Small molecules and their use as malt1 inhibitors

Patent metadata

Field	Value
Publication number	US-2024124410-A1
Application number	US-202218266525-A
Country	US
Kind code	A1
Filing date	Mar 24, 2022
Priority date	Mar 25, 2021
Publication date	Apr 18, 2024
Grant date	—

Abstract

Small molecule inhibitors that block the interaction between B-cell lymphoma 10 protein (BCL10) and mucosa- associated lymphoid tissue lymphoma translocation protein 1 (MALT1), thereby inhibiting both the protease and scaffolding activities of MALT1, and MALT1- dependent downstream signaling, including IL-6 and IL-10 secretion by B-cell lymphoma cells and IL-2 transcription and secretion by Jurkat T cells.

First claim

1 . A method comprising administering to a subject in need of, or has been recognized as being in need of, treatment with a MALT1 inhibitor, a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having a structure of:

wherein X is (—CH 2 —) y , (—CH(R 13 )—) y , (—C(R 14 )(R 15 )—) y , —O—, —S(02)—, cycloalkyl, an alkynyl, or a single bond, wherein y is 1 or 2 and each R 13 , R 14 and R 15 is independently an alkyl, substituted alkyl, halogen, cycloalkyl, or oxo; or X together with the two phenyl groups forms a fused polycyclic structure with the two benzine rings adjacent to X;
each R 1 and R 2 is independently H, (—CH 2 —) x , (—CH(R 10 )—) x , (—C(R)(R 12 )—) x , —S(O) 2 —, —C(O)—, or —NHC(O)—, wherein x is 1 or 2 and each R 10 , R 11 and R 12 is independently an alkyl;
each R 3 and R 4 is independently H, alkyl, substituted alkyl, alkoxy, or substituted alkoxy, or R 3 and R 4 together form a fused bicyclic structure with the benzene ring that is adjacent to R 3 and R 4 ;
each R 7 and R 8 is independently an alkyl; and
each of a, b, c, d, e, f, g, and h are independently 0 or 1, provided at least one of b or c is 1 and at least one of d ore is 1; and
provided that if —(R 2 ) b — is H, then a is 0, and if —(R 2 ) e — is H, then f is 0.

2 . The method of claim 1 , wherein the subject has a disease or condition in which MALT1 function is deregulated.

3 . A method for treating a T- and B-cell malignancy, a carcinoma, an autoimmune disease, an inflammatory disease, or an allergy in a subject, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having a structure of:

wherein X is (—CH 2 —) y , (—CH(R 13 )—) y , (—C(R 14 )(R 15 )—) y , —O—, —S(02)—, cycloalkyl, an alkynyl, or a single bond, wherein y is 1 or 2 and each R 13 , R 14 and R 15 is independently an alkyl, substituted alkyl, halogen, cycloalkyl, or oxo; or X together with the two phenyl groups forms a fused polycyclic structure with the two benzine rings adjacent to X;
each R 1 and R 2 is independently H, (—CH 2 —) x , (—CH(R 10 )—) x , (—C(R)(R 12 )—) x , —S(O) 2 —, —C(O)—, or —NHC(O)—, wherein x is 1 or 2 and each R 10 , R 11 and R 12 is independently an alkyl;
each R 3 and R 4 is independently H, alkyl, substituted alkyl, alkoxy, or substituted alkoxy, or R 3 and R 4 together form a fused bicyclic structure with the benzene ring that is adjacent to R 3 and R 4 ;
each R 7 and R 8 is independently an alkyl; and
each of a, b, c, d, e, f, g, and h are independently 0 or 1, provided at least one of b or c is 1 and at least one of d ore is 1; and
provided that if —(R 2 ) b — is H, then a is 0, and if —(R 2 ) e — is H, then f is 0, thereby treating the T- and B-cell malignancy, the carcinoma, the autoimmune disease, the inflammatory disease, or the allergy.

4 . The method of claim 3 , wherein the T- and B-cell malignancy is lymphoma.

5 . The method of claim 4 , wherein the lymphoma is Activated B Cell subtype of Diffuse Large B Cell Lymphoma (ABC-DLBCL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), Acute T-cell Leukemia/Lymphoma (ATLL), Cutaneous T-cell Lymphoma (CTCL), Sezary Syndrome, or peripheral T-cell Lymphoma (PTCL).

6 . The method of claim 3 , wherein the autoimmune disease or the inflammatory disease is psoriasis, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome, colitis, systemic lupus erythematosus, graft-versus-host disease (GVHD), or asthma.

7 . The method of claim 3 , wherein the carcinoma is breast cancer, pancreatic cancer, melanoma, or glioblastoma.

8 . The method of claim 2 , wherein the disease is leukemia.

9 . The method of claim 3 , wherein at least one of the

groups of formula I is

10 . The method of claim 3 , wherein the

group of formula I is

wherein R 5 and R 6 are each independently —CH 2 —, —O—or N.

11 . The method of claim 3 , wherein at least one of R 1 or R 2 is —S(O) 2 —.

12 . The method of claim 3 , wherein at least one of R 1 or R 2 is (—CH 2 —) x , wherein x is 1.

13 . The method of claim 3 , wherein X is —CH 2 —.

14 . The method of claim 3 , wherein —(R 1 ) e — is —S(O) 2 —, and —(R 1 ) d — is —S(O) 2 —.

15 . The method of 9 claim 3 , wherein —(R 2 ) b — is —CH 2 —, —(R 1 ) e — is —S(O) 2 —, X is —CH 2 —, —(R 1 ) d — is —S(O) 2 —, and —(R 2 ) e — is —CH 2 —.

16 . The method of claim 3 , wherein at least one of R 3 and R 4 is alkoxy.

17 . The method of claim 3 , wherein each of a, b, c, d, e, and f is 1.

18 . The method of claim 3 , wherein each of b, c, d, and e is 1.

19 . The method of claim 3 , wherein at least one of a or f is 0.

20 . The method of claim 3 , wherein —(R 2 ) b — is H, —(R 2 ) d — is H, —(R 1 ) e — is —S(O) 2 —, and —(R 2 ) b — is —S(O) 2 .

21 . The method of claim 3 , wherein R 3 and R 4 together form a fused bicyclic structure with the benzene ring that is adjacent to R 3 and R 4 , and the fused bicyclic structure includes at least one heteroatom.

22 . A pharmaceutical composition comprising a pharmaceutically acceptable additive and a compound, or a pharmaceutically acceptable salt thereof, having a structure of:

wherein X is (—CH 2 —) y , (—CH(R 13 )—) y , (—C(R 14 )(R 15 )—) y , —O—, —S(02)—, cycloalkyl, an alkynyl, or a single bond, wherein y is 1 or 2 and each R 13 , R 14 and R 15 is independently an alkyl, substituted alkyl, halogen, cycloalkyl, or oxo; or X together with the two phenyl groups forms a fused polycyclic structure with the two benzine rings adjacent to X;
each R 1 and R 2 is independently H, (—CH 2 —) x , (—CH(R 10 )—) x , (—C(R)(R 12 )—) x , —S(O) 2 —, —C(O)—, or —NHC(O)—, wherein x is 1 or 2 and each R 10 , R 11 and R 12 is independently an alkyl;
each R 3 and R 4 is independently H, alkyl, substituted alkyl, alkoxy, or substituted alkoxy, or R 3 and R 4 together form a fused bicyclic structure with the benzene ring that is adjacent to R 3 and R 4 ;
each R 7 and R 8 is independently an alkyl; and
each of a, b, c, d, e, f, g, and h are independently 0 or 1, provided at least one of b or c is 1 and at least one of d ore is 1; and
provided that if —(R 2 ) b — is H, then a is 0, and if —(R 2 ) e — is H, then f is 0, wherein the pharmaceutical composition is in a unit dosage form.

23 . A compound, or a pharmaceutically acceptable salt thereof, having a structure of:

wherein X is (—CH 2 —) y , (—CH(R 13 )—) y

Assignees

• Univ Pittsburgh Commonwealth Sys Higher Education
• Univ Michigan Regents
• Univ Michigan

Inventors

• Lucas Peter C
• Mcallister Linda M
• Kang Heejae
• Chen Beibei
• Maurer Lisa
• Hu Dong
• Cheng Jing
• Klei Linda
• Nikolovska-Coleska Zaneta

Classifications

• C07D317/58 Primary

  Radicals substituted by nitrogen atoms (nitro radicals C07D317/52) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07C317/26

  having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton · CPC title

• C07D209/14

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title

• C07D209/38

  in positions 2 and 3, e.g. isatin · CPC title