Inhibitors of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and methods of use thereof
Inventors
Kasibhatla, Srinivas Rao • Kalakuntla, Raman Kumar • Weston, Alexis • Thode, Trason • Sharma, Sunil • Kaadige, Mohan R.
Assignees
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Publication Number
US-11591313-B2
Publication Date
2023-02-28
Expiration Date
Abstract
Compounds and methods for their preparation and use as therapeutic or prophylactic agents, for example for treatment of cancer, bacterial or viral diseases by targeting Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 (ENPP1).
Core Innovation
The invention relates to compounds of Formula II defined by a specified core structure with variable heteroatom positions X and Z, a substituent W selected from defined groups or a direct bond, and multiple independently selected substituents R1 through R11. The compound definitions include explicit constraints on the allowable substituent sets, including n being between 1 and 3 and R11 being independently selected from hydrogen, halogen, COOEt, COOH, and CN. The scope further includes isomers, hydrates, solvates, polymorphs, tautomers, and pharmaceutically acceptable salts of the Formula II compound.
The disclosed work also describes quinazolinyl and quinoline-derived sulfamide and sulfonamide compounds, including quinazolinyl-pyridine sulfamide, quinoline-based sulfonamide/amine derivatives, and quinazoline derivatives bearing diazabicyclo[3.2.1]octane, diazepane, and azepane analogs. The examples present preparation of specific numbered compounds and intermediates, including Boc-protected sulfamoyl carbamates, free sulfamides, hydrochloride salts, and related analogs, with analytical characterization by 1H NMR, MS, and LCMS.
The chemistry further includes compounds built around dimethoxyquinoline or dimethoxyquinazoline carbonitrile motifs linked through aminoalkyl or oxy-linked chains, followed by sulfonamide installation, deprotection, and purification to obtain defined final compounds. The disclosed examples identify compounds such as Compound 047, Compound 046, Compound 035, Compound 008, and other numbered analogs, and report structures, yields, and analytical data to support compound identity.
Claims Coverage
The claim coverage centers on a broad Formula II compound class with structured heteroatom positions and constrained substituent sets. Across the independent claims, the coverage addresses the Formula II framework, W selection or a direct bond, multiple R-group constraints including n = 1 to 3 and R11 selections, and explicit inclusion of isomers, hydrates, solvates, polymorphs, tautomers, and pharmaceutically acceptable salts. Some dependent claim language further narrows halogen substitution, specific W choices, and pharmaceutical compositions.
Formula II compound with defined heteroatom positions
A compound of Formula II wherein X is N or CR11 and Z is C or N.
Defined substituent option W or direct bond
W is selected from C1-C5 alkyl, —C(=O)—(CH2)n—, —(C1-C5 alkyl)-N—, NH, and a direct bond, with n being an integer between 1 and 3.
Constrained substituent sets for R1 to R3 and related groups
Each R1, R2 and R3 is independently selected from hydrogen, halogen, CN, ORa, —C(=O)NRbRc, —NRbRc, —C(=O)Rd, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; each Ra is independently selected from hydrogen, lower alkyl, and —(CH2)n—C(=O)NRbRc, aralkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl; each Rb and Rc is independently selected from hydrogen, lower alkyl, and lower aryl, heterocycloalkyl, or cycloalkyl; Rd is independently selected from —ORe and lower alkyl; and Re is independently selected from hydrogen, lower alkyl, and lower aryl.
R11 selection and ring-bridge options
R11 is independently selected from hydrogen, halogen, COOEt, COOH, and CN; and R7, R8 and R9 are independently selected from H, halogen and lower alkyl, with R8 and R9 optionally forming a bridge across the 7-membered ring with 1 or 2 atoms.
Isomer, hydrate, solvate, polymorph, tautomer and salt coverage
The compound is covered as an isomer, hydrate, solvate, polymorph, tautomer, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with carrier
A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier.
Selected compound from group
A compound is selected from the group consisting of the specified compounds.
Specific halogen refinement
The compound of claim 1 in which R8 and R9 are both halogens, with fluorine specified for the halogen substituents in a dependent refinement.
Specific X, Z, W, and R1 to R3 narrowing
The compound in which X and Z are N, W is selected from specified carbon-containing substituents or a direct bond, and R1, R2, and R3 are selected from CH3O or H.
Specific heteroaryl options for W
W is chosen from 4,5-imidazole, 2-oxazole, 3-pyrrole, pyrazole, or thiazole.
The claim coverage is centered on a Formula II chemical scaffold defined by variable heteroatom positions, a limited set of W options or direct bond, and multiple constrained substituent groups R1 through R11, including n between 1 and 3 and R11 selected from hydrogen, halogen, COOEt, COOH, or CN. The scope also includes isomeric and salt forms, optional bridge formation across a 7-membered ring, and pharmaceutical compositions comprising a therapeutically effective amount with a pharmaceutically acceptable carrier.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Example preparation and characterization of specific quinazoline-1,4-diazepane sulfonamide derivatives and related analogs, including reported salt forms and analytical data.
ENPP1-targeting quinazoline derivatives and related in vitro ENPP1 assay results, including ENPP1 thermal shift assay, ENPP2 assay, cell-based ENPP selectivity assay, and solubility and stability assay descriptions.
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