Halogenated indole macrocycles for treatment of cancer

Abstract

The present invention relates to: compounds of formula (I) # imgabs0 # wherein R1 to R7, A1 and A2 are as described herein, and pharmaceutically acceptable salts thereof; as well as compositions comprising the compounds and methods of using the compounds.

Claims

1. A compound of formula (I), in R 1 for Hydroxyl(dihalogenated C 1-6 1-oxo-2,7-diazaspiro[4.4]nonane substituted with (dihalogenated C 1-6 1-oxo-2,8-diazaspiro[4.5]decyl substituted with (dihalogenated C 1-6 1-oxo-2,9-diazaspiro[5.5]undecyl substituted with alkyl)carbonyl, Hydroxyl(dihalogenated C 1-6 5-oxo-2,6-diazaspiro[3.4]octanyl substituted with (dihalogenated C 1-6 5-oxo-2,6-diazaspiro[3.5]nonyl substituted with (dihalogenated C 1-6 alkyl)carbonyl-substituted 6-oxo-2,7-diazaspiro[4.5]decyl, or Hydroxyl(dihalogenated C 1-6 Alkyl)carbonyl substituted azetidinyloxy C 1-6 alkyl; Where R 8 C 1-6 alkyl; R 9 For halogen and (dihalogenated C 1-6 alkyl)carbonyl substituted twice, or (dihalogenated C 1-6 alkyl)carbonyl-substituted pyrrolidinyl; R 2 C 1-6 alkyl; R 3 H, C 1-6 Alkyl or halogen; R 4 is H or halogen; R 5 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 6 C 1-6 Alkoxy C 1-6 alkyl; R 7 For morpholinyl, (halogenated C 1-6 alkyl) piperazinyl or C 1-6 Alkylpiperazinyl; A 1 is thiazolylene or phenylene substituted by hydroxyl; A 2 C 1-6 Alkylene; The condition is R 3 and R 4 Not at the same time H; or a pharmaceutically acceptable salt thereof.

2. A compound of formula (Ia), in R 1 for Hydroxyl(dihalogenated C 1-6 1-oxo-2,7-diazaspiro[4.4]nonane substituted with (dihalogenated C 1-6 1-oxo-2,8-diazaspiro[4.5]decyl substituted with (dihalogenated C 1-6 1-oxo-2,9-diazaspiro[5.5]undecyl substituted with alkyl)carbonyl, Hydroxyl(dihalogenated C 1-6 5-oxo-2,6-diazaspiro[3.4]octanyl substituted with (dihalogenated C 1-6 5-oxo-2,6-diazaspiro[3.5]nonyl substituted with (dihalogenated C 1-6 alkyl)carbonyl-substituted 6-oxo-2,7-diazaspiro[4.5]decyl, or Hydroxyl(dihalogenated C 1-6 Alkyl)carbonyl substituted azetidinyloxy C 1-6 alkyl; Where R 8 C 1-6 alkyl; R 9 For halogen and (dihalogenated C 1-6 alkyl)carbonyl substituted twice, or (dihalogenated C 1-6 alkyl)carbonyl-substituted pyrrolidinyl; R 2 C 1-6 alkyl; R 3 H, C 1-6 Alkyl or halogen; R 4 is H or halogen; R 5 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 6 C 1-6 Alkoxy C 1-6 alkyl; R 7 For morpholinyl, (halogenated C 1-6 alkyl) piperazinyl or C 1-6 Alkylpiperazinyl; A 1 is thiazolylene or phenylene substituted by hydroxyl; A 2 C 1-6 Alkylene; The condition is R 3 and R 4 Not at the same time H; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein R 1 for Hydroxyl(dihalogenated C 1-6 1-oxo-2,7-diazaspiro[4.4]nonane substituted with (dihalogenated C 1-6 1-oxo-2,8-diazaspiro[4.5]decyl substituted with (dihalogenated C 1-6 1-oxo-2,9-diazaspiro[5.5]undecyl substituted with alkyl)carbonyl, or Hydroxyl(dihalogenated C 1-6 5-oxo-2,6-diazaspiro[3.4]octanyl substituted with alkyl)carbonyl; Where R 8 C 1-6 alkyl; R 9 For halogen and (dihalogenated C 1-6 alkyl)carbonyl substituted twice, or (dihalogenated C 1-6 alkyl)carbonyl-substituted pyrrolidinyl.

4. A compound according to any one of claims 1 to 3, wherein R 1 for 1-oxo-2,7-diazaspiro[4.4]nonan-2-yl substituted with chloro(fluoro)acetyl, 1-oxo-2,8-diazaspiro[4.5]decan-2-yl substituted by chloro(fluoro)acetyl, 1-oxo-2,9-diazaspiro[5.5]undec-2-yl substituted by chloro(fluoro)acetyl, or 5-oxo-2,6-diazaspiro[3.4]octan-6-yl substituted by chloro(fluoro)acetyl; Where R 8 is methyl; R 9 It is piperidinyl substituted twice with fluorine and chloro(fluoro)acetyl, or pyrrolidinyl substituted with chloro(fluoro)acetyl.

5. A compound according to any one of claims 1 to 4, wherein R 1 (5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl, (5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl, 8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl, 9 -[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undec-2-yl, 2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl, 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-4-piperidinyl or 1-[(2R)-2-chloro-2-fluoro-acetyl]pyrrolidin-3-yl.

6. A compound according to any one of claims 1 to 5, wherein R 2 It is isopropyl.

7. A compound according to any one of claims 1 to 6, wherein R 3 is H, methyl or fluorine.

8. A compound according to any one of claims 1 to 7, wherein R 3 For fluorine.

9. A compound according to any one of claims 1 to 8, wherein R 4 is H or fluorine.

10. A compound according to any one of claims 1 to 9, wherein R 4 For H.

11. A compound according to any one of claims 1 to 10, wherein R 5 It is ethyl or 2,2,2-trifluoroethyl.

12. A compound according to any one of claims 1 to 11, wherein R 6 It is 1-methoxyethyl.

13. A compound according to any one of claims 1 to 12, wherein R 7 is morpholinyl, 4-(2,2,2-trifluoroethyl)piperazin-1-yl or 4-methylpiperazin-1-yl.

14. A compound according to any one of claims 1 to 13, wherein A 1 for Where bond "a" is attached to the indole ring.

15. A compound according to any one of claims 1 to 14, wherein A 2 It is dimethylmethylene.

16. The compound according to claim 1 or 2, wherein R 1 for Hydroxyl(dihalogenated C 1-6 1-oxo-2,7-diazaspiro[4.4]nonane substituted with (dihalogenated C 1-6 1-oxo-2,8-diazaspiro[4.5]decyl substituted with (dihalogenated C 1-6 1-oxo-2,9-diazaspiro[5.5]undecyl substituted with alkyl)carbonyl, or Hydroxyl(dihalogenated C 1-6 5-oxo-2,6-diazaspiro[3.4]octanyl substituted with alkyl)carbonyl; Where R 8 C 1-6 alkyl; R 9 For halogen and (dihalogenated C 1-6 alkyl)carbonyl substituted twice, or (dihalogenated C 1-6 alkyl)carbonyl-substituted pyrrolidinyl; R 2 C 1-6 alkyl; R 3 is a halogen; R 4 is H; R 5 C 1-6 Alkyl or halogenated C 1-6 alkyl; R 6 C 1-6 Alkoxy C 1-6 alkyl; R 7 For morpholinyl, (halogenated C 1-6 alkyl) piperazinyl or C 1-6 Alkylpiperazinyl; A 1 for wherein bond "a" is attached to the indole ring; A 2 C 1-6 Alkylene; or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 16, wherein R 1 (5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl, (5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl, 8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl, 9 -[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undec-2-yl, 2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl, 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-4-piperidinyl or 1-[(2R)-2-chloro-2-fluoro-acetyl]pyrrolidin-3-yl; R 2 is isopropyl; R 3 For fluorine; R 4 is H; R 5 is ethyl or 2,2,2-trifluoroethyl; R 6 is (1S)-1-methoxyethyl; R 7 is morpholinyl, 4-(2,2,2-trifluoroethyl)piperazin-1-yl or 4-methylpiperazin-1-yl; A 1 for wherein bond "a" is attached to the indole ring; A 2 is dimethylmethylene; or a pharmaceutically acceptable salt thereof.

18. A compound selected from: (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22 ,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22 ,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17,24-trimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undec-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(8S,14S)-25-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 ]nonaconicota-1(26),2,4,6(29),20,23(27),24-hepten-8-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17,24-trimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22 ,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.5]nonan-6-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2R)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo-[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[(5S)-2-[(2R)-2-chloro-2-fluoro-acetyl]-6-oxo-2,7-diazaspiro[4.5]decan-7-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[(5R)-2-[(2R)-2-chloro-2-fluoro-acetyl]-6-oxo-2,7-diazaspiro[4.5]decan-7-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undec-2-yl]-N-[(7S,13S)-25-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[(5R)-2-[(2S)-2-chloro-2-fluoro-acetyl]-6-oxo-2,7-diazaspiro[4.5]decan-7-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[(5S)-2-[(2S)-2-chloro-2-fluoro-acetyl]-6-oxo-2,7-diazaspiro[4.5]decan-7-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ] octadecanoic acid-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2 ,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(8S,14S)-26-fluoro-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-18,18-dimethyl-9,15-dioxo-22-(2,2,2-trifluoroethyl)-16-oxa-10,22,28-triazapentacyclo[18.5.2.1 2,6 .1 10,14 .0 23,27 ]nonaconicota-1(26),2,4,6(29),20,23(27),24-hepten-8-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undec-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2R)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9 ,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[[1-[(2R)-2-chloro-2-fluoro-acetyl]azetidin-3-yl]oxymethyl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9 ,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undec-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-4-fluoro-N-[(1S)-1-[[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2 ,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-piperidine-4-carboxamide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decane-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[9-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,9-diazaspiro[5.5]undec-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; (2S)-2-[8-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,8-diazaspiro[4.5]decan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9 ,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2, 5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[(5R)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2, 5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9 ,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; 1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-4-fluoro-N-methyl-piperidine-4-carboxamide; (3S)-1-[(2R)-2-chloro-2-fluoro-acetyl]-N-[(1S)-1-[[(7S,13S)-21-ethyl-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]carbamoyl]-2-methyl-propyl]-N-methyl-pyrrolidine-3-carboxamide; (2S)-2-[(5S)-7-[(2R)-2-chloro-2-fluoro-acetyl]-1-oxo-2,7-diazaspiro[4.4]nonan-2-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; and (2S)-2-[2-[(2R)-2-chloro-2-fluoro-acetyl]-5-oxo-2,6-diazaspiro[3.4]octan-6-yl]-N-[(7S,13S)-24-fluoro-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-morpholino-3-pyridyl]-17,17-dimethyl-8,14-dioxo-21-(2,2,2-trifluoroethyl)-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1 2,5 .1 9,13 .0 22,26 ]octacosyl-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-3-methyl-butyramide; or a pharmaceutically acceptable salt thereof.

19. A compound having the following structure:

20. A method for preparing a compound according to any one of claims 1 to 19, the method comprising any one of the following steps: a) reacting a compound of formula (II) in the presence of a coupling agent and a base, With acid (III), A coupling reaction is carried out between them to form the compound of formula (I); b) reacting a compound of formula (VI) in the presence of a coupling agent and a base, With acid (VII), A coupling reaction is carried out between them to form a compound of formula (VIII), c) reacting a compound of formula (XI) in the presence of a coupling agent and a base, With acid (XII), A coupling reaction is carried out between them to form a compound of formula (XIII), wherein Q is unsubstituted or substituted piperidinyl or pyrrolidinyl; T is a dihalogenated C 1-6 Alkyl; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , A 1 and A 2 As defined in any one of claims 1 to 17; the coupling reagent in steps a) to c) is T3P, HATU, PyBOP or EDCI / HOBt; the base in steps a) to c) is TEA, DIEPA or DMAP.

21. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 19 for use as a therapeutically active substance.

22. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 19; and a pharmaceutically acceptable excipient.

23. Use of a compound according to any one of claims 1 to 19 for treating a KRAS G12C protein-related disease.

24. Use of a compound according to any one of claims 1 to 19 for treating KRASG12C, G12D and G12V protein related diseases.

25. Use of a compound according to any one of claims 1 to 19 for inhibiting the interaction of RAS with downstream effectors, wherein the downstream effectors are RAF and PI3K.

26. Use of a compound according to any one of claims 1 to 19 for inhibiting propagated oncogenic MAPK and PI3K signalling.

27. Use of a compound according to any one of claims 1 to 19 for treating or preventing a KRAS mutation driven cancer, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma ovarian cancer and endometrial cancer.

28. Use of a compound according to any one of claims 1 to 19 for treating or preventing a KRAS mutation driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

29. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 19 for use in treating or preventing a KRAS mutation driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

30. Use of a compound according to any one of claims 1 to 19 for the preparation of a medicament for treating or preventing a KRAS mutation driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

31. A method for treating or preventing a KRAS mutation driven cancer, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer, the method comprising administering a therapeutically effective amount of a compound as defined in any one of claims 1 to 19.

32. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 19, prepared according to the process of claim 20.

33. The invention as herein described.

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