CN115819326A - A kind of amide compound, its preparation method and its application - Google Patents

Abstract

The invention discloses an amide compound, its preparation method and application. The structure of the amide compound of the present invention is shown in formula I-1 or I-2. The compound of the present invention has better inhibitory effect on soluble cyclooxygenase.

Description

A kind of amide compound, its preparation method and its application

technical field

The present invention relates to an amide compound, its preparation method and application.

Background technique

Epoxide hydrolases (EH, EC 3.3.2.3) catalyze the hydrolysis of epoxides or arene oxides to their corresponding diols (see, Oesch, F. et al., Xenobiotica, 1973, 3, 305-340). Some EHs play critical roles in the metabolism of various compounds, including hormones, chemotherapeutic drugs, carcinogens, environmental pollutants, mycotoxins, and other harmful foreign compounds.

Microsomal epoxide hydrolase (mEH) and soluble epoxide hydrolase (sEH) are two well-studied EHs. In recent years, 1,3-disubstituted ureas, carbamates and amides have been reported as potent and stable new inhibitors of sEH. Chinese patent CN101084216A reports a urea substituted with trifluoromethylphenyl and trifluoromethoxyphenyl. However, more compounds with similar or improved activities still need to be developed.

Contents of the invention

The technical problem to be solved by the present invention is the defect that the existing drugs for inhibiting soluble cyclooxygenase have a single structure. Therefore, the present invention provides an amide compound, its preparation method and its application. The compound of the present invention has better inhibitory effect on soluble cyclooxygenase.

The present invention provides a compound as shown in formula I-1 or I-2 or a pharmaceutically acceptable salt thereof,

Among them, R ¹ is 5 to 8 membered heterocycloalkyl, "cyclohexyl substituted by 1 or more R ^1-2 " or "5 to 8 membered cyclohexyl substituted by 1 or more R ^1-1 Heterocycloalkyl"; in the 5- to 8-membered heterocycloalkyl, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

苯基、“被1个或多个卤素取代的C₁-C₆烷基”或“被1个或多个R^1-1-2取代的苯基”；Each R ^1-1 is independently C ₁ -C ₆ alkyl,

Phenyl, "C ₁ -C ₆ alkyl substituted by 1 or more halogens" or "phenyl substituted by 1 or more R ^1-1-2 ";

C₃-C₆环烷基或C₁-C₆烷基；R ^1-1-1 is hydrogen,

C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl;

R ^1-1-2 is carboxyl or cyano;

R ^1-1-1-1 is hydrogen, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl;

Each R ^1-1-1-2 is independently hydrogen, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl;

Each R ^1-2 is independently

R ^1-2-1 is phenyl or "phenyl substituted by 1 or more R ^1-2-1-1 ";

each R ^1-2-1-1 is independently carboxyl or cyano;

n is 0, 1, 2 or 3;

Each R ² is independently C ₁ -C ₆ alkyl, "C ₁ -C ₆ alkyl substituted by 1 or more halogen", "C ₁ -C ₆ alkoxy substituted by 1 or more halogen base", halogen or sulfur pentafluoride;

R ^1' is "cyclohexyl substituted by 1 or more R ^1'-2 " or "5 to 8-membered heterocycloalkyl substituted by 1 or more R ^1'-1 "; the 5 In the 8-membered heterocycloalkyl group, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

Each R ^1'-1 is independently "C ₁ -C ₆ alkyl substituted by 1 or more halogens";

Each R ^1'-2 is independently

R ^1'-2-1 is phenyl or "phenyl substituted by 1 or more R ^1'-2-1-1 ";

Each R ^1'-2-1-1 is independently carboxy or cyano.

In a certain scheme, in the compound shown in I-1 or I-2 or a pharmaceutically acceptable salt thereof, some groups can be defined as follows, and other groups can be defined as any of the above Scheme described (hereinafter referred to as "in a certain scheme"): the compound shown in formula I-1 or a pharmaceutically acceptable salt thereof,

Among them, R ¹ is 5 to 8 membered heterocycloalkyl, "cyclohexyl substituted by 1 or more R ^1-2 " or "5 to 8 membered cyclohexyl substituted by 1 or more R ^1-1 Heterocycloalkyl"; in the 5- to 8-membered heterocycloalkyl, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

苯基、“被1个或多个卤素取代的C₁-C₆烷基”或“被1个或多个R^1-1-2取代的苯基”；Each R ^1-1 is independently C ₁ -C ₆ alkyl,

Phenyl, "C ₁ -C ₆ alkyl substituted by 1 or more halogens" or "phenyl substituted by 1 or more R ^1-1-2 ";

C₃-C₆环烷基或C₁-C₆烷基；R ^1-1-1 is hydrogen,

C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl;

R ^1-1-2 is carboxyl or cyano;

R ^1-1-1-1 is hydrogen, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl;

Each R ^1-1-1-2 is independently hydrogen, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl;

Each R ^1-2 is independently

R ^1-2-1 is phenyl or "phenyl substituted by 1 or more R ^1-2-1-1 ";

Each R ^1-2-1-1 is independently carboxy or cyano.

In a certain scheme, R ¹ is a 6-membered heterocycloalkyl group, "a cyclohexyl group substituted by 1 R ^1-2 " or "a 6-membered nitrogen-containing heterocycloalkyl group substituted by 1 R ^1-1 "; In the 6-membered heterocycloalkyl group, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

R ^1-1 is C ₁ -C ₆ alkyl, "C ₁ -C ₆ alkyl substituted by 2 halogens", "C ₁ -C ₆ alkyl substituted by 3 halogens" or

或C₁-C₆烷基；R ^1-1-1 for

or C ₁ -C ₆ alkyl;

R ^1-1-1-1 is C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl;

Each R ^1-1-1-2 is independently hydrogen or C ₁ -C ₆ alkyl, and two R ^1-1-1-2 are not hydrogen at the same time;

R ^1-2 for

R ^1-2-1 is phenyl or "phenyl substituted by 1 R ^1-2-1-1 ";

R ^1-2-1-1 is carboxyl or cyano;

n is 1 or ² ; each R is independently "C ₁ -C ₆ alkyl substituted by 3 halogens", "C ₁ -C ₆ alkoxy substituted by 3 halogens", halogen or pentafluoride sulfur;

R ^1' is "cyclohexyl substituted by 1 R ^1'-2 " or "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1'-1 ";

Each R ^1'-1 is independently "C ₁ -C ₆ alkyl substituted by 3 halogens";

Each R ^1'-2 is independently

R ^1'-2-1 is phenyl or "phenyl substituted by 1 R ^1'-2-1-1 ";

Each R ^1'-2-1-1 is independently carboxy or cyano.

In a certain scheme, R ¹ is a 6-membered heterocycloalkyl group, "a cyclohexyl group substituted by 1 R ^1-2 " or "a 6-membered nitrogen-containing heterocycloalkyl group substituted by 1 R ^1-1 "; In the 6-membered heterocycloalkyl group, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

R ^1-1 is C ₁ -C ₆ alkyl, "C ₁ -C ₆ alkyl substituted by 3 halogens" or

或C₁-C₆烷基；R ^1-1-1 for

or C ₁ -C ₆ alkyl;

R ^1-1-1-1 is C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl;

Each R ^1-1-1-2 is independently hydrogen or C ₁ -C ₆ alkyl, and two R ^1-1-1-2 are not hydrogen at the same time;

R ^1-2 for

R ^1-2-1 is phenyl or "phenyl substituted by 1 R ^1-2-1-1 ";

R ^1-2-1-1 is carboxyl or cyano.

In a certain scheme, R ¹ is "cyclohexyl substituted by 1 R ^1-2 " or "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1-1 ";

R ^1-1 is "C ₁ -C ₆ alkyl substituted by 3 halogens" or

或C₁-C₆烷基；R ^1-1-1 for

or C ₁ -C ₆ alkyl;

R ^1-1-1-1 is C ₁ -C ₆ alkyl;

R ^1-2 for

R ^1-2-1 is phenyl or "phenyl substituted by 1 R ^1-2-1-1 ";

R ^1-2-1-1 is carboxyl or cyano;

n is 1 or ² ; each R is independently "C ₁ -C ₆ alkyl substituted by 3 halogens", "C ₁ -C ₆ alkoxy substituted by 3 halogens", halogen or pentafluoride sulfur;

R ^1' is "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1'-1 ";

R ^1'-1 is "C ₁ -C ₆ alkyl substituted by 3 halogens".

In a certain scheme, R ¹ is "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1-1 ";

R ^1-1 is "C ₁ -C ₄ alkyl substituted by 3 fluorines" or

或c₁-C₄烷基；R ^1-1-1 for

or c ₁ -C ₄ alkyl;

R ^1-1-1-1 is C ₁ -C ₄ alkyl;

When n is 1, R ² is "C ₁ -C ₆ alkoxy substituted by 3 halogens"; R ^1' is "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1'-1 "; R ^1'-1 is "C ₁ -C ₄ alkyl substituted by 3 halogens";

When n is 2, R ² is "C ₁ -C ₆ alkoxy substituted by 3 halogens" and halogen; R ^1' is "6-membered nitrogen-containing heterocyclic ring substituted by 1 R ^1'-1 Alkyl"; R ^1'-1 is "C ₁ -C ₄ alkyl substituted by 3 halogens".

In a certain scheme, R ¹ is a 6-membered heterocycloalkyl group, "a cyclohexyl group substituted by 1 R ^1-2 " or "a 6-membered nitrogen-containing heterocycloalkyl group substituted by 1 R ^1-1 "; in the 6-membered heterocycloalkyl group, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2; preferably, R ¹ is "cyclohexyl substituted by 1 R ^1-2 " or "by 6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1-1 "; more preferably, R ¹ is "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1-1 ".

较佳地，R^1-1为“被3个卤素取代的C₁-C₆烷基”或

更佳地，R^1-1为“被3个氟取代的C₁-C₄烷基”或

In a certain scheme, R ^1-1 is C ₁ -C ₆ alkyl, "C ₁ -C ₆ alkyl substituted by 2 halogens", "C ₁ -C ₆ alkyl substituted by 3 halogens" or

Preferably, R ^1-1 is "C ₁ -C ₆ alkyl substituted by 3 halogens" or

More preferably, R ^1-1 is "C ₁ -C ₄ alkyl substituted by 3 fluorines" or

或C₁-C₆烷基；较佳地，R^1-1-1为

或C₁-C₆烷基；更佳地，R^1-1-1为

或C₁-C₄烷基。In a certain scheme, R ^1-1-1 is

or C ₁ -C ₆ alkyl; preferably, R ^1-1-1 is

or C ₁ -C ₆ alkyl; more preferably, R ^1-1-1 is

or C ₁ -C ₄ alkyl.

In a certain scheme, R ^1-1-1-1 is C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl; preferably, R ^1-1-1-1 is C ₁ -C ₆ Alkyl; more preferably, R ^1-1-1-1 is C ₁ -C ₄ alkyl.

In a certain embodiment, each R ^1-1-1-2 is independently hydrogen or C ₁ -C ₆ alkyl, and two R ^1-1-1-2 are not hydrogen at the same time.

In a certain scheme, R ^1-2 is

In a certain aspect, R ^1-2-1 is phenyl or "phenyl substituted with 1 R ^1-2-1-1 ".

In a certain aspect, R ^1-2-1-1 is carboxyl or cyano.

In a certain aspect, n is 1 or 2.

In a certain embodiment, R ² is independently "C ₁ -C ₆ alkyl substituted by 3 halogens", "C ₁ -C ₆ alkoxy substituted by 3 halogens", halogen or sulfur pentafluoride .

In a certain scheme, R ^1' is "cyclohexyl substituted by 1 R ^1'-2 " or "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1'-1 "; preferably , R ^1' is "6-membered nitrogen-containing heterocycloalkyl substituted by one R ^1'-1 ".

In a certain aspect, each R ^1'-1 is independently "C ₁ -C ₆ alkyl substituted by 3 halogens".

In a certain version, each R ^1'-2 is independently

In a certain aspect, R ^1'-2-1 is phenyl or "phenyl substituted by 1 R ^1'-2-1-1 ".

In a certain aspect, each R ^1'-2-1-1 is independently carboxy or cyano.

In a certain scheme, when n is 1, R ² is "C ₁ -C ₆ alkoxy substituted by 3 halogens".

In a certain scheme, when n is 2, R ² is "C ₁ -C ₆ alkoxy substituted by 3 halogens" and halogen.

In a certain scheme, R ¹ is "cyclohexyl substituted by 1 R ^1-2 " or "5 to 8-membered heterocycloalkyl substituted by 1 or more R ^1-1 "; said 5 In the 8-membered heterocycloalkyl group, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

或“被1个或多个卤素取代的C₁-C₆烷基”；R ^1-1 is C ₁ -C ₆ alkyl,

or "C ₁ -C ₆ alkyl substituted by 1 or more halogens";

或C₁-C₆烷基；R^1-1-1-1为C₁-C₆烷基；R ^1-1-1 for

Or C ₁ -C ₆ alkyl; R ^1-1-1-1 is C ₁ -C ₆ alkyl;

R ^1-2 for

R ^1-2-1 is phenyl or "phenyl substituted by one R ^1-2-1-1 "; R ^1-2-1-1 is carboxyl or cyano.

In a ^certain scheme, in R, the 5- to 8-membered heterocycloalkyl group can be a 5- or 6-membered heterocycloalkyl group; it can also be a piperidinyl group, such as

其中氮与R^1-1^连接。In a certain scheme, in R ¹ , the "5- to 8-membered heterocycloalkyl substituted by 1 or more R ^1-1 " may be "substituted by 1 or more R ^1-1 5- or 6-membered heterocycloalkyl"; for example

where nitrogen is ^attached to R ^1-1 .

In a certain scheme, in R ^1-1 , the C ₁ -C ₆ alkyl can be C ₁ -C ₄ alkyl; it can also be methyl, ethyl, n-propyl, isopropyl, n-butyl base, sec-butyl, isobutyl or tert-butyl, and also ethyl or isopropyl.

In a certain scheme, in R ^1-1 , _the C ₁ -C 6 alkyl in the "C 1 -C ₆ alkyl substituted by 1 or more halogens" can be C _{1 -C 4} alkyl; The C ₁ -C ₄ alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; it can also be methyl, ethyl , n-propyl or isopropyl.

In a certain scheme, in R ^1-1 , the halogen in the "C ₁ -C ₆ alkyl substituted by 1 or more halogens" can be fluorine, chlorine, bromine or iodine; further preferably, the "C ₁ -C ₆ alkyl substituted by one or more halogens" may be "C ₁ -C ₆ alkyl substituted by one or more fluorines"; for example, trifluoromethyl,

In a certain scheme, in R ^1-1 , the "phenyl substituted by 1 or more R ^1-1-2 " can be phenyl substituted by carboxyl or phenyl substituted by cyano; for example

或异丙基。In a certain scheme, in R ^1-1-1 , the C ₁ -C ₆ alkyl group can be a C ₁ -C ₄ alkyl group; it can also be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; also isobutyl

or isopropyl.

In a certain scheme, in R ^1-1-1 , the C ₃ -C ₆ cycloalkyl group can be cyclopropane, cyclobutane, cyclopentane or cyclohexane, and can also be cyclopropane.

In a certain scheme, in R ^1-1-1-1 , the C ₁ -C ₆ alkyl can be C ₁ -C ₄ alkyl; it can also be methyl, ethyl, n-propyl, isopropyl base, n-butyl, sec-butyl, isobutyl or tert-butyl; also methyl, ethyl or isopropyl.

In a certain scheme, in R ^1-1-1-1 , the C ₃ -C ₆ cycloalkyl group can be cyclopropane, cyclobutane, cyclopentane or cyclohexane; it can also be cyclopropane.

In a certain scheme, in R ^1-1-1-2 , the C ₁ -C ₆ alkyl can be C ₁ -C ₄ alkyl; it can also be methyl, ethyl, n-propyl, isopropyl base, n-butyl, sec-butyl, isobutyl or tert-butyl; also methyl or isopropyl.

In a certain scheme, in R ^1-1-1-2 , the C ₃ -C ₆ cycloalkyl group can be cyclopropane, cyclobutane, cyclopentane or cyclohexane, and can also be cyclopropane.

In _a certain scheme, in R ² , the C ₁ -C ₆ alkyl in the "C 1 -C 6 alkyl" can be a C ₁ -C ₄ alkyl; the _{C 1 -C 4} alkyl can also be It is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; it can also be ethyl.

In a certain scheme, in R ² , the C ₁ -C ₆ alkyl _in the "C 1 -C 6 alkyl substituted by 1 or more halogens" can be a C _{1 -C 4} alkyl; C ₁ -C ₄ alkyl can in turn be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; also ethyl.

In a certain scheme, in R ² , the halogen in the "C ₁ -C ₆ alkyl substituted by 1 or more halogens" can be fluorine, chlorine, bromine or iodine; more preferably, the "substituted by "C ₁ -C ₆ alkyl substituted with 1 or more halogens" may be "C ₁ -C ₆ alkyl substituted with 1 or more fluorines"; eg trifluoromethyl.

In a certain scheme, in R ² , the C ₁ -C 6 alkoxy _in the "C 1 -C ₆ alkoxy substituted by 1 or more halogens" can be C _{1 -C 4} alkoxy ; The C ₁ -C ₄ alkoxy is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy ; The C ₁ -C ₄ alkoxy group is also preferably methyl oxygen; further preferably, the "C ₁ -C ₆ alkoxy group substituted by one or more halogens is a C ₁ - C ₄ alkoxy, such as trifluoromethoxy.

In a certain scheme, in ^R2 , the halogen can be fluorine, chlorine, bromine or iodine; it can also be fluorine.

其中氮与R^1’-1连接。In a certain scheme, in R ^1' , the "5- to 8-membered heterocycloalkyl substituted by 1 or more R ^1'-1 " may be "substituted by 1 or more R ^{1'- 1} substituted 5- or 6-membered heterocycloalkyl"; for example

where the nitrogen is attached to R ^1'-1 .

In a certain scheme, in R ^1'-1 , the C ₁ -C 6 alkyl _in the "C 1 -C ₆ alkyl substituted by 1 or more halogens" is a C _{1 -C 4} alkyl; The C ₁ -C ₄ alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; it can also be methyl, ethyl or isopropyl.

In a certain scheme, in R ^1'-1 , the halogen in the "C ₁ -C ₆ alkyl substituted by 1 or more halogens" can be fluorine, chlorine, bromine or iodine; more preferably, the The "C ₁ -C ₆ alkyl substituted by 1 or more halogens" is "C ₁ -C ₆ alkyl substituted by 1 or more fluorines"; such as trifluoromethyl or trifluoroethyl.

可为

In a scheme,

Can be

优选为

R^1-1和R^1-2如前所述。In a certain scheme, ^R1 can be

preferably

R ^1-1 and R ^1-2 are as described above.

In a certain scheme, R ^1-1 can be

The present invention also provides a compound,

In a certain scheme, the compound shown in formula I-1 is

The present invention also provides a preparation method of the compound shown in formula I-1, which includes the following steps: in a solvent, the compound shown in formula II and the amine compound are subjected to a condensation reaction shown in the following formula in the presence of a base, That is, the definition of ^R1 is as mentioned above;

In a certain scheme, the solvent can be a conventional solvent in the art; the solvent can be an anhydrous solvent. The solvent may be selected from one or more of ether solvents, chlorinated alkanes and aromatic hydrocarbon solvents. The ether solvent is preferably diethyl ether, tetrahydrofuran or tert-butyl methyl ether. The chlorinated alkane is preferably dichloromethane. The aromatic hydrocarbon solvent is preferably toluene or benzene.

In a certain scheme, the amount of the solvent is conventional in the art, for example, the volume molar ratio of the solvent to the compound represented by formula II can be 1-10 mL/mmol; for example 2 mL/mmol or 8 mL/mmol.

In a certain scheme, the molar ratio of the compound represented by formula II to the amine compound may be 1:(1-3); for example, 1.5 or 1.7.

In a certain scheme, the base can be a conventional organic base in the art, for example, the base can be a nitrogen-containing organic base; for example, triethylamine.

In a certain scheme, the amount of the base can be conventional in the art; for example, the molar ratio of the compound represented by formula II to the base can be 1:(1-3); for example, 1.5 or 1.7.

The present invention also provides the application of a substance Z in the preparation of medicines for the treatment and/or prevention of diseases related to soluble cyclooxygenase; the substance Z is the aforementioned compound shown in formula I-1 or I-2 or its pharmaceutical preparation acceptable salt.

Preferably, the disease is hypertension, pain, cardiomyopathy, inflammation, adult respiratory distress syndrome, diabetic complications, nephropathy, Raynaud's syndrome or arthritis.

The pain is preferably neuropathic pain and/or inflammatory pain.

The renal disease is preferably end-stage renal disease.

The hypertension is preferably renal hypertension, hepatic hypertension or pulmonary hypertension.

The inflammation is preferably renal inflammation, vascular inflammation or pneumonia.

The present invention also provides an application of a substance Z in the preparation of a soluble cyclooxygenase inhibitor; the substance Z is the aforementioned compound represented by formula I-1 or I-2 or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical composition, which includes substance Z and pharmaceutical excipients, wherein the substance Z is the aforementioned compound represented by formula I-1 or I-2 or a pharmaceutically acceptable salt thereof.

In the pharmaceutical composition, the substance Z may be a therapeutically effective amount of substance Z.

Definition of Terms

Certain chemical groups defined herein are preceded by abbreviated symbols to indicate the total number of carbon atoms present in the group. For example, C ₁ -C ₆ alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the abbreviated notation does not include carbons that may be present in substituents of the stated group.

The term "plurality" means 2, 3, 4 or 5.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "heterocycloalkyl" refers to a specified number of ring atoms (such as 5 to 10 members), a specified number of heteroatoms (such as 1, 2 or 3), and a specified type of heteroatom (N, O and S A cyclic group of one or more of ), which is a monocyclic ring, a bridged ring or a spiro ring, and each ring is saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

The term "nitrogen-containing heterocycloalkyl" refers to a group with a specified number of ring atoms (for example, 5 to 10 members, and for example, 6 members), a specified number of heteroatoms (for example, 1, 2 or 3), and a heteroatom of A cyclic group of nitrogen, and each ring is saturated.

The term "pharmaceutically acceptable salt" means a salt formed from a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base and a compound shown in Formula I-1, which retains the properties of the compound shown in Formula I-1. biological activity.

The term "pharmaceutical excipients" refers to the excipients and additives used in the production of drugs and the preparation of prescriptions, and refers to all substances contained in pharmaceutical preparations except for active ingredients. Can refer to Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009Sixth Edition).

The term "treatment" refers to therapeutic therapy. In relation to a specific condition, treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.

The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

The term "therapeutically effective amount" refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient. A "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art.

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive progress effect of the present invention is: the compound of the present invention has better inhibitory effect to soluble cyclooxygenase, has good metabolic properties (for example: half-life, exposure AUC, maximum blood drug concentration Cmax) and has higher inhibition One or more of the effect advantages in the effect of pain.

Description of drawings

Figure 1 shows the effect of the compound on the foot mechanical pain threshold of rats with diabetic neuropathic pain. Compared with before administration (0h), "*" means P<0.05; "**" means P<0.01.

Detailed ways

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

Chromatographic conditions for preparative separation (purification):

Separation conditions:

Mobile phase: mobile phase A: water (0.225% formic acid); mobile phase B: acetonitrile

Chromatographic column: Phenomenexluna C18 150*40mm*15μm

Gradient elution: 37-67% mobile phase B

Gradient elution time: 10min

Detection wavelength: 254nm

Flow rate (ml/min): 60mL/min.

The synthesis of embodiment 1BX20-6-I05

The synthetic route is shown in the following formula:

Under N2 protection, triphosgene (0.91g, 3.07mmol) was dissolved in anhydrous DCM (15mL), cooled to -78°C in an ethanol/liquid nitrogen bath; XR020007-S1 (1.50g, 6.84mmol), TEA (triethylamine ) (1.04g, 10.3mmol) was dissolved in anhydrous DCM (15mL), added dropwise to the above reaction solution, and naturally heated to 0°C for 1 hour, then cooled to -78°C again; XR020007-S2 (2.05g, 10.3mmol ), TEA (1.04g, 10.3mmol) was dissolved in anhydrous DCM (15mL), and added dropwise to the above reaction solution. After the addition, the temperature was naturally raised to room temperature and reacted for 0.5h. After the reaction was completed, the reaction solution was directly decompressed at 40°C. After concentration, the residue was purified by column chromatography (PE/EA=10/1~1/1, V/V) to obtain white solid BX20-6-I05 (2.60 g, yield 86.6%).

¹ H NMR (400MHz, DMSO-d6) δ=8.87(s, 1H), 7.71(d, J=7.6Hz, 2H), 7.53(d, J=7.6Hz, 2H), 6.36(d, J=8.0 Hz, 1H), 3.81-3.79(m, 2H), 3.65-3.60(m, 1H), 2.92-2.85(m, 2H), 1.79-1.75(m, 2H), 1.38(s, 9H), 1.29- 1.21 (m, 2H); MS (ESI, m/z) 390.1 [Mt-Bu+H] ⁺ .

The synthesis of embodiment 2BX20-6-007

Synthesis of the first step BX20-6-I05

Proceeding according to Example 1, a white solid BX20-6-I05 was obtained.

Synthesis of the second step XR020007-I03

The synthetic route is shown in the following formula:

Compound BX20-5-I05 (0.80 g, 1.35 mmol) was added into HCl/MeOH (2M, 10 mL), and the reaction mixture was hydrogenated at room temperature for 12 h. After the reaction, the reaction solution was directly concentrated to obtain compound XR020007-I03 (0.62 g, hydrochloride, crude product) which was directly used in the next reaction, MS (ESI, m/z) 346.3 [M+H] ⁺ .

Step 3: Synthesis of BX20-6-007

The synthetic route is shown in the following formula:

Compound crude XR020007-I03 (0.62g, 1.80mmol), isobutyric acid (0.19g, 2.16mmol), T3P (3.44g, 50% solution in ethyl acetate, 5.40mmol), TEA (0.55g, 5.40mmol) Anhydrous DCM (10 mL) was added successively, and the reaction mixture was reacted at 15° C. for 18 h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at 40°C, and the obtained residue was purified by preparation and separation (formic acid system), and after lyophilization, a white powder compound BX20-6-007 was obtained (72 mg, yield 9.6%) .

¹ H NMR (400MHz, DMSO-d6) δ=8.91(s, 1H), 7.71(d, J=7.6Hz, 2H), 7.54(d, J=7.6Hz, 2H), 6.40(d, J=8.0 Hz, 1H), 4.19-4.16(m, 1H), 3.85-3.82(m, 1H), 3.72-3.69(m, 1H), 3.17-3.11(m, 1H), 2.89-2.73(m, 2H), 1.87-1.77 (m, 2H), 1.31-1.17 (m, 2H), 0.99-0.96 (m, 6H); MS (ESI, m/z) 416.4 [M+H] ⁺ .

The synthesis of embodiment 3BX20-6-010

Synthesis of the first step S4-010

Under N2 protection, dissolve triphosgene (0.49g, 1.64mmol) in anhydrous DCM (30ml), and cool to -78°C in an ethanol/liquid nitrogen bath; XR020007-S1 (0.80g, 3.65mmol), TEA (triethylamine) (0.55g, 5.50mmol) was dissolved in anhydrous DCM (15ml), added dropwise to the above reaction solution, and naturally heated to 0°C for 1h, then cooled to -78°C again; S3-010 (1.18g, 5.47mmol ), TEA (0.55g, 5.50mmol) was dissolved in anhydrous DCM (15ml), added dropwise to the above reaction solution, after the dropwise addition, the temperature was naturally raised to room temperature and reacted for 0.5h. After concentration, the residue was purified by column chromatography (PE/EA=2/1~0/1, V/V) to obtain white solid S4-010 (0.90 g, yield 53%).

Synthesis of the second step BX20-6-010

The synthetic route is shown in the following formula:

Crude compound S4-010 (0.65 g, 1.41 mmol) was added to absolute ethanol (20 mL), and then 6N NaOH solution (10 mL) was added, and the reaction mixture was reacted at 75° C. for 12 h. After the reaction is completed, adjust the pH of the reaction solution to about 2 with concentrated HCl, and solids precipitate out; filter the reaction solution to obtain a filter cake, purify it through preparative separation (formic acid system), and freeze-dry to obtain the white powder compound BX20-6- 010 (310 mg, 45.8% yield).

¹ H NMR (400MHz, DMSO-d6) δ=8.84(s, 1H), 7.86(d, J=7.6Hz, 2H), 7.73(d, J=7.6Hz, 2H), 7.55(d, J=8.0 Hz, 2H), 7.03(d, J=8.0Hz, 2H), 6.34(d, J=7.6Hz, 1H), 4.48-4.43(m, 1H), 3.57-3.54(m, 1H), 2.07-1.93 (m, 4H), 1.54-1.35 (m, 4H).

The synthesis of embodiment 4BX20-6-023

Synthesis of the first step XR020007-I03

According to the second step of Example 2, compound XR020007-I03 was obtained.

Synthesis of the second step BX20-6-023

The synthetic route is shown in the following formula:

(S)-(+)-2-Methylbutanoic acid (0.19g, 2.16mmol), HATU (912mg, 2.20mmol) were added to anhydrous DMF (5mL), stirred at 25°C for 10 minutes, and the reaction The mixture was cooled to 0°C, XR020007-I03 (0.76g, 2.00mmol) and DIPEA (1.03g, 8.00mmol) were added, and the reaction mixture was reacted at 25°C for 12h. After the reaction, add water (50mL) to the reaction solution, extract with EA (20mL*3), combine the organic phases, wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure at 40°C , the obtained residue was purified by column chromatography (PE/EA=2/1～0/1), purified by preparative separation (formic acid system), and freeze-dried to obtain white powder compound BX20-6-023 (305mg , the yield is 35.5%). ¹ HNMR (400MHz, DMSO-d6) δ = 8.87 (d, J = 11.6Hz, 1H), 7.73 (d, J = 7.6Hz, 2H), 7.56 (d, J = 7.6Hz, 2H), 6.43-6.39 (m, 1H), 4.25-4.19(m, 1H), 3.90-3.87(m, 1H), 3.76-3.69(m, 1H), 3.20-3.14(m, 1H), 2.82-2.68(m, 2H) , 1.87-1.77(m, 2H), 1.58-1.52(m, 1H), 1.33-1.23(m, 3H), 0.97(t, J=6.0Hz, 3H), 0.83-0.78(m, 3H); MS (ESI, m/z) 430.1 [M+H] ⁺ .

The synthesis of embodiment 5BX20-6-024

Synthesis of the first step XR020007-I03

According to the second step of Example 2, compound XR020007-I03 was obtained.

Synthesis of the second step BX20-6-024

The synthetic route is shown in the following formula:

XR020007-I03 (0.60g, 1.57mmol) was added to anhydrous DCM (15mL), triethylamine (0.47g, 4.71mmol) was added, the reaction mixture was stirred at 25°C for 5 minutes, and then chlorine was added dropwise at 0°C Isopropyl formate (0.23g, 1.90mmol), the reaction mixture was reacted at 25°C for 12h. After the reaction was completed, water (1 mL) was added to the reaction solution, and after concentration under reduced pressure at 40°C, the obtained residue was purified by column chromatography (PE/EA=2/1～0/1) to obtain the white powder compound BX20- 6-024 (416 mg, 61% yield).

¹ H NMR (400MHz, DMSO-d6) δ=8.88(s, 1H), 7.73(d, J=7.6Hz, 2H), 7.52(d, J=7.6Hz, 2H), 6.36(d, J=7.6 Hz, 1H), 4.79-4.73(m, 1H), 3.87-3.83(m, 2H), 3.70-3.64(m, 1H), 3.00-2.94(m, 2H), 1.82-1.77(m, 2H), 1.29-1.23 (m, 2H), 1.18 (d, J = 8.0 Hz, 6H); MS (ESI, m/z) 432.1 [M+H] ⁺ .

The synthesis of embodiment 6BX20-6-025

Synthesis of the first step XR020007-I03

According to the second step of Example 2, compound XR020007-I03 was obtained.

Synthesis of the second step BX20-6-025

The synthetic route is shown in the following formula:

Compound XR020007-I03 (0.60g, 1.57mmol) was dissolved in anhydrous DCM (10mL), TEA (0.48g, 4.72mmol) was added dropwise, stirred at 0°C for 5min, dimethyl dicarbonate (0.21g , 1.57mmol), the reaction mixture was stirred at 25°C for 12h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at 40°C, and the obtained residue was purified by silica gel column chromatography (PE:EA=1:1～0:1) to obtain light yellow solid powder compound BX20-6-025 (480 mg, yield 75.8%). m/z = 404.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )=8.88(s, 1H), 7.73(d, J=8.0Hz, 2H), 7.55(d, J=8.0Hz, 2H), 6.36(d, J=8.0 Hz, 1H), 3.86-3.83(m, 2H), 3.68-3.65(m, 1H), 3.59(s, 3H), 2.99-2.95(m, 2H), 1.83-1.79(m, 2H), 1.35- 1.23(m, 2H).

The synthesis of embodiment 7BX20-6-026

Synthesis of the first step XR020007-I03

According to the second step of Example 2, compound XR020007-I03 was obtained.

Synthesis of the second step BX20-6-026

The synthetic route is shown in the following formula:

The compound XR020007-I03 (0.50g, 1.31mmol), BX20-6-026-S2 (0.37g, 1.59mmol), TEA (0.7mL, 5.20mmol) were added to DMF (10mL) successively, and the reaction mixture was heated to 75 The reaction was stirred overnight at ℃ for 12h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at 40°C, and the obtained residue was purified by column chromatography on silica gel (PE: EA = 2: 1 ~ 1: 1), and after lyophilization, the white powder compound BX20-6 was obtained. -026 (230 mg, 41% yield). MS (ESI, m/z) 428.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )=8.86(s, 1H), 7.71-7.69(m, 2H), 7.54-7.52(m, 2H), 6.28(d, J=8.0Hz, 1H), 3.54 -3.41(m, 1H), 3.16-3.09(m, 2H), 2.84-2.81(m, 2H), 2.41(t, J=12.0Hz, 2H), 1.78-1.76(m, 2H), 1.45-1.35 (m, 2H).

The synthesis of embodiment 8BX20-6-027

Synthesis of the first step XR020007-I03

According to the second step of Example 2, compound XR020007-I03 was obtained.

Synthesis of the second step BX20-6-027

The synthetic route is shown in the following formula:

Dissolve XR020007-I03 (320mg, 0.84mmol) in MeCN (10mL), then add K ₂ CO ₃ (350mg, 2.52mmol) and 3-fluoro-1-iodopropane (377mg, 1.68mmol), react in 60 Stir at °C for 16 hours. Quenched with water, extracted with ethyl acetate (25mLx 3) and dried, concentrated under reduced pressure at 40°C, the residue was purified by column chromatography (PE/EA=10/1～5/1, V/V) to obtain crude The product was purified by preparative separation (formic acid system) and freeze-dried to obtain white powder compound BX20-6-027 (190 mg, yield 22.0%). m/z = 442.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6) δ = 8.92 (d, J = 3.6Hz, 1H), 7.72 (d, J = 9.2Hz, 2H), 7.55 (d, J = 8.8Hz, 2H), 6.37- 6.35(m, 1H), 3.48-3.44(m, 3H), 2.76(d, J=12.0Hz, 2H), 2.52-2.37(m, 2H), 2.09(t, J=11.2Hz, 2H), 1.80 -1.77(m, 2H), 1.43-1.33(m, 2H).

The synthesis of embodiment 9BX20-6-032

Step 1: Synthesis of S1

The synthetic route is shown in the following formula:

Method: SO (50 mg, 0.44 mmol) was dissolved in anhydrous DCM (2 mL), and pyridine (51 mg, 0.66 mmol) was added. At 0°C, Tf ₂ O (123 mg, 0.66 mmol) was added dropwise, and the reaction was stirred at room temperature for half an hour. The reaction solution was filtered to obtain a DCM solution containing S1 (about 0.2 mmol/mL, 2 mL), which was directly used in the next step.

Step 2: Synthesis of BX20-6-032

The synthetic route is shown in the following formula:

Method: Dissolve XR020007-103 (150mg, 0.4mmol) in ACN (10mL), then add K ₂ CO ₃ (81mg, 0.6mmol) and S1 in DCM (about 0.2mmol/mL, 2mL), react in 50 Stir at °C for 16 hours. After the reaction was completed, it was filtered, and the filtrate was prepared and purified (formic acid system), and freeze-dried to obtain light yellow powder compound BX20-6-032 (16 mg, yield 9.0%). m/z = 442.2 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ=8.86(s, 1H), 7.70(d, J=8.0Hz, 2H), 7.52(d, J=8.0Hz, 2H), 3.37-3.49(m, 2H ), 2.77-2.89(m, 2H), 2.50-2.53(m, 1H), 2.40-2.43(m, 1H), 1.76-1.79(m, 2H), 1.30-1.43(m, 2H), 1.13(d , J=4.0Hz, 2H).

The synthesis of embodiment 10BX20-6-033

The synthetic route is shown in the following formula:

Method: Dissolve compound S0' (200mg, 1.75mmol), pyridine (150mg, 1.9mmol) in anhydrous DCM (4mL) under ice bath, slowly add Tf ₂ O (535mg, 1.9mmol) dropwise, and the reaction mixture The reaction was stirred under ice bath for 30 minutes. After the reaction, the reaction solution was filtered to obtain a DCM solution of S1'. Add the above solution to ACN (10mL), then add K ₂ CO ₃ (323mg, 2.34mmol), react at 60°C and stir for 1 hour. After the reaction is complete, the reaction solution is filtered, separated and purified by preparation (formic acid system), and freeze-dried The light yellow solid powder BX20-6-033 (22 mg, yield 6.4%) was obtained.

¹ H NMR (400MHz, METHANOL-d ₄ )=7.57(d, J=9.2Hz, 2H), 7.40(d, J=8.8Hz, 2H), 3.52-3.45(m, 1H), 3.27-3.15(m , 1H), 2.86-2.79(m, 2H), 2.56(t, J=11.2Hz, 1H), 2.46(t, J=11.2Hz, 1H), 1.84-1.79(m, 2H), 1.42-1.32( m, 2H), 1.13 (d, J = 6.8 Hz, 3H).

The synthesis of embodiment 11BX20-6-034

The synthetic route is shown in the following formula:

Method: Dissolve compound XR020007-I03 (0.30g, 0.79mmol), K ₂ CO ₃ (0.33g, 2.36mmol) in DMF (6mL), slowly add iodoethane (0.11g, 0.71mmol) in DMF ( 3mL) solution, and the reaction mixture was stirred at room temperature for 12h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at 40°C, and the obtained residue was purified by preparation and separation (formic acid system), and after lyophilization, a white powder compound BX20-6-034 (90 mg, yield 31%) was obtained. . MS (ESI, m/z) 374.12 [M+H] ⁺ .

¹ H NMR (400MHz, METHANOL-d ₄ )=8.50(s, 1H), 7.69-7.66(m, 2H), 7.55-7.53(m, 2H), 3.88-3.83(m, 1H), 3.50-3.47( m, 2H), 3.12(q, J=8.0Hz, 2H), 3.07-3.01(m, 2H), 2.20-2.16(m, 2H), 1.83-1.77(m, 2H), 1.33(t, J= 8.0Hz, 3H).

The synthesis of embodiment 12BX20-6-035

The synthetic route is shown in the following formula:

Method: Dissolve compound XR020007-I03 (0.30g, 0.79mmol), K ₂ CO ₃ (0.33g, 2.36mmol) in DMF (6mL), slowly add bromoisopropane (0.12g, 0.94mmol) in DMF (3mL) solution, the reaction mixture was heated to 60°C and stirred for 12h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at 40°C, and the obtained residue was purified by preparation and separation (formic acid system), and after lyophilization, a white powder compound BX20-6-035 (110 mg, yield 36%) was obtained. . MS (ESI, m/z) 388.14 [M+H] ⁺ .

¹ H NMR (400MHz, METHANOL-d ₄ ) δ8.54(s, 1H), 7.69-7.67(m, 2H), 7.55-7.53(m, 2H), 3.87-3.82(m, 1H), 3.46-3.38 (m, 3H), 3.13-3.07 (m, 2H), 2.21-2.18 (m, 2H), 1.81-1.78 (m, 2H), 1.34-1.33 (m, 6H).

The synthesis of embodiment 13BX20-6-036

The synthetic route is shown in the following formula:

Method: XR020007-I03 (300mg, 0.78mmol) was dissolved in DMF (10mL), then TEA (162mg, 1.6mmol) and SO (377mg, 1.68mmol) were added, and the reaction was stirred at room temperature for 16 hours. Quenched with water, extracted and dried with ethyl acetate (25mLx3), concentrated under reduced pressure at 40°C, the residue was prepared and purified (formic acid system), and freeze-dried to obtain white powder compound BX20-6-036 (220mg, yield was 68.9%). m/z = 410.2 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ = 7.60-7.56 (m, 2H), 7.42 (d, J = 8.8Hz, 2H), 6.04 (tt, J = 55.2Hz, J = 4.0Hz, 1H), 3.64-3.57(m, 1H), 3.13-2.99(m, 4H), 2.66(t, J=11.2Hz, 2H), 1.97-1.93(m, 2H), 1.61-1.51(m, 2H).

The synthesis of embodiment 14BX20-6-037

Step 1: Synthesis of Intermediate XR020003-I01

The synthetic route is shown in the following formula:

Method: To a solution of compound XR02-S1 (2.00 g, 9.85 mmol) in DCM (40 mL) was added TEA (1.91 g, 14.8 mmol) at 0°C. XR02-S2 (2.37 g, 11.8 mmol) was added to the solution. Reacted at 20°C for 1 hour, and spin-dried to obtain the crude product. The crude product was purified by silica gel column to obtain white solid XR020003-I01 (2.70 g, yield 68.0%). MS (ESI, m/z) 404.2 [M+H] ⁺ .

The second step: the synthesis of intermediate XR020003-I02

The synthetic route is shown in the following formula:

Method: To a solution of XR020003-I01 (1.00 g, 2.48 mmol) in MeOH (5 mL) was added MeOH (3 mL, 12 mmol) at room temperature. After the reaction was completed, spin-dried to obtain a pale yellow crude product (1.08 g, crude product), which was directly used in the next step. MS (ESI, m/z) 304.2 [M+H] ⁺ .

Step 3: Synthesis of BX20-6-037

The synthetic route is shown in the following formula:

Method: Et ₃ N (178 mg, 1.77 mmol) was added to a solution of XR020003-I02 (200 mg, 0.59 mmol), XR02-S3 (204 mg, 0.88 mmol) in DMF (5 mL), and the reaction solution was stirred at 75° C. for 16 hours. The reaction solution was concentrated under reduced pressure and purified by preparation (formic acid system) to obtain white solid BX20-6-037 (110 mg, yield 45.0%). MS (ESI, m/z) 386.1 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ = 7.41 (d, J = 8.0Hz, 2H), 7.14 (d, J = 8.0Hz, 2H), 3.57-3.59 (m, 1H), 3.07 (q, J =10.1 Hz, 2H), 2.93-2.96 (m, 2H), 2.49-2.52 (m, 2H), 1.89-1.92 (m, 2H), 1.50-1.54 (m, 2H).

The synthesis of embodiment 15BX20-6-038

Synthesis of BX20-6-038

The synthetic route is shown in the following formula:

Method: Compound XR020007-I03 (0.30g, 0.79mmol), SM2 (0.13g, 0.79mmol), TEA (0.24g, 2.36mmol) were dissolved in DCM (6mL), and the reaction mixture was stirred at room temperature for 12h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography to obtain white powder compound BX20-6-038 (220 mg, yield 67%). MS (ESI, m/z) 418.11 [M+H] ⁺ .

¹ H NMR (400MHz, METHANOL-d ₄ ) δ7.69-7.67(m, 2H), 7.53-7.51(m, 2H), 4.12(q, J=8.0Hz, 2H), 4.05-4.02(m, 2H ), 3.80-3.75 (m, 1H), 3.01-2.99 (m, 2H), 1.96-1.92 (m, 2H), 1.43-1.33 (m, 2H), 1.26 (t, J=8.0Hz, 3H).

The synthesis of embodiment 16BX20-6-041

Step 1: Synthesis of Intermediate XR02001-S2

The synthetic route is shown in the following formula:

Method: Dissolve triphosgene (0.3g, 1.1mmol) in DCM (20mL) to obtain solution A, and replace N ₂ . XR02001-S1 (0.5 g, 2.1 mmol), TEA (0.6 g, 6.3 mmol) were dissolved in DCM (5 mL) as solution B. Solution A was cooled to -78°C with a liquid nitrogen ethanol bath, solution B was slowly added dropwise, and the temperature was naturally raised to -10°C for 1 h. Get XR02001-S2. XR02001-S2 does not process, and directly votes for the next step.

The second step: the synthesis of intermediate XR02001-S3

The synthetic route is shown in the following formula:

Method: Dissolve A1 (0.5g, 2.5mmol), TEA (0.6g, 6.3mmol) in DCM (5mL) as solution C. The reaction solution of XR02001-S2 was cooled down to -78°C, solution C was slowly added dropwise, and then reacted at 25°C for 1 h. After the reaction was completed, H ₂ O (10 mL) was added to quench excess triphosgene, the organic phase was collected and dried, concentrated under reduced pressure and purified by column chromatography to obtain compound XR02001-S3 (0.9 g, 92.5%) as a white solid powder. MS (ESI, m/z) = 464.1 [M+H] ⁺ .

Step 3: Synthesis of XR02001-S4

The synthetic route is shown in the following formula:

Method: Dissolve compound XR02001-S3 (0.5g, 1.1mmol) in MeOH (10mL), add HCl/1,4-dioxane (2.7mL, 10.8mmol) at 25°C, and stir the reaction mixture at room temperature 12h. After the reaction was completed, it was directly concentrated under reduced pressure to obtain light yellow oily compound XR02001-S4 (0.43 g, crude). MS (ESI, m/z) = 364.1 [M+H] ⁺ .

Step 4: Synthesis of BX20-6-041

The synthetic route is shown in the following formula:

Method: Dissolve compound XR02001-S4 (0.43g, crude) in DMF (10mL), add A2 (0.33g, 1.4mmol), TEA (0.33g, 3.2mmol), and heat the reaction mixture to 75°C for 12h. After the reaction is complete, add H ₂ O (10 mL) to dilute the reaction solution, extract the reaction solution with EA (20mE×3), collect the organic phase and dry it, concentrate the organic phase under reduced pressure and obtain a white powder by separation and purification (formic acid system) Compound BX20-6-041 (0.24 g, 49.9%). MS (ESI, m/z) = 446.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ=9.15(s, 1H), 7(t, J=8.0Hz, 1H), 7.66-7.62(m, 1H), 7.18(d, J=8.00Hz, 1H), 6.48(d, J=8.00Hz, 1H), 3.48-3.47(m, 1H), 3.15(q, J=8.00Hz, 2H), 2.86-2.83(m, 2H), 2.45-2.40(m , 2H), 1.79-1.76 (m, 2H), 1.46-1.38 (m, 2H).

The synthesis of embodiment 17BX20-6-042

Step 1: Synthesis of Intermediate XR02002-S2

The synthetic route is shown in the following formula:

Method: Dissolve triphosgene (2.0 g, 6.9 mmol) in DCM (20 mL) to obtain solution A, and replace N ₂ . XR02002-S1 (3.0 g, 15.4 mmol), TEA (2.3 g, 23.0 mmol) were dissolved in DCM (30 mL) as solution B. Solution A was cooled to -78°C with a liquid nitrogen ethanol bath, solution B was slowly added dropwise, and the temperature was naturally raised to -10°C for 1 h. Get XR02002-S2. XR02002-S2 does not process, and directly votes for the next step.

The second step: the synthesis of intermediate XR02002-S3

The synthetic route is shown in the following formula:

Method: Dissolve A1 (3.0g, 15.4mmol), TEA (2.3g, 23.0mmol) in DCM (20mL) as solution C. The reaction solution of XR02002-S2 was cooled to -78°C, solution C was slowly added dropwise, and then reacted at 25°C for 1 h. After the reaction was completed, H ₂ O (10 mL) was added to quench excess triphosgene, the organic phase was collected and dried, concentrated under reduced pressure and purified by column chromatography to obtain compound XR02002-S3 (4.6 g, 70.1%) as a white solid powder. MS (ESI, m/z) = 422.2 [M+H] ⁺ .

Step 3: Synthesis of XR02002-S4

The synthetic route is shown in the following formula:

Method: Dissolve compound XR02002-S3 (4.6g, 10.9mmol) in MeOH (14mL), add HCl/1,4-dioxane (13.6mL, 54.5mmol) at 25°C, and stir the reaction mixture at room temperature 2h. After the reaction was completed, it was directly concentrated under reduced pressure to obtain the colorless oily compound XR02002-S4 (3.0 g, crude). MS (ESI, m/z) = 322.1 [M+H] ⁺ .

Step 4: Synthesis of BX20-6-042

The synthetic route is shown in the following formula:

Method: Dissolve compound XR02002-S4 (1.0g, 2.8mmol) in DMF (6mL), add A2 (0.84g, 3.6mmol), TEA (0.84g, 8.4mmol), and heat the reaction mixture to 75°C for 12h . After the reaction is complete, add _H2O (25mL) to dilute the reaction solution, extract the reaction solution with EA (20mL×3), collect the organic phase and dry it, concentrate the organic phase under reduced pressure and obtain a white powder by separation and purification (formic acid system) Compound BX20-6-042 (670 mg). MS (ESI, m/z) = 404.1 [M+H] ⁺ .

The synthesis of embodiment 18BX20-6-043

Step 1: Synthesis of Intermediate XR02003-S2

The synthetic route is shown in the following formula:

Method: Dissolve A1 (12.8g, 64.2mmol), TEA (10.8g, 106.9mmol) in DCM (150mL) as solution A. Dissolve XR02003-S1 (10.0 g, 53.5 mmol) in DCM (50 mL) as solution B. Solution A was cooled to 0°C, solution B was slowly added dropwise, and then reacted at 25°C for 2h. After the reaction was completed, H ₂ O (10 mL) was added to quench excess triphosgene, the organic phase was collected and dried, concentrated under reduced pressure and purified by beating to obtain compound XR02003-S2 (20 g, 96.5%) as a white solid powder. MS (ESI, m/z) = 388.2 [M+H] ⁺ .

The second step: the synthesis of intermediate XR02003-S3

The synthetic route is shown in the following formula:

Method: Compound XR02003-S3 (20g, 51.7mmol) was dissolved in MeOH (100mL), HCl/1,4-dioxane (100mL, 400mmol) was added at 25°C, and the reaction mixture was stirred at room temperature for 12h. After the reaction was completed, it was directly concentrated under reduced pressure and purified by beating with acetone to obtain a pale white solid compound XR02003-S3 (14.7 g, 87.8%). MS (ESI, m/z) = 288.1 [M+H] ⁺ .

Step 3: Synthesis of BX20-6-043

The synthetic route is shown in the following formula:

Method: Dissolve compound XR02003-S3 (3.0g, 9.3mmol) in DMF (30mL), add A2 (2.8g, 12.1mmol), TEA (2.8g, 27.8mmol), and heat the reaction mixture to 75°C for 12h . After the reaction is complete, add H ₂ O (10 mL) to dilute the reaction solution, extract the reaction solution with EA (20 mL×3), collect the organic phase and dry it, concentrate the organic phase under reduced pressure and purify it by column chromatography to obtain the white powder compound BX20- 6-043 (1.3 g, 38.0%). MS (ESI, m/z) = 370.1 [M+H] ⁺ .

The synthesis of embodiment 19BX20-6-045

Refer to the synthesis method of BX20-6-024, MS (ESI, m/z) 431.15[M+H] ⁺

The synthesis of embodiment 20BX20-6-046

Refer to the synthesis method of BX20-6-024, MS (ESI, m/z) 445.16[M+H] ⁺

The synthesis of embodiment 21BX20-6-047

Refer to the synthesis method of BX20-6-024, MS (ESI, m/z) 430.11[M+H] ⁺

Synthesis of reference compound 1:

Refer to the synthesis method of Example 12 of patent WO2013116690 to synthesize reference compound 1

¹ H NMR (400MHz, DMSO-d6) δ = 8.55 (d, J = 11.2Hz, 1H), 7.47 (d, J = 7.6Hz, 2H), 7.21 (d, J = 7.6Hz, 2H), 6.28 ( t, J=8.0Hz, 1H), 4.23-4.21(m, 1H), 3.89-3.86(m, 1H), 3.72-3.69(m, 1H), 3.17-3.14(m, 1H), 2.84-2.68( m, 2H), 1.87-1.80(m, 2H), 1.55-1.54(m, 1H), 1.31-1.17(m, 3H), 0.97(t, J=7.6Hz, 3H), 0.83-0.78(m, 3H).

Biology Test Evaluation

Further describe and explain the present invention below in conjunction with test example

Test Example 1 Test of the inhibitory activity of the compounds of the present invention on human soluble cyclooxygenase (IC ₅₀ )

1. Purpose of the experiment

_IC50 values for the inhibitory activity of the compounds of the invention against human recombinant soluble cyclooxygenase (sEH) were determined using a sensitive fluorescence-based assay.

2. Experimental equipment and reagents

2.1 Experimental samples

Examples of the present invention and reference compounds, self-made.

2.2 Experimental Instruments

Multifunctional microplate reader (Tecan; Spark20M)

Microplate constant temperature incubator (Thermo; PST-60HL-4)

384-well white plate (Cisbio; 66PL384025)

2.3 Experimental reagents

3-Phenyl-cyano(6-methoxy-2-naphthyl)methyl ester-2-oxirane acetic acid (PHOME) (Cayman)

AUDA (positive compound) (Cayman)

Tris Buffer (trishydroxymethylaminomethane hydrochloride buffer) (pH 7.0, 25mM, Sigma)

Human soluble epoxide hydrolase (hsEH) (Cayman)

3. Experimental steps

Determination of IC50 values using a sensitive fluorescence-based assay

1) Add 8 μL/well of hsEH prepared to 2 μg/mL with Tris Buffer (final concentration 1 μg/mL) into a 384 black plate.

2) Then add the prepared compound and positive control into the plate at 4 μL/well. After mixing, centrifuge at 1000rpm for 1min. Incubate at 30°C for 5 minutes. Positive (no compound) and negative control wells (no sEH) were set at the same time.

3) Then add the prepared fluorescent substrate PHOME to the plate at 4 μL/well ([S]=1 μM). After mixing, centrifuge at 1000rpm for 1min. Incubate at 30°C for 15 minutes.

4) On-machine detection: excitation wavelength: 330nm; emission wavelength: 465nm.

4. Data analysis

The data were analyzed using GraphPad Prism, and the IC ₅₀ values of the compounds were calculated by fitting the percentage inhibition rate and ten-point concentration data to a parametric nonlinear logic formula.

5. Experimental results

Table 1 shows the test results of the inhibitory activity of the compounds of the examples of the present invention on human soluble cyclooxygenase.

Table 1

6. Experimental conclusion

It can be concluded from the above scheme that some compounds shown in the present invention have a better inhibitory effect on recombinant human soluble cyclooxygenase.

Test example 2 The compound of the present invention measures pharmacokinetics in SD rats

1. Purpose of the test

Taking SD rats as the experimental animals, study the pharmacokinetic behavior of the compound example in plasma in rats after oral administration at a dose of 6 mg/kg.

2. Test method

2.1. Test drugs

Examples of the present invention and reference compounds, self-made.

2.2. Test animals

Male SPF grade SD rats, body weight (200±20) g, Speiford (Beijing) Biotechnology Co., Ltd., animal production license number SCXK (Beijing) 2019-0010.

2.3. Preparation of test drugs

Drug preparation: the preparation drug concentration is 0.3mg/mL or 0.6mg/mL, and the preparation solution is 0.5% CMC solution.

Specific preparation: each 4.5 mg or 9 mg of the drug was weighed with a precision balance of one part per million, and evenly suspended in 15 mL of 0.5% CMC solution. Pay attention to prevent the drug from adhering to the stirring rod or the wall of the test tube during the drug preparation process.

2.4. Administration:

Male SPF grade SD rats, after 3-4 days of adaptive feeding, were administered intragastrically, with a dose of 3 mg/kg or 6 mg/kg, and a volume of 10 mL/kg.

2.5. Sample collection

Before administration (0h) and after administration, blood was collected from rats at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 24h, and blood was collected through fundus puncture. In the labeled EDTA-K2 anticoagulant test tube, immediately after blood collection, gently invert the blood collection tube 3 times and mix with anticoagulant, and immediately centrifuge at 4500rpm for 10min in an ice-water bath at 4°C until the centrifugation is over Afterwards, the plasma was collected and packed in EP tubes labeled accordingly, and stored in a -80°C refrigerator.

2.6. Sample detection

In this experiment, the briefly validated HPLC-MS/MS method was used to measure the concentrations of Example X and Example Y in plasma after administration.

2.6.1. Sample processing: Take 2 μL of blank plasma in a 96 deep-well plate, add 400 μL of precipitant methanol, vortex for 10 minutes, centrifuge at 4000 rpm for 15 minutes, take 250 μL of the supernatant in a 96 deep-well plate, and perform HPLC-MS/MS analysis , the injection volume is 5 μL.

2.6.2. Liquid mass analysis:

1) Liquid phase conditions

Chromatographic column: Waters XSelect CHS C18, 2.1*50mm, 1.8/5μm;

Pre-column: Waters online filter/Philomen AJO-4287;

Mobile phase A: 0.1% formic acid & 5mM ammonium acetate aqueous solution;

Mobile phase B: 0.1% formic acid in acetonitrile;

Flow Rate: 0.6mL/min;

Column Temperature: 40°C;

Autosampler temperature (Sample Tray Temperature): 4°C;

Injection Volume: 5.0μL;

Automatic sampling cleaning mode (Rinse Mode): before and after injection (Before and afteraspiration);

Autosampler Rinsing Volume: 500.0μL;

Rinse Dip Time when cleaning the syringe of the autosampler: 5sec;

Autosampler syringe cleaning method (Rinse Method): Rinse Port Only;

Autosampler syringe cleaning time (Rinse Time): 2sec

Autosampler cleaning solution (Rinse Pump and Port Wash Solution): 50% acetonitrile aqueous solution/50% methanol aqueous solution.

Elution method: Gradient elution

2) Mass spectrometry conditions:

Ion source: Electrospray Ionization (ESI);

Ionization mode (Ionization): Positive ion mode (Positive);

Detection mode (Mode): multiple reaction detection (MRM);

Collision cell gas (CAD): 8psi;

Curtain Gas Type: 35～45psi;

Atomizing gas (GS1): 50psi;

Auxiliary gas (GS2): 50~60psi;

Electrospray voltage (Ion Spray Voltage): 3000 ~ 4500V;

Vortex ion spray temperature (Turbo Ion Spray Temperature): 600～650℃;

Mass spectral resolution: unit;

3. Test results and analysis

The main parameters of pharmacokinetics were calculated by WinNonlin 7.0, and the results of pharmacokinetic experiments on rats are shown in Table 2 below.

Table 2 rat pharmacokinetic test results (6mg/kg dose)

4. Experimental conclusion

It can be seen from the results of the rat pharmacokinetic test in the table that the compounds of the examples of the present invention exhibit good metabolic properties.

Test Example 3: Study on Drug Efficacy of Diabetic Nerve Pain

1. Purpose of the test

To explore whether the compounds of the examples can improve the symptoms of diabetic neuropathic pain in rats.

2. Test material

Male SD rats, Sibeifu (Beijing) Biotechnology Co., Ltd., body weight: 180 ~ 220g, streptozotocin (sigma), the compound of the example

3. Diabetic Pain Model Establishment

After the rats were fed adaptively, the rats were tested for their basal pain threshold using the von Frey needle prick pain test kit (IITC Inc, Woodland Hills CA). Tail vein injection of 55mg/kg streptozotocin solution induced diabetic state, followed by tracking the development of neuropathic pain in rats. 7-10 days after modeling, the rats appeared pain attack symptoms.

4. Administration

During the onset of pain in rats, diabetic neuropathic pain rats were divided into groups, each group was no less than 6, and the compound of Example (10 mg/kg) and reference compound 1 (30 mg/kg) were applied by intragastric administration. Afterwards, the rats in each group were tested for mechanical pain threshold at different times.

5. Results

In the pharmacodynamic study using diabetic rat pain model, according to Figure 1, the compounds of the present disclosure showed higher potency and higher efficacy than the reference compound.

Effects of Example Compounds on Pedal Mechanical Pain Threshold in Diabetic Neuropathic Pain Rats. Compared with reference compound 1, the example has a higher pain-inhibiting effect. "*" means P<0.05; "**" means P<0.01 compared with before administration (0h) in each group.

Claims (10)

1. A compound or a pharmaceutically acceptable salt thereof as shown in formula I-1 or I-2, characterized in that,

Among them, R ¹ is 5 to 8 membered heterocycloalkyl, "cyclohexyl substituted by 1 or more R ^1-2 " or "5 to 8 membered cyclohexyl substituted by 1 or more R ^1-1 Heterocycloalkyl"; in the 5- to 8-membered heterocycloalkyl, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2; Each R ^1-1 is independently C ₁ -C ₆ alkyl,

Phenyl, "C ₁ -C ₆ alkyl substituted by 1 or more halogens" or "phenyl substituted by 1 or more R ^1-1-2 "; R ^1-1-1 is hydrogen,

C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl; R ^1-1-2 is carboxyl or cyano; R ^1-1-1-1 is hydrogen, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl; Each R ^1-1-1-2 is independently hydrogen, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl; Each R ^1-2 is independently

R ^1-2-1 is phenyl or "phenyl substituted by 1 or more R ^1-2-1-1 "; each R ^1-2-1-1 is independently carboxyl or cyano; n is 0, 1, 2 or 3; Each R ² is independently C ₁ -C ₆ alkyl, "C ₁ -C ₆ alkyl substituted by 1 or more halogen", "C ₁ -C ₆ alkoxy substituted by 1 or more halogen base", halogen or sulfur pentafluoride; R ^1' is "cyclohexyl substituted by 1 or more R ^1'-2 " or "5 to 8-membered heterocycloalkyl substituted by 1 or more R ^1'-1 "; the 5 In the 8-membered heterocycloalkyl group, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2; Each R ^1'-1 is independently "C ₁ -C ₆ alkyl substituted by 1 or more halogens"; Each R ^1'-2 is independently

R ^1'-2-1 is phenyl or "phenyl substituted by 1 or more R ^1'-2-1-1 "; Each R ^1'-2-1-1 is independently carboxy or cyano. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, in ^R , the 5- to 8-membered heterocycloalkyl is 5 or 6-membered heterocycloalkyl; is piperidinyl, for example

And/or, in R ¹ , the "5- to 8-membered heterocycloalkyl substituted by 1 or more R ^1-1 " is "5 or 6-membered substituted by 1 or more R ^1-1 membered heterocycloalkyl"; for example

wherein nitrogen is attached to R ^1-1 ; And/or, in R ^1-1 , the C ₁ -C ₆ alkyl is a C ₁ -C ₄ alkyl; it can also be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec Butyl, isobutyl or tert-butyl, also ethyl or isopropyl; And/or, in R ^1-1 , the C ₁ -C ₆ alkyl _{in the "C 1 -C 6 alkyl substituted by 1 or more halogens" is a C 1 -C 4 alkyl ; the} C ₁ -C ₄ alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; it can also be methyl, ethyl, n-propyl base or isopropyl; And/or, in R ^1-1 , the halogen in the "C ₁ -C ₆ alkyl substituted by 1 or more halogens" is fluorine, chlorine, bromine or iodine; preferably, the "substituted by 1 C ₁ -C ₆ alkyl substituted by one or more halogens" is "C ₁ -C ₆ alkyl substituted by one or more fluorine"; for example trifluoromethyl,

And/or, in R ^1-1 , the "phenyl substituted by 1 or more R ^1-1-2 " is phenyl substituted by carboxyl or phenyl substituted by cyano; for example

And/or, in R ^1-1-1 , the C ₁ -C ₆ alkyl is C ₁ -C ₄ alkyl; it can also be methyl, ethyl, n-propyl, isopropyl, n-butyl , sec-butyl, isobutyl or tert-butyl; can also be isobutyl or isopropyl; And/or, in R ^1-1-1 , the C ₃ -C ₆ cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclohexane; it can also be cyclopropane; And/or, in R ^1-1-1-1 , the C ₁ -C ₆ alkyl is a C ₁ -C ₄ alkyl; it can also be methyl, ethyl, n-propyl, isopropyl, n- Butyl, sec-butyl, isobutyl or tert-butyl; also methyl, ethyl or isopropyl; And/or, in R ^1-1-1-1 , the C ₃ -C ₆ cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclohexane, and can also be cyclopropane; And/or, in R ^1-1-1-2 , the C ₁ -C ₆ alkyl is a C ₁ -C ₄ alkyl; it can also be methyl, ethyl, n-propyl, isopropyl, n- Butyl, sec-butyl, isobutyl or tert-butyl; also methyl or isopropyl; And/or, in R ^1-1-1-2 , the C ₃ -C ₆ cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclohexane, and can also be cyclopropane; And/or, in R ² , the C ₁ -C ₆ alkyl in the "C ₁ -C 6 alkyl" is a C 1 -C ₄ alkyl; the _{C 1 -C 4} alkyl can also be _methyl , ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; can also be ethyl; And/or, in R ² , the C ₁ -C 6 alkyl _in the "C 1 -C ₆ alkyl substituted by 1 or more halogens" is a C _{1 -C 4} alkyl; the C ₁ - C _The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; it can also be ethyl; And/or, in R ² , the halogen in the "C ₁ -C ₆ alkyl substituted by 1 or more halogens" is fluorine, chlorine, bromine or iodine; more preferably, the "substituted by 1 or C ₁ -C ₆ alkyl substituted by multiple halogens" is "C ₁ -C ₆ alkyl substituted by 1 or more fluorine"; for example trifluoromethyl; And/or, in R ² , the C ₁ -C 6 alkoxy _in the "C 1 -C ₆ alkoxy substituted by 1 or more halogens" can be a C _{1 -C 4} alkoxy; Said C ₁ -C ₄ alkoxy is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy; The C ₁ -C ₄ alkoxy is also preferably methyl oxygen; further preferably, the "C ₁ -C ₆ alkoxy substituted by one or more halogens is C ₁ -C ₄ substituted by trifluoro Alkoxy, such as trifluoromethoxy; And/or, in R ² , the halogen is fluorine, chlorine, bromine or iodine; it can also be fluorine; And/or, in R ^1' , the "5- to 8-membered heterocycloalkyl substituted by 1 or more R ^1'-1 " is "substituted by 1 or more R ^1'-1 5- or 6-membered heterocycloalkyl"; for example

wherein nitrogen is attached to R ^1'-1 ; And/or, in R ^1'-1 , the C ₁ -C 6 alkyl _in the "C 1 -C ₆ alkyl substituted by 1 or more halogens" is a C _{1 -C 4} alkyl; C ₁ -C ₄ alkyl can also be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; it can also be methyl, ethyl or iso Propyl; And/or, in R ^1'-1 , the halogen in the "C ₁ -C ₆ alkyl substituted by 1 or more halogens" is fluorine, chlorine, bromine or iodine; more preferably, the "is C ₁ -C ₆ alkyl substituted by one or more halogens" is "C ₁ -C ₆ alkyl substituted by one or more fluorines"; such as trifluoromethyl or trifluoroethyl; And/or, R ^1'-2-1 is phenyl or "phenyl substituted by 1 R ^1'-2-1-1 "; And/or, R ^1'-2-1-1 is carboxyl or cyano. 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R is 6-membered heterocycloalkyl, "cyclohexyl substituted by 1 R ^1-2 " or "by A 6-membered nitrogen-containing heterocycloalkyl group substituted by 1 R ^1-1 "; in the 6-membered heterocycloalkyl group, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2; And/or, R ^1-1 is C ₁ -C ₆ alkyl, "C ₁ -C ₆ alkyl substituted by 2 halogens", "C ₁ -C ₆ alkyl substituted by 3 halogens" or

Preferably, R ^1-1 is C ₁ -C ₆ alkyl, "C ₁ -C ₆ alkyl substituted by 3 halogens" or

More preferably, R ^1-1 is "C ₁ -C ₄ alkyl substituted by 3 fluorines" or

and/or, R ^1-1-1 is

or C ₁ -C ₆ alkyl; preferably, R ^1-1-1 is

or C ₁ -C ₆ alkyl; more preferably, R ^1-1-1 is

or C ₁ -C ₄ alkyl; And/or, R ^1-1-1-1 is C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl; preferably, R ^1-1-1-1 is C ₁ -C ₆ alkyl ; More preferably, R ^1-1-1-1 is C ₁ -C ₄ alkyl; And/or, each R ^1-1-1-2 is independently hydrogen or C ₁ -C ₆ alkyl, and two R ^1-1-1-2 are not hydrogen at the same time; and/or, R ^1-2 is

And/or, R ^1-2-1 is phenyl or "phenyl substituted by 1 R ^1-2-1-1 "; And/or, R ^1-2-1-1 is carboxyl or cyano; And/or, n is 1 or 2; And/or, each R ² is independently "C ₁ -C ₆ alkyl substituted by 3 halogens", "C ₁ -C ₆ alkoxy substituted by 3 halogens", halogen or sulfur pentafluoride; And/or, R ^1' is "cyclohexyl substituted by 1 R ^1'-2 " or "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1'-1 "; preferably, R ^1' is a 6-membered nitrogen-containing heterocycloalkyl group substituted by 1 R ^1'-1 "; And/or, each R ^1'-1 is independently "C ₁ -C ₆ alkyl substituted by 3 halogens"; And/or, each R ^1'-2 is independently

And/or, R ^1'-2-1 is phenyl or "phenyl substituted by 1 R ^1'-2-1-1 "; And/or, each R ^1'-2-1-1 is independently carboxyl or cyano; Preferably, when n is 1, R ² is "C ₁ -C ₆ alkoxy substituted by 3 halogens"; And/or, when n is 2, R ² is "C ₁ -C ₆ alkoxy substituted by 3 halogens" and halogen. 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound shown in formula I-1 is Scheme 1, Scheme 2, Scheme 3 or Scheme 4: plan 1, Wherein, R ¹ is 6-membered heterocycloalkyl, "cyclohexyl substituted by 1 R ^1-2 " or "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1-1 "; said In the 6-membered heterocycloalkyl group, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2; R ^1-1 is C ₁ -C ₆ alkyl, "C ₁ -C ₆ alkyl substituted by 2 halogens", "C ₁ -C ₆ alkyl substituted by 3 halogens" or

R ^1-1-1 for

or C ₁ -C ₆ alkyl; R ^1-1-1-1 is C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl; Each R ^1-1-1-2 is independently hydrogen or C ₁ -C ₆ alkyl, and two R ^1-1-1-2 are not hydrogen at the same time; R ^1-2 for

R ^1-2-1 is phenyl or "phenyl substituted by 1 R ^1-2-1-1 "; R ^1-2-1-1 is carboxyl or cyano; n is 1 or ² ; each R is independently "C ₁ -C ₆ alkyl substituted by 3 halogens", "C ₁ -C ₆ alkoxy substituted by 3 halogens", halogen or pentafluoride sulfur; R ^1' is "cyclohexyl substituted by 1 R ^1'-2 " or "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1'-1 "; Each R ^1'-1 is independently "C ₁ -C ₆ alkyl substituted by 3 halogens"; Each R ^1'-2 is independently

R ^1'-2-1 is phenyl or "phenyl substituted by 1 R ^1'-2-1-1 "; each R ^1'-2-1-1 is independently carboxyl or cyano; Scenario 2, R ¹ is "cyclohexyl substituted by 1 R ^1-2 " or "5 to 8-membered heterocycloalkyl substituted by 1 or more R ^1-1 "; the 5 to 8-membered heterocycle In the alkyl group, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2; R ^1-1 is C ₁ -C ₆ alkyl,

or "C ₁ -C ₆ alkyl substituted by 1 or more halogens"; R ^1-1-1 for

Or C ₁ -C ₆ alkyl; R ^1-1-1-1 is C ₁ -C ₆ alkyl; R ^1-2 for

R ^1-2-1 is phenyl or "phenyl substituted by 1 R ^1-2-1-1 "; R ^1-2-1-1 is carboxyl or cyano; Option 3, R ¹ is "cyclohexyl substituted by 1 R ^1-2 " or "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1-1 "; R ^1-1 is "C ₁ -C ₆ alkyl substituted by 3 halogens" or

R ^1-1-1 for

or C ₁ -C ₆ alkyl; R ^1-1-1-1 is C ₁ -C ₆ alkyl; R ^1-2 for

R ^1-2-1 is phenyl or "phenyl substituted by 1 R ^1-2-1-1 "; R ^1-2-1-1 is carboxyl or cyano; n is 1 or ² ; each R is independently "C ₁ -C ₆ alkyl substituted by 3 halogens", "C ₁ -C ₆ alkoxy substituted by 3 halogens", halogen or pentafluoride sulfur; R ^1' is "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1'-1 "; Each R ^1'-1 is independently "C ₁ -C ₆ alkyl substituted by 3 halogens"; Option 4, R ¹ is "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1-1 "; R ^1-1 is "C ₁ -C ₄ alkyl substituted by 3 fluorines" or

R ^1-1-1 for

or C ₁ -C ₄ alkyl; R ^1-1-1-1 is C ₁ -C ₄ alkyl; When n is 1, R ² is "C ₁ -C ₆ alkoxy substituted by 3 halogens"; R ^1' is "6-membered nitrogen-containing heterocycloalkyl substituted by 1 R ^1'-1 "; R ^1'-1 is "C ₁ -C ₄ alkyl substituted by 3 halogens"; When n is 2, R ² is "C ₁ -C ₆ alkoxy substituted by 3 halogens" and halogen; R ^1' is "6-membered nitrogen-containing heterocyclic ring substituted by 1 R ^1'-1 Alkyl"; R ^1'-1 is "C ₁ -C ₄ alkyl substituted by 3 halogens". 5. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein: ^R1 is

and / or,

for

and/or, R ^1-1 is

6. A compound,

7. A preparation method for a compound shown in formula I-1, characterized in that it comprises the following steps: in a solvent, the compound shown in formula II and the amine compound are condensed as shown in the following formula in the presence of a base Reaction, get final product; The definition of ^R is as described in any one of claims 1-6;

8. The application of a substance Z in the preparation of medicines for the treatment and/or prevention of diseases related to soluble cyclooxygenase; it is characterized in that, the substance Z is a compound as claimed in any one of claims 1-6 or its pharmaceutically acceptable salts; Preferably, the disease is hypertension, pain, cardiomyopathy, inflammation, adult respiratory distress syndrome, diabetic complications, nephropathy, Raynaud's syndrome or arthritis; The pain is preferably neuropathic pain and/or inflammatory pain; The kidney disease is preferably end-stage renal disease; The hypertension is preferably renal hypertension, hepatic hypertension or pulmonary hypertension; The inflammation is preferably renal inflammation, vascular inflammation or pneumonia. 9. An application of a substance Z in the preparation of a soluble cyclooxygenase inhibitor; characterized in that, the substance Z is a compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition, characterized in that it comprises substance Z and pharmaceutical excipients, and said substance Z is the compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof.

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