Metalloenzyme inhibitor compounds
Inventors
Sparks, Steven • Yates, Christopher M. • Shaver, Sammy R.
Assignees
Corxel Pharmaceuticals Hong Kong Ltd • Mycovia Pharmaceuticals Inc
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Publication Number
US-10538511-B2
Publication Date
2020-01-21
Expiration Date
Abstract
Provided are compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
Core Innovation
The invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, in which A is N and W, X, Y, and Z are each CR6. The structure includes substituted benzimidazole and pyrimidine frameworks, with R1, R2, and R3 defined by broadly enumerated substituent classes, and with additional variables R4, R5, R6, and Ra-Rf allowing further substitution and, in specified cases, formation of heterocycloalkyl or cycloalkyl rings. Each n is independently 1 to 10.
The examples instantiate the Formula I framework as substituted benzimidazole/pyrimidine derivatives and related imidazo[4,5-b]pyridine or benzo[d]imidazole derivatives, including compounds bearing halogenated substituents, cyano, methoxy, trifluoromethoxy, difluoromethyl, trifluoroethyl, trifluoropropyl, carbonyl, sulfonyl, amine-bearing, and carboxylic acid or carbonitrile functionalities. Representative compounds include 2-(4-Chloropyrimidin-5-yl)-1-cyclopropyl-6-fluoro-1H-benzo[d]imidazole, 5-(1-cyclopropyl-6-fluoro-1H-benzo[d]imidazol-2-yl)pyrimidine-4-carbonitrile, and 1-cyclopropyl-2-(4-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile.
The disclosure associates selected Formula I compounds with metalloenzyme activity, including CYP11B2 inhibition and selectivity over CYP11B1, and notes that pyrimidine examples show greater metabolic stability than a pyridine counterpart. The provided content also notes in vitro assays for CYP11B2 and CYP11B1, where aldosterone and cortisol products are quantified by LC-MS to determine inhibitor IC50 values for test structures reported in Table 2.
Claims Coverage
The consolidated claim coverage includes broad compound claims to Formula I, or pharmaceutically acceptable salts thereof, together with dependent refinements to specific substituent limits and named embodiments. Across the items, the inventive features center on the A=N core with W/X/Y/Z as CR6, broad variable substituent definitions for R1-R6 and Ra-Rf, optional ring formation, selected benzimidazole-containing compounds, and pharmaceutical compositions.
Formula I compound with A=N and W/X/Y/Z = CR6
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is N and W, X, Y, and Z are CR6, with R1, R2, R3, R4, R5, R6, Ra, Rb, Rc, Rd, Re, and Rf defined by broad enumerated substituent classes and n independently 1 to 10.
Independent substituent definitions and ring formation
Each occurrence of R6 is independently hydrogen, halogen, cyano, haloalkyl, alkyl, cycloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, or carboxyl, and each occurrence of Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the enumerated classes, with Ra and Rb able to form a heterocycloalkyl ring and Re and Rf able to form a cycloalkyl ring.
Fixed R2 and R3 hydrogen
A Formula I compound, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen and R3 is hydrogen.
Restricted R6 set
A Formula I compound, or a pharmaceutically acceptable salt thereof, wherein each occurrence of R6 is independently hydrogen, halogen, or cyano.
Named Formula I sub-variants
Specific Formula I embodiments are identified through named sub-variants, including Formula I-a through Formula I-g and related Formula I variants.
Selected benzimidazole-containing compounds
A benzimidazole-containing compound selected from listed substituted 1H-benzo[d]imidazole derivatives and related compounds, including cyclopropyl- and ethyl-substituted pyrimidinyl derivatives, amides, acids, carbonitriles, methoxy, methylsulfonyl, difluoromethyl, trifluoromethyl, and fluoro-substituted members, and pharmaceutically acceptable salts thereof.
Pharmaceutical composition with carrier
A pharmaceutical composition comprising a Formula I compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Overall, the claims cover a broad Formula I scaffold with extensive variable substituent space, optional ring-forming substituent pairings, and selected narrowed embodiments through fixed substituents, restricted R6 definitions, and named Formula I variants. The scope is further extended to listed benzimidazole-containing compounds and to pharmaceutical compositions comprising a Formula I compound and a pharmaceutically acceptable carrier.
Stated Advantages
Potent CYP11B2 inhibition.
Improved selectivity versus CYP11B1.
Greater metabolic stability in cynomolgus monkey and rat liver microsomes than a pyridine counterpart.
Longer in vivo half-lives in cynomolgus monkeys than a pyridine counterpart.
Selective inhibition of aldosterone synthase (CYP11B2) to reduce aldosterone-related disease effects while avoiding cortisol suppression caused by CYP11B1 inhibition.
Documented Applications
CYP11B2 inhibition with selectivity over CYP11B1.
Treatment of metalloenzyme-mediated disorders, including aldosterone-related disease effects.
Indications noted include hypertension, primary hyperaldosteronism, resistant hypertension (RHTN), and obstructive sleep apnea (OSA).
In vitro assays for CYP11B2 and CYP11B1, with aldosterone and cortisol products quantified by LC-MS to determine inhibitor IC50 values.
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