JPWO2021110883A5 - - Google Patents

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JPWO2021110883A5
JPWO2021110883A5 JP2022532832A JP2022532832A JPWO2021110883A5 JP WO2021110883 A5 JPWO2021110883 A5 JP WO2021110883A5 JP 2022532832 A JP2022532832 A JP 2022532832A JP 2022532832 A JP2022532832 A JP 2022532832A JP WO2021110883 A5 JPWO2021110883 A5 JP WO2021110883A5
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Prior art keywords
tetrahydro
oxy
dioxide
butyl
methylthio
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JP2022532832A
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Japanese (ja)
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JP2023504645A (en
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Priority claimed from PCT/EP2020/084567 external-priority patent/WO2021110883A1/en
Publication of JP2023504645A publication Critical patent/JP2023504645A/en
Publication of JPWO2021110883A5 publication Critical patent/JPWO2021110883A5/ja
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Claims (15)

式(I)の化合物
(式中、
Mは、-CH2-及び-NR7-から選択され;
R1は、C1～4アルキルであり;
R2は独立に、水素、ハロゲン、ヒドロキシ、C1～4アルキル、C1～4ハロアルキル、C1～4アルコキシ、シアノ、ニトロ、アミノ、N-(C1～4アルキル)アミノ、N,N-ジ(C1～4アルキル)-アミノ、N-(アリール-C1～4アルキル)アミノ、C1～6アルキルカルボニルアミノ、C3～6シクロアルキルカルボニルアミノ、N-(C1～4アルキル)アミノカルボニル、N,N-ジ(C1～4アルキル)アミノカルボニル、C1～4アルキルオキシカルボニルアミノ、C3～6シクロアルキルオキシカルボニルアミノ、C1～4アルキルスルホンアミド、及びC3～6シクロアルキルスルホンアミドからなる群から選択され;
nは、1、2、又は3の整数であり;
R3は、水素、ハロゲン、シアノ、C1～4アルキル、C3～6シクロアルキル、C1～4アルコキシ、C3～6シクロアルキルオキシ、C1～4アルキルチオ、C3～6シクロアルキルチオ、アミノ、N-(C1～4アルキル)アミノ、及びN,N-ジ(C1～4アルキル)アミノからなる群から選択され;
R4及びR5の一方はカルボキシルであり、R4及びR5の他方は、水素、フルオロ、C1～4アルキル、及びC1～4ハロアルキルからなる群から選択され;
R6は、水素及びC1～4アルキルからなる群から選択され;
R7は、水素及びC1～4アルキルからなる群から選択される)
又は医薬として許容されるその塩。 Compound of formula (I)
(In the formula,
M is selected from -CH2- and -NR7- ;
R 1 is C 1-4 alkyl;
R 2 is independently hydrogen, halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, cyano, nitro, amino, N-(C 1-4 alkyl)amino, N,N -di(C 1-4 alkyl)-amino, N-(aryl- C 1-4 alkyl)amino, C 1-6 alkylcarbonylamino, C 3-6 cycloalkylcarbonylamino, N-(C 1-4 alkyl) )aminocarbonyl, N,N-di(C 1-4 alkyl)aminocarbonyl, C 1-4 alkyloxycarbonylamino, C 3-6 cycloalkyloxycarbonylamino, C 1-4 alkylsulfonamide, and C 3-4 selected from the group consisting of 6 cycloalkylsulfonamides;
n is an integer of 1, 2, or 3;
R 3 is hydrogen, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 1-4 alkylthio, C 3-6 cycloalkylthio, selected from the group consisting of amino, N-(C 1-4 alkyl)amino, and N,N-di(C 1-4 alkyl)amino;
one of R 4 and R 5 is carboxyl, and the other of R 4 and R 5 is selected from the group consisting of hydrogen, fluoro, C 1-4 alkyl, and C 1-4 haloalkyl;
R 6 is selected from the group consisting of hydrogen and C 1-4 alkyl;
R 7 is selected from the group consisting of hydrogen and C 1-4 alkyl)
or a pharmaceutically acceptable salt thereof. R1がC2～4アルキルである、請求項1に記載の化合物。 2. A compound according to claim 1, wherein R 1 is C 2-4 alkyl. R1がn-ブチルである、請求項1又は2に記載の化合物。 3. A compound according to claim 1 or 2, wherein R 1 is n-butyl. R2が独立に、水素、フルオロ、クロロ、ブロモ、ヒドロキシ、メトキシ、アミノ、メチルアミノ、ジメチルアミノ、イソプロピルカルボニルアミノ、tert-ブチルカルボニルアミノ、tert-ブチルアミノカルボニル、tert-ブトキシカルボニルアミノ、メチルスルホンアミド、及びシクロプロピルスルホンアミドからなる群から選択される、請求項1から3のいずれか一項に記載の化合物。 R 2 is independently hydrogen, fluoro, chloro, bromo, hydroxy, methoxy, amino, methylamino, dimethylamino, isopropylcarbonylamino, tert-butylcarbonylamino, tert-butylaminocarbonyl, tert-butoxycarbonylamino, methylsulfone 4. A compound according to any one of claims 1 to 3, selected from the group consisting of amide, and cyclopropylsulfonamide. R3が、水素、フルオロ、クロロ、ブロモ、メチル、シクロプロピル、メトキシ、エトキシ、メチルチオ、エチルチオ、アミノ、メチルアミノ、及びジメチルアミノからなる群から選択される、請求項1から4のいずれか一項に記載の化合物。 Any one of claims 1 to 4, wherein R 3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, cyclopropyl, methoxy, ethoxy, methylthio, ethylthio, amino, methylamino, and dimethylamino. Compounds described in Section. R4が水素又はフルオロである、請求項1から5のいずれか一項に記載の化合物。 6. A compound according to any one of claims 1 to 5, wherein R4 is hydrogen or fluoro. R5がカルボキシルである、請求項1から6のいずれか一項に記載の化合物。 7. A compound according to any one of claims 1 to 6, wherein R5 is carboxyl. R6が水素である、請求項1から7のいずれか一項に記載の化合物。 8. A compound according to any one of claims 1 to 7, wherein R 6 is hydrogen. (E)-3-((3-ブチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)アクリル酸;
(R)-(E)-3-((3-ブチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)アクリル酸;
(S)-(E)-3-((3-ブチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)アクリル酸;
(Z)-3-((3-ブチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(S)-(Z)-3-((3-ブチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(R)-(Z)-3-((3-ブチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(Z)-3-((3-エチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(E)-3-((3-エチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)アクリル酸;
(E)-3-((3-ブチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(Z)-3-((3-ブチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(Z)-3-((3-ブチル-2-メチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(S)-(Z)-3-((3-ブチル-2-メチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(R)-(Z)-3-((3-ブチル-2-メチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(E)-3-((3-ブチル-2-メチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(S)-(E)-3-((3-ブチル-2-メチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(R)-(E)-3-((3-ブチル-2-メチル-7-(メチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(E)-3-((3-ブチル-7-(エチルチオ)-2-メチル-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(S)-(E)-3-((3-ブチル-7-(エチルチオ)-2-メチル-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(R)-(E)-3-((3-ブチル-7-(エチルチオ)-2-メチル-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(E)-3-((3-ブチル-5-(4-フルオロフェニル)-2-メチル-7-(メチルチオ)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(S)-(E)-3-((3-ブチル-5-(4-フルオロフェニル)-2-メチル-7-(メチルチオ)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(R)-(E)-3-((3-ブチル-5-(4-フルオロフェニル)-2-メチル-7-(メチルチオ)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(E)-3-((3-ブチル-7-(エチルチオ)-5-(4-フルオロフェニル)-2-メチル-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(S)-(E)-3-((3-ブチル-7-(エチルチオ)-5-(4-フルオロフェニル)-2-メチル-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(R)-(E)-3-((3-ブチル-7-(エチルチオ)-5-(4-フルオロフェニル)-2-メチル-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(E)-3-((3-ブチル-5-(4-フルオロフェニル)-7-(メチルチオ)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)アクリル酸;
(S)-(E)-3-((3-ブチル-5-(4-フルオロフェニル)-7-(メチルチオ)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)アクリル酸;
(R)-(E)-3-((3-ブチル-5-(4-フルオロフェニル)-7-(メチルチオ)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)アクリル酸;
(E)-3-((3-ブチル-5-(4-フルオロフェニル)-7-(メチルチオ)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(E)-3-((3-ブチル-7-(エチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)アクリル酸;
(E)-3-((3-ブチル-7-(エチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
(E)-3-((3-ブチル-7-(エチルチオ)-5-(4-フルオロフェニル)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)アクリル酸;
(Z)-3-((3-ブチル-5-(4-フルオロフェニル)-7-(メチルチオ)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(Z)-3-((3-ブチル-7-(エチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(Z)-3-((3-ブチル-7-(エチルチオ)-5-(4-フルオロフェニル)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,5-ベンゾチアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(Z)-3-((3-ブチル-5-(4-フルオロフェニル)-2-メチル-7-(メチルチオ)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(Z)-3-((3-ブチル-7-(エチルチオ)-5-(4-フルオロフェニル)-2-メチル-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(Z)-3-((3-ブチル-7-(エチルチオ)-2-メチル-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(Z)-3-((3-ブチル-5-(4-フルオロフェニル)-7-(メチルチオ)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(Z)-3-((3-ブチル-7-(エチルチオ)-1,1-ジオキシド-5-フェニル-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;
(Z)-3-((3-ブチル-7-(エチルチオ)-5-(4-フルオロフェニル)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)-2-フルオロアクリル酸;及び
(E)-3-((3-ブチル-7-(エチルチオ)-5-(4-フルオロフェニル)-1,1-ジオキシド-2,3,4,5-テトラヒドロ-1,2,5-ベンゾチアジアゼピン-8-イル)オキシ)アクリル酸;
からなる群から選択される、請求項1に記載の化合物又は医薬として許容されるその塩。 (E)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl) oxy)acrylic acid;
(R)-(E)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine- 8-yl)oxy)acrylic acid;
(S)-(E)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine- 8-yl)oxy)acrylic acid;
(Z)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl) oxy)-2-fluoroacrylic acid;
(S)-(Z)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine- 8-yl)oxy)-2-fluoroacrylic acid;
(R)-(Z)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine- 8-yl)oxy)-2-fluoroacrylic acid;
(Z)-3-((3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl) oxy)-2-fluoroacrylic acid;
(E)-3-((3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl) oxy)acrylic acid;
(E)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8 -yl)oxy)acrylic acid;
(Z)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8 -yl)oxy)-2-fluoroacrylic acid;
(Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothi Asiazepin-8-yl)oxy)-2-fluoroacrylic acid;
(S)-(Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2, 5-benzothiadiazepin-8-yl)oxy)-2-fluoroacrylic acid;
(R)-(Z)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2, 5-benzothiadiazepin-8-yl)oxy)-2-fluoroacrylic acid;
(E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothi Asiazepin-8-yl)oxy)acrylic acid;
(S)-(E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2, 5-benzothiadiazepin-8-yl)oxy)acrylic acid;
(R)-(E)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2, 5-benzothiadiazepin-8-yl)oxy)acrylic acid;
(E)-3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothi Asiazepin-8-yl)oxy)acrylic acid;
(S)-(E)-3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2, 5-benzothiadiazepin-8-yl)oxy)acrylic acid;
(R)-(E)-3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2, 5-benzothiadiazepin-8-yl)oxy)acrylic acid;
(E)-3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2 ,5-benzothiadiazepin-8-yl)oxy)acrylic acid;
(S)-(E)-3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro -1,2,5-benzothiadiazepin-8-yl)oxy)acrylic acid;
(R)-(E)-3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro -1,2,5-benzothiadiazepin-8-yl)oxy)acrylic acid;
(E)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2 ,5-benzothiadiazepin-8-yl)oxy)acrylic acid;
(S)-(E)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro -1,2,5-benzothiadiazepin-8-yl)oxy)acrylic acid;
(R)-(E)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro -1,2,5-benzothiadiazepin-8-yl)oxy)acrylic acid;
(E)-3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine -8-yl)oxy)acrylic acid;
(S)-(E)-3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5 -benzothiazepin-8-yl)oxy)acrylic acid;
(R)-(E)-3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5 -benzothiazepin-8-yl)oxy)acrylic acid;
(E)-3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzo Thiadiazepin-8-yl)oxy)acrylic acid;
(E)-3-((3-butyl-7-(ethylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl) oxy)acrylic acid;
(E)-3-((3-butyl-7-(ethylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8 -yl)oxy)acrylic acid;
(E)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine -8-yl)oxy)acrylic acid;
(Z)-3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine -8-yl)oxy)-2-fluoroacrylic acid;
(Z)-3-((3-butyl-7-(ethylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl) oxy)-2-fluoroacrylic acid;
(Z)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine -8-yl)oxy)-2-fluoroacrylic acid;
(Z)-3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2 ,5-benzothiadiazepin-8-yl)oxy)-2-fluoroacrylic acid;
(Z)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2 ,5-benzothiadiazepin-8-yl)oxy)-2-fluoroacrylic acid;
(Z)-3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothi Asiazepin-8-yl)oxy)-2-fluoroacrylic acid;
(Z)-3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzo Thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid;
(Z)-3-((3-butyl-7-(ethylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8 -yl)oxy)-2-fluoroacrylic acid;
(Z)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzo Thiadiazepin-8-yl)oxy)-2-fluoroacrylic acid; and
(E)-3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzo Thiadiazepin-8-yl)oxy)acrylic acid;
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 治療的有効量の請求項1から9のいずれか一項に記載の化合物と、1つ又は複数の医薬として許容される賦形剤とを含む医薬組成物。 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9 and one or more pharmaceutically acceptable excipients. 請求項1から9のいずれか一項に記載の化合物を含む医薬。 A medicament comprising a compound according to any one of claims 1 to 9. 循環器疾患又は脂肪酸代謝の障害又はグルコース利用障害、例えば、高コレステロール血症;脂肪酸代謝の障害;1型及び2型真性糖尿病;糖尿病の合併症、例えば、白内障、細小及び大血管疾患、網膜症、神経障害、腎症、及び創傷治癒の遅延、組織虚血、糖尿病性足病変、動脈硬化症、心筋梗塞、急性冠症候群、不安定狭心症、安定狭心症、脳卒中、末梢動脈閉塞性疾患、心筋症、心不全、心拍障害、及び血管再狭窄;糖尿病関連疾患、例えば、インスリン抵抗性(グルコース恒常性の障害)、高血糖、高インスリン血症、脂肪酸又はグリセロールの血中レベルの上昇、肥満、脂質異常症、高脂血症、例えば、高トリグリセリド血症、メタボリック症候群(X症候群)、アテローム性動脈硬化症、及び高血圧;並びに高密度リポタンパク質レベルの増加の治療又は予防に使用するための、請求項11に記載の医薬。 Cardiovascular diseases or disorders of fatty acid metabolism or glucose utilization, e.g. hypercholesterolemia; disorders of fatty acid metabolism; type 1 and type 2 diabetes mellitus; complications of diabetes, e.g. cataracts, small and macrovascular disease, retinopathy , neuropathy, nephropathy, and delayed wound healing, tissue ischemia, diabetic foot lesions, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral artery occlusive disease. diseases, cardiomyopathy, heart failure, heart rate disorders, and vascular restenosis; diabetes-related diseases, such as insulin resistance (disturbance of glucose homeostasis), hyperglycemia, hyperinsulinemia, increased blood levels of fatty acids or glycerol; For use in the treatment or prevention of obesity, dyslipidemia, hyperlipidemia, such as hypertriglyceridemia, metabolic syndrome (Syndrome X), atherosclerosis, and hypertension; and increased levels of high-density lipoproteins. 12. The medicament according to claim 11 . 胃腸疾患又は障害、例えば、便秘(慢性便秘、機能性便秘、慢性特発性便秘(CIC)、断続的/散発性便秘、真性糖尿病に続発する便秘、脳卒中に続発する便秘、慢性腎臓病に続発する便秘、多発性硬化症に続発する便秘、パーキンソン病に続発する便秘、全身性硬化症に続発する便秘、薬物性便秘、便秘型過敏性腸症候群(IBS-C)、混合型過敏性腸症候群(IBS-M)、小児機能性便秘、及びオピオイド誘発性便秘が含まれる);クローン病;一次胆汁酸吸収不良;過敏性腸症候群(IBS);炎症性腸疾患(IBD);回腸の炎症;並びに逆流症及びその合併症、例えば、バレット食道、胆汁逆流食道炎、及び胆汁逆流胃炎の治療又は予防に使用するための、請求項11に記載の医薬。 Gastrointestinal diseases or disorders, such as constipation (chronic constipation, functional constipation, chronic idiopathic constipation (CIC), intermittent/sporadic constipation, constipation secondary to diabetes mellitus, constipation secondary to stroke, secondary to chronic kidney disease) Constipation, constipation secondary to multiple sclerosis, constipation secondary to Parkinson's disease, constipation secondary to systemic sclerosis, drug-induced constipation, constipation-type irritable bowel syndrome (IBS-C), mixed type irritable bowel syndrome ( Crohn's disease; primary bile acid malabsorption; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); ileal inflammation; and 12. The medicament according to claim 11 , for use in the treatment or prevention of reflux disease and its complications, such as Barrett's esophagus, bile reflux esophagitis, and bile reflux gastritis. 肝疾患若しくは障害、例えば、肝臓の遺伝性代謝障害;胆汁酸合成の先天性異常;先天性胆管走行異常;胆道閉鎖;葛西手術後の胆道閉鎖;肝臓移植後の胆道閉鎖;新生児肝炎;新生児胆汁うっ滞;遺伝形式の胆汁うっ滞;脳腱黄色腫症;BA合成の二次的欠陥;ツェルウェガー症候群;嚢胞性線維症に関連する肝疾患;α1アンチトリプシン欠損症;アラジール症候群(ALGS);バイラー症候群;胆汁酸(BA)合成の一次的欠陥;進行性家族性肝内胆汁うっ滞(PFIC)、例えば、PFIC-1、PFIC-2、PFIC-3、及び非特定PFIC、胆汁分流後のPFIC、並びに肝臓移植後のPFIC;良性反復性肝内胆汁うっ滞(BRIC)、例えば、BRIC1、BRIC2、及び非特定BRIC、胆汁分流後のBRIC、並びに肝臓移植後のBRIC;自己免疫性肝炎;原発性胆汁性肝硬変(PBC);肝線維症;非アルコール性脂肪性肝疾患(NAFLD);非アルコール性脂肪性肝炎(NASH);門脈圧亢進症;胆汁うっ滞;ダウン症候群の胆汁うっ滞;薬物性胆汁うっ滞;妊娠の肝内胆汁うっ滞(妊娠中の黄疸);肝内胆汁うっ滞;肝外胆汁うっ滞;経静脈栄養に関連する胆汁うっ滞(PNAC);低リン脂質に関連する胆汁うっ滞;リンパ浮腫胆汁うっ滞症候群1(LSC1);原発性硬化性胆管炎(PSC);免疫グロブリンG4に関連する胆管炎;原発性胆汁性胆管炎;胆石症(胆石);胆道結石症(biliary lithiasis);総胆管結石症;胆石性膵炎;カロリー病;胆管の悪性腫瘍;胆樹の閉塞を引き起こす悪性腫瘍;胆管狭窄;AIDS胆管症;虚血性胆管症;胆汁うっ滞若しくは黄疸によるそう痒;膵臓炎;進行性胆汁うっ滞に至る慢性自己免疫性肝疾患;肝脂肪変性;アルコール性肝炎;急性脂肪肝;妊娠の脂肪肝;薬物性肝炎;鉄過剰症;先天性胆汁酸代謝異常症1型(BAS1型);薬物性肝障害(DILI);肝線維症;先天性肝線維症;肝硬変;ランゲルハンス細胞組織球症(LCH);新生児魚鱗癬硬化性胆管炎(NISCH);骨髄性プロトポルフィリン症(EPP);特発性成人胆管減少(IAD);突発性新生児肝炎(INH);非症候性肝内胆管減少症(NS PILBD);常染色体劣性遺伝性肝内胆汁うっ滞(North American Indian childhood cirrhosis)(NAIC);肝サルコイドーシス;アミロイドーシス;壊死性腸炎;血清中胆汁酸が引き起こす毒性、例えば、異常な血清中胆汁酸プロファイルの状況での心律動障害(例えば、心房細動)、肝硬変に関連する心筋症(「コレカルディア(cholecardia)」)、及び胆汁うっ滞性肝疾患に関連する骨格筋消耗;多発性肝嚢胞性疾患;ウイルス性肝炎(A型肝炎、B型肝炎、C型肝炎、D型肝炎、及びE型肝炎が含まれる);肝細胞癌(肝細胞腫);胆管癌;胆汁酸に関係する胃腸癌;並びに肝臓、胆道、及び膵臓の腫瘍及び新生物によって引き起こされる胆汁うっ滞の治療若しくは予防に使用するための;又は肝疾患におけるコルチコステロイド療法の増強に使用するための、請求項11に記載の医薬。 Liver diseases or disorders, such as inherited metabolic disorders of the liver; congenital abnormalities of bile acid synthesis; congenital bile duct abnormalities; biliary atresia; biliary atresia after Kasai surgery; biliary atresia after liver transplantation; neonatal hepatitis; neonatal bile Stasis; inherited forms of cholestasis; cerebrotendinous xanthomatosis; secondary defects in BA synthesis; Zellweger syndrome; liver disease associated with cystic fibrosis; α1-antitrypsin deficiency; Alagille syndrome (ALGS); Beiler Syndrome; primary defect in bile acid (BA) synthesis; progressive familial intrahepatic cholestasis (PFIC), e.g. PFIC-1, PFIC-2, PFIC-3, and unspecified PFIC, PFIC after biliary diversion , and PFIC after liver transplantation; benign recurrent intrahepatic cholestasis (BRIC), such as BRIC1, BRIC2, and unspecified BRIC, BRIC after bile diversion, and BRIC after liver transplantation; autoimmune hepatitis; primary biliary cirrhosis (PBC); liver fibrosis; nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); portal hypertension; cholestasis; cholestasis of Down syndrome; Drug-induced cholestasis; Intrahepatic cholestasis of pregnancy (jaundice in pregnancy); Intrahepatic cholestasis; Extrahepatic cholestasis; Parenteral nutrition-associated cholestasis (PNAC); Associated with hypophospholipids cholestasis; lymphedema cholestasis syndrome 1 (LSC1); primary sclerosing cholangitis (PSC); cholangitis associated with immunoglobulin G4; primary biliary cholangitis; cholelithiasis (gallstones); biliary stones biliary lithiasis; choledocholithiasis; gallstone pancreatitis; Calori disease; malignant tumor of the bile duct; malignant tumor causing obstruction of the bile tree; bile duct stricture; AIDS cholangiopathy; ischemic cholangiopathy; due to cholestasis or jaundice Pruritus; pancreatitis; chronic autoimmune liver disease leading to progressive cholestasis; hepatic steatosis; alcoholic hepatitis; acute fatty liver; fatty liver of pregnancy; drug-induced hepatitis; iron overload; congenital bile acid metabolism Abnormal disease type 1 (BAS type 1); drug-induced liver injury (DILI); liver fibrosis; congenital liver fibrosis; cirrhosis; Langerhans cell histiocytosis (LCH); neonatal ichthyosis sclerosing cholangitis (NISCH); bone marrow sexual protoporphyria (EPP); idiopathic adult bile duct deficiency (IAD); idiopathic neonatal hepatitis (INH); nonsyndromic intrahepatic bile duct deficiency (NS PILBD); autosomal recessive intrahepatic cholestasis (North American Indian childhood cirrhosis (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; serum bile acid-induced toxicity, e.g., cardiac rhythm disorders (e.g., atrial fibrillation) in the setting of abnormal serum bile acid profiles; Cardiomyopathy associated with liver cirrhosis (“cholecardia”) and skeletal muscle wasting associated with cholestatic liver disease; multifocal hepatic cystic disease; viral hepatitis (hepatitis A, hepatitis B, hepatitis C hepatocellular carcinoma (hepatoma); bile duct cancer; gastrointestinal cancers related to bile acids; and tumors and neoplasms of the liver, biliary tract, and pancreas. 12. A medicament according to claim 11 for use in the treatment or prevention of cholestasis; or for use in augmenting corticosteroid therapy in liver disease. 過吸収症候群(無βリポタンパク血症、家族性低βリポタンパク血症(FHBL)、カイロミクロン停滞病(CRD)、及びシトステロール血症が含まれる);ビタミン過剰症及び大理石骨病;高血圧;糸球体過剰濾過;多発性嚢胞腎(PKD)、例えば、常染色体優性多発性嚢胞腎(ADPKD)及び常染色体劣性多発性嚢胞腎(ARPKD);並びに腎不全のそう痒の治療若しくは予防に使用するための;又は肝臓若しくは代謝疾患に関連する腎臓傷害に対する保護に使用するための、請求項11に記載の医薬。 Hyperabsorption syndromes (including abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD), and sitosterolemia); hypervitaminosis and osteopetrosis; hypertension; Glomerular hyperfiltration; used in the treatment or prevention of polycystic kidney disease (PKD), such as autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD); and pruritus in renal failure. or for use in protection against kidney damage associated with liver or metabolic diseases .
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