Substituted pyrazole and pyrrole compounds and methods for using them for inhibition of initiation of translation and treatment of diseases and disorders relating thereto
Inventors
Siddiqui, M. Arshad • Ciblat, Stephane • Dery, Martin • Constantineau-Forget, Lea • Grand-Maitre, Chantal • Guo, Xiangyu • Srivastava, Sanjay • Shipps, Gerald W. • Cooper, Alan B. • Bruneau-Latour, Nicolas • Ly, Vu Linh
Assignees
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Publication Number
US-11602526-B2
Publication Date
2023-03-14
Expiration Date
Abstract
Disclosed are pyrazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure and pharmaceutically acceptable salts and N-oxides thereof, wherein X1, X2, Z1, Z2, the ring system denoted by “a”, R1, A1A, L1B, A1B, L1A, L2, Q, L3, R3, A4A, L4B, A4B, L4A, R4, L5, and R5 are as described herein. In certain embodiments, compounds disclosed herein disrupt the eIF4E/eiF4G interaction, and can be used to treat hyperproliferative disorder, a neurological disease or disorder, or autism.
Core Innovation
The invention relates to compounds defined by a structural formula with variable positions including Y, L2, Q, L1, L3, L4A, L4B, L5, R1, R3, R4, R5, and R6. Y is selected from N or CRY, L2 is selected from a bond, —CH2—, —CH(CH3)—, and —CH2CH2—, and Q is selected from —C(O)OH, —CH2OH, —C(O)OR2A, —C(O)NR2BR2A, and related carboxylate, amide, sulfoxide, sulfone, and phosphorus-containing or phosphate-like functional forms, with optional heterocycloalkyl formation when R2A and R2B are both directly bound to the same nitrogen.
The compound definitions further specify linkage and substituent patterns in which L1 is —S—, —S(O)—, —S(O)2—, —O—, or a bond, and L3, L4A, L4B, and L5 provide additional bond, heteroatom-containing, carbonyl-containing, alkylene, alkenylene, alkynylene, thio, ether, and amine-related linkages. R3 is selected from aryl and heteroaryl optionally substituted through L3C-linked aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups, and R4, R5, and R6 are selected from optionally substituted C1-C8 alkyl, alkenyl, alkynyl, hydrogen, aryl, heteroaryl, and heteroatom-containing substituent classes.
The disclosure also includes substituted thiazole-, pyrazole-, and pyrazole-thiazole carboxylic acid compounds and related heteroaromatic carboxylic acid, carboxamide, and pyrazole compounds with variable aromatic and heteroaryl substitution patterns, including dichloro, chloro, fluoro, trifluoromethyl, difluoroethyl, methyl, ethynyl-pyrimidyl, pentafluorosulfanyl, indole, benzyl, phenylethynyl, cyclopropyl, oxetane, and alkoxy substituents. The compounds are optionally present as pharmaceutically acceptable salts or N-oxides, or as solvates or hydrates, and the document links the compounds to inhibition of translation initiation, including disruption of the eIF4E/eIF4G interaction and inhibition of cap-dependent translation initiation.
Claims Coverage
The consolidated claim coverage reflects three independent inventive features: a structurally defined compound class with extensive variable linkage and substituent definitions, a method of inhibiting translation initiation by administering the compound, and a use context tied to the claimed compound. The claims also include optional pharmaceutically acceptable salt, N-oxide, solvate, or hydrate forms.
Structural formula with defined Y, L2, and Q
A compound having a structural formula wherein Y is N or CRY, RY is selected from H, —C(O)C1-C3 alkyl, —C(O)C1-C3 fluoroalkyl, —C1-C3 alkyl, —C1-C3 fluoroalkyl, CN, or halogen, L2 is selected from a bond, —CH2—, —CH(CH3)—, and —CH2CH2—, and Q is selected from carboxyl-, amide-, sulfonyl-, sulfoxide-, phosphate-, and related functional-group forms, including cases where R2A and R2B come together with nitrogen to form a heterocycloalkyl.
Linkage and substituent framework across L1, L3, L4A, L4B, L5, R3, R4, R5, and R6
The compound further defines L1 as —S—, —S(O)—, —S(O)2—, —O—, or a bond; L3 as a bond or heteroatom- and carbonyl-containing linkage; L4A, L4B, and L5 as bond or alkylene/alkenylene/alkynylene and carbonyl/thio/ether/amine-related linkages; and R3, R4, R5, and R6 as aryl, heteroaryl, alkyl, alkenyl, alkynyl, and heteroatom-containing substituent classes with enumerated substitution limits.
Inhibiting translation initiation by administering the compound
A method of inhibiting translation initiation in a subject by administering an effective amount of a compound having the structural formula of claim 1, optionally as a pharmaceutically acceptable salt or N-oxide, or as a solvate or hydrate.
The claims define a broad compound class by a structural formula with constrained variable positions and extensive substituent and linkage options, together with use of the claimed compound for inhibiting translation initiation by administration.
Stated Advantages
Inhibits cap-dependent translation initiation.
A dose-dependent reduction in heavy polysomes in BJAB cells.
Inhibition consistent with direct translation inhibition.
Decreases in cMyc and cyclin D3 proteins without mRNA changes.
Prevents disease.
Inhibits disease.
Ameliorates disease.
Partial inhibition of translation initiation is sufficient.
Disruption of the eIF4E/eIF4G interaction.
Documented Applications
Use of the compounds to inhibit cap-dependent translation initiation for diseases such as Burkitt lymphoma.
A method of inhibiting translation initiation in a subject by administering an effective amount of the compound.
Therapeutic treatment defined as preventing disease, inhibiting disease, or ameliorating disease by administering the compound to elicit inhibition of translation initiation in a subject.
Pharmaceutical formulations and dosage forms for delivering the compound, including oral, parenteral, topical, inhalation, and rectal dosage forms using pharmaceutically acceptable carriers and excipients.
Therapeutic context including hyperproliferative disorders, neurological disease or disorder, and autism.
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