Pyrazolo piperidine (ketone)-containing derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a pyrazolo piperidine (ketone)-containing derivative, a preparation method thereof, an application of the pyrazolo piperidine (ketone)-containing derivative as an ATX enzyme inhibitor, and an application of the pyrazolo piperidine (ketone)-containing derivative in preparation of medicines for treating and / or preventing diseases caused by ATX-LPA functional axis abnormality. The invention particularly relates to application in preparation of drugs for treating and / or preventing fibrosis diseases and cancers. The derivative is a compound as shown in a general formula (I) or a general formula (I), and an optical isomer and a pharmaceutically acceptable salt thereof. In-vitro activity screening shows that the compound has outstanding ATX enzyme inhibitory activity and certain anti-tumor cell proliferation activity, shows good anti-fibrosis activity in a bleomycin-induced pulmonary fibrosis model, and has good application prospects. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and relates to a pyrazolopiperidine (ketone) derivative and a preparation method thereof, and its application as an ATX enzyme inhibitor and its application in the preparation of a drug for treating and / or preventing diseases caused by abnormal ATX-LPA functional axis, in particular, its use in the preparation of a drug for treating and / or preventing fibrotic diseases and cancer. Background Art

[0002] The process of autotaxin (ATX) hydrolyzing lysophosphatidylcholine (LPC) into biologically active lysophosphatidic acid (LPA) and choline is the main source of LPA under pathological conditions. LPA activates downstream Rho / Rock, TGF-β / Smads, MAPK and other signaling pathways by binding to its receptor, thereby stimulating the expression of fibrogenic factors such as β-catenin and TGF-β, and upregulating the levels of key fibrosis proteins such as connective tissue growth factor, collagen, and fibronectin, thereby inducing the occurrence and development of diseases such as fibrosis and inflammation. In addition, under various other pathological conditions such as tumors, ATX is also in a high expression state, resulting in LPA concentrations (10μmol / L) far higher than the normal level (100nmol / L). Excessive LPA will upregulate the level of vascular endothelial growth factor (VEGF), promote tumor angiogenesis, reduce the expression of tumor suppressor factor p53, and increase the survival and metastasis of tumor cells. Therefore, selective inhibition of ATX can reduce the production of LPA from the source, thereby effectively controlling the progression of related diseases such as fibrosis, inflammation and tumors.

[0003] At present, as the pharmacological research on ATX targets has become more mature, many inhibitors targeting it have been reported (such as: CN103201262, CN109476664, WO2022258693, CN114315825, CN113943276). In particular, the drug PAT-409 (WO2015077503) developed by Blade Therapeutics has entered the second phase of clinical research (NCT05373914) for pulmonary fibrosis as an oral effective ATX inhibitor. However, no effective ATX inhibitor has been approved for marketing so far. The ATX inhibitors reported so far face problems such as poor physical and chemical properties and poor drugability, which hinder further development. Summary of the invention

[0004] In response to the above technical problems, the present invention provides a pyrazolopiperidine (one) derivative and a preparation method thereof, and its use as an ATX enzyme inhibitor and its use in the preparation of drugs for treating and / or preventing diseases caused by abnormal ATX-LPA functional axis, especially its use in the preparation of drugs for treating and / or preventing fibrotic diseases and cancer.

[0005] To achieve the above object, the technical solution adopted by the present invention is:

[0006] A pyrazolopiperidin (one) derivative, characterized in that the derivative is a compound represented by general formula (I) or general formula (II) and its optical isomers and pharmaceutically acceptable salts;

[0007]

[0008] in,

[0009] x and y may be the same or different and may be independently selected from integers of 0-3;

[0010] R 1 Can be independently selected from 3-6 membered aliphatic rings or aromatic rings;

[0011] R 2 and R 3 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl, 3-10 membered aliphatic ring, 3-10 membered aromatic ring, 3-10 membered heteroaromatic ring containing 1-3 N or O atoms, or R 2 and R 3 Together with the nitrogen atom to which they are connected, they form a 4-6 membered aliphatic heterocyclic ring or heteroaromatic ring, wherein the heterocyclic ring is in addition to R 2 and R 3 In addition to the nitrogen atom connected, it optionally contains 0-1 heteroatoms selected from N, O or S; and the above-mentioned aliphatic ring, aliphatic heterocyclic ring, aromatic ring or heteroaromatic ring is optionally replaced by 0-3 identical or different R 5 replace;

[0012] R 4 can be independently selected from a 5-10 membered aromatic ring or a 5-10 membered heteroaromatic ring, wherein the heteroaromatic ring contains 1-3 N atoms, and the aromatic ring or heteroaromatic ring is optionally substituted by 0-3 identical or different R 6 replace;

[0013] R 5 and R 6The same or different, are independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, carboxyl, (C1-C6)alkoxycarbonyl, phosphate, nitro, amino substituted with 0-2 (C1-C6)alkyl groups, carbamoyl, thiocarbamoyl, sulfamoyl, N'-hydroxycarbamimidyl, 5-6 membered heteroaryl or aliphatic heterocyclic containing 1-4 atoms selected from N, O or S, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxymethyl, (C3-C6)cycloalkylmethyl, (C1-C6)acyl.

[0014] Preferably, the derivative is a compound represented by the general formula (I) or the general formula (II) and its optical isomers and pharmaceutically acceptable salts;

[0015] Where:

[0016] x and y may be the same or different and are independently selected from 0, 1, 2 or 3;

[0017] R 1 Can be independently selected from 3-6 membered aliphatic rings or aromatic rings;

[0018] R 2 and R 3 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, 1,3,5-triazine ring, naphthalene ring, indole ring, indazole ring, quinoline ring, or R 2 and R 3 Together with the nitrogen atom to which they are connected, they form a 4-6 membered aliphatic heterocyclic ring or heteroaromatic ring, wherein the heterocyclic ring is in addition to R 2 and R 3 In addition to the nitrogen atom connected, it optionally contains 0-1 heteroatoms selected from N, O or S; and the above benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, 1,3,5-triazine ring, naphthalene ring, indole ring, indazole ring, quinoline ring, aliphatic heterocyclic ring or heteroaromatic ring is optionally replaced by 0-3 identical or different R 5 replace;

[0019] R 4 can be independently selected from a 5-10 membered aromatic ring or heteroaromatic ring, the heteroaromatic ring contains 1-3 N atoms, the aromatic ring and heteroaromatic ring can be a benzene ring, a naphthalene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a pyridine ring, a pyrimidine ring, an indole ring, and the aromatic ring or heteroaromatic ring is optionally substituted by 0-3 identical or different R 6 replace;

[0020] R 5 and R 6The same or different, are independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, carboxyl, (C1-C6)alkoxycarbonyl, phosphate, nitro, amino substituted with 0-2 (C1-C6)alkyl groups, carbamoyl, thiocarbamoyl, sulfamoyl, N'-hydroxycarbamimidyl, 5-6 membered heteroaryl or aliphatic heterocyclic containing 1-4 atoms selected from N, O or S, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxymethyl, (C3-C6)cycloalkylmethyl, (C1-C6)acyl.

[0021] More preferably, the derivative is a compound represented by the general formula (I) or the general formula (II) and its optical isomers and pharmaceutically acceptable salts;

[0022] Where:

[0023] x and y may be the same or different and independently selected from 0 or 1;

[0024] R 1 may be independently selected from a cyclopropane ring, a cyclopentane ring, a cyclohexane ring or a benzene ring;

[0025] R 2 and R 3 are the same or different and are independently selected from hydrogen, (C1-C3) alkyl, cyclohexane ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, indole ring, or R 2 and R 3 Together with the nitrogen atom to which they are connected, they form an aliphatic heterocyclic ring, which may be a piperidine ring, a morpholine ring, a piperazine ring, or a pyrrolidine ring;

[0026] Furthermore, the above-mentioned cyclohexane ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, indole ring or aliphatic heterocyclic ring is optionally substituted by 0-2 identical or different R 5 replace;

[0027] R 4 can be independently selected from a 5-6 membered aromatic ring or a heteroaromatic ring, wherein the aromatic ring or the heteroaromatic ring is selected from a benzene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, and the aromatic ring or the heteroaromatic ring is optionally substituted by 0-2 identical or different R 6 replace;

[0028] R 5 and R 6The same or different, are independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, carboxyl, (C1-C3) alkoxycarbonyl, nitro, carbamoyl, thiocarbamoyl, sulfamoyl, N'-hydroxycarbamimidyl, 5-6 membered heteroaryl or aliphatic heterocyclic ring containing 1-4 atoms selected from N or O atoms, (C1-C4) alkyl, (C1-C3) alkoxy, (C1-C3) alkoxymethyl, (C3-C6) cycloalkylmethyl, (C1-C3) acyl.

[0029] Still more preferably, the derivative is a compound represented by the general formula (I) or the general formula (II) and its optical isomers and pharmaceutically acceptable salts;

[0030] Where:

[0031] x and y may be the same or different and independently selected from 0 or 1;

[0032] R 1 May be independently selected from a cyclopropane ring or a benzene ring.

[0033] R 2 and R 3 are the same or different and are independently selected from hydrogen, (C1-C3) alkyl, cyclohexane ring, benzene ring, pyridine ring, or R 2 and R 3 Together with the nitrogen atom to which they are connected, they form a piperidine ring, wherein the cyclohexane ring, benzene ring, pyridine ring, piperidine ring is optionally substituted by 0-2 identical or different R 5 replace;

[0034] R 4 Can be independently selected from 0-2 identical or different R 6 a substituted benzene ring or a pyrazole ring;

[0035] R 5 and R 6 The same or different, are independently selected from hydrogen, halogen, cyano, carboxyl, ethoxycarbonyl, nitro, carbamoyl, thiocarbamoyl, sulfamoyl, N'-hydroxycarbamimidyl, 1,2,4-oxadiazol-3-yl, (C1-C4) alkyl, methoxy, methoxymethyl, cyclopropylmethyl, and (C1-C3) acyl.

[0036] In further preference, the derivative is a compound represented by general formula (I) or general formula (II) and its optical isomers and pharmaceutically acceptable salts;

[0037] Where:

[0038] x and y may be the same or different and independently selected from 0 or 1;

[0039] R 1 may be independently selected from a cyclopropane ring or a benzene ring;

[0040] R 2 and R 3 are the same or different and are independently selected from hydrogen, methyl, ethyl, cyclohexane ring, benzene ring, pyridine ring, or R 2 and R 3 Together with the nitrogen atom to which they are connected, they form a piperidine ring, and the cyclohexane ring, benzene ring, pyridine ring, piperidine ring are optionally substituted by 0-2 identical or different R 5 replace;

[0041] R 4 Can be independently selected from 0-2 identical or different R 6 a substituted benzene ring or a pyrazole ring;

[0042] R 5 and R 6 are the same or different, and are independently selected from hydrogen, halogen, cyano, carboxyl, ethoxycarbonyl, nitro, carbamoyl, thiocarbamoyl, sulfamoyl, N'-hydroxycarbamimidyl, 1,2,4-oxadiazol-3-yl, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, methoxymethyl, cyclopropylmethyl, and acetyl.

[0043] Most preferably, the derivative is specifically the following compound and its optical isomers, pharmaceutically acceptable salts,

[0044] 3-{7-oxo-6-phenyl-1-(1-propyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid;

[0045] 1-(1-ethyl-1H-pyrazol-4-yl)-7-oxo-6-phenyl-N-(3-sulfonamidophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0046] N-(3-cyanophenyl)-7-oxo-6-phenyl-1-(1-isopropyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0047] (S)-1-{1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl}piperidine-3-carboxylic acid;

[0048] (R)-1-{1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl}piperidine-3-carboxylic acid;

[0049] 2-{1-[1-(Methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid;

[0050] (E)-6-phenyl-N-[3-(N'-hydroxycarbamimidoyl)phenyl]-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0051] 6-phenyl-N-cyclohexyl-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-N-ethyl-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0052] 6-phenyl-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-N-phenyl-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0053] 6-phenyl-N-(3,5-difluorophenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0054] 6-phenyl-N-(2-bromo-6-fluorophenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0055] 6-phenyl-N-(2-chlorophenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0056] 6-phenyl-N-(4-fluorophenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0057] 6-phenyl-N-(3-aminothiocarbonylphenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0058] 3-{1-(3-acetylphenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid;

[0059] 3-{1-(4-fluorophenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid;

[0060] 3-{1-(2-chlorophenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid;

[0061] 3-{1-(4-ethylphenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid;

[0062] 3-{1-(4-tert-butylphenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid;

[0063] 6-Benzyl-N-(3-carbamoylphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0064] 2-{1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-6-benzyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid;

[0065] N-[3-(1,2,3-oxadiazol-3-yl)phenyl]-6-benzyl-1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0066] 6-Benzyl-N-[4-(tert-butyl)phenyl]-1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[2,3-c]pyridine-3-carboxamide;

[0067] 6-{6-benzyl-1-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}picolinic acid;

[0068] 6-benzyl-N-cyclohexyl-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-N-methyl-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0069] 2-{6-(cyclopropylmethyl)-1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid;

[0070] Ethyl 4-{6-(cyclopropylmethyl)-1-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoate;

[0071] 4-{6-(cyclopropylmethyl)-1-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid;

[0072] N-(3-acetylphenyl)-5-benzyl-1-{4-(tert-butyl)phenyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide;

[0073] 3-{5-benzyl-1-(4-fluorobenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide}benzoic acid;

[0074] 2-{5-benzyl-1-(4-methoxybenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide}benzoic acid;

[0075] 3-{5-Benzyl-1-(4-methoxybenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide}benzoic acid.

[0076] Moreover, according to some common methods in the field to which the present invention belongs, the pyrazolopiperidin (one) derivatives of the general formula (I) and the general formula (II) of the present invention can form pharmaceutically acceptable salts with bases. Pharmaceutically acceptable addition salts include inorganic base and organic base addition salts, and the salts formed with the following bases are particularly preferred: triethylamine, sodium hydroxide, lithium hydroxide, calcium hydroxide and potassium hydroxide.

[0077] In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodine; "alkyl" refers to a straight-chain or branched alkyl;

[0078] We have found that the compound of the present invention has strong ATX enzyme inhibitory activity in vitro, therefore, it can be used to prepare drugs for treating and / or preventing tumors and fibrotic diseases, such as tumors mainly including pancreatic cancer, breast cancer or glioma, etc., and fibrotic diseases mainly including pulmonary fibrosis, liver fibrosis, myocardial fibrosis, renal fibrosis, etc.

[0079] In vivo experiments preliminarily show that the preferred compounds of the present invention have a good prognostic effect on bleomycin-induced pulmonary fibrosis tissue, indicating the possibility of this series of compounds as potential therapeutic drugs for pulmonary fibrosis.

[0080] The active compound of the present invention or its pharmaceutically acceptable salt can be used alone as the only anti-tumor or anti-fibrosis drug, or can be used in combination with the currently marketed anti-tumor / anti-fibrosis drugs (such as pirfenidone, nintedanib, paclitaxel, etc.). Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or at intervals.

[0081] The examples and preparations provided below further illustrate and illustrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparations does not limit the scope of the present invention in any way.

[0082] The following synthetic routes summarize and describe the preparation of the pyrazolopiperidin (ketone) derivatives of formula (I) and (II) of the present invention, all of which are prepared by the methods described in the routes, by methods well known to those skilled in the art of organic chemistry, or are commercially available. All derivatives of the present invention are prepared by the methods described in the routes or by methods analogous thereto, which are well known to those skilled in the art of organic chemistry. The variables used in these routes are as defined below or as defined in the claims.

[0083] Route 1

[0084]

[0085] R of formula (I) of the present invention 2 The radical is hydrogen, R 3 When the group is a phenyl / pyridyl / cyclohexyl group substituted with a group such as hydrogen, halogen, cyano, ester, aminomethylsulfonyl, carbamoyl, acetyl, 1,2,4-oxadiazol-3-yl, or the like, or R 2 and R 3When the piperidinyl group is formed together with the nitrogen atom to which they are connected and the piperidinyl group contains an ester group, the corresponding target compound can be synthesized according to route 1: First, the amino compound raw material M1 undergoes diazotization reaction and Japp-Klingemann reaction in sequence to obtain the intermediate M2. Then, 5-chlorovaleryl chloride and various amines undergo N-acylation reaction, and then undergo N-alkylation reaction, chlorination reaction, addition-elimination reaction, [3+2] cycloaddition reaction, demorpholination reaction, hydrolysis reaction and amide condensation reaction in sequence to obtain the target compound. Among them, y and R in the compound 1 and R 4 As defined in the claims.

[0086] Route 2

[0087]

[0088] R of formula (I) of the present invention 2 The radical is hydrogen, R 3 When the group is a phenyl / pyridyl group substituted by a carboxyl group, or R 2 and R 3 When the piperidinyl group is formed together with the nitrogen atom to which they are connected and the piperidinyl group contains a carboxyl group, the corresponding target compound can be synthesized according to route 2: the corresponding ester compounds (Ⅰ1 and Ⅰ2) in Ⅰ obtained by route 1 are hydrolyzed under alkaline conditions to obtain the target compound. 1 and R 4 As defined in the claims.

[0089] Route 3

[0090]

[0091] R of formula (I) of the present invention 2 The radical is hydrogen, R 3 When the phenyl group is substituted by N'-hydroxycarbamimidoyl or thiocarbamoyl, the corresponding target compound can be synthesized according to route 3: the corresponding cyano compound (I3) in I obtained by route 1 is reacted with hydroxylamine hydrochloride or amine sulfide to obtain the target compound. 1 and R 4 As defined in the claims.

[0092] Route 4

[0093]

[0094] When x=0 in formula (II) of the present invention, the corresponding target compound can be synthesized according to route 4: piperidone (M8) reacts with diethyl oxalate under the action of a strong base, and then undergoes a Knorr pyrazole synthesis reaction, a hydrolysis reaction, and an amide condensation reaction to obtain compound II1, and compound II1 undergoes a hydrolysis reaction under alkaline conditions to obtain compound II2. 1 and R 4 As defined in the claims.

[0095] Route 5

[0096]

[0097] When x=1 in formula (II) of the present invention, the corresponding target compound can be synthesized according to route 5: piperidone (M8) reacts with diethyl oxalate under the action of a strong base, and then undergoes Knorr pyrazole synthesis reaction, N-alkylation reaction, hydrolysis reaction, and amide condensation reaction in sequence to obtain compound II3, and compound II3 is hydrolyzed under alkaline conditions to obtain compound II4. 1 and R 4 As defined in the claims.

[0098] A pharmaceutical composition comprising the compound represented by the general formula (I) or (II) and its optical isomers and pharmaceutically acceptable salts.

[0099] An application of the pyrazolopiperidin (one) derivative, the compound represented by the general formula (I) or the general formula (II) and its optical isomers, pharmaceutically acceptable salts or the pharmaceutical composition in the preparation of ATX inhibitors.

[0100] An application of the pyrazolopiperidin (one) derivative, the compound represented by the general formula (I) or the general formula (II) and its optical isomers, pharmaceutically acceptable salts or the pharmaceutical composition in the preparation of anti-tumor or anti-fibrosis drugs.

[0101] The tumor is pancreatic cancer, breast cancer or glioma, and the fibrosis is pulmonary fibrosis, liver fibrosis, myocardial fibrosis or renal fibrosis.

[0102] The advantages of the present invention are:

[0103] The pyrazolopiperidine (ketone) derivatives shown in the general formula (I) and (II) of the present invention are creative applications of this type of novel skeleton structure in this field. Compared with the larger clogP value (7.6) of PAT-409, the clogP value of the molecule described in the present invention is reduced to a suitable range (1.5 to 4.5). In terms of biological activity, in addition to showing ATX inhibitory activity that is significantly better than PAT-409, the molecule described in the present invention also shows moderate anti-tumor cell proliferation activity. In addition, in the mouse pulmonary fibrosis model, the molecule described in the present invention exhibited a strong anti-fibrotic effect. In summary, in view of the current clinical scarcity of anti-fibrotic drugs, the molecules described in the present invention have better clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] Figure 1 Example 6 Compound (6) improves bleomycin-induced pulmonary fibrosis in mice;

[0105] Among them, Ctrl is normal lung tissue, BLM is bleomycin-induced pulmonary fibrosis tissue, BLM+PAT-409 is bleomycin-induced pulmonary fibrosis tissue treated with PAT-409, and BLM+6 is bleomycin-induced pulmonary fibrosis tissue treated with compound 6. DETAILED DESCRIPTION

[0106] The examples are intended to illustrate but not to limit the scope of the present invention. The NMR spectra of the compounds were determined using Bruker ARX-400 / 600, and the mass spectra were determined using Agilent 1100 LC / MSD; all reagents used were analytically pure or chemically pure.

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] Preparation of compounds

[0113] Example 1: 3-{7-oxo-6-phenyl-1-(1-propyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid

[0114] Step A Synthesis of ethyl (2Z)-chloro-2-[2-(1-propyl-1H-pyrazol-4-yl)hydrazinylidene]acetate (M2-1)

[0115] M1-1 (1-propyl-1H-pyrazole-4-amine) (4.14 g, 33.07 mmol) was added to a 0°C hydrochloric acid solution (4M), and then an aqueous solution of NaNO2 (2.40 g, 34.73 mmol) was slowly added dropwise. After reacting at 0°C for 0.5 hours, ethyl 2-chloroacetoacetate (5.61 g, 34.07 mmol), EtOH (50 mL), NaOAc (8.14 g, 99.22 mmol) and water (30 mL) were added in sequence, and the mixture was moved to room temperature and continued to react for 3 hours. The reaction solution was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, dried over anhydrous Na2SO4, and the solvent was removed by distillation under reduced pressure. The concentrate was purified by column chromatography to obtain the intermediate M2-1, a yellow solid, 4.87 g, with a yield of 56.9%. Detection data: ESI-MS [M+H] + (m / z):259.4.

[0116] Step B1-Synthesis of Phenyl-2-Piperidone (M4-1)

[0117] Et3N (21.73 g, 214.76 mmol) was added to an anhydrous tetrahydrofuran solution of aniline (10.00 g, 107.38 mmol), 5-chlorovaleryl chloride (16.65 g, 107.38 mmol) was slowly added dropwise at 0°C, and the mixture was reacted at 0°C for 2 hours. Then, NaH (7.73 g, 322.13 mmol) was slowly added, the mixture was moved to room temperature and the reaction was continued for 12 hours, 300 mL of ice water was added to quench, and the mixture was extracted with ethyl acetate (120 mL×3), the organic phases were combined, dried over anhydrous Na2SO4, and the solvent was removed by distillation under reduced pressure to obtain intermediate M4-1, a colorless oily liquid, 9.86 g, with a yield of 52.4%.

[0118] Step C Synthesis of 3-morpholinyl-1-phenyl-5,6-dihydropyridin-2(1H)-one (M5-1)

[0119] PCl5 powder (78.85g, 378.68mmol) was slowly added to the chloroform solution of M4-1 (9.86g, 126.23mmol) and refluxed for 3 hours. The reaction solution was added dropwise to ice water to quench, extracted with ethyl acetate (120mL×3), the organic phases were combined, dried over anhydrous Na2SO4, and the solvent was removed by vacuum distillation. Morpholine (40mL) was added to the obtained concentrate and reacted at 110°C for 1 hour. Morpholine was removed by vacuum distillation, 200mL of water was added to the residue, extracted with ethyl acetate (200mL×3), the organic phases were combined, dried over anhydrous Na2SO4, and the intermediate M5-1 was obtained by vacuum distillation, a colorless oily liquid, 15.63g, and a yield of 47.9%. Detection data: ESI-MS[M+H] +(m / z):259.2.

[0120] Step D Synthesis of 6-methyl-1-(1-propyl-1H-pyrazol-4-yl)-7a-morpholinyl-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (M6-1)

[0121] M5-1 (5.00 g, 19.36 mmol) and M2-1 (5.01 g, 19.36 mmol) were dissolved in toluene, and then Et3N (5.88 g, 58.07 mmol) was added and reacted at 80°C for 3 hours. The reaction solution was cooled to room temperature, filtered under reduced pressure, and the filtrate was distilled under reduced pressure to obtain the intermediate M6-1, a yellow oily liquid, 4.92 g, with a yield of 52.9%. Detection data: ESI-MS [M+H] + (m / z):481.5.

[0122] Step E Synthesis of 6-phenyl-1-(1-propyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (7-1)

[0123] M6-1 (4.92 g, 10.24 mmol) was dissolved in a mixed solution of 3 mL TFA and 30 mL DCM, and reacted at room temperature for 20 minutes. The solvent and TFA were removed by distillation under reduced pressure, and 30 mL NaOH (1 mol / L) solution was added to the residue, and reacted at room temperature for 0.5 hours. The pH of the reaction solution was adjusted to 4-5 with dilute hydrochloric acid, and the product was precipitated. The product was filtered under reduced pressure and the filter cake was collected to obtain the intermediate M7-1, which was a light yellow powder, 2.87 g, and a yield of 76.7%. Detection data: ESI-MS [M+H] - (m / z):364.1.

[0124] Step F Synthesis of ethyl 3-{7-oxo-6-phenyl-1-(1-propyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoate (I1-1)

[0125] M7-1 (200 mg, 0.55 mmol), ethyl 3-aminobenzoate (75 mg, 0.55 mmol), EDCI (141 mg, 0.74 mmol) and HOBt (99 mg, 0.74 mmol) were added to DMF and reacted at room temperature for 2 hours. Water was added to the reaction solution to precipitate the product, which was filtered under reduced pressure, and the filter cake was collected and dried to obtain the intermediate I1-1 as a white solid, 181 mg, with a yield of 64.5%.

[0126] Step G Synthesis of Example 1

[0127] I1-1 (181 mg, 0.35 mmol) was dissolved in 10 mL NaOH (1 mol / L) solution and reacted at room temperature for 0.5 hours. The reaction solution was adjusted to pH 4-5 with dilute hydrochloric acid to precipitate the product, which was filtered under reduced pressure and the filter cake was collected to obtain Example 1, a white powder, 124 mg, and a yield of 72.4%. Measurement data: mp: 259.1-260.0℃; ESI-MS [MH] - (m / z):483.2. 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),10.42(s,1H),8.51(t,J=1.9Hz,1H),8.32(s,1H),8.05(ddd,J=8.1,2.4,1.1Hz,1H),7.93(s,1H),7.69(dt ,J=7.7,1.4Hz,1H),7.53-7.34(m,5H),7.32-7.23(m,1H),4.14-4.02(m, 4H), 3.26 (t, J = 6.6Hz, 2H), 1.80 (h, J = 7.2Hz, 2H), 0.85 (t, J = 7.4Hz, 3H).

[0128] Example 2: 1-(1-ethyl-1H-pyrazol-4-yl)-7-oxo-6-phenyl-N-(3-sulfonamidophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0129] According to the method of step A in Example 1, 1-ethyl-1H-pyrazol-4-amine was used as the raw material to prepare ethyl (2Z)-chloro-2-[2-(1-ethyl-1H-pyrazol-4-yl)hydrazinylidene]acetate (M2-2) with a yield of 43.1%. Detection data: ESI-MS [M+H] + (m / z):244.9.

[0130] According to the method of step DE in Example 1, M5-1 and M2-2 were used as raw materials to prepare 6-phenyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-2) with a yield of 55.1%. Detection data: ESI-MS [MH] - (m / z):350.3.

[0131] According to the method of step F in Example 1, M7-2 and 3-aminobenzenesulfonamide were used as raw materials to prepare Example 2 with a yield of 63.1%. Measurement data: mp: 241.4-242.2°C; ESI-MS [M+H] +(m / z):506.1. 1 H NMR (600MHz, DMSO-d6) δ10.33(s,1H),8.35-8.28(m,2H),7.98-7.88(m,3H),7.60(dt,J=7.7,1.3Hz,1H),7.47-7.32( m,6H),7.32-7.24(m,1H),4.17(q,J=7.2Hz,2H),4.06(t,J=6.7Hz,2H),3.26(t,J=6.6Hz,2H),1.39(t,J=7.3Hz,3H).

[0132] Example 3: N-(3-cyanophenyl)-7-oxo-6-phenyl-1-(1-isopropyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0133] According to the method of step A in Example 1, 1-isopropyl-1H-pyrazol-4-amine was used as the raw material to prepare ethyl (2Z)-chloro-2-[2-(1-isopropyl-1H-pyrazol-4-yl)hydrazinylidene]acetate (M2-3), with a yield of 46.4%. Detection data: ESI-MS [M+H] + (m / z):259.3.

[0134] According to the method of step DE in Example 1, M5-1 and M2-3 were used as raw materials to prepare 6-phenyl-1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-3), with a yield of 35.1%. Detection data: ESI-MS [MH] - (m / z):364.2.

[0135] According to the method of step F in Example 1, M7-3 and 3-aminobenzonitrile were used as raw materials to prepare Example 3 with a yield of 84.7%. Detection data: mp: 175.4-176.3°C; ESI-MS [M+H] + (m / z):466.1. 1H NMR(600MHz,DMSO-d6)δ10.61(s,1H),8.32(s,1H),8.32-8.30(m,1H),8.16-8.13(m,1H),7.88(s,1H),7.60-7.56(m,2H),7.45-7.3 6(m,4H),7.28(tt,J=7.0,1.4Hz,1H),4.54(hept,J=6.7Hz,1H),4.06(t,J=6.7Hz,2H),3.26(t,J=6.6Hz,2H),1.43(d,J=6.6Hz,6H).

[0136] Example 4: (S)-1-{1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl}piperidine-3-carboxylic acid

[0137] According to the method of steps FG in Example 1, M7-3 and (S)-piperidine-3-carboxylic acid ethyl ester were used as raw materials to prepare Example 4 with a yield of 84.7%. Detection data: mp: 144.6-145.2°C; ESI-MS [M+H] - (m / z):475.3. 1 H NMR(600MHz,DMSO-d6)δ10.61(s,1H),8.32(s,1H),8.32-8.30(m,1H),8.16-8.13(m,1H),7.88(s,1H),7.60-7.56(m,2H),7.45-7.3 6(m,4H),7.28(tt,J=7.0,1.4Hz,1H),4.54(hept,J=6.7Hz,1H),4.06(t,J=6.7Hz,2H),3.26(t,J=6.6Hz,2H),1.43(d,J=6.6Hz,6H).

[0138] Example 5: (R)-1-{1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl}piperidine-3-carboxylic acid

[0139] According to the method of steps FG in Example 1, M7-3 and (R)-piperidine-3-carboxylic acid ethyl ester were used as raw materials to prepare Example 5 with a yield of 83.2%. Detection data: mp: 137.8-138.4°C; ESI-MS [M+H] - (m / z):475.3. 1H NMR(600MHz,DMSO-d6)δ10.61(s,1H),8.32(s,1H),8.32-8.30(m,1H),8.16-8.13(m,1H),7.88(s,1H),7.60-7.56(m,2H),7.45-7.3 6(m,4H),7.28(tt,J=7.0,1.4Hz,1H),4.54(hept,J=6.7Hz,1H),4.06(t,J=6.7Hz,2H),3.26(t,J=6.6Hz,2H),1.43(d,J=6.6Hz,6H).

[0140] Example 6: 2-{1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid

[0141] According to the method of step A in Example 1, 1-methoxymethyl-1H-pyrazol-4-amine was used as the raw material to prepare ethyl (2Z)-chloro-2-[2-(1-methoxymethyl-1H-pyrazol-4-yl)hydrazinylidene]acetate (M2-4) with a yield of 43.1%. Detection data: ESI-MS [M+H] + (m / z):261.48.

[0142] According to the method of steps DE in Example 1, M5-1 and M2-4 were used as raw materials to prepare 6-phenyl-1-(1-methoxymethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-4) with a yield of 42.9%. Detection data: ESI-MS [M+H] - (m / z):366.2.

[0143] According to the method of steps FG in Example 1, M7-4 and ethyl 2-aminobenzoate were used as raw materials to prepare Example 6, with a yield of 45.7%. Detection data: mp: 287.7-288.9°C; ESI-MS [MH] - (m / z):485.3. 1H NMR (600MHz, DMSO-d6) δ12.77(s,1H),8.78(d,J=8.3Hz,1H),8.52(s,1H),8.06(dd,J=7.9,1.7Hz,1H),8.03(s,1H),7.67-7.61(m, 1H),7.46-7.38(m,4H),7.29(tt,J=6.8,1.7Hz,1H),7.22-7.16(m,1H),5.43(s,2H),4.07(t,J=6.7Hz,2H),3.28(d,J=10.4Hz,5H). 13 CNMR(150MHz,DMSO-d6)δ169.98,160.00,157.02,142.57,141.49,141.02,135.41,134.46,133.91,131.88,12 9.19(2C),126.86,126.76,126.46(2C),126.21,124.57,123.28,119.95,117.43,82.11,56.68,51.36,21.20.

[0144] Example 7: (E)-6-phenyl-N-[3-(N'-hydroxycarbamimidoyl)phenyl]-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0145] According to the method of step F in Example 1, M7-4 and 3-aminobenzonitrile were used as raw materials to prepare N-(3-cyanophenyl)-7-oxo-6-phenyl-1-(1-methoxymethyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (I3-1) with a yield of 83.8%.

[0146] Step H: Dissolve the intermediate I3-1 (100 mg, 0.21 mmol) in ethanol, add hydroxylamine hydrochloride (22 mg, 0.32 mmol) and triethylamine (43 mg, 0.43 mmol) and react at 78°C for 2 hours. Add water (10 mL) to the reaction solution, extract with ethyl acetate (15 mL×3), combine the organic phases, dry over anhydrous Na2SO4, and distill under reduced pressure to obtain Example 7 as a white solid, 48 mg, with a yield of 44.9%. Detection data: mp: 140.8-141.3°C; ESI-MS [MH] + (m / z):501.2. 1H NMR (400MHz, DMSO-d6) δ10.26(s,1H),9.63(s,1H),8.52(s,1H),8.17(s,1H),8.07(s,1H),7.82(d,J=7.8 Hz,1H),7.66-6.99(m,7H),5.76(s,2H),5.42(s,2H),4.20-3.90(m,2H),3.27(s,3H),3.22-3.10(m,2H).

[0147] Example 8: 6-phenyl-N-cyclohexyl-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-N-ethyl-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0148] According to the method of step F in Example 1, M7-4 and N-ethylcyclohexylamine were used as raw materials to prepare Example 8 with a yield of 65.5%. Detection data: mp: 1135.4-116.5℃; ESI-MS [MH] + (m / z):477.3. 1 H NMR (400MHz, DMSO-d6) δ8.43 (s, 1H), 7.90 (d, J = 11.4Hz, 1H), 7.47-7.09 (m, 6H), 5.4 0(d,J=2.5Hz,2H),4.25(q,J=15.4,13.5Hz,1H),4.02(t,J=6.6Hz,2H),3.58(dd,J= 11.7,6.6Hz,1H),3.41(q,J=6.8Hz,1H),3.26(s,3H),3.17(d,J=5.1Hz,1H),3.04(t ,J=6.6Hz,2H),1.76(q,J=16.1,14.7Hz,4H),1.68-1.46(m,3H),1.29-1.06(m,6H).

[0149] Example 9: 6-phenyl-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-N-phenyl-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0150] According to the method of step F in Example 1, M7-4 and aniline were used as raw materials to prepare Example 9 with a yield of 82.3%. Detection data: mp: 185.1-185.6°C; ESI-MS [MH] + (m / z):443.1. 1H NMR (400MHz, DMSO-d6) δ10.23(s,1H),8.51(d,J=0.7Hz,1H),8.05(d,J=0.7Hz,1H),7.86-7.80(m,2H),7 .45-7.25(m,7H),7.11(tt,J=7.4,1.2Hz,1H),5.42(s,2H),4.06(t,J=6.6Hz,2H),3.26(t,J=6.7Hz,5H).

[0151] Example 10: 6-phenyl-N-(3,5-difluorophenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0152] According to the method of step F in Example 1, M7-4 and 3,5-difluoroaniline were used as raw materials to prepare Example 10 with a yield of 62.6%. Detection data: mp: 187.5-188.2℃; ESI-MS [MH] + (m / z):479.4. 1 H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.50(d,J=0.7Hz,1H),8.03(d,J=0.7Hz,1H),7.70-7.61(m,2H), 7.46-7.22(m,5H),6.97(tt,J=9.3,2.4Hz,1H),5.42(s,2H),4.09-4.04(m,2H),3.26(t,J=6.7Hz,5H).

[0153] Example 11: 6-phenyl-N-(2-bromo-6-fluorophenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0154] According to the method of step F in Example 1, M7-4 and 4-bromo-2-fluoroaniline were used as raw materials to prepare Example 11 with a yield of 54.2%. Detection data: mp: 144.3-144.7°C; ESI-MS [MH] + (m / z):539.2. 1H NMR (400MHz, DMSO-d6) δ10.03(s,1H),8.51(d,J=0.7Hz,1H),8.02(d,J=0.7Hz,1H),8.00(dd,J =6.8,2.5Hz,1H),7.48-7.26(m,7H),5.42(s,2H),4.06(t,J=6.8Hz,2H),3.24(t,J=6.6Hz,5H).

[0155] Example 12: 6-phenyl-N-(2-chlorophenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0156] According to the method of step F in Example 1, M7-4 and 2-chloroaniline were used as raw materials to prepare Example 12 with a yield of 57.5%. Detection data: mp: 152.2-152.7°C; ESI-MS [MH] + (m / z):477.3. 1 H NMR (400MHz, DMSO-d6) δ9.79(s,1H),8.52(d,J=0.6Hz,1H),8.02(s,1H),8.00(dd,J=8.1,1.6Hz,1H),7.58(dd, J=8.0,1.5Hz,1H),7.46-7.32(m,5H),7.32-7.22(m,2H),5.43(s,2H),4.08-4.04(m,2H),3.27(d,J=5.6Hz,5H).

[0157] Example 13: 6-phenyl-N-(4-fluorophenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0158] According to the method of step F in Example 1, M7-4 and 4-fluoroaniline aniline were used as raw materials to prepare Example 13 with a yield of 52.2%. Detection data: mp: 149.5-150.3℃; ESI-MS [MH] + (m / z):461.2. 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),8.50(d,J=0.7Hz,1H),8.04(d,J=0.7Hz,1H),7 .90-7.78(m,2H),7.49-7.10(m,7H),5.42(s,2H),4.06(t,J=6.7Hz,2H),3.27(m,5H).

[0159] Example 14: 6-phenyl-N-(3-aminothiocarbonylphenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0160] According to the method of step F in Example 1, M7-4 and 3-aminobenzonitrile were used as raw materials to prepare N-(3-carbamoylphenyl)-1-(1-methoxymethyl-1H-pyrazol-4-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (I3-2) with a yield of 70.0%.

[0161] Step I: I3-2 (100 mg, 0.21 mmol) was dissolved in DMF and (NH2)2S (16 mg, 0.25 mmol) was added, and the mixture was reacted at 45°C for 3 hours. Water was added to the reaction solution to precipitate the product, which was filtered under reduced pressure. The filter cake was collected and dried to obtain Example 14, a white solid, 92 mg, with a yield of 85.4%. Detection data: mp: 144.9-145.4°C; ESI-MS [MH] + (m / z):502.4. 1 HNMR(400MHz,DMSO-d6)δ10.39(s,1H),9.88(s,1H),9.49(s,1H),8.52(s,1H),8.37(d,J=2.0Hz,1H),8.06(s,1H),7.99-7.9 0(m,1H),7.56-7.49(m,1H),7.47-7.33(m,5H),7.28(tt,J=6.4,2.0Hz,1H),5.43(s,2H),4.07(t,J=6.7Hz,2H),3.27(s,5H).

[0162] Example 15: 3-{1-(3-acetylphenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid

[0163] According to the method of step A in Example 1, 3-aminoacetophenone was used as the raw material to prepare ethyl (2Z)-chloro-2-{2-[1-(3-acetylphenyl)-1H-pyrazol-4-yl]hydrazinylidene}acetate (M2-5) with a yield of 62.8%. Detection data: ESI-MS [M+H] + (m / z):269.1.

[0164] According to the method of steps DE in Example 1, M5-1 and M2-5 were used as raw materials to prepare 1-(3-acetylphenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-5) with a yield of 42.1%. Detection data: ESI-MS [M+H] - (m / z):374.4.

[0165] According to the method of steps FG in Example 1, M7-5 and ethyl 3-aminobenzoate were used as raw materials to prepare Example 15 with a yield of 48.8%. Detection data: mp: 162.6-163.1°C; ESI-MS [MH] + (m / z):493.1. 1 H NMR (400MHz, DMSO-d6) δ12.97(s,1H),10.55(s,1H),8.53(dt,J=7.0,2.1Hz,1H),8.25(t,J=1.9Hz,1H),8.17-8.00(m,2H),7.97(dd,J=7.9 ,2.3Hz,1H),7.76-7.61(m,2H),7.54-7.33(m,5H),7.26(tt,J=5.6,2.4Hz,1H),4.13(t,J=6.6Hz,2H),3.30(t,J=6.7Hz,2H),2.63(s,3H).

[0166] Example 16: 3-{1-(4-fluorophenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid

[0167] According to the method of step A in Example 1, 4-fluoroaniline was used as the raw material to prepare ethyl (2Z)-chloro-2-{2-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]hydrazinylidene}acetate (M2-6) with a yield of 67.4%. Detection data: ESI-MS [M+H] + (m / z):245.0.

[0168] According to the method of steps DE in Example 1, M5-1 and M2-6 were used as raw materials to prepare 1-(4-fluorophenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-6) with a yield of 44.2%. Detection data: ESI-MS [M+H] - (m / z):350.3.

[0169] According to the method of steps FG in Example 1, M7-6 and ethyl 3-aminobenzoate were used as raw materials to prepare Example 16 with a yield of 32.5%. Detection data: mp: 143.9-144.2°C; ESI-MS [MH] - (m / z):469.1. 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),10.53(s,1H),8.53(t,J=1.9Hz,1H),8.03(ddd,J=8.2,2.3,1.1Hz,1H),7 .80-7.72(m,2H),7.69(dt,J=7.7,1.4Hz,1H),7.52-7.20(m,8H),4.11(t,J=6.6Hz,2H),3.28(d,J=13.2Hz,2H).

[0170] Example 17: 3-{1-(2-chlorophenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid

[0171] According to the method of step A in Example 1, 2-chloroaniline was used as the raw material to prepare ethyl (2Z)-chloro-2-{2-[1-(2-chlorophenyl)-1H-pyrazol-4-yl]hydrazinylidene}acetate (2-7) with a yield of 56.7%. Detection data: ESI-MS [M+H] + (m / z):261.1.

[0172] According to the method of steps DE in Example 1, M5-1 and M2-7 were used as raw materials to prepare 1-(2-chlorophenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-7) with a yield of 57.2%. Detection data: ESI-MS [M+H] - (m / z):366.0.

[0173] According to the method of steps FG in Example 1, M7-7 and ethyl 3-aminobenzoate were used as raw materials to prepare Example 17 with a yield of 52.8%. Detection data: mp: 265.2-266.2°C; ESI-MS [MH] - (m / z):485.4. 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.54(t,J=1.9Hz,1H),7.99(dd,J=8.1,2.2Hz,1H),7.68(qd,J=7.7,1.8Hz,3H), 7.55(dtd,J=19.1,7.6,1.8Hz,2H),7.49-7.30(m,5H),7.30-7.17(m,1H),4.11(d,J=6.8Hz,2H),3.33(t,J=6.7Hz,2H).

[0174] Example 18: 3-{1-(4-ethylphenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid

[0175] According to the method of step A in Example 1, 4-ethylaniline was used as the raw material to prepare ethyl (2Z)-chloro-2-{2-[1-(4-ethylphenyl)-1H-pyrazol-4-yl]hydrazinylidene}acetate (2-8) with a yield of 70.3%. Detection data: ESI-MS [M+H] + (m / z):255.1.

[0176] According to the method of step DE in Example 1, M5-1 and M2-8 were used as raw materials to prepare 1-(4-ethylphenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-8) with a yield of 57.2%. Detection data: ESI-MS [M+H] - (m / z):360.2.

[0177] According to the method of steps FG in Example 1, M7-8 and ethyl 3-aminobenzoate were used as raw materials to prepare Example 18 with a yield of 64.3%. Detection data: mp: 164.8-165.0°C; ESI-MS [MH] - (m / z):479.5. 1H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.50(t,J=2.0Hz,1H),8.02(ddd,J=8.2,2.3,1.1Hz,1H),7.68(dt,J=7.7,1.4Hz,1H),7. 62-7.54(m,2H),7.50-7.20(m,8H),4.10(t,J=6.6Hz,2H),3.28(t,J=6.6Hz,2H),2.67(p,J=7.6Hz,2H),1.21(t,J=7.6Hz,3H).

[0178] Example 19: 3-{1-(4-tert-butylphenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid

[0179] According to the method of step A in Example 1, 4-tert-butylaniline was used as the raw material to prepare ethyl (2Z)-chloro-2-{2-[1-(4-tert-butylphenyl)-1H-pyrazol-4-yl]hydrazinylidene}acetate (2-9) with a yield of 68.3%. Detection data: ESI-MS [M+H] + (m / z):283.1.

[0180] According to the method of step DE in Example 1, M5-1 and M2-9 were used as raw materials to prepare 1-(4-tert-butylphenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-9) with a yield of 53.4%. Detection data: ESI-MS [M+H] - (m / z):388.3.

[0181] According to the method of steps FG in Example 1, M7-9 and ethyl 3-aminobenzoate were used as raw materials to prepare Example 19 with a yield of 56.4%. Detection data: mp: 242.3-242.6°C; ESI-MS [MH] - (m / z):507.2. 1H NMR (400MHz, DMSO-d6) δ12.95(s,1H),10.47(s,1H),8.53(t,J=2.0Hz,1H),8.03(ddd,J=8.2,2.3,1.1Hz,1H),7.68(dt,J=7.7,1.4Hz ,1H),7.63-7.54(m,2H),7.54-7.33(m,7H),7.26(tt,J=7.1,2.1Hz,1H),4.11(t,J=6.6Hz,2H),3.28(d,J=13.2Hz,2H),1.32(s,9H).

[0182] Example 20: 6-Benzyl-N-(3-carbamoylphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0183] According to the method of step A in Example 1, 1-methyl-1H-pyrazol-4-amine was used as the starting material to prepare ethyl (2Z)-chloro-2-[2-(1-methyl-1H-pyrazol-4-yl)hydrazinylidene]acetate (M2-10) with a yield of 60.5%. Detection data: ESI-MS [M+H] + (m / z):231.3.

[0184] According to the method of step BC in Example 1, 5-chlorovaleryl chloride and benzylamine were used as raw materials to prepare 3-morpholinyl-1-benzyl-5,6-dihydropyridin-2(1H)-one (M5-2) with a yield of 28.9%. Detection data: ESI-MS [M+H] + (m / z):273.3.

[0185] According to the method of step DE in Example 1, M5-2 and M2-10 were used as raw materials to prepare 6-benzyl-1-(1-methyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-10) with a yield of 32.1%. Detection data: ESI-MS [MH] - (m / z):350.4.

[0186] According to the method of step F in Example 1, M7-10 and 3-aminobenzamide were used as raw materials to prepare Example 20 with a yield of 73.3%. Detection data: mp: 214.2-214.8°C; ESI-MS [M+H] + (m / z):470.1. 1H NMR (600MHz, DMSO-d6) δ10.28(s,1H),8.35(s,1H),8.30(t,J=2.0Hz,1H),7.98-7.91(m,3H),7.59(dt,J=7 .8,1.4Hz,1H),7.43-7.27(m,7H),4.68(s,2H),3.92(s,3H),3.61(t,J=6.8Hz,2H),3.09(t,J=6.9Hz,2H).

[0187] Example 21: 2-{1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-6-benzyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid

[0188] According to the method of step DE in Example 1, M5-2 and M2-4 were used as raw materials to prepare 6-benzyl-1-(1-methoxymethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-11) with a yield of 46.7%. Detection data: ESI-MS [MH] - (m / z):381.1.

[0189] According to the method of steps FG in Example 1, M7-11 and ethyl 2-aminobenzoate were used as raw materials to prepare Example 21 with a yield of 88.1%. Detection data: mp: 242.7-243.9°C; ESI-MS [MH] - (m / z):499.2.mp:240.7-243.9℃. 1 H NMR (400MHz, DMSO-d6) δ13.79(s,1H),12.52(s,1H),8.76(dd,J=8.5,1.1Hz,1H),8.57(d,J=0.7Hz,1H),8.07-8.03(m,2H),7.64(ddd,J=8.7, 7.3,1.7Hz,1H),7.39-7.25(m,5H),7.20(ddd,J=8.2,7.4,1.2Hz,1H),5.46(s,2H),4.70(s,2H),3.62(t,J=6.8Hz,2H),3.12(t,J=6.8Hz,2H).

[0190] Example 22: N-[3-(1,2,3-oxadiazol-3-yl)phenyl]-6-benzyl-1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0191] According to the method of step DE in Example 1, M5-2 and M2-3 were used as raw materials to prepare 6-benzyl-1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-12) with a yield of 41.7%. Detection data: ESI-MS [MH] - (m / z):378.3.

[0192] According to the method of step F in Example 1, M7-12 and 3-(1,2,4-oxadiazole-3-yl)-aniline were used as raw materials to prepare Example 22 with a yield of 74.2%. Detection data: mp: 188.5-189.2°C; ESI-MS [M+H] + (m / z):523.4. 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),9.72(s,1H),8.66(t,J=1.9Hz,1H),8.38(s,1H),8.07-7.99(m,1H),7.95(s,1H),7.78(dt,J=7.7,1.4Hz,1H) ,7.55(t,J=7.9Hz,1H),7.41-7.26(m,5H),4.68(s,2H),4.58(p,J=6.6Hz ,1H),3.61(t,J=6.8Hz,2H),3.11(t,J=6.8Hz,2H),1.47(d,J=6.7Hz,6H).

[0193] Example 23: 6-Benzyl-N-[4-(tert-butyl)phenyl]-1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[2,3-c]pyridine-3-carboxamide

[0194] According to the method of step F in Example 1, M7-12 and 4-tert-butylaniline were used as raw materials to prepare Example 23 with a yield of 72.1%. Detection data: mp: 100.5-102.6°C; ESI-MS [M+H] + (m / z):511.1.

[0195] Example 24: 6-{6-benzyl-1-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}picolinic acid

[0196] According to the method of step A in Example 1, 1-cyclopropylmethyl-1H-pyrazol-4-amine was used as the raw material to prepare ethyl (2Z)-chloro-2-[2-(1-cyclopropylmethyl-1H-pyrazol-4-yl)hydrazinylidene]acetate (M2-11) with a yield of 38.6%. Detection data: ESI-MS [M+H] + (m / z):271.3.

[0197] According to the method of step DE in Example 1, M5-2 and M2-11 were used as raw materials to prepare 6-benzyl-1-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-13) with a yield of 32.4%. Detection data: ESI-MS [MH] - (m / z):390.2.

[0198] According to the method of steps FG in Example 1, M7-13 and ethyl 6-aminopyridine-2-carboxylate were used as raw materials to prepare Example 24 with a yield of 29.4%. Detection data: mp: 299.7-300.2°C; ESI-MS [M+H] + (m / z):510.2. 1 HNMR(600MHz,DMSO-d6)δ10.30(s,1H),8.39(s,1H),8.30(t,J=1.9Hz,1H),7 .95(s,1H),7.94-7.90(m,2H),7.59(dt,J=7.7,1.4Hz,1H),7.42-7.26(m,7H) ,4.67(s,2H),4.04(d,J=7.1Hz,2H),3.61(t,J=6.8Hz,2H),3.09(t,J=6.8Hz, 2H),1.29(ddt,J=9.5,7.6,3.8Hz,1H),0.59-0.52(m,2H),0.44-0.35(m,2H).

[0199] Example 25: 6-Benzyl-N-cyclohexyl-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-N-methyl-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

[0200] According to the method of step DE in Example 1, M5-2 and M2-4 were used as raw materials to prepare 6-benzyl-1-(1-methoxymethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-14) with a yield of 39.6%. Detection data: ESI-MS [MH]- (m / z):380.2.

[0201] According to the method of step F in Example 1, M7-14 and N-methylcyclohexylamine were used as raw materials to prepare Example 25 with a yield of 37.2%. Detection data: mp: 117.5-119.4°C; ESI-MS [M+H] + (m / z):477.5.

[0202] Example 26: 2-{6-(Cyclopropylmethyl)-1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid

[0203] According to the method of step BC in Example 1, 5-chlorovaleryl chloride and cyclopropylmethylamine were used as raw materials to prepare 3-morpholinyl-1-cyclopropylmethyl-5,6-dihydropyridin-2(1H)-one (M5-3) with a yield of 23.8%. Detection data: ESI-MS [M+H] + (m / z):237.2.

[0204] According to the method of step DE in Example 1, M5-3 and M2-3 were used as raw materials to prepare 6-cyclopropylmethyl-1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-15) with a yield of 38.3%. Detection data: ESI-MS [MH] - (m / z):342.1.

[0205] According to the method of steps FG in Example 1, M7-15 and ethyl 2-aminobenzoate were used as raw materials to prepare Example 26 with a yield of 54.2%. Detection data: mp: 239.6-241.5°C; ESI-MS [MH] - (m / z):461.2. 1H NMR(600MHz,DMSO-d6)δ13.78(s,1H),12.50(s,1H),8.77(dd,J=8.5,1.2Hz,1H),8.35(s,1H),8 .05(dd,J=7.9,1.7Hz,1H),7.90(s,1H),7.64(ddd,J=8.7,7.3,1.8Hz,1H),7.20(td,J=7.6,1.2 Hz,1H),4.57(hept,J=6.7Hz,1H),3.74(t,J=6.8Hz,2H),3.34(d,J=7.0Hz,3H),3.13(t,J=6.8H z,2H),1.46(d,J=6.7Hz,7H),1.05(dq,J=7.7,5.2Hz,1H),0.51-0.44(m,2H),0.31-0.22(m,2H).

[0206] Example 27: Ethyl 4-{6-(cyclopropylmethyl)-1-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoate

[0207] According to the method of step DE in Example 1, M5-3 and M2-11 were used as raw materials to prepare 6-cyclopropylmethyl-1-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (M7-16) with a yield of 44.3%. Detection data: ESI-MS [MH] - (m / z):354.2.

[0208] According to the method of step F in Example 1, M7-16 and ethyl 4-aminobenzoate were used as raw materials to prepare Example 27 (yield: 57.4%). Detection data: mp: 208.4-209.1℃; ESI-MS [MH] - (m / z):503.1.

[0209] Example 28: 4-{6-(cyclopropylmethyl)-1-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid

[0210] According to the method of step G in Example 1, Example 28 was prepared using Example 27 as the raw material with a yield of 53.9%. Detection data: mp: 260.4-261.5°C; ESI-MS [MH] - (m / z):473.2. 1H NMR(600MHz,DMSO-d6)δ12.74(s,1H),10.49(s,1H),8.35(s,1H),7.98-7.89 (m,5H),4.03(d,J=7.1Hz,2H),3.74(t,J=6.9Hz,2H),3.32(s,2H),3.12(t,J =6.8Hz,2H),1.28(pt,J=8.0,5.1Hz,1H),1.04(ddt,J=9.2,7.4,3.7Hz,1H), 0.58-0.53(m,2H),0.49-0.44(m,2H),0.42-0.38(m,2H),0.28-0.24(m,2H).

[0211] Example 29: N-(3-acetylphenyl)-5-benzyl-1-{4-(tert-butyl)phenyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

[0212] Step J Synthesis of ethyl 5-benzyl-1-[4-(tert-butyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (M9)

[0213] At -78 ° C, a solution of LHMDS (4.42 g, 26.42 mmol) in anhydrous tetrahydrofuran was slowly added dropwise to a solution of LHMDS (4.42 g, 26.42 mmol) in anhydrous tetrahydrofuran. After 30 minutes of reaction, diethyl oxalate (3.86 g, 26.42 mmol) was added dropwise. The mixture was moved to room temperature and continued to react for 30 minutes. Then, ethanol (200 mL), glacial acetic acid (50 mL) and 4-tert-butylphenylhydrazine (4.34 g, 26.42 mmol) were added to the reaction solution and refluxed for 1 hour. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. Saturated sodium bicarbonate solution (100 mL) was added to the concentrate, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Intermediate M9 was obtained by column chromatography as a white solid, 5.87 g, with a yield of 53.2%. Detection data: ESI-MS [M+H] + (m / z): 418.3.

[0214] Step K Synthesis of 5-benzyl-1-[4-(tert-butyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (M10)

[0215] M9 (5.87 g, 14.06 mmol) was dissolved in 40 mL NaOH solution (1 mol / L) and reacted at room temperature for 0.5 hours. The pH of the reaction solution was adjusted to 4-5 with dilute hydrochloric acid to precipitate the product. The product was filtered under reduced pressure and the filter cake was collected to obtain the intermediate M10, a light yellow powder, 4.80 g, with a yield of 87.6%. Detection data: ESI-MS [M+H] - (m / z):388.3.

[0216] According to the method of step F in Example 1, M10 and 3-aminoacetophenone were used as raw materials to prepare Example 29 with a yield of 44.5%. Detection data: mp: 199.0-199.4°C; ESI-MS [MH] + (m / z):507.4. 1 H NMR (600MHz, DMSO-d6) δ7.55(s,4H),7.47-7.43(m,1H),7.38(d,J=1.7Hz,1H),7.38-7.37(m,2H),7.36(s,1H),7.34(d,J=7.9Hz ,2H),7.32-7.26(m,2H),4.24(q,J=7.1Hz,2H),3.73(s,2H),3.60(s,2H),2.85(t,J=5.7Hz,2H),2.76-2.68(m,3H),1.32(s,9H).

[0217] Example 30: 3-{5-Benzyl-1-(4-fluorobenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide}benzoic acid

[0218] According to the synthesis method of step J of Example 29, 5-benzyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester (M11) was synthesized by Knorr pyrazole using hydrazine hydrate, with a yield of 47.6%. Detection data: ESI-MS [M+H]+ (m / z): 286.0.

[0219] Step L Synthesis of ethyl 5-benzyl-1-(4-fluorobenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (M12-1)

[0220] M11 (200 mg, 0.70 mmol) was dissolved in DMF, and then 4-fluorobenzyl bromide (132 mg, 0.70 mmol), cesium carbonate (343 mg, 1.05 mmol) and potassium iodide (23 mg, 0.14 mmol) were added in sequence, and stirred at 70°C overnight. Water was added to the reaction solution to precipitate the product, which was filtered, and the filter cake was collected and dried to obtain the intermediate M12-1, a white solid, 192 mg, and a yield of 69.6%. Detection data: ESI-MS [M+H] + (m / z):394.3.

[0221] According to the synthesis method of step K of Example 29, compound M12-1 was hydrolyzed to obtain a white solid compound 5-benzyl-1-(4-fluorobenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (M13-1) with a yield of 82.4%. Detection data: ESI-MS [M+H] - (m / z):364.1.

[0222] According to the method of steps FG in Example 1, M13-1 and ethyl 3-aminobenzoate were used as raw materials to prepare Example 30 with a yield of 63.1%. Detection data: mp: 177.8-178.4°C; ESI-MS [MH] - (m / z):483.1. 1 H NMR (600MHz, DMSO-d6) δ10.17(s,1H),8.49(s,1H),7.96(dd,J=8.1,2.1Hz,1H),7.63(d,J=7.7Hz,1H),7.41(t,J=7.9Hz,1H),7.34(d,J=4.4Hz,4H ),7.28(ddd,J=19.5,8.7,5.0Hz,3H),7.21(t,J=8.7Hz,2H),5.37(s,2H) ,3.70(s,2H),3.60(s,2H),2.73(t,J=5.7Hz,2H),2.65(t,J=5.7Hz,2H).

[0223] Example 31: 2-{5-benzyl-1-(4-methoxybenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide}benzoic acid

[0224] According to the synthetic method of step L of Example 30, M11 and 4-methoxybenzyl bromide were used as raw materials to prepare 5-benzyl-1-(4-methoxybenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester (M12-2) with a yield of 54.3%. Detection data: ESI-MS [M+H]+ (m / z):406.2.

[0225] According to the synthesis method of step K of Example 29, compound M12-2 was hydrolyzed to obtain a white solid compound 5-benzyl-1-(4-methoxybenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (M13-2) with a yield of 80.6%. Detection data: ESI-MS [MH] - (m / z):376.2.

[0226] According to the method of steps FG in Example 1, M13-2 and methyl 2-aminobenzoate were used as raw materials to prepare Example 31 with a yield of 49.2%. Detection data: mp: 164.4-165.7°C; ESI-MS [MH] - (m / z):496.2. 1 H NMR (400MHz, DMSO-d6) δ12.58(s,1H),8.68(dd,J=8.5,1.2Hz,1H),8.02(dd,J =7.9,1.8Hz,1H),7.53(ddd,J=8.7,7.3,1.8Hz,1H),7.41-7.30(m,4H),7.30-7 .19(m,3H),7.11(td,J=7.6,1.2Hz,1H),6.95-6.85(m,2H),5.25(s,2H),3.74( s,2H),3.72(s,3H),3.64(s,2H),2.76(t,J=5.6Hz,2H),2.70(t,J=5.6Hz,2H).

[0227] Example 32: 3-{5-benzyl-1-(4-methoxybenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide}benzoic acid

[0228] According to the method of steps FG in Example 1, M13-2 and ethyl 3-aminobenzoate were used as raw materials to prepare Example 32 with a yield of 64.4%. Detection data: mp: 169.6-170.1°C; ESI-MS [MH] - (m / z):496.2. 1H NMR (600MHz, DMSO-d6) δ10.11(s,1H),8.46(t,J=1.9Hz,1H),7.93(ddd,J=8.2,2. 3,1.2Hz,1H),7.63(dt,J=7.7,1.4Hz,1H),7.38(t,J=7.9Hz,1H),7.33(d,J=4.3H z,4H),7.29-7.23(m,1H),7.23-7.18(m,2H),6.95-6.89(m,2H),5.30(s,2H),3.7 3(s,3H),3.68(s,2H),3.58(s,2H),2.71(t,J=5.7Hz,2H),2.64(t,J=5.6Hz,2H).

[0229] The compounds prepared in the above examples were tested for in vitro and in vivo pharmacological activity:

[0230] 1. Study on inhibition of ATX enzyme activity

[0231] 1. Preparation of enzyme activity assay buffer: Add 1.51 g Tris, 238 mg MgCl2, 277 mg CaCl2 and 25 mg Triton X-100 to 230 mL double distilled water, stir thoroughly to dissolve the solids completely, adjust the pH to 7.4 with dilute hydrochloric acid, make up to volume with a 250 mL volumetric flask, and store at 4°C.

[0232] 2. Preparation of compound stock solutions: All compounds and positive drugs (PAT-409) were dissolved in DMSO to prepare 4 mM stock solutions and stored at -20°C.

[0233] 3. Enzyme Activity Inhibition Test

[0234] The test compound and the positive drug (PAT-409) stock solution obtained above were diluted into 8 gradient concentrations, and 10 μL was added to each well of the 96-well plate. Then, 20 μL of ATX (1 μg / mL) solution was added to each well and incubated at room temperature for 30 minutes. Then, 20 μL (1 μM) FS-3 solution was added to each well and incubated at 37°C for 1 hour. Then, the 96-well plate was placed on an ELISA reader to read the fluorescence value (λ ex / λ em =487 / 520nm); the experimental results were input into GraphPad Prism software, and the IC of each compound was obtained by fitting calculation. 50 The results are shown in Table 1.

[0235] Table 1 Results of the ATX enzyme inhibitory activity and anti-MCF-7 cell proliferation activity of the compounds

[0236]

[0237]

[0238] Note: A<10, 10≤B<100, 100≤C<500, 500≤D≤1000.

[0239] The experimental results show that the compounds of the present invention have good inhibitory activity against ATX enzyme (IC 50 Values ​​less than 1000 nM are considered to have strong activity), IC 50 The values ​​were all less than 1000nM, and the IC 50 The values ​​were less than 10 nM, especially compound 1 (IC 50 =4.3nM), 2(IC 50 =3.7 nM), 6 (IC 50 =0.7 nM), 21 (IC 50 =2.8 nM), 24 (IC 50 =1.1 nM), 26 (IC 50 =3.2 nM) and other inhibitory activities against ATX enzyme were better than PAT-409 (IC 50 =4.9nM).

[0240] 2. In vitro anti-tumor cell proliferation activity study

[0241] The example compounds of the present invention were screened for their in vitro anti-proliferation activity against MCF-7 breast cancer cells.

[0242] 1. Inoculate MCF-7 cells in the logarithmic growth phase into a 96-well plate and control the cell density to 10 4 Place the cells in an incubator overnight to allow them to adhere to the wall.

[0243] 2. The next day, discard the old culture medium, add 200 μL of culture medium containing test samples of different concentrations (30 μM, 10 μM, 1 μM, 333 nM, 111 nM, 37 nM, 12 nM, 4 nM) to each well, and set up a blank control group (0.1% DMSO) and a positive drug group (PAT-409). Each group has 3 replicate wells in parallel and cultured in a conventional incubator for 72 h.

[0244] 3. After the cells were treated with drugs for 72 hours, MTT solution (5 mg / mL, 20 μL / well) was added to the 96-well plate, incubated in the incubator for 4 hours, the supernatant was discarded, and DMSO (150 μL / well) was added to dissolve the formazan crystals.

[0245] 4. Use an enzyme-labeled instrument to read the absorbance value of each well at a wavelength of 492 nm. Input the experimental results into GraphPadPrism software and obtain the IC value of each compound through fitting calculation.50 The results are shown in Table 1.

[0246] As shown in Table 1, like the positive control (PAT-409), the compound of the present invention also exhibited moderate antiproliferative activity against breast cancer MCF-7 cells.

[0247] 3. In vivo anti-pulmonary fibrosis study

[0248] 1. Modeling

[0249] C57BL / 6J mice were raised and adapted to the environment for one week under standard SPF laboratory conditions. The mice were weighed and randomly divided into 4 groups: control group, BLM (bleomycin) model group, BLM+PAT-409 group, and BLM+compound 6 group, with 8 mice in each group. The BLM+PAT-409 group and the BLM+compound 6 group were pre-protected with PAT-409 and compound 6, respectively, three days before modeling. All mice were fasted and had free access to water the night before modeling.

[0250] C57BL / 6J mice were anesthetized by intraperitoneal injection of isoflurane (130 mg / kg). After the righting reflex disappeared, the upper incisors of the mice were hung on cotton thread. The tongue and jaw of the mice were clamped with tweezers, the mouth was gently opened, and the bleomycin solution (3.5 mg / kg) was dripped into the mouse trachea with a pipette. After the dripping was completed, the mouse could be heard to choke and cough. The mouse was continued to be hung on the cotton thread for 10-15 minutes, and finally the mouse was returned to the mouse cage and waited for it to wake up.

[0251] 2. Drug administration

[0252] Preparation of drug solution: First, add the drug to 1% DMSO and 50% PEG 400 and sonicate for 5 minutes, then add 5% Tween 80 and 44% normal saline and sonicate for 5 minutes. The drug-containing preparation is finally clear and transparent.

[0253] Dosage: BLM+compound 6 group was intragastrically administered with 60 mg / kg. The control group and BLM model group were intragastrically administered with blank preparation.

[0254] Administration time: Pre-protection administration was carried out 3 days before modeling, and the administration was continued for 28 days. The administration was carried out once a day, and the weight, hair gloss and autonomous activity status of the mice were recorded.

[0255] 3. Masson staining of lung tissue

[0256] After continuous administration for 28 days, the mice were killed, and the lung tissues of the mice in each experimental group were taken and Masson staining was performed to compare and observe the pathological changes.

[0257] Depend on Figure 1It can be seen that in the BLM-induced pulmonary fibrosis model, collagen tissue increased significantly, inflammatory infiltration was severe, and pulmonary interstitium thickened. After treatment with compound 6, collagen tissue was significantly reduced compared with the BLM group, inflammation was alleviated, and pulmonary interstitium tended to be normal. The experimental results show that the compounds of the present invention can be used as new ATX inhibitors for the prevention and treatment of fibrotic diseases related to the ATX-LPA signaling pathway, such as pulmonary fibrosis, myocardial fibrosis, liver fibrosis, etc.

Claims

1. A pyrazolopiperidin (one) derivative, characterized in that: The derivatives are compounds represented by general formula (I) or general formula (II) and their optical isomers and pharmaceutically acceptable salts; in, x and y may be the same or different and may be independently selected from integers of 0-3; R 1 Can be independently selected from 3-6 membered aliphatic rings or aromatic rings; R 2 and R 3 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl, 3-10 membered aliphatic ring, 3-10 membered aromatic ring, 3-10 membered heteroaromatic ring containing 1-3 N or O atoms, or R 2 and R 3 Together with the nitrogen atom to which they are connected, they form a 4-6 membered aliphatic heterocyclic ring or heteroaromatic ring, wherein the heterocyclic ring is in addition to R 2 and R 3 In addition to the nitrogen atom connected, it optionally contains 0-1 heteroatoms selected from N, O or S; The above aliphatic ring, aliphatic heterocyclic ring, aromatic ring or heteroaromatic ring is optionally replaced by 0-3 identical or different R 5 replace; R 4 can be independently selected from a 5-10 membered aromatic ring or a 5-10 membered heteroaromatic ring, wherein the heteroaromatic ring contains 1-3 N atoms, and the aromatic ring or heteroaromatic ring is optionally substituted by 0-3 identical or different R 6 replace; R 5 and R 6 The same or different, are independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, carboxyl, (C1-C6)alkoxycarbonyl, phosphate, nitro, amino substituted with 0-2 (C1-C6)alkyl groups, carbamoyl, thiocarbamoyl, sulfamoyl, N'-hydroxycarbamimidyl, 5-6 membered heteroaryl or aliphatic heterocyclic containing 1-4 atoms selected from N, O or S, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxymethyl, (C3-C6)cycloalkylmethyl, (C1-C6)acyl.

2. The pyrazolopiperidine (ketone) derivative according to claim 1, characterized in that: The derivatives are compounds represented by general formula (I) or general formula (II) and their optical isomers and pharmaceutically acceptable salts; Where: x and y may be the same or different and independently selected from integers of 0-3; R 1 Can be independently selected from 3-6 membered aliphatic rings or aromatic rings; R 2 and R 3 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, 1,3,5-triazine ring, naphthalene ring, indole ring, indazole ring, quinoline ring, or R 2 and R 3 Together with the nitrogen atom to which they are connected, they form a 4-6 membered aliphatic heterocyclic ring or heteroaromatic ring, wherein the heterocyclic ring is in addition to R 2 and R 3 In addition to the nitrogen atom connected, it optionally contains 0-1 heteroatoms selected from N, O or S; Furthermore, the above benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, 1,3,5-triazine ring, naphthalene ring, indole ring, indazole ring, quinoline ring, aliphatic heterocyclic ring or heteroaromatic ring is optionally replaced by 0-3 identical or different R 5 replace; R 4 can be independently selected from a 5-10 membered aromatic ring or heteroaromatic ring, the heteroaromatic ring contains 1-3 N atoms, the aromatic ring and heteroaromatic ring can be a benzene ring, a naphthalene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, a pyridine ring, a pyrimidine ring, an indole ring, and the aromatic ring or heteroaromatic ring is optionally substituted by 0-3 identical or different R 6 replace; R 5 and R 6 The same or different, are independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, carboxyl, (C1-C6)alkoxycarbonyl, phosphate, nitro, amino substituted with 0-2 (C1-C6)alkyl groups, carbamoyl, thiocarbamoyl, sulfamoyl, N'-hydroxycarbamimidyl, 5-6 membered heteroaryl or aliphatic heterocyclic containing 1-4 atoms selected from N, O or S, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxymethyl, (C3-C6)cycloalkylmethyl, (C1-C6)acyl.

3. The pyrazolopiperidine (ketone) derivative according to claim 2, characterized in that: The derivatives are compounds represented by general formula (I) or general formula (II) and their optical isomers and pharmaceutically acceptable salts; Where: x and y may be the same or different and independently selected from 0 or 1; R 1 may be independently selected from a cyclopropane ring, a cyclopentane ring, a cyclohexane ring or a benzene ring; R 2 and R 3 are the same or different and are independently selected from hydrogen, (C1-C3) alkyl, cyclohexane ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, indole ring, or R 2 and R 3 Together with the nitrogen atom to which they are connected, they form an aliphatic heterocyclic ring, which may be a piperidine ring, a morpholine ring, a piperazine ring, or a pyrrolidine ring; and the cyclohexane ring, benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, indole ring or aliphatic heterocyclic ring may be optionally substituted by 0-2 identical or different R 5 replace; R 4 can be independently selected from a 5-6 membered aromatic ring or a heteroaromatic ring, wherein the aromatic ring or the heteroaromatic ring is selected from a benzene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a 1,2,3-triazole ring, a 1,2,4-triazole ring, and the aromatic ring or the heteroaromatic ring is optionally substituted by 0-2 identical or different R 6 replace; R 5 and R 6 The same or different, are independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, carboxyl, (C1-C3) alkoxycarbonyl, nitro, carbamoyl, thiocarbamoyl, sulfamoyl, N'-hydroxycarbamimidyl, 5-6 membered heteroaryl or aliphatic heterocyclic ring containing 1-4 atoms selected from N or O atoms, (C1-C4) alkyl, (C1-C3) alkoxy, (C1-C3) alkoxymethyl, (C3-C6) cycloalkylmethyl, (C1-C3) acyl.

4. The pyrazolopiperidine (ketone) derivative according to claim 3, characterized in that: The derivatives are compounds represented by general formula (I) or general formula (II) and their optical isomers and pharmaceutically acceptable salts; Where: x and y may be the same or different and independently selected from 0 or 1; R 1 May be independently selected from a cyclopropane ring or a benzene ring. R 2 and R 3 are the same or different and are independently selected from hydrogen, (C1-C3) alkyl, cyclohexane ring, benzene ring, pyridine ring, or R 2 and R 3 Together with the nitrogen atom to which they are connected, they form a piperidine ring, wherein the cyclohexane ring, benzene ring, pyridine ring, piperidine ring is optionally substituted by 0-2 identical or different R 5 replace; R 4 can be independently selected from 0-2 identical or different R 6 a substituted benzene ring or a pyrazole ring; R 5 and R 6 The same or different, are independently selected from hydrogen, halogen, cyano, carboxyl, ethoxycarbonyl, nitro, carbamoyl, thiocarbamoyl, sulfamoyl, N'-hydroxycarbamimidyl, 1,2,4-oxadiazol-3-yl, (C1-C4) alkyl, methoxy, methoxymethyl, cyclopropylmethyl, and (C1-C3) acyl.

5. The pyrazolopiperidine (ketone) derivative according to claim 4, characterized in that: The derivatives are compounds represented by general formula (I) or general formula (II) and their optical isomers and pharmaceutically acceptable salts; Where: x and y may be the same or different and independently selected from 0 or 1; R 1 may be independently selected from a cyclopropane ring or a benzene ring; R 2 and R 3 are the same or different and are independently selected from hydrogen, methyl, ethyl, cyclohexane ring, benzene ring, pyridine ring, or R 2 and R 3 Together with the nitrogen atom to which they are connected, they form a piperidine ring, and the cyclohexane ring, benzene ring, pyridine ring, piperidine ring are optionally substituted by 0-2 identical or different R 5 replace; R 4 can be independently selected from 0-2 identical or different R 6 a substituted benzene ring or a pyrazole ring; R 5 and R 6 are the same or different, and are independently selected from hydrogen, halogen, cyano, carboxyl, ethoxycarbonyl, nitro, carbamoyl, thiocarbamoyl, sulfamoyl, N'-hydroxycarbamimidyl, 1,2,4-oxadiazol-3-yl, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, methoxymethyl, cyclopropylmethyl, and acetyl.

6. The pyrazolopiperidine (ketone) derivative according to claim 5, characterized in that: The derivatives are specifically the following compounds and their optical isomers and pharmaceutically acceptable salts, 3-{7-oxo-6-phenyl-1-(1-propyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid; 1-(1-ethyl-1H-pyrazol-4-yl)-7-oxo-6-phenyl-N-(3-sulfonamidophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(3-cyanophenyl)-7-oxo-6-phenyl-1-(1-isopropyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; (S)-1-{1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl}piperidine-3-carboxylic acid; (R)-1-{1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl}piperidine-3-carboxylic acid; 2-{1-[1-(Methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid; (E)-6-phenyl-N-[3-(N'-hydroxycarbamimidoyl)phenyl]-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 6-phenyl-N-cyclohexyl-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-N-ethyl-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 6-phenyl-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-N-phenyl-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 6-phenyl-N-(3,5-difluorophenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 6-phenyl-N-(2-bromo-6-fluorophenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 6-phenyl-N-(2-chlorophenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 6-phenyl-N-(4-fluorophenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 6-phenyl-N-(3-aminothiocarbonylphenyl)-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 3-{1-(3-acetylphenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid; 3-{1-(4-fluorophenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid; 3-{1-(2-chlorophenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid; 3-{1-(4-ethylphenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid; 3-{1-(4-tert-butylphenyl)-7-oxo-6-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid; 6-Benzyl-N-(3-carbamoylphenyl)-1-(1-methyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 2-{1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-7-oxo-6-benzyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid; N-[3-(1,2,3-oxadiazol-3-yl)phenyl]-6-benzyl-1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 6-Benzyl-N-[4-(tert-butyl)phenyl]-1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[2,3-c]pyridine-3-carboxamide; 6-{6-benzyl-1-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}picolinic acid; 6-benzyl-N-cyclohexyl-1-[1-(methoxymethyl)-1H-pyrazol-4-yl]-N-methyl-7-oxo-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 2-{6-(cyclopropylmethyl)-1-(1-isopropyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid; Ethyl 4-{6-(cyclopropylmethyl)-1-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoate; 4-{6-(cyclopropylmethyl)-1-(1-cyclopropylmethyl-1H-pyrazol-4-yl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide}benzoic acid; N-(3-acetylphenyl)-5-benzyl-1-{4-(tert-butyl)phenyl}-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide; 3-{5-benzyl-1-(4-fluorobenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide}benzoic acid; 2-{5-benzyl-1-(4-methoxybenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide}benzoic acid; 3-{5-Benzyl-1-(4-methoxybenzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide}benzoic acid.

7. A pharmaceutical composition, characterized in that: Contains the compound represented by the general formula (I) or (II) as claimed in claim 1 and its optical isomers and pharmaceutically acceptable salts.

8. An application of the pyrazolopiperidin (one) derivative according to claim 1, characterized in that: Use of the compound represented by general formula (I) or general formula (II) and its optical isomers, pharmaceutically acceptable salts or the pharmaceutical composition according to claim 7 in the preparation of ATX inhibitors.

9. An application of the pyrazolopiperidin (one) derivative according to claim 1, characterized in that: Use of the compound represented by general formula (I) or general formula (II) and its optical isomers, pharmaceutically acceptable salts or the pharmaceutical composition according to claim 7 in the preparation of anti-tumor or anti-fibrosis drugs.

10. The use according to claim 9, characterized in that The tumor is pancreatic cancer, breast cancer or glioma, and the fibrosis is pulmonary fibrosis, liver fibrosis, myocardial fibrosis or renal fibrosis.

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