CN-122003430-A - Compounds and uses

Abstract

Provided herein is a compound of formula (I) as defined in formula (I), Wherein Ra, rb, rc, A and p have the meanings given in the specification, and pharmaceutically acceptable salts and solvates thereof, which are useful in the treatment of diseases in which ubiquitin proteasome inhibition is desired or required, and in particular in the treatment of cancer.

Inventors

• E. Mauritani
• P. M. Decker
• H. S. Overcliffe
• B. I. Floria
• GROLL MAX
• E. HUBER

Assignees

• 莱顿大学
• 慕尼黑工业大学

Dates

Publication Date

20260508

Application Date

20240809

Priority Date

20230810

Claims (16)

1. 1. A compound of the formula (I), Wherein the method comprises the steps of One of R a and R b represents H, and the other represents- [ CH 2 ] m -X; X represents-OC (O) -Y, -C (O) -Y, -OH or OY; Y represents-C 1-6 alkyl (optionally substituted by-Z 1 -Z 2 ) or-CH (R y )-(Z 1 -Z 2 ) n ; R y represents a side chain of a methylbiphenyl or proteinogenic amino acid, optionally wherein the side chain is in a chemically protected form; each Z 1 is independently-NH-, -N (R z ) -or-O-; r z , if present, combines with R y to form a proline ring; Each Z 2 is independently H, -C (O) -C 1-4 alkyl, -C (O) O-C 1-4 alkyl, or-Si (C 1-4 alkyl) 3 ; m is 0,1 or 2; n is 1 or 2; p is 0 or 1; r c represents H or-C 1-4 alkyl optionally substituted by one or more Q substituents; q represents-OR d 、-NHR e OR-C (O) NHR f ; R d 、R e and R f represent H, -C 1-4 alkyl (optionally substituted by phenyl or methylphenyl), -C (O) -C 1-4 alkyl, -C (O) O-C 1-4 alkyl, -C (O) -C 1-4 alkenyl, -C (O) O-C 1-4 alkenyl, -C (=N) -NH 2 , -C (=N) -NH- (protecting group) or pyrimidinyl; a represents a cyclic moiety selected from the group consisting of: R h represents H, C 1-4 alkyl or-C (O) O-C 1-4 alkyl; R i represents H, C 1-4 alkyl, -N (R j )(R k ) or-OH; R j and R k independently represent H or C 1-4 alkyl; or a pharmaceutically acceptable salt or solvate thereof.
2. 2. A compound according to claim 1, wherein R b represents hydrogen.
3. 3. A compound according to claim 1 or claim 2, wherein X represents-OC (O) -Y, -C (O) -Y or-OY.
4. 4. A compound according to any one of the preceding claims, wherein Y represents-C 3-5 alkyl (optionally substituted by-Z 1 -Z 2 ) or-CH (R y )-(Z 1 -Z 2 ) n ).
5. 5. The compound according to any one of the preceding claims, wherein R y represents a methyl biphenyl group, a side chain of a proteinogenic amino acid or a chemically protected form of a side chain of a proteinogenic amino acid, wherein the chemical protection involves the attachment of a moiety selected from the group consisting of a benzoyl group, a benzyl group and a trityl group.
6. 6. A compound according to any one of the preceding claims, wherein: (i) m is 0 or 1, and/or (Ii) n is 1.
7. 7. A compound according to any one of the preceding claims, wherein Q represents-NH 2 、-NH-C(O)-CH 3 、-NH(Alloc)、-NH-C(=N)-NH 2 , -NH-C (=n) -NH- (protecting group), -C (O) -NH 2 , -OH, -O-benzyl, -O-xylyl or-NH (pyrimidinyl).
8. 8. A compound according to any one of claims 1 to 6, wherein R c represents a side chain of serine, a protected derivative of a side chain of serine, or methyl.
9. 9. A compound according to any one of the preceding claims, wherein a represents a morpholinyl group.
10. 10. The compound of any one of the preceding claims, wherein the compound is selected from the group consisting of:
11. 11. A pharmaceutical formulation comprising a compound as defined in any one of claims 1 to 10 in combination with a pharmaceutically acceptable excipient.
12. 12. A compound as defined in any one of claims 1 to 10 or a pharmaceutical formulation as defined in claim 11 for use in medicine.
13. 13. A compound as defined in any one of claims 1 to 10 or a pharmaceutical formulation as defined in claim 11 for use in the treatment or prophylaxis of a disease or condition in which ubiquitin proteasome inhibition is desired or required.
14. 14. The compound or pharmaceutical formulation for use according to claim 13, wherein the disease or condition is a hematological malignancy, solid tumor, autoimmune disease or inflammatory disease.
15. 15. The compound or pharmaceutical formulation for use according to claim 13 or claim 14, wherein the disease or condition is selected from the group consisting of leukemia, lymphoma, myeloma (including multiple myeloma), myelodysplastic syndrome, myeloproliferative syndrome, prostate cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer, renal cancer, ovarian cancer, osteosarcoma, alzheimer's disease, brain inflammation, colitis-related cancer, angiogenesis, viral myocarditis, acute kidney injury, ischemic stroke, premature labor, abdominal aortic aneurysm, atherosclerosis, cardiac remodeling, graft-versus-host disease (GvHD), inflammatory bowel disease, arthritis, polymyositis, dermatomyositis, autoimmune hepatitis and lupus nephritis.
16. 16. A process for the preparation of a compound of formula (I) as defined in claim 1, which comprises the step of reacting a compound of formula (II), Wherein A, p and R c are as defined in claim 1, with a compound of formula (III), (III) Wherein Y is as defined in claim 1.

Description

Compounds and uses Technical Field The present invention relates to novel compounds, compositions comprising such compounds and the use of such compounds and compositions in medicine. In particular, the invention relates to the use of such compounds and compositions in methods for treating or preventing diseases or conditions in which ubiquitin proteasome inhibition is desired or required (such as proliferative and autoimmune diseases). Background The proteasome is critical for maintaining protein homeostasis and is involved in a variety of critical cellular processes, including cell division, cell signaling and antigen processing (Coux, O.; Tanaka, K.; Goldberg, A. L., Structure and functions of the 20S and 26S proteasomes. Annu. Rev. Biochem. 1996, 65, 801-47). the dominant proteasome types in mammals are constitutive proteasomes found in all somatic cells and both immunoproteasome (Kniepert, A.; Groettrup, M., The unique functions of tissue-specific proteasomes. Trends in biochemical sciences 2014, 39 (1), 17-24.). constitutive and immunoproteasome expressed primarily by cells of hematopoietic origin are characterized by 20S core particles (CP; cCP stands for constitutive proteasome and iCP for immunoproteasome) consisting of 14 alpha and 14 beta subunit proteins arranged in a α 1-7β1-7β1-7α1-7 fashion to form a hollow cylinder. The β1, β2 and β5 subunits have proteolytic activity and hydrolyze polypeptides fed into the CP barrel into oligopeptides of eight to ten amino acids. cCP differ structurally from iCP mainly in the catalytically active site and its substrate binding channel. cCP incorporate β1c (caspase-like activity (C-L)), β2c (trypsin-like activity (T-L)) and β5c (chymotrypsin/elastase-like (ChT-L activity)) subunits that are replaced in the iCP by β1i (ChT-L), β2i (T-L) and β5i (ChT-L). Proteasome inhibition studies began in the beginning of the 90 s of the 20 th century and these compounds were mainly targeted to β5c and β5i of cCP and iCP, respectively, with the drugs bortezomib (2003), carfilzomib (carfilzomib) (2012) and ifer Sha Zuo m (ixazomib) (2015) approved for the treatment of multiple myeloma and finally (Manasanch, E. E.; Orlowski, R. Z., Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol 2017, 14 (7), 417-433.).. However, other catalytic activities may also be co-inhibited depending on the dosage. Constitutive proteasomes are present in all healthy tissues and are classified as off-target when proteasome inhibition is viewed in a clinical setting. Selective inhibition of immunoproteasome has been sought in the past 10 years in order to minimize side effects, reduce cytotoxicity and explore potential anti-inflammatory applications. However, it is apparent that co-inhibition of several subunits is required to produce a therapeutically relevant effect (Johnson, H.W. B.; et al , Required Immuno-proteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2S,3R)-N-((S)-3-( Cyclopent-1-en-1-yl) -1- ((R) -2-methyl-oxiran-2-yl) -1-oxo-propan-2-yl) -3-hydroxy-3- (4-methoxy-phenyl) -2- ((S) -2- (2-morpholino-acetamido) propanamido) -acrylamide). J Med Chem 2018, 61 (24), 11127-11143.). Proteasome inhibitors (i.e., carfilzomib and bortezomib) have also been shown to induce resistance pathways, thereby rendering proteasome inhibition unusable as a treatment for these hematologic cancers. One possible way to overcome the resistance observed in hematologic cancers and the cytotoxicity caused by constitutive proteasome inhibition is to develop a proteasome inhibitor that specifically inhibits the immune proteasome, an ubiquitination proteasome inhibitor. Although compounds targeting at least two immune subunits with good affinity have been reported (ONX 0914 (Muchamuel, t.; et al , A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat. Med. 2009, 15 (7), 781-7), KZR-616（Johnson, H. W. B.; , supra) and LU-005i (see below)), there is still a lack of a true ubiquitin proteasome inhibitor that blocks all three immune subunits with equally high potency and leaves the c-subunit unaffected. It has now surprisingly been found that certain compounds are capable of acting as inhibitors of the immune proteasome, in particular ubiquitin proteasome inhibitors, which may be useful in the treatment or prevention of diseases or conditions in which inhibition of the ubiquitin proteasome is desired or required (such as proliferative and autoimmune diseases). The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge. Disclosure of Invention In a first aspect of the invention, there is provided a compound of formula (I), Wherein: one of R a and R b represents H, and the other represents- [ CH 2]m -X; X represents-OC (O) -Y,