Substituted pyrazole compounds and methods of using them for treatment of hyperproliferative diseases
Inventors
Siddiqui, M. Arshad • Ciblat, Stephane • Dery, Martin • Constantineau-Forget, Lea • Grand-Maitre, Chantal • Bruneau-Latour, Nicolas • Shipps, Gerald W. • Cooper, Alan B. • Oza, Vibha • Kostura, Matthew J. • Luther, Michael • Levine, Jedd
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11325903-B2
Publication Date
2022-05-10
Expiration Date
Abstract
Disclosed are compounds useful, for example, in methods of treating hyperproliferative disorders such as cancer, methods of arresting the cell cycle in cancer cells, methods of inhibiting glutathione synthesis in cancer cells, and associated compounds for use and uses in medicaments. In certain embodiments, the methods, uses and compounds are provided with reference to compounds of the structural formulae (Ia), (Ib), (Ic), (Id) and (Ie), in which R1, L1, L2, Q, L3, R3, L4, R4, L5, and R5 are as described herein. In certain embodiments, compounds disclosed herein are especially active against cancers having a mutant KRAS gene.
Core Innovation
The invention relates to substituted compounds of structural formula (Ia), including pharmaceutically acceptable salts, N-oxides, solvates, and hydrates. The compounds are defined by variable groups L1, L2, Q, L3, L4, L5, R1, R3, R4, and R5, with specified bond and heteroatom-containing linkages and constrained substituent selections. The disclosure also includes selected substituted thiazole-pyrazole carboxylic acids and related methyl carboxylate forms.
In one aspect, the structural definition includes Q selected from carboxylic acid, ester, amide, sulfonamide, and phosphate-like groups, together with further constraints on R2A and R2B. R1 is defined across phenyl or monocyclic heteroaryl with defined substitution options, and R3 is aryl or heteroaryl with optional substitution through linked aryl, heteroaryl, cycloalkyl, or heterocycloalkyl fragments. R5 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, with defined ring-size and heteroatom constraints.
In another aspect, the invention covers specific substituted 1H-pyrazole-5-carboxylic acid compounds with thiazol-2-yl and aryl or heterocyclic substituents, including fluorophenyl, trifluoromethyl-containing aryl or cycloalkyl groups, isopropylthio, oxadiazolyl, piperidinyl, and piperazinyl motifs. The disclosure further includes stereoisomer and tautomer inclusion, including enantiomers, diastereomers, cis/trans configurations, Z/E configurations, and N-oxides.
Claims Coverage
The consolidated claim coverage includes three independent themes: a general structural formula (Ia) compound claim with extensive linker and substituent definitions, a second structural formula (Ia) claim with alternative aromatic or heteroaryl constraints, and a claim set selecting specific substituted thiazole-pyrazole carboxylic acid compounds. Across these independent claims, the inventive features center on constrained linkage types L1-L5, defined functional group Q, and tightly limited R1, R3, R4, and R5 selections, with optional salt/N-oxide/solvate/hydrate forms.
Substituted compounds of structural formula (Ia) with constrained linkage and substituent sets
A compound having structural formula (Ia), optionally in the form of a pharmaceutically acceptable salt or N-oxide, and/or a solvate or hydrate, wherein L1 is a bond, —S—, —S(O)1-2—, or —O—; L2 is a bond, —CH2—, —CH(CH3)—, or —CH2CH2—; Q is selected from —C(O)OH, —C(O)OR2A, —C(O)NR2BR2A, —C(O)NR2BS(O)2R2A, —C(O)NR2BS(O)2NR2BR2A, —S(O)2OH, and —P(O)(OH)2; L3, L4, and L5 are selected from listed bond and heteroatom-containing linker options; and R1, R3, R4, and R5 are constrained to the defined substituent sets and ring-size or heteroatom limits.
Substituted compounds of structural formula (Ia) with alternative aromatic and heteroaryl constraints
A compound having structural formula (Ia), optionally in the form of a pharmaceutically acceptable salt or N-oxide, and/or a solvate or hydrate, wherein R1 is phenyl or monocyclic heteroaryl with defined substituent options, R3 is aryl or monocyclic heteroaryl with optional -L3C- substitution, and R5 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl with defined substitution and ring constraints.
Selected substituted thiazole-pyrazole carboxylic acid compounds
A compound selected from the listed substituted 1H-pyrazole-5-carboxylic acid and related methyl carboxylate examples, optionally in the form of a pharmaceutically acceptable salt or N-oxide, or a solvate or hydrate.
The claims cover both a broad structural-formula (Ia) compound class and a fixed list of specific substituted thiazole-pyrazole carboxylic acid compounds, all defined by extensive constraints on linkers, functional groups, and substituent selections, with optional pharmaceutically acceptable salt, N-oxide, solvate, and hydrate forms.
Stated Advantages
Cell cycle arrest and induction of apoptosis for cancer treatment.
Inhibition of glutathione synthesis.
Enhanced activity in cancers with mutant KRAS, including heterozygous mutant KRAS.
Documented Applications
Treating hyperproliferative cancers and hyperproliferative disorders by administering the claimed compounds.
Treating a hyperproliferative disorder in a subject by administering an effective amount of a compound according to claim 1.
Treating a hyperproliferative disorder in a subject by administering an effective amount of a compound referenced in claim 21.
Interested in licensing this patent?