PRMT5 inhibitors and their use
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- GILEAD SCIENCES INC
- Filing Date
- 2024-04-19
- Publication Date
- 2026-06-02
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Figure 2026517701000001_ABST
Abstract
Claims
1. Compound of formula (I) 【Chemistry 2001】 or a pharmaceutically acceptable salt thereof, in the formula, R is, 【Chemistry 2002】 And; Each R ３ａ However, independently, H, -CN, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy, C ３～４ It is a cycloalkyl or halo; Each R ３ｂ is independently H, -CN, C １～３ alkyl, C １～３ haloalkyl, C １～３ alkoxy, C １～３ haloalkoxy, C ３～４ cycloalkyl, or halo; Y １ However, N or CR Ｙ１ And; R Ｙ１ However, H, F, Cl, Br, CN, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, -CH ２ OCH ３ , or C １～３ It is a haloalkoxy; R １ and R ２ However, together with the N that they bind to, they form a heterocycline; R １ and R ２ Therefore, the heterocyclyl formed together with the N to which they are bound contains 1 to 4 Z which may be the same or different ６ It is optionally substituted with; R １ and R ２ The heterocyclyl formed from is a 10-20 membered heterocyclyl having 0-3 additional heteroatoms, each independently being N, O, or S; R １ and R ２ Therefore, the heterocyclyl formed together with the N to which they are bound is tricyclic or tetracyclic; Alternatively, R １ However, C １～３ Alkyl, C ３～１０ Cycloalkyl, C ６～１２ It is an aryl, heterocyclyl, or heteroaryl; R １ The cycloalkyl, heterocyclyl, heteroaryl, or aryl in the above is one to four Z which may be the same or different. １ It is optionally substituted with; R １ The alkyl group may be the same or different 1 to 4 R １ａ It is optionally replaced by each R １ａ However, independently, -CN, C ２～６ Alkinyl, C ３～１０ Cycloalkyl, C １～６ Haloalkyl, C ６～１２ It is an aryl, heterocyclyl, or heteroaryl; R １ａ The cycloalkyl, aryl, heterocyclyl, or heteroaryl in the above-mentioned 1 to 4 Zs may be the same or different. ７ It is optionally replaced by R ２ However, NR ２ａ R ２ｂ And, R ２ａ However, H, C １～６ Alkyl, C １～６ Haloalkyl, -COR ２ａ１ , -COOR ２ａ１ , -CONR ２ａ１ R ２ｂ１ , -SO ２ R ２ａ１ , -SO ２ NR ２ａ１ R ２ｂ１ , C ６～１０ Ariel, C ３～１０ It is a cycloalkyl, heterocyclyl, or heteroaryl; R ２ａ The alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl in each of the 1 to 4 Zs may be the same or different. ３ It is optionally replaced by R ２ｂ However, H, C １～６ Alkyl, C １～６ Haloalkyl, C ６～１０ Ariel, C ３～１０ It is a cycloalkyl, heterocyclyl, or heteroaryl; R ２ｂ The alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl in each of the 1 to 4 Zs may be the same or different. ４ It is optionally replaced by Alternatively, R ２ａ and R ２ｂ However, together with the nitrogen to which they are bound, they form a heterocyclyl or heteroaryl, R ２ａ and R ２ｂ The heterocyclyl or heteroaryl formed together with the nitrogen to which they are bound may be the same or different 1 to 4 Z ５ It is optionally substituted with; R ２ａ and R ２ｂ The heterocyclyl formed from is a 3- to 10-membered heterocyclyl having 0-3 additional heteroatoms, each independently being N, O, or S; R ２ａ and R ２ｂ The heteroaryl formed from is a 3- to 10-membered heteroaryl having 0 to 3 additional heteroatoms, each independently being N, O, or S. Each Z １ , Z ３ Z ４ Z ５ Z ６ or Z ７ is independently C １～９ alkyl, C １～８ haloalkyl, C １～６ alkoxy, C １～６ haloalkoxy, C ２～６ alkenyl, C ２～６ alkynyl, halogen, C ３～１５ cycloalkyl, heterocyclyl, C ６～１０ aryl, heteroaryl, oxo, -NO ２ , -N ３ , -CN, -O-R １２ａ , -C(O)-R １２ａ , -C(O)O-R １２ａ , -C(O)-N(R １２ａ )(R １２ｂ ), -N(R １２ａ )(R １２ｂ ), -N(R １２ａ ) ２ (R １２ｂ ) ＋ , -N(R １２ａ )C(O)-R １２ｂ , -N(R １２ａ )C(O)O-R １２ｂ , -N(R １２ａ )C(O)N(R １２ｂ )(R １２ｃ ), -N(R １２ａ )S(O) ２ (R １２ｂ ), -NR １２ａ S(O) ２ N(R １２ｂ )(R １２ｃ ), -NR １２ａ S(O) ２ O(R １２ｂ ), -OC(O)R １２ａ , -OC(O)OR １２ａ , -OC(O)-N(R １２ａ )(R １２ｂ ), -S-R １２ａ , -SF ５ , -S(O)R １２ａ , -S(O)(NH)R １２ａ , -S(O) ２ R １２ａ , -S(O) ２ N(R) １２ａ ) (Caution １２ｂ ), or -S(O)(NR １２ａ ) R １２ｂ and; each Z １ Z ３ Z ４ Z ５ Z ６ , or Z ７ The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are each one to four Z which may be the same or different. １ａ It is optionally replaced by; Each Z １ａ However, independently, C １～９ Alkyl, C １～８ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ２～６ Alkenil, C ２～６ Alkynyl, halogen, C ３～１５ Cycloalkyl, heterocyclyl, C ６～１０ Aryl, heteroaryl, oxo, -NO ２ -CN, -N ３ , -O-R １２ａ , -C(O)R １２ａ , -C(O)O-R １２ａ , -C(O)N(R １２ａ ) (Caution １２ｂ ), -N(R １２ａ ) (Caution １２ｂ ), -N(R １２ａ ) ２ (R １２ｂ ) ＋ , -N(R １２ａ )-C(O)R １２ｂ , -N(R １２ａ )C(O)O(R １２ｂ ), -N(R １２ａ ) C(O)N(R １２ｂ ) (Caution １２ｃ ), -N(R １２ａ ) S(O) ２ (R １２ｂ ), -N(R １２ａ ) S(O) ２ -N(R) １２ｂ ) (Caution １２ｃ ), -N(R １２ａ ) S(O) ２ O(R) １２ｂ ), -OC(O)R １２ａ , -OC(O)OR １２ａ , -OC(O)-N(R １２ａ ) (Caution １２ｂ ), -S-R １２ａ , -S(O)R １２ａ , -S(O)(NH)R １２ａ , -S(O) ２ R １２ａ , -S(O) ２ N(R) １２ａ ) (Caution １２ｂ ), or -S(O)(NR １２ａ ) R １２ｂ And; Z １ａ The alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are each one to four Z which may be the same or different. １ｂ It is optionally replaced by; Each Z １ｂ However, independently, C １～９ Alkyl, C １～８ Haloalkyl, C ２～６ Alkenil, C ２～６ Alkynyl, halogen, C ３～１５ Cycloalkyl, heterocyclyl, C ６～１０ Aryl, heteroaryl, oxo, -OH, -CN, -NO ２ , -NH ２ , -N ３ , -SH, -O(C １～９ Alkyl)-O(C １～８ Haloalkyl), -O(C) ２～６ Alkenyl), -O(C ２～６ Alkinyl), -O(C ３～１５ Cycloalkyl), -O (heterocyclyl), -O (C ６～１０ aryl), -O (heteroaryl), -NH (C １～９ Alkyl), -NH(C １～８ Haloalkyl), -NH(C) ２～６ Alkenyl), -NH(C) ２～６ Alkinyl), -NH(C) ３～１５ Cycloalkyl), -NH (heterocyclyl), -NH (C ６～１０ aryl), -NH (heteroaryl), -N (C １～９ Alkyl) ２ , -N(C １～８ (Haloalkyl) ２ , -N(C ２～６ Alkenil) ２ , -N(C ２～６ Alkinyl) ２ , -N(C ３～１５ Cycloalkyl) ２ , -N (heterocycline) ２ , -N(C ６～１０ Ariel) ２ , -N (heteroaryl) ２ , -N(C １～９ (Alkyl) (C １～８ Haloalkyl), -N(C) １～９ (Alkyl) (C ２～６ Alkenyl), -N(C) １～９ (Alkyl) (C ２～６ Alkinyl), -N(C) １～９ (Alkyl) (C ３～１５ Cycloalkyl), -N(C １～９ Alkyl) (heterocyclyl), -N (C １～９ (Alkyl) (C ６～１０ Aryl), -N(C １～９ Alkyl)(heteroaryl)-C(O)(C １～９ Alkyl), -C(O)(C １～８ Haloalkyl), -C(O)(C ２～６ Alkenyl), -C(O)(C ２～６ Alkinyl), -C(O)(C ３～１５ Cycloalkyl), -C(O)(heterocyclyl), -C(O)(C ６～１０ aryl), -C(O)(heteroaryl), -C(O)O(C １～９ Alkyl), -C(O)O(C １～８ Haloalkyl), -C(O)O(C ２～６ Alkenyl), -C(O)O(C ２～６ Alkinyl), -C(O)O(C ３～１５ Cycloalkyl), -C(O)O (heterocyclyl), -C(O)O (C ６～１０ aryl), -C(O)O (heteroaryl), -C(O)NH ２ , -C(O)NH(C １～９ Alkyl), -C(O)NH(C １～８ Haloalkyl), -C(O)NH(C ２～６ Alkenyl), -C(O)NH(C ２～６ Alkinyl), -C(O)NH(C ３～１５ Cycloalkyl), -C(O)NH(heterocyclyl), -C(O)NH(C ６～１０ aryl), -C(O)NH(heteroaryl)-C(O)N(C １～９ Alkyl) ２ , -C(O)N(C １～８ (Haloalkyl) ２ , -C(O)N(C ２～６ Alkenil) ２ , -C(O)N(C ２～６ Alkinyl) ２ , -C(O)N(C ３～１５ Cycloalkyl) ２ -C(O)N (heterocycline) ２ , -C(O)N(C ６～１０ Ariel) ２ -C(O)N(heteroaryl) ２ , -NHC(O)(C １～９ Alkyl), -NHC(O)(C １～８ Haloalkyl), -NHC(O)(C ２～６ Alkenyl), -NHC(O)(C) ２～６ Alkinyl), -NHC(O)(C) ３～１５ Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C ６～１０ aryl), -NHC(O)(heteroaryl), -NHC(O)O(C) １～９ Alkyl), -NHC(O)O(C １～８ Haloalkyl), -NHC(O)O(C) ２～６ Alkenyl), -NHC(O)O(C) ２～６ Alkinyl), -NHC(O)O(C) ３～１５ Cycloalkyl), -NHC(O)O (heterocyclyl), -NHC(O)O (C ６～１０ aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C １～９ Alkyl), -NHC(O)NH(C １～８ Haloalkyl), -NHC(O)NH(C) ２～６ Alkenyl), -NHC(O)NH(C) ２～６ Alkinyl), -NHC(O)NH(C) ３～１５ Cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C ６～１０ (aryl), -NHC(O)NH(heteroaryl), -NHS(O)(C １～９ Alkyl), -N(C １～９ Alkyl) (S(O)(C １～９ Alkyl), -S (C １～９ Alkyl), -S (C １～８ Haloalkyl), -S (C ２～６ Alkenyl), -S (C ２～６ Alkinyl), -S (C ３～１５ Cycloalkyl), -S (heterocyclyl), -S (C ６～１０ aryl), -S (heteroaryl), -S(O)N(C) １～９ Alkyl) ２ , -S(O)(C １～９ Alkyl), -S(O)(C １～８ Haloalkyl), -S(O)(C) ２～６ Alkenyl), -S(O)(C) ２～６ Alkinyl), -S(O)(C) ３～１５ Cycloalkyl), -S(O)(heterocyclyl), -S(O)(C) ６～１０ aryl), -S(O) (heteroaryl), -S(O) ２ (C １～９ Alkyl), -S(O) ２ (C １～８ Haloalkyl), -S(O) ２ (C ２～６ Alkenyl), -S(O) ２ (C ２～６ Alkinyl), -S(O) ２ (C ３～１５ Cycloalkyl), -S(O) ２ (Heterocyclyl), -S(O) ２ (C ６～１０ Aryl), -S(O) ２ (heteroaryl), -S(O)(NH)(C １～９ Alkyl), -S(O) ２ NH(C) １～９ Alkyl), or -S(O) ２ N(C) １～９ Alkyl) ２ And; Z １ｂ The alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of the above is 1 to 3 C １～９ Alkyl, C １～８ Haloalkyl, halogen, -OH, -NH ２ , -O(C １～９ Alkyl), -O (C １～８ Haloalkyl), -O(C) ３～１５ Cycloalkyl), -O (heterocyclyl), -O (aryl), -O (heteroaryl), -NH(C １～９ Alkyl), -NH(C １～８ Haloalkyl), -NH(C) ３～１５ Cycloalkyl), -NH (heterocyclyl), -NH (aryl), -NH (heteroaryl), -N (C １～９ Alkyl) ２ , -N(C ３～１５ Cycloalkyl) ２ , -NHC(O)(C １～８ Haloalkyl), -NHC(O)(C ３～１５ Cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)O(C) １～９ Alkyl), -NHC(O)O(C １～８ Haloalkyl), -NHC(O)O(C) ２～６ Alkinyl), -NHC(O)O(C) ３～１５ Cycloalkyl), -NHC(O)O (heterocyclyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)NH(C １～９ Alkyl), S(O) ２ (C １～９ Alkyl), -S(O) ２ (C １～８ Haloalkyl), -S(O) ２ (C ３～１５ Cycloalkyl), -S(O) ２ (Heterocyclyl), -S(O) ２ (Aryl), -S(O) ２ (heteroaryl), -S(O)(NH)(C １～９ Alkyl), -S(O) ２ NH(C) １～９ Alkyl), or -S(O) ２ N(C) １～９ Alkyl) ２ It is optionally replaced by; Each R ２ａ１ , R ２ｂ１ , R １２ａ , R １２ｂ , or R １２ｃ However, independently, H, C １～６ Alkyl, C ３～１０ Cycloalkyl, heterocyclyl, C ６～１０ It is an aryl or heteroaryl; R ２ａ１ , R ２ｂ１ , R １２ａ , R １２ｂ , or R １２ｃ Each of the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl elements may be the same or different of 1 to 4 Z １ｂ It is optionally replaced by; Each heteroaryl in the compound of formula (I) is a 5- to 14-membered heteroaryl having 1 to 4 heteroatoms that are N, O, or S, unless otherwise specified; A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein each heterocyclyl of the compound of formula (I) is, unless otherwise specified, a 3- to 20-membered heterocyclyl having 1 to 4 heteroatoms that are N, O, or S independently.
2. Structure of equation (Ia) 【Chemistry 2003】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the above.
3. R ３ａ However, H, CH ３ A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein the compound is F, or Cl.
4. R ３ａ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is H.
5. R ３ｂ However, H, CH ３ F, Cl, OCH ３ CF ２ H, or CF ３ The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
6. R ３ｂ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is H.
7. Y １ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is N.
8. Y １ CR Ｙ１ And; R Ｙ１ However, H, CH ３ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is F, Cl, or CN.
9. Y １ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is -CF.
10. R １ However, 1 to 3 R １ａ C is optionally replaced by １～３ It is alkyl; Each R １ａ However, independently, -CN, OH, C ２～６ Alkinyl, C ３～１０ Cycloalkyl, C １～６ Haloalkyl, C １～６ Alkoxy, C ６～１２ It is an aryl, a 3- to 10-membered heterocyclyl, or a 5- to 10-membered heteroaryl; R １ａ The cycloalkyl, aryl, heterocyclyl, or heteroaryl in the above-mentioned 1 to 4 Zs may be the same or different. ７ It is optionally replaced by; R １ａ The aforementioned heteroaryl is a heteroaryl having 1 to 3 heteroatoms, each independently being N, O, or S; The aforementioned heterocycline R １ａ The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein the compound is a heterocyclyl having 1 to 3 heteroatoms, each independently being N, O, or S.
11. R １ However, R １ａ C is optionally replaced by １～３ It is alkyl, R １ａ However, C ６～１２ It is an aryl, a 3-16 member heterocyclyl, or a 5-10 member heteroaryl, R １ａ The aryl, heterocyclyl, or heteroaryl in the above-mentioned aryl, heterocyclyl, or heteroaryl is one to four Z which may be the same or different ７ It is optionally replaced by; R １ａ The aforementioned heteroaryl is a heteroaryl having 1 to 3 heteroatoms, each independently being N, O, or S; R １ａ The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl is a heterocyclyl having 1 to 3 heteroatoms, each independently being N, O, or S.
12. Structure of formula (Id) 【Chemistry 2004】 During the ceremony, R １ａ However, C ６～１２ It is an aryl, a 3-10 membered heterocyclyl, or a 5-10 membered heteroaryl, R １ａ The aryl, heterocyclyl, or heteroaryl in the above-mentioned aryl, heterocyclyl, or heteroaryl is one to four Z which may be the same or different ７ It is optionally replaced by; R １ｃ However, H, -CH ３ , or cyclopropyl; R １ａ The aforementioned heteroaryl is a heteroaryl having 1 to 3 heteroatoms, each independently being N, O, or S; R １ａ The heterocyclyl is a heterocyclyl having 1 to 3 heteroatoms, each independently being N, O, or S. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, having the above.
13. R １ｃ The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein is H.
14. R １ａ However, these are phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzodioxolyl, or benzoxazolyl; each R １ａ However, there are one to three Zs that may be the same or different. ７ A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, which is optionally substituted with.
15. R １ａ However, there are one to three Zs that may be the same or different. ７ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein the compound is optionally substituted with phenyl.
16. R １ａ However, phenyl, 【Chemistry 2005】 and; each R １ａ However, 1 to 3 Z ７ It is optionally replaced by; Z ７ａ However, H, C １～６ Alkyl, or C １～６ A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.
17. Each Z ７ However, they became independent: Halo, CN, C １～６ Alkoxy, C １～６ Alkyl, C １～６ It is a haloalkyl or a 5-6 member heteroaryl, Z ７ The aforementioned heteroaryl is one to four Z which may be the same or different １ａ It is optionally replaced by each Z １ａ However, independently, Halo, or C １～６ A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.
18. Each Z ７ However, independently, F, Cl, CN, -CF ３ , -OCHF ２ , -CF ３ , -OCH ３ , 【Chemistry 2006】 The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.
19. R ２ However, NR ２ａ R ２ｂ And; R ２ａ However, H, C １～６ Alkyl, C １～６ Haloalkyl, -COR ２ａ１ , -COOR ２ａ１ , -CONR ２ａ１ R ２ｂ１ , -SO ２ R ２ａ１ , -SO ２ NR ２ａ１ R ２ｂ１ , C ６～１０ Ariel, C ３～１０ It is a cycloalkyl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; R ２ａ The alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl in each of the 1 to 4 Zs may be the same or different. ３ It is optionally replaced by R ２ｂ However, H, C １～６ Alkyl, C １～６ Haloalkyl, C ６～１０ Ariel, C ３～１０ It is a cycloalkyl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; R ４ The alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl in each of the 1 to 4 Zs may be the same or different. ４ Is it being replaced by an arbitrary choice? or R ２ａ and R ２ｂ However, together with the nitrogen to which they are bound, they form a 3- to 10-membered heterocycline or heteroaryl; R ２ａ and R ２ｂ The heterocyclyl or heteroaryl formed from the same or different 1 to 4 Z ５ A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, which is optionally substituted with.
20. R ２ａ However, -COR ２ａ１ Or -COOR ２ａ１ And; R ２ａ１ However, C １～６ Alkyl, C １～６ Haloalkyl or C ３～６ It is a cycloalkyl; R ２ｂ However, C １～６ Alkyl or C １～６ Is it a haloalkyl? or R ２ａ and R ２ｂ However, together with the nitrogen to which they are bound, they form 3-8 membered heterocyclines; R ２ａ and R ２ｂ The heterocyclil formed from may have 1 to 3 Z which may be the same or different ５ It is optionally replaced by each Z ５ However, they became independent: oxo, halo, C １～６ Alkyl or C １～６ A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.
21. R ２ but, 【Chemistry 2007】 The compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.
22. R １ and R ２ However, together with the nitrogen to which they are bound, they form a heterocycline; R １ and R ２ The heterocyclyl formed from is a triring with 13 to 18 members; R １ and R ２ The heterocyclil formed from 1 to 4 Z ６ A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which may be optionally substituted with.
23. R １ and R ２ However, together with the N that they bind to, they form a heterocycline; R １ and R ２ The heterocyclyl formed together with the N to which they are bonded is a triring, and any two bonded rings of the triring may be condensed or bridged, R １ and R ２ The heterocyclil formed from is 1 to 4 Z ６ A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which may be optionally substituted with.
24. R １ and R ２ However, together with the N that they bind to, they form a heterocycline, R １ and R ２ The heterocyclyl formed together with the N to which they are bonded is tricyclic, and any two bonded rings of the tricyclic may be condensed or spiro, R １ and R ２ The heterocyclil formed from is 1 to 4 Z ６ A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which may be optionally substituted with.
25. -NR １ R ２ but 【Chemistry 2008】 And; Q, Q １ Q ２ , and Q ３ Each of these independently corresponds to N or Z ６ C is optionally substituted with Q, where Q １ Q ２ , and Q ３ N is two or fewer of these; X ４ is 1 or 2 Z ６ CH is optionally substituted with ２ And; X ６ However, the bond, O, CH ２ ,CH ２ O, CH ２ CH ２ , or OCH ２ X ６ CH ２ ,CH ２ O, CH ２ CH ２ , and OCH ２ Each of them is one or two Z ６ It is optionally replaced by; X ７ However, a combination or one or two Z ６ CH is optionally substituted with ２ And; X ８ However, bond, CH ２ , or CH ２ O and X ８ CH ２ and CH ２ Each of O has one or two Z ６ It is optionally replaced by; X ９ However, CH ２ ,CH ２ O, or CH ２ CH ２ X ９ CH ２ ,CH ２ O, and CH ２ CH ２ Each of them is one or two Z ６ A compound according to any one of claims 1 to 9, 22, and 23, or a pharmaceutically acceptable salt thereof, which is optionally substituted with.
26. -NR １ R ２ but 【Chemistry 2009】 And, -NR １ R ２ However, there are 1 to 4 Zs that may be the same or different. ６ It is optionally replaced by; Q, Q １ Q ２ , and Q ３ Each of these independently corresponds to N or Z ６ C is optionally substituted with Q, where Q １ Q ２ , and Q ３ N is two or fewer of these; X ５ However, -OCH ２ -ien-CH ２ -ien-CH ２ CH ２ - or -CF ２ - The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
27. -NR １ R ２ but 【Chemistry 2010】 It is a heterocycline of; Q, Q １ Q ２ , and Q ３ Each of these independently corresponds to N or Z ６ C is optionally substituted with Q, where Q １ Q ２ , and Q ３ N is two or fewer of these; X １ However, -OCF ２ -, -OCH ２ -ien-CH ２ -ien-CH ２ CH ２ -, -OCH ２ CH ２ -, -CF ２ -, or -CH ２ NR １ｂ - and; R １ｂ However, C １～６ Alkyl, C １～６ Haloalkyl, oxetanyl, -C(O)-R １２ａ , -S(O)R １２ａ , or C ３～６ It is a cycloalkyl; X ２ However, O, -OCH ２ -, -CF ２ -, or -CH ２ - and; The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein q is 0, 1, or 2.
28. -NR １ R ２ but 【Chemistry 2011】 And; Y ７ However, O, -OCH ２ -, or -CH ２ CH ２ - and; Y ７ -OCH ２ - and -CH ２ CH ２ Each of the - is one or two Z ６ It is optionally replaced by; Q, Q １ Q ２ , and Q ３ Each of these independently corresponds to N or Z ６ C is optionally substituted with Q, where Q １ Q ２ , and Q ３ N is two or fewer of these; Each Z ６ａ Z ６ Is it, or two Z ６ａ bonded to one carbon, and the two Z ６ａ However, together with the carbon atoms to which they are bonded, C ３～５ Forming a cycloalkyl or 3-6 membered heterocycline, the two Z ６ａ Therefore, the heterocyclyl formed together with the carbon atoms to which they are bonded each independently has one or two heteroatoms which are N, O, or S; A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.
29. -NR １ R ２ but 【Chemistry 2012】 And; Q, Q １ Q ２ , and Q ３ Each of these independently corresponds to N or Z ６ C is optionally substituted with Q, where Q １ Q ２ , and Q ３ N is two or fewer of these; Y ５ However, O, NR １ｄ ,CH ２ ,CH ２ CH ２ ,CH ２ O, CONR １ｄ ,CH ２ NR １ｄ Y ５ CH ２ ,CH ２ CH ２ , and CH ２ Each of O has one or two Z ６ It is optionally replaced by; Y ６ However, bond, O, NR １ｄ ,CH ２ ,CH ２ CH ２ ,CH ２ O, CONR １ｄ , or CH ２ NR １ｄ Y ６ CH ２ ,CH ２ CH ２ , and CH ２ Each of O has one or two Z ６ It is optionally replaced by; R １ｄ However, H, C １～６ Alkyl, or C １～６ It is a haloalkyl; Each Z ６ａ Z ６ Is it, or two Z ６ａ bonded to one carbon, and the two Z ６ａ However, together with the carbon atoms to which they are bonded, C ３～５ Forming a cycloalkyl or 3-6 membered heterocycline, the two Z ６ａ Therefore, the heterocyclyl formed together with the carbon atoms to which they are bonded each independently has one or two heteroatoms which are N, O, or S; The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
30. -NR １ R ２ but 【Chemistry 2013】 And; Q, Q １ Q ２ , and Q ３ Each of these independently corresponds to N or Z ６ C is optionally substituted with Q, where Q １ Q ２ , and Q ３ N is two or fewer of these; X ２ However, O, -OCH ２ -, -CF ２ -, or -CH ２ - and; Each Z ６ａ Z ６ Is it, or two Z ６ａ bonded to one carbon, and the two Z ６ａ However, together with the carbon atoms to which they are bonded, C ３～５ Forming a cycloalkyl or 3-6 membered heterocycline, the two Z ６ａ Therefore, the heterocyclyl formed together with the carbon atoms to which they are bonded each independently has one or two heteroatoms that are N, O, or S; A compound according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein r is 0, 1, or 2.
31. Each Z ６ However, independently, C １～６ Alkyl, -OH, CN, Halo, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ２～６ Alkinyl, C ３～１５ Cycloalkyl, 3-18 member heterocyclyl, C ６～１０ Aryl, 5-10 member heteroaryl, -C(O)-R １２ａ , -C(O)O-R １２ａ The alkyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl is one to four Z which may be the same or different. １ａ It is optionally replaced by; Each Z １ａ However, independently, -OH, CN, C １～６ Alkyl, Halo, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～１０ Cycloalkyl, 5-18 member heterocyclyl, C ６～１０ The aryl or 5-10 membered heteroaryl is a cycloalkyl, heterocyclyl, aryl, or heteroaryl, each having 1-4 Zs, which may be the same or different. １ｂ It is optionally replaced by; Each Z １ｂ However, independently, CN, -OH, C １～６ Alkyl, Halo, C １～６ Haloalkyl, C １～６ Alkoxy, or C １～６ It is a haloalkoxy; Each R １２ａ However, independently, H, C １～６ Alkyl, or C ３～１０ A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl compound.
32. Each Z ６ However, independently, -OH, CN, C １～６ Alkyl, Halo, C １～６ Haloalkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, phenyl, or 5-6 member heteroaryl, Z ６ The phenyl or heteroaryl in the above is one to three Z which may be the same or different. １ａ It is optionally replaced by each Z １ａ However, independently, Halo, or C １～６ A compound according to any one of claims 1 to 9 and 22 to 30, or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.
33. Each Z ６ However, independently, C １～３ Alkyl, Halo, C １～３ Haloalkyl, C １～３ Alkoxy, C １～３ The haloalkoxy, phenyl, or pyridyl is a haloalkoxy or C １～３ A compound according to any one of claims 1 to 9 and 22 to 30, or a pharmaceutically acceptable salt thereof, optionally substituted with one to three substituents independently selected from a haloalkyl group.
34. Each Z ６ However, independently, -CF ３ F, OCF ３ , Cl, -OCHF ２ A compound according to any one of claims 1 to 9 and 22 to 30, or a pharmaceutically acceptable salt thereof, which is Br.
35. Each Z ６ However, independently, CF ３ A compound according to any one of claims 1 to 9 and 22 to 30, or a pharmaceutically acceptable salt thereof, wherein the compound is F.
36. -NR １ R ２ but 【Chemistry 2014】 And; Q, Q １ Q ２ , and Q ３ Each of these independently corresponds to N or Z ６ C is optionally substituted with Q, where Q １ Q ２ , and Q ３ One of these is less than or equal to N; X ２ However, O or CH ２ - and X １０ However, O or -CH ２ - and; Each Z ６ａ Z ６ Is it, or two Z ６ａ bonded to one carbon, and the two Z ６ａ However, together with the carbon atoms to which they are bonded, C ３～５ Forming a cycloalkyl or 3-6 membered heterocycline, the two Z ６ａ Therefore, the heterocyclyl formed together with the carbon atoms to which they are bonded each independently has one or two heteroatoms which are N, O, or S; A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein r is 0, 1, or 2.
37. -NR １ R ２ but 【Chemistry 2015】 And; X ２ However, O or -CH ２ - and; X １０ However, O or -CH ２ - and; Each Z ６ｂ However, independently, H or Z ６ And; Each Z ６ａ However, independently Z ６ Is it, or two Z ６ａ bonded to one carbon, and the two Z ６ａ However, together with the carbon to which they are bonded, they form a cyclopropyl; A compound according to any one of claims 1 to 9 and 36, or a pharmaceutically acceptable salt thereof, wherein r is 0, 1, or 2.
38. -NR １ R ２ but, 【Chemistry 2016】 And; X ２ However, O or -CH ２ - and; X １０ However, O or -CH ２ - and; Each Z ６ｂ However, independently, H or Z ６ The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
39. -NR １ R ２ but, 【Chemistry 2017】 And; X ２ However, O or -CH ２ - and; X １０ However, O or -CH ２ - and; Each Z ６ｂ However, independently, H or Z ６ The compound according to any one of claims 1 to 9 and 38, or a pharmaceutically acceptable salt thereof.
40. -NR １ R ２ but, 【Chemistry 2018】 And; X ２ However, O or -CH ２ - and; X １０ However, O or -CH ２ - and; Each Z ６ｂ However, independently, H or Z ６ And; Each Z ６ａ However, independently, Z ６ Is it, or two Z ６ａ bonded to one carbon, and the two Z ６ａ However, together with the carbon to which they are bonded, they form a cyclopropyl; A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein r is 0, 1, or 2.
41. -NR １ R ２ but, 【Chemistry 2019】 And; A compound according to any one of claims 1 to 9, 22, 23, and 31 to 35, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.
42. -NR １ R ２ but, 【Chemistry 2020】 And; Z ６ｂ However, H or Z ６ The compound according to any one of claims 1 to 9, 22, 23, and 31 to 35, or a pharmaceutically acceptable salt thereof.
43. Each Z ６ However, independently, F and C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, or C １～３ A compound according to any one of claims 1 to 9, 22 to 30, and 36 to 42, or a pharmaceutically acceptable salt thereof, which is a haloalkoxy.
44. Each Z ６ However, independently, F, -CH ３ , -CF ３ , -C ２ F ５ , or -OCF ３ The compound according to any one of claims 1 to 9, 22 to 30, and 36 to 42, or a pharmaceutically acceptable salt thereof.
45. Each Z ６ｂ The compound according to any one of claims 37 to 44 or a pharmaceutically acceptable salt thereof, wherein independently, H or F.
46. at least one Z ６ｂ A compound according to any one of claims 37 to 44 or a pharmaceutically acceptable salt thereof, wherein F is present.
47. Z ６ｂ A compound according to any one of claims 37 to 44, or a pharmaceutically acceptable salt thereof, wherein is H.
48. X ２ O is X １０ ga CH ２ The compound according to any one of claims 36 to 47 or a pharmaceutically acceptable salt thereof.
49. X ２ ga-CH ２ X １０ A compound according to any one of claims 36 to 47, or a pharmaceutically acceptable salt thereof, wherein the compound is O.
50. R is 【Chemistry 2021】 The compound according to any one of claims 1 to 7 and 10 to 49, or a pharmaceutically acceptable salt thereof.
51. R is 【Chemistry 2022】 The compound according to any one of claims 1 to 6 and 8 to 49, or a pharmaceutically acceptable salt thereof.
52. Compounds shown in Table 1A, or pharmaceutically acceptable salts thereof.
53. Compounds shown in Table 1B, or pharmaceutically acceptable salts thereof.
54. Compounds shown in Table 1C, or pharmaceutically acceptable salts thereof.
55. Compounds shown in Table 1D, or pharmaceutically acceptable salts thereof.
56. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
57. The pharmaceutical composition according to claim 56, further comprising an additional therapeutic agent.
58. A method for treating a disease or condition associated with chromosome 9p21 deletion, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 56 or 57.
59. A method for treating a disease or condition associated with MTAP deletion or any other MTAP loss-of-function event, including but not limited to loss of mRNA expression, mRNA splicing deficiency, stop codon or frameshift mutation in an open reading frame, or any mutation resulting in enhanced methylthioadenosine phosphorylase (MTAP) proteolysis, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 56 or 57.
60. A method for treating cancer, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 56 or 57.
61. The method according to claim 60, wherein the cancer is selected from lung cancer, urothelial carcinoma, pancreatic cancer, esophageal cancer, bladder cancer, melanoma, mature B-cell neoplasm, non-Hodgkin lymphoma, head and neck cancer, bile duct cancer, esophageal cancer, glioblastoma, gastric cancer, adrenal cancer, breast cancer, ovarian cancer, thymic epithelial tumor, liver cancer, kidney cancer, colorectal cancer, prostate cancer, leukemia, cervical cancer, endometrial cancer, and soft tissue cancer.
62. The method according to claim 60, wherein the cancer is selected from ovarian cancer, lung cancer, lymphoid cancer, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, and bladder cancer.
63. The method according to any one of claims 58 to 62, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent or mode of treatment.
64. The method according to claim 63, wherein the additional therapeutic agent or additional therapeutic mode comprises one, two, three, or four additional therapeutic agents and / or therapeutic modes.
65. The pharmaceutical composition according to claim 57 or the method according to claim 63, wherein the additional therapeutic agent or mode of treatment is selected from an immune checkpoint modulator, an antibody-drug conjugate (ADC), an anti-apoptotic agent, a targeted anticancer drug, a chemotherapeutic agent, surgery, or radiotherapy.
66. The pharmaceutical composition or method according to claim 65, wherein the immune checkpoint modulator is selected from anti-PD-(L)1 antibody, anti-TIGIT antibody, anti-CTLA4 antibody, anti-CCR8 antibody, anti-TREM1 antibody, anti-TREM2 antibody, CD47 inhibitor, DGKα inhibitor, Helios (IKZF2) degrading agent, HPK1 degrading agent, HPK1 inhibitor, FLT3 agonist, CD39 inhibitor, CD73 inhibitor, adenosine A2a and / or A2b receptor antagonist, natural killer cell engager, and CAR-T cell therapy.
67. Use of a compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical product for the treatment of a disease or condition associated with chromosome 9p21 deletion or any other MTAP deficiency.
68. The use of the compound according to claim 67, wherein the disease or condition is cancer.
69. A compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof, for use in therapy.
70. A compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 55 or 56, for use in a method of treating a disease or condition such as a disease or condition associated with chromosome 9p21 deletion or any other MTAP deficiency.
71. The compound for use according to claim 70, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, wherein the disease or condition is cancer.
72. The compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 70 or 71, wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent or mode of treatment.