Compounds
Inventors
Novak, Andrew • Jones, Geraint • WRIGGLESWORTH, JOSEPH • Duffy, Lorna • Birch, Louise • George, Pascal
Assignees
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Publication Number
US-11505547-B2
Publication Date
2022-11-22
Expiration Date
Abstract
Compounds of formula (I) and related aspects.
Core Innovation
The invention relates to substituted compounds of formula (I) and pharmaceutically acceptable salts thereof. The compound structure is defined by variable substituents including R1, R3, R4, R5, R6, Ar1, Ar2, R10, R11, and R12, and in some formulations R23 and R24, with Ar1 and Ar2 as 6-membered aryl or 6-membered heteroaryl groups and Ar2 attached to Ar1 in the para position relative to the amide.
R12 is attached to Ar2 in the meta or ortho position relative to Ar1, and the disclosure includes an N-oxide formation possibility. R4 and R5 are independently defined or together with the carbon atom to which they are attached form a C3-6 cycloalkyl or C3-6 heterocycloalkyl ring. The compounds are further characterized by broad allowed substituent classes for the remaining variable positions.
The compounds of formula (I) inhibit CTPS1 and are used for treatment or prophylaxis of CTPS1-beneficial diseases, especially those involving T- and/or B-cell proliferation. The disclosure also includes salts, solvates, isomers, enantiomers, isotopic variants, and pharmaceutical compositions containing the compounds.
Claims Coverage
The independent claims center on a substituted compound of formula (I) and a pharmaceutically acceptable salt of formula (I), with multiple inventive features defined by substituent classes and positional constraints. Across the claims, the core features are the formula (I) scaffold, the para relationship of Ar2 to the amide, the meta or ortho placement of R12 relative to Ar1, and the optional ring formation from R4 and R5.
Substituted compound of formula (I)
A compound of formula (I) with defined substituent classes for R1, R3, R4, R5, R6, Ar1, Ar2, R10, R11, and R12, including pharmaceutically acceptable salt coverage in some claims.
Aryl-heteroaryl architecture with positional control
Ar1 is a 6-membered aryl or 6-membered heteroaryl, Ar2 is a 6-membered aryl or 6-membered heteroaryl attached to Ar1 in the para position relative to the amide, and R12 is attached to Ar2 in the meta or ortho position relative to Ar1.
Ring formation from R4 and R5
R4 and R5 are independently defined or together with the carbon atom to which they are attached form a C3-6 cycloalkyl or C3-6 heterocycloalkyl ring.
Optional N-oxide formation
An N-oxide formation possibility is included when specified in relation to a nitrogen atom.
Pharmaceutically acceptable salt of formula (I)
A pharmaceutically acceptable salt of a compound of formula (I), with the same structural constraints and, in some formulations, additional definition of R23 and R24 as H or C1-2 alkyl.
The claims are directed to a substituted formula (I) scaffold with explicit substituent definitions and positional relationships between the aryl or heteroaryl groups and the amide, together with ring-formation and N-oxide options. A separate independent claim expressly covers pharmaceutically acceptable salts of the formula (I) compounds.
Stated Advantages
The compounds inhibit CTPS1.
CTPS1 inhibition is used to reduce T-cell and B-cell proliferation.
CTPS1 IC50 values are stated as at or below 1 μM, notably at or below 100 nM.
CTPS1 selectivity over CTPS2 is stated as 2–3 fold or more.
The compounds are used for treatment or prophylaxis of CTPS1-beneficial diseases.
The diseases emphasized include those involving T- and/or B-cell proliferation.
Broadly covered forms include salts, solvates, isomers, enantiomers, and isotopic variants.
Documented Applications
Treatment or prophylaxis of CTPS1-beneficial diseases, especially diseases involving T- and/or B-cell proliferation.
Immunological indications including GVHD, ALPS, lupus, and transplantation.
Cancer treatment.
Vascular injury/neointima-restenosis.
Pharmaceutical compositions containing the compounds.
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