KRAS protein degradation-targeted chimera

Abstract

This specification provides KRAS proteolytically targeted chimeras (PROTACs), compositions comprising KRAS PROTACs, methods for preparing KRAS PROTACs, and methods for using KRAS PROTACs, for example, to promote KRAS degradation and / or to treat KRAS-related cancers. In one embodiment, a KRAS PROTAC has the following structural formula or is a pharmaceutically acceptable salt thereof [wherein a variable element (e.g., ring A, X)]. 4 , Y, R 2 , R 3 , R 4 The values ​​for L', Degron are as specified herein.

Claims

1. Compounds with the following formula: 【Chemical 654】 or a pharmaceutically acceptable salt thereof [in the formula, 【Chemical 655】 teeth, 【Chemical Formula 656】 And, X ５ is O or CH ２ And, Two Rs ｏ together with the same carbon atom form a C ３－７ cycloalkyl or 4- to 7-membered heterocycloalkyl, and each (C ３ -C ７ ) cycloalkyl or 4- to 7-membered heterocycloalkyl is halogen, oxo, (C １ -C ４ ) alkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) haloalkyl, hydroxyl, cyano, -S(O) ２ (C １ -C ４ ) alkyl, =NH, =N(C １ -C ４ ) alkyl, -NH ２ , -N(H)(C １ -C ４ ) alkyl or -N((C １ -C ４ ) alkyl) ２ and is optionally substituted with one, two or three substituents independently selected from, and when p is 3 or 4, each remaining R ｏ is hydroxyl, halogen, oxo, cyano, -N((C １ -C ４ ) alkyl) ２ , (C １ -C ４ ) alkyl, (C １ -C ４ ) alkoxy, (C １ -C ４ ) haloalkyl or (C １ -C ４ ) haloalkoxy and is independently selected from, o is 2, 3, or 4. p is 0, 1, or 2. q is 0, 1, or 2. X ４ is N or C (R ４２ ) and R ４２ is hydrogen, halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Haloalkoxy, (C ２ ~C ６ ) Alkenil, (C ２ ~C ６ ) Alkinyl, -CN, (C １ ~C ６ ) Alkoxy, -S-(C １ ~C ６ ) alkyl or -S-(C １ ~C ６ ) is a haloalkyl, Y is a bond, O or NR ５ And, R ２ is hydrogen, -N(R ５ ), ２ (C ３ ~C １２ ) heterocyclyl, (C １ ~C ６ ) alkyl, -L-(C ３ ~C １２ ) heterocyclyl, -L-(C ６ ~C １４ ) aryl, -L-(C ５ ~C １４ ) heteroaryl, -L-(C ３ ~C １２ ) cycloalkyl, -L-N(R ５ ) ２ , -L-N(H)C(NH)NH ２ , -L-C(O)N(R ５ ) ２ , -L-(C １ ~C ６ ) haloalkyl, -L-OR ５ , -L-NR ５ C(O)-(C ６ ~C １４ ) aryl, -L-COOH or -L-C(O)O(C １ ~C ６ ) alkyl, wherein the (C ３ ~C<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ ５ ~C １４ ) A heteroaryl is one or more R ７ It is arbitrarily replaced with, L is hydroxy, (C １ ~C ４ ) Hydroxyalkyl or (C ５ ~C １４ ) optionally substituted with heteroaryls, (C １ ~C ４ ) is alkylene, R ３ teeth, 【Chemical Formula 657】 And, R ４ is hydrogen, halogen or (C １ ~C ３ ) is alkyl, Each R ５ These are, independently, hydrogen or (C １ ~C ３ ) is alkyl, Each R ６ These are, independently, halogen, hydroxyl, (C １ ~C ３ ) Hydroxyalkyl, (C １ ~C ３ ) alkyl, (C １ ~C ３ ) Haloalkyl, (C １ ~C ３ ) Alkoxy, cyano, -Q-phenyl, -Q-phenyl-SO ２ F,-N(H)C(O)-phenyl,-N(H)C(O)-phenyl-SO ２ F, (C １ ~C ３ ) alkyl-substituted pyrazole, (C ６ ~C １４ ) Aryl (C １ ~C ３ ) Alkyl, tert-butyldimethylsilyloxy-CH ２ -, -N(R ５ ) ２ , (C １ ~C ３ ) Alkoxy (C １ ~C ３ ) alkyl, (C １ ~C ３ ) Alkyl-C(O)-, oxo, (C １ ~C ３ ) Haloalkyl-C(O)-,-SO ２ F, (C １ ~C ３ ) Alkoxy (C １ ~C ３ ) Alkyl, -CH ２ OC(O)N(R) ５ ) ２ ien-CH ２ N(H)C(O)O-(C １ ~C ６ ) alkyl, -CH ２ N(H)C(O)N(R ５ ) ２ ien-CH ２ N(H)C(O)(C １ ~C ６ ) alkyl, -CH ２ (Pyrazolyl), -CH ２ N(H)S(O) ２ (C １ ~C ６ ) alkyl, -CH ２ OC(O)(C ３ ~C １２ ) Heterocyclyl, -OC(O)N(R ５ ) ２ , -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ ) Alkyl, -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ ) Alkyl-phenyl-(C １ ~C ３ ) Alkyl-N (CH ３ ) ２ , -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ ) Alkyl-phenyl, -OC(O)(C ３ ~C １２ ) Heterocyclyl or -CH ２ - (C ３ ~C １２ ) is a heterocyclyl, and the -N(H)C(O)phenyl and the -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ The phenyl in alkylphenyl is optionally substituted with -C(O)H or -OH, and the -CH ２ - (C ３ ~C １２ ) Heterocyclyl (C ３ ~C １２ ) Heterocyclyls are arbitrarily substituted with oxo, Q is a combination or O, Each R ７ These are independently halogen, hydroxyl, -C(O)H, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, (C １ ~C ４ ) Haloalkyl, (C １ ~C ４ ) Hydroxyalkyl or -N(R ５ ) ２ And, L' is either covalently bonded or a divalent saturated or unsaturated linear or branched carbon. １ ~C １５ It is a hydrocarbon chain, in which 0 to 5 methylene groups of L' are replaced by X. Each X is independently -O-, -N(R)-, -S-, -OC(O)-, -C(O)-, -C(H)(F)-, -C(F) ２ -, -Cy-, -S(O)-, -S(O) ２ -, -N(R)S(O) ２ -, -N(R)C(O)-, -OC(O)N(R)-, -N(R)C(O)N(R)-, 【Chemical Formula 658】 And, Each -Cy- is independently an optionally substituted divalent ring selected from a 4-7 member saturated or partially unsaturated carbocyclilenyl, a 4-11 member saturated or partially unsaturated spirocarbocyclilenyl, an 8-10 member bicyclic saturated or partially unsaturated carbocyclilenyl, a 4-7 member saturated or partially unsaturated heterocyclilenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 member saturated or partially unsaturated spiroheterocyclilenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 member bicyclic saturated or partially unsaturated heterocyclilenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Each R is independently hydrogen or (C １ ~C ３ ) is alkyl, r is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Degron is the cereblon binding site.

2. The compound according to claim 1, wherein Y is O.

3. R ２ However, -L-(C ３ ~C １２ ) is a heterocyclyl, and the -L-(C ３ ~C １２ ) Heterocyclyl (C ３ ~C １２ ) Heterocyclines have one or more R ６ The compound according to claim 1 or 2, which is optionally substituted with

4. The compound according to any one of claims 1 to 3, wherein L is methylene.

5. The compound of the following formula: 【Chemistry 659】 or a pharmaceutically acceptable salt thereof [in the formula, 【Chemical Formula 660】 teeth, 【Chemical Formula 661】 And, X ５ is O or CH ２ And, Two R's ｏ It combines with the same carbon atom, C ３－７ Forms a cycloalkyl or 4-7 member heterocycloalkyl, each (C ３ ~C ７ ) Cycloalkyl or 4-7 member heterocycloalkyl groups include halogens, oxo, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, (C １ ~C ４ ) Haloalkyl, hydroxyl, cyano, -S(O) ２ (C １ ~C ４ ) alkyl, =NH, =N(C １ ~C ４ ) alkyl, -NH ２ , -N(H)(C １ ~C ４ ) alkyl or -N((C １ ~C ４ )alkyl) ２ It is optionally substituted with one, two, or three substituents independently selected from, and if p is 3 or 4, then each of the remaining R ｏ is hydroxyl, halogen, oxo, cyano, -N((C １ ~C ４ )alkyl) ２ , (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, (C １ ~C ４ ) Haloalkyl or (C １ ~C ４ ) Selected independently from haloalkoxys, o is 2, 3, or 4. p is 0, 1, or 2. q is 0, 1, or 2. X ４ is N or C (R ４２ ) and R ４２ is hydrogen, halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Haloalkoxy, (C ２ ~C ６ ) Alkenil, (C ２ ~C ６ ) Alkinyl, -CN, (C １ ~C ６ ) Alkoxy, -S-(C １ ~C ６ ) alkyl or -S-(C １ ~C ６ ) is a haloalkyl, R １ (C) １ ~C ３ ) alkyl, (C １ ~C ３ ) cyanoalkyl, (C １ ~C ３ ) Hydroxyalkyl, -C(O)H, -CO ２ R ５ , -CO ２ N(R) ５ ) ２ or (C ５ ~C ６ ) is a heteroaryl, R ３ teeth, 【Chemical 662】 And, R ４ is hydrogen, halogen or (C １ ~C ３ ) is alkyl, Each R ５ These are, independently, hydrogen or (C １ ~C ３ ) is alkyl, Each R ６ These are, independently, halogen, hydroxyl, (C １ ~C ３ ) Hydroxyalkyl, (C １ ~C ３ ) alkyl, (C １ ~C ３ ) Haloalkyl, (C １ ~C ３ ) Alkoxy, cyano, -Q-phenyl, -Q-phenyl-SO ２ F,-N(H)C(O)-phenyl,-N(H)C(O)-phenyl-SO ２ F, (C １ ~C ３ ) alkyl-substituted pyrazole, (C ６ ~C １４ ) Aryl (C １ ~C ３ ) Alkyl, tert-butyldimethylsilyloxy-CH ２ -, -N(R ５ ) ２ , (C １ ~C ３ ) Alkoxy (C １ ~C ３ ) alkyl, (C １ ~C ３ ) Alkyl-C(O)-, oxo, (C １ ~C ３ ) Haloalkyl-C(O)-,-SO ２ F, (C １ ~C ３ ) Alkoxy (C １ ~C ３ ) Alkyl, -CH ２ OC(O)N(R) ５ ) ２ ien-CH ２ N(H)C(O)O-(C １ ~C ６ ) alkyl, -CH ２ N(H)C(O)N(R ５ ) ２ ien-CH ２ N(H)C(O)(C １ ~C ６ ) alkyl, -CH ２ (Pyrazolyl), -CH ２ N(H)S(O) ２ (C １ ~C ６ ) alkyl, -CH ２ OC(O)(C ３ ~C １２ ) Heterocyclyl, -OC(O)N(R ５ ) ２ , -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ ) Alkyl, -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ ) Alkyl-phenyl-(C １ ~C ３ ) Alkyl-N (CH ３ ) ２ , -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ ) Alkyl-phenyl, -OC(O)(C ３ ~C １２ ) Heterocyclyl or -CH ２ - (C ３ ~C １２ ) is a heterocyclyl, and the -N(H)C(O)phenyl and the -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ The phenyl in alkylphenyl is optionally substituted with -C(O)H or -OH, and the -CH ２ - (C ３ ~C １２ ) Heterocyclyl (C ３ ~C １２ ) Heterocyclyls are arbitrarily substituted with oxo, Q is a combination or O, R ２１ and R ２２ These are, independently, H, D, or F. n' is 1, 2, 3, or 4. R ２３ and R ２４ These are, independently, H, D, or F. L' is either covalently bonded or a divalent saturated or unsaturated linear or branched carbon. １ ~C １５ It is a hydrocarbon chain, in which 0 to 5 methylene groups of L' are replaced by X. Each X is independently -O-, -N(R)-, -S-, -OC(O)-, -C(O)-, -C(H)(F)-, -C(F) ２ -, -Cy-, -S(O)-, -S(O) ２ -, -N(R)S(O) ２ -, -N(R)C(O)-, -OC(O)N(R)-, -N(R)C(O)N(R)-, 【Chemical Formula 663】 And, Each -Cy- is independently an optionally substituted divalent ring selected from a 4-7 member saturated or partially unsaturated carbocyclilenyl, a 4-11 member saturated or partially unsaturated spirocarbocyclilenyl, an 8-10 member bicyclic saturated or partially unsaturated carbocyclilenyl, a 4-7 member saturated or partially unsaturated heterocyclilenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 member saturated or partially unsaturated spiroheterocyclilenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 member bicyclic saturated or partially unsaturated heterocyclilenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Each R is independently hydrogen or (C １ ~C ３ ) is alkyl, r is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Degron is the cereblon binding site.

6. The compound of the following formula: 【Chemical 664】 or a pharmaceutically acceptable salt thereof [in the formula, 【Chemical Formula 665】 teeth, 【Chemical Formula 666】 And, X ５ is O or CH ２ And, Two R's ｏ It combines with the same carbon atom, C ３－７ Forms a cycloalkyl or 4-7 member heterocycloalkyl, each (C ３ ~C ７ ) Cycloalkyl or 4-7 member heterocycloalkyl groups include halogens, oxo, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, (C １ ~C ４ ) Haloalkyl, hydroxyl, cyano, -S(O) ２ (C １ ~C ４ ) alkyl, =NH, =N(C １ ~C ４ ) alkyl, -NH ２ , -N(H)(C １ ~C ４ ) alkyl or -N((C １ ~C ４ )alkyl) ２ It is optionally substituted with one, two, or three substituents independently selected from, and if p is 3 or 4, then each of the remaining R ｏ is hydroxyl, halogen, oxo, cyano, -N((C １ ~C ４ )alkyl) ２ , (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, (C １ ~C ４ ) Haloalkyl or (C １ ~C ４ ) Selected independently from haloalkoxys, o is 2, 3, or 4. p is 0, 1, or 2. q is 0, 1, or 2. X ４ is N or C (R ４２ ) and R ４２ is hydrogen, halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Haloalkoxy, (C ２ ~C ６ ) Alkenil, (C ２ ~C ６ ) Alkinyl, -CN, (C １ ~C ６ ) Alkoxy, -S-(C １ ~C ６ ) alkyl or -S-(C １ ~C ６ ) is a haloalkyl, R １ (C) １ ~C ３ ) alkyl, (C １ ~C ３ ) cyanoalkyl, (C １ ~C ３ ) Hydroxyalkyl, -C(O)H, -CO ２ R ５ , -CO ２ N(R) ５ ) ２ or (C ５ ~C ６ ) is a heteroaryl, R ３ teeth, 【Chemical 667】 And, R ４ is hydrogen, halogen or (C １ ~C ３ ) is alkyl, Each R ５ These are, independently, hydrogen or (C １ ~C ３ ) is alkyl, Each R ６ These are, independently, halogen, hydroxyl, (C １ ~C ３ ) Hydroxyalkyl, (C １ ~C ３ ) alkyl, (C １ ~C ３ ) Haloalkyl, (C １ ~C ３ ) Alkoxy, cyano, -Q-phenyl, -Q-phenyl-SO ２ F,-N(H)C(O)-phenyl,-N(H)C(O)-phenyl-SO ２ F, (C １ ~C ３ ) alkyl-substituted pyrazole, (C ６ ~C １４ ) Aryl (C １ ~C ３ ) Alkyl, tert-butyldimethylsilyloxy-CH ２ -, -N(R ５ ) ２ , (C １ ~C ３ ) Alkoxy (C １ ~C ３ ) alkyl, (C １ ~C ３ ) Alkyl-C(O)-, oxo, (C １ ~C ３ ) Haloalkyl-C(O)-,-SO ２ F, (C １ ~C ３ ) Alkoxy (C １ ~C ３ ) Alkyl, -CH ２ OC(O)N(R) ５ ) ２ ien-CH ２ N(H)C(O)O-(C １ ~C ６ ) alkyl, -CH ２ N(H)C(O)N(R ５ ) ２ ien-CH ２ N(H)C(O)(C １ ~C ６ ) alkyl, -CH ２ (Pyrazolyl), -CH ２ N(H)S(O) ２ (C １ ~C ６ ) alkyl, -CH ２ OC(O)(C ３ ~C １２ ) Heterocyclyl, -OC(O)N(R ５ ) ２ , -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ ) Alkyl, -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ ) Alkyl-phenyl-(C １ ~C ３ ) Alkyl-N (CH ３ ) ２ , -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ ) Alkyl-phenyl, -OC(O)(C ３ ~C １２ ) Heterocyclyl or -CH ２ - (C ３ ~C １２ ) is a heterocyclyl, and the -N(H)C(O)phenyl and the -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ The phenyl in alkylphenyl is optionally substituted with -C(O)H or -OH, and the -CH ２ - (C ３ ~C １２ ) Heterocyclyl (C ３ ~C １２ ) Heterocyclyls are arbitrarily substituted with oxo, Q is a combination or O, R ２１ and R ２２ These are, independently, H, D, or F. n' is 1, 2, 3, or 4. R ２３ and R ２４ These are, independently, H, D, or F. L' is either covalently bonded or a divalent saturated or unsaturated linear or branched carbon. １ ~C １５ It is a hydrocarbon chain, in which 0 to 5 methylene groups of L' are replaced by X. Each X is independently -O-, -N(R)-, -S-, -OC(O)-, -C(O)-, -C(H)(F)-, -C(F) ２ -, -Cy-, -S(O)-, -S(O) ２ -, -N(R)S(O) ２ -, -N(R)C(O)-, -OC(O)N(R)-, -N(R)C(O)N(R)-, 【Chemical 668】 And, Each -Cy- is independently an optionally substituted divalent ring selected from a 4-7 member saturated or partially unsaturated carbocyclilenyl, a 4-11 member saturated or partially unsaturated spirocarbocyclilenyl, an 8-10 member bicyclic saturated or partially unsaturated carbocyclilenyl, a 4-7 member saturated or partially unsaturated heterocyclilenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 member saturated or partially unsaturated spiroheterocyclilenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 member bicyclic saturated or partially unsaturated heterocyclilenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Each R is independently hydrogen or (C １ ~C ３ ) is alkyl, r is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Degron is the cereblon binding site. 【Request Item 7】 【Chemistry 669】 but, 【Chemical 670】 The compound according to claim 6.

8. R １ The compound according to claim 7, wherein H is present. 【Request Item 9】 【Chemistry 671】 but, 【Transformation 672】 The compound according to claim 6. 【Request Item 10】 【Chemistry 673】 but, 【Transformation 674】 The compound according to any one of claims 1 to 9. 【Request Item 11】 【Chemistry 675】 but, 【Chemical 676】 The compound according to claim 10. 【Request Item 12】 【Chemistry 677】 but, 【Chemical Formula 678】 The compound according to claim 10. 【Request Item 13】 【Chemistry 679】 but, 【Chemical 680】 The compound according to any one of claims 1 to 9.

14. The compound of the following formula: 【Chemistry 681】 or a pharmaceutically acceptable salt thereof [in the formula, X ４ is N or C (R ４２ ) and R ４２ is hydrogen, halogen, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Haloalkyl, (C １ ~C ６ ) Haloalkoxy, (C ２ ~C ６ ) Alkenil, (C ２ ~C ６ ) Alkinyl, -CN, (C １ ~C ６ ) Alkoxy, -S-(C １ ~C ６ ) alkyl or -S-(C １ ~C ６ ) is a haloalkyl, R ３ teeth, 【Chemical Formula 682】 And, R ４ is hydrogen, halogen or (C １ ~C ３ ) is alkyl, Each R ５ These are, independently, hydrogen or (C １ ~C ３ ) is alkyl, Each R ６ These are, independently, halogen, hydroxyl, (C １ ~C ３ ) Hydroxyalkyl, (C １ ~C ３ ) alkyl, (C １ ~C ３ ) Haloalkyl, (C １ ~C ３ ) Alkoxy, cyano, -Q-phenyl, -Q-phenyl-SO ２ F,-N(H)C(O)-phenyl,-N(H)C(O)-phenyl-SO ２ F, (C １ ~C ３ ) alkyl-substituted pyrazole, (C ６ ~C １４ ) Aryl (C １ ~C ３ ) Alkyl, tert-butyldimethylsilyloxy-CH ２ -, -N(R ５ ) ２ , (C １ ~C ３ ) Alkoxy (C １ ~C ３ ) alkyl, (C １ ~C ３ ) Alkyl-C(O)-, oxo, (C １ ~C ３ ) Haloalkyl-C(O)-,-SO ２ F, (C １ ~C ３ ) Alkoxy (C １ ~C ３ ) Alkyl, -CH ２ OC(O)N(R) ５ ) ２ ien-CH ２ N(H)C(O)O-(C １ ~C ６ ) alkyl, -CH ２ N(H)C(O)N(R ５ ) ２ ien-CH ２ N(H)C(O)(C １ ~C ６ ) alkyl, -CH ２ (Pyrazolyl), -CH ２ N(H)S(O) ２ (C １ ~C ６ ) alkyl, -CH ２ OC(O)(C ３ ~C １２ ) Heterocyclyl, -OC(O)N(R ５ ) ２ , -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ ) Alkyl, -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ ) Alkyl-phenyl-(C １ ~C ３ ) Alkyl-N (CH ３ ) ２ , -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ ) Alkyl-phenyl, -OC(O)(C ３ ~C １２ ) Heterocyclyl or -CH ２ - (C ３ ~C １２ ) is a heterocyclyl, and the -N(H)C(O)phenyl and the -OC(O)N(H)(C １ ~C ３ ) Alkyl-O-(C １ ~C ３ The phenyl in alkylphenyl is optionally substituted with -C(O)H or -OH, and the -CH ２ - (C ３ ~C １２ ) Heterocyclyl (C ３ ~C １２ ) Heterocyclyls are arbitrarily substituted with oxo, Q is a combination or O, R ２１ and R ２２ These are, independently, H, D, or F. n' is 1, 2, 3, or 4. R ２３ and R ２４ These are, independently, H, D, or F. L' is either covalently bonded or a divalent saturated or unsaturated linear or branched carbon. １ ~C １５ It is a hydrocarbon chain, in which 0 to 5 methylene groups of L' are replaced by X. Each X is independently -O-, -N(R)-, -S-, -OC(O)-, -C(O)-, -C(H)(F)-, -C(F) ２ -, -Cy-, -S(O)-, -S(O) ２ -, -N(R)S(O) ２ -, -N(R)C(O)-, -OC(O)N(R)-, -N(R)C(O)N(R)-, 【Chemical Formula 683】 And, Each -Cy- is independently an optionally substituted divalent ring selected from a 4-7 member saturated or partially unsaturated carbocyclilenyl, a 4-11 member saturated or partially unsaturated spirocarbocyclilenyl, an 8-10 member bicyclic saturated or partially unsaturated carbocyclilenyl, a 4-7 member saturated or partially unsaturated heterocyclilenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 member saturated or partially unsaturated spiroheterocyclilenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 member bicyclic saturated or partially unsaturated heterocyclilenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Each R is independently hydrogen or (C １ ~C ３ ) is alkyl, r is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Degron is the cereblon binding site.

15. R ２１ and R ２２ The compound according to any one of claims 5 to 14, wherein each of them is H.

16. R ２３ and R ２４ The compound according to any one of claims 5 to 15, wherein each of them is H.

17. The compound according to any one of claims 5 to 16, wherein n' is 1.

18. X ４ The compound according to any one of claims 1 to 17, wherein N is present.

19. R ３ but, 【Chemical Formula 684】 The compound according to any one of claims 1 to 18.

20. R ３ but, 【Chemical 685】 The compound according to any one of claims 1 to 18.

21. R ３ but, 【Chemical 686】 The compound according to any one of claims 1 to 18.

22. R ４ The compound according to any one of claims 1 to 21, wherein the compound is a halogen.

23. R ４ The compound according to claim 22, wherein it is fluoro.

24. Each R ６ However, independently, deutero, halogen, hydroxy, (C １ ~C ３ ) Hydroxyalkyl, (C １ ~C ３ ) alkyl, (C １ ~C ３ ) Haloalkyl, (C １ ~C ３ The compound according to any one of claims 1 to 23, wherein it is an alkoxy or cyano compound.

25. L' is a divalent saturated or unsaturated linear or branched C １ ~C １５ It is a hydrocarbon chain in which one or two methylene groups of L' are replaced by Cy, and one to three methylene groups of L' are replaced by X, where, The compound according to any one of claims 1 to 24, wherein each X is independently -O-, -C(O)-, -N(R)-, or -N(R)C(O)-.

26. The compound according to claim 25, wherein each -Cy- is independently a 4-7 member saturated or partially unsaturated heterocyclenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 member saturated or partially unsaturated spiroheterocyclenyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 member bicyclic saturated or partially unsaturated heterocyclenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

27. The compound according to 26, wherein each -Cy- is a 4- to 7-membered saturated or partially unsaturated heterocyclenyl having one nitrogen atom and one additional heteroatom optionally selected from nitrogen, oxygen, and sulfur, a 4- to 11-membered saturated or partially unsaturated spiroheterocyclenyl having one nitrogen atom and one or two additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered bicyclic saturated or partially unsaturated heterocyclenyl having one nitrogen atom and one additional heteroatom independently selected from nitrogen, oxygen, and sulfur, and linked via a nitrogen atom.

28. The compound according to claim 25, wherein each -Cy- is independently selected from cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazine, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecarnylene, 3-azaspiro[5.5]undecarnylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, or 3,9-diazaspiro[5.5]undecarnylene.

29. L' is -Cy １ - (CH ２ ) ０－１ -X-(CH ２ ) ０－１ -Cy ２ -Includes, in the formula, Cy １ and Cy ２ The compound according to any one of claims 1 to 25, wherein each is independently -Cy-.

30. Cy １ The compound according to claim 29, wherein the compound is a 4-7 member saturated or partially unsaturated heterocyclenyl having one nitrogen atom and one additional heteroatom optionally selected from nitrogen, oxygen, and sulfur; a 4-11 member saturated or partially unsaturated spiroheterocyclenyl having one nitrogen atom and one or two additional heteroatoms optionally independently selected from nitrogen, oxygen, and sulfur; or an 8-10 member bicyclic saturated or partially unsaturated heterocyclenyl having one nitrogen atom and one additional heteroatom optionally independently selected from nitrogen, oxygen, and sulfur, linked via a nitrogen atom.

31. Cy １ The compound according to claim 30, wherein the compound is piperidinylene, azetidinylene, pyrrolidinylene, piperazine, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecarnylene, 3-azaspiro[5.5]undecarnylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, or 3,9-diazaspiro[5.5]undecarnylene.

32. Cy ２ The compound according to any one of claims 29 to 31, wherein the compound is cyclohexylene, piperidinylene, azetidinylene, pyrrolidinylene, piperazine, morpholinylene, 1-oxa-4,9-diazaspiro[5.5]undecarnylene, 3-azaspiro[5.5]undecarnylene, 2-azaspiro[3.3]heptanylene, 7-azaspiro[3.5]nonanylene, 3-azabicyclo[3.2.1]octanylene, 2,7-diazaspiro[3.5]nonanylene, or 3,9-diazaspiro[5.5]undecarnylene.

33. Degron, 【Chemical Formula 687】 The compound according to any one of claims 1 to 32, wherein one or more hydrogen atoms on the benzene ring of Degron are optionally replaced by fluorine atoms.

34. Degron, 【Chemical Formula 688】 The compound according to claim 33, wherein one or more hydrogen atoms on the benzene ring of Degron are optionally replaced by fluorine atoms.

35. Degron, 【Chemical 689】 The compound according to claim 33, wherein one or more hydrogen atoms on the benzene ring of Degron are optionally replaced by fluorine atoms.

36. The compounds listed in Table 2, or their pharmaceutically acceptable salts.

37. The compounds listed in Table 3, or their pharmaceutically acceptable salts.

38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

39. A combination of pharmaceuticals comprising a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 38, and at least one additional therapeutic agent.

40. A method for reducing the level or activity of KRAS in cells expressing KRAS, comprising contacting the cells with a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 38, or a combination of pharmaceuticals according to claim 39.

41. A method for reducing the level or activity of KRAS in a subject requiring a reduction in the level or activity of KRAS, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 38, or a combination of pharmaceuticals according to claim 39.

42. A method for treating KRAS-related cancer in a subject requiring treatment for KRAS-related cancer, comprising administering to the subject a therapeutically effective amount of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 38, or a combination of pharmaceuticals according to claim 39.

43. The method according to any one of claims 40 to 42, wherein the KRAS is KRAS G12D.

44. The method according to claim 42 or 43, wherein the cancer is a solid tumor carcinoma.

45. The method according to claim 42 or 43, wherein the cancer is a blood cancer.

46. The method according to claim 42 or 43, wherein the cancer is cardiac cancer, gastrointestinal cancer, urogenital tract cancer, liver cancer, biliary tract cancer, bone cancer, nervous system cancer, gynecological cancer, hematological cancer, skin cancer, or adrenal cancer.

47. The method according to claim 42 or 43, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

48. The method according to any one of claims 42 to 47, further comprising determining that the subject has KRAS-related cancer.

49. The method according to any one of claims 41 to 48, further comprising administering at least one additional therapeutic agent to the subject.

50. The method according to claim 49, wherein the at least one additional therapeutic agent comprises a receptor tyrosine kinase (RTK) inhibitor.

51. The method according to claim 50, wherein the RTK inhibitor is selected from epidermal growth factor receptor (EGFR) inhibitors, vascular endothelial growth factor receptor (VEGFR) inhibitors, anaplastic lymphoma kinase (ALK) inhibitors, RET proto-oncogene inhibitors, ROS proto-oncogene inhibitors, fibroblast growth factor receptor (FGFR) inhibitors, neurotrophic tyrosine receptor kinase (NTRK) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, FMS-like tyrosine kinase 3 (FLT3), or platelet-derived growth factor receptor (PDGF-R) inhibitors.

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