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-10537558-B2
Publication Date
2020-01-21
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 (I) and pharmaceutically acceptable salts and/V-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 provides compounds having a structural formula in which multiple variable groups are defined by specific allowed bond types and functional groups, including L2, Q, L1, L3, R1, R3, L4, L5, R4, R5, and R6. Q is selected from carboxylic acid, ester, and carboxamide variants, with further options in which amide substituents either remain separate or form a heterocycloalkyl. The scaffold further constrains linker elements and substituent groups by selecting permitted alkyl, alkenyl, alkynyl, heteroaryl, cycloalkyl, and heterocycloalkyl structures, and by specifying optional salt, N-oxide, solvate, or hydrate forms.
The structural formula includes L2 selected from a bond, —CH2—, —CH(CH3)—, or —CH2CH2—, and L1 selected from —S—, —S(O)—, or —S(O)2—. L3 is selected from defined linkage groups including —C(O)—, —S—, —S(O)1-2—, —O—, —NR6—, —CH2—, —CH(CH3)(OH)—, —CH(OH)—, and —CH2CH2—, while R1 is selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, optionally substituted C1-C8 alkynyl, and hydrogen. R3 is selected from phenyl and heteroaryl optionally substituted with single L3C-linked phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl forms.
Additional structural variability is defined through L4 and L5 as selected from bonds and a range of linkage types including C(O) variants, S and O linkers, NR6-containing linkers, and S(O)1-2 and OS(O)1-2 forms, together with R4, R5, and R6 choices. The claim scope further includes constraints on cycloalkyl, heterocycloalkyl, and optionally substituted heteroaryl ring sizes and heteroatom content. The compounds are optionally provided as pharmaceutically acceptable salts or N-oxides, or as solvates or hydrates.
Claims Coverage
The consolidated claim coverage reflects 2 independent claim themes: a structurally defined compound scaffold with multiple constrained variable regions, and a method of inhibiting initiation of translation of mRNA into protein by administering the compound.
Structural scaffold with constrained variable groups
A compound having a structural formula wherein L2 is selected from a bond, —CH2—, —CH(CH3)—, or —CH2CH2—; Q is selected from C(O)OH, C(O)O(C1-C3 alkyl), or C(O)NR2BR2A, including a heterocycloalkyl-forming option with defined R2A and R2B selections; L1 is selected from —S—, —S(O)—, or —S(O)2—; and R1 is selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, optionally substituted C1-C8 alkynyl, and hydrogen.
Phenyl or heteroaryl R3 with L3C-linked substitution
R3 is selected from phenyl and heteroaryl each optionally substituted with a single substituent selected from —L3C-(phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl optionally substituted), where each L3C is selected from a bond, methylene, ethylene, —C(O)—, —S—, —S(O)1-2—, —O—, or —NR3G—, and the allowed substituent classes include oxo, halogen, —CN, SF5, and multiple carbonyl- and thio/oxy-containing groups.
Terminal linker and substituent framework
L4 and L5 are selected from bonds and defined linker types including C(O), S, S(O)1-2, O, NR6, and related carbonyl/thio/oxy linkers; R4 is selected from optionally substituted C1-C8 alkyl, alkenyl, alkynyl, and hydrogen; R5 is selected from phenyl and heteroaryl optionally substituted with 1-5 R5E groups; and R6 is selected from hydrogen and specified C1-C3 alkyl, fluoroalkyl, hydroxyalkyl, aminoalkyl, thioalkyl, and related sulfonyl/carboxylate/ether options.
Optional salt, N-oxide, solvate, or hydrate forms
The compound is optionally in the form of a pharmaceutically acceptable salt or N-oxide, or a solvate or hydrate.
Inhibiting initiation of translation of mRNA into protein
A method of inhibiting initiation of translation of mRNA into protein by administering to a subject an effective amount of the compound, optionally as a pharmaceutically acceptable salt or N-oxide, or as a solvate or hydrate.
The claim coverage centers on a single highly constrained compound scaffold with defined linker, functional group, and ring-substitution selections, together with optional salt, N-oxide, solvate, and hydrate forms, and a method claim directed to inhibiting initiation of translation of mRNA into protein.
Stated Advantages
Disrupts the eIF4E-eIF4G interaction.
Inhibits cap-dependent initiation of mRNA translation.
Inhibits initiation of translation of mRNA into protein.
Used for treatment of hyperproliferative disorders.
Used for treatment of neurological diseases/disorders.
Used for treatment of autism.
Provides prophylaxis.
Inhibits disease.
Ameliorates disease.
Reduces symptoms.
Elicits a biological effect including inhibition of translation initiation of mRNA into protein.
Documented Applications
Treatment of hyperproliferative disorders.
Treatment of neurological diseases/disorders.
Treatment of autism.
Therapeutic treatment by inhibiting initiation of mRNA translation to protein, including cap-dependent translation, with treatment described for conditions such as Burkitt lymphoma.
A method for inhibiting initiation of translation of mRNA into protein by administering to a subject an effective amount of the compound.
Prophylaxis and inhibition of disease, including treatment contexts aimed at amelioration of disease and symptom reduction.
A biological activity example is provided using BJAB cell proliferation with EC50 categorization.
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