Somatostatin modulators and uses thereof
Inventors
Zhao, Jian • Han, Sangdon • Kim, Sun Hee • Wang, Shimiao • ZHU, Yunfei
Assignees
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Publication Number
US-11414397-B2
Publication Date
2022-08-16
Expiration Date
Abstract
Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.
Core Innovation
The invention relates to compounds having a quinoline-containing core and variable substituents defined by multiple R-group positions, together with pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof. The structure includes substituents such as hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, monocyclic carbocycle, monocyclic heterocycle, —CN, —OH, —OR14, —CO2R15, —CH2CO2R15, carbonyl-, amide-, sulfonyl-, and related functional-group options. The aromatic ring RB is phenyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, with substitution rules and adjacent-substituent ring-forming rules.
The disclosed compound set includes quinolin-6-yl derivatives linked to 2-hydroxybenzonitrile, benzonitrile, phenol, carboxamide, benzodiazol-2-one, benzoxazol-2-one, and pyridine carboxamide or carbonitrile motifs. The examples include fluorinated aromatic substitution patterns and cyclic amine-containing fragments such as 4-aminopiperidin-1-yl, aminomethylazetidinyl, azetidin-1-yl, morpholinyl, piperazinyl, and fused bicyclic amine motifs, together with trans, cis, racemic, and defined enantiomeric configurations. The named compounds also include methoxy, methoxymethoxy, hydroxyimino, and methoxyimino substitutions.
The document additionally describes a small-molecule somatostatin modulator framework, with Formula (A) and Formula (I) using variable ring A and ring B and substituent groups R^A and R^B. The compounds are non-peptidyl somatostatin modulators intended to modulate somatostatin receptor subtypes, including SSTR2, and to inhibit hormone secretion.
Claims Coverage
The consolidated claim coverage includes broad structural genus claims and multiple enumerated compound claims, with four inventive feature groupings across the inputs. The core coverage is a quinoline-containing or related heteroaryl scaffold with extensive variable substituent options, adjacent-ring-closure rules, and pharmaceutically acceptable salt, solvate, diastereomeric mixture, and individual enantiomer coverage.
Variable quinoline-containing scaffold
A compound having a specified structure with multiple independently variable substituents, including hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, monocyclic carbocycle, monocyclic heterocycle, —CN, —OH, —OR14, —CO2R15, —CH2CO2R15, carbonyl-, amide-, sulfonyl-, and related functional groups, together with pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof.
Substituted aromatic ring defined by RB
RB is an unsubstituted or substituted phenyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, with substitution by pRc and qRd and additional substitution limits across Rc and Rd.
Ring-formation rules for adjacent substituents
When one Rc and one Rd are on adjacent atoms of RB, the adjacent Rc and Rd groups are taken together with the intervening atoms to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or 5- or 6-membered monocyclic heterocycle; related ring-forming rules also apply to other substituent pairs in the broader claim framework.
Enumerated quinoline-containing compound set
A compound selected from the explicitly listed quinoline-containing structures, including quinolin-6-yl derivatives linked to 2-hydroxybenzonitrile, benzonitrile, phenol, carboxamide, benzodiazol-2-one, benzoxazol-2-one, and related motifs, with fluorinated aromatic substitution patterns and amino-containing heterocycles such as 4-aminopiperidin-1-yl, aminomethylazetidinyl, azetidin-1-yl, morpholinyl, piperazinyl, and fused bicyclic amine motifs; pharmaceutically acceptable salts are included.
The claims cover a broad variable-substituent quinoline-containing compound class plus specific enumerated quinoline-based compounds, with repeated inclusion of pharmaceutically acceptable salts and, where stated, solvates, diastereomeric mixtures, and individual enantiomers.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Pharmaceutical composition comprising the compound and at least one pharmaceutically acceptable excipient.
Modulating somatostatin receptor subtype 2 (SSTR2) activity in a mammal by administering the compound or a pharmaceutically acceptable salt thereof.
Non-peptidyl somatostatin modulators intended to modulate somatostatin receptor subtypes and inhibit hormone secretion.
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