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., Horner-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., Horner-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 are a deuterated compound of fomula (I), or a salt thereof, and methods for preparation thereof. The present disclosure may provide a mild, versatile organophotoredox method for the preparation of diverse, enantioenriched α-deuterated α-amino acids. In particular, the present disclosure may address the long-standing challenge of installing sterically demanding side chains into α-amino acids, including late-stage modifications on medicinal agents and natural products.

Disclosed are a deuterated compound of fomula (I), or a salt thereof, and methods for preparation thereof. The present disclosure may provide a mild, versatile organophotoredox method for the preparation of diverse, enantioenriched α-deuterated α-amino acids. In particular, the present disclosure may address the long-standing challenge of installing sterically demanding side chains into α-amino acids, including late-stage modifications on medicinal agents and natural products.

The present invention includes in one aspect substituted 2-oxo-1,2,5,6-tetrahydrobenzo[h]quinoline-3-carboxylic acids, analogues thereof, and compositions comprising the same, which can be used to treat and/or prevent hepatitis B virus (HBV) infection and/or hepatitis D virus (HDV) in a patient. In certain embodiments, the invention provides a compound of formula (I), or a salt, solvate, geometric isomer, stereoisomer, tautomer, and any mixtures thereof: ##STR00001##

The present invention includes in one aspect substituted 2-oxo-1,2,5,6-tetrahydrobenzo[h]quinoline-3-carboxylic acids, analogues thereof, and compositions comprising the same, which can be used to treat and/or prevent hepatitis B virus (HBV) infection and/or hepatitis D virus (HDV) in a patient. In certain embodiments, the invention provides a compound of formula (I), or a salt, solvate, geometric isomer, stereoisomer, tautomer, and any mixtures thereof: ##STR00001##

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.

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.

A compound of Formula I: ##STR00001##
wherein: X.sup.1-X.sup.8 are each independently C or N, wherein two adjacent X.sup.1-X.sup.8 are carbon-fused to a structure of Formula II: ##STR00002## X.sup.9-X.sup.12 are each independently C or N; A.sup.1, A.sup.2, and A.sup.3 are each independently selected from the group consisting of O, S, Se, N, NR, CR, CRR′, SiR, SiRR′, GeR, and GeRR′, with at least one of A.sup.1 and A.sup.2 being N or NR; each occurrence of is independently a single bond or a double bond, wherein one occurrence of is a single bond and one occurrence of is a double bond; each of R.sup.A, R.sup.B, and R.sup.c independently represents zero, mono, or up to a maximum allowed substitution to its associated ring; each of occurrence R, R′, R.sup.A, R.sup.B, and R.sup.C is independently a hydrogen or a substituent selected from the group consisting of Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, 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, R′, R.sup.A, R.sup.B, and R.sup.C comprising a group of Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX: ##STR00003## ##STR00004## each occurrence of Y.sup.1, Y.sup.2, and Y.sup.3 is independently absent, O, S, Se, NR, CRR′, SiRR′, or GeRR′; each occurrence of Ar.sup.1, and Ar.sup.2 is independently an optionally substituted aryl group or an optionally substituted heteroaryl group, wherein Ar.sup.1 and Ar.sup.2 are optionally joined or fused together to form a ring; each occurrence of X.sup.13-X.sup.20 is independently C or N, with the proviso that at least one of X.sup.13-X.sup.20 is N; each occurrence of A.sup.4 is selected from the group consisting of O, S, Se, NR, CRR′, SiRR′, and GeRR′; each occurrence of R.sup.X independently represents zero, mono, or up to a maximum allowed substitution to its associated ring; each occurrence of R.sup.X is in

A compound of Formula I: ##STR00001##
wherein: X.sup.1-X.sup.8 are each independently C or N, wherein two adjacent X.sup.1-X.sup.8 are carbon-fused to a structure of Formula II: ##STR00002## X.sup.9-X.sup.12 are each independently C or N; A.sup.1, A.sup.2, and A.sup.3 are each independently selected from the group consisting of O, S, Se, N, NR, CR, CRR′, SiR, SiRR′, GeR, and GeRR′, with at least one of A.sup.1 and A.sup.2 being N or NR; each occurrence of is independently a single bond or a double bond, wherein one occurrence of is a single bond and one occurrence of is a double bond; each of R.sup.A, R.sup.B, and R.sup.c independently represents zero, mono, or up to a maximum allowed substitution to its associated ring; each of occurrence R, R′, R.sup.A, R.sup.B, and R.sup.C is independently a hydrogen or a substituent selected from the group consisting of Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, 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, R′, R.sup.A, R.sup.B, and R.sup.C comprising a group of Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, or Formula IX: ##STR00003## ##STR00004## each occurrence of Y.sup.1, Y.sup.2, and Y.sup.3 is independently absent, O, S, Se, NR, CRR′, SiRR′, or GeRR′; each occurrence of Ar.sup.1, and Ar.sup.2 is independently an optionally substituted aryl group or an optionally substituted heteroaryl group, wherein Ar.sup.1 and Ar.sup.2 are optionally joined or fused together to form a ring; each occurrence of X.sup.13-X.sup.20 is independently C or N, with the proviso that at least one of X.sup.13-X.sup.20 is N; each occurrence of A.sup.4 is selected from the group consisting of O, S, Se, NR, CRR′, SiRR′, and GeRR′; each occurrence of R.sup.X independently represents zero, mono, or up to a maximum allowed substitution to its associated ring; each occurrence of R.sup.X is in