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US-20260125396-A1 - MACROCYCLIC RIP2-KINASE INHIBITORS

US20260125396A1US 20260125396 A1US20260125396 A1US 20260125396A1US-20260125396-A1

Abstract

The present invention relates to macrocyclic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of RIP2-kinase, and/or mutants thereof, for use in the diagnosis, prevention and/or treatment of RIP2-kinase associated diseases. Moreover, the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent.

Inventors

  • Yann Lamotte
  • Nérina DODIC
  • Aurélien TAP
  • Alexis Denis
  • Jean-Marie BRUSO
  • Mourad Daoubi Khamlichi
  • Pascal André René BENDERITTER

Assignees

  • ONCODESIGN S.A.

Dates

Publication Date
20260507
Application Date
20251229
Priority Date
20200131

Claims (8)

  1. 1 . A method for treating a RIP2-kinase associated disease, the method comprising administering to a subject in need thereof an effective amount of a compound according to Formula (I) or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form, or solvate thereof, optionally in combination with at least one pharmaceutically acceptable carrier, diluent, excipient, or adjuvant, wherein the RIP2-kinase associated disease is an inflammatory disorder selected from the group consisting of bowel disease, sarcoidosis, psoriasis, atopic dermatitis, allergic rhinitis, rheumatoid arthritis, asthma, insulin-resistant type 2 diabetes, obesity metabolic syndrome, cardiac hypertrophy, lupus, uveitis, Blau syndrome, granulomatous inflammation, Behget's disease, immune-mediated colitis, and multiple sclerosis; or a cancer selected from the list consisting of breast cancers (including Inflammatory Breast Cancer), head and neck cancers and gliomas, and wherein the compound according to Formula (I) is: wherein: R 1 is selected from -halo, —O—C 1-6 alkyl, -alkynyl, —C 1-6 alkyl, —C 3-6 -cycloalkyl, —C(O)—C 1-6 -alkyl, —C(O)—C 1-6 cycloalkyl, —C(O)—Het 2 , —C(O)—NR a R b , -Het 1 and —CN, wherein: each —C 1-6 alkyl in R 1 is optionally substituted with one or more substituents selected from -D, -halo, —O—C 1-3 alkyl, —C 3-6 -cycloalkyl, -Ph, -Het 1 , -Het 2 , and —OH; the -alkynyl in R 1 is optionally substituted with one substituent selected from —C 1-6 alkyl, and —CH 2 —O—C 1-6 alkyl; R 2 and R 10 are each independently selected from —H, and -halo; R 3a , R 3b , R 4a , R 4b , R 7 , and R 8 are each independently selected from —H, and —C 1-6 alkyl, wherein: each —C 1-6 alkyl in R 3a , R 3b , R 4a , R 4b , R 7 , and R 8 is optionally substituted with one or more —O—C 1-6 alkyl; when R 3a and/or R 3b is —C 1-6 alkyl, then R 4a and R 4b are each —H; and when R 4a and/or R 4b is —C 1-6 alkyl, then R 3 and R 3b are each —H: R 5 is selected from —OH, —NR c R d , —NHC(O)R c , —NC(O)R c R d , —NC(O)OR c , —NHS(O 2 )R c , -halo, —O—C 1-6 alkyl, —O—C 3-5 -cycloalkyl, —O-Het 2 , —C 1-6 alkyl, and —CN, wherein: each —C 1-6 alkyl in R 5 is optionally substituted with one or more substituents selected from -D, —OH, —C 1-6 alkyl, —C 3-5 -cycloalkyl, —O—C 1-6 alkyl and -Het 2 ; R 6 is selected from —H, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —O-Het 4 , and -Het 3 , wherein: each —C 1-6 alkyl in R 6 is optionally substituted with one or more substituents selected from -D, and —O—C 1-6 alkyl; R 9 is selected from —H, —C 1-6 alkyl, —C(O)—C 1-6 alkyl, and —C(O)—O—C 1-6 alkyl; C A and C B are carbon atoms; R a is selected from —H, and —C 1-6 alkyl, wherein: the —C 1-6 alkyl in R a is optionally substituted with one or more substituents selected from -D, and —C 1-6 alkyl; R b is selected from —H, —C 1-6 alkyl, and —O—C 1-6 alkyl, wherein: each —C 1-6 alkyl in R b is optionally substituted with one or more substituents selected from -D, —C 1-6 alkyl, and —C 3-5 -cycloalkyl; R c and R d are each independently selected from —H, and —C 1-6 alkyl, wherein: each —C 1-6 alkyl in R c and R d is optionally substituted with one or more substituents selected from -D, and —C 1-6 alkyl; Het 1 and Het 3 are each independently a 5 or 6-membered aromatic heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein: each Het 1 and each Het 3 are optionally substituted with from 1 to 3 —C 1-6 alkyl; and each —C 1-6 alkyl in Het 1 and Het 3 is optionally substituted with one or more substituents selected from -D, -halo, —O—C 1-3 alkyl, and —OH; Het 2 is a 4-to-6-membered saturated heterocycle having from 1 to 3 heteroatoms selected from 0 and N, wherein: each Het 2 is optionally substituted with from 1 to 3 —C 1-6 alkyl; each —C 1-6 alkyl in Het 2 is optionally substituted with one or more substituents selected from -D, -halo, —O—C 1-3 alkyl, and —OH; and Het 4 is a 4-to-10-membered saturated heterocycle having from 1 to 3 heteroatoms selected from 0 and N, wherein: each Het 4 is optionally substituted with from 1 to 3 —C 1-6 alkyl; and each —C 1-6 alkyl in Het 4 is optionally substituted with one or more substituents selected from -D, -halo, —O—C 1-3 alkyl, and —OH.
  2. 2 . The method of claim 1 , wherein: R 1 is selected from -halo, —O—C 1-6 alkyl, -alkynyl, —C 1-6 alkyl, —C 3-6 -cycloalkyl, —C(O)—C 1-6 -alkyl, —C(O)—C 1-6 cycloalkyl, —C(O)—Het 2 , —C(O)—NR a R b , -Het 1 , and —CN, wherein: each —C 1-6 alkyl in R 1 is optionally substituted with one or more substituents selected from -D, -halo, —O—C 1-3 alkyl, —C 3-6 -cycloalkyl, -Ph, -Het 1 , -Het 2 , and —OH; R 5 is selected from —OH, —NR c R d , —NHC(O)R c , -halo, —O—C 1-6 alkyl, —O—C 3-5 -cycloalkyl, —O-Het 2 , —C 1-6 alkyl, and —CN, wherein: each —C 1-6 alkyl in R 5 is optionally substituted with one or more substituents selected from -D, —OH, —C 1-6 alkyl, —C 3-5 -cycloalkyl, —O—C 1-6 alkyl and -Het 2 ; R a is selected from —H, and —C 1-6 alkyl; R b is selected from —H, —C 1-6 alkyl, and —O—C 1-6 alkyl; R c and R d are each independently selected from —H, and —C 1-6 alkyl; Het 1 and Het 3 are each independently a 5 or 6-membered aromatic heterocycle having from 1 to 3 heteroatoms selected from O and N, wherein: each Het 1 and each Het 3 is optionally substituted with from 1 to 3 —C 1-6 alkyl; and Het 2 is a 4 to 6-membered saturated heterocycle having from 1 to 3 O atoms.
  3. 3 . The method of claim 1 , wherein: R 1 is selected from -halo, —O—C 1-6 alkyl, -alkynyl, —C 1-6 alkyl, —C 3-6 -cycloalkyl, —C(O)—C 1-6 -alkyl, —C(O)—C 1-6 cycloalkyl, —C(O)—Het 2 , —C(O)—NR a R b , -Het 1 and —CN, wherein: each —C 1-6 alkyl in R 1 is optionally substituted with one or more substituents selected from -D, -halo, —O—C 1-3 alkyl, —C 3-6 -cycloalkyl, -Ph, -Het 1 , -Het 2 , and —OH; R 3a , R 3b , R 4a , R 4b , R 7 , and R 8 are each —H; R 5 is selected from —OH, -halo, —O—C 1-6 alkyl, —O—C 3-5 -cycloalkyl, and —C 1-6 alkyl, wherein: each —C 1-6 alkyl in R 5 is optionally substituted with one or more substituents selected from -D, —OH, —C 1-6 alkyl, —C 3-5 -cycloalkyl, and —O—C 1-6 alkyl; R 6 is selected from —H, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —O-Het 4 , and -Het 3 , wherein: each —C 1-6 alkyl in R 6 is optionally substituted with one or more —O—C 1-6 alkyl; R a is selected from —H, and —C 1-6 alkyl; R b is selected from —H, —C 1-6 alkyl, and —O—C 1-6 alkyl; Het 1 and Het 3 are each independently selected from a 5 or 6-membered aromatic heterocycle having from 1 to 3 heteroatoms selected from O and N, wherein: each Het 1 and each Het 3 is optionally substituted with from 1 to 3 —C 1-6 alkyl; and Het 2 is a 4 to 6-membered saturated heterocycle having from 1 to 3 O atoms.
  4. 4 . The method of claim 1 , wherein: R 1 is selected from -halo, —O—C 1-6 alkyl, -alkynyl, —C 1-6 alkyl, —C 3-6 -cycloalkyl, —C(O)—C 1-6 -alkyl, —C(O)—NR a R b , -Het 1 and —CN, wherein: each —C 1-6 alkyl in R 1 is optionally substituted with one or more substituents selected from -D, -halo, and —O—C 1-3 alkyl; R 2 is selected from —H, and -halo; R 10 is —H; R 3a , R 3b , R 4a , R 4b , R 7 , and R 8 are each —H; R 5 is selected from —OH, -halo, —O—C 1-6 alkyl, —O—C 3-5 -cycloalkyl, and —C 1-6 alkyl, wherein: each —C 1-6 alkyl in R 5 is optionally substituted with one or more substituents selected from -D, —OH, —C 1-6 alkyl, —C 3-5 -cycloalkyl, and —O—C 1-6 alkyl; R 6 is selected from —H, -halo, —C 1-6 alkyl, —O—C 1-6 alkyl, —O-Het 4 , and -Het 3 , wherein: each —C 1-6 alkyl in R 6 is optionally substituted with one or more —O—C 1-6 alkyl; R 9 is —H; R a is selected from —H, and —C 1-6 alkyl; R b is selected from —H, —C 1-6 alkyl, and —O—C 1-6 alkyl; Het 1 is a 5-membered aromatic heterocycle having from 1 to 3 heteroatoms selected from O and N; and Het 1 is optionally substituted with from 1 to 3 —C 1-6 alkyl.
  5. 5 . The method of claim 1 , wherein the compound is selected from the group consisting of compounds (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), (27), (28), (29), (30), (31), (32), (33), (34), (35), (36), (37), (38), (39), (40), (41), (42), (43), (44), (45), (46), (47), (48), (49), (50), (51), (52), (53), (54), (55), (56), (57), (58), (59), (60), (61), (62), (63), (64), (65), (66), (67), (68), (69), (70), (71), (72), (73), (74), (75), (76), (77), (78), (79), (80), (81), (82), (83), (84), (85), (86), (87), (88), (89), (90), (91), (92), (93), (94), (95), (96), (97), (98), (99), (100), (101), (102), (103), (104), (105), (106), (107), (108), (109), (110), (111), (112), (113), (114), (115), (116), (117), (118), (119), (120), (121), (122), (123), (124), (125), (126), (127), (128), (129), (130), (131), (132), (133), (134), (135), (136), (137), (138), (139), (140), (141), (142), (143), (144), (145), (146), and (147):
  6. 6 . The method of claim 1 , wherein carbon atom C A is in the S-configuration.
  7. 7 . The method of claim 1 , wherein the carbon atom C B is in the R-configuration.
  8. 8 . The method of claim 1 , wherein the compound is part of a pharmaceutical composition comprising the compound according to claim 1 in combination with at least one pharmaceutically acceptable carrier, diluent, excipient, or adjuvant.

Description

CROSS REFERENCES TO RELATED APPLICATIONS This application is a continuation of and claims priority to U.S. Non-Provisional patent application Ser. No. 17/759,644 entitled “MACROCYCLIC RIP2-KINASE INHIBITORS,” filed Jul. 28, 2022, which itself is a national-stage application under 35 U.S.C. § 371 of International Application No. PCT/EP2021/052255, filed Feb. 1, 2021, which itself claims benefit of priority to European Patent Application No. 20154852.6, filed Jan. 31, 2020, the entire contents of each of which are incorporated by reference herein. FIELD OF THE INVENTION The present invention relates to macrocyclic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of RIP2-kinase, and/or mutants thereof, for use in the diagnosis, prevention and/or treatment of RIP2-kinase associated diseases. Moreover, the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent. BACKGROUND TO THE INVENTION Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes in the cell. They have been shown to be key regulators in most cellular functions including proliferation, cell metabolism, cell survival, apoptosis, DNA damage repair, cell motility . . . . Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, cancer, inflammation, allergies, immune diseases, CNS disorders, angiogenesis. Amongst the families of protein kinases, one particular example is the Receptor-Interacting Serine/Threonine Kinases including RIP2. RIP2 (Receptor-Interacting Protein 2) is also referred to as Card-Containing Ice-Associated Kinase (CARDIAK), CARD3 (C-terminal CAspase-Recruitment Domain 3), Receptor-Interacting Protein Kinase 2 (RIPK2), or Rip-Like Interacting Clarp Kinase (RICK). RIP2 kinase is composed of an N-terminal kinase domain and a C-terminal caspase-recruitment domain (CARD) linked via an intermediate (IM) region (Chin et al., Curr. Med. Chem. 2005 4 1:35-42). The CARD domain of RIP2 kinase mediates interaction with other CARD-containing proteins, such as the Nucleotide Oligomerization Domain Proteins, NOD1 and NOD2 (Inohara et al., J. Biol. Chem. 2000 36:27823-31 and Girardin et al., EMBO Rep. 2001 2:736-742). NOD1 and NOD2 are cytoplasmic receptors which are activated by specific bacterial peptidoglycan motifs and play a key role in innate immune surveillance. Upon intracellular bacterial exposure, NOD1 or NOD2 binds to the protein kinase RIP2 to coordinate NF-κB (nuclear factor κB)-mediated cytokine responses. Once associated with NOD1/2, RIP2 undergoes autophosphorylation on Tyr 474 (Y474), and acts as a molecular scaffold to bring together other kinases (TAK1, IKKβ involved in NF-κB and MAPK activation (Strober et al., Nat. Rev. Immunol. 2006 1:9-20). Both NOD1/2 and RIP2 are NF-κB regulated genes, and as such, their activation causes a positive feedback loop in which activation of NOD1/2:RIP2 stimulates further activation and further inflammation. Additionally, NOD1/2 and RIP2 expression are stimulated by a variety of mediators of inflammation, including TNF (Tumor Necrosis Factor) and IFN (Interferon). In addition to NF-κB pathway activation, the NOD1/2:RIP2 complex stimulates autophagy, bactericidal activity, MHC Class II presentation and MAPK (Mitogen-Activated Protein Kinase) activation. Overall, this pathway modulates the innate immune system to help tailor the adaptive immune response to eradicate the offending pathogen. Dysregulation of RIP2-dependent signaling has been linked to autoinflammatory diseases. Patients with loss-of-function NOD2 alleles are prone to the development of Crohn's disease, an inflammatory disorder of the gastrointestinal tract (Lesage et al., Am. J. Hum. Genet. 2002 70:845-857 and Yamamoto et al., Microbes & Infections 2009 12:912-918). Several groups showed that the NOD2/RIPK2 pathway is involved in the pathogenesis of IBD (Negroni et al., Inflamm. Bowel. Dis. 2009 8:1145-1154; Stronati et al., Digestive and Liver Disease 2010 12:848-853; Haile et al., J. Med. Chem. 2019 14:6482-6494; Chen et al., J. Pathol. 2020 250 2:170-182). Negroni showed for the first time an upregulation of both NOD2 and RIPK in colon biopsies from CD patients (Negroni et al., Inflamm. Bowel Dis. 2009 8:1145-1154). Stronati confirmed this finding in a UC pediatric population. Interestingly, beyond RIPK2 and NOD2 upregulations and the subsequent cytokines increase this group also suggested that HD5 and HD6 upregulation (two human defensins, acting as a major component of epithelial innate immune system) could be attributed to NOD2/RIPK2 (Stronati et al., Digestive and Liver Disease 2010 12:848-853). Finally, Haile et al. showed that a selective RIPK2 inhibitor could block the spontaneous pro-inflammatory cytokines secretion from UC