Granted Patent B2

US 12,391,679 · App. 17/614,854 · Granted Aug 19, 2025

Inventors: Luke Jonathan Alvey (Romainville, FR); Denis Bucher (Rheinfelden, CH); Nicolas Desroy (Romainville, FR); Hélène Marie Jary (Romainville, FR); Christophe Peixoto (Romainville, FR); Taoues Temal-Laïb (Romainville, FR); Amynata Tirera (Romainville, FR); Florence Marie-Emilie Bonnaterre (Romainville, FR); Béranger Duthion (Romainville, FR)

Assignee: ONCO3R Therapeutics BV

C07D405/10A61P1/00A61P9/00A61P11/00A61P19/02A61P37/00C07D235/16C07D401/10C07D471/04C07D519/00

Abstract

Claims (114)

1. A compound according to Formula I:

wherein,

W 1 is N or CR 3 and W 2 is N or CH, with the proviso that W 1 and W 2 cannot both be N;

one of X 1 , X 2 and X 3 is N and the other two are C;

Y is N or CR 2b ;

Z is

—NR 4a R 4b ,

—R 4c —, wherein the N atom and R 2a together with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one double bond, or

N-linked 4-7 membered monocyclic or spirocyclic heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected R 5 groups;

R 1a is selected from

H,

halo,

—OH,

—CN,

C 1-6 alkyl optionally substituted with one or more independently selected R 6 ,

C 1-4 alkoxy optionally substituted with one or more —OH or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S,

—C(O)—R 7 ,

—NR 8a R 8b ,

—S(═O) 2 —C 1-4 alkyl,

5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl, and

4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S;

R 1b and R 1c are independently selected from

halo,

—OH,

—CN,

C 1-4 alkyl optionally substituted with one or more independently selected —OH, —CN, or C 2-4 alkenyl,

C 3-7 cycloalkyl,

4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R 9 groups, and

—NR 10a R 10b ,

or R 1b and R 1c together with the atom onto which they are attached form a C 3-6 cycloalkyl,

or R 1b and R 1c together with the atom onto which they are attached form a 4-6 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R 11 groups;

R 2a and R 2b are independently selected from

halo,

C 1-4 alkyl,

C 1-4 alkoxy optionally substituted with one or more independently selected halo, —OH, or C 1-4 alkoxy,

—NR 12a R 12b , and

—OH;

R 3 is H, halo, or C 1-4 alkoxy optionally substituted with one or more independently selected —OH or C 1-4 alkoxy;

R 4a is H or C 1-4 alkyl;

R 4b is selected from

C 1-6 alkyl optionally substituted with one or more independently selected R 13 ,

C 3-7 cycloalkyl optionally substituted with one or more independently selected R 14a ,

4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected R 14b , and

5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl;

R 4c is H, C 3-7 cycloalkyl, or C 1-6 alkyl optionally substituted with one or more independently selected halo or —CN;

each R 5 is independently selected from

oxo,

halo,

—CN,

—OH,

—NR 15a R 15b ,

phenyl,

C 3-7 cycloalkyl,

C 2-4 alkynyl,

—C(═O)—C 1-4 alkoxy,

C 1-4 alkoxy optionally substituted with one or more independently selected halo or phenyl,

C 1-4 alkyl optionally substituted with one or more independently selected halo, —OH, or C 1-4 alkoxy, and

4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S;

each R 6 is independently selected from

halo,

—O—R 16 ,

—NR 17a R 17b ,

5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, and

4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected halo;

R 7 is —OH, C 1-4 alkyl, C 1-4 alkoxy, —NR 18a R 18b , or 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more —OH;

R 8a and R 8b are independently H, —C(═O)—C 1-4 alkoxy, or C 1-4 alkyl optionally substituted with one or more independently selected halo, —CN or —OH;

each R 9 is independently halo, —OH, or C 1-4 alkyl optionally substituted with one or more —OH;

each R 10a and R 10b is independently H or C 1-4 alkyl optionally substituted with one or more —OH;

each R 11 is independently selected from

C 1-4 alkyl optionally substituted with one or more independently selected-CN or C 1-4 alkoxy,

—C(═O)—C 1-6 alkyl, and

—C(═O)—C 1-6 alkoxy;

each R 12a and R 12b is independently H or C 1-4 alkyl optionally substituted with one —OH or C 1-4 alkoxy;

each R 13 is independently selected from

halo,

—CN,

—NR 19a R 19b ,

—OH,

C 1-4 alkoxy,

C 3-7 cycloalkyl,

—S(═O) 2 —C 1-4 alkyl,

4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, and

5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected C 1-4 alkyl;

each R 14a and R 14b is independently selected from

halo,

oxo,

C 1-4 alkyl optionally substituted with one or more independently selected halo, —OH, or C 1-4 alkoxy,

—OH,

C 1-4 alkoxy, and

—NR 20a R 20b ;

each R 15a and R 15b is independently H, C 1-4 alkyl, or —C(═O)—C 1-4 alkoxy;

each R 16 is independently selected from

H,

—S(═O) 2 —C 1-4 alkyl,

C 1-4 alkyl optionally substituted with one or more —C(═O)—NR 21a R 21b or 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, and

4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S;

each R 17a and R 17b is independently H or C 1-4 alkyl optionally substituted with one or more independently selected-OH or C 1-4 alkoxy;

R 18a and R 18b are independently H or C 1-4 alkyl optionally substituted with one or more independently selected —OH or C 1-4 alkoxy;

each R 19a , R 19b , R 20a , R 20b , R 21a , and R 21b is independently H or C 1-4 alkyl;

or a pharmaceutically acceptable salt thereof.

2. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein W 1 is CR 3 , and R 3 is H.

3. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein Y is CR 2b and R 2b is C 1-4 alkoxy.

4. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 2a is —O—CH 3 , substituted with one, two, or three independently selected halo.

5. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein Z is —NR 4a R 4b , and R 4a is H.

6. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is according to Formula IIIa, IIIb, IIIc, or IIId:

7. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 1b and R 1c together with the atom onto which they are attached form a cyclobutyl.

8. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 1b and R 1c together with the atom onto which they are attached form an oxetanyl or tetrahydropyranyl.

9. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is according to Formula IVe, IVf, IVg, or IVh:

10. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 4b is cyclopropyl or 2-fluorocyclopropyl.

11. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 1a is H, —OH, or —CN.

12. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 1a is C 1-6 alkyl substituted with one —OH.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 1 .

14. A method for prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases, comprising administering a compound or pharmaceutically acceptable salt thereof, according to claim 1 , to a human in need thereof.

15. A method for prophylaxis and/or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and/or abnormal angiogenesis associated diseases, comprising administering a pharmaceutical composition of claim 13 to a human in need thereof.

Assignments (7)

Priority Claims (1)

Continuity (1)

References Cited (53)