Small molecules for the treatment of autoimmune diseases and cancer
Inventors
Iliopoulos, Dimitrios • Ho, David G. • Karagiannidis, Iordanis • Nguyen, Phithi • Chalkia, Dimitra
Assignees
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Publication Number
US-11485728-B2
Publication Date
2022-11-01
Expiration Date
Abstract
Disclosed herein are quinazolinyl compounds, compositions, and methods of use thereof. The compounds may be used in the treatment of autoimmune disorders or cancer.
Core Innovation
The invention provides compounds of Formula (I), including stereoisomers, tautomers, and pharmaceutically acceptable salts. The compounds are quinazolinyl compounds defined by structural variables X1 through X4, with X3 represented by Formula (IX3) and X4 represented by a defined group that includes Formula (IX4) and related substituent options. The structural definition is further refined by allowed substituent lists for Ra, R1, R2, R3, R4, R5, Rg, and by positional placement rules on the “A” ring and the “F” ring.
X1 is either a covalent bond or —(CH2)o—, with o selected from 1, 2, 3, 4, 5, or 6, and X2 is hydrogen. X3 is represented by Formula (IX3), where Xa is selected from CH and N, m and n are selected from defined integer ranges, and Xb is selected from CH2, —NRa, NH, O, S, and SO2. Each Ra is selected from an enumerated substituent list, including amino, —OH, halogen, cyano, hydroxy, optionally substituted C1-C3 alkyl, C-carboxy, and optionally substituted C1-C6 alkoxy(C1-C6)alkyl, and each Ra is provided at any position of the “A” ring by replacing one or more —H atoms.
X4 is selected from —CN, —OR1, —SR1, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkenyl, optionally substituted C1-C10 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, and —NR2R3. R4 is represented by one of the recited structures with f, g, Xi, and h integer selections, and each Rg is provided at any position of the “F” ring by replacing one or more —H atoms. The claim set also includes a proviso that restricts X4 under specified X3, R5, and Ra conditions, and it lists selected substituted quinazoline-based example compounds together with pharmaceutical compositions containing the compound and a pharmaceutically acceptable excipient.
Claims Coverage
The consolidated claim coverage includes one independent claim defining a Formula (I) compound, plus dependent claims that narrow integer parameters, linker and heteroatom choices, Formula (IX4) constraints, specific example compounds, and a pharmaceutical composition. The main inventive framework is the Formula (I) quinazolinyl chemical space with constrained X1 to X4 definitions and explicit exclusion conditions.
Formula (I) quinazolinyl compound with stereoisomers, tautomers, and salts
A compound of Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, with X1, X2, X3, and X4 defined by the claim framework.
Defined X1 and X2 linkage
X1 is a covalent bond or —(CH2)o—, with o selected from 1, 2, 3, 4, 5, or 6, and X2 is hydrogen.
X3 represented by Formula (IX3)
X3 is represented by Formula (IX3), where Xa is selected from CH and N; m and n are selected from defined integer ranges; Xb is selected from CH2, —NRa, NH, O, S, and SO2; and Ra is selected from an enumerated substituent list and can be placed at any position of the “A” ring by replacing one or more —H atoms.
X4 structural options and R1 to R3 definitions
X4 is selected from —CN, —OR1, —SR1, optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkenyl, optionally substituted C1-C10 alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, and —NR2R3, with R1 hydrogen or optionally substituted C1-C10 alkyl and R2 and R3 independently hydrogen and optionally substituted C1-10 alkyl, or together forming an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-10 membered heteroaryl when attached to the same nitrogen atom.
R4 representation with Formula (IX4) and “F” ring placement
R4 is represented by one of the recited structures with f, g, Xi, and h integer selections, Xi selected from CH2, NH, O, S, and SO2, and each Rg placed at any position of the “F” ring by replacing one or more —H atoms.
Conditional restriction on X4
R5 is selected from hydrogen, halogen, and —OMe, with a proviso that restricts X4 under specified X3, R5, and Ra conditions.
Selected example compounds and pharmaceutical composition
The claim set includes selected substituted quinazoline-based example compounds and a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable excipient.
Overall, the claim coverage centers on a Formula (I) quinazolinyl compound space with tightly controlled X1 to X4 definitions, Formula (IX3) and Formula (IX4) features, a specific proviso limiting X4 in a defined scenario, selected example compounds, and a pharmaceutical composition.
Stated Advantages
Not explicitly described in patent.
Documented Applications
treating gastrointestinal and autoimmune disorders, including inflammatory bowel disease (IBD), ulcerative colitis, and Crohn’s disease
G9a-mediated inflammation contexts, including effects described as inducing/activity of T regulatory (Treg) cells and reduction of pro-inflammatory cytokines and inflammatory markers
treating autoimmune disorders including ulcerative colitis, Crohn’s disease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, celiac disease, and graft versus host disease (GVHD)
treating cancers including colorectal, gastric/stomach, esophageal, liver, pancreatic, breast, prostate, bladder, renal, ovarian, lung, melanoma, and multiple myeloma
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