PATENT CLAIM ANALYSIS

Application Number: 16067158
Application Type: Utility
Filing Date: 2018-06
Publication Date: 2019-01
Patent Classification: ["514", "063000"]

Abstract:
The present invention discloses a nitrogen-containing fused heterocyclic compound, as well as a preparation method, intermediate, composition and application thereof. The nitrogen-containing fused heterocyclic compound of the present invention as represented by formula (I), as well as the pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, metabolite or drug precursor thereof, exhibit a high selectivity and a high inhibitory activity with respect to CDK4 and CDK6 at a molecular level, an excellent inhibitory activity with respect to breast cancer cells at a cellular level, and significant inhibition of tumor cell proliferation associated with cyclin-dependent kinase activity at an animal level. The invention also exhibits a good stability with respect to human or mouse liver microsomes without significant inhibition of metabolic enzymes, good in vivo absorption in mice and rats, a high bioavailability and good druggability.

Claim (Index 6):
A preparation method for the nitrogen-containing fused heterocyclic compound according to  claim 1 , which is any of the following methods;\n method 1: when R 5  is hydrogen, the preparation method for the compound represented by formula I comprises conducting the Suzuki coupling reaction to give 1C, followed by Buchwald coupling with and removing the protecting group to give the compound represented by formula I; PG in the compound represented by formula 1D is a protecting group; method 2: when R 5  is hydrogen, the preparation method for the compound represented by formula I comprises conducting ammonolysis reaction with 1C, followed by reacting with to give 2A, then removing the protecting group to give the compound represented by formula I; PG in the compound represented by formula 2B is a protecting group; method 3: when R 5  is and R 11  is substituted or unsubstituted C 1 -C 6  alkyl, or substituted or unsubstituted C 3 -C 8  cycloalkyl, the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of condensing agent, conducting condensation reaction with compound 3A and to give compound I; method 4: when R 5  is the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of base, conducting a reaction with compound 4A and to give compound 4B, followed by hydrolysis reaction to give compound I; method 5: when R 5  is R 11  is substituted C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl, and the substituent is and R 13b  is H, the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of condensing agent, conducting compound 5A with to give compound 5B, then removing the protecting group of the amino group to give compound I; R 13a NH\u2014(CH 2 ) n1 \u2014C(\u2550O)\u2014 is R 5 ; the \u2014(CH 2 ) n1 \u2014 is the substituted C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl; PG in the compound represented by formula 5B is a protecting group; method 6: when R 5  is R 11  is substituted C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl, and the substituent is each R 13a  and R 13b  is not H, the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of condensing agent, conducting a reaction with compound 6A and to give compound 6B, then removing the protecting group of the amino group, followed by the reductive amination to give compound I; the is R 5 ; PG in the compound represented by formula 6B is a protecting group; method 7: when R 5  is R 11  is substituted C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl, and the substituent is R 13b  and R 13b  are the same, the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of condensing agent, conducting a reaction with compound 7A and to give reductive amination to give compound I; is R 5 ; PG in the compound represented by formula 7B is a protecting group; method 8: when R 5  is substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted C 3 -C 8  heterocycloalkyl, the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of base, conducting substitution reaction with compound 8A and R 5 \u2014X to give compound I; X is halogen or CH 3 SO 3 \u2014; method 9: when R 5  is substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, or substituted or unsubstituted C 3 -C 8  heterocycloalkyl, the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of reductive agent, conducting reductive amination reaction with compound 9A and R 5a \u2014CHO to give compound I; R 5a CH 2 \u2014 is R 5 ; method 10: when R 5  is substituted C 1 -C 6  alkyl, substituted C 3 -C 8  cycloalkyl, or substituted C 3 -C 8  heterocycloalkyl, and the substituent is R 16  is hydroxyl, the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of base, conducting substitution reaction with compound 10A and R 5b \u2014OC(\u2550O)\u2014(CH 2 ) n2 \u2014X, followed by hydrolysis reaction to give compound I; X is halogen or CH 3 SO 3 \u2014; R 5b  is C 1 -C 6  alkyl; \u2014(CH 2 ) n2  is substituted C 1 -C 6  alkyl, substituted C 3 -C 8  cycloalkyl, or substituted C 3 -C 8  heterocycloalkyl in R 5 ; is R 5 ; method 11: when R 5  is substituted C 1 -C 6  alkyl, substituted C 3 -C 8  cycloalkyl, and the substituent is or hydroxyl, or unsubstituted C 3 -C 8  heterocycloalkyl, the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of reductive agent, conducting reductive amination reaction with compound 11A and PG-R 5c \u2014CHO, removing the protecting group to give compound I; R 5c CH 2 \u2014 is R 5 ; PG in the compound represented by formula 11B is a protecting group; method 12: when R 5  is R 11  is and R 12a  and R 12b  are independently substituted or unsubstituted C 1 -C 20  alkyl, the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of triphosgene, conducting condensation reaction with compound 11A and substituted or unsubstituted amino to give compound I; R 12a NR 12b \u2014C(\u2550O)\u2014 is R 5 ; method 13: when R 5  is substituted C 1 -C 20  alkyl, or substituted C 1 -C 9  heterocycloalkyl and the substituent is C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, substituted C 1 -C 9  heterocycloalkyl, or C 3 -C 12  cycloalkyl, and R 13a  and R 13b  are independently hydrogen, C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, C 3 -C 12  cycloalkyl, borono, phospho, guanidino, thioureido, and the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of reductive agent, conducting reductive amination reaction with compound 13A and PG-NR 13a \u2014(CH 2 )n-CHO, then removing the protecting group, followed by substitution reaction to give compound I; R 13a NR 13b \u2014(CH 2 )n- is R 5 ; LG in the formula compound is a leaving group; X, Y, m, n, p, q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 6c  and R 6d  are defined as above; method 14: when R 5  is substituted C 1 -C 20  alkyl, or substituted C 1 -C 9  heterocycloalkyl and the substituent is C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, substituted C 1 -C 9  heterocycloalkyl, or C 3 -C 12  cycloalkyl, and R 14a , R 14b  and R 14c  are independently hydrogen, C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, C 3 -C 12  cycloalkyl, borono, phospho, guanidino, thioureido, the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of reductive agent, conducting reductive amination reaction with compound 14A and PG-NR 14a \u2014(CH 2 )n-CHO, then removing the protecting group, followed by substitution reaction to give compound I; R 14b NR 14c \u2014(CH 2 )n-R 14a  is R 5 ; LG in the formula compound is a leaving group; X, Y, m, n, p, q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 6c  and R 6d  are defined as above; method 15: when R 5  is substituted C 1 -C 20  alkyl, or substituted C 1 -C 9  heterocycloalkyl and the substituent is C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, substituted C 1 -C 9  heterocycloalkyl, or C 3 -C 12  cycloalkyl, and R 13a  and R 13b  are independently hydrogen, C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, C 3 -C 12  cycloalkyl, borono, phospho, guanidino, thioureido, and the preparation method for the compound represented by formula I comprises in organic solvent, in the presence of reductive agent, conducting substitution reaction with compound 15A and LG-(CH 2 )n-CN, followed by addition reaction to give compound I; LG in the formula compound is a leaving group; X, Y, m, n, p, q, R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 6c  and R 6d  are defined as above.

Metadata:
- Claim Count in Document: 1.0
- Percentile: 94.0
- Lexical Diversity: 1.8
- Patent Class: 514.0
- Transitional Phrase Type: none
- Component Type: 0
- Foreign Priority: True
- Related Applications: ['12723137', '14132877', '14883720', '10572958', '15612670']

Analysis Scores:
- 35 USC 101 Eligibility (BERT): 0.820247814053437
- 35 USC 102 Novelty (BERT): 0.5360652802272896
- Combined Prediction Score: 0.7918295606708223
- Mean Citation Score: 369.647188
- Max Citation Score: 375.8492
- Similarity Product: 240.4522154167176

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