Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors

11814,386

18/048079

October 20, 2022

The disclosure relates to USP30 Inhibitor Compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising same, and medical uses involving same.

FORMA Therapeutics, Inc. (Watertown, MA, US)

FORMA Therapeutics, Inc. (Watertown, MA, US)

1. A method of inhibiting USP30 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula I: [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein: R a , R b , R c , R d , R e , R f , R g , and R h are defined as follows: (i) R a and R b form a C 1 -C 4 alkylene group between the atoms to which they are attached, wherein said C 1 -C 4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and R c , R d , R e , R f , R g , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (ii) R a and R e form a C 1 -C 2 alkylene group between the atoms to which they are attached, wherein said C 1 -C 2 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and R b , R c , R d , R f , R g , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (iii) R a and R g form a C 1 -C 3 alkylene group between the atoms to which they are attached, wherein said C 1 -C 3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and R b , R c , R d , R e , R f , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (iv) R b and R e form a C 1 -C 4 alkylene group between the atoms to which they are attached, wherein said C 1 -C 4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and R a , R d , R e , R f , R g , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (v) R b and R e form a C 1 -C 3 alkylene group between the atoms to which they are attached, wherein said C 1 -C 3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and R a , R c , R d , R f , R g , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (vi) R b and R g form a C 1 -C 4 alkylene group between the atoms to which they are attached, wherein said C 1 -C 4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and R a , R e , R d , R e , R f , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (vii) R e and R d , together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and R a , R b , R e , R f , R g , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (viii) R e and R d together form ═O; and R a , R b , R e , R f , R g , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (ix) R c and R e form a C 1 -C 4 alkylene group between the atoms to which they are attached, wherein said C 1 -C 4 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and R a , R b , R d , R f , R g , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (x) R c and R g form a C 1 -C 3 alkylene group between the atoms to which they are attached, wherein said C 1 -C 3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and R a , R b , R d , R e , R f , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (xi) R e and R f , together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and R a , R b , R c , R d , R g , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (xii) R e and R f together form ═O; and R a , R b , R c , R d , R g , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (xiii) R e and R g form a C 1 -C 3 alkylene group between the atoms to which they are attached, wherein said C 1 -C 3 alkylene group is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and R a , R b , R e , R d , R f , and R h are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (xiv) R g and R h , together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl, wherein said 3-6 membered cycloalkyl or heterocycloalkyl is substituted with 0-4 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; and R a , R b , R e , R d , R e , and R f are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; or (xv) R g and R h together form ═O; and R a , R b , R c , R d , R e , and R f are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl; and Ar 1 is phenylene or 5-6 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with m R 1 groups; and Ar 2 is phenylene or 5-6 membered heteroarylene, wherein said phenylene or heteroarylene is substituted with n R 2 groups; L is —O—, —S—, —NR 3 —, —C(R 4) 2 —, —S(O) 2 —, or —S(O)—; M is 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said cycloalkyl, phenyl, or heteroaryl is substituted with p R 5 groups; each occurrence of R 1 , R 2 , and R 5 is independently halo, cyano, NO 2 , oxo, hydroxyl, —R 6 , —OR 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —C 1 -C 6 alkylene-R 6 , C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —C 0 -C 3 alkylene-NR 6 R 7 , —C 0 -C 3 alkylene-NR 7 R 8 , —C 0 -C 3 alkylene-C(O)NR 6 R 7 , —C 0 -C 3 alkylene-C(O)NR 7 R 8 , —C 0 -C 3 alkylene-NR 7 C(O)R 6 , —C 0 -C 3 alkylene-NR 7 C(O)R 8 , —C 0 -C 3 alkylene-NR 7 S(O) 2 R 6 , —C 0 -C 3 alkylene-C(O)R 6 , —C 0 -C 3 alkylene-C(O)R 7 , —C 0 -C 3 alkylene-SR 6 , —C 0 -C 3 alkylene-S(O)R 6 , —C 0 -C 3 alkylene-S(O) 2 R 6 , —C 0 -C 3 alkylene-S(O) 2 R 7 , —C 0 -C 3 alkylene-S(O) 2 NR 6 R 7 , —C 0 -C 3 alkylene-S(O) 2 NR 7 R 8 , —C 0 -C 3 alkylene-NR 7 C(O)NR 8 R 9 , —C 0 -C 3 alkylene-NR 7 S(O) 2 NR 8 R 9 , —C 0 -C 3 alkylene-C(O)OR 7 , —C 0 -C 3 alkylene-C(O)OR 6 , —C 0 -C 3 alkylene-OC(O)R 7 , —C 0 -C 3 alkylene-OC(O)R 6 , —C 0 -C 3 alkylene-NR 7 C(O)OR 8 , or —C 0 -C 3 alkylene-NR 7 S(O) 2 R 8 ; R 3 is H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; each R 4 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, or two R 4 groups together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl or heterocycloalkyl; each R 6 is 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl, wherein said heteroaryl, heterocycloalkyl, aryl, or cycloalkyl is optionally substituted with 1-5 substituents independently selected from the group consisting of halo, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, 3-8 membered cycloalkyl, —NR 10 C(O)NR 11 R 12 , —NR 10 R 11 , —C(O)R 10 , —NR 10 C(O)R 11 , —NR 10 C(O)OR 11 , —S(O) 2 R 10 , —C(O)NR 11 R 11 , —C(O)OR 10 , —S(O) 2 NR 10 R 11 , —NR 10 S(O) 2 R 11 , —OR 10 , —OC(O)R 10 , —OS(O) 2 R 10 , —OC(O)NR 10 R 11 , —OC(O)OR 10 , —OS(O) 2 NR 10 R 11 , —C(O)NR 10 C(O)NR 11 R 12 , —C(O)C(O)R 10 , —C(O)NR 10 C(O)R 11 , —C(O)NR 10 C(O)OR 11 , —C(O)S(O) 2 R 10 , —C(O)C(O)NR 10 R 11 , —C(O)C(O)OR 10 , —C(O)S(O) 2 NR 10 R 11 , —C(O)NR 10 S(O) 2 R 11 , —C 1 -C 6 alkylene-R 10 , —C 1 -C 6 alkylene-NR 10 C(O)NR 11 R 12 , —C 1 -C 6 alkylene-NR 10 R 11 , —C 1 -C 6 alkylene-C(O)R 10 , —C 1 -C 6 alkylene-NR 10 C(O)R 11 , —C 1 -C 6 alkylene-NR 1 ºC(O)OR 11 , —C 1 -C 6 alkylene-S(O) 2 R 10 , —C 1 -C 6 alkylene-C(O)NR 10 R 11 , —C 1 -C 6 alkylene-C(O)OR 10 , —C 1 -C 6 alkylene-S(O) 2 NR 10 R 11 , —C 1 -C 6 alkylene-NR 10 S(O) 2 R 11 , —C 1 -C 6 alkenylene-R 10 , —C 1 -C 6 alkenylene-NR 10 C(O)NR 11 R 12 , —C 1 -C 6 alkenylene-NR 10 R 11 , —C 1 -C 6 alkenylene-C(O)R 10 , —C 1 -C 6 alkenylene-NR 10 C(O)R 11 , —C 1 -C 6 alkenylene-NR 1 ºC(O)OR 11 , —C 1 -C 6 alkenylene-S(O) 2 R 10 , —C 1 -C 6 alkenylene-C(O)NR 10 R 11 , —C 1 -C 6 alkenylene-C(O)OR 10 , —C 1 -C 6 alkenylene-S(O) 2 NR 10 R 11 , and —C 1 -C 6 alkenylene-NR 10 S(O) 2 R 11 ; each R 7 , R 8 , and R 9 is independently hydrogen or C 1 -C 6 alkyl; each R 10 , R 11 , and R 12 is independently hydrogen, C 1 -C 6 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered aryl, or 3-8 membered cycloalkyl; m is 0-4; n is 0-4; and p is 0-4.

2. The method of claim 1 , wherein the compound is of formula (I-C): [chemical expression included] or a pharmaceutically acceptable salt thereof.

3. The method of claim 2 , wherein R b and R c form a C 1 -C 4 alkylene group between the atoms to which they are attached, and R a , R d , R e , R f , R g , and R h are each hydrogen.

4. The method of claim 1 , wherein the compound is of formula (I-1): [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein R j , R k , R m , and R n are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.

5. The method of claim 4 , wherein the compound is of formula (I-2): [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein R j and R k are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.

6. The method of claim 1 , wherein the compound is of formula (I-3): [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein R j , R k , R m , R n , R o , and R p are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.

7. The method of claim 1 , wherein R c and R e form a C 1 -C 4 alkylene group between the atoms to which they are attached; and R a , R b , R d , R f , R g , and R h are each hydrogen.

8. The method of claim 1 , wherein the compound is of formula (I-4): [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein R q and R r are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.

9. The method of claim 8 , wherein R a and R e form a C 1 -C 2 alkylene group between the atoms to which they are attached; and R b , R c , R d , R f , R g , and R h are each hydrogen.

10. The method of claim 1 , wherein R c and R d , together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and R a , R b , R e , R f , R g , and R h are each hydrogen.

11. The method of claim 1 , wherein R c and R g form a C 1 -C 3 alkylene group between the atoms to which they are attached; and R a , R b , R d , R e , R f , and R h are each hydrogen.

12. The method of claim 1 , wherein R e and R f , together with the atom to which they are attached, form a 3-6 membered cycloalkyl or heterocycloalkyl; and R a , R b , R c , R d , R g , and R h are each hydrogen.

13. The method of claim 1 , wherein R e and R g form a C 1 -C 3 alkylene group between the atoms to which they are attached; and R a , R b , R c , R d , R f , and R h are each hydrogen.

14. The method of claim 1 , wherein Ar 1 is 5-6 membered heteroarylene.

15. The method of claim 14 , wherein Ar 2 is phenylene.

16. The method of claim 15 , wherein L is —O—.

17. The method of claim 16 , wherein M is phenyl substituted with p R 5 groups.

18. The method of claim 17 , wherein each occurrence of R 1 , R 2 , and R 5 is independently halo, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl.

19. The method of claim 1 , wherein each occurrence of R 1 , R 2 , and R 5 is independently halo, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 hydroxyalkyl.

20. A method of inhibiting USP30 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound selected from: [table included] or a pharmaceutically acceptable salt thereof.

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