Compounds and methods to treat or prevent CNS diseases, such as Alzheimer's disease and brain injury inflammation, are disclosed herein. The compounds are soluble epoxide hydrolase (sEH) inhibitors and have improved physical properties, blood-brain-barrier (BBB) penetration and long drug-target residence time. Pharmaceutical compositions and kits comprising the compounds are also disclosed herein.

Compounds and methods to treat or prevent CNS diseases, such as Alzheimer's disease and brain injury inflammation, are disclosed herein. The compounds are soluble epoxide hydrolase (sEH) inhibitors and have improved physical properties, blood-brain-barrier (BBB) penetration and long drug-target residence time. Pharmaceutical compositions and kits comprising the compounds are also disclosed herein.

The present invention provides certain substituted chromane, isochromane, and dihydroisobenzofuran compounds of formula (I):

##STR00001## or a pharmaceutically acceptable salt thereof, wherein ring A is a moiety selected from:

##STR00002##

and ring B, n, R.sup.1, R.sup.2, R.sup.2A, R.sup.3, and R.sup.3A are as defined herein. The compounds of the invention are useful as mGluR2 inhibitors, or mGluR2 negative allosteric modulators (NAMs), and may be useful in methods of treating a patient for diseases or disorders in which the mGluR2-NAM receptor is involved, such as Alzheimer's disease, cognitive impairment, mild cognitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, (optionally in combination with one or more additional active ingredients), and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.

The present invention provides certain substituted chromane, isochromane, and dihydroisobenzofuran compounds of formula (I):

##STR00001## or a pharmaceutically acceptable salt thereof, wherein ring A is a moiety selected from:

##STR00002##

and ring B, n, R.sup.1, R.sup.2, R.sup.2A, R.sup.3, and R.sup.3A are as defined herein. The compounds of the invention are useful as mGluR2 inhibitors, or mGluR2 negative allosteric modulators (NAMs), and may be useful in methods of treating a patient for diseases or disorders in which the mGluR2-NAM receptor is involved, such as Alzheimer's disease, cognitive impairment, mild cognitive impairment, schizophrenia and other mood disorders, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. The invention is also directed to pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, (optionally in combination with one or more additional active ingredients), and a pharmaceutically acceptable carrier, and the use of the compounds and pharmaceutical compositions of the invention in the treatment of such diseases.

A C.sub.19 diterpenoid alkaloid represented by

##STR00001##

where R.sub.1 is hydrogen, methyl or ethyl; R.sub.2 is hydroxyl, methoxy or ethoxy; R.sub.3 is hydroxyl or methoxy; and R.sub.4 is hydroxyl or methoxy. The C.sub.19 diterpenoid alkaloid is prepared from a plant material belonging to the genus Aconitum of the family Ranunculaceae through extraction, concentration and separation using silica gel column chromatography. An application of the C.sub.19 diterpenoid alkaloid in the preparation of cardiotonic drugs and drugs for preventing and/or treating heart failure is also provided.

A C.sub.19 diterpenoid alkaloid represented by

##STR00001##

where R.sub.1 is hydrogen, methyl or ethyl; R.sub.2 is hydroxyl, methoxy or ethoxy; R.sub.3 is hydroxyl or methoxy; and R.sub.4 is hydroxyl or methoxy. The C.sub.19 diterpenoid alkaloid is prepared from a plant material belonging to the genus Aconitum of the family Ranunculaceae through extraction, concentration and separation using silica gel column chromatography. An application of the C.sub.19 diterpenoid alkaloid in the preparation of cardiotonic drugs and drugs for preventing and/or treating heart failure is also provided.

Provided herein, inter alia, are compounds and methods of treating diseases including cancer, neurological disease, alcohol withdrawal, depression and anxiety, and neuropathic pain.

Provided herein, inter alia, are compounds and methods of treating diseases including cancer, neurological disease, alcohol withdrawal, depression and anxiety, and neuropathic pain.