RAS inhibitors

JP2022553857A5Active Publication Date: 2025-04-07REVOLUTION MEDICINES INC
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Patent Information

Application Number
JP2022526198
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2020-06-24
Filing Date
2020-11-04
Publication Date
2025-04-07
Estimated Expiration
2040-11-04

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Abstract

This disclosure features macrocyclic compounds capable of inhibiting the Ras protein, as well as pharmaceutical compositions and protein conjugates thereof, and their use in cancer treatment.
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Claims

Claim 1. The structure of formula Ie: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, In the formula, A is -N(H or CH ３ )C(O)-(CH ２ )—[wherein the amino nitrogen is —CH(R １０ )—, or an optionally substituted 6-membered arylene; B is -CH(R ９ )-, where the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or has the structure of formula II: A 1 - (B 1 ) f - (C 1 ) g - (B 2 ) h - (D 1 ) - (B 3 ) i - (C 2 ) j - (B 4 ) k - A 2 Formula II wherein A 1 is the bond between the linker and B; A 2 is the bond between W and the linker; B 1 , B 2 , B 3 , and B 4 are each independently selected from optionally substituted C 1 -C 2 alkylene, optionally substituted C 1 -C 3 heteroalkylene, O, S, and NR N ; R N is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted C 1 -C 7 heteroalkyl; are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; D 1 is an optionally substituted C 1 -C 10 alkylene, an optionally substituted C 2 -C 10 alkenylene, an optionally substituted C 2 -C 10 alkynylene, an optionally substituted 3- to 14-membered heterocycloalkylene, an optionally substituted 5- to 10-membered heteroarylene, an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 6- to 10-membered arylene, an optionally substituted C 2 -C 10 polyethyleneglycolene, or an optionally substituted C 1 -C 10 heteroalkylene, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h - is -(B 3) i -(C 2 ) j -(B 4 ) k -A 2 , W is a bridging group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethylcarbamate, a chloroethylthiocarbamate, an aziridine, a trifluoromethylketone, a boronic acid, a boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, an epoxide, an oxazolium, or a glycal; R ２ is C １ -C ６ alkyl or 3-6 membered cycloalkyl; R ７ is C １ -C ３ is alkyl, R ８ is C １ -C ３ is alkyl, and R ９ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; X ｅ and X ｆ is independently N or CH, and R １２ is an optionally substituted C １ -C ６ Alkyl or optionally substituted C １ -C ６ heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; The compound, or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein A is an optionally substituted 6-membered arylene.

3. B is -CHR ９ 3. The compound according to claim 1 or 2, wherein: -, or a pharma- ceutically acceptable salt thereof.

4. R ９ is optionally substituted C １ -C ６ 4. The compound of claim 3, wherein R is an alkyl, or an optionally substituted 3-6 membered cycloalkyl, or a pharma- ceutically acceptable salt thereof.

5. 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein B is an optionally substituted 6-membered arylene.

6. 6. The compound of any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein the linker is acyclic.

7. The linker has the structure of Formula IIa: 【Chemistry 2】 [In the formula, X ａ is absent or is N, R １４ is absent, hydrogen, or optionally substituted C １ -C ６ is alkyl, and L ２ does not exist or -SO ２ -, optionally substituted C １ -C ４ Alkylene, or optionally substituted C １ -C ４ is heteroalkylene, X ａ , R １４ , or L ２ At least one of the following is present.

7. The compound of claim 6, having the formula: or a pharma- ceutically acceptable salt thereof.

8. Any one of claims 1 to 5, wherein the linker is or comprises a cyclic group. or a pharma- ceutically acceptable salt thereof.

9. The linker has the structure of formula IIb: 【Chemistry 3】 [In the formula, o is 0 or 1, R １５ is hydrogen or an optionally substituted C １ -C ６ is alkyl, Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heterocycloalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; and L ３ does not exist or -SO ２ -, optionally substituted C １ -C ４ Alkylene, or optionally substituted C １ -C ４ is heteroalkylene.

9. The compound of any one of claims 1 to 5, or 8, having the formula: or a pharma- ceutically acceptable salt thereof.

10. 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein W comprises a carbodiimide.

11. W has the structure of formula IIIa: 【Chemistry 4】 [In the formula, R １４ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl.

11. The compound of claim 10, having the formula: or a pharma- ceutically acceptable salt thereof.

12. 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein W comprises an oxazoline or a thiazoline.

13. W has the structure of formula IIIb: 【Chemistry 5】 [In the formula, X １ is O or S, X ２ is not present or NR １９ and R １５ , R １６ , R １７ , and R １８ are independently hydrogen or optionally substituted C １ -C ６ is alkyl, and R １９ is hydrogen, C(O) (optionally substituted C １ -C ６ alkyl), optionally substituted C １ -C ６ alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl.

13. The compound of claim 12, having the formula: or a pharma- ceutically acceptable salt thereof.

14. 10. The compound of any one of claims 1 to 9, wherein W comprises chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, or chloroethyl thiocarbamate, or a pharma- ceutically acceptable salt thereof.

15. W has the structure of formula IIIc: 【Chemistry 6】 [In the formula, X ３ is O or S, X ４ is O, S, or NR ２６ and R ２１ , R ２２ , R ２３ , R ２４ , and R ２６ are independently hydrogen or optionally substituted C １ -C ６ is alkyl, and R ２５ is hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl.

15. The compound of claim 14, having the formula: or a pharma- ceutically acceptable salt thereof.

16. 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein W comprises aziridine.

17. W has the structure of formula IIId1, IIId2, IIId3, or IIId4: 【Chemistry 7】 [In the formula, X ５ is not present or NR ３０ and Y is absent or is C(O), C(S), S(O), SO ２ or optionally substituted C １ -C ３ is alkylene, R ２７ is hydrogen, -C(O)R ３２ , -C(O)OR ３２ , -SO ２ R ３３ , -SOR ３３ , optionally substituted C １ -C ６ alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; R ２８ and R ２９ are independently hydrogen, CN, C(O)R ３１ , CO ２ R ３１ , C(O)R ３１ R ３１ , optionally substituted C １ -C ６ alkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; Each R ３１ are independently hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl; R ３０ is hydrogen or an optionally substituted C １ -C ６ is alkyl, and R ３２ and R ３３ are independently hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted 6-10 membered aryl, optionally substituted 3-14 membered heterocycloalkyl, or optionally substituted 5-10 membered heteroaryl.

17. The compound of claim 16, having the formula: or a pharma- ceutically acceptable salt thereof.

18. 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein W comprises an epoxide.

19. The compound of claim 18, wherein: 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 【Chemistry 8-4】 【Chemistry 8-5】 【Chemistry 8-6】 【Chemistry 8-7】 【Chemistry 8-8】 【Chemistry 8-9】 【Chemistry 8-10】 【Chemistry 8-11】 【Chemistry 8-12】 【Chemistry 8-13】 【Chemistry 8-14】 【Chemistry 8-15】 【Chemistry 8-16】 【Chemistry 8-17】 【Chemistry 8-18】 【Chemistry 8-19】 【Chemistry 8-20】 【Chemistry 8-21】 【Chemistry 8-22】 【Chemistry 8-23】 【Chemistry 8-24】 【Chemistry 8-25】 【Chemistry 8-26】 【Chemistry 8-27】 【Chemistry 8-28】 【Chemistry 8-29】 【Chemistry 8-30】 【Chemistry 8-31】 【Chemistry 8-32】 【Chemistry 8-33】 【Chemistry 8-34】 【Chemistry 8-35】 【Chemistry 8-36】 【Chemistry 8-37】 【Chemistry 8-38】 【Chemistry 8-39】 2. The compound of claim 1, selected from the group consisting of:

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

21. 21. The pharmaceutical composition of claim 20 for use in the treatment of cancer.

22. 22. The pharmaceutical composition of claim 21, wherein the cancer is pancreatic cancer, non-small cell lung cancer, colorectal cancer, or endometrial cancer.

23. 23. The pharmaceutical composition of claim 21 or 22, wherein the cancer comprises a Ras mutation.

24. 24. The pharmaceutical composition of claim 23, wherein the Ras mutation is K-Ras G12D or K-Ras G13D.

25. 21. The pharmaceutical composition according to claim 20 for use in the treatment of a Ras protein-associated disease.

26. The pharmaceutical composition according to any one of claims 21 to 25, wherein the pharmaceutical composition is used in combination with an additional anti-cancer therapy.

27. 27. The pharmaceutical composition of claim 26, wherein the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

28. 28. The pharmaceutical composition of claim 26 or 27, wherein the additional anti-cancer therapy is an SHP2 inhibitor.