Inhibitors of APOL1 and methods of using same
The disclosure provides at least one entity chosen from compounds of Formula I, a tautomer thereof, a deuterated derivative of that compound or tautomer, and a pharmaceutically acceptable salt of any of the foregoing, compositions comprising the same, and methods of using the same, including uses in treating APOL1-mediated diseases, including pancreatic cancer, focal segmental glomerulosclerosis (FSGS), and/or non-diabetic kidney disease (NDKD).
1. A compound represented by:
a tautomer thereof, a deuterated derivative of that compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
R 1 is selected from hydrogen, halogen, cyano, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, and phenyl, wherein:
the C 1 -C 6 alkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , and C 1 -C 4 alkoxy;
the C 1 -C 6 alkoxy of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen;
the C 3 -C 6 cycloalkyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 alkyl), and —C(═O)N(C 1 -C 4 alkyl) 2 ; and
the phenyl of R 1 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 alkyl), and —C(═O)N(C 1 -C 4 alkyl) 2 ;
R 2a is selected from hydrogen, halogen, cyano, —OH, ═O, and C 1 -C 6 alkyl, wherein:
the C 1 -C 6 alkyl of R 2a is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, and C 1 -C 4 alkoxy;
R 2b is selected from hydrogen, halogen, cyano, —OH, ═O, and C 1 -C 6 alkyl;
R 3a is selected from halogen, cyano, —OH, C 1 -C 6 alkyl, and ═O; wherein:
the C 1 -C 6 alkyl of R 3a is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH;
R 4 is selected from C 1 -C 6 alkyl, —C(═O)O(C 1 -C 4 alkyl), C 2 -C 6 alkynyl, and wherein:
the C 1 -C 6 alkyl of R 4 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkoxy, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 alkyl), —C(═O)N(C 1 -C 4 alkyl) 2 , C 3 -C 6 cycloalkyl, 5 to 10-membered heterocyclyl, phenyl, and 5 to 10-membered heteroaryl;
Ring A is selected from C 3 -C 12 carbocyclyl, 3 to 12-membered heterocyclyl, C 6 and C 10 aryl, and 5 to 10-membered heteroaryl, wherein Ring A is optionally substituted with 1, 2, 3, 4, or 5 R a groups; wherein:
R a , for each occurrence, is independently selected from halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkenyl, C 1 -C 6 haloalkoxy, —C(═O)NR h R i , —NR h R i , —NR h C(═O)R k , —NR h C(═O)OR k , —NR h C(═O)NR i R j , —NR h S(═O) p R k , —OR k , —OC(═O)R k , —OC(═O)OR k , —OC(═O)NR h R i , —[O(CH 2 ) q ] r O(C 1 -C 6 alkyl), —S(═O) p R k , —S(═O) p NR h R i , —C(═O)OR k , C 3 -C 12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6 and C 10 aryl, and 5- to 10-membered heteroaryl; wherein:
the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and the C 2 -C 6 alkenyl of R a are each optionally substituted with 1 to 3 groups independently selected from C 6 to C 10 aryl (optionally substituted with 1 to 3 R m groups), 5- to 10-membered heterocyclyl (optionally substituted with 1 to 3 R m groups), 5- to 10-membered heteroaryl (optionally substituted with 1 to 3 R m groups), cyano, —C(═O)R k , —C(═O)OR k , —C(═O)NR h R i , —NR h R i , —NR h C(═O)R k , —NR h C(═O)OR k , —NR h C(═O)NR i R j , —NR h S(═O) p R k , —OR k , —OC(═O)R k , —OC(═O)OR k , —OC(═O)NR h R i , —S(═O) p R k , —S(═O) p NR h R i , and C 3 -C 6 carbocyclyl (optionally substituted with 1 to 3 R m groups);
the C 3 -C 12 carbocyclyl, the 3 to 12-membered heterocyclyl, the C 6 and C 10 aryl, and the 5 to 10-membered heteroaryl of R a are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, C 1 -C 4 alkyl, —NR h R i , and —OR k ; wherein:
R h , R i , and R j , for each occurrence, are each independently selected from hydrogen, C 1 -C 4 alkyl, C 6 -C 10 aryl, and C 3 -C 6 cycloalkyl; wherein:
the C 1 -C 4 alkyl of any one of R h , R i , and R j is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH;
R k , for each occurrence, are each independently selected from hydrogen, C 1 -C 4 alkyl, 5- to 10-membered heterocyclyl, and C 3 -C 6 carbocyclyl; wherein:
the C 1 -C 4 alkyl of any one of R k is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH;
R m , for each occurrence, is independently selected from halogen, cyano, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —S(═O) p R k , and —OR k ; wherein:
the C 1 -C 6 alkyl of R m is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, and —OH;
R 5 is selected from C 1 -C 6 alkyl, —C(═O)O(C 1 -C 4 alkyl), C 3 -C 12 carbocyclyl, 3- to 12-membered heterocyclyl, C 6 and C 10 aryl, and 5- to 10-membered heteroaryl; wherein:
the C 1 -C 6 alkyl of R 5 is optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkoxy, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 alkyl), and —C(═O)N(C 1 -C 4 alkyl) 2 ;
the C 3 -C 12 carbocyclyl, the 3 to 12-membered heterocyclyl, the C 6 and C 10 aryl, and the 5 to 10-membered heteroaryl of R 5 are each optionally substituted with 1 to 3 groups independently selected from halogen, cyano, —OH, —NH 2 , —NH(C 1 -C 4 alkyl) (optionally substituted with —OH), —N(C 1 -C 4 alkyl) 2 , C 1 -C 5 alkyl (optionally substituted with —OH), C 1 -C 4 alkoxy, —C(═O)NH 2 , —C(═O)NH(C 1 -C 4 alkyl), —NHC(═O) (C 1 -C 4 alkyl), —C(═O) (C 1 -C 4 alkoxy), and —C(═O)N(C 1 -C 4 alkyl) 2 ;
p is an integer selected from 1 and 2; and
q and r are each an integer selected from 1, 2, 3, and 4.
2. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring A is selected from
each of which is optionally substituted with 1, 2, 3, 4, or 5 R a groups.
3. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 4 is selected from —CH 3 and Ring A; wherein Ring A is selected from
each of which is optionally substituted with 1, 2, 3, 4, or 5 R a groups.
4. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein Ring A is selected from
which is optionally substituted with 1 or 2 R a groups.
5. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R a , for each occurrence, is independently selected from F, cyano, —OH, —CH 3 , —CF 3 , —CH(CH 3 ) 2 , —(CH 2 ) 2 OH, —(CH 2 ) 2 OCH 3 , —CH 2 CH(OH)C 2 H 5 , —CH 2 C(CH 3 )(CH 2 OH) 2 , —OCH 3 , —OCH 2 CH 3 , [O(CH 2 ) 2 ] 2 OCH 3 , —CH 2 C(═O)NHCH 3 , —(CH 2 ) 2 SO 2 CH 3 , —CH 2 C(═O)N(CH 3 ) 2 , —CH 2 (cyclopropyl), —C(═O)NH 2 , —C(═O)NH(cyclopropyl), —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(CH 3 ) 2 CH 2 OH, —NHC(═O)CH 3 , —SO 2 CH 3 , —SO 2 NH 2 , cyclopropyl, 2-methoxyphenyl, N-methylpiperazinyl, tetrahydro-2H-pyranyl, methylpyrazolyl, pyridinyl, and tetrahydrothiophenyl 1,1-dioxide.
6. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R a , for each occurrence, is C 1 -C 6 alkyl.
7. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is selected from Cl, Br, —CH 3 , —CF 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CHF 2 , —CH 2 CH(CH 3 ) 2 , difluorocyclobutyl, and cyclohexyl.
8. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is Cl or CF 3 .
9. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 3a is selected from F, —OH, —CH 3 , —CHF 2 , and CH 2 OH.
10. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 3a is —OH.
11. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein R 5 is selected from —CH 3 , —CH 2 CH 3 , —CH 2 OH, —C(═O)OCH 3 , —CH 2 OCH 3 , —CH(CH 3 ) 2 , cyclopropyl, difluorocyclopropyl, and tetrahydro-2H-pyranyl.
12. The compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 , wherein the compound is selected from:
tautomers thereof, deuterated derivatives of those compounds and tautomers, and pharmaceutically acceptable salts of any of the foregoing.
13. A compound selected from Compound 174:
and a pharmaceutically acceptable salt thereof.
14. A compound selected from Compound 181:
and a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable carrier.
16. A method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 .
17. A method of treating an APOL1-mediated disease comprising administering to a patient in need thereof the compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt according to claim 1 .
18. The method according to claim 17 , wherein the APOL1-mediated disease is cancer.
19. The method according to claim 17 , wherein the APOL1-mediated disease is pancreatic cancer.
20. The method according to claim 17 , wherein the APOL1-mediated disease is an APOL1-mediated kidney disease.
21. A compound that is Compound 174:
22. A compound that is Compound 181:
23. A compound selected from: