Pyrazolo heteroaryl compound as well as preparation method and application thereof

Abstract

The invention relates to a pyrazolo heteroaryl compound which can be used for preparing a medicine serving as a COX inhibitor, and further, the compound can be used for preventing and / or treating inflammation and pain.

Description

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. Further, the compound can be used to prevent and / or treat inflammation and pain. Background Art

[0002] Inflammation plays a vital 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), as a major category of anti-inflammatory drugs, have become the most commonly used class of drugs. Prostaglandins (PG) play an important regulatory role in inflammation, and all NSAIDs work by inhibiting the production of PG. Cyclooxygenase (COX) can catalyze the metabolism of arachidonic acid (AA) to produce PG and its analogs, so COX has become 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but most of these drugs were later controversial due to the risk of heart attack and stroke, and some drugs were even withdrawn from the market. In some meta-analyses, it was 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 The selective COX-2 inhibitor rofecoxib was withdrawn from the market because of its risk of cardiovascular side effects. Moderately selective COX-2 inhibitors may reduce their cardiotoxicity. In addition, studies have shown that COX-1 inhibitors have potential value in the treatment of thrombosis, and COX-2 inhibitors have potential value in the prevention and treatment of tumors. Therefore, the design and synthesis of new COX inhibitors are of great significance to human health.

[0004] In short, the existing non-steroidal 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 non-steroidal anti-inflammatory drugs. Summary of the invention

[0005] The purpose of the present invention is to design and prepare a new class of COX inhibitors to improve the effectiveness and / or safety of existing non-steroidal anti-inflammatory drugs. The two subtypes of cyclooxygenase (COX-1 and COX-2) are selectively inhibited and a weakly selective inhibitor of COX-2 is sought to minimize the toxic side effects of COX inhibitors.

[0006] 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.

[0007]

[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 substituted with 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 substituted with 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 substituted with one or more R c replace;

[0014] R4 is selected from H and -LR d , the -LR d is 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 with 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 R a 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 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;

[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, wherein 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 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, wherein 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), Rd Selected from 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 by 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 1-6 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 1-3Alkyl, -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 of formula (I), R4 is selected from phenyl, pyridyl, cyclopentyl, cyclohexyl, -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)-C H2(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)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 by 1, 2, 3, 4 or 5 R.

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

[0036]

[0037] In certain embodiments, in the compound represented by formula (I), each R eEach 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 by 1, 2, 3, 4 or 5 F, Cl, Br, I or morpholino groups.

[0038] 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

[0039] 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 substituted by 1, 2, 3, 4 or 5 R e replace.

[0040] In certain embodiments, in the compound represented by formula (I), R5 is selected from

[0041] In certain embodiments, the compound is selected from the compounds represented by formula (I-1) and (I-2),

[0042]

[0043] wherein R1, R2, R4 and R5 are as defined in the present invention.

[0044] In certain embodiments, the compound is selected from the compound represented by formula (I-1), wherein R1 is defined as described in the present invention, 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 5-6Cycloalkyl, 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.

[0045] 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.

[0046] 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.

[0047] In certain embodiments, in the compound represented by formula (I-1), L is selected from a bond and -C(=O)-.

[0048] In certain embodiments, in the compound represented by formula (I-1), 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.

[0049] In certain embodiments, in the compound represented by formula (I-1), R d Selected from COOH,

[0050] 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 group is optionally substituted with 1, 2, 3, 4 or 5 R groups, respectively, independently.

[0051] In certain embodiments, in the compound represented by formula (I-1), R4 is selected from 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 and -CH(OH)-thiophene. 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 are each independently optionally substituted by 1, 2, 3, 4 or 5 R.

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

[0053] In certain embodiments, in the compound represented by formula (I-1), R4 is selected from

[0054] In certain embodiments, the compound represented by formula (I-1), wherein R4 is selected from

[0055] 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 morpholino groups.

[0056] 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

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

[0058] In certain embodiments, in the compound represented by formula (I-1), R5 is selected from

[0059] In certain embodiments, in the compound represented by formula (I-1), R5 is selected from

[0060] 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 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)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.

[0061] In certain embodiments, in the compound represented by formula (I-2), R1 is CF3.

[0062] In certain embodiments, in the compound represented by formula (I-2), R2 is selected from CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2, and CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2 are independently optionally replaced by 1, 2, 3, 4 or 5 R b replace.

[0063] In certain embodiments, in the compound represented by formula (I-2), R2 is selected from CH3 and CF3.

[0064] In certain embodiments, in the compound represented by formula (I-2), L is selected from a bond, -C(=O)-, -CH2-, -CH2CH2- and -CH(CH3)-.

[0065] In certain embodiments, in the compound represented by formula (I-2), L is selected from a bond and -CH2-.

[0066] In certain embodiments, in the compound represented by formula (I-2), R is selected from F, Cl, OH, CH3, OCH3 and -S(=O)NH2.

[0067] 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, 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 are each independently and optionally substituted by 1, 2, 3, 4 or 5 R, and R is defined as described above.

[0068] In certain embodiments, in the compound represented by formula (I-2), R d Selected from OH, COOH,

[0069] 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.

[0070] 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 and optionally substituted by 1, 2, 3, 4 or 5 R.

[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), R4 is selected from

[0074] In certain embodiments, in the compound represented by formula (I-2), R4 is selected from

[0075] 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.

[0076] In certain embodiments, in the compound represented by formula (I-2), R eSelected from Cl, OCH3, SCH3, S(=O)2CH3 and S(=O)2NH2.

[0077] 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 substituted by 1, 2, 3, 4 or 5 R e replace.

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

[0079] In certain embodiments, in the compound represented by formula (I-2), R5 is selected from

[0080] In certain embodiments, in the compound represented by formula (I-2), R5 is selected from

[0081] In certain embodiments, the compound is selected from:

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090] The present invention also relates to a pharmaceutical composition, which comprises the compound or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, polymorph or isotope-labeled compound, and one or more pharmaceutically acceptable carriers or excipients.

[0091] 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 drugs as COX inhibitors.

[0092] 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.

[0093] The present invention also relates to a general method for preparing the compound, which comprises:

[0094]

[0095] Route 1;

[0096]

[0097] Route 2;

[0098]

[0099] Route 3; or

[0100]

[0101] Route 4;

[0102] in,

[0103] 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.

[0104] Definition of terms

[0105] 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.

[0106] When the name of the compound used in the present invention is inconsistent with the chemical structural formula, the chemical structural formula shall prevail.

[0107] As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.

[0108] 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.

[0109] As used in the present invention, "C1-3 "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.

[0110] 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 in the present invention, "C 1-3 "Alkoxy" refers to a C 1-3 The group obtained by connecting the carbon atom on the alkyl group with the oxygen atom includes, but is not limited to, methoxy, ethoxy or propoxy.

[0111] As used in the present invention, "C 1-3 "Deuterated alkoxy" refers to a C 1-3 The group obtained by replacing the hydrogen atoms on the alkoxy group with 1, 2, 3, 4, 5, 6 or 7 deuterium atoms, specific examples include but are not limited to deuterated methoxy (such as OCD3) or deuterated ethoxy (such as OCH2CD3 or OCD2CD3) and the like.

[0112] As used in the present invention, "C 1-3 "Alkylthio" refers to a C 1-3 The group obtained by connecting a carbon atom on the alkyl group to a sulfur atom includes, but is not limited to, methylthio, ethylthio or propylthio.

[0113] As used in the present invention, "C 1-4 "Alkylamino" refers to a C 1-4 The group obtained by connecting a carbon atom on the alkyl group with a nitrogen atom or NH includes, but is not limited to, methylamino, dimethylamino, ethylamino, diethylamino or propylamino.

[0114] 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 furanyl.

[0115] 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.

[0116] As used in the present invention, "C5-6 "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.

[0117] As used in the present invention, "pharmaceutically acceptable salt" means a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids or with organic acids; or salts formed when the acidic protons present on the parent compound are replaced by metal ions; or coordination compounds formed with organic bases.

[0118] Beneficial Effects

[0119] The compounds of the present invention have a good inhibitory effect on COX2; the compounds of the present invention can inhibit PGE2 by inhibiting COX protein. In addition, the compounds of the present invention have good metabolic stability and have preventive and therapeutic effects on inflammation and pain in vivo. DETAILED DESCRIPTION

[0120] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0121] 1. Synthesis Examples of Compounds

[0122] Example 1: I-1-30

[0123]

[0124] Step 1: 3-Amino-4-tert-butoxycarbonylpyrazole

[0125] Take tert-butyl cyanoacetate (120 g) and dissolve it in methanol (500 mL). Add DMF-DMA (100 g) to it and reflux at 70°C for 2 hours. After cooling, add 52.5 g of hydrazine hydrate (80%) and reflux at 70°C for 3 hours. Concentrate the reaction solution to dryness to obtain a yellow to reddish brown crude product of the title compound (154 g). After adding water to the crude product, extract it with ethyl acetate several times, separate the liquids, and combine the organic phases and concentrate to obtain a refined product. (ESI) m / z=184.2[M+H] + .

[0126] Step 2: 4,4,4-Trifluoro-1-(4-methoxyphenyl)-1,3-butanedione

[0127] Take p-methoxyacetophenone (60g) and dissolve it in N,N-dimethylformamide (600mL). Add NaH (60%, 32g) in batches under ice bath. After adding, maintain ice bath and drop ethyl trifluoroacetate (62.5g). After dropping, warm to room temperature and continue to react for 1h. Pour the reaction solution into ice water, adjust pH to acidity with hydrochloric acid, add ethyl acetate for extraction, separate the liquids, wash the organic phase with water three times and concentrate under reduced pressure to dryness to obtain a yellow crude product of the title compound (118g), which can be directly used in the next step. The crude product can be slurried with n-hexane or ethanol to obtain a refined product.

[0128] Step 3: 5-(4-methoxyphenyl)-7-(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0129] Take crude 4,4,4-trifluoro-1-(4-methoxyphenyl)-1,3-butanedione (55g), add glacial acetic acid (50mL) and crude 3-amino-4-tert-butoxycarbonylpyrazole (37g), and reflux for 3h. After cooling to room temperature, add trifluoroacetic acid (50mL), and then react at 60°C for 30min. Pour the reaction solution into ice water, a large amount of solid precipitates, filter and dry the filter cake to obtain the crude title compound, and beat the crude product with ethanol to obtain a refined product (20.0g).

[0130] Step 4: (5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl)(thiophen-2-yl)methanone (I-1-30)

[0131] Take 5-(4-methoxyphenyl)-7-(trifluoromethyl)-3-pyrazolo[1,5-a]pyrimidinecarboxylic acid (10 g), add trifluoroacetic acid (20 mL) and thiophene (15 g), add trifluoroacetic anhydride (12.5 g) dropwise, and react at room temperature for 30 min. Pour the reaction solution into ice water, a large amount of solid precipitates, filter, wash the filter cake with water, and dry 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] + .

[0132] Example 2: I-1-9

[0133]

[0134] Step 1: Referring to Example 1, p-methoxyacetophenone was replaced with p-bromoacetophenone to obtain [5-(p-bromophenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl](thiophene-2-yl)methanone.

[0135] Step 2: (5-(4-bromophenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl)(thiophen-2-yl)methanol (I-1-9)

[0136] Take [5-(p-bromophenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl](thiophene-2-yl)methanone (2g), add dichloromethane (10mL), slowly add sodium borohydride (0.3g), and react at room temperature for 1h. Pour the reaction solution into water, extract with dichloromethane, separate the liquids, and concentrate the organic phase under reduced pressure to obtain a crude product. The crude product can be slurried with ethanol to obtain the yellow solid title compound (1.8g). 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] + .

[0137] Example 3: I-1-39 and I-1-40

[0138]

[0139] Step 1: 5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine

[0140] Take the crude product of 4,4,4-trifluoro-1-(4-methoxyphenyl)-1,3-butanedione (55 g), add glacial acetic acid (50 mL) and 3-aminopyrazole (17 g), and reflux for 1 hour. Pour the reaction solution into ice water, and a large amount of solid precipitates. After filtering, dry the filter cake to obtain the title compound (48 g). (ESI) m / z = 294.1 [M + H] + .

[0141] Step 2: [5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]cyclopentylmethanone (I-1-39)

[0142] Weigh cyclopentanoic acid (22.9 g) in a reaction bottle, add thionyl chloride (50 mL), react at 50 ° C for about 0.5 h, and concentrate under reduced pressure to obtain cyclopentanecarbonyl chloride for use. Weigh 5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (14.7 g), add dichloromethane (100 mL) to dissolve, add AlCl3 (26.7 g), and slowly drip the obtained cyclopentanecarbonyl chloride into the above reaction solution. After dripping, react at room temperature for 0.5 h. Pour the system into water, extract with dichloromethane, separate the liquids, add silica gel to the organic phase and mix the sample, purify by column chromatography (eluent is n-hexane: ethyl acetate = 10:1), and obtain the title compound (5.5 g). 1 HNMR(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] + .

[0143] Step 3: [5-(4-Hydroxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]cyclopentylmethanone (I-1-40)

[0144] Take [5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]cyclopentylmethanone (2.0 g), add dichloromethane (50 mL) to dissolve, add boron tribromide (3.0 g) dropwise at room temperature, and continue to react for 1 hour. After quenching with water, the organic phase is separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude title compound, which is purified by medium pressure preparative chromatography (chromatographic 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] + .

[0145] Example 4: I-1-45

[0146]

[0147] Step 1: 3-(Dimethylamino)-1-[5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]propan-1-one (I-1-45)

[0148] Weigh 5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (2.0 g) into a reaction bottle, add dichloromethane (30 mL) and aluminum chloride (2.0 g), add 3-chloropropionyl chloride (2.0 g) dropwise under stirring at room temperature, and react for about 30 minutes after the addition. Pour the reaction solution into water, add dichloromethane for extraction, separate the liquids, and concentrate the organic phase under reduced pressure to dryness to obtain a crude product of 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, and the obtained 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), and half of it was dropped into the above reaction solution, and the reaction was continued for 1 hour after the dropwise addition. Then the reaction solution was poured into water, ethyl acetate was added for extraction, and the liquids were separated. 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).

[0149] Example 5: I-1-56 and I-1-57

[0150]

[0151] Step 1: 3-Bromo-5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine

[0152] At room temperature, add 5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (15.0 g, which can be prepared by referring to the method of Example 1, or the synthetic route disclosed on page 28 or 32 of JP2004277377A) and acetonitrile (75 mL) to a 100 mL single-mouth bottle, add NBS (10.0 g) in batches, and react at room temperature for 1 h. Pour the system into water, precipitate solid, filter and dry the filter cake to obtain a yellow solid (18.5 g). (ESI) m / z=372.0[M+H] + .

[0153] Step 2: (2E)-3-[5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoic acid methyl ester (I-1-56)

[0154] 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 to a 10 mL sealed tube, replaced with nitrogen, and heated to 100°C for 1 h. The reaction solution was poured into water, extracted with ethyl acetate, separated, the organic phase was washed with water and dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 1.7 g of the crude product of the title compound. 0.5 g of the crude product was purified by 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] + .

[0155] Step 3: (2E)-3-[5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoic acid (I-1-57)

[0156] Weigh (2E)-3-[5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoic acid methyl ester (0.75 g) into a reaction bottle, add ethanol (100 mL) and sodium hydroxide (0.5 g), and heat to 80°C for 3 h. After the reaction solution was concentrated to dryness under reduced pressure, a dilute potassium carbonate solution and ethyl acetate were added for extraction, and the liquids were separated. The aqueous phase was acidified and then extracted with ethyl acetate, and the liquids were separated. The organic phase was concentrated to dryness under reduced pressure to obtain a crude product of the title compound, and 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]+ .

[0157] Example 6: I-1-58 and I-1-60

[0158]

[0159] Step 1: 5-(4-methoxyphenyl)-3-(2-methoxypyridin-3-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (I-1-58)

[0160] 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)boric acid (7.4 g), DMF (180 mL) and PdCl2(dppf)DCM (500 mg) were added to a 10 mL sealed tube, replaced with nitrogen, and heated to 110°C for 2 h. The reaction solution was poured into water, extracted with ethyl acetate, separated, and the organic phase was mixed with silica gel and purified by 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] + .

[0161] Step 2: 3-[5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]-1,2-dihydropyridin-2-ol (I-1-60)

[0162] Take 5-(p-methoxyphenyl)-3-(2-methoxypyridin-3-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (2.0 g), add hydrobromic acid solution (48%, 10 mL) and 1,4-dioxane (50 mL), and heat to 100°C for 2 h. After the reaction is completed, pour the reaction solution into water, precipitate solid, filter, and slurry the solid 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] + .

[0163] Example 7: I-1-71

[0164]

[0165] Step 1: 3-Bromo-5-(4-(methylsulfonyl)phenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine

[0166] Take 3-bromo-5-(4-(methylthio)phenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (1.9 g, which can be prepared by referring to the methods of Examples 1 and 5, for example, replace p-methoxyacetophenone in Example 1 with p-methylthioacetophenone, and replace 3-amino-4-tert-butyloxycarbonylpyrazole with 3-amino-4-bromo-pyrazole), add dichloromethane (10 mL) to dissolve, slowly add m-chloroperbenzoic acid (1.7 g), and react at room temperature for 4 hours. After the reaction is completed, pour the reaction solution into water, extract with dichloromethane, separate the liquids, and concentrate the organic phase under reduced pressure to obtain a crude product, which can be pulped with ethanol to obtain the light red solid title compound (1.4 g).

[0167] Step 2: 3-(2-methoxypyridin-3-yl)-5-(4-(methylsulfonyl)phenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (I-1-71)

[0168] Take 3-bromo-5-(4-(methylsulfonyl)phenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (0.5 g), add 1,4-dioxane (8 mL), potassium carbonate (1.4 g), PdCl2(dppf)·DCM (20 mg) and (2-methoxypyridin-3-yl)boric acid (1.5 g), protect with nitrogen, and reflux for 2 h. After the reaction is completed, the system solvent is removed by concentration under reduced pressure to obtain a crude product, which is purified by C18 reverse preparative chromatography (0%-80% water-acetonitrile system, 1 h) to obtain 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] + .

[0169] Example 8: I-2-8

[0170]

[0171] Step 1: 6-(4-methoxyphenyl)-1-phenyl-3,4-bis(trifluoromethyl)pyrazolo[3,4-b]pyridine (I-2-8)

[0172] Weigh acetonitrile (32g) in a reaction bottle, add NaH (60%, 8.0g), stir at room temperature for 10min, add ethyl trifluoroacetate (14.2g) dropwise thereto, and continue to react for 3h after the addition. Then pour the reaction solution into water, add hydrochloric acid to adjust the pH to acidic, add ethyl acetate for extraction, separate the liquids, and concentrate the organic phase under reduced pressure to dryness to obtain a crude trifluoroacetyl acetonitrile. Add acetic acid (40mL) and phenylhydrazine (10.8g) to the crude trifluoroacetyl acetonitrile, heat to 100℃ and react for 3h, add water and ethyl acetate to the reaction solution for extraction, separate the liquids, and concentrate the organic phase under reduced pressure to dryness to obtain a crude 2-phenyl-5-(trifluoromethyl)pyrazole-3-amine (14.0g). Take the crude product of 2-phenyl-5-(trifluoromethyl)pyrazol-3-amine (7.0g), add 4,4,4-trifluoro-1-(4-methoxyphenyl)-1,3-butanedione (7.6g) and acetic acid (20mL), and react at 120°C for 5h. Then pour the reaction solution into water, add ethyl acetate for extraction, separate the liquids, mix the organic phase with silica gel and purify it on a silica gel column (eluent: Hex:EA=10:1) to obtain the crude product of the title compound, and purify the crude product by reverse medium pressure preparative chromatography (chromatographic column specifications: C18spherical, 120g; eluent: acetonitrile / water; flow rate: 80mL / min, eluent organic phase ratio: 0%~100%) to obtain the pure product (0.4g). 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] + .

[0173] Example 9: I-2-18

[0174]

[0175] Step 1: p-Acetylbenzenesulfonamide

[0176] Weigh p-ethylbenzenesulfonamide (100 g) into a reaction bottle, add acetic acid (500 mL), add chromium trioxide (60 g) in batches, and stir at room temperature for 6 hours. 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 the filter cake to obtain the gray title compound (80 g).

[0177] Step 2: 4-(4,4,4-trifluoro-1,3-dioxybutylidene)benzene-1-sulfonamide

[0178] Weigh 4-acetylbenzenesulfonamide (40 g) into a reaction bottle, add DMF (300 mL) to dissolve, add NaH (60%, 24 g) under stirring, and stir at room temperature for 0.5 h. Then slowly drop ethyl trifluoroacetate (40 g) into it, and after the drop is complete, transfer to 50 ° C and heat to react for 3 h. After the reaction is completed, pour the reaction solution into water, adjust the pH to acidic, add ethyl acetate to extract twice, filter, combine the organic phases, and concentrate the organic phases under reduced pressure to dryness to obtain the title compound (100 g) as a yellow to brown oil.

[0179] Step 3: 4-[3-methyl-1-phenyl-4-(trifluoromethyl)pyrazolo[3,4-b]pyridin-6-yl]benzene-1-sulfonamide (I-2-18)

[0180] Weigh 3-oxobutyronitrile (20 g) into a reaction bottle, add acetic acid (30 mL) and phenylhydrazine (20 g), heat to 100 ° C for 4 h, cool slightly, add 4-(4,4,4-trifluoro-1,3-dioxybutyl)benzene-1-sulfonamide crude product (60 g), and continue to react at 120 ° C for 3 h. After cooling, pour the reaction solution into water, precipitate a large amount of solid, filter to obtain the crude title compound. The crude product is recrystallized from ethanol to obtain the off-white powder solid title compound (16 g). 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] + .

[0181] Example 10: 1-1-27 and 1-2-28

[0182]

[0183] Step 1: Ethyl 2-(6-(4-methoxyphenyl)-3-methyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetate (I-1-27)

[0184] Take ethyl hydrazinoacetate hydrochloride (1.6 g), add 3-oxobutyronitrile (0.9 g) and acetic acid (8 mL), heat to reflux for 2 h, then add 4,4,4-trifluoro-1-(4-(methoxy)phenyl)butane-1,3-dione (2.5 g), and continue to react for 2 h. After the reaction is completed, the system is cooled to room temperature, water is added for crystallization, and the crude product is filtered to obtain the crude product, which 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] + .

[0185] Step 2: 2-(6-(4-methoxyphenyl)-3-methyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (I-1-28)

[0186] 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 for 2 h. After the reaction is completed, the remaining tetrahydrofuran and ethanol in the system are removed by rotary evaporation, and then the system is adjusted to acidity to precipitate a white solid, which is filtered to obtain a crude product, and the crude product is slurried with ethanol to obtain a 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] + .

[0187] Example 11: 1-2-31

[0188]

[0189] Step 1: 1-(tert-butyl)-3-methyl-6-(4-(methylthio)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine

[0190] Take tert-butylhydrazine hydrochloride (5.0 g), add 3-oxobutanenitrile (3.3 g), 10 ml of acetic acid, raise the temperature to reflux and react for 2 hours, then add 4,4,4-trifluoro-1-(4-(methylthio)phenyl)butane-1,3-dione (10.5 g), continue to react for 2 hours, after the reaction is completed, cool the system to room temperature, add water, a large amount of white solid precipitated, filter to obtain a crude product, and slurry the crude product with ethanol to obtain the title compound (7.2 g).

[0191] Step 2: 1-(tert-Butyl)-3-methyl-6-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine

[0192] Take 1-(tert-butyl)-3-methyl-6-(4-(methylthio)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (7.2 g), add dichloromethane (40 mL) solvent, slowly add m-chloroperbenzoic acid (6.4 g), and react at room temperature for 4 hours. After the reaction is completed, pour the reaction solution into water and extract with dichloromethane.

[0193] The organic phase was separated and concentrated under reduced pressure to obtain a crude product, which was slurried with ethanol to obtain the target compound (7.4 g) as a white solid. (ESI) m / z = 412.1 [M+H] + .

[0194] Step 3: 3-Methyl-6-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine

[0195] Take 1-(tert-butyl)-3-methyl-6-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (4.1 g), add trifluoroacetic acid (20 mL), and heat to 80°C to react overnight. After the reaction is completed, pour the reaction solution into water, and a large amount of white solid precipitates. Filter by suction to obtain a filter cake, which is 3.2 g of the title compound. (ESI) m / z=356.1[M+H] + .

[0196] 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)

[0197] Take 3-methyl-6-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (0.5 g), add dichloromethane (5 mL), isovaleric acid (0.5 mL) and HATU (1.5 g), and react at room temperature for 4 h. After the reaction is completed, dichloromethane is removed by rotary evaporation to obtain a crude product, which is purified by C18 reverse preparative chromatography (0%-80% water-acetonitrile system, 1 h) to obtain 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] + .

[0198] The compounds shown in Table A below can be prepared by using corresponding commercially available reagents, catalysts, solvents and other raw materials according to the above-mentioned methods.

[0199] Table A

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209] Table B. H NMR and mass spectrometry data of the compounds prepared in the examples of the present invention and their COX-2 inhibition rates

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233] Note: a Inhibition rate of representative compounds at a test concentration of 556 nM

[0234] 2. In vitro biological activity test

[0235] (I) Cyclooxygenase inhibition activity test

[0236] COX-2 inhibitory activity

[0237] 1. Materials

[0238] Cyclooxygenase-2 (COX-2) inhibitor screening kit (Shanghai Biotech Co., Ltd., catalog number: S0168)

[0239] 96-well black board (Corning)

[0240] Gun head (Epend)

[0241] 2. Test process

[0242] 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.

[0243] 2) Add the probe and substrate arachidonic acid.

[0244] 3) Incubate at 37°C for 10 min.

[0245] 4) Detection (excitation wavelength is 560 nm, emission wavelength is 590 nm).

[0246] 3. Handling of test samples and positive drugs

[0247] Take an appropriate amount of the inhibitor to be tested and prepare a solution of appropriate concentration with DMSO. If necessary, prepare an appropriate concentration gradient for later use.

[0248] Take an appropriate amount of celecoxib (100 μM) and dilute it with DMSO to the desired concentration (eg, 200 nM).

[0249] 4. Calculation

[0250] 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 sample concentration that causes 50% inhibition of enzyme activity.

[0251] COX-1 inhibitory activity

[0252] 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.

[0253] The activity test results of some compounds are shown in Table 1 below.

[0254] Table 1. IC of some compounds for COX-1 and COX-2 inhibition 50

[0255]

[0256]

[0257] (II) PGE2 inhibitory activity

[0258] Screening test of the inhibitory effect of compounds on PGE2 in mouse macrophage Raw264.7

[0259] 1. Purpose of the test

[0260] The compounds were tested for their inhibitory effects in the LPS-induced PGE2 elevation model in Raw264.7 cells.

[0261] 2. Reagent and instrument information

[0262] Sample name Batch No. / Model factory RMPI 1640 Medium 118750593 GIBCO Fetal bovine serum cl-0233 Ikosai Raw264.7 cells CL-0190 Wuhan Punosai PGE2 ELISA Kit 514010 Cayman Lipopolysaccharide (LPS) L4391 SIGMA DMSO T3760300 CNW CCK-8 Kit Ck04 Japan Tongren Chemical Automatic cell counter Auto T4 Nexcelom Biological Safety Cabinets 1384 Thermo Fisher Multifunctional ELISA reader SPARK TECAN 24-well plate FCP126 Blue Sky Cell culture dishes CLS430167 corning Carbon dioxide incubator 3111 Thermo Fisher Penicillin-Streptomycin 15140122 Thermo Fisher

[0263] 3. Test process

[0264] 1) Raw264.7 cells were cultured in a CO2 incubator using 1640 medium containing 10% serum and 1% double antibody 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 pcs / well, inoculated in 12-well plates and cultured for 24 h;

[0265] 2) After 24 hours of cell culture, add the compound at a final concentration of 8-1000 nM to the cells. After 1 hour of incubation, add LPS at a final concentration of 1 μg / mL to the cells in each well except the control group for 24 hours;

[0266] 3) After 24 h of cell culture, 200 μL of cell supernatant was taken and the PGE2 content was detected using a PGE2 ELISA kit;

[0267] 4) Add 10% CCK-8 reagent to the remaining cell culture medium, place in a cell culture incubator for 15-30 minutes, and use an ELISA reader to detect the absorbance at 450 nm. The absorbance value is used to characterize the cell survival rate for compound cytotoxicity judgment.

[0268] 4. Calculation

[0269] The result calculation refers to the instruction manual of Cayman PGE2 ELISA kit (Cat. No.: 514010).

[0270] All compounds of the present invention had a cell survival rate greater than 90% within the concentration range of 8-1000 nM, and no obvious toxicity was observed on Raw264.7 cells. The results of the preliminary activity screening are shown in Table 2 below.

[0271] Table 2. Inhibition rate of compounds on PGE2 secretion in Raw264.7 (%)

[0272]

[0273]

[0274] (III) Liver microsome metabolic stability test

[0275] Test methods

[0276] The metabolic stability of the compound (final concentration 1 μM) was incubated with liver microsomes (final concentration 0.5 mg / mL, midazolam group 0.2 mg / mL), β-NADPH (final concentration 1 mM) and magnesium chloride (final concentration 3 mM) in phosphate buffer were added to the positive control, and magnesium chloride (final concentration 3 mM) in phosphate buffer were added to the negative control. The reaction was terminated with 50% acetonitrile aqueous solution (0°C) at 0 min, 5 min, 15 min, 30 min and 60 min, vortexed and centrifuged, 150 μL of the supernatant was added to 150 μL of water, vortexed and mixed, and LC-MS / MS injection analysis was performed. (Among them, the liver microsomes used in the experiment were mouse liver microsomes purchased from Corning; β-NADPH was purchased from Ruji Biotechnology)

[0277] Test parameters: in vitro clearance rate Clint, in μl / min / mg protein; half-life T1 / 2, in min.

[0278] The test results are shown in Table 3 below.

[0279] Table 3. Clearance of compounds in mouse liver microsomes

[0280]

[0281]

[0282] (IV) In vivo efficacy

[0283] 1. Rat toe swelling test

[0284] A total of 54 SD rats that passed the quarantine were selected, half of which were male and half were female, weighing 180-220 g, and were randomly divided into a normal control group, a model 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 according to their body weight, with 6 animals in each group. Before administration, different drugs were prepared into a concentration of 0.5 mg / mL using an aqueous solution containing 0.5% methylcellulose and 0.1% Tween 80. Different test substances were orally gavaged at 10 mL / kg in each group of animals, 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, 0.5% carrageenan 0.2 mL / rat was injected under the plantar fascia of the right hind paw of rats in other groups to induce inflammation, and the normal group was given an equal volume of 0.9% sodium chloride injection. The volume of the right hind toes of rats in each group was measured with a toe volume meter at 30 min, 1 h, 2 h, 4 h, 6 h, and 8 h after inflammation, and the swelling degree was calculated.

[0285] The results are shown in Table 4 below.

[0286] 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.

[0287] Table 4. Results of rat toe swelling test

[0288]

[0289]

[0290] Note: Compared with the normal control group ++ P≤0.01; **P≤0.01, *P≤0.05 compared with the model control group.

[0291] 2. Acetic acid writhing test in mice

[0292] 48 ICR mice that passed the quarantine were selected, half male and half female, weighing 18-22g, and randomly divided into normal 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 into a concentration of 1 mg / mL using an aqueous solution containing 0.5% methylcellulose and 0.1% Tween 80. Each group of animals was given different test substances by oral gavage at 20 mL / kg, once a day, for 7 consecutive days, and the model control group was given an equal volume of solvent. 0.6% acetic acid was injected intraperitoneally at 10 mL / kg 1 hour after the last administration, and the state of the mice after the injection of acetic acid was immediately observed. One time of extension of the hind limbs and trunk, inward abdomen, and high buttocks of the mice was defined as one twisting reaction, and the latency of the twisting reaction and the number of twists within 15 minutes were recorded.

[0293] The results are shown in Table 5 below.

[0294] Table 5. Results of the acetic acid writhing test in mice

[0295]

[0296] Note: Compared with the normal control group ++ P≤0.01, + P≤0.05.

[0297] (V) Comparative ratio

[0298] The present invention synthesized multiple compounds in Sumitomo Pharma JP 2004277337 A, including representative compounds with higher anti-inflammatory activity, and compared them with the compounds in the present invention 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.

[0299] The relevant experimental process is shown in the in vitro biological activity experimental method in this article, and the comparative results are shown in Table 6 below.

[0300] Table 6

[0301]

[0302]

[0303] The above results show that after the "N" atom in the general structure of Sumitomo Pharma's original patent is replaced by "C", it has higher activity and better metabolic stability. This conclusion shows a similar rule in most compound cases in the present invention.

[0304] Comparative synthesis methods and identification data of compounds

[0305] Comparative Example 1 Compound

[0306] Step 1: Ethyl 5-(thiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0307] Take 2-acetylthiophene (30g) and dissolve it in N,N-dimethylformamide (150mL). Add NaH (60%, 19.2g) in batches under ice bath. After adding, keep ice bath and drip ethyl trifluoroacetate (75g). After dripping, warm to room temperature and continue to react for 1h. Pour the reaction solution into ice water, add hydrochloric acid to adjust pH to acidic, add ethyl acetate to extract, separate the liquids, and concentrate the organic phase under reduced pressure to dryness to obtain crude 4,4,4-trifluoro-1-(thiophene-2-yl)butane-1,3-dione. Take half of it and add 3-amino-4-ethoxycarbonylpyrazole (19.5g). Heat to 120℃ and react for 2h. Pour the reaction solution into water to precipitate a large amount of solids. Filter to obtain crude 5-(thiophene-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester. The crude product is beaten with ethanol to obtain a refined product (21g). (ESI) m / z = 342.1 [M + H] + .

[0308] Step 2: 5-(Thiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0309] Take 5-(thiophene-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (3g), add ethanol (500mL), water (100mL) and lithium hydroxide monohydrate (1.5g), and react at 80°C for 7h. After cooling to room temperature, concentrate the remaining ethanol under reduced pressure, adjust the pH to 1-2 with hydrochloric acid, and wash out a yellow solid. After filtering, dry the filter cake to obtain the title compound (1.0g). (ESI) m / z=314.1[M+H] + .

[0310] Step 3: N-(Propan-2-yl)-5-(thiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0311] Take 5-(thiophene-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.5 g), add dithionyl chloride (10 mL), react at 50°C for 15 min, remove dithionyl chloride under reduced pressure to obtain 5-(thiophene-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid chloride. The obtained acid chloride was dissolved in dichloromethane (10 mL), isopropylamine (1 mL), reacted for 15 min, quenched with water, extracted with dichloromethane (50 mL), and the organic phase was concentrated under reduced pressure to dryness to obtain the crude product of N-(propan-2-yl)-5-(thiophene-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, and the crude product was slurried with a small amount of ethanol to obtain a refined product (150 mg). (ESI) m / z=355.1[M+H] + . 1H 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).

[0312] Comparative Example 2 Compound (Synthesized by referring to Comparative Example 1 Compound)

[0313] N-propyl-5-(thiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0314] (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).

[0315] Comparative Example 3 Compound (Synthesized by referring to Comparative Example 1 Compound)

[0316] [5-(4-Chlorophenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl](tetrahydro-1H-pyrrol-1-yl)methanone

[0317] (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).

[0318] Comparative Example 4 Compound (Synthesized by referring to Comparative Example 1 Compound)

[0319] [5-(4-methoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl](tetrahydro-1H-pyrrol-1-yl)methanone

[0320] (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).

[0321] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the 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 solution of the present invention, which should be included in the scope of the technical solution for protection of 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 yl, -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 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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