Rapidly Progressive Fibrosarcoma Proteolytic Compounds and Related Methods of Use

Abstract

This provides effective treatment for RAF-related diseases and disorders. [Solution] This specification describes bifunctional compounds that have been found useful as regulators of rapidly progressive fibrosarcomas (Rafs such as c-Raf, A-Raf, and / or B-Raf). Specifically, the heterobifunctional compounds of this disclosure include a portion that binds to cereblon E3 ubiquitin ligase on one end and a portion that binds to Raf on the other end, such that the target protein is positioned in close proximity to the ubiquitin ligase, resulting in the degradation (and inhibition) of the target protein. The heterobifunctional compounds of this disclosure exhibit a broad range of pharmacological activity related to the degradation / inhibition of target proteins. Diseases or disorders resulting from abnormal regulation of target proteins are treated or prevented using the compounds and compositions of this disclosure.

Claims

1. Chemical structure: A heterobifunctional compound having PTM-L-CLM, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, (a) L is a chemical linker group that is covalently bonded to CLM or PTM, (b) The PTM is a small molecule rapidly progressive fibrosarcoma (Raf) targeting portion, represented by its chemical structure, 【Chemistry 1】 During the ceremony, X ＰＴＭ１ , X ＰＴＭ２ , X ＰＴＭ３ , X ＰＴＭ４ , X ＰＴＭ５ or X ＰＴＭ６ Each of these is independently selected from CH or N. R ＰＴＭ５ but, Optionally substituted alkyl, optionally substituted cycloalkyl, -NR ＰＴＭ５ｃ R ＰＭＴ５ｄ , 【Chemistry 2】 Selected from the group consisting of, R ＰＴＭ５ｃ and R ＰＭＴ５ｄ Each of these is independently selected from H, an optionally substituted alkyl (e.g., linear or branched, optionally substituted with one, two, or three halogens or hydroxyls), or R ＰＴＭ５ｃ , R ＰＭＴ５ｄ , and the nitrogen to which they are attached forms optionally substituted 4-6 member heterocycloalkyls (for example, optionally substituted 5 member heterocycloalkyls, or combinations thereof, which are optionally substituted with one, two, or three halogens or hydroxyls), R ＰＴＭ６ａ and R ＰＴＭ６ｂ However, independently, halogens (e.g., F, Cl, or Br), C1-C3 alkoxys (e.g., methoxy or ethoxy), C1-C3 haloalkyls (e.g., CF ３ ), or C1-C3 alkyl (for example, methyl or ethyl), R ＰＴＭ６ , R ＰＴＭ７ , R ＰＴＭ８ , and R ＰＴＭ１１ Each of these independently exists as: non-existent (bonded), hydrogen, halogen (e.g., F, Cl, or Br), CN, -NR ＰＴＭ１２ R ＰＭＴ１３ , or C1-C3 alkyl (e.g., methyl or ethyl), R ＰＴＭ９ and R ＰＴＭ１０ Each of these independently produces hydrogen, halogens (e.g., F, Cl, or Br), CN, and -NR ＰＴＭ１２ R ＰＭＴ１３ , or C1-C3 alkyl (e.g., methyl or ethyl), or R ＰＴＭ９ , R ＰＴＭ１０ , and the rings to which they are attached form a 5-7 membered (e.g., 6 membered) cycloalkyl or heterocycloalkyl group, which is optionally substituted with one or two groups selected from a halogen (e.g., F, Cl, or Br) and a C1-C3 alkyl group (e.g., methyl or ethyl). R ＰＴＭ１２ and R ＰＴＭ１３ Each of these is independently either absent (bonded), hydrogen, or a C1-C3 alkyl group (e.g., methyl or ethyl). R ＰＴＭ７ , R ＰＴＭ８ , R ＰＴＭ９ , R ＰＴＭ１０ , R ＰＴＭ１１ , or R ＰＴＭ９ and R ＰＴＭ１０ One of the cycloalkyl or heterocycloalkyl groups formed from is modified to be covalently bonded to a chemical linker group (L) or CLM. (c) The CLM is a small molecule that binds to cereblon E3 ubiquitin ligase, and is represented by its chemical structure. 【Transformation 3】 Represented by, During the ceremony, Q １ Q ２ Q ３ Q ４ Q ５ Each of these independently represents a C or N substituted with a group selected from R, R', NRR', or N-oxide. X' is N or C, W is the base CH ２ , or selected from C=O, A is H or linear or branched C １～３ Alkyl (for example, methyl or ethyl), n is an integer between 1 and 2, G is H or a linear or branched C １～３ It is alkyl (for example, methyl), Each R independently corresponds to H, O, OH, N, NH, NH ２ -Cl, -F, -Br, linear or branched C １～３ Alkyl (e.g., methyl or ethyl), or linear or branched C １～３ Selected from alkoxy groups (e.g., methoxy or ethoxy), one R is modified so as to be covalently bonded to the PTM via a chemical linker group (L). R ４ However, it is H or methyl, R' is H, halogen (e.g., F, Cl, Br), C １～３ Alkyl (e.g., methyl or ethyl), or C １～３ Alkoxy (e.g., methoxy or ethoxy), 【Chemistry 4】 However, it is either a single bond or a double bond. 【Transformation 5】 However, a heterobifunctional compound, or a pharmaceutically acceptable salt or solvate thereof, representing a bond that may be stereospecific ((R) or (S)) or non-stereospecific.

2. Chemical structure: A heterobifunctional compound having PTM-L-CLM, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, (a) L is a chemical linker group that is covalently bonded to CLM or PTM, (b) The PTM is a small molecule rapidly progressive fibrosarcoma (Raf) targeting moiety, and its chemical structure is: 【Transformation 6】 【change】 Represented by, During the ceremony, X ＰＴＭ１ , X ＰＴＭ２ , X ＰＴＭ３ , X ＰＴＭ４ , X ＰＴＭ５ or X ＰＴＭ６ Each of these is independently selected from CH or N. R ＰＴＭ５ but, Optionally substituted alkyl groups, optionally substituted cycloalkyl groups, -NR ＰＴＭ５ｃ R ＰＭＴ５ｄ , 【Transformation 7】 Selected from the group consisting of, R ＰＴＭ５ｃ and R ＰＭＴ５ｄ Each of these is independently selected from H, an optionally substituted alkyl (e.g., linear or branched, optionally substituted with one, two, or three halogens or hydroxyls), or R ＰＴＭ５ｃ , R ＰＭＴ５ｄ , and the nitrogen to which they are attached forms optionally substituted 4-6 member heterocycloalkyls (for example, optionally substituted 5 member heterocycloalkyls, or combinations thereof, which are optionally substituted with one, two, or three halogens or hydroxyls), R ＰＴＭ６ａ and R ＰＴＭ６ｂ However, independently, halogens (e.g., F, Cl, or Br), C1-C3 alkoxys (e.g., methoxy or ethoxy), C1-C3 haloalkyls (e.g., CF ３ ), or C1-C3 alkyl (for example, methyl or ethyl), R ＰＴＭ６ , R ＰＴＭ７ , R ＰＴＭ８ , and R ＰＴＭ１１ Each of these independently exists as: non-existent (bonded), hydrogen, halogen (e.g., F, Cl, or Br), CN, -NR ＰＴＭ１２ R ＰＭＴ１３ , or C1-C3 alkyl (e.g., methyl or ethyl), R ＰＴＭ９ and R ＰＴＭ１０ Each of these independently produces hydrogen, halogens (e.g., F, Cl, or Br), CN, and -NR ＰＴＭ１２ R ＰＭＴ１３ , or C1-C3 alkyl (e.g., methyl or ethyl), or R ＰＴＭ９ , R ＰＴＭ１０ , and the rings to which they are attached form a 5-7 membered (e.g., 6 membered) cycloalkyl or heterocycloalkyl group, which is optionally substituted with one or two groups selected from a halogen (e.g., F, Cl, or Br) and a C1-C3 alkyl group (e.g., methyl or ethyl). ＰＴＭ１２ and R ＰＴＭ１３ Each of these is independently either absent (bonded), hydrogen, or a C1-C3 alkyl group (e.g., methyl or ethyl). R ＰＴＭ７ , R ＰＴＭ８ , R ＰＴＭ９ , R ＰＴＭ１０ , R ＰＴＭ１１ , or R ＰＴＭ９ and R ＰＴＭ１０ One of the cycloalkyl or heterocycloalkyl groups formed from is modified to be covalently bonded to a chemical linker group (L) or CLM. (c) The CLM is a small molecule that binds to cereblon E3 ubiquitin ligase, and is represented by its chemical structure. 【Transformation 8】 Represented by, During the ceremony, Q １ 、Q ２ 、Q ３ 、Q ４ 、Q ５ each independently represents C or N substituted with a group selected independently from R, R', NRR', or an N-oxide, X' is N or C, W is the base CH ２ , or selected from C=O, A is H or linear or branched C １～３ Alkyl (for example, methyl or ethyl), n is an integer between 1 and 2, G is H or a linear or branched C １～３ It is alkyl (for example, methyl), Each R is independently H, O, OH, N, NH, NH ２ , -Cl, -F, -Br, linear or branched C １～３ alkyl (e.g., methyl or ethyl), or linear or branched C １～３ alkoxy (e.g., methoxy or ethoxy), and one R is modified to be covalently bonded to the PTM via a chemical linker group (L). R ４ However, it is H or methyl, R' is H, halogen (e.g., F, Cl, Br), C １～３ Alkyl (e.g., methyl or ethyl), or C １～３ Alkoxy (e.g., methoxy or ethoxy), 【Chemistry 9】 However, it is either a single bond or a double bond. 【Chemistry 10】 However, a heterobifunctional compound, or a pharmaceutically acceptable salt or solvate thereof, representing a bond that may be stereospecific ((R) or (S)) or non-stereospecific.

3. Chemical structure: A heterobifunctional compound having PTM-L-CLM, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, (a) L is a chemical linker group that is covalently bonded to CLM or PTM, (b) The PTM is a small molecule rapidly progressive fibrosarcoma (Raf) targeting portion, represented by its chemical structure, 【Chemistry 11】 During the ceremony, X ＰＴＭ１ , X ＰＴＭ２ , X ＰＴＭ３ , X ＰＴＭ４ , X ＰＴＭ５ or X ＰＴＭ６ Each of these is independently selected from CH or N. R ＰＴＭ５ but, Optionally substituted alkyl groups, optionally substituted cycloalkyl groups, -NR ＰＴＭ５ｃ R ＰＭＴ５ｄ , 【Chemistry 12】 Selected from the group consisting of, R ＰＴＭ５ｃ and R ＰＭＴ５ｄ Each of these is independently selected from H, an optionally substituted alkyl (e.g., linear or branched, optionally substituted with one, two, or three halogens or hydroxyls), or R ＰＴＭ５ｃ , R ＰＭＴ５ｄ , and the nitrogen to which they are attached forms optionally substituted 4-6 member heterocycloalkyls (for example, optionally substituted 5 member heterocycloalkyls, or combinations thereof, which are optionally substituted with one, two, or three halogens or hydroxyls), R ＰＴＭ６ａ and R ＰＴＭ６ｂ However, independently, halogens (e.g., F, Cl, or Br), C1-C3 alkoxys (e.g., methoxy or ethoxy), C1-C3 haloalkyls (e.g., CF ３ ), or C1-C3 alkyl (for example, methyl or ethyl), R ＰＴＭ６ , R ＰＴＭ７ , R ＰＴＭ８ , and R ＰＴＭ１１ Each of these independently exists as: non-existent (bonded), hydrogen, halogen (e.g., F, Cl, or Br), CN, -NR ＰＴＭ１２ R ＰＭＴ１３ , or C1-C3 alkyl (e.g., methyl or ethyl), R ＰＴＭ９ and R ＰＴＭ１０ Each of these independently produces hydrogen, halogens (e.g., F, Cl, or Br), CN, and -NR ＰＴＭ１２ R ＰＭＴ１３ , or C1-C3 alkyl (e.g., methyl or ethyl), or R ＰＴＭ９ , R ＰＴＭ１０ , and the rings to which they are attached form a 5-7 membered (e.g., 6 membered) cycloalkyl or heterocycloalkyl group, which is optionally substituted with one or two groups selected from a halogen (e.g., F, Cl, or Br) and a C1-C3 alkyl group (e.g., methyl or ethyl). R ＰＴＭ１２ and R ＰＴＭ１３ Each of these is independently either absent (bonded), hydrogen, or a C1-C3 alkyl group (e.g., methyl or ethyl). R ＰＴＭ７ , R ＰＴＭ８ , R ＰＴＭ９ , R ＰＴＭ１０ , R ＰＴＭ１１ , or R ＰＴＭ９ and R ＰＴＭ１０ One of the cycloalkyl or heterocycloalkyl groups formed from is modified to be covalently bonded to a chemical linker group (L) or CLM. (c) The CLM is a small molecule that binds to cereblon E3 ubiquitin ligase, and is represented by its chemical structure. (i) 【Chemistry 13】 【change】 It is expressed by, in the formula, Q １ Q ２ Q ３ Q ４ Q ５ Each of these independently represents a C or N substituted with a group selected from R, R', NRR', or N-oxide. X' is N or C, W is the base CH ２ , or selected from C=O, A is H or linear or branched C １～３ Alkyl (for example, methyl or ethyl), n is an integer between 1 and 2, G is H or a linear or branched C １～３ It is alkyl (for example, methyl), Each R independently corresponds to H, O, OH, N, NH, NH ２ -Cl, -F, -Br, linear or branched C １～３ Alkyl (e.g., methyl or ethyl), or linear or branched C １～３ Selected from alkoxy groups (e.g., methoxy or ethoxy), one R is modified so as to be covalently bonded to the PTM via a chemical linker group (L). R ４ However, it is H or methyl, R' is H, halogen (e.g., F, Cl, Br), C １～３ Alkyl (e.g., methyl or ethyl), or C １～３ Alkoxy (e.g., methoxy or ethoxy), 【Chemistry 14】 However, it is either a single bond or a double bond. 【Chemistry 15】 However, a heterobifunctional compound, or a pharmaceutically acceptable salt or solvate thereof, representing a bond that may be stereospecific ((R) or (S)) or non-stereospecific.

4. The aforementioned PTM is represented by its chemical structure, 【Chemistry 16】 During the ceremony, X ＰＴＭ７ and X ＰＴＭ８ However, they are independently selected from CH and N, R ＰＴＭ１２ However, it is hydrogen, a halogen (e.g., F, Cl, or Br), or a C1-C3 alkyl (e.g., methyl or ethyl), R ＰＴＭ１３ However, it is hydrogen, a halogen (e.g., F, Cl, or Br), or a C1-C3 alkyl (e.g., methyl or ethyl), R ＰＴＭ８ , R ＰＴＭ１２ , or R ＰＴＭ１３ The compound according to claim 1, wherein one of the compounds is modified to be covalently bonded to a chemical linker group (L) or CLM.

5. The compound has the following chemical structure: 【Chemistry 17】 【change】 【change】 【change】 It is expressed by, in the formula, R' is H, halogen (e.g., F, Cl, Br), C １～３ Alkyl (e.g., methyl or ethyl), or C １～３ The compound according to claim 1 or 4, wherein the compound is an alkoxy (e.g., methoxy or ethoxy) and is modified such that R' is covalently bonded to the PTM via a chemical linker group (L).

6. Compounds are represented by their chemical structure. [Chemistry 18] 【change】 The compound according to claim 2, represented by [the given expression].

7. The compound has the following chemical structure: 【Chemistry 19】 【change】 It is expressed as follows, where each R is independently H, O, OH, N, NH, NH ２ -Cl, -F, -Br, linear or branched C １～３ Alkyl (e.g., methyl or ethyl), or linear or branched C １～３ The compound according to claim 3, selected from alkoxys (e.g., methoxy or ethoxy), wherein one R is modified so as to be covalently bonded to the PTM via a chemical linker group (L).

8. The aforementioned PTM has the following chemical structure: 【Chemistry 20】 【change】 【change】 It is expressed by, in the formula, 【change】 The compound according to any one of claims 1 to 4, wherein the PTM is attached to a chemical linker group (L) or CLM.

9. The aforementioned PTM has a chemical structure, 【Chemistry 21】 【change】 【change】 【change】 【change】 It is expressed by, in the formula, 【change】 The compound according to claim 2, wherein the PTM is attached to a chemical linker group (L) or CLM.

10. The PTM has a chemical structure, 【Chemistry 22】 【change】 【change】 【change】 【change】 During the ceremony, 【Chemistry 23】 The compound according to any one of claims 1, 4, 5, or 8, wherein the PTM is attached to a chemical linker group (L) or CLM.

11. The aforementioned PTM has the following chemical structure: 【Chemistry 24】 【change】 【change】 【change】 During the ceremony, 【Chemistry 25】 The compound according to any one of claims 2, 6, or 9, wherein the PTM is attached to a chemical linker group (L) or CLM.

12. The aforementioned PTM has the following chemical structure: 【Chemistry 26】 【change】 【change】 【change】 During the ceremony, 【Chemistry 27】 The compound according to claim 3 or 7, wherein the PTM is attached to a chemical linker group (L) or CLM.

13. The aforementioned CLM 【Chemistry 28】 【change】 It has a chemical structure represented by, During the ceremony, X' is N, C, or CH, A is H or linear or branched C １～３ Alkyl (for example, methyl or ethyl), G is H or a linear or branched C １～３ It is alkyl (for example, methyl), One R is hydrogen, and the other R is H, O, OH, N, NH, NH ２ -Cl, -F, -Br, linear or branched C １～３ Alkyl (e.g., methyl or ethyl), or linear or branched C １～３ It is an alkoxy (e.g., methoxy or ethoxy), and R' is H, a halogen (e.g., F, Cl, Br), or C １～３ Alkyl (e.g., methyl or ethyl), or C １～３ Alkoxy (e.g., methoxy or ethoxy), 【Chemistry 29】 However, this represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific, N* is (i) covalently bonded to the PTM via the chemical linker group (L) having H or methyl completion value, or (ii) a nitrogen atom shared with the chemical linker group (L) (for example, a heteroatom shared with an optionally substituted heterosiloalkyl of the chemical linker group (L)), 【Transformation 30】 However, it is either a single bond or a double bond. 【Chemistry 31】 The compound according to any one of claims 1, 2, 4-6, or 8-11, wherein the compound shows a PTM attachment site via a chemical linker group.

14. The aforementioned CLM 【Chemistry 32】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 It has a chemical structure represented by, The compound according to any one of claims 1, 2, 4-6, 8-11, or 13, wherein N* is (i) covalently bonded to the PTM via the chemical linker group (L) having H or methyl completion value, or (ii) a nitrogen atom shared with the chemical linker group (L) (for example, a heteroatom shared with an optionally substituted heterosiloalkyl of the chemical linker group (L)).

15. The aforementioned CLM 【Transformation 33】 【change】 【change】 【change】 【change】 【change】 【change】 It has a chemical structure represented by, The compound according to any one of claims 3, 7, or 12, wherein N* is (i) covalently bonded to the PTM via the chemical linker group (L) having H or methyl completion value, or (ii) a nitrogen atom shared with the chemical linker group (L) (for example, a heteroatom shared with an optionally substituted heterosiloalkyl of the chemical linker group (L)).

16. The aforementioned chemical linker group (L) is represented by the following chemical structure: 【Transformation 34】 【change】 Includes, During the ceremony, Y Ｌ２ However, bond, O, N-C1~C6 alkyl, 【Chemistry 35】 4-6 member cycloalkyl, 4-6 member heterocycloalkyl, 4-6 member heterocycloalkyl-C １～２ Alkyl, unsubstituted or substituted linear or branched C1-C6 alkyl (e.g., optionally substituted C1-C4 alkyl and / or one or more (e.g., one, two, or three) halogens (e.g., F, Cl, Br), OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl, or ethyl, optionally substituted), unsubstituted or substituted linear or branched C2-C6 alkenyl (e.g., optionally substituted C2-C4 alkenyl and / or one or more (e.g., one, two, or three) halogens) The alkyl, alkenyl, and alkyl are each optionally substituted with O, NH, or NCH ３ It has one or more C atoms that have been replaced by, W Ｌ３ However, each has 0 to 4 heteroatoms and is optionally substituted with one or more (e.g., one, two, or three) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl, or ethyl, and is a 3- to 7-membered ring (e.g., a 4- to 6-membered cycloalkyl or heterocycloalkyl), an 8- to 12-membered spiro ring, or an 8- to 10-membered non-aromatic bicyclic group. Y Ｌ３ However, bond or C1-C6 alkyl (C １ , C ２ , C ３ , C ４ , C ５ , or C ６ It is an alkyl group in which one or more C atoms are optionally replaced by O, and each carbon is optionally replaced by one or more (e.g., one, two, or three) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl, or ethyl. Y Ｌ４ However, it is bonded, O, or unsubstituted or substituted linear or branched C1-C4 alkyl, and one or more carbons are O, NH, or NCH ３ It can be optionally replaced with one or more (for example, one, two, or three) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl, or ethyl, Each W Ｌ４ However, it is a 3-8 membered cycloalkyl or heterocycloalkyl (e.g., a 4-6 membered cycloalkyl or heterocycloalkyl) having 0-4 heteroatoms and optionally substituted with one or more (e.g., one, two, or three) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl, or ethyl. Y Ｌ５ However, it is a bonded, or unsubstituted or substituted C1-C3 alkyl, where one or two C atoms are optionally replaced with O, and are optionally substituted with one or more (e.g., one, two, or three) halogens, OH, C1-C3 alkyl, C1-C2 hydroxyalkyl, methyl, or ethyl. W Ｌ５ The compound according to any one of claims 1 to 15, wherein the compound is a 5-6 membered aromatic ring having 0 to 4 heteroatoms.

17. The aforementioned chemical linker group (L) 【Transformation 36】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 It has a chemical structure represented by, During the ceremony, 【Chemistry 37】 However, this indicates a site that is covalently bonded to the CLM or PTM, The compound according to any one of claims 1 to 16, wherein * indicates a site that is covalently bonded to the CLM or PTM, or is an atom shared with the CLM or PTM.

18. The aforementioned chemical linker group (L) 【Transformation 38】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 Represented by, During the ceremony, 【Chemistry 39】 However, this indicates a site that is covalently bonded to the CLM or PTM, The compound according to any one of claims 1 to 17, wherein * indicates a site that is covalently bonded to the CLM or PTM, or is an atom shared with the CLM or PTM.

19. The aforementioned chemical linker group (L) 【Chemistry 40】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 Represented by, During the ceremony, 【Chemistry 41】 However, this indicates a site that is covalently bonded to the CLM or PTM, The compound according to any one of claims 1 to 18, wherein * indicates a site which is an atom covalently bonded to or shared with the CLM or PTM.

20. The PTM is selected from the compounds in Table 1. The CLM is selected from the compounds in Table 1, and The compound according to any one of claims 1 to 3, wherein L is at least one of L selected from the compounds in Table 1.

21. The aforementioned compound is a group consisting of compounds 1 to 200 in Table 1: 【Chemistry 42】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 （２００） A compound according to claim 1, selected from the following.

22. The aforementioned compound is a group consisting of compounds 201 to 212 in Table 1: 【Chemistry 43】 【change】 【change】 【change】 A compound according to claim 2, selected from the above.

23. The aforementioned compound is a group consisting of compounds 213 to 380 in Table 1: 【Chemistry 44-1】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound according to claim 3, selected from the above.

24. The aforementioned compounds are compounds 3, 4, 6, 7, 9, 10, 11, 12, 16, 18, 19, 20, 21, 22, 24, 25, 26, 28, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 80, 81, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 97, 98, 99, 100, 101, 103, 104, 105, 106, 107, 108, 109, 110, 111, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123 ,124,125,126,127,128,129,130,131,132,133,134,135,137,138,139,140,141,142,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,160,161,163,164,165,166,167,168, A compound according to claim 1 or 2, selected from the group consisting of 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 182, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 198, 199, 201, 202, 203, 204, 205, 206, and 207.

25. The compound according to claim 1 or 2, wherein the compound is selected from the group consisting of compounds 6, 12, 13, 18, 24, 26, 27, 28, 33, 41, 57, 58, 62, 75, 78, 80, 83, 85, 87, 88, 89, 90, 92, 93, 102, 104, 111, 118, 119, 127, 138, 144, 153, 160, 177, 190, 201, 202, 203, and 204 of Table 1.

26. A composition comprising an effective amount of a bifunctional compound according to any one of claims 1 to 23 and a pharmaceutically acceptable carrier.

27. The composition according to claim 26, wherein the composition further comprises at least one of an additional bioactive agent or a second bifunctional compound selected from any of claims 1 to 15.

28. The composition according to claim 27, wherein the additional biological agent is an anticancer agent.

29. A composition comprising a pharmaceutically acceptable carrier for treating a disease, disorder, or symptom incidentally associated with RAF in a subject, and an effective amount of at least one compound according to any one of claims 1 to 28, wherein the composition is effective in treating or improving the disease, disorder, or at least one symptom of the disease or disorder.

30. The composition according to claim 29, wherein the disease or disorder is cancer, cardiac-facial-skin syndrome, neurofibromatosis type 1, Costello syndrome, Noonan syndrome, or moles, electrocardiogram abnormalities, binocular eccentricity, pulmonary valve stenosis, genital abnormalities, developmental delay, or hearing loss (LEOPARD) syndrome.

31. The composition according to claim 30, wherein the cancer is renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, or melanoma.

32. A compound selected from the group consisting of compounds 213 to 380 in Table I.

33. The compound according to claim 1, wherein the compound is selected from the group consisting of compounds 213, 219-221, 223-225, 227, 228-245, 247-264, 268-271, 276, 278, 280, 281, 283-287, 295-301, 303, 305, 307, 310-312, 319, 320, 325, 326, 328, 329, 331, 334, 337, 339, 340, 342, 343, 345-347, 351, 352, 354, 357-359, 361, 362, 364-370, and 373-380.

34. A method for treating or preventing a disease, disorder, or symptom associated with RAF, comprising providing a therapeutically effective amount of a compound described herein or a composition comprising the compound thereof to a patient in need of treatment or prevention, and administering the said patient, wherein the compound or composition is effective in treating or improving the disease, disorder, or at least one symptom of the said disease or disorder.

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