A kind of amide compound, preparation method and application thereof

Abstract

The present invention discloses an amide compound, a preparation method thereof and an application thereof. 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 a good inhibitory effect on soluble cyclooxygenase.

Description

Technical Field

[0001] The invention relates to an amide compound, a preparation method and application thereof. Background Art

[0002] 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 a vital role in the metabolism of various compounds, including hormones, chemotherapeutic drugs, carcinogens, environmental pollutants, mycotoxins and other harmful xenobiotics.

[0003] 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 new effective and stable inhibitors of sEH. Chinese patent CN101084216A reported ureas substituted with trifluoromethylphenyl and trifluoromethoxyphenyl. However, more compounds with similar or improved activity need to be developed. Summary of the invention

[0004] The technical problem to be solved by the present invention is the defect that the existing drugs for inhibiting soluble cyclooxygenase have a relatively simple structure. To this end, the present invention provides an amide compound, a preparation method thereof and an application thereof. The compound of the present invention has a good inhibitory effect on soluble cyclooxygenase.

[0005] The present invention provides a compound as shown in Formula I-1 or I-2 or a pharmaceutically acceptable salt thereof,

[0006]

[0007] Among them, R 1 is a 5- to 8-membered heterocycloalkyl group, "surrounded by one or more R 1-2 "substituted cyclohexyl" or "substituted by one or more R 1-1 "substituted 5- to 8-membered heterocycloalkyl"; in the 5- to 8-membered heterocycloalkyl, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

[0008] Each R 1-1 are independently C1-C6 alkyl, Phenyl, "C1-C6 alkyl substituted by 1 or more halogens" or "C1-C6 alkyl substituted by 1 or more R 1-1-2 "substituted phenyl";

[0009] R 1-1-1 For hydrogen, C3-C6 cycloalkyl or C1-C6 alkyl;

[0010] R 1-1-2 is a carboxyl group or a cyano group;

[0011] R 1-1-1-1 is hydrogen, C3-C6 cycloalkyl or C1-C6 alkyl;

[0012] Each R 1-1-1-2 are independently hydrogen, C3-C6 cycloalkyl or C1-C6 alkyl;

[0013] Each R 1-2 Independently

[0014] R 1-2-1 is phenyl or "with 1 or more R 1-2-1-1 "substituted phenyl";

[0015] Each R 1-2-1-1 are independently carboxyl or cyano;

[0016] n is 0, 1, 2 or 3;

[0017] Each R 2 are independently C1-C6 alkyl, "C1-C6 alkyl substituted by 1 or more halogens", "C1-C6 alkoxy substituted by 1 or more halogens", halogen or sulfur pentafluoride;

[0018] R 1’ For "by one or more R 1’-2 "substituted cyclohexyl" or "substituted by one or more R 1’-1 "substituted 5- to 8-membered heterocycloalkyl"; in the 5- to 8-membered heterocycloalkyl, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

[0019] Each R 1’-1 are independently "C1-C6 alkyl substituted by 1 or more halogens";

[0020] Each R 1’-2 Independently

[0021] R 1’-2-1 is phenyl or "with 1 or more R 1’-2-1-1 "substituted phenyl";

[0022] Each R 1’-2-1-1 are independently carboxyl or cyano.

[0023] In a certain embodiment, in the compound shown in formula I-1 or I-2 or a pharmaceutically acceptable salt thereof, the definitions of certain groups may be as described below, and the definitions of other groups may be as described in any of the above embodiments (hereinafter referred to as "in a certain embodiment"): the compound shown in formula I-1 or a pharmaceutically acceptable salt thereof,

[0024]

[0025] Among them, R 1 is a 5- to 8-membered heterocycloalkyl group, "surrounded by one or more R 1-2 "substituted cyclohexyl" or "substituted by one or more R 1-1 "substituted 5- to 8-membered heterocycloalkyl"; in the 5- to 8-membered heterocycloalkyl, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

[0026] Each R 1-1 are independently C1-C6 alkyl, Phenyl, "C1-C6 alkyl substituted by 1 or more halogens" or "C1-C6 alkyl substituted by 1 or more R 1-1-2 "substituted phenyl";

[0027] R 1-1-1 For hydrogen, C3-C6 cycloalkyl or C1-C6 alkyl;

[0028] R 1-1-2 is a carboxyl group or a cyano group;

[0029] R 1-1-1-1 is hydrogen, C3-C6 cycloalkyl or C1-C6 alkyl;

[0030] Each R 1-1-1-2 are independently hydrogen, C3-C6 cycloalkyl or C1-C6 alkyl;

[0031] Each R 1-2 Independently

[0032] R 1-2-1 is phenyl or "with 1 or more R 1-2-1-1 "substituted phenyl";

[0033] Each R 1-2-1-1 are independently carboxyl or cyano.

[0034] In one scenario, R 1 is a 6-membered heterocycloalkyl group, "surrounded by 1 R 1-2 "substituted cyclohexyl" or "substituted by 1 R 1-1 "substituted 6-membered nitrogen-containing heterocycloalkyl"; in the 6-membered heterocycloalkyl, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

[0035] R 1-1 is C1-C6 alkyl, "C1-C6 alkyl substituted by 2 halogens", "C1-C6 alkyl substituted by 3 halogens" or

[0036] R1-1-1 for or C1-C6 alkyl;

[0037] R 1-1-1-1 is C3-C6 cycloalkyl or C1-C6 alkyl;

[0038] Each R 1-1-1-2 are independently hydrogen or C1-C6 alkyl, and both R 1-1-1-2 Not at the same time hydrogen;

[0039] R 1-2 for

[0040] R 1-2-1 is phenyl or "with 1 R 1-2-1-1 "substituted phenyl";

[0041] R 1-2-1-1 is a carboxyl group or a cyano group;

[0042] n is 1 or 2; each R 2 are independently "C1-C6 alkyl substituted by 3 halogens", "C1-C6 alkoxy substituted by 3 halogens", halogen or sulfur pentafluoride;

[0043] R 1’ For "being 1 R 1’-2 "substituted cyclohexyl" or "substituted by 1 R 1’-1 "substituted 6-membered nitrogen-containing heterocycloalkyl";

[0044] Each R 1’-1 are independently "C1-C6 alkyl substituted by 3 halogens";

[0045] Each R 1’-2 Independently

[0046] R 1’-2-1 is phenyl or "with 1 R 1’-2-1-1 "substituted phenyl";

[0047] Each R 1’-2-1-1 are independently carboxyl or cyano.

[0048] In one scenario, R 1 is a 6-membered heterocycloalkyl group, "surrounded by 1 R 1-2 "substituted cyclohexyl" or "substituted by 1 R 1-1 "substituted 6-membered nitrogen-containing heterocycloalkyl"; in the 6-membered heterocycloalkyl, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

[0049] R 1-1 is C1-C6 alkyl, "C1-C6 alkyl substituted by 3 halogens" or

[0050] R 1-1-1 for or C1-C6 alkyl;

[0051] R 1-1-1-1 is C3-C6 cycloalkyl or C1-C6 alkyl;

[0052] Each R 1-1-1-2 are independently hydrogen or C1-C6 alkyl, and both R 1-1-1-2 Not at the same time hydrogen;

[0053] R 1-2 for

[0054] R 1-2-1 is phenyl or "with 1 R 1-2-1-1 "Substituted phenyl";

[0055] R 1-2-1-1 It is carboxyl or cyano.

[0056] In one scenario, R 1 For "being 1 R 1-2 "substituted cyclohexyl" or "substituted by 1 R 1-1 "substituted 6-membered nitrogen-containing heterocycloalkyl";

[0057] R 1-1 "C1-C6 alkyl substituted by 3 halogens" or

[0058] R 1-1-1 for or C1-C6 alkyl;

[0059] R 1-1-1-1 is a C1-C6 alkyl group;

[0060] R 1-2 for

[0061] R 1-2-1 is phenyl or "with 1 R 1-2-1-1 "Substituted phenyl";

[0062] R 1-2-1-1 is a carboxyl group or a cyano group;

[0063] n is 1 or 2; each R 2 are independently "C1-C6 alkyl substituted by 3 halogens", "C1-C6 alkoxy substituted by 3 halogens", halogen or sulfur pentafluoride;

[0064] R 1’ For "being 1 R 1’-1 "substituted 6-membered nitrogen-containing heterocycloalkyl";

[0065] R 1’-1 It is "C1-C6 alkyl substituted by 3 halogens".

[0066] In one scenario, R 1 For "being 1 R 1-1 "substituted 6-membered nitrogen-containing heterocycloalkyl";

[0067] R 1-1 "C1-C4 alkyl substituted by 3 fluorine groups" or

[0068] R 1-1-1 for or C1-C4 alkyl;

[0069] R 1-1-1-1 is a C1-C4 alkyl group;

[0070] When n is 1, R 2 is a "C1-C6 alkoxy group substituted by 3 halogens"; R 1’ For "being 1 R 1’-1 "substituted 6-membered nitrogen-containing heterocycloalkyl"; R 1’-1 is "C1-C4 alkyl substituted by 3 halogens";

[0071] When n is 2, R 2 is "C1-C6 alkoxy substituted by 3 halogens" and halogen; R 1’ For "being 1 R 1’-1 "substituted 6-membered nitrogen-containing heterocycloalkyl"; R 1’-1 It is "C1-C4 alkyl substituted by 3 halogens".

[0072] In one scenario, R 1 is a 6-membered heterocycloalkyl group, "surrounded by 1 R 1-2 "substituted cyclohexyl" or "substituted by 1 R 1-1 "substituted 6-membered nitrogen-containing heterocycloalkyl"; in the 6-membered heterocycloalkyl, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2; preferably, R 1 For "being 1 R 1-2 "substituted cyclohexyl" or "substituted by 1 R 1-1 "substituted 6-membered nitrogen-containing heterocycloalkyl"; more preferably, R 1 For "being 1 R 1-1 "substituted 6-membered nitrogen-containing heterocycloalkyl".

[0073] In one scenario, R 1-1 is C1-C6 alkyl, "C1-C6 alkyl substituted by 2 halogens", "C1-C6 alkyl substituted by 3 halogens" or Preferably, R1-1 "C1-C6 alkyl substituted by 3 halogens" or More preferably, R 1-1 "C1-C4 alkyl substituted by 3 fluorine groups" or

[0074] In one scenario, R 1-1-1 for or C1-C6 alkyl; preferably, R 1-1-1 for or C1-C6 alkyl; more preferably, R 1-1-1 for Or C1-C4 alkyl.

[0075] In one scenario, R 1-1-1-1 is C3-C6 cycloalkyl or C1-C6 alkyl; preferably, R 1-1-1-1 is C1-C6 alkyl; more preferably, R 1-1-1-1 It is a C1-C4 alkyl group.

[0076] In one scheme, each R 1-1-1-2 are independently hydrogen or C1-C6 alkyl, and both R 1-1-1-2 Not hydrogen at the same time.

[0077] In one scenario, R 1-2 for

[0078] In one scenario, R 1-2-1 is phenyl or "with 1 R 1-2-1-1 "Substituted phenyl".

[0079] In one scenario, R 1-2-1-1 It is carboxyl or cyano.

[0080] In one embodiment, n is 1 or 2.

[0081] In one scenario, R 2 are independently "C1-C6 alkyl substituted by 3 halogens", "C1-C6 alkoxy substituted by 3 halogens", halogen or sulfur pentafluoride.

[0082] In one scenario, R 1’ For "being 1 R 1’-2 "substituted cyclohexyl" or "substituted by 1 R 1’-1 "substituted 6-membered nitrogen-containing heterocycloalkyl"; preferably, R 1’ For "being 1 R 1’-1 "substituted 6-membered nitrogen-containing heterocycloalkyl".

[0083] In one scheme, each R 1’-1are independently "C1-C6 alkyl substituted by 3 halogens".

[0084] In one scheme, each R 1’-2 Independently

[0085] In one scenario, R 1’-2-1 is phenyl or "with 1 R 1’-2-1-1 "Substituted phenyl".

[0086] In one scheme, each R 1’-2-1-1 are independently carboxyl or cyano.

[0087] In one scheme, when n is 1, R 2 It is "C1-C6 alkoxy substituted by 3 halogens".

[0088] In one scheme, when n is 2, R 2 It is "C1-C6 alkoxy substituted by 3 halogens" and halogen.

[0089] In one scenario, R 1 For "being 1 R 1-2 "substituted cyclohexyl" or "substituted by one or more R 1-1 "substituted 5- to 8-membered heterocycloalkyl"; in the 5- to 8-membered heterocycloalkyl, the heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;

[0090] R 1-1 is a C1-C6 alkyl group, or "C1-C6 alkyl substituted by 1 or more halogens";

[0091] R 1-1-1 for or C1-C6 alkyl; R 1-1-1-1 is a C1-C6 alkyl group;

[0092] R 1-2 for

[0093] R 1-2-1 is phenyl or "with 1 R 1-2-1-1 "Substituted phenyl"; R 1-2-1-1 It is carboxyl or cyano.

[0094] In one scenario, R 1 In the above, the 5- to 8-membered heterocycloalkyl group may be a 5- or 6-membered heterocycloalkyl group; or may be a piperidinyl group, for example

[0095] In one scenario, R 1 In the above, the term “is represented by one or more R 1-1The substituted 5- to 8-membered heterocycloalkyl group may be a substituted 5- to 8-membered heterocycloalkyl group. 1-1 "substituted 5- or 6-membered heterocycloalkyl"; for example Among them, nitrogen and R 1- 1 连 catch.

[0096] In one scenario, R 1-1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group; it may also be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group; it may also be an ethyl group or an isopropyl group.

[0097] In one scenario, R 1-1 In the “C1-C6 alkyl group substituted by one or more halogens”, the C1-C6 alkyl group may be a C1-C4 alkyl group; the C1-C4 alkyl group may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group; it may also be a methyl group, an ethyl group, a n-propyl group or an isopropyl group.

[0098] In one scenario, R 1-1 In the above, the halogen in the "C1-C6 alkyl substituted by one or more halogens" may be fluorine, chlorine, bromine or iodine; further preferably, the "C1-C6 alkyl substituted by one or more halogens" may be "C1-C6 alkyl substituted by one or more fluorines"; for example, trifluoromethyl,

[0099] In one scenario, R 1-1 In the above, the term “is represented by one or more R 1-1-2 The "substituted phenyl" may be a phenyl substituted by a carboxyl group or a phenyl substituted by a cyano group; for example

[0100] In one scenario, R 1-1-1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group; may also be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group; may also be an isobutyl group. Or isopropyl.

[0101] In one scenario, R 1-1-1 In the above, the C3-C6 cycloalkyl group may be cyclopropane, cyclobutane, cyclopentane or cyclohexane, and may also be cyclopropane.

[0102] In one scenario, R 1-1-1-1 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group; it may also be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group; it may also be a methyl group, an ethyl group or an isopropyl group.

[0103] In one scenario, R 1-1-1-1In the above, the C3-C6 cycloalkyl group may be cyclopropane, cyclobutane, cyclopentane or cyclohexane; or cyclopropane.

[0104] In one scenario, R 1-1-1-2 In the above, the C1-C6 alkyl group may be a C1-C4 alkyl group; it may also be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group; it may also be a methyl group or an isopropyl group.

[0105] In one scenario, R 1-1-1-2 In the above, the C3-C6 cycloalkyl group may be cyclopropane, cyclobutane, cyclopentane or cyclohexane, and may also be cyclopropane.

[0106] In one scenario, R 2 In the “C1-C6 alkyl”, the C1-C6 alkyl group may be a C1-C4 alkyl group; the C1-C4 alkyl group may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group; and may also be an ethyl group.

[0107] In one scenario, R 2 In the “C1-C6 alkyl group substituted by one or more halogens”, the C1-C6 alkyl group may be a C1-C4 alkyl group; the C1-C4 alkyl group may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group; and may also be an ethyl group.

[0108] In one scenario, R 2 In the above, the halogen in the “C1-C6 alkyl substituted by one or more halogens” may be fluorine, chlorine, bromine or iodine; further preferably, the “C1-C6 alkyl substituted by one or more halogens” may be “C1-C6 alkyl substituted by one or more fluorines”; for example, trifluoromethyl.

[0109] In one scenario, R 2 In the “C1-C6 alkoxy group substituted by one or more halogens”, the C1-C6 alkoxy group may be a C1-C4 alkoxy group; the C1-C4 alkoxy group is preferably a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a sec-butoxy group, an isobutoxy group or a tert-butoxy group; the C1-C4 alkoxy group is also preferably a methyloxy group; further preferably, the “C1-C6 alkoxy group substituted by one or more halogens is a trifluoro-substituted C1-C4 alkoxy group, such as a trifluoromethoxy group.

[0110] In one scenario, R 2 In the above, the halogen may be fluorine, chlorine, bromine or iodine; it may also be fluorine.

[0111] In one scenario, R 1’ In the above, the term “is represented by one or more R 1’-1The substituted 5- to 8-membered heterocycloalkyl group may be a substituted 5- to 8-membered heterocycloalkyl group. 1’-1 "substituted 5- or 6-membered heterocycloalkyl"; for example Among them, nitrogen and R 1’-1 connect.

[0112] In one scenario, R 1’-1 In the “C1-C6 alkyl group substituted by one or more halogens”, the C1-C6 alkyl group is a C1-C4 alkyl group; the C1-C4 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; it may also be methyl, ethyl or isopropyl.

[0113] In one scenario, R 1’-1 In the above, the halogen in the “C1-C6 alkyl substituted by one or more halogens” may be fluorine, chlorine, bromine or iodine; further preferably, the “C1-C6 alkyl substituted by one or more halogens” is “C1-C6 alkyl substituted by one or more fluorines”; for example, trifluoromethyl or trifluoroethyl.

[0114] In one plan, Can

[0115] In one scenario, R 1 Can Preferably R 1-1 and R 1-2 As mentioned before.

[0116] In one scenario, R 1-1 Can

[0117] The present invention also provides a compound,

[0118]

[0119] In one embodiment, the compound shown in formula I-1 is

[0120]

[0121] The present invention also provides a method for preparing a compound as shown in formula I-1, which comprises the following steps: in a solvent, a compound as shown in formula II and an amine compound are subjected to a condensation reaction as shown in the following formula in the presence of a base; R 1 The definition of is as mentioned above;

[0122]

[0123] In a certain embodiment, the solvent may be a conventional solvent in the art; the solvent may be an anhydrous solvent. The solvent may be selected from one or more of an ether solvent, a chlorinated alkane and an aromatic solvent. The ether solvent is preferably diethyl ether, tetrahydrofuran or tert-butyl methyl ether. The chlorinated alkane is preferably dichloromethane. The aromatic solvent is preferably toluene or benzene.

[0124] In one embodiment, the amount of the solvent used is the conventional amount 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.

[0125] In one embodiment, the molar ratio of the compound represented by Formula II to the amine compound can be 1:(1-3); for example, 1.5 or 1.7.

[0126] In a certain embodiment, the base may be an organic base conventionally used in the art, for example, the base may be a nitrogen-containing organic base, such as triethylamine.

[0127] In a certain embodiment, the amount of the base used can be the conventional amount 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.

[0128] The present invention also provides a use of a substance Z in the preparation of a drug for treating and / or preventing diseases associated with soluble cyclooxygenase; the substance Z is the aforementioned compound as shown in formula I-1 or I-2 or a pharmaceutically acceptable salt thereof.

[0129] Preferably, the disease is hypertension, pain, cardiomyopathy, inflammation, adult respiratory distress syndrome, diabetic complications, kidney disease, Raynaud's syndrome or arthritis.

[0130] The pain is preferably neuropathic pain and / or inflammatory pain.

[0131] The renal disease is preferably end-stage renal disease.

[0132] The hypertension is preferably renal hypertension, hepatic hypertension or pulmonary hypertension.

[0133] The inflammation is preferably kidney inflammation, vascular inflammation or lung inflammation.

[0134] 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 as shown in formula I-1 or I-2 or a pharmaceutically acceptable salt thereof.

[0135] The present invention also provides a pharmaceutical composition, which comprises a substance Z and a pharmaceutical excipient, wherein the substance Z is the aforementioned compound as shown in Formula I-1 or I-2 or a pharmaceutically acceptable salt thereof.

[0136] In the pharmaceutical composition, the substance Z may be a therapeutically effective amount of substance Z.

[0137] Definition of terms

[0138] Certain chemical groups defined herein are preceded by simplified notations to indicate the total number of carbon atoms present in the group. For example, a C1-C6 alkyl group 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 simplified notation does not include carbons that may be present in substituents of the group.

[0139] The term "plurality" refers to 2, 3, 4 or 5.

[0140] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0141] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom type (one or more of N, O, and S), which is a monocyclic, bridged, or spirocyclic ring, and each ring is saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

[0142] The term "nitrogen-containing heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10 members, and for example, 6 members), a specified number of heteroatoms (e.g., 1, 2 or 3), wherein the heteroatom is nitrogen, and each ring is saturated.

[0143] The term "pharmaceutically acceptable salt" refers to a salt formed by a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base with a compound of formula I-1, which retains the biological activity of the compound of formula I-1.

[0144] The term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0145] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering 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 condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0146] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0147] The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a patient."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 needed by those skilled in the art.

[0148] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0149] The reagents and raw materials used in the present invention are commercially available.

[0150] The positive and progressive effects of the present invention are that the compounds of the present invention have one or more of the advantages of better inhibitory effect on soluble cyclooxygenase, good metabolic properties (e.g., half-life, exposure AUC, maximum blood concentration Cmax) and higher pain inhibition effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0151] Figure 1 The effects of the compounds on the mechanical pain threshold of the foot of rats with diabetic neuropathic pain. Compared with the group before administration (0 h), "*" indicates P < 0.05; "**" indicates P < 0.01. DETAILED DESCRIPTION

[0152] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0153] Chromatographic conditions for preparative separation (purification):

[0154] Separation conditions:

[0155] Mobile phase: Mobile phase A: water (0.225% formic acid); Mobile phase B: acetonitrile

[0156] Chromatographic column: Phenomenexluna C18 150*40mm*15μm

[0157] Gradient elution: 37-67% mobile phase B

[0158] Gradient elution time: 10min

[0159] Detection wavelength: 254nm

[0160] Flow rate (ml / min): 60mL / min.

[0161] Example 1 Synthesis of BX20-6-I05

[0162] The synthetic route is shown below:

[0163]

[0164] Under N2 protection, triphosgene (0.91 g, 3.07 mmol) was dissolved in anhydrous DCM (15 mL), and the temperature was cooled to -78 °C in an ethanol / liquid nitrogen bath; XR020007-S1 (1.50 g, 6.84 mmol) and TEA (triethylamine) (1.04 g, 10.3 mmol) were dissolved in anhydrous DCM (15 mL), and added dropwise to the above reaction solution, and the temperature was naturally raised to 0 °C for reaction for 1 h, and then the temperature was lowered to -78 °C again; XR020007-S 2 (2.05 g, 10.3 mmol), TEA (1.04 g, 10.3 mmol) was dissolved in anhydrous DCM (15 mL) and added dropwise to the above reaction solution. After the addition was completed, the temperature was naturally raised to room temperature for reaction for 0.5 h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at 40 °C, and the residue was purified by column chromatography (PE / EA=10 / 1~1 / 1, V / V) to obtain a white solid BX20-6-I05 (2.60 g, yield was 86.6%).

[0165] 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 = 8.0Hz, 1H), 3.81-3.79 (m, 2 H), 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] + .

[0166] Example 2 Synthesis of BX20-6-007

[0167] The first step is the synthesis of BX20-6-I05

[0168] According to Example 1, a white solid BX20-6-I05 was obtained.

[0169] Step 2 Synthesis of XR020007-I03

[0170] The synthetic route is shown below:

[0171]

[0172] Compound BX20-5-I05 (0.80 g, 1.35 mmol) was added to HCl / MeOH (2 M, 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 step. MS (ESI, m / z) 346.3 [M+H] + .

[0173] Step 3: Synthesis of BX20-6-007

[0174] The synthetic route is shown below:

[0175]

[0176] The crude compound XR020007-I03 (0.62 g, 1.80 mmol), isobutyric acid (0.19 g, 2.16 mmol), T3P (3.44 g, 50% ethyl acetate solution, 5.40 mmol), TEA (0.55 g, 5.40 mmol) were added to anhydrous DCM (10 mL) in sequence, and the reaction mixture was reacted at 15° C. for 18 h. After the reaction, the reaction solution was directly concentrated under reduced pressure at 40° C., and the residue was purified by preparative separation (formic acid system) and freeze-dried to obtain a white powder compound BX20-6-007 (72 mg, yield 9.6%).

[0177] 1H 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=8.0Hz, 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] + .

[0178] Example 3 Synthesis of BX20-6-010

[0179] First step: Synthesis of S4-010

[0180]

[0181] Under N2 protection, triphosgene (0.49 g, 1.64 mmol) was dissolved in anhydrous DCM. 30ml), cooled to -78°C in an ethanol / liquid nitrogen bath; XR020007-S1 (0.80g, 3.65mmol), TEA (triethylamine) (0.55g, 5.50mmol) were dissolved in anhydrous DCM (15ml), added dropwise to the above reaction solution, naturally warmed to 0°C for reaction for 1h, and then cooled to -78°C again; S3-010 (1.18g, 5.47mmol), TEA (0.55g, 5.50mmol) were dissolved in anhydrous DCM (15ml), added dropwise to the above reaction solution, and naturally warmed to room temperature for reaction for 0.5h after the addition was completed. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure at 40°C, and the residue was purified by column chromatography (PE / EA=2 / 1~0 / 1, V / V) to obtain white solid S4-010 (0.90g, yield was 53%).

[0182] Step 2: Synthesis of BX20-6-010

[0183] The synthetic route is shown below:

[0184]

[0185] The crude compound S4-010 (0.65 g, 1.41 mmol) was added to anhydrous ethanol (20 mL), and then 6NNaOH solution (10 mL) was added, and the reaction mixture was reacted at 75°C for 12 h. After the reaction, the reaction solution was adjusted to pH 2 with concentrated HCl, and solids precipitated; the reaction solution was filtered to obtain a filter cake, which was purified by preparative separation (formic acid system) and freeze-dried to obtain a white powder compound BX20-6-010 (310 mg, yield 45.8%).

[0186] 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 = 8.0Hz, 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).

[0187] Example 4 Synthesis of BX20-6-023

[0188] Step 1 Synthesis of XR020007-I03

[0189] According to the second step of Example 2, compound XR020007-I03 was obtained.

[0190] Step 2 Synthesis of BX20-6-023

[0191] The synthetic route is shown below:

[0192]

[0193] (S)-(+)-2-Methylbutanoic acid (0.19 g, 2.16 mmol) and HATU (912 mg, 2.20 mmol) were added to anhydrous DMF (5 mL), stirred at 25 °C for 10 min, and the reaction mixture was cooled to 0 °C, XR020007-I03 (0.76 g, 2.00 mmol) and DIPEA (1.03 g, 8.00 mmol) were added, and the reaction mixture was reacted at 25 °C for 12 h. After the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with EA (20 mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 40°C to obtain the residue, which was purified by column chromatography (PE / EA=2 / 1 to 0 / 1) and then purified by preparative separation (formic acid system). After freeze-drying, a white powder compound BX20-6-023 (305 mg, yield was 35.5%) was obtained. 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] + .

[0194] Example 5 Synthesis of BX20-6-024

[0195] Step 1 Synthesis of XR020007-I03

[0196] According to the second step of Example 2, compound XR020007-I03 was obtained.

[0197] Step 2 Synthesis of BX20-6-024

[0198] The synthetic route is shown below:

[0199]

[0200] XR020007-I03 (0.60 g, 1.57 mmol) was added to anhydrous DCM (15 mL), triethylamine (0.47 g, 4.71 mmol) was added, the reaction mixture was stirred at 25°C for 5 minutes, and then isopropyl chloroformate (0.23 g, 1.90 mmol) was added dropwise at 0°C, and the reaction mixture was reacted at 25°C for 12 hours. After the reaction, water (1 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure at 40°C to obtain a residue, which was purified by column chromatography (PE / EA=2 / 1 to 0 / 1) to obtain a white powder compound BX20-6-024 (416 mg, yield 61%).

[0201] 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 = 7.6Hz, 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=8.0Hz, 6H); MS (ESI, m / z) 432.1 [M+H] + .

[0202] Example 6 Synthesis of BX20-6-025

[0203] Step 1 Synthesis of XR020007-I03

[0204] According to the second step of Example 2, compound XR020007-I03 was obtained.

[0205] Step 2 Synthesis of BX20-6-025

[0206] The synthetic route is shown below:

[0207]

[0208] Compound XR020007-I03 (0.60 g, 1.57 mmol) was dissolved in anhydrous DCM (10 mL), TEA (0.48 g, 4.72 mmol) was added dropwise, and stirred at 0°C for 5 min. Dimethyl dicarbonate (0.21 g, 1.57 mmol) was added dropwise, and the reaction mixture was stirred at 25°C for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure at 40°C, and the residue was purified by silica gel column chromatography (PE: EA = 1: 1 to 0: 1) to obtain a light yellow solid powder compound BX20-6-025 (480 mg, yield 75.8%). m / z = 404.1 [M+H] + .

[0209] 1 H NMR (400MHz, DMSO-d6) = 8.88 (s, 1H), 7.73 (d, J = 8.0Hz, 2H), 7.55 (d, J = 8.0Hz, 2H), 6.36 (d, J = 8.0Hz, 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).

[0210] Example 7 Synthesis of BX20-6-026

[0211] Step 1 Synthesis of XR020007-I03

[0212] According to the second step of Example 2, compound XR020007-I03 was obtained.

[0213] Step 2 Synthesis of BX20-6-026

[0214] The synthetic route is shown below:

[0215]

[0216] Compound XR020007-I03 (0.50 g, 1.31 mmol), BX20-6-026-S2 (0.37 g, 1.59 mmol), TEA (0.7 mL, 5.20 mmol) were added to DMF (10 mL) in sequence, and the reaction mixture was heated to 75°C overnight and stirred for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure at 40°C, and the residue was purified by column chromatography on silica gel (PE: EA = 2: 1 to 1: 1), and freeze-dried to obtain a white powder compound BX20-6-026 (230 mg, yield 41%). MS (ESI, m / z) 428.0 [M+H] + .

[0217] 1 H NMR (400MHz, DMSO-d6) = 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).

[0218] Example 8 Synthesis of BX20-6-027

[0219] Step 1 Synthesis of XR020007-I03

[0220] According to the second step of Example 2, compound XR020007-I03 was obtained.

[0221] Step 2 Synthesis of BX20-6-027

[0222] The synthetic route is shown below:

[0223]

[0224] XR020007-I03 (320 mg, 0.84 mmol) was dissolved in MeCN (10 mL), and K2CO3 (350 mg, 2.52 mmol) and 3-fluoro-1-iodopropane (377 mg, 1.68 mmol) were added, and the reaction was stirred at 60°C for 16 hours. Water was added to quench, and the mixture was extracted with ethyl acetate (25 mL x 3) and dried. After concentration under reduced pressure at 40°C, the residue was purified by column chromatography (PE / EA=10 / 1-5 / 1, V / V) to obtain a crude product, which was purified by preparative separation (formic acid system) and freeze-dried to obtain a white powder compound BX20-6-027 (190 mg, yield 22.0%). m / z=442.1[M+H] + .

[0225] 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).

[0226] Example 9 Synthesis of BX20-6-032

[0227] Step 1: Synthesis of S1

[0228] The synthetic route is shown below:

[0229]

[0230] Method: S0 (50 mg, 0.44 mmol) was dissolved in anhydrous DCM (2 mL), and pyridine (51 mg, 0.66 mmol) was added. Tf2O (123 mg, 0.66 mmol) was added dropwise at 0°C, 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.

[0231] Step 2: Synthesis of BX20-6-032

[0232] The synthetic route is shown below:

[0233]

[0234] Method: XR020007-103 (150 mg, 0.4 mmol) was dissolved in ACN (10 mL), and K2CO3 (81 mg, 0.6 mmol) and S1 DCM solution (about 0.2 mmol / mL, 2 mL) were added, and the reaction was stirred at 50°C for 16 hours. After the reaction, the filtrate was filtered, and the filtrate was purified by preparative purification (formic acid system) and freeze-dried to obtain a light yellow powder compound BX20-6-032 (16 mg, yield 9.0%). m / z = 442.2 [M+H] + .

[0235] 1 H NMR (400MHz, CD3OD) 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).

[0236] Example 10 Synthesis of BX20-6-033

[0237] The synthetic route is shown below:

[0238]

[0239] Method: Under ice bath, compound S0' (200 mg, 1.75 mmol) and pyridine (150 mg, 1.9 mmol) were dissolved in anhydrous DCM (4 mL), Tf2O (535 mg, 1.9 mmol) was slowly added dropwise, and the reaction mixture was stirred for 30 minutes under ice bath. After the reaction, the reaction solution was filtered to obtain a DCM solution of S1'. The above solution was added to ACN (10 mL), and K2CO3 (323 mg, 2.34 mmol) was added, and the reaction was stirred at 60°C for 1 hour. After the reaction, the reaction solution was filtered, purified by preparative separation (formic acid system), and freeze-dried to obtain a light yellow solid powder BX20-6-033 (22 mg, yield 6.4%).

[0240] 1 H NMR (400MHz, METHANOL-d4) = 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=6.8Hz, 3H).

[0241] Example 11 Synthesis of BX20-6-034

[0242] The synthetic route is shown below:

[0243]

[0244] Method: Compound XR020007-I03 (0.30 g, 0.79 mmol) and K2CO3 (0.33 g, 2.36 mmol) were dissolved in DMF (6 mL), and a solution of iodoethane (0.11 g, 0.71 mmol) in DMF (3 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure at 40 ° C. The residue was purified by preparative separation (formic acid system) and freeze-dried to obtain a white powder compound BX20-6-034 (90 mg, yield 31%). MS (ESI, m / z) 374.12 [M+H] + .

[0245] 1H NMR (400MHz, METHANOL-d4) = 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).

[0246] Example 12 Synthesis of BX20-6-035

[0247] The synthetic route is shown below:

[0248]

[0249] Method: Compound XR020007-I03 (0.30 g, 0.79 mmol) and K2CO3 (0.33 g, 2.36 mmol) were dissolved in DMF (6 mL), and a solution of isopropyl bromide (0.12 g, 0.94 mmol) in DMF (3 mL) was slowly added dropwise. The reaction mixture was heated to 60°C and stirred for 12 h. After the reaction, the reaction solution was directly concentrated under reduced pressure at 40°C to obtain a residue which was purified by preparative separation (formic acid system) and freeze-dried to obtain a white powder compound BX20-6-035 (110 mg, yield 36%). MS (ESI, m / z) 388.14 [M+H] + .

[0250] 1 H NMR (400MHz, METHANOL-d4) 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).

[0251] Example 13 Synthesis of BX20-6-036

[0252] The synthetic route is shown below:

[0253]

[0254] Method: XR020007-I03 (300 mg, 0.78 mmol) was dissolved in DMF (10 mL), and TEA (162 mg, 1.6 mmol) and SO (377 mg, 1.68 mmol) were added, and the reaction was stirred at room temperature for 16 hours. Water was added to quench, and ethyl acetate (25 mL x 3) was extracted and dried. After reduced pressure concentration at 40 ° C, the residue was purified by preparative purification (formic acid system), and freeze-dried to obtain a white powder compound BX20-6-036 (220 mg, yield 68.9%). m / z = 410.2 [M + H] + .

[0255] 1 H NMR (400MHz, CD3OD) 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).

[0256] Example 14 Synthesis of BX20-6-037

[0257] Step 1: Synthesis of intermediate XR020003-I01

[0258] The synthetic route is shown below:

[0259]

[0260] Method: Add TEA (1.91 g, 14.8 mmol) to a DCM (40 mL) solution of compound XR02-S1 (2.00 g, 9.85 mmol) at 0°C. Add XR02-S2 (2.37 g, 11.8 mmol) to the solution. React at 20°C for 1 hour and spin dry to obtain a crude product. The crude product is purified by silica gel column to obtain a white solid XR020003-I01 (2.70 g, yield 68.0%). MS (ESI, m / z) 404.2 [M+H] + .

[0261] Step 2: Synthesis of intermediate XR020003-I02

[0262] The synthetic route is shown below:

[0263]

[0264] Method: Add MeOH (3 mL, 12 mmol) to a solution of XR020003-I01 (1.00 g, 2.48 mmol) in MeOH (5 mL) at room temperature. After the reaction is complete, spin dry to obtain a pale yellow crude product (1.08 g, crude product), which is used directly in the next step. MS (ESI, m / z) 304.2 [M+H] + .

[0265] Step 3: Synthesis of BX20-6-037

[0266] The synthetic route is shown below:

[0267]

[0268] Method: Et3N (178 mg, 1.77 mmol) was added to a DMF (5 mL) solution of XR020003-I02 (200 mg, 0.59 mmol) and XR02-S3 (204 mg, 0.88 mmol), and the reaction solution was stirred at 75°C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by preparative (formic acid system) to obtain a white solid BX20-6-037 (110 mg, yield 45.0%). MS (ESI, m / z) 386.1 [M+H] + .

[0269] 1 H NMR (400MHz, CD3OD) 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=10.1Hz, 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).

[0270] Example 15 Synthesis of BX20-6-038

[0271] Synthesis of BX20-6-038

[0272] The synthetic route is shown below:

[0273]

[0274] Method: Compound XR020007-I03 (0.30 g, 0.79 mmol), SM2 (0.13 g, 0.79 mmol), TEA (0.24 g, 2.36 mmol) were dissolved in DCM (6 mL), and the reaction mixture was stirred at room temperature for 12 h. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a white powder compound BX20-6-038 (220 mg, yield 67%). MS (ESI, m / z) 418.11 [M+H] + .

[0275] 1 H NMR (400MHz, METHANOL-d4) 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).

[0276] Example 16 Synthesis of BX20-6-041

[0277] Step 1: Synthesis of intermediate XR02001-S2

[0278] The synthetic route is shown below:

[0279]

[0280] Method: Dissolve triphosgene (0.3 g, 1.1 mmol) in DCM (20 mL) to obtain solution A, and replace N2. Dissolve XR02001-S1 (0.5 g, 2.1 mmol) and TEA (0.6 g, 6.3 mmol) in DCM (5 mL) to obtain solution B. Cool solution A to -78°C using a liquid nitrogen ethanol bath, slowly drop solution B, and naturally warm to -10°C for 1 h. XR02001-S2 is obtained. XR02001-S2 is not treated and is directly used in the next step.

[0281] Step 2: Synthesis of intermediate XR02001-S3

[0282] The synthetic route is shown below:

[0283]

[0284] Method: A1 (0.5 g, 2.5 mmol) and TEA (0.6 g, 6.3 mmol) were dissolved in DCM (5 mL) to obtain solution C. The reaction solution of XR02001-S2 was cooled to -78°C, and solution C was slowly added dropwise, followed by reaction at 25°C for 1 h. After the reaction, H2O (10 mL) was added to quench the excess triphosgene, and the organic phase was collected and dried, concentrated under reduced pressure, and purified by column chromatography to obtain a white solid powder compound XR02001-S3 (0.9 g, 92.5%). MS (ESI, m / z) = 464.1 [M+H] + .

[0285] Step 3: Synthesis of XR02001-S4

[0286] The synthetic route is shown below:

[0287]

[0288] Method: Compound XR02001-S3 (0.5 g, 1.1 mmol) was dissolved in MeOH (10 mL), HCl / 1,4-dioxane (2.7 mL, 10.8 mmol) was added at 25°C, and the reaction mixture was stirred at room temperature for 12 h. After the reaction, the mixture was directly concentrated under reduced pressure to obtain a light yellow oil compound XR02001-S4 (0.43 g, crude). MS (ESI, m / z) = 364.1 [M+H] + .

[0289] Step 4: Synthesis of BX20-6-041

[0290] The synthetic route is shown below:

[0291]

[0292] Method: Compound XR02001-S4 (0.43 g, crude) was dissolved in DMF (10 mL), A2 (0.33 g, 1.4 mmol) and TEA (0.33 g, 3.2 mmol) were added, and the reaction mixture was heated to 75°C for 12 h. After the reaction, H2O (10 mL) was added to dilute the reaction solution, and the reaction solution was extracted with EA (20mE×3), the organic phase was collected and dried, and the organic phase was concentrated under reduced pressure and purified by preparative separation (formic acid system) to obtain a white powder compound BX20-6-041 (0.24 g, 49.9%). MS (ESI, m / z) = 446.1 [M+H] + .

[0293] 1H NMR (400MHz, DMSO-d6) 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).

[0294] Example 17 Synthesis of BX20-6-042

[0295] Step 1: Synthesis of intermediate XR02002-S2

[0296] The synthetic route is shown below:

[0297]

[0298] Method: Dissolve triphosgene (2.0 g, 6.9 mmol) in DCM (20 mL) to obtain solution A, and replace N2. Dissolve XR02002-S1 (3.0 g, 15.4 mmol) and TEA (2.3 g, 23.0 mmol) in DCM (30 mL) to obtain solution B. Cool solution A to -78°C using a liquid nitrogen ethanol bath, slowly drop solution B, and naturally warm to -10°C for 1 h. XR02002-S2 is obtained. XR02002-S2 is directly used in the next step without further treatment.

[0299] Step 2: Synthesis of intermediate XR02002-S3

[0300] The synthetic route is shown below:

[0301]

[0302] Method: A1 (3.0 g, 15.4 mmol) and TEA (2.3 g, 23.0 mmol) were dissolved in DCM (20 mL) to obtain solution C. The reaction solution of XR02002-S2 was cooled to -78°C, and solution C was slowly added dropwise, followed by reaction at 25°C for 1 h. After the reaction, H2O (10 mL) was added to quench the excess triphosgene, and the organic phase was collected and dried. After reduced pressure concentration, it was purified by column chromatography to obtain a white solid powder compound XR02002-S3 (4.6 g, 70.1%). MS (ESI, m / z) = 422.2 [M+H] + .

[0303] Step 3: Synthesis of XR02002-S4

[0304] The synthetic route is shown below:

[0305]

[0306] Method: Compound XR02002-S3 (4.6 g, 10.9 mmol) was dissolved in MeOH (14 mL), HCl / 1,4-dioxane (13.6 mL, 54.5 mmol) was added at 25°C, and the reaction mixture was stirred at room temperature for 2 h. After the reaction, the mixture was directly concentrated under reduced pressure to obtain a colorless oil compound XR02002-S4 (3.0 g, crude). MS (ESI, m / z) = 322.1 [M+H] + .

[0307] Step 4: Synthesis of BX20-6-042

[0308] The synthetic route is shown below:

[0309]

[0310] Method: Compound XR02002-S4 (1.0 g, 2.8 mmol) was dissolved in DMF (6 mL), A2 (0.84 g, 3.6 mmol) and TEA (0.84 g, 8.4 mmol) were added, and the reaction mixture was heated to 75 ° C for 12 h. After the reaction, H2O (25 mL) was added to dilute the reaction solution, and the reaction solution was extracted with EA (20 mL × 3). The organic phase was collected and dried, and the organic phase was concentrated under reduced pressure and purified by preparative separation (formic acid system) to obtain a white powder compound BX20-6-042 (670 mg). MS (ESI, m / z) = 404.1 [M+H] + .

[0311] Example 18 Synthesis of BX20-6-043

[0312] Step 1: Synthesis of intermediate XR02003-S2

[0313] The synthetic route is shown below:

[0314]

[0315] Method: A1 (12.8 g, 64.2 mmol) and TEA (10.8 g, 106.9 mmol) were dissolved in DCM (150 mL) to obtain solution A. XR02003-S1 (10.0 g, 53.5 mmol) was dissolved in DCM (50 mL) to obtain solution B. Solution A was cooled to 0°C, solution B was slowly added dropwise, and then reacted at 25°C for 2 h. After the reaction, H2O (10 mL) was added to quench the excess triphosgene, the organic phase was collected and dried, concentrated under reduced pressure, and purified by beating to obtain a white solid powder compound XR02003-S2 (20 g, 96.5%). MS (ESI, m / z) = 388.2 [M+H] + .

[0316] Step 2: Synthesis of intermediate XR02003-S3

[0317] The synthetic route is shown below:

[0318]

[0319] Method: Compound XR02003-S3 (20 g, 51.7 mmol) was dissolved in MeOH (100 mL), HCl / 1,4-dioxane (100 mL, 400 mmol) was added at 25°C, and the reaction mixture was stirred at room temperature for 12 h. After the reaction, it was directly concentrated under reduced pressure and purified by acetone beating to obtain a pale white solid compound XR02003-S3 (14.7 g, 87.8%). MS (ESI, m / z) = 288.1 [M+H] + .

[0320] Step 3: Synthesis of BX20-6-043

[0321] The synthetic route is shown below:

[0322]

[0323] Method: Compound XR02003-S3 (3.0 g, 9.3 mmol) was dissolved in DMF (30 mL), A2 (2.8 g, 12.1 mmol) and TEA (2.8 g, 27.8 mmol) were added, and the reaction mixture was heated to 75°C for 12 h. After the reaction, H2O (10 mL) was added to dilute the reaction solution, and the reaction solution was extracted with EA (20 mL × 3), the organic phase was collected and dried, and the organic phase was concentrated under reduced pressure and purified by column chromatography to obtain a white powder compound BX20-6-043 (1.3 g, 38.0%). MS (ESI, m / z) = 370.1 [M+H] + .

[0324] Example 19 Synthesis of BX20-6-045

[0325] Refer to the synthesis method of BX20-6-024, MS (ESI, m / z) 431.15 [M+H] +

[0326]

[0327] Example 20 Synthesis of BX20-6-046

[0328] Refer to the synthesis method of BX20-6-024, MS (ESI, m / z) 445.16 [M+H] +

[0329]

[0330] Example 21 Synthesis of BX20-6-047

[0331] Refer to the synthesis method of BX20-6-024, MS (ESI, m / z) 430.11 [M+H] +

[0332]

[0333] Synthesis of reference compound 1:

[0334] Reference compound 1 was synthesized by referring to the synthesis method of Example 12 of patent WO2013116690

[0335]

[0336] 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).

[0337] Biological test evaluation

[0338] The present invention is further described below in conjunction with test examples.

[0339] Test Example 1 Test of the inhibitory activity of the compounds of the present invention on human soluble cyclooxygenase (IC 50 )

[0340] 1. Purpose of the experiment

[0341] The IC values ​​of the compounds of the present invention against human recombinant soluble cyclooxygenase (sEH) were determined using a sensitive fluorescence-based assay. 50 value.

[0342] 2. Experimental instruments and reagents

[0343] 2.1 Experimental samples

[0344] The examples and reference compounds of the present invention were prepared in-house.

[0345] 2.2 Experimental instruments

[0346] Multifunctional microplate reader (Tecan; Spark20M)

[0347] Microplate constant temperature incubator (Thermo; PST-60HL-4)

[0348] 384-well white plate (Cisbio; 66PL384025)

[0349] 2.3 Experimental reagents

[0350] 3-Phenyl-cyano(6-methoxy-2-naphthyl)methyl ester-2-oxiraneacetic acid (PHOME)(Cayman)

[0351] AUDA (positive compound) (Cayman)

[0352] Tris Buffer (Tris(2-hydroxymethylaminomethane) hydrochloride buffer) (pH 7.0, 25 mM, Sigma)

[0353] Human soluble epoxide hydrolase (hsEH) (Cayman)

[0354] 3. Experimental Procedure

[0355] Determination of IC50 values ​​using a sensitive fluorescence-based assay

[0356] 1) Add 8 μL / well of hsEH prepared with Tris Buffer to 2 μg / mL (final concentration 1 μg / mL) into a 384-well black plate.

[0357] 2) Then add the prepared compound and positive control to the plate at 4 μL / well. After mixing, centrifuge at 1000 rpm for 1 min. Incubate at 30°C for 5 min. At the same time, set up positive (no compound) and negative control wells (no sEH).

[0358] 3) Then, add the prepared fluorescent substrate PHOME to the plate at 4 μL / well ([S] = 1 μM), mix well, centrifuge at 1000 rpm for 1 min, and incubate at 30°C for 15 min.

[0359] 4) On-machine detection: excitation wavelength: 330nm; emission wavelength: 465nm.

[0360] 4. Data Analysis

[0361] Data were analyzed using GraphPad Prism, and the IC of compounds was calculated by fitting the percent inhibition and ten-point concentration data to a parametric nonlinear logistic formula. 50 value.

[0362] 5. Experimental Results

[0363] The results of the test on the inhibitory activity of the compounds of the present invention on human soluble cyclooxygenase are shown in Table 1.

[0364] Table 1

[0365]

[0366]

[0367]

[0368] 6. Experimental Conclusion

[0369] The above schemes show that some of the compounds shown in the present invention show good inhibitory effects on recombinant human soluble cyclooxygenase.

[0370] Test Example 2 Pharmacokinetics of the compounds of the present invention in SD rats

[0371] 1. Purpose of the experiment

[0372] SD rats were used as test animals to study the pharmacokinetic behavior of the following compound examples in rat plasma after oral administration at a dose of 6 mg / kg.

[0373] 2. Test methods

[0374] 2.1. Test drugs

[0375] The examples and reference compounds of the present invention were prepared in-house.

[0376] 2.2. Experimental animals

[0377] Male SPF SD rats, weighing (200±20) g, from Sibeifu (Beijing) Biotechnology Co., Ltd., animal production license number SCXK (Beijing) 2019-0010.

[0378] 2.3. Preparation of experimental drugs

[0379] Drug preparation: Prepare the drug concentration to 0.3 mg / mL or 0.6 mg / mL, and the prepared solution is 0.5% CMC solution.

[0380] Specific preparation: Weigh 4.5 mg or 9 mg of each drug using a 1 / 10000 precision balance and evenly suspend in 15 mL of 0.5% CMC solution. Be careful to prevent the drug from adhering to the stirring rod or the wall of the test tube during the drug preparation process.

[0381] 2.4. Administration:

[0382] Male SPF SD rats were fed adaptively for 3-4 days and then given oral administration at a dose of 3 mg / kg or 6 mg / kg in a volume of 10 mL / kg.

[0383] 2.5. Sample collection

[0384] Before (0h) and after administration, blood was collected from rats at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 24h. Blood was collected by fundus puncture, and the blood volume was about 0.5mL. The blood was placed in a labeled EDTA-K2 anticoagulant tube. Immediately after blood collection, the blood collection tube was gently and completely inverted 3 times to mix with the anticoagulant, and immediately centrifuged at 4500rpm in an ice water bath at 4℃ for 10min. After the centrifugation operation was completed, the plasma was promptly dispensed into EP tubes with corresponding labels and stored in a -80℃ refrigerator.

[0385] 2.6. Sample testing

[0386] This experiment used a simple validated HPLC-MS / MS method to determine the concentrations of Example X and Example Y in plasma after administration.

[0387] 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 min, centrifuge at 4000 rpm for 15 min, take 250 μL of supernatant in a 96-deep-well plate, and perform HPLC-MS / MS analysis with an injection volume of 5 μL.

[0388] 2.6.2. Liquid quality analysis:

[0389] 1) Liquid phase conditions

[0390] Chromatographic column: Waters XSelect CHS C18, 2.1*50mm, 1.8 / 5μm;

[0391] Pre-column: Waters online filter / Phenomen AJO-4287;

[0392] Mobile phase A: 0.1% formic acid & 5 mM ammonium acetate aqueous solution;

[0393] Mobile phase B: 0.1% formic acid in acetonitrile;

[0394] Flow Rate: 0.6 mL / min;

[0395] Column Temperature: 40°C;

[0396] Sample Tray Temperature: 4°C

[0397] Injection Volume: 5.0 μL;

[0398] Automatic sampling cleaning mode (Rinse Mode): before and after aspiration;

[0399] Automatic sampler needle washing volume (Rinsing Volume): 500.0μL;

[0400] Rinse Dip Time for cleaning the autosampler needle: 5 sec;

[0401] Automatic sampler needle cleaning method (Rinse Method): Rinse Port Only;

[0402] Automatic sampler needle cleaning time (Rinse Time): 2sec

[0403] Rinse Pump and Port Wash Solution: 50% acetonitrile aqueous solution / 50% methanol aqueous solution.

[0404] Elution method: gradient elution

[0405] 2) Mass spectrometry conditions:

[0406] Ion source: Electrospray Ionization (ESI);

[0407] Ionization mode: positive ion mode (Positive);

[0408] Detection mode: multiple reaction monitoring (MRM);

[0409] Collision cell gas (CAD): 8 psi;

[0410] Curtain Gas Type: 35-45 psi;

[0411] Atomizing gas (GS1): 50psi;

[0412] Auxiliary gas (GS2): 50~60psi;

[0413] Electrospray voltage: 3000-4500 V;

[0414] Turbo Ion Spray Temperature: 600-650°C;

[0415] Mass spectrometry resolution: unit;

[0416] 3. Test results and analysis

[0417] The main pharmacokinetic parameters were calculated using WinNonlin 7.0. The results of the rat pharmacokinetic experiment are shown in Table 2 below.

[0418] Table 2 Pharmacokinetic test results in rats (6 mg / kg dose)

[0419]

[0420]

[0421] 4. Experimental Conclusion

[0422] It can be seen from the rat pharmacokinetic test results in the table that the example compounds of the present invention exhibit good metabolic properties.

[0423] Test Example 3: Study on the efficacy of diabetic neuropathy

[0424] 1. Purpose of the experiment

[0425] The aim of this study was to investigate whether the compounds in the examples could improve the symptoms of diabetic neuropathic pain in rats.

[0426] 2. Test Materials

[0427] Male SD rats, Sibeifu (Beijing) Biotechnology Co., Ltd., body weight: 180-220 g, streptozotocin (Sigma), Example compounds

[0428] 3. Establishment of Diabetes Pain Model

[0429] After the rats were fed adaptively, the basal pain threshold of the rats was tested using the von Frey needle pain test kit (IITC Inc, Woodland Hills CA). The diabetic state was induced by tail vein injection of 55 mg / kg streptozotocin solution, and the development of neuropathic pain in the rats was subsequently tracked. The rats showed symptoms of pain attacks 7 to 10 days after modeling.

[0430] 4. Drug administration

[0431] During the pain attack period of rats, rats with diabetic neuropathic pain were divided into groups, with no less than 6 rats in each group, and the Example Compound (10 mg / kg) and Reference Compound 1 (30 mg / kg) were administered by gavage. Mechanical pain threshold tests were performed on rats in each group at different times after administration.

[0432] 5. Results

[0433] In the efficacy study using the diabetic rat pain model, according to Figure 1 , the compounds of the present disclosure showed higher potency and higher efficacy than the reference compounds.

[0434] Effects of Example Compounds on Mechanical Pain Threshold of the Foot of Rats with Diabetic Neuropathic Pain. Compared with Reference Compound 1, Example Compounds have a higher pain-inhibiting effect. Compared with the group before administration (0 h), "*" indicates P < 0.05; "**" indicates P < 0.01.

Claims

1. A compound as shown in formula I-1 or a pharmaceutically acceptable salt thereof, characterized in that: Among them, R 1 For "1 R 1-2 Substituted cyclohexyl" or "substituted by 1 R 1-1 "substituted 6-membered nitrogen-containing heterocycloalkyl"; R 1-1 is "C1-C6 alkyl substituted by 3 halogens" or R 1-1-1 for or C1-C6 alkyl; R 1-1-1-1 is a C1-C6 alkyl group; R 1-2 for R 1-2-1 is phenyl or is replaced by 1 R 1-2-1-1 "substituted phenyl"; R 1-2-1-1 It is a carboxyl group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R 1 In the above, the "is 1 R 1-1 The substituted 6-membered nitrogen-containing heterocycloalkyl group is Among them, nitrogen and R 1-1 connect; or, R 1-1 In the “C1-C6 alkyl group substituted by 3 halogens”, the C1-C6 alkyl group is a C1-C4 alkyl group; or, R 1-1 In the "C1-C6 alkyl substituted by 3 halogens", the halogen is fluorine, chlorine, bromine or iodine; or, R 1-1-1 wherein the C1-C6 alkyl group is a C1-C4 alkyl group; or, R 1-1-1-1 wherein the C1-C6 alkyl group is a C1-C4 alkyl group.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that: R 1-1 wherein the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; or, R 1-1 In the above, the "C1-C6 alkyl group substituted by 3 halogens" is "C1-C6 alkyl group substituted by 3 fluorines"; or, R 1-1-1 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; or, R 1-1-1-1 In the above, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that: R 1-1 wherein the C1-C4 alkyl group is methyl, ethyl, n-propyl or isopropyl; or, R 1-1 In the above, the "C1-C6 alkyl group substituted by 3 halogens" is trifluoromethyl, or, R 1-1-1 wherein the C1-C6 alkyl group is isobutyl or isopropyl; or, R 1-1-1-1 In the above, the C1-C6 alkyl group is a methyl group, an ethyl group or an isopropyl group.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R 1 In the 6-membered nitrogen-containing heterocycloalkyl group, the number of heteroatoms is 1 or 2; or, R 1-1 is "C1-C4 alkyl substituted by 3 fluorine groups" or or, R 1-1-1 for or C1-C4 alkyl; or, R 1-1-1-1 It is a C1-C4 alkyl group.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound shown in formula I-1 is as follows: R 1 For "1 R 1-1 "substituted 6-membered nitrogen-containing heterocycloalkyl"; R 1-1 is "C1-C4 alkyl substituted by 3 fluorine groups" or R 1-1-1 for or C1-C4 alkyl; R 1-1-1-1 It is a C1-C4 alkyl group.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R 1 for or, R 1-1 for 8. A compound, 9. A method for preparing a compound as shown in formula I-1, characterized in that: The method comprises the following steps: in a solvent, a compound as shown in formula II and an amine compound are subjected to a condensation reaction as shown in the following formula in the presence of a base; R 1 The definition as described in any one of claims 1 to 7; 10. Use of a substance Z in the preparation of a drug for treating and / or preventing a disease associated with soluble cyclooxygenase; characterized in that: The substance Z is a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

11. The use according to claim 10, characterized in that The disease is hypertension, pain, cardiomyopathy, inflammation, adult respiratory distress syndrome, diabetic complications, kidney disease or Raynaud's syndrome.

12. The use according to claim 10, characterized in that The disease is arthritis.

13. The use according to claim 11, characterized in that The pain is neuropathic pain and / or inflammatory pain.

14. The use according to claim 11, characterized in that The kidney disease is end-stage renal disease.

15. The use according to claim 11, characterized in that The hypertension is renal hypertension, hepatic hypertension or pulmonary hypertension.

16. The use according to claim 11, characterized in that The inflammation is kidney inflammation, vascular inflammation or lung inflammation.

17. Use 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 to 8 or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition, characterized in that It comprises a substance Z and a pharmaceutical excipient, wherein the substance Z is a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

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