Methods of using substituted pyrazole and pyrazole compounds and for treatment of hyperproliferative diseases
Inventors
Siddiqui, Arshad M. • Ciblat, Stephane • Constantineau-Forget, Lea • Grand-Maitre, Chantal • Guo, Xiangyu • Srivastava, Sanjay • Shipps, Gerald W. • Cooper, Alan B. • Oza, Vibha • Kostura, Matthew W. • 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-12150934-B2
Publication Date
2024-11-26
Expiration Date
Abstract
Disclosed are 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 formula (I), in which X1, X2, Z1, Z2, the ring system denoted by “a”, 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 provides a method for treating a hematopoietic cancer in a subject in need thereof by administering an effective amount of a compound having a structural formula. The compound includes a pyrazole-5-carboxylic acid or thiazole-containing carboxylic acid scaffold with specified linkage constraints, including L1 being —S—, —S(O)—, or —S(O)2—, Q being —COOH, and L2, L3, L4, and L5 being bonds. The compound is optionally provided as a pharmaceutically acceptable salt or N-oxide, or as a solvate or hydrate.
The structural definition constrains R1 and R4 to unsubstituted or fluorinated C1-C8 alkyl, alkenyl, or alkynyl groups. R3 and R5 are phenyl or monocyclic heteroaryl optionally substituted with 1-5 substituents from explicitly defined sets including oxo, halogen, —CN, —N3, SF5, carbonyl, thioether, sulfoxide, sulfone, oxy, and amino variants, with additional rules for R3F, R3G, R5F, and R5G. The definitions also include ring-size and heteroatom limits for cycloalkyl, heterocycloalkyl, and heteroaryl groups, including optional fused cycloalkyl or heterocycloalkyl rings.
The provided content also includes characterization data and structural depictions for multiple specific derivatives within the claimed scaffold. Reported examples feature substituted pyrazole- and thiazole-containing carboxylic acids or carboxamides with varied aryl and heteroaryl substituents, including fluorophenyl, chlorophenyl, methoxy, trifluoromethoxy, cyano, pyrimidinyl, imidazo[1,2-a]pyridinyl, benzofuran-2-yl, and thioether substituents.
Claims Coverage
The consolidated claim coverage includes one independent treatment method claim directed to administering an effective amount of a structurally defined compound for treating hematopoietic cancer. The claim centers on the compound scaffold and its defined linkage, substituent, and ring constraints, with optional pharmaceutically acceptable salt, N-oxide, solvate, or hydrate forms.
Method of treating hematopoietic cancer by administering a structurally defined compound
A method for treating a hematopoietic cancer in a subject in need thereof comprising administering an effective amount of a compound having a structural formula in which L1 is —S—, —S(O)—, or —S(O)2—; Q is —COOH; L2, L3, L4, and L5 are bonds; and R1, R3, R4, and R5 are defined by constrained alkyl, alkenyl, alkynyl, phenyl, and monocyclic heteroaryl options.
Constrained phenyl and heteroaryl substituent patterns
R3 is phenyl or monocyclic heteroaryl optionally substituted with 1-5 R3E from defined groups including oxo, optionally substituted alkyl, fluoroalkyl, halogen, —CN, —N3, SF5, and carbonyl-, thio-, sulfoxide-, sulfone-, oxy-, and amino-containing variants; R5 is phenyl or monocyclic heteroaryl optionally substituted with 1-5 R5E under analogous selection rules, with additional definitions for R3F, R3G, R5F, and R5G.
Optional pharmaceutically acceptable salt, N-oxide, solvate, or hydrate
The compound is optionally in the form of a pharmaceutically acceptable salt or N-oxide, or a solvate or hydrate.
The claim coverage is centered on a hematopoietic cancer treatment method using a structurally constrained compound scaffold with specific sulfur-containing linkage options, a carboxylic acid group, and tightly defined substituent and ring classes, including optional salt/N-oxide/solvate/hydrate forms.
Stated Advantages
Compound efficacy is especially pronounced for cancers with heterozygous mutant KRAS.
The disclosed treatment is associated with cell-cycle inhibition, including G0/G1 phase, apoptosis and/or cytotoxic effect, and glutathione synthesis inhibition.
Documented Applications
Treating a hematopoietic cancer in a subject in need thereof.
Treating hyperproliferative disorders and cancer, including KRAS-mutant cancers.
Treating diffuse large B-cell lymphoma.
Therapeutic use for cancers with heterozygous mutant KRAS.
Interested in licensing this patent?