Disclosed herein, inter alia, are prodrug compositions and methods of using the same for treatment and detection of disease. Specifically, disclosed herein is a compound of formula (I) having spiro-fused 1,2,4-trioxolane and piperidine rings, namely, 1,2,4-trioxa-8-azaspiro[4.5] decane. Also disclosed is a pharmaceutical composition containing the compound and a pharmaceutically acceptable carrier.

##STR00001##

Disclosed herein, inter alia, are prodrug compositions and methods of using the same for treatment and detection of disease. Specifically, disclosed herein is a compound of formula (I) having spiro-fused 1,2,4-trioxolane and piperidine rings, namely, 1,2,4-trioxa-8-azaspiro[4.5] decane. Also disclosed is a pharmaceutical composition containing the compound and a pharmaceutically acceptable carrier.

##STR00001##

The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.

The present invention provides unified synthesis of the C1-C19 building blocks of halichondrins and analogs thereof using selective coupling of poly-halogenated nucleophiles in chromium-mediated coupling reactions. The present invention also provides a practical and efficient synthesis of C20-C38 building blocks of halichondrins and analogs thereof. Also provided herein are general methods of selective activation and coupling of poly-halogenated analogs with an aldehyde. The provided coupling reactions are selective for halo-enone and halo-acetylenic ketal over vinyl halide and halide attached to a sp hybridized carbon. The provided efficient selective coupling reactions can allow easy access to the C1-C19 building blocks and C20-C38 building blocks of halichondrins and analogs thereof with limited or no purification or separation of the intermediates. ##STR00001##

The present invention provides unified synthesis of the C1-C19 building blocks of halichondrins and analogs thereof using selective coupling of poly-halogenated nucleophiles in chromium-mediated coupling reactions. The present invention also provides a practical and efficient synthesis of C20-C38 building blocks of halichondrins and analogs thereof. Also provided herein are general methods of selective activation and coupling of poly-halogenated analogs with an aldehyde. The provided coupling reactions are selective for halo-enone and halo-acetylenic ketal over vinyl halide and halide attached to a sp hybridized carbon. The provided efficient selective coupling reactions can allow easy access to the C1-C19 building blocks and C20-C38 building blocks of halichondrins and analogs thereof with limited or no purification or separation of the intermediates. ##STR00001##

A compound of Formula I ##STR00001## wherein: ring B is a 5-membered heterocyclic ring, or a 6-membered carbocyclic ring; each of X.sup.1 and X.sup.2 is independently C, CR, or N, with at least one of them being C; each of X.sup.3-X.sup.11 is independently C, CR, or N, with at least one of them being N, and two adjacent of X.sup.3-X.sup.7 are carbon-fused to the shown moiety through the linkage indicated by the two squiggly lines; Y is selected from the group consisting of O, S, Se, NR′, CR′R″, and SiR′R″; each of R.sup.A and R.sup.B independently represents zero, mono, or up to a maximum allowed substitution to its associated ring; each of R, R′, R″, R.sup.A, and R.sup.B is independently a hydrogen or a substituent selected from the group consisting of —SiR.sup.1R.sup.2R.sup.3 or —GeR.sup.1R.sup.2R.sup.3, deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, boryl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof, with at least one of R.sup.A or R.sup.B comprising —SiR.sup.1R.sup.2R.sup.3 or —GeR.sup.1R.sup.2R.sup.3; each of R.sup.1, R.sup.2, and R.sup.3 is independently selected from the group consisting of alkyl, aryl group, heteroaryl group, and combinations thereof; and any two substituents are optionally joined or fused to form a ring where chemically feasible.

A compound of Formula I ##STR00001## wherein: ring B is a 5-membered heterocyclic ring, or a 6-membered carbocyclic ring; each of X.sup.1 and X.sup.2 is independently C, CR, or N, with at least one of them being C; each of X.sup.3-X.sup.11 is independently C, CR, or N, with at least one of them being N, and two adjacent of X.sup.3-X.sup.7 are carbon-fused to the shown moiety through the linkage indicated by the two squiggly lines; Y is selected from the group consisting of O, S, Se, NR′, CR′R″, and SiR′R″; each of R.sup.A and R.sup.B independently represents zero, mono, or up to a maximum allowed substitution to its associated ring; each of R, R′, R″, R.sup.A, and R.sup.B is independently a hydrogen or a substituent selected from the group consisting of —SiR.sup.1R.sup.2R.sup.3 or —GeR.sup.1R.sup.2R.sup.3, deuterium, halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, arylalkyl, alkoxy, aryloxy, amino, silyl, boryl, alkenyl, cycloalkenyl, heteroalkenyl, alkynyl, aryl, heteroaryl, acyl, carboxylic acid, ether, ester, nitrile, isonitrile, sulfanyl, sulfinyl, sulfonyl, phosphino, and combinations thereof, with at least one of R.sup.A or R.sup.B comprising —SiR.sup.1R.sup.2R.sup.3 or —GeR.sup.1R.sup.2R.sup.3; each of R.sup.1, R.sup.2, and R.sup.3 is independently selected from the group consisting of alkyl, aryl group, heteroaryl group, and combinations thereof; and any two substituents are optionally joined or fused to form a ring where chemically feasible.

The invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Homer-Wadsworth-Emmons olefination), Dieckmann reaction, catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate. The invention also provides compounds useful as intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof and methods for preparing the same.

The invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Homer-Wadsworth-Emmons olefination), Dieckmann reaction, catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate. The invention also provides compounds useful as intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof and methods for preparing the same.

Disclosed herein are tricyclic compounds, including pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine-8-amine, pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-4-amine, pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidin-4-amine, pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine, and pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine compounds, which may be useful as positive allosteric modulators of the muscarinic acetylcholine receptor M.sub.4 (mAChR M.sub.4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions.