (the group is (A) a halogen atom, (B) carboxyl, (C) cyano, (D) C 1-4 alkyl (the group is 1 to 3 halogen atoms, Carboxyl, Amino (the amino is (I) C 1-6 alkyl (the alkyl is C 1-4 alkoxy, 5- or 6-membered heterocycle, It may be substituted with 4- to 7-membered cyclic amino or C 3-6 cycloalkyl.
  • X 2 is an oxygen atom or a sulfur atom.
  • the compound which is 3- (3,4-dichlorophenoxy) -N-phenyl-8-azabicyclo [3.2.1] octane-8-carboxamide, or a pharmaceutically acceptable salt thereof is excluded.
  • R 12 is (1) a C 3-6 cycloalkyl group, (2) a C 6-10 aryl group (the group is (A) a halogen atom, (B) a 4-7 membered cyclic amino, (C) C 1-4 alkyl (the group may be substituted with 1 to 3 fluorine atoms), (D) C 1-4 alkoxy (the group may be substituted with 1 to 3 fluorine atoms), (E) a 5- or 6-membered saturated heterocyclic oxy, (F) C 6-10 aryl, and (g) 1 to 3 groups of the same or different types selected from the group consisting of C 6-10 aryloxy may be substituted. Or a pharmaceutically acceptable salt thereof, or (3) a compound having a 5- to 10-membered monocyclic or polycyclic heteroaryl group, or a pharmaceutically acceptable salt thereof.
  • R42 is (1) a C 6-10 aryl group (the group is (A) a halogen atom, (B) carboxyl, (C) cyano, (D) C 1-4 alkyl (the group is 1 to 3 halogen atoms, Carboxyl, amino, C 1-6 alkylcarbonylamino, It may be substituted with C 1-6 alkylsulfonylamino or C 1-4 alkoxycarbonyl. ), (E) C 2-6 alkenyl (the group is It may be substituted with carboxyl or C 1-4 alkoxycarbonyl.
  • Item 26 A pharmaceutical composition comprising the compound according to any one of Items 1 to 25 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item 27 An sEH inhibitor comprising the compound according to any one of Items 1 to 25 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item 28 Hypertension, acute and chronic congestive heart failure, primary and secondary pulmonary hypertension, primary and secondary aldosteronemia, renovascular hypertension, primary and secondary kidney disease, cardiac hypertrophy Left ventricular hypertrophy, left ventricular fibrosis, left ventricular diastolic failure, left ventricular failure, atrial fibrillation, unstable angina, myocardial infarction, cardiomyopathy, stroke, restenosis after vascular reconstruction, diabetic retinopathy, Item 27.
  • a disease selected from the group consisting of cognitive impairment, obstructive arteriosclerosis, diabetes, obesity, dyslipidemia, fatty liver, vascular disorder, and atherosclerosis The described sEH inhibitor.
  • Item 29 The sEH inhibitor according to Item 27 or 28, which is useful for the treatment and / or prevention of hypertension and / or primary and secondary renal diseases.
  • Item 30 A therapeutic agent for hypertension and / or primary and secondary renal diseases containing the compound according to any one of items 1 to 25 or a pharmaceutically acceptable salt thereof as an active ingredient .
  • Item 31 Use of the compound according to any one of Items 1 to 25 or a pharmaceutically acceptable salt thereof for the manufacture of an sEH inhibitor.
  • Item 32 Hypertensive and / or primary, wherein an effective amount of the compound according to any one of Items 1 to 25 or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment And methods for treating secondary kidney disease.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as the compound of the present invention) is useful as a prophylactic and / or therapeutic agent for hypertension.
  • the compounds of the present invention are also useful for the management of acute and chronic congestive heart failure.
  • primary and secondary pulmonary hypertension primary and secondary aldosteronemia, renovascular hypertension, primary and secondary kidney disease (eg, glomerulonephritis, IgA nephropathy, diabetic kidney) , Hypertensive nephropathy (nephrosis syndrome, nephrotic syndrome, renal failure, etc.), left ventricular hypertrophy, left ventricular fibrosis, left ventricular diastolic failure, left ventricular failure, atrial fibrillation, unstable angina, myocardial infarction , Cardiomyopathy, stroke, restenosis after revascularization, diabetic retinopathy, cognitive impairment (eg, Alzheimer's disease, treatment of cerebrovascular dementia), and vascular disorders (eg, migraine, Raynaud's disease) It is also useful for the prevention and / or treatment of and for minimizing the atherosclerotic process. It is also useful for treating diseases associated with high intraocular pressure (eg glaucoma).
  • diseases associated with high intraocular pressure
  • the number of carbons in the definition of “substituent” may be expressed as “C 1-6 ”, for example.
  • C 1-6 alkyl is synonymous with an alkyl group having 1 to 6 carbon atoms.
  • a substituent that does not particularly indicate the term “which may be substituted” or “substituted” means an “unsubstituted” substituent.
  • C 1-6 alkyl means “unsubstituted”.
  • group means a monovalent group.
  • alkyl group means a monovalent saturated hydrocarbon group.
  • group may be omitted.
  • the number of substituents in the group defined as “may be substituted” or “substituted” is not particularly limited as long as substitution is possible, and is one or more.
  • the description of each group also applies when the group is a part of another group or a substituent.
  • Halogen atom includes, for example, fluorine atom, chlorine atom, bromine atom or iodine atom.
  • C 1-6 alkyl group means a straight chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferable examples include “C 1-4 alkyl group”. Specific examples of “C 1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • the “C 2-6 alkenyl group” means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one double bond. Specific examples include vinyl, propenyl, methylpropenyl, butenyl and methylbutenyl.
  • C 2-6 alkynyl group means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one triple bond.
  • specific examples include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, pentynyl, hexynyl and the like.
  • C 3-9 cycloalkyl group means a cyclic saturated or unsaturated hydrocarbon group having 3 to 9 carbon atoms. Preferred is “C 3-6 cycloalkyl group”. Specific examples of “C 3-9 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexynyl and the like.
  • the “C 3-6 cycloalkyl group” includes one or different hetero atoms selected from “C 3-6 cycloalkyl” and phenyl or 5-membered or 6-membered nitrogen, sulfur or oxygen atoms.
  • a group condensed with a ring containing the above (for example, 1 to 4) is also included. Specific examples of the group include groups represented by the following formulas.
  • C 6-10 aryl group means an aromatic hydrocarbon group having 6 to 10 carbon atoms.
  • C 6 aryl group phenyl
  • Specific examples of “C 6-10 aryl group” include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.
  • C 6-10 aryl group “C 6 aryl” and one or more hetero atoms selected from a 5- or 6-membered nitrogen atom, sulfur atom or oxygen atom are the same or different (for example, 1 to 4).
  • C 7-14 aralkyl group means a “C 6-10 aryl C 1-4 alkyl group”, and means a group in which the “aryl group” is substituted on the “alkyl group”.
  • Preferred examples include “C 7-10 aralkyl group” (C 6 aryl C 1-4 alkyl group).
  • Specific examples of “C 7-14 aralkyl group” include, for example, benzyl, 2-phenylethyl, 1-phenylpropyl, 1-naphthylmethyl and the like.
  • heteroaryl group examples include a 5- to 10-membered monocyclic or polycyclic aromatic group, and the group includes a heteroatom selected from a nitrogen atom, a sulfur atom or an oxygen atom. 1 or more (for example, 1 to 4) containing the same or different.
  • the “monocyclic heteroaryl group” is preferably 5 or 6 members.
  • the “polycyclic heteroaryl group” is preferably a bicyclic or tricyclic group, and more preferably a bicyclic group.
  • the polycyclic heteroaryl group includes a condensed ring of the monocyclic heteroaryl group and an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexyl, etc.).
  • aromatic ring benzene, pyridine, etc.
  • non-aromatic ring cyclohexyl, etc.
  • heteroaryl group include a group represented by the following formula.
  • the bond across the ring means that the “group” is bonded at a substitutable position in the ring.
  • heteroaryl group it means a 2-furyl group or a 3-furyl group.
  • heteroaryl group is a polycyclic group, for example, the following formula
  • heteroaryl C 1-4 alkyl group means a group in which the “heteroaryl group” is substituted on the “alkyl group”.
  • heteroaryl moiety are the same as the specific examples exemplified as the heteroaryl group.
  • An example is “heteroaryl C 1-4 alkyl”. Specific examples include 2-pyridylmethyl.
  • heterocyclic group examples include a 4-membered to 6-membered heterocyclic group having 1 to 3 of the same or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • the nitrogen atom, oxygen atom and sulfur atom are all atoms constituting a ring.
  • the heterocyclic group may be either saturated or partially unsaturated.
  • the nitrogen atom constituting the ring is not a bond of the “group”. That is, the group does not include concepts such as a pyrrolidino group.
  • the “heterocyclic group” may form a condensed ring with a 6-membered aromatic hydrocarbon or a 6-membered unsaturated heterocycle.
  • a 6-membered aromatic hydrocarbon or a 6-membered unsaturated heterocycle for example, the bicyclic 11- or 12-membered “heterocycle” in which the 5-membered or 6-membered “heterocyclic group” and the 6-membered aromatic hydrocarbon or the 6-membered unsaturated heterocycle are condensed is mentioned. It is done.
  • the 6-membered aromatic hydrocarbon include benzene.
  • Examples of the 6-membered unsaturated heterocycle include pyridine, pyrimidine, pyridazine and the like.
  • dihydroindolyl dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, pyrrololidinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl , Decahydroisoquinolinyl, tetrahydronaphthyridinyl, tetrahydropyridazepinyl and the like.
  • heterocyclic-C 1-4 alkyl group means a group in which the “heterocyclic group” is substituted on the “alkyl group”.
  • heterocyclic moiety are the same as the specific examples exemplified as the heterocyclic group.
  • C 1-6 alkyl part of the “C 1-6 alkoxy group” has the same meaning as the above “C 1-6 alkyl”.
  • Preferable examples include “C 1-4 alkoxy group”.
  • Specific examples of “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • C 1-6 alkyl part of the “C 1-6 alkylthio group” has the same meaning as the above “C 1-6 alkyl”.
  • Preferable examples include “C 1-4 alkylthio group”.
  • Specific examples of “C 1-6 alkylthio group” include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.
  • C 3-6 cycloalkyl part of the “C 3-6 cycloalkylthio group” has the same meaning as the above “C 3-6 cycloalkyl”.
  • Specific examples of “C 3-6 cycloalkylthio group” include, for example, cyclopropylthio and the like.
  • C 6-10 aryl part of the “C 6-10 arylthio group” has the same meaning as the above “C 6-10 aryl”.
  • Specific examples of the “C 6-10 arylthio group” include, for example, phenylthio, 1-naphthylthio, 2-naphthylthio and the like.
  • C 7-14 aralkyl part of the “C 7-14 aralkylthio group” has the same meaning as the above “C 7-14 aralkyl”.
  • Specific examples of the “C 7-14 aralkylthio group” include benzylthio and the like.
  • heteroaryl part of the “heteroarylthio group” has the same meaning as the “heteroaryl group”. Specific examples include pyridylthio and the like.
  • heteroaryl C 1-4 alkyl part of the “heteroaryl C 1-4 alkylthio group” has the same meaning as the “heteroaryl C 1-4 alkyl group”. Specific examples include pyridylmethylthio.
  • heterocyclic part of the “heterocyclic thio group” has the same meaning as the “heterocyclic group”. Specific examples include 4-pyranylthio and the like.
  • the “C 1-6 alkyl” part of the “C 1-6 alkylsulfinyl group” has the same meaning as the above “C 1-6 alkyl”.
  • Preferable examples include “C 1-4 alkylsulfinyl group”.
  • Specific examples of the “C 1-6 alkylsulfinyl group” include, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl, hexylsulfinyl and the like.
  • C 3-6 cycloalkyl part of the “C 3-6 cycloalkylsulfinyl group” has the same meaning as the above “C 3-6 cycloalkyl”. Specific examples include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl and the like.
  • C 6-10 aryl part of the “C 6-10 arylsulfinyl group” has the same meaning as the above “C 6-10 aryl”. Specific examples include phenylsulfinyl, 1-naphthylsulfinyl and the like.
  • C 7-14 aralkyl portion of the “C 7-14 aralkylsulfinyl group” has the same meaning as the above “C 7-14 aralkyl”. Specific examples include benzylsulfinyl and the like.
  • Heteroaryl C 1-4 alkyl moiety of the "heteroaryl C 1-4 alkylsulfinyl group” is synonymous with the term “heteroaryl C 1-4 alkyl group”. Specific examples include pyridylmethylsulfinyl and the like.
  • heterocyclic part of the “heterocyclic sulfinyl group” has the same meaning as the “heterocyclic group”. Specific examples include 4-pyranylsulfinyl and the like.
  • C 1-6 alkyl part of the “C 1-6 alkylsulfonyl group” has the same meaning as the above “C 1-6 alkyl”.
  • Preferable examples include “C 1-4 alkylsulfonyl group”.
  • Specific examples of “C 1-6 alkylsulfonyl group” include, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
  • C 3-6 cycloalkyl part of the “C 3-6 cycloalkylsulfonyl group” has the same meaning as the above “C 3-6 cycloalkyl”. Specific examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl and the like.
  • C 6-10 aryl part of the “C 6-10 arylsulfonyl group” has the same meaning as the above “C 6-10 aryl”. Specific examples include phenylsulfonyl, 1-naphthylsulfonyl and the like.
  • C 7-14 aralkyl part of the “C 7-14 aralkylsulfonyl group” has the same meaning as the above “C 7-14 aralkyl”. Specific examples include benzylsulfonyl and the like.
  • heteroaryl part of the “heteroarylsulfonyl group” has the same meaning as the “heteroaryl group”. Specific examples include pyridylsulfonyl and the like.
  • Heteroaryl C 1-4 alkyl moiety of the “heteroaryl C 1-4 alkylsulfonyl group” is the same as defined in the “heteroaryl C 1-4 alkyl group”. Specific examples include pyridylmethylsulfonyl and the like.
  • heterocyclic part of the “heterocyclic sulfonyl group” has the same meaning as the “heterocyclic group”. Specific examples include 4-pyranylsulfonyl and the like.
  • C 3-6 cycloalkyl part of the “C 3-6 cycloalkoxy group” has the same meaning as the above “C 3-6 cycloalkyl”. Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • C 6-10 aryl part of the “C 6-10 aryloxy group” has the same meaning as the above “C 6-10 aryl”. “C 6 aryloxy” (phenyloxy) is preferred. Specific examples of the “C 6-10 aryloxy group” include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
  • C 7-14 aralkyl moiety of the "C 7-14 aralkyloxy group” (C 6-10 aryl C 1-4 alkyloxy group) is the same as defined in the "C 7-14 aralkyl".
  • C 7-10 aralkyloxy group (“phenyl C 1-4 alkyl group”) and the like can be mentioned.
  • Specific examples of “C 7-14 aralkyloxy group” include, for example, benzyloxy, phenethyloxy, naphthylmethyloxy and the like.
  • heteroaryloxy group means a group in which the “aralkyl” part of the “aralkyloxy group” is replaced with “heteroaryl”.
  • “5- to 10-membered monocyclic or polycyclic heteroaryloxy group” and the like can be mentioned.
  • it is a “5-membered or 6-membered monocyclic heteroaryloxy group”.
  • Heteroaryl C 1-4 alkyl moiety of the “heteroaryl C 1-4 alkyl group” is the same as defined in the “heteroaryl C 1-4 alkyl group”. Specific examples include pyridylmethyloxy and the like.
  • heterocyclic part of the “heterocyclic oxy group” has the same meaning as the “heterocyclic group”. Specific examples include 4-pyranyloxy and the like.
  • the “C 1-4 alkoxycarbonyl group” means a group in which the “C 1-4 alkoxy group” is bonded to a carbonyl group. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, tert-butoxycarbonyl, and the like.
  • C 3-6 cycloalkoxycarbonyl group means a group in which the “C 3-6 cycloalkoxy group” is bonded to a carbonyl group.
  • examples of the C 3-6 cycloalkoxy moiety include those exemplified as the aforementioned C 3-6 cycloalkoxy group.
  • the “C 6-10 aryloxycarbonyl group” means a group in which the “C 6-10 aryloxy group” is bonded to a carbonyl group.
  • examples of the C 6-10 aryloxy moiety include those exemplified as the C 6-10 aryloxy group.
  • C 1-4 alkylcarbonyl group means a group in which the “C 1-4 alkyl group” is bonded to a carbonyl group. Specific examples include acetyl, propionyl, butyryl and the like.
  • C 3-6 cycloalkylcarbonyl group means a group in which the “C 3-6 cycloalkyl group” is bonded to a carbonyl group. Specific examples include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like.
  • C 6-10 aryl part of the “C 6-10 arylcarbonyl group” has the same meaning as the above “C 6-10 aryl”. Specific examples include phenylcarbonyl.
  • C 7-14 aralkyl part of the “C 7-14 aralkylcarbonyl group” has the same meaning as the above “C 7-14 aralkyl”. Specific examples include benzylcarbonyl and the like.
  • heteroaryl part of the “heteroarylcarbonyl group” has the same meaning as the “heteroaryl group”. Specific examples include pyridylcarbonyl and the like.
  • Heteroaryl C 1-4 alkyl moiety of the “heteroaryl C 1-4 alkylcarbonyl group” is the same as defined in the “heteroaryl C 1-4 alkyl group”. Specific examples include pyridylmethylcarbonyl and the like.
  • heterocyclic part of the “heterocyclic carbonyl group” has the same meaning as the “heterocyclic group”. Specific examples include 4-pyranylcarbonyl and the like.
  • C 1-4 alkyl moiety of the "C 1-4 alkylcarbonyloxy group” is the same as defined in the "C 1-4 alkyl group”. Specific examples include methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy and the like.
  • C 5-6 cycloalkenyl group examples include cyclopentenyl and the like.
  • C 5-6 cycloalkenyl part of the “C 5-6 cycloalkenyloxy group” has the same meaning as the above “C 5-6 cycloalkenyl”.
  • C 5-6 cycloalkenyloxycarbonyl group and “C 5-6 cycloalkenyl” moiety have the same meanings as the above “C 5-6 cycloalkenyl”.
  • “4- to 7-membered cyclic amino group” means a 4- to 7-membered cyclic amino group.
  • a group in which the nitrogen atom of the ring is a direct bond of the “group” is meant. Preferably, it is 5 to 7 members, more preferably 5 or 6 members. Specific examples include pyrrolidino, piperidino, morpholino, thiomorpholino, thiomorpholino oxide, thiomorpholino oxide, piperazino, 2-pyrrolidone-1-yl and the like.
  • the ring may be substituted with, for example, a halogen atom, C 1-4 alkyl, or C 6 aryl which may be substituted with C 1-4 alkoxy.
  • the group also includes a cyclic amino group that is a ring containing partial unsaturation.
  • the “4- to 7-membered cyclic amino group” may form a condensed ring with a 6-membered aromatic hydrocarbon and a 5-membered or 6-membered heterocycle. Specific examples include “groups” shown below.
  • substituent of the “optionally substituted C 1-6 alkyl group” for example, (1) a halogen atom, (2) hydroxyl group, (3) carboxyl group, (4) a cyano group, (5) formyl group, (6) an oxo group, (7) an optionally substituted amino group, (8) an optionally substituted aminocarbonyl group, (9) an optionally substituted aminosulfonyl group, (10) C 1-4 alkoxy group, (11) C 1-4 alkylcarbonyl group, (12) a C 1-4 alkylcarbonyloxy group, (13) C 1-4 alkoxycarbonyl group, (14) a C 1-6 alkylthio group, (15) a C 1-6 alkylsulfinyl group, (16) a C 1-6 alkylsulfonyl group, (17) a C 3-6 cycloalkyl group, (18) a C 3-6 cycloalkyloxy group, (19) C 3-6 cycloalkylcarbonyl group
  • Optionally substituted C 1-6 alkoxy group “optionally substituted C 1-4 alkylcarbonyl group”, “optionally substituted C 3-6 cycloalkyl group”, and “substituted”
  • substituent of “optionally C 3-6 cycloalkylcarbonyl group” include groups selected from the above (1) to (52).
  • Optionally substituted C 3-9 cycloalkyl group “optionally substituted C 3-9 cycloalkyl C 1-4 alkyl group”, “optionally substituted heterocyclic group”, “ “Optionally substituted heterocyclic-C 1-4 alkyl group”, “optionally substituted C 6-10 aryl group”, “ optionally substituted C 7-14 aralkyl group”, “5-membered”
  • substituent of “ ⁇ 10- membered monocyclic or polycyclic heteroaryl group” and “5- to 10-membered monocyclic or polycyclic heteroaryl C 1-4 alkyl group” include, for example, (A1) a halogen atom, (A2) a hydroxyl group, (A3) a carboxyl group, (A4) a cyano group, (A5) a nitro group, (A6) formyl group, (A7) an optionally substituted amino group, (A8) an optionally substituted aminocarbonyl group, (A9) an optionally substituted aminosul
  • the groups (a11) to (a19) are, for example, (B1) a halogen atom, (B2) a hydroxyl group, (B3) a carboxyl group, (B4) formyl group, (B5) an oxo group, (B6) a cyano group, (B7) an optionally substituted amino group, (B8) an optionally substituted aminocarbonyl group, (B9) an optionally substituted aminosulfonyl group, (B10) C 1-4 alkoxy group, (B12) a C 1-4 alkoxycarbonyl group, (B13) a C 1-6 alkylthio group, (B14) a C 1-6 alkylsulfinyl group, (B15) a C 1-6 alkylsulfonyl group, (B16) a C 3-6 cycloalkyl group, (B17) a C 3-6 cycloalkyloxy group, (B18) a C 3-6 cycloalkylthio group
  • the groups (a20) to (a31) are, for example, (B1) a halogen atom, (B2) a hydroxyl group, (B3) a carboxyl group, (B4) formyl group, (B5) an oxo group, (B10) C 1-4 alkoxy group, (B12) a C 1-4 alkoxycarbonyl group, (B13) a C 1-6 alkylthio group, (B14) a C 1-6 alkylsulfinyl group, (B15) a C 1-6 alkylsulfonyl group, (B16) a C 3-6 cycloalkyl group, (B17) a C 3-6 cycloalkyloxy group, (B21) a heterocyclic group, (B22) a heterocyclic oxy group, (B26) a C 6-10 aryl group, (B27) a C 6-10 aryloxy group, (B28) a C 6-10 arylthio group, (
  • the groups (a32) to (a45) are, for example, (B1) a halogen atom, (B2) a hydroxyl group, (B3) a carboxyl group, (B4) formyl group, (B6) a cyano group, (B10) C 1-4 alkoxy group, (B12) a C 1-4 alkoxycarbonyl group, (B13) a C 1-6 alkylthio group, (B14) a C 1-6 alkylsulfinyl group, (B15) a C 1-6 alkylsulfonyl group, (B16) a C 3-6 cycloalkyl group, (B21) a heterocyclic group, (B22) a heterocyclic oxy group, (B26) a C 6-10 aryl group, (B27) a C 6-10 aryloxy group, (B28) a C 6-10 arylthio group, (B29) a C 6-10 arylsulfonyl group
  • the groups (b10) to (b15) substituted with the groups (a11) to (a19) are (C1) a halogen atom, (C2) a hydroxyl group, (C3) a carboxyl group, (C4) formyl group, (C5) an oxo group, (C6) a cyano group, (C7) an optionally substituted amino group, (C8) an optionally substituted aminocarbonyl group, (C9) an optionally substituted aminosulfonyl group, (C10) C 3-6 cycloalkyl group, (C11) a C 3-6 cycloalkyloxy group, (C12) a C 3-6 cycloalkylthio group, (C13) a C 3-6 cycloalkylsulfinyl group, (C14) C 3-6 cycloalkylsulfonyl group, (C15) C 5-6 cycloalkenyl group, (C16) C 5-6 cycloalkenyloxy group,
  • the groups (c10) to (c31) are (D1) a halogen atom, (D2) a hydroxyl group, (D3) a carboxyl group, (D4) formyl group, (D5) a cyano group, (D6) a C 1-4 alkyl group (the group may be substituted with carboxy), (D7) C 2-6 alkenyl group (the group may be substituted with carboxy), (D8) C 1-4 alkoxy group (this group may be substituted with carboxy), (D9) C 1-4 alkylcarbonyl group, (D10) C 1-4 alkoxycarbonyl group, (D11) a C 1-6 alkylsulfonyl group (the group may be substituted with carboxy), (D12) an optionally substituted amino group, It may be substituted with (d13) an optionally substituted aminocarbonyl group, or (d14) an optionally substituted aminosulfonyl group. ).
  • the groups (b16) to (b34) substituted with the groups (a11) to (a19) are It may be substituted with a group selected from the group consisting of (d1) to (d14).
  • a C 1-4 alkyl group an amino group, an aminocarbonyl group and an aminosulfonyl group, which are substituted on the groups (a20) to (a45), (C1) a halogen atom, (C2) a hydroxyl group, (C3) a carboxyl group, A C 1-4 alkyl group, A C 1-4 alkoxy group, A C 1-4 alkoxycarbonyl group, A C 1-6 alkylsulfonyl group, An amino group, A group selected from the group consisting of an aminocarbonyl group and an aminosulfonyl group (amino in amino, aminocarbonyl and aminosulfonyl may be substituted with the same or different 1-2 C 1-6 alkyl) Etc. may be substituted.
  • “An optionally substituted amino group” means an amino group, a mono- or di-substituted amino group, or an optionally substituted 4- to 7-membered cyclic amino group.
  • Examples of the substituent of “mono- or di-substituted amino group” include, for example, (E1) a C 1-6 alkyl group, (E2) C 1-4 alkylcarbonyl group, (E3) a C 1-4 alkoxycarbonyl group, (E4) a C 1-6 alkylsulfonyl group, (E5) a C 2-6 alkenyl group, (E6) a C 6-10 aryl group, (E7) a 5- to 10-membered monocyclic or polycyclic heteroaryl group, (E8) a C 3-6 cycloalkyl group, (E9) a heterocyclic group, (E10) C 3-6 cycloalkylcarbonyl, (E11) C 6-10 arylcarbonyl, (E12) C 7-14 aralkylcarbonyl, (E13) 5- to 10-membered monocyclic or polycyclic heteroarylcarbonyl, (E14) 5- to 10-membered monocyclic or polycyclic heteroaryl
  • the groups (e1) to (e5) are (F1) a halogen atom, (F2) a hydroxyl group, (F3) a carboxyl group, (F4) an oxo group, (F5) C 1-4 alkoxy group, (F6) C 1-4 alkoxycarbonyl group, (F7) a C 1-6 alkylthio group, (F8) a C 1-6 alkylsulfinyl group, (F9) a C 1-6 alkylsulfonyl group, (F10) an amino group (the amino may be substituted with the same or different 1-2 C 1-6 alkyl), (F11) an aminocarbonyl group (the amino may be substituted with the same or different 1-2 C 1-6 alkyl), (F12) a C 3-6 cycloalkyl group, (F13) C 3-6 cycloalkyloxy group, (F14) C 3-6 cycloalkyloxycarbonyl group, (F15) C 3-6 cycloalkylthio
  • the groups (f12) to (f31) further include (g1) a halogen atom, (G2) hydroxy, (G3) carboxyl, (G4) C 1-4 alkyl (the alkyl may be substituted with carboxy), (G5) C 1-4 alkoxy (the alkoxy may be substituted with carboxy), (G6) amino (the amino may be substituted with the same or different 1-2 C 1-6 alkyl), (G7) aminocarbonyl (the amino may be substituted with the same or different 1-2 C 1-6 alkyl), (G8) aminosulfonyl (the amino may be substituted with the same or different 1-2 C 1-6 alkyl), (G9) C 1-6 alkylsulfonyl, (g10) cyano or the like may be substituted. ).
  • the groups (e6) to (e19) further include (f1) a halogen atom, (f2) a hydroxyl group, (f3) a carboxyl group, (f5) a C 1-4 alkoxy group, and (f9) a C 1-6 alkylsulfonyl. group, cyano group, C 1-6 alkyl group, an amino group, an aminocarbonyl group or an aminosulfonyl group (said amino, aminocarbonyl and aminosulfonyl, is substituted with C 1-6 alkyl the same or different 1-2 Etc.) and the like.
  • the substituents in the groups (e6) to (e19) are as follows: (f5) C 1-4 alkoxy group, (f9) C 1-6 alkylsulfonyl group, C 1-6 alkyl group, (f10) aminocarbonyl group, Alternatively, (f11) aminosulfonyl group may be further substituted with (g1), (g2), (g3), (g4), (g6), (g7) or a C 1-6 alkylsulfonyl group.
  • substituent of the “optionally substituted 4- to 7-membered cyclic amino group” include, for example, (H1) a halogen atom, (H2) a hydroxyl group, (H3) a carboxyl group, (H4) C 1-4 alkyl group, (H5) a C 1-4 alkylcarbonyl group, (H6) C 1-4 alkylsulfonyl (h7) C 1-4 alkoxy group, (H8) C 1-4 alkoxycarbonyl group, (H9) C 6-10 aryl group, or (h10) C 7-14 aralkyl group, etc.
  • the groups (f4) to (f6) are (I1) hydroxy, (I2) C 1-4 alkoxy, (I3) carboxy, (I4) amino (the amino may be substituted with the same or different 1-2 C 1-6 alkyl), or (i5) aminocarbonyl (the amino is the same or different 1-2 And may be substituted with C 1-6 alkyl. ).
  • R 2a and R 2b together form a C 3-6 cycloalkyl ring or a 4- to 6-membered saturated heterocyclic ring
  • R 2c represents a halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, or mono-C 1. -6 alkylamino, in a 4-membered to 6-membered saturated heterocyclic ring, R 2c may be substituted with a nitrogen atom constituting the ring).
  • R 2a and R 2b substituted on each carbon atom are each independent.
  • R 2a and R 2b substituted on each carbon atom are each independent.
  • R 5a and R 5b together form a C 3-6 cycloalkyl ring or a 4-membered to 6-membered saturated heterocyclic ring” in the group represented by And a group represented by the formula group (wherein, R is a halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, or mono-C 1-6 alkylamino)
  • R may be substituted with a nitrogen atom constituting the ring.
  • R 5a and R 5b substituted on each carbon atom are independent of each other.
  • n 2 or 3
  • n 3 is the same as the case where n is 2.
  • C 3-6 cycloalkyl group (the group is (A) 1-2 fluorine atoms, (B) C 3-6 cycloalkyl, (C) C 6-10 aryl (the group is Halogen atoms, C 1-4 alkyl ( optionally substituted with 1 to 3 fluorine atoms), C 1-4 alkoxy (optionally substituted with 1 to 3 fluorine atoms), or C 1-4 alkylsulfonyl may be substituted.
  • a C 6-10 aryloxy (the group may be substituted with a halogen atom, C 1-4 alkyl, or C 1-4 alkoxy), or It may be substituted with 1 to 3 different groups.
  • a C 6-10 aryl group (the group is (A) a halogen atom, (B) a 4-7 membered cyclic amino, (C) C 1-4 alkyl (the group may be substituted with 1 to 3 fluorine atoms, hydroxy, or C 1-4 alkoxy), (D) C 1-4 alkoxy (the group may be substituted with 1 to 3 fluorine atoms, or C 1-4 alkoxy), (E) C 1-6 alkylsulfonyl, (F) C 3-6 cycloalkylsulfonyl, (G) C 6-10 arylsulfonyl (the aryl may be substituted with C 1-4 alkoxy), (H) aminosulfonyl, (I) 5- to 10-membered monocyclic or polycyclic heteroaryl (the group may be substituted with a halogen atom, C 1-4 alkyl, or C 1-4 alkoxy), (J) a 5- or 6-membered saturated
  • a 5- to 10-membered monocyclic or polycyclic heteroaryl group (the group includes (A) a halogen atom, and (b) the same or different 1-2 selected from the group consisting of C 1-4 alkyl (the group may be substituted with 1 to 3 fluorine atoms). It may be substituted with groups. ), Or (4) a heterocyclic group (the ring is (A) C 1-4 alkoxycarbonyl, or (b) C 6-10 arylsulfonyl (wherein the aryl may be substituted with C 1-4 alkyl) may be substituted. ) Is preferred.
  • R 2a and R 2b are preferably hydrogen atoms.
  • M is preferably 0, 1, or 2.
  • R 3a ”, “R 3b ” and “R 3c ” are any two of these are hydrogen atoms, and the remaining one is represented by the following formula:
  • R 4 (1) a C 6-10 aryl group (the group is (A) a halogen atom, (B) carboxyl, (C) cyano, (D) C 1-4 alkyl (the group is 1 to 3 halogen atoms, Carboxyl, Amino (the amino is (I) C 1-6 alkyl (the alkyl is C 1-4 alkoxy, 5- or 6-membered heterocycle, It may be substituted with 4- to 7-membered cyclic amino or C 3-6 cycloalkyl.
  • R 5a and “R 5b ” are preferably each independently a hydrogen atom or a C 1-6 alkyl group.
  • N is preferably 0.
  • X is preferably an oxygen atom or a sulfur atom.
  • Ring A is represented by the following formula (a ')
  • the present invention also includes a compound represented by formula (I) or a prodrug thereof, or a pharmacologically acceptable salt thereof. Also included are solvates such as this hydrate or ethanol solvate. Further, all forms of crystal forms are also included.
  • the term “prodrug of the compound of formula (I)” means a compound that is converted into a compound of formula (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, It means a compound that undergoes reduction, hydrolysis or the like and changes to a compound of formula (I), or a compound that undergoes hydrolysis by gastric acid or the like and changes to a compound of compound (I).
  • the compound of formula (I) may exist as a tautomer. Accordingly, the present invention also includes tautomers of the compounds of formula (I).
  • the compound of the present invention may have at least one asymmetric carbon atom. Accordingly, the present invention includes not only racemic forms of the compounds of the present invention but also optically active forms of these compounds. When the compound of the present invention has two or more asymmetric carbon atoms, stereoisomerism may occur. Accordingly, the present invention also includes stereoisomers of these compounds and mixtures thereof.
  • the compound represented by the formula (I) can be synthesized from known compounds by combining known synthesis methods. For example, it can be synthesized by the following method.
  • the compound represented by the formula (I) can be synthesized by appropriately selecting and combining the methods shown below according to the type of the starting material.
  • the compound represented by the formula (I) or a salt thereof is produced by, for example, the following two methods.
  • the compound of the present invention represented by the formula (I) is appropriately combined with known methods from methods shown in the following production methods 1 to 9, methods similar to the following production methods, or synthesis methods well known to those skilled in the art. Can be manufactured. In this specification, the following abbreviations may be used for the sake of simplicity.
  • Step 1 Compound (1-3) is obtained by reacting an amine (1-1) obtained by a known or known synthesis method with an isocyanate (1-2) obtained by a known or known synthesis method in the presence of a base in an organic solvent. Can be manufactured.
  • organic solvents examples include aprotic solvents (N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ether solvents (tetrahydrofuran, 1,4-dioxane, etc.), halogenated hydrocarbons ( Dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbons (toluene, benzene, etc.), or mixed solvents thereof, preferably N, N-dimethylformamide, N-methylpiperidone, toluene And tetrahydrofuran. It can also be produced in an organic solvent-water two-layer system.
  • aprotic solvents N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.
  • ether solvents tetrahydrofuran, 1,4-dioxane, etc.
  • an organic base either an organic base or an inorganic base can be used.
  • the organic base include (1-hydroxybenztriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4. 3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, or picoline.
  • Inorganic bases include alkali hydroxide (sodium hydroxide, potassium hydroxide), sodium bicarbonate, alkali carbonate (sodium carbonate, potassium carbonate, cesium carbonate), alkali alkoxide (sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide) Etc.) and alkali metals (n-butyllithium, methyllithium, isopropylmagnesium bromide, etc.).
  • the reaction temperature can be selected from the range of about ⁇ 78 ° C. to about 200 ° C.
  • the amount of compound (1-2) to be used is generally 1 to 5 mol, preferably 1.2 to 3 mol, per 1 mol of compound (1-1).
  • the amount of the base to be used is generally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (1-1).
  • the reaction time is usually about 0.5 to about 48 hours, preferably about 0.5 to about 12 hours.
  • the reaction temperature is usually about ⁇ 20 to about 180 ° C., preferably about 0 to about 120 ° C.
  • Step 1 This step is carried out in the presence of various bases in the compound (1-1) in a suitable solvent in a suitable solvent (N—N′-carbonyldiimidazole, N—N′-carbonyldipyrrole, phosgene, diphosgene, triphosgene, Alternatively, it is a step of activating the compound (2-1) using phenyl chloroformate or the like.
  • Examples of the base include (1-hydroxybenztriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, pyridine, dimethylaminopyridine, picoline, etc.).
  • organic solvents include aprotic solvents (N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ether solvents (tetrahydrofuran, 1,4-dioxane, etc.), halogenated hydrocarbons ( Dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene and the like).
  • the amount of urea to be used is generally 0.3-5 mol, preferably 0.3-3 mol, relative to 1 mol of compound (1-1).
  • the amount of the base to be used is generally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (1-1).
  • the reaction time is usually about 0.5 to about 48 hours, preferably about 0.5 to about 24 hours.
  • the reaction temperature is usually about ⁇ 20 to about 180 ° C., preferably about 0 to about 120 ° C.
  • Step 2 This step is a step of reacting compound (2-2) activated in step 1 above with compound (2-2) in the presence of various bases in an appropriate solvent to obtain compound (1-3). It is. Moreover, it is also possible to perform the process 1 and this process continuously. The production is carried out by the same method as in step 1 described in production method 1.
  • Step 1 This step is a step for producing an isocyanate compound (1-2) using phosgene, diphosgene or triphosgene in a suitable solvent in the presence of various bases for the compound (2-2).
  • bases include (1-hydroxybenztriazole, N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, pyridine, dimethylaminopyridine, picoline, etc.).
  • organic solvents examples include aprotic solvents (N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ether solvents (tetrahydrofuran, 1,4-dioxane, etc.), halogenated hydrocarbons ( Dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene and the like).
  • the amount of phosgene to be used is generally 0.3-5 mol, preferably 0.3-3 mol, per 1 mol of compound (2-2).
  • the amount of the base to be used is generally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (2-2).
  • the reaction time is usually about 0.5 to about 48 hours, preferably about 0.5 to about 24 hours.
  • the reaction temperature is usually about ⁇ 20 to about 180 ° C., preferably about 0 to about 120 ° C.
  • L 1 represents a leaving group (for example, iodine atom, bromine atom, chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, etc.).
  • Prot represents an amino protecting group ⁇ Protective Groups in Organic Synthesis 4th Edition (WILEY-INTERSCIENCE) ⁇ .
  • Step 1 In this step, compound (4-2) can be produced from compound (4-1) by a method similar to the method described in the literature ⁇ Protective Groups in Organic Synthesis 4th Edition (WILEY-INTERSCIENCE) ⁇ . it can.
  • Step 2 The compound (4-3) can be produced from the compound (4-2) by a method described in literature (for example, see Comprehensive Organic transformation, R. C. Larroc, VCH publisher Inc., 1989).
  • Step 3 Compound (4-4) can be produced by reacting compound (4-3) and compound (4-5) in the presence or absence of a base in an inert solvent.
  • a base in an inert solvent.
  • the compound (4-5) is an amine, alcohol, thiol, phenol, thiophenol, or aniline
  • examples of the base include organic bases (1-hydroxybenztriazole, N-methyl).
  • Morpholine triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4- Diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, picoline, etc.), alkali carbonate (such as potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate) as an inorganic base, alkali hydride (Such as sodium hydride or potassium hydride) or alkali hydroxide (potassium hydroxide or Sodium hydroxide, etc.), and preferable examples include triethylamine, potassium carbonate, and the like.
  • alkali carbonate such as potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate
  • alkali hydride Sud as sodium hydride or potassium hydride
  • the amount of the base used is usually selected from the range of 1 to 3 equivalents relative to the compound (1-10).
  • the inert solvent include aprotic solvents (N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ether solvents (tetrahydrofuran, 1,4-dioxane, etc.), halogenated hydrocarbons (Dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, etc.).
  • a mixed solvent thereof and the like can be mentioned, and N, N-dimethylformamide and the like are preferable.
  • the reaction temperature can be selected from the range of about ⁇ 78 ° C. to about 180 ° C.
  • L 1 represents a leaving group (for example, iodine atom, bromine atom, chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, etc.).
  • Prot represents an amino protecting group ⁇ Protective Groups in Organic Synthesis 4th Edition (WILEY-INTERSCIENCE) ⁇ .
  • Step 1 This step is a step for producing compound (4-4) by reacting compound (5-1) with (4-5) or (5-3).
  • Mitsunobu reaction for example, Mitsunobu, O. Synthesis, 1 (1981), Hughes, DL Org. React. 335, 42 (1992), Tsunoda, T. Tetrahedron., 2463, 37 (1996), Dembinski, R. Eur. J. Org. Chem. 2763 (2004).
  • (4-4) can be produced.
  • (4-4) can be produced by reacting with a base in an inert solvent.
  • the amount of compound (5-3) to be used is generally selected from the range of 1 equivalent to excess with respect to compound (5-1).
  • the inert solvent include ether solvents (tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, etc.), aprotic polar solvents (N, N-dimethylformamide, N, N-dimethyl). Acetamide, dimethyl sulfoxide, acetonitrile, etc.), ketones (acetone, etc.), or a mixed solvent thereof.
  • Examples of the base include alkali carbonate (potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), alkali hydride (sodium hydride, potassium hydride, etc.) or alkali hydroxide (potassium hydroxide, sodium hydroxide, etc.) ), Alkali alkoxides (sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), preferably potassium carbonate, potassium tert-butoxide and the like.
  • the amount of the base used is usually selected from the range of 1 to 5 equivalents relative to compound (1-4).
  • the reaction temperature is selected from the range of about 0 ° C. to about 150 ° C., but the reaction is usually carried out under reflux.
  • L 1 represents a leaving group (for example, iodine atom, bromine atom, chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, etc.).
  • Prot represents an amino protecting group ⁇ Protective Groups in Organic Synthesis 4th Edition (WILEY-INTERSCIENCE) ⁇ .
  • Step 1 In this step, compound (6-2) can be produced from compound (6-1) by a method similar to the method described in the literature ⁇ Protective Groups in Organic Synthesis 4th Edition (WILEY-INTERSCIENCE) ⁇ . it can.
  • Step 2 This step can be produced by carrying out a reduction reaction of ketone (6-2) and amine (6-4) in an organic solvent in the presence or absence of an acid.
  • the reducing agent include borohydride reagents (sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) or 2-picoline-borane.
  • Reference literature Abdel-Magid, A. F. J. Org. Chem. 3849, 61 (1996), Sato, S. Tetrahedron. 7899, 60 (2004), etc.
  • Step 3 This step is performed by the same method as Step 1 described in Production Method 5.
  • R 3a , R 3b , R 4 , R 5a , R 5b , R 6 and n are as defined above.
  • Prot represents an amino protecting group ⁇ Protective Groups in Organic Synthesis 4th Edition (WILEY-INTERSCIENCE) ⁇ .
  • Step 1 This step is performed by the same method as in step 2 described in production method 6.
  • R 3a , R 3b , R 4 , R 5a , R 5b , R 6 and n are as defined above.
  • L 1 represents a leaving group (for example, iodine atom, bromine atom, chlorine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, etc.).
  • Prot and Prot 2 represent an amino protecting group ⁇ Protective Groups in Organic Synthesis 4th Edition (WILEY-INTERSCIENCE) ⁇ . ]
  • Process 1 This step is performed by the same method as in step 2 described in production method 6.
  • Process 2 This step is performed by the same method as in step 2 described in production method 6.
  • Process 3 This step is performed by the same method as Step 1 described in Production Method 5.
  • Process 4 This step is performed by the same method as Step 1 described in Production Method 5.
  • Process 5 This step is performed by the same method as Step 1 described in Production Method 5.
  • (6-1) represents (a-3) to (d-3) as defined above, and R 3a is the same as described above.
  • L 2 represents a trifluoromethanesulfonyl group.
  • L 3 represents an iodine atom, a bromine atom, a chlorine atom or boron.
  • M 1 represents tin, silicon or boron.
  • Prot represents an amino protecting group ⁇ Protective Groups in Organic Synthesis 4th Edition (WILEY-INTERSCIENCE) ⁇ . ]
  • Steps 1 to 4 This process (1 to 4) can be performed according to literature ⁇ for example, Bioorg. Med. Chem. Lett. 1817, 13 (2003), US2009 / 0023934, Palladium Reagents and Catalysts, by Jiro Tsuji, John Wiley & Sons Ltd, 2004, Molandar, GA Aldrichimica Acta 49, 38 (2005), J. Am. Chem. Soc. 6716, 129 (2007) ⁇ and the like. ) Or the compound (9-4) can be used to produce the compound (1-1).
  • ring A, R 1 , R 2a , R 2b , and m are the same as described above.
  • n ′ is 0 or 1.
  • Step 1 is a step for producing a tetrazole compound (10-2) using an azide compound in a solvent suitable for the compound (10-1).
  • the azide compound include sodium azide, trimethylsilyl azide, tributyltin azide and the like, and ammonium chloride, alkylamine hydrochloride, dibutyltin oxide and the like can also be used as additives.
  • Solvents include aprotic solvents (N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ether solvents (tetrahydrofuran, 1,4-dioxane, etc.), halogenated hydrocarbons (dichloromethane) , Chloroform, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbons (toluene, benzene, etc.), or mixed solvents thereof, preferably N, N-dimethylformamide, N-methylpiperidone, dimethyl sulfoxide And toluene.
  • aprotic solvents N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.
  • ether solvents tetrahydrofuran, 1,4-dioxane, etc.
  • halogenated hydrocarbons dimethoxycarbons
  • Chloroform
  • the amount of the azide compound to be used is 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (10-1).
  • the additive is used in an amount of 0.1 to 10 mol, preferably 0.3 to 3 mol.
  • the reaction time is usually about 0.5 to about 48 hours, preferably about 0.5 to about 24 hours.
  • the reaction temperature is usually about ⁇ 20 to about 180 ° C., preferably about 0 to about 120 ° C.
  • Step 1 This step is a step for producing an unsaturated ester compound (11-2) using various alcohols in a suitable solvent in the presence of a suitable condensing agent for the available unsaturated carboxylic acid (11-1).
  • condensing agent examples include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 2,4,6-trichlorobenzoyl chloride, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt, benzotriazole-1 And -yloxy-trisdimethylaminophosphonium salt.
  • Solvents include aprotic solvents (N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ether solvents (tetrahydrofuran, 1,4-dioxane, etc.), halogenated hydrocarbons (dichloromethane, Chloroform, 1,2-dichloroethane, chlorobenzene and the like). Further, an appropriate additive may be added, and examples of the additive include 4-dimethylaminopyridine and 1-hydroxybenzotriazole.
  • the amount of the condensing agent to be used is 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (11-1).
  • the additive is used in an amount of 0.1 to 10 mol, preferably 0.1 to 3 mol.
  • the reaction time is usually about 0.5 to about 48 hours, preferably about 0.5 to about 24 hours.
  • the reaction temperature is usually about ⁇ 20 to about 180 ° C., preferably about 0 to about 120 ° C.
  • Step 2 is a step for producing a cyclopropane compound (11-3) by reacting the compound (11-2) with trimethylsulfoxonium in a solvent in the presence of a suitable base.
  • trimethylsulfoxonium include trimethylsulfoxonium bromide and trimethylsulfoxonium iodide.
  • the base include metal alkoxide (sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide), alkali hydride (such as sodium hydride or potassium hydride), or alkali hydroxide (such as potassium hydroxide or sodium hydroxide). Is mentioned.
  • Solvents include aprotic solvents (N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ether solvents (tetrahydrofuran, 1,4-dioxane, etc.), halogenated hydrocarbons (dichloromethane, Chloroform, 1,2-dichloroethane, chlorobenzene and the like).
  • the amount of trimethylsulfoxonium to be used is 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (11-2).
  • the amount of the base to be used is 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (11-2).
  • the reaction time is usually about 0.5 to about 48 hours, preferably about 0.5 to about 24 hours.
  • the reaction temperature is usually about ⁇ 20 to about 180 ° C., preferably about 0 to about 120 ° C.
  • Step 3 is a step for producing a carboxylic acid compound (11-4) by hydrolyzing the compound (11-3) in a solvent in the presence of a suitable base.
  • the base include metal alkoxide (sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide), alkali hydride (such as sodium hydride or potassium hydride), or alkali hydroxide (such as potassium hydroxide or sodium hydroxide). Is mentioned.
  • Solvents include aprotic solvents (N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc.), ether solvents (tetrahydrofuran, 1,4-dioxane, etc.), halogenated hydrocarbons (dichloromethane, Chloroform, 1,2-dichloroethane, chlorobenzene and the like), or a mixture thereof may be used.
  • the amount of the base to be used is 1 to 10 mol per 1 mol of compound (11-3).
  • the reaction temperature is usually about ⁇ 20 to about 180 ° C., preferably about 0 to about 120 ° C.
  • Step 4 the isocyanate compound (11-5) is produced from the compound (11-4) by a known method (for example, J. Org. Chem., 65, 7977 (2000), Tetrahedron, 58, 4917 (2002), etc.). It is a process.
  • Step 5 This step can be performed by the same method as in step 1 described in production method 1. Moreover, this process and the process 4 can also be performed continuously.
  • the compounds of formula (I) also include those having an optically active center, so that they can be obtained as racemates or in optically active form when optically active starting materials are used. it can. If necessary, the racemates obtained can be physically or chemically resolved into their optical enantiomers by known methods. Preferably, diastereomers are formed from the racemate by a reaction using an optically active resolving agent. Different forms of diastereomers can be resolved by known methods such as fractional crystallization.
  • the compound of the present invention can be converted into a salt by mixing with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, acetone or the like.
  • pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfate, phosphoric acid and nitric acid, or acetic acid, propionic acid, oxalic acid, succinic acid, lactic acid, malic acid, tartaric acid and citric acid.
  • organic acids such as maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, and ascorbic acid.
  • the compound of the present invention can be applied to the prevention or treatment of various diseases because of its inhibitory action on soluble epoxide hydrolase (sEH).
  • the compounds described herein are useful as preventive or therapeutic agents for hypertension.
  • the compounds of the present invention are also useful for the management of acute and chronic congestive heart failure.
  • the compounds of the present invention can be used for primary and secondary pulmonary hypertension, primary and secondary aldosteronemia, renovascular hypertension, primary and secondary renal diseases (eg, glomerulonephritis, IgA nephropathy, Diabetic nephropathy, hypertensive nephropathy (nephrosis syndrome, nephrotic syndrome, renal failure, etc.), left ventricular hypertrophy, left ventricular fibrosis, left ventricular diastolic failure, left ventricular failure, atrial fibrillation, unstable angina , Myocardial infarction, cardiomyopathy, stroke, restenosis after revascularization, diabetic retinopathy, cognitive impairment (eg, treatment of Alzheimer's disease, cerebrovascular dementia), and vascular disorders (eg, migraine, Raynaud) It is also expected to be useful for the prevention or treatment of diseases, etc.) and for minimizing the atherosclerotic process. It is also useful for treating diseases associated with high intraocular pressure (eg
  • compositions for oral or parenteral eg, intravenous, subcutaneous, or intramuscular injection, topical, rectal, transdermal, or nasal Administration
  • compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, etc.
  • compositions for parenteral administration include, for example, injections.
  • Aqueous agents or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like can be mentioned.
  • These preparations can be prepared using conventionally known techniques, and can contain non-toxic and inert carriers or excipients usually used in the pharmaceutical field.
  • the dose varies depending on the individual compound and the patient's disease, age, weight, sex, symptom, route of administration, etc., but the compound of the present invention or a pharmaceutically acceptable salt thereof is usually used for adults (body weight 50 kg).
  • the salt is administered at 0.1 to 1000 mg / day, preferably 1 to 300 mg / day once a day or divided into 2 to 3 times a day. It can also be administered once every few days to several weeks.
  • the compound of the present invention is for the purpose of enhancing its effect, and is a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent (hereinafter abbreviated as a concomitant drug).
  • a concomitant drug a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent (hereinafter abbreviated as a concomitant drug).
  • a concomitant drug can be used in combination.
  • the administration timing 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 may be administered with a time difference. Moreover, it is good also as a mixture of this invention compound and a concomitant drug.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the administration subject is a human
  • 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • diabetes therapeutic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast), insulin resistance improving agents ( Examples, pioglitazone or its hydrochloride, troglitazone, rosiglitazone or its maleate, DSP-8658, etc.), ⁇ -glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, metformin, etc.) , Insulin secretagogues (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride and other sulfonylurea agents; repaglinide, senaglinide, nateglinide, mitiglinide ), GLP-1
  • aldose reductase inhibitors eg, torrestat, epalrestat, zenarestat, zopolestat, minarestat, fidarestat, SK-860, CT-112 etc.
  • neurotrophic factors eg, NGF, NT) -3, BDNF, etc.
  • PKC inhibitors eg, LY-333531
  • AGE inhibitors eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), etc.
  • active oxygen scavengers eg, ALT766) Examples, thioctic acid, etc.
  • cerebral vasodilators eg, thioprid, mexiletine, etc.
  • Antihyperlipidemic agents include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, rosuvastatin or their sodium or calcium salts), squalene synthase inhibitors, And ACAT inhibitors.
  • HMG-CoA reductase inhibitors eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, rosuvastatin or their sodium or calcium salts
  • squalene synthase inhibitors eg, squalene synthase inhibitors, And ACAT inhibitors.
  • Antihypertensive agents include angiotensin-converting enzyme inhibitors (eg, captopril, enalapril, alacepril, delapril, lizinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, etc.), angiotensin II antagonists (eg, olmesartan medoxomilrexilmil, candesalcimilrexilmil) Losartan, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, azilsartan, etc.), calcium antagonists (eg, nicardipine hydrochloride, manidipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, amlodipine etc.), ACE / NEP inhibitors (eg, omapa
  • anti-obesity agents examples include central anti-obesity agents (eg, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, SR-141716A, etc.), pancreatic lipase inhibitors (eg, orlistat, etc.), peptide anorectic agents (Eg, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynchtrypto, FPL-15849, etc.) and the like.
  • central anti-obesity agents eg, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, SR-141716A, etc.
  • pancreatic lipase inhibitors eg, orlistat, etc.
  • peptide anorectic agents Eg, leptin, CNTF (ciliary neurotrophic factor), etc.
  • diuretics examples include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide.
  • xanthine derivatives eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.
  • thiazide preparations eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide.
  • the above concomitant drugs may be used in combination of two or more at an appropriate ratio.
  • the amount of these drugs used can be reduced within a safe range considering the side effects of the drug. Therefore, side effects that may be caused by these drugs can be safely prevented.
  • Example 1 (3-endo) -3- (Pyridin-2-yloxy) -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1] octane-8-carboxamide (3-endo) -3- (pyridin-2-yloxy) -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1] octane-8-carboxamide
  • Example 27 Methyl 4-[((3-endo) -8- ⁇ [(2,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) oxy] benzoate Methyl 4-[((3-endo) -8- ⁇ [(2,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) oxy] benzoate
  • Example 28 4-[((3-endo) -8- ⁇ [(2,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) oxy] benzoic acid 4-[((3-endo) -8- ⁇ [(2,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) oxy] benzoic acid
  • Example 29 4-[((3-endo) -8- ⁇ [(3,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) oxy] benzoic acid 4-[((3-endo) -8- ⁇ [(3,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) oxy] benzoic acid
  • Example 30 ⁇ 4-[((3-endo) -8- ⁇ [(2,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) thio] phenyl ⁇ acetic acid ⁇ 4-[((3-endo) -8- ⁇ [(2,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) thio] phenyl ⁇ acetic acid
  • Methanesulfonyl chloride (1.39 ml) was slowly added to a solution of the compound obtained in Reference Example 11 (3.4 g) and triethylamine (3.14 ml) in tetrahydrofuran (35 ml) at 0 ° C. After stirring at 0 ° C. for 1 hour, saturated brine and ethyl acetate were added. Subsequently, extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (4.8 g).
  • Example 31 (3-endo) -3- [4-cyano-2- (trifluoromethyl) phenoxy] -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1] octane-8-carboxamide (3-endo) -3- [4-cyano-2- (trifluoromethyl) phenoxy] -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1] octane-8-carboxamide
  • Example 32 (3-endo) -3- [4- (Aminomethyl) -2- (trifluoromethyl) phenoxy] -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1] octane-8 -Carboxamide (3-endo) -3- [4- (aminomethyl) -2- (trifluoromethyl) phenoxy] -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1] octane-8-carboxamide
  • Example 33 (3-endo) -3- [4-[(acetylmino) methyl] -2- (trifluoromethyl) phenoxy] -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1] octane -8-carboxamide (3-endo) -3- [4-[(acetylamino) methyl] -2- (trifluoromethyl) phenoxy] -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1] octane-8-carboxamide
  • Example 34 (3-endo) -3- [4- ⁇ [(Methylsulfonyl) amino] methyl ⁇ -2- (trifluoromethyl) phenoxy] -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2 .1]
  • Octane-8-carboxamide (3-endo) -3- [4- ⁇ [(methylsulfonyl) amino] methyl ⁇ -2- (trifluoromethyl) phenoxy] -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1] octane- 8-carboxamide
  • Example 35 Ethyl (2E) -3- ⁇ 4-[((3-endo) -8- ⁇ [(2,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) oxy ] -3-Fluorophenyl ⁇ acrylate ethyl (2E) -3- ⁇ 4-[((3-endo) -8- ⁇ [(2,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) oxy] -3-fluorophenyl ⁇ acrylate
  • reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (771 mg).
  • Example 36 (2E) -3- ⁇ 4-[((3-endo) -8- ⁇ [(2,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) oxy] -3-Fluorophenyl ⁇ acrylic acid (2E) -3- ⁇ 4-[((3-endo) -8- ⁇ [(2,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) oxy]- 3-fluorophenyl ⁇ acrylic acid
  • Example 37 3- ⁇ 4-[((3-endo) -8- ⁇ [(2,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) oxy] -3-fluoro Phenyl ⁇ propanoic acid 3- ⁇ 4-[((3-endo) -8- ⁇ [(2,4-dichlorobenzyl) amino] carbonyl ⁇ -8-azabicyclo [3.2.1] oct-3-yl) oxy] -3-fluorophenyl ⁇ propanoic acid
  • Examples 38-55 The following compounds were obtained in the same manner as in Examples 27, 28 and 37.
  • Examples 74-83 The following compounds were obtained in the same manner as in Examples 27, 28 and 37.
  • Examples 84-92 The following compounds were obtained in the same manner as in Examples 27 and 28.
  • Examples 93-124 The following compounds were obtained using commercially available reagents and corresponding aldehydes by methods similar to those described in literature (for example, see J. Org. Chem. 61, 3849 (1996), etc.).
  • Examples 125-131 The following compounds were obtained using commercially available reagents and corresponding aldehydes by methods similar to those described in literature (for example, see J. Org. Chem. 61, 3849 (1996), etc.).
  • Examples 132-164 The following compounds were obtained in the same manner as in Examples 28 and 304.
  • Examples 165-184 The following compounds were obtained in the same manner as in Examples 28 and 304.
  • Examples 185-223 The following compounds were obtained in the same manner as in Examples 28 and 304 using Reference Examples 20, 21, 24, 26, 30, 32, and commercially available reagents.
  • Trichlorosilane (452 ⁇ l) was added to a toluene (4 ml) solution of 2-chloro-4-methanesulfonylbenzaldehyde (500 mg), tert-butyl carbamate (247 mg), and trifluoroacetic acid (313 ⁇ l) at room temperature, and stirred for 2 hours. Ethyl acetate was added to the reaction solution, and the solid was collected by filtration and washed with ethyl acetate. The obtained solid was dried under reduced pressure at 40 ° C. to give the title compound (457 mg).
  • Acetic anhydride (437 mg) was added to a solution of the compound of Reference Example 21 (1.0 g) in pyridine (10 ml) at room temperature and stirred for 4 hours. The reaction was quenched with 1N HCl and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the precipitated solid was triturated with hexane / ethyl acetate and collected by filtration. The obtained solid was dried under reduced pressure at 40 ° C. to obtain the title compound (760 mg).
  • Titanium tetraisopropoxide (1.60 ml) was added to a toluene (5 ml) solution of the compound of Reference Example 25 (600 mg) and tetramethyldisiloxane (952 ⁇ l), and the mixture was stirred at 60 ° C. for 18 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. 4M HCl / dioxane was added to the resulting residue, followed by concentration under reduced pressure to obtain the title compound (360 mg). MS (ESI +) 227 (M + +1).
  • Examples 224 to 252 The following compounds were obtained in the same manner as in Examples 28 and 304.
  • Examples 253 to 266 The following compounds were obtained in the same manner as in Examples 28, 267 and 304.
  • Example 267 (3-endo) -3- [4- (5-tetrazolyl) -2- (trifluoromethyl) phenoxy] -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1] octane- 8-carboxamide (3-endo) -3- [4- (tetrazolyl) -2- (trifluoromethyl) phenoxy] -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1] octane-8-carboxamide
  • Example 31 A solution of the compound obtained in Example 31 (120 mg), trimethylsilyl azide (86 mg) and dibutyltin oxide (18 mg) in toluene (3 ml) was stirred at 120 ° C. for 17 hours. Methanol was added to the reaction mixture and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (46 mg).
  • Examples 268-277 The following compounds were obtained in the same manner as in Examples 28, 267 and 304.
  • Example 280 (3-Chloro-4- ⁇ [(3-endo) -8- ⁇ [(1S * , 2R * )-2- (2-chlorophenyl) cyclopropyl] carbamoyl ⁇ -8-azabicyclo [3.2.1] octa- 3-yl] oxy ⁇ phenyl) acetic acid (3-chloro-4- ⁇ [(3-endo) -8- ⁇ [(1S * , 2R * ) -2- (2-chlorophenyl) cyclopropyl] carbamoyl ⁇ -8-azabicyclo [3.2.1] oct-3 -yl] oxy ⁇ phenyl) acetic acid
  • Triethylamine (109 ⁇ l) and diphenylphosphoric acid azide (73 ⁇ l) were added to a toluene (2 ml) solution of the compound of Reference Example 35 (60 mg) and stirred at 100 ° C. for 2 hours to prepare the compound of Reference Example 43. It was then cooled to room temperature and used in subsequent reactions without purification.
  • Examples 281 to 303 The following compounds were obtained in the same manner as in Examples 27 and 280 using Reference Examples 33, 34, 35, and 36 and commercially available reagents.
  • Example 304 Ethyl [3-chloro-4-( ⁇ (3-endo) -8-[(4-chloro-2-fluorobenzyl) carbamoyl] -8-azabicyclo [3.2.1] oct-3-yl ⁇ oxy) phenyl] acetate ethyl [3-chloro-4-( ⁇ (3-endo) -8-[(4-chloro-2-fluorobenzyl) carbamoyl] -8-azabicyclo [3.2.1] oct-3-yl ⁇ oxy) phenyl]] acetate
  • N-dimethylformamide 300 ml was added 1,1′-carbonyldiimidazole (7.48 g) and triethylamine (6.18 g) at 25 ° C. . After stirring at the same temperature for 3 days, water was added to the reaction solution, followed by extraction with ethyl acetate, followed by washing with saturated brine, drying over sodium sulfate, and filtration. The filtrate was concentrated under reduced pressure to give the title compound (10.7 g).
  • Example 305 Ethyl [3-chloro-4-( ⁇ (3-endo) -9-[(2,4-dichlorobenzyl) carbamoyl] -9-azabicyclo [3.3.1] non-3-yl ⁇ oxy) phenyl] acetate ethyl [3-chloro-4-( ⁇ (3-endo) -9-[(2,4-dichlorobenzyl) carbamoyl] -9-azabicyclo [3.3.1] non-3-yl ⁇ oxy) phenyl] acetate
  • Example 306 [3-Chloro-4-( ⁇ (3-endo) -9-[(2,4-dichlorobenzyl) carbamoyl] -9-azabicyclo [3.3.1] non-3-yl ⁇ oxy) phenyl] acetec acid [[3-chloro-4-( ⁇ (3-endo) -9-[(2,4-dichlorobenzyl) carbamoyl] -9-azabicyclo [3.3.1] non-3-yl ⁇ oxy) phenyl] acetic acid
  • Example 307 (3-endo) -3- (2-methoxy-4- ⁇ 2-[(methylsulfonyl) amino] -2-oxoethyl ⁇ phenoxy) -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [ 3.2.1]
  • Octane-8-carboxamide (3-endo) -3- (2-methoxy-4- ⁇ 2-[(methylsulfonyl) amino] -2-oxoethyl ⁇ phenoxy) -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1 ] octane-8-carboxamide
  • Carbodiimidazole (31 mg) was added to a solution of the compound of Example 280 (60 mg) in THF (2 ml), and the mixture was stirred at 70 ° C. for 1 hour. After cooling to room temperature, methanesulfonamide (15 mg) and diazabicycloundecene (28 ⁇ l) were added and stirred for 3 days. A 5% KHSO 4 aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (68 mg).
  • Example 308 (3-endo) -3- (2-methoxy-4- ⁇ 2-[(methylsulfonyl) amino] -2-oxoethyl ⁇ phenoxy) -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [ 3.2.1]
  • Octane-8-carboxamide (3-endo) -3- (2-methoxy-4- ⁇ 2-[(methylsulfonyl) amino] -2-oxoethyl ⁇ phenoxy) -N- [4- (trifluoromethyl) phenyl] -8-azabicyclo [3.2.1 ] octane-8-carboxamide
  • Example 309 (3-endo) -3- (2-chloro-4- ⁇ 2-[(methylsulfonyl) amino] -2-oxoethyl ⁇ phenoxy) -N- (2,4-dichlorobenzyl) -8-azabicyclo [3.2. 1]
  • Octane-8-carboxamide (3-endo) -3- (2-chloro-4- ⁇ 2-[(methylsulfonyl) amino] -2-oxoethyl ⁇ phenoxy) -N- (2,4-dichlorobenzyl) -8-azabicyclo [3.2.1] octane-8-carboxamide
  • Pharmacological test example in vitro sEH inhibitory activity measurement test
  • Recombinant human sEH was obtained by purifying a protein obtained by fusing human sEH and maltose-binding protein expressed in Escherichia coli and used in the experiment.
  • 60 ng of recombinant human sEH was reacted with a substrate and a test compound for 1 hour at 25 ° C. in 25 mM Bis-Tris buffer pH 7.0 containing 0.1 mg / mL BSA.
  • Epoxy Fluor 7 (Cayman Chemical) was added to a final concentration of 25 ⁇ M.
  • An increase in fluorescence intensity at an excitation wavelength of 330 nm and a fluorescence wavelength of 465 nm was detected using a fluorescence plate reader, and the enzyme inhibitory activity when the test compound was added was calculated.
  • the compound of the present invention is useful for the prevention and / or treatment of various diseases (for example, hypertension) because of its inhibitory action on soluble epoxide hydrolase (sEH).
  • various diseases for example, hypertension

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Abstract

L'invention concerne un dérivé d'urée bicyclique inhibant l'époxyde hydrolase soluble (sEH), représenté par la formule (I), y compris un sel pharmaceutiquement acceptable correspondant. Dans cette formule, R1 est un groupe cycloalkyle C3-9 substituable, un groupe aryle C6-10 substituable, ou autre; R2a et R2b sont chacun indépendamment un atome d'hydrogène ou autre; m vaut 0, 1, ou autre; et la chaîne A est représentée par la formule (a) ou autre (dans cette formule, R3a, R3b, et R3c sont chacun indépendamment un atome d'hydrogène ou autre et peuvent être identiques ou différents, et n vaut 0 ou autre).
PCT/JP2010/063945 2009-08-19 2010-08-18 Dérivé d'urée bicyclique ou sel pharmaceutiquement acceptable correspondant WO2011021645A1 (fr)

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WO2015092610A1 (fr) * 2013-12-20 2015-06-25 Pfizer Limited Inhibiteurs de kinase apparentés à la n-acylpipéridine éther tropomyosine
WO2018081285A1 (fr) * 2016-10-26 2018-05-03 Enanta Pharmaceuticals, Inc. Dérivés d'isoxazole contenant de l'urée utilisés comme agonistes de fxr et leurs procédés d'utilisation
US10080741B2 (en) 2016-04-26 2018-09-25 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US10080743B2 (en) 2016-04-26 2018-09-25 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US10080742B2 (en) 2016-04-26 2018-09-25 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US10138228B2 (en) 2016-05-18 2018-11-27 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use therof
US10144729B2 (en) 2016-05-18 2018-12-04 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10149835B2 (en) 2016-05-18 2018-12-11 Elmore Patent Law Group, P.C. Isoxazole derivatives as FXR agonists and methods of use thereof
CN109575022A (zh) * 2017-12-25 2019-04-05 成都海博锐药业有限公司 一种化合物及其用途
US10450306B2 (en) 2016-10-04 2019-10-22 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
JP2020506878A (ja) * 2016-12-15 2020-03-05 小野薬品工業株式会社 Ｔｒｅｋ（ｔｗｉｋ関連ｋチャネル）チャネルのアクチベータ
US10689391B2 (en) 2017-12-12 2020-06-23 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10829486B2 (en) 2018-02-14 2020-11-10 Enanta Pharmacueticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
WO2021055630A1 (fr) * 2019-09-17 2021-03-25 Bial- Biotech Investments, Inc. Carboxamides n-hétérocycliques substitués, saturés et insaturés et composés apparentés pour leur utilisation dans le traitement de troubles médicaux
WO2022221493A1 (fr) * 2021-04-14 2022-10-20 Neuropn Therapeutics, Llc Dérivés d'urée de pipéridine utilisés en tant qu'inhibiteurs d'époxyde hydrolase soluble
US11555032B2 (en) 2019-05-13 2023-01-17 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US11958879B2 (en) 2015-03-31 2024-04-16 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US11998538B2 (en) 2022-04-14 2024-06-04 Neuropn Therapeutics Piperidine urea derivatives as soluble epoxide hydrolase inhibitors

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JP2007502324A (ja) * 2003-05-06 2007-02-08 アベンティス・ファーマスーティカルズ・インコーポレイテツド Ｐ３８キナーゼの阻害剤および／または炎症治療のためのｔｎｆ阻害剤としての１−（２ｈ−ピラゾール−３−イル）−３−｛４−［１−（ベンゾイル）−ピペリジン−４−イルメチル］−フェニル｝−ウレア誘導体および関連化合物
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015092610A1 (fr) * 2013-12-20 2015-06-25 Pfizer Limited Inhibiteurs de kinase apparentés à la n-acylpipéridine éther tropomyosine
US11958879B2 (en) 2015-03-31 2024-04-16 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US10080741B2 (en) 2016-04-26 2018-09-25 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US10080743B2 (en) 2016-04-26 2018-09-25 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US10080742B2 (en) 2016-04-26 2018-09-25 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US10138228B2 (en) 2016-05-18 2018-11-27 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use therof
US10144729B2 (en) 2016-05-18 2018-12-04 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10149835B2 (en) 2016-05-18 2018-12-11 Elmore Patent Law Group, P.C. Isoxazole derivatives as FXR agonists and methods of use thereof
US11034684B2 (en) 2016-10-04 2021-06-15 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10450306B2 (en) 2016-10-04 2019-10-22 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10597391B2 (en) 2016-10-26 2020-03-24 Enanta Pharmaceuticals, Inc. Urea-containing isoxazole derivatives as FXR agonists and methods of use thereof
WO2018081285A1 (fr) * 2016-10-26 2018-05-03 Enanta Pharmaceuticals, Inc. Dérivés d'isoxazole contenant de l'urée utilisés comme agonistes de fxr et leurs procédés d'utilisation
JP7120549B2 (ja) 2016-12-15 2022-08-17 小野薬品工業株式会社 Ｔｒｅｋ（ｔｗｉｋ関連ｋチャネル）チャネルのアクチベータ
JP2020506878A (ja) * 2016-12-15 2020-03-05 小野薬品工業株式会社 Ｔｒｅｋ（ｔｗｉｋ関連ｋチャネル）チャネルのアクチベータ
US11851428B2 (en) 2016-12-15 2023-12-26 Ono Pharmaceutical Co., Ltd. Activator of TREK (TWIK RElated K+channels) channels
US10689391B2 (en) 2017-12-12 2020-06-23 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
CN109575022A (zh) * 2017-12-25 2019-04-05 成都海博锐药业有限公司 一种化合物及其用途
CN109575022B (zh) * 2017-12-25 2021-09-21 成都海博锐药业有限公司 一种化合物及其用途
US10829486B2 (en) 2018-02-14 2020-11-10 Enanta Pharmacueticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
US11555032B2 (en) 2019-05-13 2023-01-17 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
WO2021055630A1 (fr) * 2019-09-17 2021-03-25 Bial- Biotech Investments, Inc. Carboxamides n-hétérocycliques substitués, saturés et insaturés et composés apparentés pour leur utilisation dans le traitement de troubles médicaux
WO2022221493A1 (fr) * 2021-04-14 2022-10-20 Neuropn Therapeutics, Llc Dérivés d'urée de pipéridine utilisés en tant qu'inhibiteurs d'époxyde hydrolase soluble
US11998538B2 (en) 2022-04-14 2024-06-04 Neuropn Therapeutics Piperidine urea derivatives as soluble epoxide hydrolase inhibitors

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