PATENT CLAIM ANALYSIS

Application Number: 15575903
Application Type: Utility
Filing Date: 2018-04
Publication Date: 2018-08
Patent Classification: ["514", "230800"]

Abstract:
The present invention discloses a pyrido-azacyclic compound represented by formula I, an isomer thereof, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, a preparation process thereof and a composition comprising the compound, and a use thereof as a multi-target protein kinase inhibitor in the preparation of a medicament for the treatment of diseases that are associated with protein kinase, especially c-Met, such as cancer and the like. The compound represented by formula I has potent inhibitory activity on tumor cells with overexpression of c-Met kinase, can effectively target c-Met-mediated signaling pathway, and can be used in the treatment of diseases such as cancer and the like that is caused by the overexpression of c-Met kinase.

Claim (Index 6):
A process for preparing the compound, the isomer thereof, the pharmaceutically acceptable salt thereof or the pharmaceutically acceptable solvate thereof according to  claim 1 , the process is carried out by one of the following reaction schemes: Wherein R 8  is R 9  is the definitions of Y, R 2 , R 3 , R 7 , Z, m and n are the same as those defined in  claims 1  to  5 , respectively;\n (1) Compound 5 is obtained by the chlorination reaction of compound 4, the reagent for chlorination is sulfoxide chloride (SOCl 2 )/N,N-dimethylformamide (DMF), phosphorus oxychloride (POCl 3 )/DMF or POCl 3 /N,N-diisopropylethylamine (DIEA)/acetonitrile (MeCN) and the like, and POCl 3 /DMF is preferred; \n (2) Compound 6 is obtained by the deprotection of compound 5, the reagent for deprotection is: boron tribromide (BBr 3 )/dichloromethane (DCM), 40% aqueous hydrogen bromide (HBr), pyridine hydrochloride, hydrochloric acid or sulfuric acid, hydrochloric acid-aluminum chloride, aluminum chloride-ethanethiol, trimethylchlorosilane (TMSCl)/sodium iodide (NaI), trifluoromethanesulfonic acid, and trifluoromethanesulfonic acid is preferred; \n (3) Compound 7 is produced from compound 6 via the Mitsunobu reaction, the selected reagent is diethyl azodicarboxylate (DEAD)/triphenylphosphine (PPh 3 ), N\u2032,N\u2032-tetraisopropylazodicarboxamide (TIPA)-tributylphosphine TBP, 1,1\u2032-(azodicarboxylic acid)dipiperidine (ADDP)-TBP, tetramethylazodicarboxamide (TMAD)-TBP, 4,7-dimethyl-3,4,5,6,7,8-hexahydro-1,2,4,7-tetraazocin-3,8-dione (DHTD)-TBP, cyanomethylene tri n-butylphosphine (CMBP) or cyanomethylene trimethylphosphine (CMMP), and DEAD/PPh 3  is preferred; \n (4) Compound 8 is produced from compound 7 via the nucleophilic substitution reaction, the selected reagent is a common organic or inorganic base, such as anhydrous potassium carbonate, cesium carbonate, triethylamine (TEA), DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide; and anhydrous potassium carbonate, cesium carbonate, TEA, DIEA and potassium tert-butoxide are preferred; \n (5) Compound 9 is obtained by the debromination of compound 8, preferably, the reaction condition is palladium on carbon Pd/C-ammonium formate, Pd/C-acetamide, Pd/C-hydrogen; and Pd/C-ammonium formate is preferred; \n Wherein R 8  is R 9  is the definitions of Y, R 2 , R 3 , R 7 , Z, m and n are the same as those defined in  claims 1  to  5 , respectively;\n (1) Compound 10 is obtained by the debromination of compound 5, preferably, the reaction condition is Pd/C-ammonium formate, Pd/C-acetamide, Pd/C-hydrogen; and Pd/C-ammonium formate is preferred; \n (2) Compound 11 is obtained by the deprotection of compound 10, the reagent for deprotection is: BBr 3 /DCM, 40% aqueous HBr, pyridine hydrochloride, hydrochloric acid or sulfuric acid, hydrochloric acid-aluminum chloride, aluminum chloride-ethanethiol, TMSCl/NaI, trifluoromethanesulfonic acid, and trifluoromethanesulfonic acid is preferred; \n (3) Compound 12 is produced from compound 11 via the Mitsunobu reaction, the selected reagent is DEAD/PPh 3 , TIPA-TBP, ADDP-TBP, TMAD-TBP, DHTD-TBP, CMBP or CMMP; DEAD/PPh 3  is preferred; \n (4) Compound 9 is produced from compound 12 via the nucleophilic substitution reaction, the selected reagent is a common organic or inorganic base, such as anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide; and anhydrous potassium carbonate, cesium carbonate, TEA, DIEA and potassium tert-butoxide are preferred; \n Wherein R 10  is R 9  is the definitions of X, Y, R 2 , R 3 , R 6 , R 7 , Z, m and n are the same as those defined in  claims 1  to  5 , respectively; X\u2032 is Cl or Br;\n (1) Compound 15 is obtained by the dechloridation of compound 14, the reaction reagent is zinc (Zn)/acetic acid (MeCOOH); \n (2) Compound 17 is obtained by the chlorination of compound 16, the reagent for chlorination is SOCl 2 /DMF, POCl 3 /DMF, POCl 3 /DIEA/MeCN and the like, and POCl 3 /DIEA/MeCN is preferred; \n (3) Compound 18 is produced from compound 17 via the nucleophilic substitution reaction, the selected reagent is a common organic or inorganic base, such as anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide; and anhydrous potassium carbonate, cesium carbonate, TEA, DIEA and potassium tert-butoxide are preferred; \n Wherein R 10  is R 9  is the definitions of X, Y, R 2 , R 3 , R 6 , R 7 , Z, m and n are the same as those defined in  claims 1  to  5 , respectively; X\u2032 is Cl or Br;\n (1) Compound 15I is obtained by the chlorination of compound 15, the reagent for chlorination is SOCl 2 /DMF, POCl 3 /DMF, POCl 3 /DIEA/MeCN and the like, and POCl 3 /DIEA/MeCN is preferred; \n (2) Compound 15II is produced from compound 15I via the nucleophilic substitution reaction, the selected reagent is a common organic or inorganic base, such as anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide; and anhydrous potassium carbonate, cesium carbonate, TEA, DIEA and potassium tert-butoxide are preferred; \n (3) Compound 18 is produced from compound 15II via the Suzuki coupling reaction, the base being used is potassium acetate, potassium phosphate or potassium carbonate; the solvent being used is dimethylsulfoxide, DMF, dioxane or toluene, and an appropriate amount of water is added; The catalyst being used is tetrakis(triphenylphosphine)palladium, [1,1\u2032-Bis(diphenylphosphino)ferrocene]dichloropalladium PdCl 2 (dppf); \n Wherein R 10  is R 9  is the definitions of X, Y, R 2 , R 3 , R 6 , R 7 , Z, m and n are the same as those defined in  claims 1  to  5 , respectively;\n (1) Compound 19 is produced via a substitution reaction, the selected reagent is a common organic or inorganic base, such as anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide; and anhydrous potassium carbonate, cesium carbonate, TEA, DIEA and potassium tert-butoxide are preferred; \n (2) Compound 20 is obtained by reducing compound 19, the reducing agents being used is nickel chloride (NiCl 2 )/sodium borohydride (NaBH 4 ), Zn/AcOH, Pd/C\u2014H 2 , Fe/hydrogen chloride (HCl) and sodium sulfide (Na 2 S)/ethanol (EtOH), ammonium hydrogen sulfide (NH 4 HS), lithium aluminum hydride (LiAlH 4 ); and NiCl 2 /NaBH 4  and Pd/C\u2014H 2  are preferred; \n (3) Compounds 21 and 22 are obtained by the ring-closure reaction of compound 20, the condition for the ring-closure reaction is ethyl formyl acetate, the solvent is various common solvents, such as methanol (MeOH), EtOH, acetonitrile (MeCN), dioxane and the like; \n (4) a chlorination reaction, the reagent for chlorination is SOCl 2 /DMF, POCl 3 /DMF, POCl 3 /DIEA/MeCN and the like, and POCl 3 /DIEA/MeCN is preferred; \n (5) a nucleophilic substitution reaction, the selected reagent is a common organic or inorganic base, such as anhydrous potassium carbonate, cesium carbonate, TEA, DIEA, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide; and anhydrous potassium carbonate, cesium carbonate, TEA, DIEA and potassium tert-butoxide are preferred.

Metadata:
- Claim Count in Document: 11.0
- Percentile: 91.0
- Lexical Diversity: 1.92424
- Patent Class: 514.0
- Transitional Phrase Type: none
- Component Type: 0
- Foreign Priority: True
- Related Applications: ['14916177', '14763468', '13509442', '13801753', '14383803']

Analysis Scores:
- 35 USC 101 Eligibility (BERT): 0.7547752212594883
- 35 USC 102 Novelty (BERT): 0.5460755228767221
- Combined Prediction Score: 0.7339052514212117
- Mean Citation Score: 360.248268
- Max Citation Score: 382.27582
- Similarity Product: 279.7830611088538

Labels:
- Claim Label 101: 1
- Claim Label 102: 1
- Claim Label 103: 1
- Claim Label 112: 1
- Combined Label: 1
- Label 101 Adjusted: 1

Dataset: test