Search

CN-121986105-A - Benzazepine ketones and uses thereof

CN121986105ACN 121986105 ACN121986105 ACN 121986105ACN-121986105-A

Abstract

The invention discloses a benzazepine The invention also discloses the benzoazepine compound, in particular to the free alkali, isomer or pharmaceutically acceptable salt and other substance forms of the compound The preparation method and the pharmaceutical application of the ketone compound can be used as RIPK1 inhibitors for treating diseases related to the abnormal expression of the RIPK1 signal pathway, including but not limited to tumors, and have great clinical development value.

Inventors

  • FENG ENGUANG
  • ZHANG JINZHU
  • LIU JIACHENG
  • Lei Shaowei
  • WANG TINGTING
  • LI YUANYUAN
  • SHEN XIMING
  • LOU JINFANG

Assignees

  • 杭州百诚医药科技股份有限公司

Dates

Publication Date
20260505
Application Date
20241031
Priority Date
20230831

Claims (12)

  1. Benzazepine A ketone compound, which is a compound of formula I, an isomer, or a pharmaceutically acceptable salt thereof: wherein ring A is selected from 6-10 membered aromatic or 5-10 membered heteroaromatic ring, ring A being substituted with at least one substituent Substitution; Ring B is selected from 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, ring B being substituted with at least one substituent R 2 ; X, Y are each independently selected from CR 4 、OR 4 、SR 4 or NR 4 , and X and Y are not both NR 4 ; R 1 is selected from the group consisting of C 1-6 alkyl substituted with at least one substituent, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, said substituents being selected from one or more of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, amino, hydroxy, cyano, amido, sulfone, sulfoxide, C 1-6 haloalkyl, C 1-6 Alkylhydroxy, C 1-6 Alkylamino, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 alkyl sulfoxide, C 1-6 haloalkoxy, C 1-6 alkoxyhydroxy, C 1-6 alkoxyamino, C 1-6 -membered alkoxyamide group, C 1-6 -alkoxysulfone group, C 1-6 -alkoxysulfoxide group, 3-6-membered cycloalkyl group, 3-6-membered heterocyclic group, 5-8-membered aryl group, 5-8-membered heteroaryl group; R 2 is selected from hydrogen, halogen, C 1-6 alkyl or halogenated C 1-6 alkyl; l is selected from a 5-6 membered heteroaromatic ring substituted with at least one substituent selected from one or more of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, amino, hydroxy, cyano, amido, sulfone, sulfoxide, C 1-6 haloalkyl, C 1-6 alkyl hydroxy, C 1-6 alkylamino, C 1-6 alkylamide, C 1-6 alkyl sulfone, C 1-6 alkyl sulfoxide, C 1-6 haloalkoxy, C 1-6 alkoxy hydroxy, C 1-6 alkoxyamino, C 1-6 alkoxyamide, C 1-6 alkoxy sulfone, C 1-6 alkoxy sulfoxide; W is selected from one of the connection keys 、-(CH 2 ) n -、-O-、-(CH 2 ) n O(CH 2 ) m -、-CO-、-(CH 2 ) n CO(CH 2 ) m -; R 3 is selected from a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring substituted with at least one substituent selected from one or more of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, amino, hydroxy, cyano, amido, sulfone, sulfoxide, C 1-6 haloalkyl, C 1-6 alkyl hydroxy, C 1-6 alkylamino, C 1-6 alkylamide, C 1-6 alkyl sulfone, C 1-6 alkyl sulfoxide, C 1-6 haloalkoxy, C 1-6 alkoxy hydroxy, C 1-6 alkoxy amino, C 1-6 alkoxy amide, C 1-6 alkoxy sulfone, C 1-6 alkoxy sulfoxide; R 4 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkyl hydroxy, C 1-6 alkylamino, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 alkylsulfoxide, C 1-6 haloalkoxy, C 1-6 alkoxyhydroxy, C 1-6 alkoxyamino, C 1-6 alkoxyamido, C 1-6 alkoxysulfone, or C 1-6 alkoxysulfoxide; n, m are each independently selected from 0, 1,2,3 or 4, and n and m are not both 0; the 5-10 membered heteroaromatic ring, the 5-8 membered heteroaryl and the 3-6 membered heterocyclic group contain at least one heteroatom, and the heteroatom is N, O or S.
  2. According to claim 1 said benzazepine A ketone compound, characterized by being a compound represented by formula II, an isomer, or a pharmaceutically acceptable salt thereof: wherein X is selected from CR 4 、OR 4 or SR 4 ; R 1 is selected from the group consisting of C 1-6 alkyl substituted with at least one substituent, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, said substituents being selected from one or more of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, amino, hydroxy, cyano, amido, sulfone, sulfoxide, C 1-6 haloalkyl, C 1-6 Alkylhydroxy, C 1-6 Alkylamino, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 alkyl sulfoxide, C 1-6 haloalkoxy, C 1-6 alkoxyhydroxy, C 1-6 alkoxyamino, C 1-6 -membered alkoxyamide group, C 1-6 -alkoxysulfone group, C 1-6 -alkoxysulfoxide group, 3-6-membered cycloalkyl group, 3-6-membered heterocyclic group, 5-8-membered aryl group, 5-8-membered heteroaryl group; L is selected from triazole, pyridine, pyrazole or pyrazolotetrahydropyridinone substituted by at least one substituent selected from one or more of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, amino, hydroxyl, cyano, amido, sulfonyl, sulfoxide, C 1-6 haloalkyl, C 1-6 alkyl hydroxyl, C 1-6 alkylamino, C 1-6 alkylamide, C 1-6 alkyl sulfonyl, C 1-6 alkyl sulfoxide, C 1-6 haloalkoxy, C 1-6 alkoxyl, C 1-6 alkoxyamino, C 1-6 alkoxyamide, C 1-6 alkoxy sulfone and C 1-6 alkoxy sulfoxide; W is selected from one of- (CH 2 ) n -, -O-, -CO-; each R 4 、R 5 、R 6 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 alkyl hydroxy, C 1-6 alkylamino, C 1-6 alkylamido, C 1-6 alkyl sulfonyl, C 1-6 alkyl sulfoxide, C 1-6 haloalkoxy, C 1-6 alkoxyhydroxy, C 1-6 alkoxyamino, C 1-6 alkoxyamide, C 1-6 alkoxysulfone, or C 1-6 alkoxysulfoxide; n is selected from 1,2,3 or 4; the 5-10 membered heteroaromatic ring, the 5-8 membered heteroaryl and the 3-6 membered heterocyclic group contain at least one heteroatom, and the heteroatom is N, O or S.
  3. According to claim 2 said benzazepine A ketone compound, which is a compound represented by formula II-1, an isomer, or a pharmaceutically acceptable salt thereof: wherein X is selected from CR 4 、OR 4 or SR 4 ; R 1 is selected from the group consisting of C 1-6 alkyl substituted with at least one substituent, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, said substituents being selected from one or more of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, amino, hydroxy, cyano, amido, sulfone, sulfoxide, C 1-6 haloalkyl, C 1-6 Alkylhydroxy, C 1-6 Alkylamino, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 alkyl sulfoxide, C 1-6 haloalkoxy, C 1-6 alkoxyhydroxy, C 1-6 alkoxyamino, C 1-6 -membered alkoxyamide group, C 1-6 -alkoxysulfone group, C 1-6 -alkoxysulfoxide group, 3-6-membered cycloalkyl group, 3-6-membered heterocyclic group, 5-8-membered aryl group, 5-8-membered heteroaryl group; R 4 、R 5 、R 6 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkylhydroxy, C 1-6 haloalkoxy, or C 1-6 alkoxyhydroxy.
  4. According to claim 2 said benzazepine A ketone compound, which is a compound represented by formula II-2, an isomer, or a pharmaceutically acceptable salt thereof: wherein X is selected from CR 4 、OR 4 or SR 4 ; R 1 is selected from the group consisting of C 1-6 alkyl substituted with at least one substituent, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, said substituents being selected from one or more of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, amino, hydroxy, cyano, amido, sulfone, sulfoxide, C 1-6 haloalkyl, C 1-6 Alkylhydroxy, C 1-6 Alkylamino, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 alkyl sulfoxide, C 1-6 haloalkoxy, C 1-6 alkoxyhydroxy, C 1-6 alkoxyamino, C 1-6 -membered alkoxyamide group, C 1-6 -alkoxysulfone group, C 1-6 -alkoxysulfoxide group, 3-6-membered cycloalkyl group, 3-6-membered heterocyclic group, 5-8-membered aryl group, 5-8-membered heteroaryl group; R 4 、R 5 、R 6 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkylhydroxy, C 1-6 haloalkoxy, or C 1-6 alkoxyhydroxy.
  5. According to claim 2 said benzazepine A ketone compound, which is a compound represented by formula II-3, an isomer, or a pharmaceutically acceptable salt thereof: wherein X is selected from CR 4 、OR 4 or SR 4 ; R 1 is selected from the group consisting of C 1-6 alkyl substituted with at least one substituent, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, said substituents being selected from one or more of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, amino, hydroxy, cyano, amido, sulfone, sulfoxide, C 1-6 haloalkyl, C 1-6 Alkylhydroxy, C 1-6 Alkylamino, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 alkyl sulfoxide, C 1-6 haloalkoxy, C 1-6 alkoxyhydroxy, C 1-6 alkoxyamino, C 1-6 -membered alkoxyamide group, C 1-6 -alkoxysulfone group, C 1-6 -alkoxysulfoxide group, 3-6-membered cycloalkyl group, 3-6-membered heterocyclic group, 5-8-membered aryl group, 5-8-membered heteroaryl group; R 4 、R 5 、R 6 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkylhydroxy, C 1-6 haloalkoxy, or C 1-6 alkoxyhydroxy.
  6. According to claim 2 said benzazepine A ketone compound, which is a compound represented by formula II-4, an isomer, or a pharmaceutically acceptable salt thereof: wherein X is selected from CR 4 、OR 4 or SR 4 ; R 1 is selected from the group consisting of C 1-6 alkyl substituted with at least one substituent, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, said substituents being selected from one or more of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, amino, hydroxy, cyano, amido, sulfone, sulfoxide, C 1-6 haloalkyl, C 1-6 Alkylhydroxy, C 1-6 Alkylamino, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 alkyl sulfoxide, C 1-6 haloalkoxy, C 1-6 alkoxyhydroxy, C 1-6 alkoxyamino, C 1-6 -membered alkoxyamide group, C 1-6 -alkoxysulfone group, C 1-6 -alkoxysulfoxide group, 3-6-membered cycloalkyl group, 3-6-membered heterocyclic group, 5-8-membered aryl group, 5-8-membered heteroaryl group; R 4 、R 5 、R 6 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkylhydroxy, C 1-6 haloalkoxy, or C 1-6 alkoxyhydroxy.
  7. According to claim 2 said benzazepine A ketone compound, which is a compound represented by formula II-5, an isomer, or a pharmaceutically acceptable salt thereof: wherein X is selected from CR 4 、OR 4 or SR 4 ; R 1 is selected from the group consisting of C 1-6 alkyl substituted with at least one substituent, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl or C 5-10 heteroaryl, said substituents being selected from one or more of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, amino, hydroxy, cyano, amido, sulfone, sulfoxide, C 1-6 haloalkyl, C 1-6 Alkylhydroxy, C 1-6 Alkylamino, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 alkyl sulfoxide, C 1-6 haloalkoxy, C 1-6 alkoxyhydroxy, C 1-6 alkoxyamino, C 1-6 -membered alkoxyamide group, C 1-6 -alkoxysulfone group, C 1-6 -alkoxysulfoxide group, 3-6-membered cycloalkyl group, 3-6-membered heterocyclic group, 5-8-membered aryl group, 5-8-membered heteroaryl group; R 4 、R 5 、R 6 、R 7 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkylhydroxy, C 1-6 haloalkoxy, or C 1-6 alkoxyhydroxy.
  8. Benzazepine A ketone compound which is a compound, isomer or pharmaceutically acceptable salt thereof of the following structure: 5-benzyl-N- [9- (cyclopropylethynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazapenta-3-carboxamide; 5-benzyl-N- [ 4-oxy-9- (pyridin-2-ylethynyl) -1,2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazacyclopent-3-carboxamide; 5-benzyl-N- [ 4-oxy-9- (pyridin-3-ylethynyl) -1,2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazacyclopent-3-carboxamide; 5-benzyl-N- [ 4-oxy-9- (pyridin-4-ylethynyl) -1,2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazacyclopent-ne-3-carboxamide; 5-benzyl-N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl } -4H-1,2, 4-triazacyclopent-3-carboxamide; 5-benzyl-N- [ 4-oxy-9- (3, 4,5, 6-tetrahydro-2H-pyran-4-ylethynyl) -1,2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazapenta-3-carboxamide; 5-benzyl-N- [9- (3-hydroxy-3-methylbut-1-ynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazacyclopenta-3-carboxamide; 5- [ (4-fluorophenyl) methyl ] -N- [ 4-oxy-9- (pyridin-4-ylethynyl) -1,2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazacyclopent-3-carboxamide; 5- [ (4-chlorophenyl) methyl ] -N- [ 4-oxy-9- (pyridin-4-ylethynyl) -1,2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazacyclopent-3-carboxamide; 5- [ (2-chlorophenyl) methyl ] -N- [ 4-oxy-9- (pyridin-4-ylethynyl) -1,2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazacyclopent-3-carboxamide; 5- [ (2-fluorophenyl) methyl ] -N- [ 4-oxy-9- (pyridin-4-ylethynyl) -1,2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazacyclopent-3-carboxamide; 5- [ (2, 6-difluorophenyl) methyl ] -N- [ 4-oxy-9- (pyridin-4-ylethynyl) -1,2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazapenta-3-carboxamide; 5- [ (2, 6-dichlorophenyl) methyl ] -N- [ 4-oxy-9- (pyridin-4-ylethynyl) -1,2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazapenta-3-carboxamide; 5-benzyl-N- [ 4-oxy-10- (pyridin-2-ylethynyl) -1,2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazacyclopent-3-carboxamide; 5-benzyl-N- [ 4-oxy-10- (pyridin-3-ylethynyl) -1,2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazacyclopent-3-carboxamide; 5-benzyl-N- [10- (cyclopropylethynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazapenta-3-carboxamide; 5-benzyl-N- [ 4-oxy-10- (pyridin-4-ylethynyl) -1,2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazacyclopent-3-carboxamide; 1- [ (2, 6-difluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxolano-1, 2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl } -1,2, 4-triazacyclopent-3-carboxamide; 1- [ (2, 6-difluorophenyl) methyl ] -N- [ 4-oxy-9- (pyridin-4-ylethynyl) -1,2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -1,2, 4-triazacyclopent-3-carboxamide; 1-benzyl-N- [ 4-oxy-9- (pyridin-4-ylethynyl) -1,2,4,5,6, 7-hexahydroazepin-e-p-c-a [3,2,1-hi ] indol-5-yl ] -1,2, 4-triazacyclopent-ne-3-carboxamide; 1- [ (2, 6-difluorophenyl) methyl ] -N- [9- (3-hydroxy-3-methylbut-1-ynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -1,2, 4-triazacyclopent-3-carboxamide; 1- [ (2, 6-difluorophenyl) methyl ] -N- [9- (3-methoxyprop-1-ynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl ] -1,2, 4-triazacyclopenta-3-carboxamide; n- [9- (cyclopropylethynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepin-2, 3,2,1-hi ] indol-5-yl ] -1- [ (2, 6-difluorophenyl) methyl ] -1,2, 4-triazapentalene-3-carboxamide; 1- [ (2-fluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl } -1,2, 4-triazacyclopenta-3-carboxamide; 1- [ (4-fluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl } -1,2, 4-triazacyclopenta-3-carboxamide; 1- [ (2, 4-difluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxolano-1, 2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl } -1,2, 4-triazacyclopent-3-carboxamide; 1- [ (2, 5-difluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxolano-1, 2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl } -1,2, 4-triazacyclopent-3-carboxamide; 1- [ (3, 5-difluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxolano-1, 2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl } -1,2, 4-triazacyclopent-3-carboxamide; 1- [ (3, 4-difluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxolano-1, 2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl } -1,2, 4-triazacyclopent-3-carboxamide; 1- [ (2-methylphenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxolano-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl } -1,2, 4-triazacyclopenta-3-carboxamide; 1- [ (4-methylphenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl } -1,2, 4-triazacyclopenta-3-carboxamide; 1- [ (2, 6-difluorophenyl) methyl ] -N- (4-oxo-9- (piperidin-4-ylethynyl) -1,2,3,4,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl) -1,2, 4-triazapenta-3-carboxamide; Tert-butyl 4- ((3- (1- (2, 6-difluorobenzyl) -1H-1,2, 4-triazole-3-carboxamide) -4-oxo-1, 2,3,4,6, 7-hexahydroazepino [3,2,1-hi ] indol-9-yl) ethynyl) piperidine-1-carboxamide; 1- (2, 6-difluorobenzyl) -N- (9- ((1- (difluoromethyl) -1H-pyrazol-4-yl) ethynyl) -4-oxy-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1- (3, 5-difluorobenzyl) -N- (9- ((1- (difluoromethyl) -1H-pyrazol-4-yl) ethynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1- (2, 5-difluorobenzyl) -N- (9- ((1- (difluoromethyl) -1H-pyrazol-4-yl) ethynyl) -4-oxy-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1- (2, 4-difluorobenzyl) -N- (9- ((1- (difluoromethyl) -1H-pyrazol-4-yl) ethynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1- (2-fluorobenzyl) -N- (9- ((1- (difluoromethyl) -1H-pyrazol-4-yl) ethynyl) -4-oxy-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1- (2-methylbenzyl) -N- (9- ((1- (difluoromethyl) -1H-pyrazol-4-yl) ethynyl) -4-oxy-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1- (3, 4-difluorobenzyl) -N- (9- ((1- (difluoromethyl) -1H-pyrazol-4-yl) ethynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1- (4-fluorobenzyl) -N- (9- ((1- (difluoromethyl) -1H-pyrazol-4-yl) ethynyl) -4-oxy-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1- (4-methylbenzyl) -N- (9- ((1- (difluoromethyl) -1H-pyrazol-4-yl) ethynyl) -4-oxy-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1- (2, 6-difluorobenzyl) -N- (9-ethynyl-4-oxo-1, 2,4,5,6, 7-hexahydroazepan-o [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1- (2, 6-difluorobenzyl) -N- (9- ((6, 7-dihydro-4H-pyrazolo [5,1-c ] [1,4] oxazin-3-yl) ethynyl) -4-oxa-no-1, 2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-3-yl) -1H-1,2, 4-triazole-3-carboxamide; 1- (2, 6-difluorobenzyl) -N- (9- ((5-formyl-1-vinyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1- (2, 6-difluorobenzyl) -N- (9- ((1- (oxetan-3-yl) -1H-pyrazol-4-yl) ethynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1- (2, 6-difluorobenzyl) -N- (9- ((1- (oxetan-3-yl) -1H-pyrazol-4-yl) ethynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; N- (9- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl) -1- (pyridin-2-ylmethyl) -1H-1,2, 4-triazole-3-carboxamide; 1- (4-benzyl) -N- (9- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -1,2, 4-triazole-3-carboxamide; 1-benzyl-N- [ 4-oxy-10- (pyridin-4-ylethynyl) -1,2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl ] -4H-1,2, 4-triazacyclopent-3-carboxamide; N- (9- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-1, 2,3,4,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -6-phenoxypyridine amide; n- (9- ((1-methyl-1H-pyrazol-4-yl) ethynyl) -4-oxo-1, 2,3,4,6, 7-hexahydroazepino [3,2,1-hi ] indol-3-yl) -5-phenoxypyridine amide; 5- [ (2, 6-difluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxosubunit-3, 4,6, 7-tetrahydro-2H- [1,4] oxazepino [2,3,4-hi ] indol-3-yl } -4H-1,2, 4-triazapenta-3-carboxamide; 5- [ (2, 6-difluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxolano-3, 4,6, 7-tetrahydro-2H- [1,4] thiazepino [2,3,4-hi ] indol-3-yl } -4H-1,2, 4-triazapenta-3-carboxamide; N- {7, 7-difluoro-9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxo-1, 2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl } -5- [ (2, 6-difluorophenyl) methyl ] -4H-1,2, 4-triazapenta-ne-3-carboxamide; 5-benzyl-N- [8- (cyclopropylethynyl) -4-oxo-3, 4,6, 7-tetrahydro-2H- [1,4] oxazepino [2,3,4-hi ] indol-3-yl ] -4H-1,2, 4-triazapenta-3-carboxamide; 1- [ (2, 6-difluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxosubunit-3, 4,6, 7-tetrahydro-2H- [1,4] oxazepino [2,3,4-hi ] indol-3-yl } -1,2, 4-triazapenta-3-carboxamide; 1- [ (2, 6-difluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxolanyl-3, 4,6, 7-tetrahydro-2H- [1,4] thiazepino [2,3,4-hi ] indol-3-yl } -1,2, 4-triazapenta-3-carboxamide; N- {7, 7-difluoro-9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxo-1, 2,4,5,6, 7-hexahydroazepin-o [3,2,1-hi ] indol-5-yl } -1- [ (2, 6-difluorophenyl) methyl ] -1,2, 4-triazapenta-3-carboxamide; 1- [ (2, 6-difluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxon-ylidene-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl } pyrazole-3-carboxamide; 1- [ (4-fluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl } pyrazole-3-carboxamide; 5- (2-benzyl-3-chloro-7-oxy-4, 5,6, 7-tetrahydropyrazolo [3,4-c ] pyridin-6-yl) -9- [ (1-methylpyrazol-4-yl) ethynyl ] -1,2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-4-one; 4- [ (3-fluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxo-1, 2,4,5,6, 7-hexahydroazepino [3,2,1-hi ] indol-5-yl } pyrazole-1-carboxamide; 4- [ (3-fluorophenyl) methyl ] -N- {9- [ (1-methylpyrazol-4-yl) ethynyl ] -4-oxo-3, 4,6, 7-tetrahydro-2H- [1,4] oxazepino [2,3,4-hi ] indol-3-yl ] -4H-1,2, 4-triazapenta-3-carboxamide.
  9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 as active ingredient, and at least one pharmaceutically acceptable carrier.
  10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the prophylaxis or treatment of a disease associated with a receptor-interacting protein kinase.
  11. The use according to claim 10, wherein the disease is a disease associated with altered receptor interacting protein kinase 1 activity.
  12. The use according to claim 11, wherein the disease is selected from the group consisting of tumors including but not limited to intestinal cancer, lung cancer, liver cancer, pancreatic cancer, breast cancer, lymphoma, melanoma, and the like.

Description

Benzazepine ketones and use thereof Technical Field The invention belongs to the technical field of small molecule targeted chemical drugs, and relates to a benzazepineThe ketone compounds, in particular to the free alkali, isomer or pharmaceutically acceptable salt and other structural forms of the compounds; further, the invention also discloses the benzazepineThe preparation method and the pharmaceutical application of the ketone compound can be used as RIPK1 inhibitor for treating diseases related to the abnormal expression of the RIPK1 signal pathway, including but not limited to tumors. Background Receptor interacting protein kinase 1 (receptor-INTERACTING PROTEIN KINASE, RIPK 1), belongs to serine/threonine protein kinases. The C end of the polypeptide contains death domains, and the polypeptide participates in signal transduction after stimulation of TNF and FasL by being combined with each other or other molecules (such as TRADD, fas, TNFRI) containing the death domains, mediates NF- κB activation and induces apoptosis, and the functions of the polypeptide are regulated by ubiquitination, zinc finger proteins, heat shock proteins and the like. Diseases or conditions mediated in part by receptor interacting protein kinase 1, dependent apoptosis, necrosis or cytokine production include hematological and solid organ malignancies (general dev.2013,27, 1640-1649), bacterial and viral infections ((Cell Host & Microbe,2014,15,23-35), including but not limited to tuberculosis and influenza (Cell, 2013,153,1-14)). Taken together, receptor interacting protein kinase 1 acts as a key regulator of apoptosis, which is involved not only in pro-cell survival signaling, but also in apoptosis signaling in a variety of pathways. Inhibitors of receptor-interacting protein kinase 1 have potential therapeutic effects for the treatment of a variety of diseases such as cancer, neurodegenerative diseases, autoimmune diseases, and the like. Currently, receptor-interacting protein kinase 1 inhibitors are being studied globally and are structurally divided into three major classes, indoles (e.g., necrostatin-1 s), benzazepineClasses (e.g., GSK-2982772) and pyrazole amides (e.g., GSK-963, GSK 547) are currently in preclinical or clinical research stage, and no marketed drugs have appeared yet, and the potential of the future market is considerable. Yuan Junying teaches that Necrostatin-1s, which was found in 2005 as the first small molecule receptor-interacting protein kinase 1 inhibitor, is the authoritative and pioneering in the field of receptor-interacting protein kinase 1 inhibitors, and has been widely used for the study of the role and mechanism of receptor-interacting protein kinase 1 in human diseases and animal models. In 2008, the mode of action of the necrotic statin drugs is determined, so that the necrotic statin drugs are determined to be key regulating factors of the programmed necrosis, and the highest global research and development state of the drugs is preclinical. Patent WO2014125444 discloses a novel benzazepineThe derivative is obtained by screening a gene coding library, the GSK-2982772 is obtained in batches to enter clinic, 2016 years GSK-2982772 is pushed to second-phase clinic, indications entering clinic second-phase clinic are psoriasis, rheumatoid arthritis and ulcerative colitis, and except GSK-2982772, 2018, 11, 16 and 3145095 are subjected to clinical second-phase experiments, so that the derivative is used for treating pancreatic cancer, and research on treating pancreatic cancer by GSK-3145095 in 2019, 09, 12 and 09 is terminated. Patent WO2016185423 discloses a pyrazole amide derivative, which represents a compound GSK-963, but the oral effect of the pyrazole amide derivative is poor, the development is limited, then the compound is used as a lead compound to perform structural optimization, GSK-547 is obtained, and the molecule does not enter clinic finally due to poor pharmacokinetic data. The receptor interaction protein kinase 1 inhibitor based on the three main structures has the defects of low selectivity, strong toxic and side effects, poor patent medicine property and the like, and scientific researchers at home and abroad continue to reform the structure of the compound on the basis of the structure, so that safer and more effective receptor interaction protein kinase 1 inhibitor is expected to be found so as to fill the blank of the target medicine. The patent literature on GSK-2982772 and structural modifications and improvements around GSK-2982772 is searched for, for example, as follows: The patent WO2014125444 discloses a compound of the structural formula 1, which is structurally characterized in that a parent nucleus is benzazepine Ring and azaThe ring being bound to a benzene ring or to a nitrogen-containing six-membered aromatic heterocyclic ring, benzazepineThe ring is connected with the ring A through an amide bond, the ring A is connected with the ring B through an L-co