阅读说明：本技术 用作血浆激肽释放酶抑制剂的双环烷类化合物 (Bicycloalkanes as plasma kallikrein inhibitors ) 是由 孙广龙 沈春莉 吴成德 陈曙辉 于 2020-04-22 设计创作，主要内容包括：属于医药领域,具体而言公开了式(I)化合物、其制备方法、含有该化合物的药物组合物、以及它们在制备治疗血浆激肽释放酶介导的相关疾病的药物的用途。(Belongs to the field of medicine, and is especially the compound of the formula (I), its preparation process, medicine composition containing the compound and their use in preparing medicine for treating plasma kallikrein mediated relevant diseases.)

A compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

E ₁、E ₂and E₃Are each independently selected from- (CH)₂) _n-；

Each n is independently 0,1 or 2;

ring A is selected from

T ₁、T ₂And T₃Are each independently selected from N and CR₆；

T ₄Selected from N and CR₇；

T ₅Selected from N and CR₈；

R ₁Is selected from C_1-6Alkyl radical, C_4-8Cycloalkyl, 5-6 membered heteroaryl and C_6-10Aryl radical, said C_1-6Alkyl radical, C_4-8Cycloalkyl, 5-6 membered heteroaryl and C_{6- 10}Aryl is optionally substituted by 1,2 or 3R_aSubstitution;

R ₂and R₃Are each independently selected from H and C_1-3An alkyl group;

R ₄selected from H, F, Cl, Br, I, OH, NH₂、C _1-3Alkyl and C_1-3Alkoxy, wherein said C_1-3Alkyl and C_1-3Alkoxy is optionally substituted by 1,2 or 3R_bSubstitution;

R ₅selected from H and C_1-3An alkyl group;

R ₆each independently selected from H, F, Cl, Br, I, OH, NH₂And C_1-3Alkyl radical, wherein said C_1-3Alkyl is optionally substituted by 1,2 or 3R_cSubstitution;

R ₇selected from H, F, Cl, Br, I, OH, NH₂And C_1-3Alkyl radical, wherein said C_1-3Alkyl is optionally substituted by 1,2 or 3R_dSubstitution;

R ₈selected from H, F, Cl, Br, I, OH, NH₂And C_1-3Alkyl radical, wherein said C_1-3Alkyl is optionally substituted by 1,2 or 3R_eSubstitution;

or, R₇And R₈And the C atom to which they are attached form together a phenyl group optionally substituted by 1,2 or 3R_fSubstitution;

R _aeach independently selected from H, F, Cl, Br, I, OH, NH₂And C_1-3An alkyl group;

R _beach independently selected from H, F, Cl, Br, I, OH, NH₂And C_1-3Alkoxy, wherein said C_1-3Alkoxy is optionally substituted with 1,2 or 3R;

R _c、R _d、R _eand R_fEach independently selected from H, F, Cl, Br, I, OH and NH₂；

R is respectively and independently selected from F, Cl, Br, I, OH and NH₂；

The 5-6 membered heteroaryl group contains 1,2,3 or 4 heteroatoms or groups of heteroatoms independently selected from-NH-, -O-, -S-and N.

A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R_aEach independently selected from H, F, Cl, Br, I, OH, NH₂、CH ₃and-CH₂-CH ₃。

A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R_bEach independently selected from H, F, Cl, Br, I, OH, NH₂and-O-CH₃。

The compound, an isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the R₁Is selected from C_1-3Alkyl, aryl, heteroaryl, and heteroaryl,

Wherein the content of the first and second substances,

E ₄and E₅Are each independently selected from- (CH)₂) _m-；

E ₆、E ₇And E₈Are each independently selected from- (CH)₂) _j-；

m is 0,1 or 2;

j is 0,1 or 2;

T ₆、T ₇、T ₈、T ₉and T₁₀Each independently selected from N and CH;

said C is_1-3Alkyl, aryl, heteroaryl, and heteroaryl,Optionally substituted by 1,2 or 3R_aSubstitution;

R _aas defined in claim 1 or 2.

A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 4, wherein R₁Is selected from CH₃-CH ₂-、 The CH₃-CH ₂-、 Optionally substituted by 1,2 or 3R_aAnd (4) substitution.

A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 5, wherein R₁Is selected from CH₃-CH ₂-、

A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 6, wherein R₁Is selected from CH₃-CH ₂-、

A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R₂And R₃Are each independently selected from H and CH₃。

A compound, isomer thereof or pharmaceutically acceptable salt thereof according to claim 1 or 3, wherein R₄Selected from H, F, Cl, Br, I, OH, NH₂、CH ₃、-CH ₂-CH ₃、-O-CH ₃and-O-CH₂-CH ₃Wherein, the CH₃、-CH ₂-CH ₃、-O-CH ₃and-O-CH₂-CH ₃Optionally substituted by 1,2 or 3R_bAnd (4) substitution.

A compound, isomer, or pharmaceutically acceptable salt according to claim 9, wherein R₄Selected from H, F, Cl, Br, I, OH, NH₂、CH ₃、-CH ₂-CH ₃、-O-CH ₃、-O-CH ₂-CH ₃And

a compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R₅Is selected from H and CH₃。

A compound, isomer thereof or pharmaceutically acceptable salt thereof according to claim 10 or 11, wherein the structural unitIs selected from

A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R₆Each independently selected from H, F, Cl, Br, I, OH and NH₂。

A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R₇Selected from H, F, Cl, Br, I, OH and NH₂。

A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R₈Selected from H, F, Cl, Br, I, OH and NH₂。

A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R₇And R₈And the C atoms to which they are attached form together

A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein the ring a is selected from

A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein the ring a is selected from

A compound, isomer thereof or pharmaceutically acceptable salt thereof according to claim 1, wherein said structural unitIs selected from

The compound according to any one of claims 1 to 18, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of compounds of formula (Γ):

wherein the content of the first and second substances,

R ₁as defined in claims 1 to 7;

R ₂and R₃As defined in claim 1 or 8;

R ₄and R₅As defined in claim 1, 9, 10 or 11;

ring a is as defined in claim 1, 17 or 18;

E ₁、E ₂and E₃As defined in claim 1.

The compound of claim 20, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of compounds of formula (I-1) and formula (I-2):

wherein the content of the first and second substances,

R ₁as defined in claims 1 to 7;

R ₂and R₃As defined in claim 1 or 8;

R ₄and R₅As defined in claim 1, 9, 10 or 11;

ring a is as defined in claim 1, 17 or 18.

The compound of claim 21, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of compounds of formulae (I-1A), (I-2B), and (I-2C):

wherein the content of the first and second substances,

R ₂and R₃As defined in claim 1 or 8;

R ₄and R₅As defined in claim 1, 9, 10 or 11;

T ₁、T ₂、T ₃、T ₄and T₅As defined in claim 1;

T ₆、T ₇、T ₈、T ₉and T₁₀As defined in claim 4.

A compound of the formula, an isomer thereof or a pharmaceutically acceptable salt thereof,

the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein the salt is selected from hydrochloride salts.

Use of a compound according to any one of claims 1 to 23, an isomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a plasma kallikrein mediated associated disease.

Use of the hydrochloride salt of claim 24 in the manufacture of a medicament for the treatment of a plasma kallikrein mediated related disorder.