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BR-112025016688-B1 - Pharmaceutical Compounds and Compositions

BR112025016688B1BR 112025016688 B1BR112025016688 B1BR 112025016688B1BR-112025016688-B1

Abstract

PHARMACEUTICAL COMPOUNDS AND COMPOSITIONS. The present invention relates to compounds of formula (Ib), (Ib), wherein R1 to R3, M and L are as described herein, and their pharmaceutically acceptable salts, enantiomers and diastereomers thereof, and compositions including the compounds and methods of use of the compounds.

Inventors

  • Jianguo Chen
  • Haixia Liu
  • Hong Shen
  • Junwei XI
  • Weixing ZHANG
  • Dan Zhao
  • Wei Zhu
  • Lei Guo

Assignees

  • F. HOFFMANN-LA ROCHE AG

Dates

Publication Date
20260317
Application Date
20240208
Priority Date
20230214

Claims (20)

  1. 1. COMPOUND of formula (Ib), characterized by: R1 being 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl twice substituted with halogen, 6-tricyclo[3.1.1.03,6]heptanil, C3-7cycloalkyl substituted once, twice or three times by substituents independently selected from C1-6 alkyl, C1-6 alkylpyridinyl, C1-6 alkylpyrimidinyl, C1-6 alkyltetrazolyl, C3-7cycloalkyl, haloC1-6alkyl, halophenyl, halophenyl, hydroxyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl, or tetrahydropyranyl; R2 being 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, morpholinyl, or piperazinyl, unsubstituted or substituted by substituents independently selected from C1-6alkoxyC1-6alkyl, C1-6alkyl, C3-7cycloalkyl, haloC1-6alkyl, hydroxyC1-6alkyl, morpholinylC1-6alkyl, oxetanyl, oxopyrrolidinylC1-6alkyl and tetrahydrofuranyloxyC1-6alkyl; R3 being H or halogen; M being C1-6alkylene or O; eL be C1-6-alkylene, hydroxyC1-6-alkylene or haloC1-6-alkylene; or a pharmaceutically acceptable salt thereof.
  2. 2. COMPOUND, according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R1 being C3-7cycloalkyl substituted one, two or three times by substituents independently selected from C1-6alkyl, C1-6alkylpyridinyl, C1-6alkylpyrimidinyl, C1-6alkyltetrazolyl, C3-7cycloalkyl, haloC1-6alkyl, halogen, halophenyl, hydroxyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl; eR2 be morpholinyl, or piperazinel unsubstituted or substituted by substituents independently selected from C1-6 alkoxyC1-6 alkyl, C1-6 alkyl, C3-7 cycloalkyl, haloC1-6 alkyl, hydroxyC1-6 alkyl, morpholinylC1-6 alkyl, oxetanyl, oxopyrrolidinylC1-6 alkyl and tetrahydrofuranyloxyC1-6 alkyl.
  3. 3. COMPOUND, according to claim 1, characterized in that the compound of formula (Ib) is a compound of formula (Ic): where R1 is 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl twice-halogen-substituted, 6-tricyclo[3.1.1.03,6]heptanyl, C3-7cycloalkyl substituted once, twice or three times by substituents independently selected from C1-6alkyl, C1-6alkylpyridinyl, C1-6alkylpyrimidinyl, C1-6alkyltetrazolyl, C3-7cycloalkyl, haloC1-6alkyl, halophenyl, halophenyl, hydroxyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl, or tetrahydropyranyl; R2 is 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, morpholinyl, or piperazinyl, unsubstituted or substituted by substituents independently selected from C1-6alkoxyC1-6alkyl, C1-6alkyl, C3-7cycloalkyl, haloC1-6alkyl, hydroxyC1-6alkyl, morpholinylC1-6alkyl, oxetanyl, oxopyrrolidinylC1-6alkyl and tetrahydrofuranyloxyC1-6alkyl; R3 is H or halogen; M is C1-6alkylene or O; eL is C1-6-alkylene, hydroxyC1-6-alkylene or haloC1-6-alkylene; or a pharmaceutically acceptable salt thereof.
  4. 4. COMPOUND, according to claim 3, characterized in that R1 is C3-7cycloalkyl substituted once or twice by substituents independently selected from C1-6alkyl and pyridinyl.
  5. 5. COMPOUND, according to claim 3, characterized in that R1 is 2,3-dimethylcyclopropyl or 2-(3-pyridinyl)cyclopropyl.
  6. 6. COMPOUND, according to claim 3, characterized in that R2 is morpholinyl or C1-6 alkylpiperazinyl.
  7. 7. COMPOUND, according to claim 3, characterized in that R2 is morpholinyl or 4-methylpiperazin-1-yl.
  8. 8. COMPOUND, according to claim 3, characterized in that M is C1-6 alkylene.
  9. 9. COMPOUND, according to claim 3, characterized in that L is ethylene or difluoroethylene.
  10. 10. COMPOUND, according to claim 3, characterized by: R1 being C3-7cycloalkyl substituted once or twice by substituents independently selected from C1-6alkyl and pyridinyl; R2 being morpholinyl or C1-6alkylpiperazinyl; R3 being H; M being C1-6alkylene; and L being C1-6alkylene or haloC1-6alkylene; or a pharmaceutically acceptable salt thereof.
  11. 11. COMPOUND, characterized by being selected from:(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;(1S,2S)-2-(difluoromethyl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]cyclopropanecarboxamide;(1S,5R,6r)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;(1S,2S)-2-(difluoromethyl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]cyclopropanecarboxamide;(1S,5R,6r)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19,25(29),26-hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6- carboxamide;(1S,2S)-2-(difluoromethyl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15,24-dioxa-4-tia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]cyclopropanecarboxamide;(1S,5R,6r)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19,25(29),26-hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6- carboxamide;(1S,5R,6r)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6- carboxamide;(1S,2S)-2-(difluoromethyl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- tia-9,21,30,31-tetraza-hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]cyclopropanecarboxamide;(1S,5R,6r)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19,25(29),26-hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6- carboxamide;(1R,2S)-2-cyclopropyl-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetraza-hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19,25(29),26-hexaen-7-yl]cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;2,2-difluoro-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-1-methyl-cyclopropanecarboxamide;(1S,2S)-2-(difluoromethyl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) 1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl- 8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;(1R,2R)-2-(2-fluorophenyl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]cyclopropanecarboxamide; (1S,2S)-2-(2-fluorophenyl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- tia-9,21,30,31-tetraza-hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19,25(29),26-hexaen-7-yl]cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-(2-pyridyl)cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-23,23-difl uoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- tia-9,21,30,31-tetraza-hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-2-(difluoromethyl)cyclopropanecarboxamide;(1S,2R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;(1S,2S)-2-(difluoromethyl)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]cyclopropanecarboxamide;(1S,5R,6r)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19,25(29),26-hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6- carboxamide;(1R,2S)-2-cyclopropyl-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2.5(31),19,25,27- hexaen-7-yl]cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;(1S,5R,6r)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexa- hydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-3-oxabicyclo[3.1.0]hexane-6-carboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro- 1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl- 8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-(difluoromethyl)cyclopropanecarboxamide;(1R,5S,6s)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2.5(31),19,25,27- hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-tetraza-hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide;(1r,2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-tetraza-hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2.5(31),19,25,27- hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) (4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta- 1(28) hydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19,25(29),26-hexaen-7-yl]-2-pyrimidin-4-yl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-tetraza-hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide;(1R,5S,6s)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) morpholino-3-pyridyl]-17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;2,2-difluoro-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-1-methyl-cyclopropanecarboxamide;N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- il)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(29),2,5(31),19,25,27- hexaen-7-yl]-1,2-dimethyl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-(3-pyridyl) cyclopropanecarboxamide; methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-(4-pyridial)cyclopropanecarboxamide; (1R,2R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetraza-hexaciclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-(4-pyridyl)cyclopropanecarboxamide; methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]cyclopropanecarboxamide;(1S,5R,6r)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) morpholino-3-pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19.25(29),26-hexaen-7-yl]-2-pyridazin-3-yl- cyclopropanecarboxamide;(1R,2S)-2-cyclopropyl-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-tetraza-hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]cyclopropanecarboxamide;3,3-difluoro-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19,25(29),26-hexaen-7-yl]cyclopentanecarboxamide;N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-oxabicyclo[2.1.1]hexane-1-carboxamide;(1S,2S)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;(1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1r,2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17,23,23-tetramethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;trans-N-[(7S,13S)-(20M)-20-[2- [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-4-(1-methyltetrazol-5-yl)cyclo- Hexanecarboxamide tetraza-hexaciclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-4-methyl-cyclohexanecarboxamide;N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]tricyclo[3.1.1.03.6]heptane-6-carboxamide;(1r,2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;(1r,2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1- yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]tetrahydropyran-4-carboxamide;(1S,2S)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-phenyl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19.25(29),26-hexaen-7-yl]-2-pyrimidin-2-yl- cyclopropanecarboxamide;(1R,2R)-N-[(7S,13S)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-pyrimidin-2-yl-cyclopropanecarboxamide;(1r,2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(29),2,5(31),19,25,27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1r,2S,3R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1r,2S,3R)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-pyrimidin-5-yl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]-2-(3-pyridyl)cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-(3-pyridyl)cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1- methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-(3-pyridyl)cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-23,23-difl uoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- tia-9,21,30,31-tetraza-hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-(3-pyridyl) cyclopropanecarboxamide; methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta-1(28),2,5(31),19,25(29),26- hexaen-7-yl]-2-pyrimidin-5-yl-cyclopropanecarboxamide; (1S,2S)-N-[(7S,13S)-23,23-difluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4- tia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-pyrimidin-5-yl- cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-tetraza-hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-(3-pyridyl)cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2-(3-pyridyl) cyclopropanecarboxamide; methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,25-dioxa-4-thia-9,21,31,32-tetraza-hexacyclo[24.3.1.12,5.19,13.019,28.021.27]dotriaconta- 1(29) hydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octa- hydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-(3-pyridyl)cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aR)-1,3,4,6,7,8,9,9a-octa- hydropyrido[1,2-a]pyrazin-2-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14- dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-pyrimidin-5-yl-cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro- 1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl- 8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-(3-pyridyl)cyclopropanecarboxamide;(1S,2S)-N-[(7S,13S)-(20M)-20-[5-[(9aS)-3,4,6,7,9,9a-hexahydro- 1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl- 8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2-pyrimidin-5-yl-cyclopropanecarboxamide;(1r,2R,3S)-N-[(7S,13S)-(20M)-20-[5-(4-cyclopropylpiperazin-1-yl)-2- [(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-tetraza-hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1r,2R,3S)-N-[(7S,13S,23S)- 23-hydroxy-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia- 9,21,30,31-tetraza-hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- piperazin-1-yl-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1r,2R,3S)-N-[(7S,13S)-20-[5-[4-(2,2-difluoroethyl)piperazin-1-yl]-2- [(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1r,2R,3S)-N-[(7S,13S)-(20M)-20-[5-[4-(2-fluoroethyl)piperazin-1-yl]- 2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1r,2R,3S)-N-[(7S,13S)-(20M)-20-[5-[4-(3-hydroxypropyl)piperazin- 1-yl]-2-[(1S)-1-methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1R,2R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19,25(29),26-hexaen-7-yl]-2-(4-methylpyrimidin-5- il)cyclopropanecarboxamide;(1r,2R,3S)-N-[(7S,13S)-(20M)-20-[5-(4-ethylpiperazin-1-yl)-2-[(1S)-1- methoxyethyl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza- hexacycle[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2.5(31),19,25(29),26- hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide;(1R,2R)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) methoxyethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19,25(29),26-hexaen-7-yl]-2-(2-methyl-3- pyridyl)cyclopropanecarboxamide;(1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-tetra- hydropyran-4-ylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) (oxetan-3-yl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) morpholin-2-yl]methyl]piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2.5(31),19,25(29),26-hexaen-7-yl]-2-(5-methyl-3- pyridyl)cyclopropanecarboxamide;(1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-[2-(2- oxopyrrolidin-1-yl)ethyl]piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) tetrahydrofuran-3-yloxyethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) methoxy-3-methyl-butyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraza-hexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28) (4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta- 1(28) pyridyl]-17,17,22,22-tetramethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13,019,27,021,26]hentriaconta-1(29),2,5(31),19,25,27- hexaen-7-yl]-2-methyl-cyclopropanecarboxamide;(1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5- morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,31,32-tetraza- hexacyclo[24.3.1.12,5.19,13,019,28,021,27]dotriaconta-1(29),2,5(32),19,26(30),27-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; e(1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,32,33-tetraza-hexacyclo[25.3.1.12,5.19,13.019,29.021,28]tritriaconta-1(30),2,5(33),19,27(31),28-hexaen-7-yl]-2,3-dimethyl-cyclopropanecarboxamide; or a pharmaceutically acceptable salt thereof.
  12. 12. COMPOUND of formula (Ia), characterized by: R1 being 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl twice substituted with halogen, 6-tricyclo[3.1.1.03,6]heptanyl, C3-7cycloalkyl substituted once, twice or three times by substituents independently selected from C1-6alkyl, C1-6alkyltetrazolyl, C3-7cycloalkyl, haloC1-6alkyl, halogen, halophenyl, hydroxyl, phenyl, pyridazinyl, pyridinyl and pyrimidinyl, or tetrahydropyranyl; R2 being 1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazinyl, 3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazinyl, morpholinyl, (haloC1-6alkyl)piperazinyl or C1-6alkylpiperazinyl; M being C1-6alkylene or O; and L being C1-6alkylene or haloC1-6alkylene; or a pharmaceutically acceptable salt thereof.
  13. 13. COMPOUND, according to claim 12, characterized in that: R1 is 2,3-dimethylcyclopropyl or 2-(3-pyridinyl)cyclopropyl; R2 is morpholinyl or 4-methylpiperazin-1-yl; M is CH2; and L is , where the linkage “a” connects to M; or a pharmaceutically acceptable salt thereof.
  14. 14. COMPOUND, according to claim 12, characterized by being: or a pharmaceutically acceptable salt thereof.
  15. 15. COMPOUND, according to claim 12, characterized by being:
  16. 16. COMPOUND, according to claim 12, characterized by being: or a pharmaceutically acceptable salt thereof.
  17. 17. COMPOUND, according to claim 12, characterized by being:
  18. 18. COMPOUND, according to claim 12, characterized by being: or a pharmaceutically acceptable salt thereof.
  19. 19. COMPOUND, according to claim 12, characterized by being:
  20. 20. COMPOUND, according to claim 12, characterized by being: or a pharmaceutically acceptable salt thereof.

Description

[0001] The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal and, in particular, to the inhibition of the KRAS mutant useful for treating cancers. FIELD OF THE INVENTION [0002] RAS is one of the best-known proto-oncogenes. Approximately 30% of human cancers contain mutations in three of the most notable members, KRAS, HRAS, and NRAS, making them the most prevalent oncogenic factors. KRAS mutations are generally associated with poor prognosis, especially in colorectal cancer, pancreatic cancer, and lung cancer. As the most frequently mutated RAS isoform, KRAS has been intensively studied in recent years. Among the most commonly occurring KRAS alleles (including G12D, G12V, G12C, G13D, G12R, G12A, G12S, Q61H, etc.), G12C, G12D, and G12V account for more than half of all KRAS-induced cancers in colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and lung adenocarcinoma (ADP). It is worth noting that wild-type amplifications of KRAS are also found in about 7% of all KRAS-altered cancers (ovarian, esophagogastric, uterine), ranking among the major alterations. [0003] All RAS proteins belong to a family of small GTPase proteins that hydrolyze GTP to GDP. The KRAS is structurally divided into an effector-binding lobe, followed by the allosteric lobe and a carboxy-terminal region that is responsible for membrane anchoring. The effector lobe comprises the P-loop, switch I, and switch II regions. The switch I/II loops play an important role in downstream KRAS signaling by mediating protein-protein interactions with effector proteins including RAF in the mitogen-activated protein kinase (MAPK) pathway or PI3K in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. [0004] The KRAS protein alternates between an inactive and an active form by binding to GTP and GDP, respectively. Under physiological conditions, the transition between these two states is regulated by guanine nucleotide exchange factors (GEFs), such as Son Of Sevenless homolog 1 (SOS1) or GTPase activating proteins (GAPs), which involve catalyzing the exchange of GDP for GTP, enhancing the intrinsic activity of GTPase, or accelerating RAS-mediated GTP hydrolysis. In response to extracellular stimuli, inactive RAS-GDP is converted into active RAS-GTP, which binds directly to RAS RAF binding domains (RAFRBD), recruiting the RAF kinase family from the cytoplasm to the membranes, where they dimerize and become active. The activated RAF subsequently performs a chain of phosphorylation reactions on its downstream Mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK), and propagates the growth signal. Of the RAF family of protein kinases (three known isoforms: ARAF, BRAF, CRAF/RAF1), BRAF is the most frequently mutated and remains the most potent activator of MEK. Although individual members of the RAS and RAF families exhibit distinct binding preferences, all RAFs possess the conserved RBD for direct transmission of MAPK signaling, frequently used to characterize KRAS inhibition (e.g., KRAS-BRAFRBD in this document). For KRAS, mutations at positions 12, 13, 61, and 146 lead to a shift toward the active form of KRAS, through impaired nucleotide hydrolysis or activation of nucleotide exchange, leading to hyperactivation of the MAPK pathway which results in tumorigenesis. [0005] Despite its well-recognized importance against cancer malignancy, ongoing efforts in the past failed to develop approved therapies for KRAS mutant cancer until recently, when the first selective drug, AMG510, received rapid approval as a second-line treatment for KRAS G12C-induced non-small cell lung cancer (NSCLC). However, acquired clinical resistance to KRAS G12C inhibitors arises rigorously with disease progression after approximately 6 months of treatment. All mutations converge to reactivate RAS-MAPK signaling, with secondary RAS mutants at oncogenic hotspots (e.g., G12/G13/Q61) and within the switch II pocket (e.g., H95, R68, and Y96) observed; furthermore, over 85% of all KRAS-mutant or wild-type amplified cancers still lack novel agents. Overall, both the myriad of escape mechanisms and the various oncogenic alleles highlight the urgent medical need for additional RAS therapies. Thus, we invented oral compounds that target and inhibit RAS alleles for the treatment of cancers induced by RAS mutants. BRIEF DESCRIPTION OF THE INVENTION [0006] The present invention relates to new compounds of formula (Ib), wherein: R1 is 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6-bicyclo[3.1.0]hexanyl twice substituted with halogen, 6-tricyclo[3.1.1.03,6]heptanyl, C3-7-cycloalkyl substituted once, twice or three times by substituents independently selected from C1-6-alkyl, C1-6-alkylpyridinyl, C1-6-alkylpyrimidinyl, C1-6-alkyltetrazolyl, C3-7-cycloalkyl, haloC1-6alkyl, halogen, halophenyl, hydroxyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl and thiazolyl, or tet