Pyrazoloheteroaryl compound, and preparation method therefor and use thereof

Abstract

Provided is a pyrazoloheteroaryl compound. The compound can be used for preparing a drug as a COX inhibitor; furthermore, the compound can be used for preventing and / or treating inflammations and pains.

Description

A pyrazoloheteroaryl compound and its preparation method and application Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a pyrazoloheteroaryl compound. The compound can be used to prepare a drug as a COX inhibitor. Furthermore, the compound can be used to prevent and / or treat inflammation and pain. Background Art

[0002] Inflammation plays a crucial role in the development of many complex diseases, such as autoimmune diseases, metabolic syndrome, neurodegenerative diseases, cardiovascular diseases, and tumors. Nonsteroidal anti-inflammatory drugs (NSAIDs), a major class of anti-inflammatory drugs, have become the most commonly used class of drugs. Prostaglandins (PGs) play an important regulatory role in inflammation, and all NSAIDs work by inhibiting the production of PGs. Cyclooxygenase (COX) catalyzes the metabolism of arachidonic acid (AA) to produce PGs and their analogs, making COX an important target for anti-inflammatory drugs.

[0003] Long-term use of non-selective COX inhibitors is associated with toxic side effects such as gastric ulcers and gastric bleeding, which limits their use. Selective COX-2 inhibitors were initially considered safer alternatives to traditional NSAIDs, but most of these drugs later became controversial due to the risk of heart attack and stroke, and some were even withdrawn from the market. Some meta-analyses have reported that the higher the selectivity of COX-2 drugs, the higher the risk of cardiovascular toxicity. The selective COX-2 inhibitor rofecoxib was withdrawn from the market due to its risk of cardiovascular side effects. Moderately selective COX-2 inhibitors may reduce their cardiotoxicity. Furthermore, studies have shown that COX-1 inhibitors have potential value in the treatment of thrombosis, while COX-2 inhibitors have potential value in the prevention and treatment of tumors. Therefore, the design and synthesis of novel COX inhibitors are of great significance to human health.

[0004] In short, existing nonsteroidal anti-inflammatory drugs still have adverse reactions in the gastrointestinal tract and cardiovascular aspects, so the present invention hopes to develop safer and more effective small molecule nonsteroidal anti-inflammatory drugs.

[0005] Summary of the Invention

[0006] The present invention aims to design and prepare a new class of COX inhibitors to improve the efficacy and / or safety of existing nonsteroidal anti-inflammatory drugs. The design aims to selectively inhibit the two cyclooxygenase isoforms (COX-1 and COX-2), identifying weakly selective inhibitors of COX-2 to minimize the toxic side effects of COX inhibitors.

[0007] The present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof.

[0008] in,

[0009] T1 is selected from C and N; T2 is selected from CR2, N and NR2; T3 is selected from CR3 and N; T4 is selected from CR4, N and NR4;

[0010] Preferably, T1 is selected from N, T2 is selected from N, T3 is selected from CR3, T4 is selected from CR4 or T1 is selected from C, T2 is selected from CR2, T3 is selected from N, T4 is selected from NR4;

[0011] R1 is selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally replaced by one or more R a replace;

[0012] R2 is selected from H and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally replaced by one or more R b replace;

[0013] R3 is selected from H and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally replaced by one or more R c replace;

[0014] R4 is selected from H and -LR d , the-LR d optionally substituted with one or more R;

[0015] R5 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl are each independently optionally substituted by one or more R e replace;

[0016] L is selected from a bond, -C(=O)-, -CH(OH)-, -CH=CH- and -C 1-3 Alkylene-, preferably, L is selected from a bond, -C(=O)-, -CH(OH)-, -CH=CH-, -CH2-, -CH2CH2- or -CH(CH3)-;

[0017] Each Ra are independently selected from halogen; each R b are independently selected from halogen; each R c are each independently selected from halogen;

[0018] R d Selected from phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkyl, OH, COOH and -C(=O)OC 1-3 Alkyl, the phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkyl or -C(=O)OC 1-3 The alkyl groups are each independently optionally substituted with one or more R;

[0019] Each R e are independently selected from halogen, OH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Alkylthio, S(=O)2-C 1-3 Alkyl and S(=O)2NH2, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Alkylthio or S(=O)2-C 1-3 The alkyl groups are each independently optionally substituted with one or more halogen or morpholinyl groups;

[0020] Each R is independently selected from halogen, OH, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-4 Alkylamino, -C(=O)OC 1-3 Alkyl and S(=O)2NH2, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-4 Alkylamino or -C(=O)OC 1-3 The alkyl groups are each independently optionally substituted with one or more halogens.

[0021] In certain embodiments, in the compound of formula (I), R1 is selected from CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2, and the CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2 are independently optionally replaced by 1, 2, 3, 4 or 5 R a replace.

[0022] In certain embodiments, in the compound of formula (I), R1 is selected from CH2F, CHF2 and CF3.

[0023] In certain embodiments, in the compound of formula (I), R1 is selected from CHF2 and CF3.

[0024] In certain embodiments, in the compound represented by formula (I), R1 is selected from CF3.

[0025] In certain embodiments, in the compound of formula (I), R2 is selected from H, CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2, and the CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2 are independently optionally replaced by 1, 2, 3, 4 or 5 R b replace.

[0026] In certain embodiments, in the compound of formula (I), R3 is selected from H, CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2, and the CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2 are independently optionally replaced by 1, 2, 3, 4 or 5 R c replace.

[0027] In certain embodiments, in the compound of formula (I), R2 and R3 are independently selected from H, CH3, CH2F, CHF2 and CF3.

[0028] In certain embodiments, in the compound represented by formula (I), R2 is selected from CH3 and CF3, and R3 is selected from H.

[0029] In certain embodiments, in the compound represented by formula (I), each R is independently selected from F, Cl, Br, I, OH, COOH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, N(CH3)2, NHCH2CH3, N(CH2CH3)2, COOCH3, COOCH2CH3 and S(=O)2NH2, and CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, N(CH3)2, NHCH2CH3, N(CH2CH3)2, COOCH3 or COOCH2CH3 are independently optionally substituted with 1, 2, 3, 4 or 5 F, Cl, Br or I.

[0030] In certain embodiments, in the compound represented by formula (I), each R is independently selected from F, Cl, Br, OH, COOH, CH3, CH2CH3, CF3, OCH3, N(CH3)2, NHCH2CH3, COOCH3 and -S(=O)NH2.

[0031] In certain embodiments, in the compound represented by formula (I), R d is selected from phenyl, furyl, thienyl, thiazolyl, pyridinyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, morpholinyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2(CH2)2CH3, CH2(CH2)3CH3, CH2(CH2)4CH3, OH, COOH, COOCH3 and COOCH3, and the phenyl, furyl, thienyl, thiazolyl, pyridinyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, morpholinyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2(CH2)2CH3, CH2(CH2)3CH3, CH2(CH2)4CH3, OH, COOH, COOCH3 or COOCH3 are each independently optionally substituted with 1, 2, 3, 4 or 5 R.

[0032] In certain embodiments, in the compound represented by formula (I), R d Selected from OH, COOH,

[0033] In certain embodiments, in the compound represented by formula (I), R4 is selected from phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, -C(=O)-phenyl, -C(=O)-5-6 membered heteroaryl, -C(=O)-C 5-6 Cycloalkyl, -C(=O)-5-6 membered heterocycloalkyl, -C(=O)-C 1-6 Alkyl, -CH=CH-COOH, -CH=CH-C(=O)OC 1-3 Alkyl, -CH2-phenyl, -CH2-5-6 membered heteroaryl, -CH2-COOH, -CH2-C(=O)OC 1-3 Alkyl, -CH2CH2-5-6 membered heterocycloalkyl, -CH2CH2-OH, -CH(CH3)-COOH and -CH(OH)-5-6 membered heteroaryl, the phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, -C(=O)-phenyl, -C(=O)-5-6 membered heteroaryl, -C(=O)-C 5-6 Cycloalkyl, -C(=O)-5-6 membered heterocycloalkyl, -C(=O)-C 1-6Alkyl, -CH=CH-COOH, -CH=CH-C(=O)OC 1-3 Alkyl, -CH2-phenyl, -CH2-5-6 membered heteroaryl, -CH2-COOH, -CH2-C(=O)OC 1-3 Alkyl, -CH2CH2-5-6 membered heterocycloalkyl, -CH2CH2-OH, -CH(CH3)-COOH or -CH(OH)-5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4 or 5 R.

[0034] In certain embodiments, in the compound represented by formula (I), R4 is selected from phenyl, pyridyl, cyclopentyl, cyclohexyl, -C(=O)-phenyl, -C(=O)-furyl, -C(=O)-thienyl, -C(=O)-thiazolyl, -C(=O)-pyridyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-tetrahydropyranyl, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH2(CH2)2CH3, -C(=O)-CH2(CH2)3CH3, -C(=O)-CH2 (CH2)4CH3, -CH=CH-COOH, -CH=CH-COOCH3, -CH2-phenyl, -CH2-pyridyl, -CH2-COOH, -CH2-COOCH2CH3, -CH2CH2-morpholinyl, -CH2CH2-OH, -CH(CH3)-COOH and -CH(OH)-thienyl, the phenyl, pyridyl, cyclopentyl, cyclohexyl, -C(=O)-phenyl, -C(=O)-furyl, -C(=O)-thienyl, -C(=O)-thiazolyl, -C(=O)-pyridyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-tetrahydropyranyl, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH2(CH2)2CH3, -C(=O)-CH2(CH2)3CH3, -C(=O)-CH2(CH2)3CH3, O)-CH2(CH2)4CH3, -CH=CH-COOH, -CH=CH-COOCH3, -CH2-phenyl, -CH2-pyridyl, -CH2-COOH, -CH2-COOCH2CH3, -CH2CH2-morpholinyl, -CH2CH2-OH, -CH(CH3)-COOH or -CH(OH)-thienyl, each independently optionally substituted with 1, 2, 3, 4 or 5 R.

[0035] In certain embodiments, in the compound represented by formula (I), R4 is selected from

[0036] In certain embodiments, in the compound represented by formula (I), each R e Each of the following is independently selected from F, Cl, Br, I, OH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCD3, OCD2CD3, SCH3, SCH2CH3, SCH2CH2CH3, SCH(CH3)2, S(=O)2CH3, S(=O)2CH2CH3 and S(=O)2NH2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCD3, OCD2CD3, SCH3, SCH2CH3, SCH2CH2CH3, SCH(CH3)2, S(=O)2CH3 or S(=O)2CH2CH3 are each independently optionally substituted with 1, 2, 3, 4 or 5 F, Cl, Br, I or morpholino groups.

[0037] In certain embodiments, in the compound represented by formula (I), each R e are independently selected from F, Cl, Br, OH, CH3, OCH3, OCD3, SCH3, S(=O)2CH3, S(=O)2NH2 and

[0038] In certain embodiments, in the compound represented by formula (I), R5 is selected from furanyl, thienyl, phenyl and pyridyl, and the furanyl, thienyl, phenyl or pyridyl are independently optionally replaced by 1, 2, 3, 4 or 5 R e replace.

[0039] In certain embodiments, in the compound represented by formula (I), R5 is selected from

[0040] In certain embodiments, the compound is selected from the compounds represented by formula (I-1) and (I-2),

[0041] wherein R1, R2, R4 and R5 are as defined in the present invention.

[0042] In certain embodiments, the compound is selected from the compound represented by formula (I-1), wherein R1 is defined as described herein, and R4 is selected from H and -LR d , the-LR d is optionally substituted with one or more R, L is selected from a bond, -C(=O)-, -CH(OH)- and -CH=CH-, R d Selected from phenyl, 5-6 membered heteroaryl, C5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkyl, COOH and -C(=O)OC 1-3 Alkyl, the phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkyl or -C(=O)OC 1-3 The alkyl groups are each independently optionally substituted with one or more R; R5 is selected from phenyl and 5-6 membered heteroaryl, the phenyl or 5-6 membered heteroaryl groups are each independently optionally substituted with one or more R e Replace; each R e are independently selected from halogen, OH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, S(=O)2-C 1-3 Alkyl and S(=O)2NH2, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or S(=O)2-C 1-3 The alkyl groups are each independently optionally substituted with one or more halogen or morpholinyl groups; each R is independently selected from halogen, OH, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-4 Alkylamino and -C(=O)OC 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, -C(=O)OC 1-3 Alkyl or C 1-4 The alkylamino groups are each independently optionally substituted with one or more halogens.

[0043] In certain embodiments, in the compound represented by formula (I-1), each R is independently selected from F, Cl, Br, I, OH, COOH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, N(CH3)2, NHCH2CH3, N(CH2CH3)2, COOCH3 and COOCH2CH3, and the CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, N(CH3)2, NHCH2CH3, N(CH2CH3)2, COOCH3 or COOCH2CH3 are independently optionally substituted with 1, 2, 3, 4 or 5 F, Cl, Br or I.

[0044] In certain embodiments, in the compound represented by formula (I-1), each R is independently selected from F, Cl, Br, OH, COOH, CH3, CH2CH3, CF3, OCH3, N(CH3)2, NHCH2CH3 and COOCH3.

[0045] In certain embodiments, in the compound represented by formula (I-1), L is selected from a bond and -C(=O)-.

[0046] In certain embodiments, in the compound represented by formula (I-1), R d is selected from phenyl, furyl, thienyl, thiazolyl, pyridinyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2(CH2)2CH3, CH2(CH2)3CH3, CH2(CH2)4CH3, COOH and COOCH3, wherein the phenyl, furyl, thienyl, thiazolyl, pyridinyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2(CH2)2CH3, CH2(CH2)3CH3, CH2(CH2)4CH3, COOH or COOCH3 is optionally substituted with 1, 2, 3, 4 or 5 R.

[0047] In certain embodiments, in the compound represented by formula (I-1), R d Selected from COOH,

[0048] In certain embodiments, in the compound represented by formula (I-1), R4 is selected from phenyl, 5-6 membered heteroaryl, -C(=O)-phenyl, -C(=O)-5-6 membered heteroaryl, -C(=O)-C 5-6 Cycloalkyl, -C(=O)-5-6 membered heterocycloalkyl, -C(=O)-C 1-6 Alkyl, -CH=CH-COOH, -CH=CH-C(=O)OC 1-3 Alkyl and -CH(OH)-5-6 membered heteroaryl, the phenyl, 5-6 membered heteroaryl, -C(=O)-phenyl, -C(=O)-5-6 membered heteroaryl, -C(=O)-C 5-6 Cycloalkyl, -C(=O)-5-6 membered heterocycloalkyl, -C(=O)-C 1-6 Alkyl, -CH=CH-COOH, -CH=CH-C(=O)OC 1-3 The alkyl or -CH(OH)-5-6 membered heteroaryl groups are each independently optionally substituted with 1, 2, 3, 4 or 5 R groups.

[0049] In certain embodiments, in the compound represented by formula (I-1), R4 is selected from phenyl, pyridyl, -C(=O)-phenyl, -C(=O)-furyl, -C(=O)-thienyl, -C(=O)-thiazolyl, -C(=O)-pyridyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-tetrahydropyranyl, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH2(CH2)2CH3, -C(=O)-CH2(CH2)3CH3, -C(=O)-CH2(CH2)4CH3, -CH=CH-COOH, -CH=CH-COOCH3 and -CH(OH)-thiophene R is optionally substituted with 1, 2, 3, 4 or 5 R groups, wherein the phenyl, pyridyl, -C(=O)-phenyl, -C(=O)-furyl, -C(=O)-thienyl, -C(=O)-thiazolyl, -C(=O)-pyridyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-tetrahydropyranyl, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH2(CH2)2CH3, -C(=O)-CH2(CH2)3CH3, -C(=O)-CH2(CH2)4CH3, -CH=CH-COOH, -CH=CH-COOCH3 or -CH(OH)-thienyl group is optionally substituted with 1, 2, 3, 4 or 5 R groups, respectively, independently.

[0050] In certain embodiments, in the compound represented by formula (I-1), R4 is selected from

[0051] In certain embodiments, in the compound represented by formula (I-1), R4 is selected from

[0052] In certain embodiments, the compound represented by formula (I-1), wherein R4 is selected from

[0053] In certain embodiments, the compound represented by formula (I-1), wherein R eselected from F, Cl, Br, I, OH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCD3, OCD2CD3, S(=O)2CH3, S(=O)2CH2CH3 and S(=O)2NH2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCD3, OCD2CD3, S(=O)2CH3 or S(=O)2CH2CH3 are each independently optionally substituted with 1, 2, 3, 4 or 5 F, Cl, Br, I or morpholinyl.

[0054] In certain embodiments, the compound represented by formula (I-1), R e selected from F, Cl, Br, OH, CH3, OCH3, OCD3, S(=O)2CH3, S(=O)2NH2 and

[0055] In certain embodiments, in the compound represented by formula (I-1), R5 is selected from

[0056] In certain embodiments, in the compound represented by formula (I-1), R5 is selected from

[0057] In certain embodiments, in the compound represented by formula (I-1), R5 is selected from

[0058] In certain embodiments, the compound is selected from the compound represented by formula (I-2), wherein R1 is as defined in the present invention, and R2 is selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally replaced by one or more R b Substituted, R4 is selected from -LR d , the-LR d Optionally substituted with one or more R; R5 is selected from phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl being independently optionally substituted with one or more R e Substituted; L is selected from a bond, -C(=O)- and -C 1-3 Alkylene-; each R b are independently selected from halogen, R d Selected from phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkyl, OH, COOH and -C(=O)OC1-3 Alkyl, the phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkyl or -C(=O)OC 1-3 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 R groups, each of which is independently e are independently selected from halogen, OH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2-C 1-3 Alkyl and S(=O)2NH2, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or S(=O)2-C 1-3 The alkyl groups are each independently optionally substituted with one or more halogens, and each R is independently selected from halogen, OH, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-4 Alkylamino and -C(=O)OC 1-3 Alkyl, the halogen, OH, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-4 Alkylamino or -C(=O)OC 1-3 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 F, Cl, Br or I, respectively, independently.

[0059] In certain embodiments, in the compound represented by formula (I-2), R1 is CF3.

[0060] In certain embodiments, in the compound represented by formula (I-2), R2 is selected from CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2 are independently optionally replaced by 1, 2, 3, 4 or 5 R b replace.

[0061] In certain embodiments, in the compound represented by formula (I-2), R2 is selected from CH3 and CF3.

[0062] In certain embodiments, in the compound represented by formula (I-2), L is selected from a bond, -C(=O)-, -CH2-, -CH2CH2-, and -CH(CH3)-.

[0063] In certain embodiments, in the compound represented by formula (I-2), L is selected from a bond and -CH2-.

[0064] In certain embodiments, in the compound represented by formula (I-2), R is selected from F, Cl, OH, CH3, OCH3 and -S(=O)NH2.

[0065] In certain embodiments, in the compound represented by formula (I-2), R d Selected from phenyl, pyridyl, cyclopentyl, cyclohexyl, morpholinyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2(CH2)2CH3, CH2(CH2)3CH3, CH2(CH2)4CH3, OH, COOH, COOCH3 and COOCH2CH3, said phenyl, pyridyl, cyclopentyl, cyclohexyl, morpholinyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2(CH2)2CH3, CH2(CH2)3CH3, CH2(CH2)4CH3, COOCH3 or COOCH2CH3 are each independently optionally substituted by 1, 2, 3, 4 or 5 R, and R is defined as described above.

[0066] In certain embodiments, in the compound represented by formula (I-2), R d Selected from OH, COOH,

[0067] In certain embodiments, in the compound represented by formula (I-2), R4 is selected from phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, -C(=O)-C 1-6 Alkyl, -CH2-phenyl, -CH2-5-6 membered heteroaryl, -CH2-COOH, -CH2-C(=O)OC 1-3 Alkyl, -CH2CH2-5-6 membered heterocycloalkyl, -CH2CH2-OH and -CH(CH3)-COOH, the phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, -C(=O)-C 1-6 Alkyl, -CH2-phenyl, -CH2-5-6 membered heteroaryl, -CH2-COOH, -CH2-C(=O)OC 1-3 Alkyl, -CH2CH2-5-6 membered heterocycloalkyl, -CH2CH2-OH or -CH(CH3)-COOH are each independently optionally substituted with 1, 2, 3, 4 or 5 Rs.

[0068] In certain embodiments, in the compound shown in formula (I-2), R4 is selected from phenyl, pyridyl, cyclopentyl, cyclohexyl, -C(=O)-CH2CH2CH3, -CH2-phenyl, -CH2-pyridyl, -CH2-COOH, -CH2-COOCH2CH3, -CH2CH2-morpholinyl, -CH2CH2-OH and -CH(CH3)-COOH, and the phenyl, pyridyl, cyclopentyl, cyclohexyl, -C(=O)-CH2CH2CH3, -CH2-phenyl, -CH2-pyridyl, -CH2-COOH, -CH2-COOCH2CH3, -CH2CH2-morpholinyl, -CH2CH2-OH or -CH(CH3)-COOH are independently optionally substituted with 1, 2, 3, 4 or 5 R.

[0069] In certain embodiments, in the compound represented by formula (I-2), R4 is selected from

[0070] In certain embodiments, in the compound represented by formula (I-2), R4 is selected from

[0071] In certain embodiments, in the compound represented by formula (I-2), R4 is selected from

[0072] In certain embodiments, in the compound represented by formula (I-2), R4 is selected from

[0073] In certain embodiments, in the compound represented by formula (I-2), R e selected from F, Cl, Br, I, OH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, SCH3, SCH2CH3, SCH2CH2CH3, SCH(CH3)2, S(═O)2CH3, S(═O)2CH2CH3 and S(═O)2NH2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, SCH3, SCH2CH3, SCH2CH2CH3, SCH(CH3)2, S(═O)2CH3 or S(═O)2CH2CH3 are each independently optionally substituted with 1, 2, 3, 4 or 5 F, Cl, Br or I.

[0074] In certain embodiments, in the compound represented by formula (I-2), R eSelected from Cl, OCH3, SCH3, S(=O)2CH3 and S(=O)2NH2.

[0075] In certain embodiments, in the compound represented by formula (I-2), R5 is selected from phenyl and pyridyl, and the phenyl or pyridyl is independently optionally replaced by 1, 2, 3, 4 or 5 R e replace.

[0076] In certain embodiments, in the compound represented by formula (I-2), R5 is selected from

[0077] In certain embodiments, in the compound represented by formula (I-2), R5 is selected from

[0078] In certain embodiments, in the compound represented by formula (I-2), R5 is selected from

[0079] In certain embodiments, the compound is selected from:

[0080] The present invention also relates to a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0081] The present invention also relates to the use of the compound or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound or the pharmaceutical composition in the preparation of a drug as a COX inhibitor.

[0082] In certain embodiments, the present invention relates to the use of the compound or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound or the pharmaceutical composition in the preparation of a medicament for preventing and / or treating inflammation and pain.

[0083] The present invention also relates to a general method for preparing the compound, which comprises:

[0084] Route 1;

[0085] Route 2;

[0086] Route 3; or

[0087] Route 4;

[0088] in,

[0089] R1, R2, R3, R4, R5 and R d The definition of R is as described in the present invention; x Selected from C1-3 alkyl.

[0090] Definition of terms

[0091] The various terms and phrases used in the present invention have general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases herein. If the mentioned terms and phrases are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail.

[0092] When the name of the compound used in the present invention is inconsistent with the chemical structural formula, the chemical structural formula shall prevail.

[0093] As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.

[0094] As used in the present invention, "C 1-6 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6 carbon atoms, for example, C 1-4 Alkyl or C 1-3 Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl.

[0095] As used in the present invention, "C 1-3 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 3 carbon atoms, such as 1, 2 or 3 carbon atoms. Specific examples include, but are not limited to, methyl, ethyl, propyl or isopropyl.

[0096] As used in the present invention, "C 1-3 "Alkylene" refers to a straight or branched chain alkylene group having 1 to 3 carbon atoms, such as 1, 2 or 3 carbon atoms. Specific examples include, but are not limited to, methylene, ethylene, propylene or isopropylene. As used herein, "C 1-3 "Alkoxy" refers to a C 1-3 Examples of the group formed by connecting a carbon atom on an alkyl group to an oxygen atom include, but are not limited to, methoxy, ethoxy, or propoxy.

[0097] As used in the present invention, "C 1-3 "Deuterated alkoxy" refers to a C 1-3The groups obtained by replacing the hydrogen atoms on the alkoxy group with 1, 2, 3, 4, 5, 6 or 7 deuterium atoms include, but are not limited to, deuterated methoxy (such as OCD3) or deuterated ethoxy (such as OCH2CD3 or OCD2CD3).

[0098] As used in the present invention, "C 1-3 "Alkylthio" refers to a C 1-3 Examples of the group obtained by connecting a carbon atom on an alkyl group to a sulfur atom include, but are not limited to, methylthio, ethylthio, or propylthio.

[0099] As used in the present invention, "C 1-4 "Alkylamino" refers to a C 1-4 Examples of the group obtained by connecting a carbon atom on the alkyl group to a nitrogen atom or NH include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, or propylamino.

[0100] As used herein, "5-6 membered heteroaryl" refers to an aromatic system containing 1, 2, 3 or 4 heteroatoms, wherein the aromatic system contains 5 or 6 ring atoms, preferably the heteroatoms are selected from N, O or S. Specific examples include, but are not limited to, imidazolyl, thiazolyl, pyridyl, thienyl or furyl.

[0101] As used herein, "5-6 membered heterocycloalkyl" refers to an aliphatic ring system containing 1, 2, 3 or 4 heteroatoms, wherein the aliphatic ring system contains 5 or 6 ring atoms, preferably the heteroatoms are selected from N, O or S. "5-6 membered heterocycloalkyl" includes monocyclic, bicyclic or polycyclic rings, including spirocyclic, fused or bridged rings. Specific examples include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl or morpholinyl.

[0102] As used in the present invention, "C 5-6 "Cycloalkyl" refers to an aliphatic ring system containing 5 or 6 ring carbon atoms. 5-6 "Cycloalkyl" includes monocyclic, bicyclic or polycyclic rings, including spirocyclic, fused or bridged rings. Specific examples include, but are not limited to, cyclopentyl or cyclohexyl.

[0103] As used herein, "pharmaceutically acceptable salt" means a salt of a compound of the invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic or organic acids; salts formed when an acidic proton present on the parent compound is replaced by a metal ion; or coordination compounds formed with organic bases. Beneficial effects

[0104] The compounds of the present invention have a good inhibitory effect on COX2 and can inhibit PGE2 by inhibiting COX proteins. In addition, the compounds of the present invention have good metabolic stability and have preventive and therapeutic effects on inflammation and pain in the body. DETAILED DESCRIPTION

[0105] The embodiments of the present invention will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be obtained commercially.

[0106] 1. Synthesis Examples of Compounds

[0107] Example 1: I-1-30

[0108] Step 1: 3-Amino-4-tert-butoxycarbonylpyrazole

[0109] Tert-butyl cyanoacetate (120 g) was dissolved in methanol (500 mL), and DMF-DMA (100 g) was added. The mixture was refluxed at 70°C for 2 h. After cooling, 52.5 g of hydrazine hydrate (80%) was added, and the mixture was refluxed at 70°C for 3 h. The reaction solution was concentrated to dryness to obtain a yellow to reddish-brown crude title compound (154 g). The crude product was extracted with ethyl acetate several times, separated, and the organic phases were combined and concentrated to obtain the refined product. (ESI) m / z = 184.2 [M+H] + .

[0110] Step 2: 4,4,4-Trifluoro-1-(4-methoxyphenyl)-1,3-butanedione

[0111] Dissolve p-methoxyacetophenone (60 g) in N,N-dimethylformamide (600 mL). Add NaH (60%, 32 g) portionwise in an ice bath. After complete addition, add ethyl trifluoroacetate (62.5 g) dropwise while maintaining the ice bath. Warm the mixture to room temperature and continue the reaction for 1 h. Pour the reaction mixture into ice water, adjust the pH to acidic with hydrochloric acid, and extract with ethyl acetate. Separate the layers. Wash the organic phase three times with water and concentrate under reduced pressure to dryness to obtain a crude yellow title compound (118 g). Use directly in the next reaction. Slurry the crude product with n-hexane or ethanol to obtain a refined product.

[0112] Step 3: 5-(4-Methoxyphenyl)-7-(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0113] Crude 4,4,4-trifluoro-1-(4-methoxyphenyl)-1,3-butanedione (55 g) was added to glacial acetic acid (50 mL) and crude 3-amino-4-tert-butoxycarbonylpyrazole (37 g). The mixture was refluxed for 3 hours. After cooling to room temperature, trifluoroacetic acid (50 mL) was added and the mixture was allowed to react at 60°C for 30 minutes. The reaction solution was poured into ice water, whereupon a large amount of solid precipitated. The filter cake was filtered and dried to obtain the crude title compound. The crude product was then slurried with ethanol to obtain a refined product (20.0 g).

[0114] Step 4: (5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl)(thiophen-2-yl)methanone (I-1-30)

[0115] 5-(4-Methoxyphenyl)-7-(trifluoromethyl)-3-pyrazolo[1,5-a]pyrimidinecarboxylic acid (10 g) was added to trifluoroacetic acid (20 mL) and thiophene (15 g). Trifluoroacetic anhydride (12.5 g) was added dropwise and allowed to react at room temperature for 30 minutes. The reaction solution was poured into ice water to precipitate a large amount of solid. The filter cake was filtered, washed with water, and dried to obtain the title compound (11.4 g) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.74 (s, 1H), 8.20–8.15 (m, 1H), 8.11 (d, J = 8.9Hz, 2H), 7.75(d,J=5.9Hz,2H),7.26–7.20(m,1H),7.00(d,J=8.9Hz,2H),3.90(s,3H). (ESI)m / z=403.9[M+H] + .

[0116] Example 2: I-1-9

[0117] Step 1: Referring to Example 1, replace p-methoxyacetophenone with p-bromoacetophenone to synthesize [5-(p-bromophenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl](thiophen-2-yl)methanone.

[0118] Step 2: (5-(4-bromophenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl)(thiophen-2-yl)methanol (I-1-9)

[0119] [5-(p-Bromophenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl](thiophen-2-yl)methanone (2 g) was added to dichloromethane (10 mL) and sodium borohydride (0.3 g) was slowly added. The mixture was allowed to react at room temperature for 1 h. The reaction solution was poured into water and extracted with dichloromethane. The layers were separated and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was slurried with ethanol to obtain the title compound (1.8 g) as a yellow solid.1 H NMR (400MHz, DMSO-d6) δ9.43(s,1H),8.40(s,1H),8.15(s,1H),8.03(d,J=4.9Hz,1H),7.72(d,J=8. 1Hz, 2H), 7.61 (d, J = 8.2Hz, 2H), 7.30 (t, J = 4.3Hz, 1H), 6.13 (p, J = 5.3Hz, 1H), 5.37 (d, J = 4.7Hz, 1H). (ESI)m / z=455.9[M+H] + .

[0120] Example 3: I-1-39 and I-1-40

[0121] Step 1: 5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine

[0122] Crude 4,4,4-trifluoro-1-(4-methoxyphenyl)-1,3-butanedione (55 g) was added to glacial acetic acid (50 mL) and 3-aminopyrazole (17 g) and refluxed for 1 h. The reaction mixture was poured into ice water, whereupon a large amount of solid precipitated. The filter cake was filtered and dried to obtain the title compound (48 g). (ESI) m / z = 294.1 [M+H] + .

[0123] Step 2: [5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]cyclopentylmethanone (I-1-39)

[0124] Weigh 22.9 g of cyclopentanoic acid into a reaction flask, add thionyl chloride (50 mL), and react at 50°C for approximately 0.5 h. Concentrate under reduced pressure to obtain cyclopentanecarbonyl chloride for use. Weigh 14.7 g of 5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine, dissolve it in dichloromethane (100 mL), add AlCl₃ (26.7 g), and slowly add the resulting cyclopentanecarbonyl chloride dropwise to the reaction mixture. After addition, react at room temperature for 0.5 h. Pour the mixture into water, extract with dichloromethane, separate the layers, add silica gel to the organic phase, and purify by column chromatography (eluent: n-hexane:ethyl acetate = 10:1) to obtain the title compound (5.5 g). 1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.37(d,J=9.0Hz,2H),8.29(s,1H),7.16(d,J=8.9Hz,2 H),4.26–4.14(m,1H),3.88(s,3H),2.05–1.94(m,2H),1.89–1.81(m,2H),1.72–1.65(m,4H). (ESI)m / z=390.1[M+H] + .

[0125] Step 3: [5-(4-Hydroxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]cyclopentylmethanone (I-1-40)

[0126] [5-(4-Methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]cyclopentylmethanone (2.0 g) was dissolved in dichloromethane (50 mL). Boron tribromide (3.0 g) was added dropwise at room temperature and the reaction continued for 1 hour. After quenching with water, the organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound. The crude product was purified by medium-pressure preparative chromatography (column specifications: C18 spherical, 120 g; eluent: acetonitrile / water; flow rate: 80 mL / min, eluent organic phase ratio: 0% to 60%) to obtain the pure title compound (1.3 g). 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.70(s,1H),8.27(d,J=8.9Hz,2H),8.21(s,1H),6.97( d,J=8.8Hz,2H),4.25–4.13(m,1H),2.06–1.93(m,2H),1.91–1.78(m,2H),1.74–1.62(m,4H). (ESI)m / z=376.2[M+H] + .

[0127] Example 4: I-1-45

[0128] Step 1: 3-(dimethylamino)-1-[5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]propan-1-one (I-1-45)

[0129] 5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (2.0 g) was weighed into a reaction flask, dichloromethane (30 mL) and aluminum chloride (2.0 g) were added, and 3-chloropropionyl chloride (2.0 g) was added dropwise with stirring at room temperature. The reaction mixture was allowed to react for approximately 30 minutes. The reaction solution was poured into water and extracted with dichloromethane. The layers were separated, and the organic phase was concentrated under reduced pressure to dryness to obtain crude 3-chloro-1-[5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]propan-1-one. Potassium iodide (0.5 g), potassium carbonate (1.0 g), N,N-dimethylformamide (5 mL), and dimethylamine methanol solution (1 mL) were stirred at room temperature. The resulting crude 3-chloro-1-[5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]propan-1-one was dissolved in N,N-dimethylformamide (5 mL). Half of the solution was added dropwise to the reaction mixture. The reaction was continued for 1 hour. The reaction mixture was then poured into water and extracted with ethyl acetate. The layers were separated, and the organic phase was concentrated to dryness under reduced pressure and purified by preparative thin-layer chromatography (developing solvent: methanol:dichloromethane = 1:10) to obtain the title compound (70 mg).

[0130] Example 5: I-1-56 and I-1-57

[0131] Step 1: 3-Bromo-5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine

[0132] At room temperature, 5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (15.0 g, prepared as described in Example 1 or the synthetic route disclosed on pages 28 or 32 of JP2004277377A) and acetonitrile (75 mL) were added to a 100 mL single-necked flask. NBS (10.0 g) was added portionwise and allowed to react at room temperature for 1 h. The mixture was poured into water, and a solid precipitated. The filter cake was filtered and dried to yield a yellow solid (18.5 g). (ESI) m / z = 372.0 [M+H] + .

[0133] Step 2: Methyl (2E)-3-[5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoate (I-1-56)

[0134] To a 10 mL sealed tube at room temperature, 3-bromo-5-(4-methylphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (1.7 g), potassium carbonate (1.1 g), methyl acrylate (1.1 g), PdCl2(dppf)·DCM (0.1 g), and N,N-dimethylformamide (20 mL) were added. The atmosphere was replaced with nitrogen and the temperature was raised to 100°C for 1 h. The reaction solution was poured into water and extracted with ethyl acetate. The layers were separated, and the organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 1.7 g of the crude title compound. 0.5 g of the crude product was purified on a silica gel column (eluent: Hex:EA = 5:1) to obtain a yellow solid (280 mg). 1 H NMR (400MHz, CDCl3) δ8.35(s,1H),8.17(d,J=8.9Hz,2H),7.96(d,J=16.0Hz,1H),7. 65(s,1H),7.07(d,J=8.9Hz,2H),6.89(d,J=16.0Hz,1H),3.93(s,3H),3.86(s,3H). (ESI)m / z=378.2[M+H] + .

[0135] Step 3: (2E)-3-[5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoic acid (I-1-57)

[0136] Methyl (2E)-3-[5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoate (0.75 g) was weighed into a reaction flask, ethanol (100 mL) and sodium hydroxide (0.5 g) were added, and the mixture was heated to 80°C for 3 h. The reaction solution was concentrated to dryness under reduced pressure, extracted with dilute potassium carbonate solution and ethyl acetate, and the layers were separated. The aqueous phase was acidified and extracted with ethyl acetate. The layers were separated, and the organic phase was concentrated to dryness under reduced pressure to obtain the crude title compound. The crude product was slurried with ethyl acetate / n-hexane (1:5) to obtain a yellow solid (80 mg). 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),8.73(s,1H),8.35(d,J=8.9Hz,2H),8.17( s,1H),7.81(d,J=15.9Hz,1H),7.16(s,2H),6.81(d,J=16.0Hz,1H),3.88(s,3H). (ESI)m / z=364.1[M+H] + .

[0137] Example 6: I-1-58 and I-1-60

[0138] Step 1: 5-(4-methoxyphenyl)-3-(2-methoxypyridin-3-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (I-1-58)

[0139] To a 10 mL sealed tube at room temperature, 3-bromo-5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (18.0 g), K2CO3 (13.4 g), (2-methoxypyridin-3-yl)boronic acid (7.4 g), DMF (180 mL), and PdCl2(dppf)DCM (500 mg) were added. The atmosphere was replaced with nitrogen and the temperature was raised to 110°C for 2 h. The reaction solution was poured into water and extracted with ethyl acetate. The layers were separated, and the organic phase was added to silica gel and purified on a silica gel column (eluent: n-hexane:ethyl acetate = 10:1 to 5:1) to obtain an orange-red solid (10.5 g). 1 H NMR (400MHz, CDCl3) δ8.89(s,1H),8.86(dd,J=7.5,1.9Hz,1H),8.15(dd,J=4.9,1.9Hz,1H),8.12( d,J=8.9Hz,2H),7.60(s,1H),7.11–7.08(m,1H),7.07(d,J=8.8Hz,2H),4.11(s,3H),3.92(s,3H). (ESI)m / z=401.0[M+H] + .

[0140] Step 2: 3-[5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]-1,2-dihydropyridin-2-ol (I-1-60)

[0141] 5-(p-Methoxyphenyl)-3-(2-methoxypyridin-3-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (2.0 g) was added to a hydrobromic acid solution (48%, 10 mL) and 1,4-dioxane (50 mL). The temperature was raised to 100°C and the reaction was allowed to react for 2 h. After the reaction was complete, the reaction solution was poured into water to precipitate a solid, which was filtered and slurried with ethyl acetate / n-hexane (1 / 5) to obtain an orange-red solid (1.7 g). 1H NMR (400MHz, DMSO-d6) δ11.93(s,1H),9.24(s,1H),8.83(dd,J=7.1,2.1Hz,1H),8.35(d,J=9.1Hz,2H) ,8.13(s,1H),7.39(dd,J=6.4,2.1Hz,1H),7.13(d,J=9.1Hz,2H),6.47(t,J=6.7Hz,1H),3.88(s,3H). (ESI)m / z=387.1[M+H] + .

[0142] Example 7: I-1-71

[0143] Step 1: 3-Bromo-5-(4-(methylsulfonyl)phenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine

[0144] 3-Bromo-5-(4-(methylthio)phenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (1.9 g, prepared by the methods of Examples 1 and 5, for example, replacing p-methoxyacetophenone in Example 1 with p-methylthioacetophenone and 3-amino-4-tert-butyloxycarbonylpyrazole with 3-amino-4-bromo-pyrazole) was dissolved in dichloromethane (10 mL). Meta-chloroperbenzoic acid (1.7 g) was slowly added and allowed to react at room temperature for 4 hours. After completion of the reaction, the reaction solution was poured into water and extracted with dichloromethane. The layers were separated, and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was slurried with ethanol to obtain the title compound (1.4 g) as a light red solid.

[0145] Step 2: 3-(2-methoxypyridin-3-yl)-5-(4-(methylsulfonyl)phenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (I-1-71)

[0146] 3-Bromo-5-(4-(methylsulfonyl)phenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (0.5 g) was added to 1,4-dioxane (8 mL), potassium carbonate (1.4 g), PdCl2(dppf)·DCM (20 mg), and (2-methoxypyridin-3-yl)boronic acid (1.5 g). The mixture was refluxed under nitrogen for 2 hours. After completion, the solvent was removed by concentration under reduced pressure to obtain a crude product, which was then purified by C18 reverse-phase preparative chromatography (0%-80% water-acetonitrile system, 1 hour) to afford the pure title compound (0.2 g). 1H NMR (400MHz, DMSO-d6) δ8.92 (s, 1H), 8.80 (dd, J = 7.4, 1.9Hz, 1H), 8.64 –8.56(m,2H),8.34(s,1H),8.21–8.09(m,3H),7.21(dd,J=7.5,4.9Hz,1H),4.03(s,3H),3.33(s,3H). (ESI)m / z=449.1[M+H] + .

[0147] Example 8: I-2-8

[0148] Step 1: 6-(4-methoxyphenyl)-1-phenyl-3,4-bis(trifluoromethyl)pyrazolo[3,4-b]pyridine (I-2-8)

[0149] Acetonitrile (32 g) was weighed into a reaction flask, and NaH (60%, 8.0 g) was added. The mixture was stirred at room temperature for 10 min, and ethyl trifluoroacetate (14.2 g) was added dropwise. The reaction mixture was allowed to react for 3 h. The reaction mixture was then poured into water, the pH was adjusted to acidic by adding hydrochloric acid, and ethyl acetate was added for extraction. The organic phase was separated and concentrated under reduced pressure to dryness to obtain crude trifluoroacetoacetonitrile. Acetic acid (40 mL) and phenylhydrazine (10.8 g) were added to the crude trifluoroacetoacetonitrile, and the mixture was heated to 100°C for 3 h. The reaction mixture was extracted with water and ethyl acetate, separated and the organic phase was concentrated under reduced pressure to dryness to obtain crude 2-phenyl-5-(trifluoromethyl)pyrazol-3-amine (14.0 g). To the crude product of 2-phenyl-5-(trifluoromethyl)pyrazol-3-amine (7.0 g), 4,4,4-trifluoro-1-(4-methoxyphenyl)-1,3-butanedione (7.6 g) and acetic acid (20 mL) were added and reacted at 120°C for 5 h. The reaction solution was then poured into water and extracted with ethyl acetate. The layers were separated, and the organic phase was mixed with silica gel and purified on a silica gel column (eluent: Hex:EA = 10:1) to obtain the crude title compound. The crude product was then purified by reverse medium-pressure preparative chromatography (column specifications: C18 spherical, 120 g; eluent: acetonitrile / water; flow rate: 80 mL / min, eluent organic phase ratio: 0% to 100%) to obtain the pure product (0.4 g). 1 H NMR (400MHz, CDCl3) δ8.28 (dd, J=8.6, 1.0Hz, 2H), 8.19–8.11 (m, 2H), 8.07 (s ,1H),7.66–7.58(m,2H),7.52–7.43(m,1H),7.11–7.03(m,2H),3.93(s,3H). (ESI)m / z=438.1[M+H] + .

[0150] Example 9: I-2-18

[0151] Step 1: p-Acetylbenzenesulfonamide

[0152] Weigh p-ethylbenzenesulfonamide (100 g) into a reaction flask, add acetic acid (500 mL), and add chromium trioxide (60 g) in portions. Stir at room temperature for 6 h. Then pour the reaction solution into ice water to precipitate a large amount of solid. Filter, wash the filter cake with ice water, and dry to obtain the gray title compound (80 g).

[0153] Step 2: 4-(4,4,4-trifluoro-1,3-dioxybutylidene)benzene-1-sulfonamide

[0154] Weigh 40 g of p-acetylbenzenesulfonamide into a reaction flask and dissolve it in DMF (300 mL). Add NaH (60%, 24 g) with stirring and stir at room temperature for 0.5 h. Then, slowly add ethyl trifluoroacetate (40 g) dropwise. After completion of the addition, transfer the mixture to 50°C and heat for 3 h. After completion of the reaction, pour the reaction solution into water, adjust the pH to acidic, and extract twice with ethyl acetate. Filter, combine the organic phases, and concentrate under reduced pressure to dryness to obtain the title compound (100 g) as a yellow to brown oil.

[0155] Step 3: 4-[3-Methyl-1-phenyl-4-(trifluoromethyl)pyrazolo[3,4-b]pyridin-6-yl]benzene-1-sulfonamide (I-2-18)

[0156] 3-Oxobutyronitrile (20 g) was weighed into a reaction flask, and acetic acid (30 mL) and phenylhydrazine (20 g) were added. The reaction was heated to 100°C for 4 hours. After cooling slightly, crude 4-(4,4,4-trifluoro-1,3-dioxybutylidene)benzene-1-sulfonamide (60 g) was added and the reaction continued at 120°C for 3 hours. After cooling, the reaction solution was poured into water, whereupon a large amount of solid precipitated. Filter the crude title compound, which was then recrystallized from ethanol to obtain the title compound (16 g) as an off-white solid powder. 1 H NMR (400MHz, CDCl3) δ8.32(d,J=8.3Hz,2H),8.29(d,J=7.8Hz,2H),8.12(d,J=8.1Hz,2H ),7.95(s,1H),7.59(t,J=7.8Hz,2H),7.39(t,J=7.5Hz,1H),4.99(s,2H),2.78(s,3H). (ESI)m / z=433.1[M+H] + .

[0157] Example 10: I-1-27 and 1-2-28

[0158] Step 1: Ethyl 2-(6-(4-methoxyphenyl)-3-methyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetate (I-1-27)

[0159] To ethyl hydrazinoacetate hydrochloride (1.6 g), add 3-oxobutyronitrile (0.9 g) and acetic acid (8 mL). Heat to reflux and react for 2 h. Then add 4,4,4-trifluoro-1-(4-(methoxy)phenyl)butane-1,3-dione (2.5 g) and continue the reaction for 2 h. After completion of the reaction, cool the system to room temperature, add water for crystallization, and filter to obtain the crude product. The crude product is slurried with ethanol to obtain the title compound (0.8 g) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.25(d,J=8.9Hz,2H),8.05(s,1H),7.08(d,J=8.9Hz,2H),5.41( s, 2H), 4.17 (q, J = 7.1Hz, 2H), 3.84 (s, 3H), 2.53 (d, J = 1.5Hz, 3H), 1.21 (t, J = 7.1Hz, 3H). (ESI)m / z=394.2[M+H] + .

[0160] Step 2: 2-(6-(4-methoxyphenyl)-3-methyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (I-1-28)

[0161] Take ethyl 2-(6-(4-methoxyphenyl)-3-methyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetate (0.4 g), add 2 mL of tetrahydrofuran, ethanol (2 mL), water (2 mL), and sodium hydroxide (0.1 g), and heat to 50°C to react for 2 hours. After the reaction is complete, the remaining tetrahydrofuran and ethanol in the system are removed by rotary evaporation, and the system is adjusted to acidity to precipitate a white solid. The crude product is filtered and slurried with ethanol to obtain the pure product (0.2 g). 1 H NMR (400MHz, DMSO-d6) δ13.29(br,1H),8.25(d,J=8.9Hz,2H),8.04(s,1H),7.09(d,J=8.9Hz,2H),5.29(s,2H),3.84(s,3H),2.53(d,J=1.9Hz,3H). (ESI)m / z=366.2[M+H] + .

[0162] Example 11: 1-2-31

[0163] Step 1: 1-(tert-Butyl)-3-methyl-6-(4-(methylthio)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine

[0164] Take tert-butylhydrazine hydrochloride (5.0 g), add 3-oxobutanenitrile (3.3 g) and 10 ml of acetic acid, raise the temperature to reflux and react for 2 h, then add 4,4,4-trifluoro-1-(4-(methylthio)phenyl)butane-1,3-dione (10.5 g), and continue the reaction for 2 h. After the reaction is completed, cool the system to room temperature, add water, and a large amount of white solid precipitates. Filter to obtain a crude product, and slurry the crude product with ethanol to obtain the title compound (7.2 g).

[0165] Step 2: 1-(tert-Butyl)-3-methyl-6-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine

[0166] 1-(tert-butyl)-3-methyl-6-(4-(methylthio)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (7.2 g) was added to dichloromethane (40 mL) and slowly added with m-chloroperbenzoic acid (6.4 g). The mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, the reaction solution was poured into water and extracted with dichloromethane. The layers were separated and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was slurried with ethanol to obtain the title compound (7.4 g) as a white solid. (ESI) m / z = 412.1 [M+H] + .

[0167] Step 3: 3-Methyl-6-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine

[0168] 1-(tert-butyl)-3-methyl-6-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (4.1 g) was added to trifluoroacetic acid (20 mL) and the mixture was heated to 80°C and allowed to react overnight. After completion of the reaction, the reaction mixture was poured into water, whereupon a large amount of white solid precipitated. Filtering afforded a filter cake, 3.2 g of the title compound. (ESI) m / z = 356.1 [M+H] + .

[0169] Step 4: 3-Methyl-1-(3-methyl-6-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)butan-1-one (I-2-31)

[0170] 3-Methyl-6-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (0.5 g) was added with dichloromethane (5 mL), isovaleric acid (0.5 mL), and HATU (1.5 g) and allowed to react at room temperature for 4 hours. After completion of the reaction, the dichloromethane was removed by rotary evaporation to obtain a crude product, which was purified by C18 reverse-phase preparative chromatography (0%-80% water-acetonitrile system, 1 hour) to afford the title compound (0.2 g). 1 H NMR (400MHz, DMSO-d6) δ8.53(d,J=8.3Hz,2H),8.41(s,1H),8.11(d,J=8.3Hz,2H),3.31(s, 3H), 3.21 (d, J = 6.9 Hz, 2H), 2.58 (d, J = 2.1 Hz, 3H), 2.35–2.20 (m, 1H), 1.04 (d, J = 6.6 Hz, 6H). (ESI)m / z=440.2[M+H] + .

[0171] The compounds listed in Table A below can be prepared by selecting corresponding commercially available reagents, catalysts, solvents and other raw materials according to the methods of the above examples.

[0172] Table A

[0173] Table B. H NMR and MS data of the compounds prepared in the examples of the present invention and their COX-2 inhibition rates Note: aInhibition rate of representative compounds at a test concentration of 556 nM

[0174] 2. In vitro biological activity test

[0175] (1) Cyclooxygenase inhibition activity test

[0176] COX-2 inhibitory activity

[0177] 1. Materials

[0178] Cyclooxygenase-2 (COX-2) inhibitor screening kit (Shanghai Beyotime Biotechnology Co., Ltd., catalog number: S0168)

[0179] 96-well black board (Corning)

[0180] Spearhead (Epend)

[0181] 2. Test process

[0182] 1) Add the test buffer, COX-2 working solution, cofactor working solution, and sample solution provided in the kit to a 100 μL reaction system in sequence and incubate at 37°C for 10 min.

[0183] 2) Add the probe and substrate arachidonic acid.

[0184] 3) Incubate at 37°C for 10 min.

[0185] 4) Detection (excitation wavelength: 560 nm, emission wavelength: 590 nm).

[0186] 3. Handling of test samples and positive drugs

[0187] Take an appropriate amount of the inhibitor to be tested and prepare a solution of appropriate concentration with DMSO. If necessary, an appropriate concentration gradient can be prepared for use.

[0188] Take an appropriate amount of celecoxib (100 μM) and dilute it with DMSO to the desired concentration (e.g., 200 nM).

[0189] 4. Calculation

[0190] Inhibition rate (%) = (RFU 100％酶活性对照 -RFU 样品 ) / (RFU 100％酶活性对照 -RFU 空白对照 )×100%; IC50 is defined as the concentration of the assay sample that results in 50% inhibition of enzyme activity.

[0191] COX-1 inhibitory activity

[0192] Recombinant human cyclooxygenase 1 (Cat. No. 17616) from Cayman Chemical Co., Ltd. was used, and the method was the same as that for COX-2 inhibitory activity test.

[0193] The activity test results of some compounds are shown in Table 1 below.

[0194] Table 1. IC values ​​of some compounds for COX-1 and COX-2 inhibition 50

[0195] (2) PGE2 inhibitory activity

[0196] Screening test of the inhibitory effect of compounds on PGE2 in mouse macrophage Raw264.7 cells

[0197] 1. Purpose of the test

[0198] The inhibitory effects of the compounds were tested in the lipopolysaccharide-induced PGE2 elevation model in Raw264.7 cells.

[0199] 2. Reagent and instrument information

[0200] 3. Test process

[0201] 1) Raw264.7 cells were cultured in 1640 medium containing 10% serum and 1% double-antibody in a CO2 incubator at 37°C and 5% CO2. When the cells reached a confluence of 80-90%, cells with good growth were scraped and counted using a cell counter. The cell density was 5×10 5 / well, inoculated into 12-well plates and cultured for 24 h;

[0202] 2) After 24 days of cell culture, add the compound to the cells at a final concentration of 8-1000 nM and incubate for 1 hour. Then, except for the control group, add LPS to the cells in each well at a final concentration of 1 μg / mL for 24 hours;

[0203] 3) After 24 h of cell culture, 200 μL of cell supernatant was collected and PGE2 content was detected using a PGE2 ELISA kit;

[0204] 4) Add 10% CCK-8 reagent to the remaining cell culture medium, place in a cell culture incubator for 15-30 minutes, and then use a microplate reader to measure the absorbance at 450 nm. The absorbance value is used to characterize the cell viability for compound cytotoxicity judgment.

[0205] 4. Calculation

[0206] The results were calculated according to the instructions of the Cayman PGE2 ELISA kit (Cat. No. 514010).

[0207] All compounds of the present invention had a cell viability greater than 90% within the concentration range of 8-1000 nM and showed no significant toxicity to Raw264.7 cells. The results of the preliminary activity screening are shown in Table 2 below.

[0208] Table 2. Inhibition rate of compounds on PGE2 secretion in Raw264.7 (%)

[0209] (III) Liver microsome metabolic stability test

[0210] Test methods

[0211] Metabolic stability incubation of the compound (final concentration 1 μM) was performed using liver microsomes (final concentration 0.5 mg / mL, midazolam group 0.2 mg / mL). A phosphate buffered saline solution containing β-NADPH (final concentration 1 mM) and magnesium chloride (final concentration 3 mM) was added to the positive control, while a phosphate buffered saline solution containing magnesium chloride (final concentration 3 mM) was added to the negative control. The reaction was terminated at 0, 5, 15, 30, and 60 minutes with 50% acetonitrile in water (0°C). The supernatant was vortexed and centrifuged. 150 μL of the supernatant was added to 150 μL of water, vortexed to mix, and analyzed by LC-MS / MS. (The liver microsomes used in the experiment were mouse liver microsomes purchased from Corning; β-NADPH was purchased from Ruji Biotechnology.)

[0212] Test parameters: in vitro clearance rate Clint, unit is μl / min / mg protein; half-life T1 / 2, unit is min.

[0213] The test results are shown in Table 3 below.

[0214] Table 3. Clearance of compounds in mouse liver microsomes

[0215] (IV) In vivo efficacy

[0216] 1. Rat toe swelling test

[0217] Fifty-four SD rats that passed quarantine were selected, half male and half female, weighing 180-220 g, and were randomly divided into normal control group, model control group, celecoxib group, flurbiprofen group, I-1-15 group, I-1-30 group, I-1-39 group, and I-1-58 group according to body weight, with 6 animals in each group. Before administration, different drugs were prepared to a concentration of 0.5 mg / mL using an aqueous solution containing 0.5% methylcellulose and 0.1% Tween 80. The animals in each group were orally gavaged with different test substances at 10 mL / kg, once a day for 7 consecutive days. The normal control group was given an equal volume of pure water, and the model control group was given an equal volume of solvent. After the last administration, except for the normal group, the rats in the other groups were injected with 0.5% carrageenan 0.2 mL / rat under the plantar fascia of the right hind paw to induce inflammation. The normal group was given an equal volume of 0.9% sodium chloride injection. The volume of the right hind paw of each group of rats was measured with a toe volume meter at 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after inflammation, and the swelling degree was calculated.

[0218] The results are shown in Table 4 below.

[0219] Inhibitors I-1-30 / 39 / 58 significantly reduced the swelling of rat toes within the test period after inflammation in rats, and had an anti-acute inflammatory effect.

[0220] Table 4. Results of rat toe swelling test Note: Compared with the normal control group ++ P≤0.01; **P≤0.01, *P≤0.05 compared with the model control group.

[0221] 2. Acetic acid writhing test in mice

[0222] Forty-eight ICR mice (half male and half female, weighing 18-22 g) that had passed quarantine were randomly divided into a normal control group, a celecoxib group, a flurbiprofen group, an I-1-15 group, an I-1-30 group, an I-1-39 group, and an I-1-58 group, with six animals per group. Before administration, the different drugs were prepared at a concentration of 1 mg / mL using an aqueous solution containing 0.5% methylcellulose and 0.1% Tween 80. Each group received the test compound by oral gavage at 20 mL / kg once daily for 7 consecutive days. The model control group received an equal volume of solvent. One hour after the last dose, 0.6% acetic acid was injected intraperitoneally at 10 mL / kg. The mice were immediately observed after the acetic acid injection. A writhing response was defined as one instance of hind limb and trunk extension, abdominal indentation, or buttock elevation. The latency of the writhing response and the number of writhings within 15 minutes were recorded.

[0223] The results are shown in Table 5 below.

[0224] Table 5. Results of the acetic acid writhing test in mice Note: Compared with the normal control group ++ P≤0.01, + P≤0.05.

[0225] (V) Comparative Example

[0226] The present invention synthesized multiple compounds from Sumitomo Pharmaceuticals JP 2004277337 A, including representative compounds with high anti-inflammatory activity. These compounds were then compared with the compounds of the present invention in in vitro biological activity and metabolic stability tests, confirming that the compounds prepared by the present invention have better biological activity, higher metabolic stability, and higher chemical stability.

[0227] The relevant experimental process can be found in the in vitro biological activity experimental method in this article, and the comparative results are shown in Table 6 below.

[0228] Table 6

[0229] The above results show that after the "N" atom in the general structure of Sumitomo Pharmaceuticals' original patent is replaced by "C", it has higher activity and better metabolic stability. This conclusion shows a similar pattern in most compound cases in this invention.

[0230] Comparative synthesis methods and identification data of compounds

[0231] Comparative Case 1 Compound

[0232] Step 1: Ethyl 5-(thiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0233] 2-Acetylthiophene (30 g) was dissolved in N,N-dimethylformamide (150 mL). NaH (60%, 19.2 g) was added portionwise under ice-cooling. After complete addition, ethyl trifluoroacetate (75 g) was added dropwise while maintaining the ice-cooling temperature. The mixture was warmed to room temperature and the reaction continued for 1 h. The reaction solution was poured into ice-water, and the pH was adjusted to acidic with hydrochloric acid. Ethyl acetate was added for extraction. The layers were separated, and the organic phase was concentrated to dryness under reduced pressure to obtain crude 4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione. Half of the mixture was added with 3-amino-4-ethoxycarbonylpyrazole (19.5 g). The temperature was raised to 120°C and the reaction continued for 2 h. The reaction solution was poured into water to precipitate a large amount of solid. Filtration gave crude ethyl 5-(thiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate. The crude product was slurried with ethanol to obtain a refined product (21 g). (ESI) m / z = 342.1 [M+H] + .

[0234] Step 2: 5-(Thien-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0235] Ethyl 5-(thiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (3 g) was added to ethanol (500 mL), water (100 mL), and lithium hydroxide monohydrate (1.5 g). The mixture was reacted at 80°C for 7 h. After cooling to room temperature, the remaining ethanol was concentrated under reduced pressure. The pH was adjusted to 1-2 with hydrochloric acid, and a yellow solid was washed out. The filter cake was dried after filtration to obtain the title compound (1.0 g). (ESI) m / z = 314.1 [M+H] + .

[0236] Step 3: N-(Propan-2-yl)-5-(thiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0237] 5-(Thiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.5 g) was added to thionyl chloride (10 mL) and reacted at 50°C for 15 minutes. The thionyl chloride was removed under reduced pressure to obtain 5-(thiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid chloride. The resulting acid chloride was dissolved in dichloromethane (10 mL) and isopropylamine (1 mL). After reacting for 15 minutes, the reaction was quenched with water and extracted with dichloromethane (50 mL). The organic phase was concentrated under reduced pressure to dryness to obtain crude N-(propan-2-yl)-5-(thiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. The crude product was slurried with a small amount of ethanol to obtain a purified product (150 mg). (ESI) m / z = 355.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.43(dd,J=3.9,1.2Hz,1H),8.34(s,1H),8.02(dd,J=5.0,1.1H z, 1H), 7.82 (d, J = 7.4Hz, 1H), 7.33 (dd, J = 5.0, 3.9Hz, 1H), 4.21–4.04 (m, 1H), 1.29 (d, J = 6.5Hz, 6H).

[0238] Comparative Example 2 Compound (Synthesized with reference to Comparative Example 1 Compound)

[0239] N-propyl-5-(thiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0240] (ESI) m / z = 355.1 [M+H] + .1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.42(dd,J=3.9,1.2Hz,1H),8.32(s,1H),8.02(dd,J=5.0,1.1Hz,1H),7.85( t, J=5.5Hz, 1H), 7.32 (dd, J=5.0, 3.8Hz, 1H), 3.37 (q, J=6.8Hz, 2H), 1.64 (h, J=7.2Hz, 2H), 1.02 (t, J=7.4Hz, 3H).

[0241] Comparative Example 3 Compound (Synthesized with reference to Comparative Example 1 Compound)

[0242] [5-(4-Chlorophenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl](tetrahydro-1H-pyrrol-1-yl)methanone

[0243] (ESI) m / z = 395.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.37(d,J=8.5Hz,2H),8.31(s,1H),7.67(d ,J=8.5Hz,2H),3.67(t,J=6.4Hz,2H),3.56(t,J=6.7Hz,2H),1.97–1.82(m,4H).

[0244] Comparative Example 4 Compound (Synthesized with reference to Comparative Example 1 Compound)

[0245] [5-(4-Methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl](tetrahydro-1H-pyrrol-1-yl)methanone

[0246] (ESI) m / z = 391.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),8.32(d,J=8.9Hz,2H),8.21(s,1H),7.13(d,J=8. 9Hz, 2H), 3.87 (s, 3H), 3.69 (t, J = 6.5Hz, 2H), 3.56 (t, J = 6.9Hz, 2H), 1.99–1.80 (m, 4H).

[0247] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solutions of the present invention. They should all be included in the scope of the technical solutions claimed for protection by the present invention.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof, in, T1 is selected from C and N; T2 is selected from CR2, N and NR2; T3 is selected from CR3 and N; T4 is selected from CR4, N and NR4; Preferably, T1 is selected from N, T2 is selected from N, T3 is selected from CR3, T4 is selected from CR4 or T1 is selected from C, T2 is selected from CR2, T3 is selected from N, T4 is selected from NR4; R1 is selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more R a replace; R2 is selected from H and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more R b replace; R3 is selected from H and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more R c replace; R4 is selected from H and -LR d , the -LR d is optionally substituted with one or more R; R5 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl are each independently optionally substituted with one or more R e replace; L is selected from a bond, -C(=O)-, -CH(OH)-, -CH=CH- and -C 1-3 Alkylene-, preferably, L is selected from a bond, -C(=O)-, -CH(OH)-, -CH=CH-, -CH2-, -CH2CH2- and -CH(CH3)-; Each R a are each independently selected from halogen; Each R b are each independently selected from halogen; Each R c are each independently selected from halogen; R d is selected from phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkyl, OH, COOH and -C(=O)OC 1-3 Alkyl, the phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkyl or -C(=O)OC 1-3 The alkyl groups are each independently optionally substituted with one or more R; Each R e are independently selected from halogen, OH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Alkylthio, S(=O)2-C 1-3 Alkyl and S(=O)2NH2, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Alkylthio or S(=O)2-C 1-3 The alkyl groups are each independently optionally substituted with one or more halogen or morpholinyl groups; Each R is independently selected from halogen, OH, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-4 Alkylamino, -C(=O)OC 1-3 Alkyl and S(=O)2NH2, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-4 Alkylamino or -C(=O)OC 1-3 The alkyl groups are each independently optionally substituted with one or more halogens.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof, wherein: R1 is selected from CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2 are independently optionally replaced by 1, 2, 3, 4 or 5 R a replace; Preferably, R1 is selected from CH2F, CHF2 and CF3; More preferably, R1 is selected from CHF2 and CF3; More preferably, R1 is CF3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof, wherein: R2 is selected from H, CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2 are independently optionally replaced by 1, 2, 3, 4 or 5 R b replace; R3 is selected from H, CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2 are independently optionally replaced by 1, 2, 3, 4 or 5 R c replace; Preferably, R2 and R3 are independently selected from H, CH3, CH2F, CHF2 and CF3; More preferably, R2 is selected from CH3 and CF3, and R3 is selected from H.

4. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof, wherein: Each R is independently selected from F, Cl, Br, I, OH, COOH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, N(CH3)2, NHCH2CH3, N(CH2CH3)2, COOCH3, COOCH2CH3 and S(=O)2NH2, and CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, N(CH3)2, NHCH2CH3, N(CH2CH3)2, COOCH3 or COOCH2CH3 are independently optionally substituted with 1, 2, 3, 4 or 5 F, Cl, Br or I; Preferably, each R is independently selected from F, Cl, Br, OH, COOH, CH3, CH2CH3, CF3, OCH3, N(CH3)2, NHCH2CH3, COOCH3 and -S(=O)NH2.

5. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof, wherein: R d phenyl, furanyl, thienyl, thiazolyl, pyridinyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, morpholinyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2(CH2)2CH3, CH2(CH2)3CH3, CH2(CH2)4CH3, OH, COOH, COOCH3 and COOCH3, wherein the phenyl, furanyl, thienyl, thiazolyl, pyridinyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, morpholinyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2(CH2)2CH3, CH2(CH2)3CH3, CH2(CH2)4CH3, OH, COOH, COOCH3 or COOCH3 are each independently optionally substituted with 1, 2, 3, 4 or 5 R; Preferably, R d Selected from OH, COOH, 6. The compound according to any one of claims 1, 4 or 5, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof, wherein: R4 is selected from phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, -C(=O)-phenyl, -C(=O)-5-6 membered heteroaryl, -C(=O)-C 5-6 Cycloalkyl, -C(=O)-5-6 membered heterocycloalkyl, -C(=O)-C 1-6 Alkyl, -CH=CH-COOH, -CH=CH-C(=O)OC 1-3 Alkyl, -CH2-phenyl, -CH2-5-6 membered heteroaryl, -CH2-COOH, -CH2-C(=O)OC 1-3 alkyl, -CH2CH2-5-6 membered heterocycloalkyl, -CH2CH2-OH, -CH(CH3)-COOH and -CH(OH)-5-6 membered heteroaryl, the phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, -C(=O)-phenyl, -C(=O)-5-6 membered heteroaryl, -C(=O)-C 5-6 Cycloalkyl, -C(=O)-5-6 membered heterocycloalkyl, -C(=O)-C 1-6 Alkyl, -CH=CH-COOH, -CH=CH-C(=O)OC 1-3 Alkyl, -CH2-phenyl, -CH2-5-6 membered heteroaryl, -CH2-COOH, -CH2-C(=O)OC 1-3 Alkyl, -CH2CH2-5-6 membered heterocycloalkyl, -CH2CH2-OH, -CH(CH3)-COOH or -CH(OH)-5-6 membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4 or 5 R; Preferably, R4 is selected from phenyl, pyridyl, cyclopentyl, cyclohexyl, -C(=O)-phenyl, -C(=O)-furyl, -C(=O)-thienyl, -C(=O)-thiazolyl, -C(=O)-pyridyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-tetrahydropyranyl, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH2(CH2)2CH3, -C(=O)-CH2(CH2)3CH3, -C(=O)-CH2(CH2)4CH3, -CH=CH-COOH, -CH=CH-COOCH3, -CH2-phenyl, -CH2-pyridyl, -CH2-COOH, -CH2-COOCH2CH3, -CH2CH2-morpholinyl, -CH2CH2-OH, -CH(CH3)-COOH and -CH(OH)-thienyl, the phenyl, pyridyl, cyclopentyl, cyclohexyl, -C(=O)-phenyl, -C(=O)-furyl, -C(=O)-thienyl, -C(=O)-thiazolyl, -C(=O)-pyridyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-tetrahydropyranyl, -C(=O)-CH2CH3, -C(=O)-CH2 CH2CH3, -C(=O)-CH2(CH2)2CH3, -C(=O)-CH2(CH2)3CH3, -C(=O)-CH2(CH2)4CH3, -CH=CH-COOH, -CH=CH-COOCH3, -CH2-phenyl, -CH2-pyridyl, -CH2-COOH, -CH2-COOCH2CH3, -CH2CH2-morpholinyl, -CH2CH2-OH, -CH(CH3)-COOH or -CH(OH)-thienyl are each independently optionally substituted with 1, 2, 3, 4 or 5 R; More preferably, R4 is selected from 7. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof, wherein: Each R e Each of the following is independently selected from F, Cl, Br, I, OH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCD3, OCD2CD3, SCH3, SCH2CH3, SCH2CH2CH3, SCH(CH3)2, S(=O)2CH3, S(=O)2CH2CH3 and S(=O)2NH2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCD3, OCD2CD3, SCH3, SCH2CH3, SCH2CH2CH3, SCH(CH3)2, S(=O)2CH3 or S(=O)2CH2CH3 are each independently optionally substituted with 1, 2, 3, 4 or 5 F, Cl, Br, I or morpholinyl; Preferably, each R e are independently selected from F, Cl, Br, OH, CH3, OCH3, OCD3, SCH3, S(=O)2CH3, S(=O)2NH2 and 8. The compound according to claim 1 or 7, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof, wherein: R5 is selected from furanyl, thienyl, phenyl and pyridyl, wherein the furanyl, thienyl, phenyl or pyridyl are independently optionally substituted by 1, 2, 3, 4 or 5 R e replace; Preferably, R5 is selected from 9. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof, wherein the compound is selected from the compounds represented by formula (I-1) and (I-2), Wherein R1, R2, R4 and R5 are defined as in any one of claims 1 to 8; Preferably, the compound is selected from the compound represented by formula (I-1), wherein R1 is defined as in any one of claims 1 to 8, and R4 is selected from H and -LR d , the -LR d is optionally substituted with one or more R, L is selected from a bond, -C(=O)-, -CH(OH)- and -CH=CH-, R d is selected from phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkyl, COOH and -C(=O)OC 1-3 Alkyl, the phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkyl or -C(=O)OC 1-3 The alkyl groups are each independently optionally substituted by one or more R; R5 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl groups are each independently optionally substituted by one or more R e Replace; each R e are independently selected from halogen, OH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, S(=O)2-C 1-3 Alkyl and S(=O)2NH2, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or S(=O)2-C 1-3 The alkyl groups are each independently optionally substituted by one or more halogen or morpholinyl groups; each R is independently selected from halogen, OH, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-4 Alkylamino and -C(=O)OC 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, -C(=O)OC 1-3 Alkyl or C 1-4 The alkylamino groups are each independently optionally substituted with one or more halogens; preferably, each R is each independently selected from F, Cl, Br, I, OH, COOH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, N(CH3)2, NHCH2CH3, N(CH2CH3)2, COOCH3 and COOCH2CH3, wherein CH3, CH2CH3, CH2CH2CH3, CH( CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, N(CH3)2, NHCH2CH3, N(CH2CH3)2, COOCH3 or COOCH2CH3 are each independently optionally substituted with 1, 2, 3, 4 or 5 F, Cl, Br or I; preferably, each R is independently selected from F, Cl, Br, OH, COOH, CH3, CH2CH3, CF3, OCH3, N(CH3)2, NHCH2CH3 and COOCH3; Preferably, L is selected from a bond and -C(=O)-; Preferably, R d is selected from phenyl, furanyl, thienyl, thiazolyl, pyridinyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2(CH2)2CH3, CH2(CH2)3CH3, CH2(CH2)4CH3, COOH and COOCH3, wherein the phenyl, furanyl, thienyl, thiazolyl, pyridinyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2(CH2)2CH3, CH2(CH2)3CH3, CH2(CH2)4CH3, COOH or COOCH3 is optionally substituted by 1, 2, 3, 4 or 5 R; further preferably, R d Selected from COOH, Preferably, R4 is selected from phenyl, 5-6 membered heteroaryl, -C(=O)-phenyl, -C(=O)-5-6 membered heteroaryl, -C(=O)-C 5-6 Cycloalkyl, -C(=O)-5-6 membered heterocycloalkyl, -C(=O)-C 1-6 Alkyl, -CH=CH-COOH, -CH=CH-C(=O)OC 1-3 alkyl and -CH(OH)-5-6 membered heteroaryl, the phenyl, 5-6 membered heteroaryl, -C(=O)-phenyl, -C(=O)-5-6 membered heteroaryl, -C(=O)-C 5-6 Cycloalkyl, -C(=O)-5-6 membered heterocycloalkyl, -C(=O)-C 1-6 Alkyl, -CH=CH-COOH, -CH=CH-C(=O)OC 1-3 The alkyl or -CH(OH)-5-6 membered heteroaryl group is optionally substituted by 1, 2, 3, 4 or 5 R groups, respectively. Preferably, R4 is selected from phenyl, pyridyl, -C(=O)-phenyl, -C(=O)-furyl, -C(=O)-thienyl, -C(=O)-thiazolyl, -C(=O)-pyridyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-tetrahydropyranyl, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH2(CH2)2CH3, -C(=O)-CH2(CH2)3CH3, -C(=O)-CH2(CH2)4CH3, -CH=CH-COOH, -CH=CH-COOCH 3 and -CH(OH)-thienyl, said phenyl, pyridyl, -C(=O)-phenyl, -C(=O)-furanyl, -C(=O)-thienyl, -C(=O)-thiazolyl, -C(=O)-pyridyl, -C(=O)-cyclopentyl, -C(=O)-cyclohexyl, -C(=O)-tetrahydropyranyl, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH2(CH2)2CH3, -C(=O)-CH2(CH2)3CH3, -C(=O)-CH2(CH2)4CH3, -CH=CH-COOH, -CH=CH-COOCH3 or -CH(OH)-thienyl being optionally substituted with 1, 2, 3, 4 or 5 R, respectively; More preferably, R4 is selected from More preferably, R4 is selected from More preferably, R4 is selected from Preferably, R e is selected from F, Cl, Br, I, OH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCD3, OCD2CD3, S(=O)2CH3, S(=O)2CH2CH3 and S(=O)2NH2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCD3, OCD2CD3, S(=O)2CH3 or S(=O)2CH2CH3 are independently and optionally substituted by 1, 2, 3, 4 or 5 F, Cl, Br, I or morpholinyl; further preferably, R e Selected from F, Cl, Br, OH, CH3, OCH3, OCD3, S(=O)2CH3, S(=O)2NH2 and Preferably, R5 is selected from More preferably, R5 is selected from More preferably, R5 is selected from or Preferably, the compound is selected from the compound represented by formula (I-2), wherein R1 is defined as in any one of claims 1 to 8, and R2 is selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more R b Substituted, R4 is selected from -LR d , the -LR d R5 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl are independently and optionally substituted by one or more R e substituted; L is selected from a bond, -C(=O)- and -C 1-3 Alkylene-; each R b are independently selected from halogen, R d is selected from phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkyl, OH, COOH and -C(=O)OC 1-3 Alkyl, the phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 1-6 Alkyl or -C(=O)OC 1-3 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 R groups, each of which is independently e are independently selected from halogen, OH, C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, S(=O)2-C 1-3 Alkyl and S(=O)2NH2, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or S(=O)2-C 1-3 The alkyl groups are each independently optionally substituted with one or more halogens, and each R is independently selected from halogen, OH, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-4 Alkylamino and -C(=O)OC 1-3 Alkyl, halogen, OH, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-4 Alkylamino or -C(=O)OC 1-3 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 F, Cl, Br or I, respectively, independently; Preferably, R1 is CF3; Preferably, R2 is selected from CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2, wherein CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2 are independently optionally replaced by 1, 2, 3, 4 or 5 R b Substitution; More preferably, R2 is selected from CH3 and CF3; Preferably, L is selected from a bond, -C(=O)-, -CH2-, -CH2CH2- and -CH(CH3)-; more preferably, L is selected from a bond and -CH2-; Preferably, R is selected from F, Cl, OH, CH3, OCH3 and -S(=O)NH2; Preferably, R d is selected from phenyl, pyridyl, cyclopentyl, cyclohexyl, morpholinyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2(CH2)2CH3, CH2(CH2)3CH3, CH2(CH2)4CH3, OH, COOH, COOCH3 and COOCH2CH3, wherein the phenyl, pyridyl, cyclopentyl, cyclohexyl, morpholinyl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2(CH2)2CH3, CH2(CH2)3CH3, CH2(CH2)4CH3, COOCH3 or COOCH2CH3 is independently and optionally substituted by 1, 2, 3, 4 or 5 R, wherein R is as defined above; preferably, R d Selected from OH, COOH, Preferably, R4 is selected from phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, -C(=O)-C 1-6 Alkyl, -CH2-phenyl, -CH2-5-6 membered heteroaryl, -CH2-COOH, -CH2-C(=O)OC 1-3 alkyl, -CH2CH2-5-6 membered heterocycloalkyl, -CH2CH2-OH and -CH(CH3)-COOH, the phenyl, 5-6 membered heteroaryl, C 5-6 Cycloalkyl, -C(=O)-C 1-6 Alkyl, -CH2-phenyl, -CH2-5-6 membered heteroaryl, -CH2-COOH, -CH2-C(=O)OC 1-3 alkyl, -CH2CH2-5-6 membered heterocycloalkyl, -CH2CH2-OH or -CH(CH3)-COOH, each independently optionally substituted by 1, 2, 3, 4 or 5 R; further preferably, R4 is selected from phenyl, pyridyl, cyclopentyl, cyclohexyl, -C(=O)-CH2CH2CH3, -CH2-phenyl, -CH2-pyridyl, -CH2-COOH, -CH2-COOCH2CH3, -CH2CH2-morpholine R, -CH2CH2-OH and -CH(CH3)-COOH, wherein the phenyl, pyridyl, cyclopentyl, cyclohexyl, -C(=O)-CH2CH2CH3, -CH2-phenyl, -CH2-pyridyl, -CH2-COOH, -CH2-COOCH2CH3, -CH2CH2-morpholinyl, -CH2CH2-OH or -CH(CH3)-COOH are each independently optionally substituted by 1, 2, 3, 4 or 5 R; More preferably, R4 is selected from More preferably, R4 is selected from More preferably, R4 is selected from More preferably, R4 is selected from Preferably, R e is selected from F, Cl, Br, I, OH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, SCH3, SCH2CH3, SCH2CH2CH3, SCH(CH3)2, S(=O)2CH3, S(=O)2CH2CH3 and S(=O)2NH2, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, SCH3, SCH2CH3, SCH2CH2CH3, SCH(CH3)2, S(=O)2CH3 or S(=O)2CH2CH3 are independently and optionally substituted by 1, 2, 3, 4 or 5 F, Cl, Br or I; further preferably, R e Selected from Cl, OCH3, SCH3, S(=O)2CH3 and S(=O)2NH2; Preferably, R5 is selected from phenyl and pyridyl, wherein the phenyl or pyridyl is independently optionally substituted by 1, 2, 3, 4 or 5 R e replace; More preferably, R5 is selected from More preferably, R5 is selected from More preferably, R5 is selected from 10. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof, wherein: The compound is selected from 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof, and one or more pharmaceutically acceptable carriers or excipients.

12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound thereof or a pharmaceutical composition according to claim 11 in the preparation of a medicament as a COX inhibitor; Alternatively, use in the preparation of a medicament for preventing and / or treating inflammation and pain.

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