Process for the synthesis of (s)-3-amino-4-(difluoromethylidene)cyclopent-1-en-1-carboxylic acid

Abstract

The present application relates to processes for the synthesis of (S)-3-amino-4- (difluoromethylidene)cyclopent-1-en-1-carboxylic acid. Provided herein are processes, compounds, and compositions for the preparation of (S)-3-amino-4- (difluoromethylidene)cyclopent-1-en-1-carboxylic acid. Also provided herein are pharmaceutical compositions containing (S)-3-amino-4- (difluoromethylidene)cyclopent-1-en-1-carboxylic acid.

Description

[0001] This application is a divisional application of the application filed on May 28, 2019, with application number 201980049170.X and invention title "Process for synthesizing (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid".

[0002] This invention was carried out with government support under license number R01DA030604 granted by the National Institutes of Health (NIH). The government holds certain rights in this invention.

[0003] Cross-reference to related applications

[0004] This application claims the benefits and priorities of U.S. Provisional Application No. 62 / 676,373, filed May 25, 2018; U.S. Provisional Application No. 62 / 814,026, filed March 5, 2019; and U.S. Provisional Application No. 62 / 835,776, filed April 18, 2019, all of which are incorporated herein by reference in their entirety. Technical Field

[0005] Synthesis of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid. background

[0006] (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid is an inhibitor of gamma-aminobutyric acid aminotransferase (GABA-AT) and has been shown as a potential treatment for epilepsy, addiction, and hepatocellular carcinoma. See, for example, U.S. Patent No. 9,670,141 and Juncos et al., J. Am. Chem. Soc. 2018, 140, 2151-2164. GABA is an inhibitory neurotransmitter in the central nervous system (CNS). Seizures may occur when the concentration of GABA in the brain drops below a threshold level. Elevating GABA levels has been shown to stop seizures. Furthermore, increasing GABA concentration antagonizes the release of dopamine from the nucleus accumbens and is considered a potential treatment for addiction, the nucleus accumbens being a hypothalamic region associated with reward and motivation. Unfortunately, direct administration of GABA is not feasible because GABA does not cross the blood-brain barrier. However, GABA concentration can be increased by inhibiting GABA aminotransferase (GABA-AT). 4-Aminohexanoic acid, also known as aminohexenoic acid (as... VIMPAT® (marketed), which is currently the only FDA-approved inhibitor of GABA-AT for the treatment of infantile spasms and has been shown to be a possible treatment for addiction. However, vigabatrin requires large doses (1 g / day - 3 g / day), inhibits multiple GABA receptors, and causes retinal damage in 25-40% of patients with prolonged use.

[0007] In vivo studies in rats indicate that (S)-3-amino-4-(difluoromethylidene)cyclopent-1- ene-1-carboxylic acid is superior to previous inhibitors of GABA-AT in inhibiting the release of dopamine in the striatum after exposure to cocaine or nicotine. (S)-3-amino-4- (difluoromethylidene)cyclopent-1 -ene-1 -carboxylic acid does not inhibit off-target aminotransferases such as alanine aminotransferase and aspartate aminotransferase. Additionally, it does not inhibit the hERG potassium ion channel or multiple microsomal cytochrome P450 enzymes.

[0008] According to the prior art, (S)-3-amino-4-(difluoromethylidene)cyclopent-1 -ene-1 - carboxylic acid has been synthesized from (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid ((1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid) (also known as CPP-115) in six steps.

[0009]

[0010] See also, for example, Juncosa et al., J. Am. Chem. Soc., supra, and U.S. Patent Nos. 7,381,748, 6,794,413, and 9,670,141, each incorporated by reference herein in their entirety.

[0011] CPP-115 is an inhibitor of GABA-AT and is currently in clinical trials for the treatment of epilepsy. It has been determined that (S)-3-amino-4-(difluoromethylidene)cyclopent-l- ene-1-carboxylic acid is 9.8 times more potent as an activator of GABA-AT than CPP-115. Since the synthesis of CPP-115 requires 8 steps, the total synthesis step count from commercial starting materials to (S)-3-amino-4-(difluoromethylidene)cyclopent-l-enel-carboxylic acid is 14 steps with a total yield of 3.7%. The synthesis of CPP-115 involves the use of highly flammable tert-butyllithium (in gram quantities) to install the 1,1'-difluoroalkene, which limits the scale at which the reaction can be run. In addition, the existing synthesis relies on the introduction of the cyclopentene via selenium oxide elimination. The protected CPP-115 is selenized in 70% yield, although the yield can vary depending on scale. The a-elimination of Compound A produces a mixture of isomers that are chromatographically inseparable in a 5:3 ratio favoring (S)-3-amino-4-(difluoromethylidene)cyclopent-l-enel-carboxylic acid. Compound B is selectively degraded using thiosalicylic acid to produce (S)-3-amino-4-(difluoromethylidene)cyclopent-l-enel-carboxylic acid in 36% overall yield from Compound A. Only small batches of (S)-3-amino-4-(difluoromethylidene)cyclopent-l-enel-carboxylic acid can be obtained using the existing technology. In addition, the production of selenols in the penultimate step complicates the synthesis and purification of (S)-3-amino-4-(difluoromethylidene)cyclopent-l-enel-carboxylic acid since selenium is toxic and regulated by the FDA at levels below 80 μg / day - 150 μg / day.

[0012] Accordingly, there is a need for a process that is more amenable to large scale preparation of (S)-3-amino-4-(difluoromethylidene)cyclopent-l-enel-carboxylic acid that will reduce costs, reduce the number of preparation steps, reduce hazardous environmental waste, and improve the efficiency of preparation.

[0013] SUMMARY

[0014] A process for preparing (S)-3-amino-4-(difluoromethylidenyl)cyclopent-1 - ene-1 -carboxylic acid (1) or a salt thereof is provided, which process comprises converting (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (2) to (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3). Converting (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3) to (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4). Converting (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4) to (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25). Converting (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25) to (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5). Converting (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) to (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6). Converting (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-azabicyclo[2.2.1]heptan-3-one (7). Converting (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-azabicyclo[2.2.1]heptan-3-one (7) to (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8). Converting (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) to (S)-methyl 3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-1 - ene-1 -carboxylate (9). Converting (S)-methyl 3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-1 - ene-1 -carboxylate (9) to (S)-3-amino-4-(difluoromethylidenyl)cyclopent-1 - ene-1 -carboxylic acid (1).

[0015] (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l-en- 1 -carboxylic acid (1) is prepared by the processes described herein. Compositions comprising (S)-3-amino-4- (difluoromethylidenyl)cyclopent-l-en-l-carboxylic acid (1) are described herein. Pharmaceutical compositions comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l-en-l-carboxylic acid (1) are described herein.

[0016] Provided herein is (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3). Provided herein is a composition comprising (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3). Provided herein is a pharmaceutical composition comprising (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3). (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3) is prepared by the processes disclosed herein.

[0017] Provided herein is (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6-yl acetate (4). Provided herein is a composition comprising (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6-yl acetate (4). Provided herein is a pharmaceutical composition comprising (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6-yl acetate (4). (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6-yl acetate (4) is prepared by the processes disclosed herein.

[0018] Provided herein is (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (25). Provided herein is a composition comprising (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25). Provided herein is a pharmaceutical composition comprising (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25). (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25) is prepared by the processes disclosed herein.

[0019] Provided herein is (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane- 3,6-dione (5). Provided herein is a composition comprising (1R,4R,7R)-7-bromo-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5). Provided herein is a pharmaceutical composition comprising (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptane-3,6-dione (5). (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptane-3,6-dione (5) is prepared by the processes described herein.

[0020] Provided herein is (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6). Provided herein is a composition comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3- one (6). Provided herein is a pharmaceutical composition comprising (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6). (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan- 3-one (6) is prepared by the processes described herein.

[0021] Provided herein is (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]heptan-3-one (7). Provided herein is a composition comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7). Provided herein is a pharmaceutical composition comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7). (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7) is prepared by the processes described herein.

[0022] Provided herein is (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]heptan-3-one (7). Provided herein is a composition comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7). Provided herein is a pharmaceutical composition comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7). (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7) is prepared by the processes described herein.

[0023] Provided herein is (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]heptan-3-one (7). Provided herein is a composition comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7). Provided herein is a pharmaceutical composition comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7). (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7) is prepared by the processes described herein.

[0024] Provided herein is (S)-3-((tert-butoxycarbonyl)amino)-4- (difluoromethyl)cyclopent-1 -en-1 -carboxylic acid (19). Provided herein is a composition comprising (S)-3-((tert-butoxycarbonyl)amino)-4- (difluoromethyl)cyclopent-1 -en-1 -carboxylic acid (19). Provided herein is a pharmaceutical composition comprising (S)-3-((tert- butoxycarbonyl)amino)-4-(difluoromethyl)cyclopent-1 -en-1 -carboxylic acid (19). (S)-3-((tert-butoxycarbonyl)amino)-4- (difluoromethyl)cyclopent-1 -en-1 -carboxylic acid (19) is prepared by a process described herein.

[0025] Provided is a composition comprising (S)-3-amino-4- (difluoromethyl)cyclopent-1 -en-1 -carboxylic acid (1) and (1S,3S)-3- amino-4-(difluoromethyl)cyclopentane-1 -carboxylic acid. Provided is a pharmaceutical composition comprising (S)-3-amino-4- (difluoromethyl)cyclopent-1 -en-1 -carboxylic acid (1) and (1S,3S)-3- amino-4-(difluoromethyl)cyclopentane-1 -carboxylic acid.

[0026] Provided is a composition comprising (S)-3-amino-4- (difluoromethyl)cyclopent-1 -en-1 -carboxylic acid (1) and one or more of (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5- en-3-one (3), (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2- azabicyclo[2.2.1]heptan-6-yl acetate (4), (1R,4R,6S,7R)-7-bromo-6- hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25), (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6- dione (5), (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6), (1R,4R,7R)-7-bromo-6- (difluoromethyl)-2-azabicyclo[2.2.1]heptan-3-one (7), (1R,4R,7R)-7-bromo-6- (difluoromethyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8), (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl)cyclopent-1 -en-1 - carboxylic acid methyl ester (9), or (S)-3-((tert-butoxycarbonyl)amino)-4- (difluoromethyl)cyclopent-1 -en-1 -carboxylic acid (19).

[0027] A process for preparing (S)-3-amino-4-(difluoromethylidene)cyclopent-l-en- 1 -carboxylic acid (1) is provided, which process comprises converting cyclopent-3- enecarboxylic acid ethyl ester (10) to (3R,4S)-3-((tert-butoxycarbonyl)amino)- 4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11). Converting (3R,4S)-3- ((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11) to (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentane carboxylic acid ethyl ester (12). Converting (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo- cyclopentane carboxylic acid ethyl ester to (9S)-9-(tert-butoxycarbonylamino)- 1,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13). Converting (9S)-9- (tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13) to (S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonene-7- carboxylic acid ethyl ester (14). Converting (S)-9-(tert-butoxycarbonylamino)-l,4- dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14) to (S)-3-((tert- butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-l-en-l-carboxylic acid ethyl ester (15). Converting (S)-3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidene)cyclopent-l-en-l-carboxylic acid ethyl ester (15) to (S)-3- amino-4-(difluoromethylidene)cyclopent-l-en-l-carboxylic acid (1).

[0028] Provided herein is (3R,4S)-3-((tert-butoxycarbonyl)amino)-4- (hydroxy)cyclopentane carboxylic acid ethyl ester (11). Provided herein is a composition comprising (3R,4S)-3-((tert-butoxycarbonyl)amino)-4- (hydroxy)cyclopentane carboxylic acid ethyl ester (11). Provided herein is a pharmaceutical composition comprising (3R,4S)-3-((tert-butoxycarbonyl)amino)-4- (hydroxy)cyclopentane carboxylic acid ethyl ester (11). (3R,4S)-3-((tert- butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11) is prepared by a process described herein.

[0029] Provided herein is (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo- cyclopentane carboxylic acid ethyl ester (12). Provided herein is a composition comprising (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo- cyclopentane carboxylic acid ethyl ester (12). Provided herein is a pharmaceutical composition comprising (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo- cyclopentane carboxylic acid ethyl ester (12). (3R)-3-((tert-butoxycarbonyl)amino)-4- oxo-cyclopentane carboxylic acid ethyl ester (12) is prepared by a process described herein.

[0030] Provided herein is (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13). Provided herein is a composition comprising (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13). Provided herein is a pharmaceutical composition comprising (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13). (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13) is prepared by a process described herein.

[0031] Provided herein is (S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14). Provided herein is a composition comprising (S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14). Provided herein is a pharmaceutical composition comprising (S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14). (S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14) is prepared by a process described herein.

[0032] Provided herein is (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1-ene-1-carboxylic acid ethyl ester (15). Provided herein is a composition comprising (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1-ene-1-carboxylic acid ethyl ester (15). Provided herein is a pharmaceutical composition comprising (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1-ene-1-carboxylic acid ethyl ester (15). (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1-ene-1-carboxylic acid ethyl ester (15) is prepared by a process described herein.

[0033] Provided are compositions comprising (S)-3-amino-4-(difluoromethylidene)cyclopent-l- ene-1-carboxylic acid (1) and one or more of the following: cyclopent-3-ene-carboxylic acid ethyl ester (10), (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11), (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentane carboxylic acid ethyl ester (12), (9S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13), (S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14), or (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-l-ene-l-carboxylic acid ethyl ester (15). BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 is the 500 MHz1H NMR spectrum of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6). 1 H NMR spectrum (CDC13).

[0035] Figure 2 is the 500 MHz1H NMR spectrum of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6). 13 C NMR spectrum (CDC13; 126 MHz).

[0036] Figure 3 is the 127.5 MHz F NMR spectrum of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6). 19 F NMR spectrum (CDC13).

[0037] Figure 4 is the 500 MHz1H NMR spectrum of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]heptan-3-one (7). 1 H NMR spectrum (CDC13).

[0038] Figure 5 is the 500 MHz1H NMR spectrum of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]heptan-3-one (7). 13 C NMR spectrum (CDC13; 126 MHz).

[0039] Figure 6It is (1R,4R,7R)-7-bromo-6-(difluoromethylene)-2-azabicyclo[2.2.1]hepta-3-one (7) at 127.5 MHz. 19 F NMR spectrum (CDCl3).

[0040] Figure 7 It is the 500 MHz of (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid methyl ester (9). 1 1H NMR spectrum (CDCl3).

[0041] Figure 8 It is (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid methyl ester (9) 13 C10 NMR spectrum (CDCl3; 126 MHz).

[0042] Figure 9 It is methyl (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylate (9) at 127.5 MHz. 19 F NMR spectrum.

[0043] Figure 10 It is (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid (1) at 500 MHz 1 1H NMR spectrum (CDCl3).

[0044] Figure 11 It is (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid (1). 13 C10 NMR spectrum (CDCl3; 126 MHz).

[0045] Figure 12 It is (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid (1) at 127.5 MHz. 19 F NMR spectrum.

[0046] Xiangshu

[0047] This document provides a process, compound, and composition for the preparation of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid (1). The process described herein is scalable and yield-efficient compared to existing techniques, avoids the use of selenium and tert-butyllithium, and avoids the formation of multiple isomers from α-elimination. In embodiments, the process described herein involves eliminating the leaving group from the β-position, eliminating the resulting mixture of isomers, reducing the number of synthetic steps from 14 to 9 compared to existing techniques, and increasing the yield from 3.7% to 8.1%.

[0048] In embodiments, the synthesis of (S)-3-amino-4-(difluoromethylidene)cyclopent-l- ene-1-carboxylic acid (1) is shown in Scheme 1, starting from ((1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one) (2).

[0049] Scheme 1

[0050]

[0051] AC = acetyl, PMB = 4-methoxybenzyl, PG = protecting group

[0052] According to Scheme 1, a process for preparing (S)-3-amino-4- (difluoromethylidene)cyclopent-1 -en-1 -carboxylic acid (1), or a salt thereof, is provided, which process comprises converting ((1R,4S)-2-azabicyclo[2.2.1]heptan-5- en-3-one) (2) to (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-5- en-3-one (3). Converting (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-5- en-3-one (3) to (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan- 6-yl acetate (4). Converting (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2- azabicyclo[2.2.1]heptan-6-yl acetate (4) to (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptane-3,6-dione (5). Converting (1R,4R,7R)-7-bromo-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) to (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6). Converting (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]heptan-3-one (7). Converting (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7) to (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8). Converting (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert-butoxycarbonyl)-2- azabicyclo[2.2.1]heptan-3-one (8) to (S)-methyl 3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidene)cyclopent-1 -en-1 -carboxylate (9). Converting (S)-methyl 3-((tert- butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1 -en-1 -carboxylate (9) to (S)-3-amino-4-(difluoromethylidene)cyclopent-1 -en-1 -carboxylic acid (1).

[0053] In embodiments, the synthesis of (S)-3-amino-4-(difluoromethylidene)cyclopent-1 - en-1 -carboxylic acid (1) is shown in Scheme 1A.

[0054] Scheme 1A

[0055]

[0056] Abbreviations: PMBOH: 4-methoxybenzyl alcohol; DMF: N-N- dimethylformamide; DBDMH: 1,3-dibromo-5,5-dimethylhydantoin; TPAP: tetrapropylammonium perruthenate; NMO: N-methylmorpholine N-oxide; CAN: cerium ammonium nitrate; DMAP: N,N-dimethylaminopyridine

[0057] In an embodiment, starting from ((1R,4S)-2-azabicyclo[2.2.1]heptan-5-one) (2) (also known as Vince lactam) and following a modification of the literature procedure, such as using PMBOH / HCl (see, Qiu, J.; Silverman, R. B. J. Med. Chem. 2000, 43, 706-720), (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4) was obtained in multi-gram scale (Scheme 1A): a. PMBOH, HCl, NaH, THF / DMF; b. DBDMH, AcOH. Alcoholysis and oxidation of the acetate produced ketone (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3,6-dione (5): c. K2CO3, alcohol; d. TPAP, NMO, MS, CH2Cl2. The foregoing allowed the difluoro-Horner-Wadsworth-Emmons olefination of ketone 5. When 2-((difluoromethyl)sulfinyl)pyridine (20) (also known as Hu reagent) was used as the base and KO t Bu together with the use of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6): e. 2-((difluoromethyl)sulfinyl)pyridine (20), KO tBu, DMF, then NH4CI, then HC1. Alternatively, e. can be tert-butyllithium and F2CHP(O)(OEt)2(see, Pan, Y.; Qiu, J.; Silverman, R. B. J. Med. Chem. 2003, 46, 5292-5293). The next step is alcoholysis and elimination of the lactam. Deprotection of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) to produce (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7): f. CAN, MeCN, H2O. A small amount of the 4-methoxybenzoyl protected lactam can also be isolated. Boc protection of the lactam (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]heptan-3-one (7) produces (1R,4R,7R)-7-bromo-6-(difluoromethylidene)- 2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8): g. Boc2O, DMAP, Et3N, CH2Cl2. Alcoholysis of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert- butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) with K2CO3 and an alcohol leads, in two steps, to the subsequent elimination of the bromide to produce (S)-3-((tert- butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1 -ene-1 -carboxylate or (S)-3- ((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1 -ene-1 -carboxylate (9): h. K2CO3, alcohol. Final deprotection in HC1 produces (S)-3-amino-4- (difluoromethylidene)cyclopent-1 -ene-1 -carboxylic acid (1) without observable isomerization or degradation: i. HC1, dioxane. Although methanol is shown in the above scheme, it is understood that an alcohol such as ethanol or propanol can be used as the alcohol.

[0058] In an embodiment, (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (2) (Vince lactam) is started with and following a modification of literature procedures (see, Qiu et al. supra) such as using PMBOH / HCl to obtain (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4) on a multi-gram scale (Scheme 1A): a. PMBOH (1-2 equiv), HCl, NaH (0.8-1.5 equiv) 0 °C-5 °C, THF / DMF (0.75-1.5:0.75-1.5), 4 h-8 h; b. DBDMH (0.4-0.8 equiv), AcOH, 15 °C-30 °C, 4 h-8 h; methanolysis and oxidation of the acetate to the ketone (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3,6-dione (5): c. K2CO3(2-4 equiv), MeOH 0.5 h-2 h; d. TPAP (0.001-0.2 equiv), NMO (1.0-3.0 equiv), MS, CH2Cl2, 15 h-25 h. The foregoing allows for difluoro-Horner-Wadsworth-Emmons olefination of ketone 5. When 2-((difluoromethyl)sulfinyl)pyridine (20) (Hu reagent) is used with KO t Bu together with 6 M HCl quench in 15 min to 2 h: e. 2-((difluoromethyl)sulfinyl)pyridine (20) (1.0-1.5 equiv), KO tBu (1.25-1.75 equivalents), DMF, -80 °C to 40 °C, 15 min-60 min, then NH4CI, then HCl, then 15 °C to 30 °C, then 40 °C to 80 °C, 1 h. Alternatively, e. can be tert-butyllithium and F2CHP(O)(OEt)2(see, Pan, Y. et al. supra). The next step is the methanolysis and elimination of the lactam. Deprotection of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) to produce (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7): f. CAN (2-4 equivalents), MeCN, H2O, -10 °C to 10 °C, 0.75 h-2 h. A small amount of the 4-methoxybenzoyl protected lactam can also be isolated. Boc protection of the lactam (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]heptan-3-one) (7) produces (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8): g. Boc2O (1.0-1.5 equivalents), DMAP (0.01-0.5 equivalents), Et3N (1.0-2.0 equivalents), CH2CI2, 0.5 h-2.0 h. Methanolysis of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert- butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) with K2CO3 and methanol in two steps leads to the subsequent elimination of the bromide to produce (S)-3-((tert- butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1 -ene-1 -carboxylate: h. K2CO3 (2-4 equivalents), MeOH, 4 h-8 h. Final deprotection in 6 M HCl at 70 °C-90 °C produces (S)-3-amino-4-(difluoromethylidene)cyclopent-1 -ene-1 -carboxylic acid (1) without observable isomerization or degradation: i. HCl (6 M), dioxane, 70 °C-90 °C, 1 h-3 h.

[0059] In an embodiment, (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) was obtained in small amounts (<10% yield) when the conditions reported by Hu (see, Zhao, Y.; Huang, W.; Zhu, L.; Hu, J. Org. Lett. 2010, 12, 1444-1447) were used with slow injection of base over 30 minutes, quenching with NH4Cl / 6 M HC1, the yield was significantly increased to 45%. Prolonging the injection of base to 1 hour increased the yield to 58%. See Table 1 below. The reaction was not greatly affected by scale, allowing scale up to 3.5 g of (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3,6-dione (5) with no decrease in yield: e. 2-((difluoromethyl)sulfinyl)pyridine (20) (1.2 eq), KO MS, CH2Cl2, 18 h, 52%. The foregoing provided a format for running these steps at a multi-gram scale, allowing the difluoro-Horner-Wadsworth-Emmons olefination of ketone 5. When 2-((difluoromethyl)sulfinyl)pyridine (20) (Hu reagent) was used with KO t Bu, using the conditions reported by Hu (see, Zhao, Y.; Huang, W.; Zhu, L.; Hu, J. Org. Lett. 2010, 12, 1444-1447) when used with slow injection of base over 30 minutes, quenching with NH4Cl / 6 M HC1, the yield was significantly increased to 45%. Prolonging the injection of base to 1 hour increased the yield to 58%. See Table 1 below. The reaction was not greatly affected by scale, allowing scale up to 3.5 g of (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3,6-dione (5) with no decrease in yield: e. 2-((difluoromethyl)sulfinyl)pyridine (20) (1.2 eq), KO tBu (1.5 eq), DMF, -60 °C, 30 min, then NH4CI, then 6 M HC1, then 23 °C, then 60 °C, 1 h. Alternatively, e. can be tert-butyllithium and F2CHP(O)(OEt)2(see, Pan, et al., supra). The next step is the methanolysis and elimination of the lactam. Deprotection of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) to yield (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7) in 80% yield: f. CAN (3 eq), MeCN, H2O, 0 °C, 1 h. A small amount of the 4-methoxybenzoyl protected lactam can also be isolated. Boc protection of the lactam (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one) (7) yields (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8): g. Boc2O (1.2 eq), DMAP (0.1 eq), Et3N (1.5 eq), CH2CI2, 1 h. Methanolysis of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert-butoxycarbonyl)-2- azabicyclo[2.2.1]heptan-3-one (8) with K2CO3 and methanol results in the subsequent elimination of the bromide to yield (S)-3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidene)cyclopent-1 -ene-1 -carboxylate (9): h. K2CO3 (3 eq), MeOH, 6 h, 52% over two steps. Final deprotection in 6 M HC1 at 80 °C yields (S)-3-amino-4- (difluoromethylidene)cyclopent-1 -ene-1 -carboxylic acid (1) in 97% yield without observable isomerization or degradation: i. HC1 (6 M), dioxane, 80 °C, 2 h. Overall yield from Vince lactam (2) to (S)-3-amino-4-(difluoromethylidene)cyclopent-1 -ene-1 -carboxylic acid (1) is 8.1%.

[0060] Table 1. Fluorination a Optimization

[0061]

[0062]

[0063]

[0064] aConditions: 5 (1 equiv), 20 (1.2 equiv), DMF (0.3 M), -60 °C, then KO t Bu (1.5 equiv) (0.5 M), then quenched at -60 °C, then 23 °C, then 60 °C for 1 h; b Time before addition of the quenching solution; c Yield of isolated after chromatography.

[0065] In embodiments, without wishing to be bound by any theory, the following fluorination mechanism is proposed for (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptane-3,6-dione (5):

[0066]

[0067] As shown above, multiple intermediates are formed during the course of the fluorination reaction. The first intermediate formed, 21, rearranges via a cyclic intermediate, 22, to form the sulfonate salt, 23, which is then protonated, triggering elimination and formation of the olefin (see above). If KO t Bu, 5 min later, the reaction was quenched with 6 M HC1 at -60 °C, then only 21 was observed by LC / MS (entry 1, Table 1). KO t Bu, then 6 M HC1 at -60 °C (entry 2, Table 1), and subsequent heating at 60 °C for 1 h, provided 6 in 9% yield along with starting material and intermediate 21. The yield was slightly improved after quenching with saturated NH4C1 solution for 1 h, then with 6 M HC1 (entry 3, Table 1). The yield was significantly increased to 45% with slow injection of base over 30 min using a syringe pump, quenching with NH4C1 / 6 M HC1. Prolonging the injection of base to 1 h increased the yield to 58%.

[0068] In embodiments, the synthesis of (S)-3-amino-4-(difluoromethylidene)cyclopent-1- ene-1-carboxylic acid (1) is shown in Scheme 2.

[0069] Scheme 2

[0070]

[0071] Yield (%) of racemic synthesis is provided relative to yield (%) of (s)-isomer.

[0072] Abbreviations: LiHMDS: lithium bis(trimethylsilyl)amide; THF: tetrahydrofuran; PMB: 4-methoxybenzyl; DBDMH: 1,3-dibromo-5,5-dimethylhydantoin; TPAP: tetrapropylammonium perruthenate; CAN: cerium ammonium nitrate; DMAP: N,N-dimethylaminopyridine

[0073] According to Scheme 2, a process for preparing (S)-3-amino-4- (difluoromethylidene)cyclopent-1 -en-1 -carboxylic acid (1), or a salt thereof, is provided that includes converting ((1R,4S)-2-azabicyclo[2.2.1]heptan-5-ene-3-one) (2) to (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-5-ene-3-one (3). Converting (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-5-ene-3-one (3) to (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4). Converting (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4) to (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25). Converting (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25) to (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5). Converting (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) to (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6). Converting (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7). Converting (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7) to (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8). Converting (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) to (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1 -en-1 -carboxylic acid (19).(S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-1 - ene-1 -carboxylic acid (19) is converted to (S)-3-amino-4- (difluoromethylidenyl)cyclopent-1 -ene-1 -carboxylic acid (1).

[0074] In embodiments, the following compounds are provided:

[0075]

[0076] (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-ene-3-one (3)

[0077]

[0078] (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6- yl acetate (4)

[0079]

[0080] (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3- one (25)

[0081]

[0082] (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5)

[0083]

[0084] (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6)

[0085]

[0086] (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-azabicyclo[2.2.1]heptan-3-one (7)

[0087]

[0088] (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8)

[0089]

[0090] (S)-methyl 3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl)cyclopenta-1 - ene-1 -carboxylate (9)

[0091]

[0092] (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl)cyclopenta-1 - ene-1 -carboxylic acid (19)

[0093] In embodiments, provided herein are compositions comprising (1R,4S)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3) or a salt thereof can comprise polar solvents, e.g., aqueous, methanol, ethanol, DMF, acetic acid, and the like; or non-polar solvents, e.g., diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (1R,4S)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-5-ene-3-one (3), or a pharmaceutically acceptable salt thereof, in an amount of greater than 0.0001 mg, for example from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0094] In embodiments, provided herein are compositions comprising (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6-yl acetate (4) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6-yl acetate (4) or a salt thereof can comprise polar solvents, e.g., water, methanol, ethanol, DMF, acetic acid, and the like; or non-polar solvents, e.g., diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6-yl acetate (4) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6-yl acetate (4) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (1R,4R,6S,7R)-7-bromo-2-(4- methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6-yl acetate (4), or a pharmaceutically acceptable salt thereof, in an amount of greater than 0.0001 mg, for example from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0095] In embodiments, provided herein are compositions comprising (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25) or a salt thereof can comprise polar solvents, e.g., water, methanol, ethanol, DMF, acetic acid, and the like; or non-polar solvents, e.g., diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (1R,4R,6S,7R)-7-bromo-6- hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25), or a pharmaceutically acceptable salt thereof, in an amount greater than 0.0001 mg, for example, from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0096] In embodiments, provided herein are compositions comprising (1R,4R,7R)-7-bromo-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) or a salt thereof can comprise polar solvents, e.g., water, methanol, ethanol, DMF, acetic acid, and the like; or non-polar solvents, e.g., diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, the pharmaceutical composition can comprise (1R,4R,7R)-7-bromo-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5), or a pharmaceutically acceptable salt thereof, in an amount of greater than 0.0001 mg, for example from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0097] In embodiments, provided herein are compositions comprising (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6) or a salt thereof can comprise polar solvents, e.g., water, methanol, ethanol, DMF, acetic acid, and the like; or non-polar solvents, e.g., diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) or a pharmaceutically acceptable salt thereof in an amount of greater than 0.0001 mg, for example from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0098] In embodiments, provided herein are compositions comprising (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7) or a salt thereof can comprise polar solvents, e.g., water, methanol, ethanol, DMF, acetic acid, and the like; or non-polar solvents, e.g., diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7), or a pharmaceutically acceptable salt thereof, in an amount of greater than 0.0001 mg, for example from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0099] In embodiments, provided herein are compositions comprising (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert- butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) or a salt thereof can comprise a polar solvent, e.g., water, methanol, ethanol, DMF, acetic acid, and the like; or a non-polar solvent, e.g., diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert- butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) or a pharmaceutically acceptable salt thereof in an amount of greater than 0.0001 mg, for example, from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0100] In embodiments, provided herein are compositions comprising (S)-methyl 3-((tert- butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-1 -en-1 -carboxylate (9) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (S)-methyl 3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidenyl)cyclopent-1 -en-1 -carboxylate (9) or a salt thereof can comprise a polar solvent, for example, water, methanol, ethanol, DMF, acetic acid, and the like; or a non-polar solvent, for example, diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (S)-methyl 3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidenyl)cyclopent-1 -en-1 -carboxylate (9) or a pharmaceutically acceptable salt thereof can be a pharmaceutical composition. The composition can comprise (S)-methyl 3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-1 -en-1 -carboxylate (9) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-l-en- 1 -carboxylic acid methyl ester (9), or a pharmaceutically acceptable salt thereof, in an amount greater than 0.0001 mg, for example from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0101] In embodiments, provided herein are compositions comprising (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl)cyclopent-1 -en-1 -carboxylic acid (19) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl)cyclopent-1 -en-1 -carboxylic acid (19) or a salt thereof can comprise polar solvents, e.g., water, methanol, ethanol, DMF, acetic acid, and the like; or non-polar solvents, e.g., diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl)cyclopent-1 -en-1 -carboxylic acid (19) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl)cyclopent-1 -en-1 -carboxylic acid (19) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-1 -en-1 -carboxylic acid (19) or a pharmaceutically acceptable salt thereof in an amount greater than 0.0001 mg, for example from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0102] In embodiments, the synthesis of (S)-3-amino-4-(difluoromethylidenyl)cyclopent-1 -en-1 - carboxylic acid (1) is shown in Scheme 3, starting with ethyl cyclopent-3-ene-carboxylate (10).

[0103] Scheme 3

[0104]

[0105] As depicted in Scheme 3, a process for preparing (S)-3-amino-4- (difluoromethylidene)cyclopent-l -en- 1 -carboxylic acid (1) is provided, which comprises converting cyclopent-3-ene-carboxylic acid ethyl ester (10) to (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11). Converting (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11) to (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentane carboxylic acid ethyl ester (12). Converting (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentane carboxylic acid ethyl ester to (9S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13). Converting (9S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13) to (S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14). Converting (S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14) to (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-l-en-l-carboxylic acid ethyl ester (15). Converting (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-l-en-l-carboxylic acid ethyl ester (15) to (S)-3-amino-4-(difluoromethylidene)cyclopent-l-en-l-carboxylic acid (1).

[0106] In embodiments, the synthesis of (S)-3-amino-4-(difluoromethylidene)cyclopent-l-en-l-carboxylic acid (1) is shown in Scheme 3A.

[0107] Scheme 3A

[0108]

[0109] In embodiments, as shown in Scheme 3A, cyclopent-3-ene-carboxylic acid ethyl ester (10) (commercially available from Sigma Aldrich, St. Louis, MO) is converted to (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11) by Sharpless aminohydroxylation and Boc protection. Sharpless aminohydroxylation allows the selective preparation of 1,2-amino alcohols by the reaction of olefins with salts of N-halosulfonamides, N-halosamides, and N-halocarbamates using OsO4 as a catalyst. Enantioselectivity is achieved by the addition of dihydroquinine-derived and dihydroquinidine-derived chiral ligands. Oxidation of (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11) yields ketone (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentane carboxylic acid ethyl ester (12). (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentane carboxylic acid ethyl ester (12) is converted to (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13). (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13) is subjected to phenyl selenyl bromide, base, and H2O2 to yield (S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14). (S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14) is deprotected and subjected to a Horner-Wittig reaction to yield (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1-en-1-carboxylic acid ethyl ester (15). The Horner-Wittig reaction involves the reaction of an aldehyde or ketone with a stable phosphorus ylide (phosphonate carbanion) and results in an olefin with E-selectivity. (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1-en-1-carboxylic acid ethyl ester (15) is converted to (S)-3-amino-4-(difluoromethylidene)cyclopent-1-en-1-carboxylic acid (1) with trifluoroacetic acid (TFA), dichloromethane (DCM), and saturated NaHCO3.

[0110] In embodiments, the following compounds are provided:

[0111]

[0112] (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11)

[0113]

[0114] (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentanecarboxylic acid ethyl ester (12)

[0115]

[0116] (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13)

[0117]

[0118] (S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14)

[0119]

[0120] (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopenta-1 - ene-1 -carboxylic acid ethyl ester (15)

[0121] In embodiments, provided herein are compositions comprising (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentanecarboxylic acid ethyl ester (11) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentanecarboxylic acid ethyl ester (11) or a salt thereof can comprise polar solvents, e.g., water, methanol, ethanol, DMF, acetic acid, and the like; or non-polar solvents, e.g., diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentanecarboxylic acid ethyl ester (11) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentanecarboxylic acid ethyl ester (11) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (3R,4S)-3-((tert- butoxycarbonyl)amino)-4-(hydroxy)cyclopentanecarboxylic acid ethyl ester (11), or a pharmaceutically acceptable salt thereof, in an amount of greater than 0.0001 mg, for example from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0122] In embodiments, provided herein are compositions comprising (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentanecarboxylic acid ethyl ester (12) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentanecarboxylic acid ethyl ester (12) or a salt thereof can comprise polar solvents, e.g., water, methanol, ethanol, DMF, acetic acid, and the like; or non-polar solvents, e.g., diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentanecarboxylic acid ethyl ester (12) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentanecarboxylic acid ethyl ester (12) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentane carboxylic acid ethyl ester (12), or a pharmaceutically acceptable salt thereof, in an amount greater than 0.0001 mg, for example from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0123] In embodiments, provided herein are compositions comprising (9S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (9S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13) or a salt thereof can comprise polar solvents, e.g., water, methanol, ethanol, DMF, acetic acid, and the like; or non-polar solvents, e.g., diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (9S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (9S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (9S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13), or a pharmaceutically acceptable salt thereof, in an amount greater than 0.0001 mg, for example from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0124] In embodiments, provided herein are compositions comprising (S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14) or a salt thereof can comprise polar solvents, e.g., water, methanol, ethanol, DMF, acetic acid, and the like; or non-polar solvents, e.g., diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (S)-9-(tert-butoxycarbonylamino)- 1,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14), or a pharmaceutically acceptable salt thereof, in an amount greater than 0.0001 mg, for example, from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0125] In embodiments, provided herein are compositions comprising (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl)cyclopent-1 -en-1 -carboxylic acid ethyl ester (15) or a salt thereof. Such compositions can comprise reaction mixtures, such as those described herein. Compositions comprising (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl)cyclopent-1 -en-1 -carboxylic acid ethyl ester (15) or a salt thereof can comprise polar solvents, for example, water, methanol, ethanol, DMF, acetic acid, and the like; or non-polar solvents, for example, diethyl ether, hexane, dichloromethane, ethyl acetate, and the like. Compositions comprising (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl)cyclopent-1 -en-1 -carboxylic acid ethyl ester (15) or a pharmaceutically acceptable salt thereof can be pharmaceutical compositions. The compositions can comprise (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl)cyclopent-1 -en-1 -carboxylic acid ethyl ester (15) or a salt thereof in an amount from 0.0001 mg to 50 mg or more.For example, a pharmaceutical composition can comprise (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-1 -en-1 -carboxylic acid ethyl ester (15), or a pharmaceutically acceptable salt thereof, in an amount greater than 0.0001 mg, for example from 0.0001 mg to 0.0002 mg, 0.0001 mg to 0.0003 mg, 0.0002 mg to 0.0003 mg, 0.0003 mg to 0.0004 mg, 0.0004 mg to 0.0005 mg, 0.0005 mg to 0.0006 mg, 0.0006 mg to 0.0007 mg, 0.0007 mg to 0.0008 mg, 0.0008 mg to 0.0009 mg, 0.0009 mg to 0.001 mg, 0.001 mg to 0.002 mg, 0.002 mg to 0.003 mg, 0.003 mg to 0.004 mg, 0.004 mg to 0.005 mg, 0.005 mg to 0.006 mg, 0.006 mg to 0.007 mg, 0.007 mg to 0.008 mg, 0.008 mg to 0.009 mg, 0.009 mg to 0.01 mg, 0.01 mg to 0.02 mg, 0.02 mg to 0.03 mg, 0.03 mg to 0.04 mg, 0.04 mg to 0.05 mg, 0.05 mg to 0.06 mg, 0.06 mg to 0.07 mg, 0.07 mg to 0.08 mg, 0.08 mg to 0.09 mg, 0.09 mg to 0.1 mg, 0.1 mg to 0.2 mg, 0.2 mg to 0.3 mg, 0.3 mg to 0.4 mg, 0.4 mg to 0.5 mg, 0.5 mg to 0.6 mg, 0.6 mg to 0.7 mg, 0.7 mg to 0.8 mg, 0.8 mg to 0.9 mg, 0.9 mg to 1.0 mg, 1.0 mg to 2.0 mg, 2.0 mg to 3.0 mg, 3.0 mg to 4.0 mg, 4.0 mg to 5.0 mg, 5.0 mg to 6.0 mg, 6.0 mg to 7.0 mg, 7.0 mg to 8.0 mg, 8.0 mg to 9.0 mg, or 9.0 mg to 10 mg.

[0126] In embodiments, the pharmaceutical composition can comprise (S)-3-amino-4- (difluoromethyl) cyclopent-1 -en-1 -carboxylic acid, or a pharmaceutically acceptable salt thereof, in an amount of, e.g., about 0.001 mg to 500 mg, 0.01 mg to 500 mg, 0.01 mg to 450 mg, 0.01 mg to 300 mg, 0.01 mg to 250 mg, 0.01 mg to 200 mg, 0.01 mg to 175 mg, 0.01 mg to 150 mg, 0.01 mg to 125 mg, 0.01 mg to 100 mg, 0.01 mg to 75 mg, 0.01 mg to 50 mg, 0.01 mg to 30 mg, 0.01 mg to 25 mg, 0.01 mg to 20 mg, 0.01 mg to 15 mg, 0.01 mg to 10 mg, 0.01 mg to 5 mg, 0.01 mg to 1 mg, 0.025 mg to 500 mg, 0.025 mg to 450 mg, 0.025 mg to 300 mg, 0.025 mg to 250 mg, 0.025 mg to 200 mg, 0.025 mg to 175 mg, 0.025 mg to 150 mg, 0.025 mg to 125 mg, 0.025 mg to 100 mg, 0.025 mg to 75 mg, 0.025 mg to 50 mg, 0.025 mg to 30 mg, 0.025 mg to 25 mg, 0.025 mg to 20 mg, 0.025 mg to 15 mg, 0.025 mg to 10 mg, 0.025 mg to 5 mg, 0.025 mg to 1 mg, 0.05 mg to 500 mg, 0.05 mg to 450 mg, 0.05 mg to 300 mg, 0.05 mg to 250 mg, 0.05 mg to 200 mg, 0.05 mg to 175 mg, 0.05 mg to 150 mg, 0.05 mg to 125 mg, 0.05 mg to 100 mg, 0.05 mg to 75 mg, 0.05 mg to 50 mg, 0.05 mg to 30 mg, 0.05 mg to 25 mg, 0.05 mg to 20 mg, 0.05 mg to 15 mg, 0.05 mg to 10 mg, 0.05 mg to 5 mg, 0.05 mg to 1 mg, 0.075 mg to 500 mg, 0.075 mg to 450 mg, 0.075 mg to 300 mg, 0.075 mg to 250 mg, 0.075 mg to 200 mg, 0.075 mg to 175 mg, 0.075 mg to 150 mg, 0.075 mg to 125 mg, 0.075 mg to 100 mg, 0.075 mg to 75 mg, 0.075 mg to 50 mg, 0.075 mg to 30 mg, 0.075 mg to 25 mg, 0.075 mg to 20 mg, 0.075 mg to 15 mg, 0.075 mg to 10 mg, 0.075 mg to 5 mg, 0.075 mg to 1 mg, 0.1 mg to 500 mg, 0.1 mg to 450 mg, 0.1 mg to 300 mg, 0.1 mg to 250 mg, 0.1 mg to 200 mg, 0.1 mg to 175 mg, 0.1 mg to 150 mg, 0.1 mg to 125 mg, 0.1 mg to 100 mg, 0.1 mg to 75 mg, 0.1 mg to 50 mg, 0.1 mg to 30 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 5 mg, or 0.1 mg to 1 mg.mg, 0.075 mg to 75 mg, 0.075 mg to 50 mg, 0.075 mg to 30 mg, 0.075 mg to 25 mg, 0.075 mg to 20 mg, 0.075 mg to 15 mg, 0.075 mg to 10 mg, 0.075 mg to 5 mg, 0.075 mg to 1 mg, 0.1 mg to 500 mg, 0.1 mg to 450 mg, 0.1 mg to 300 mg, 0.1 mg to 250 mg, 0.1 mg to 200 mg, 0.1 mg to 175 mg, 0.1 mg to 150 mg, 0.1 mg to 125 mg, 0.1 mg to 100 mg, 0.1 mg to 75 mg, 0.1 mg to 50 mg, 0.1 mg to 30 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 5 mg, 0.1 mg to 1 mg, 0.25 mg to 500 mg, 0.25 mg to 450 mg, 0.25 mg to 300 mg, 0.25 mg to 250 mg, 0.25 mg to 200 mg, 0.25 mg to 175 mg, 0.25 mg to 150 mg, 0.25 mg to 125 mg, 0.25 mg to 100 mg, 0.25 mg to 75 mg, 0.25 mg to 50 mg, 0.25 mg to 30 mg, 0.25 mg to 25 mg, 0.25 mg to 20 mg, 0.25 mg to 15 mg, 0.25 mg to 10 mg, 0.25 mg to 5 mg, 0.25 mg to 1 mg, 0.5 mg to 500 mg, 0.5 mg to 450 mg, 0.5 mg to 300 mg, 0.5 mg to 250 mg, 0.5 mg to 200 mg, 0.5 mg to 175 mg, 0.5 mg to 150 mg, 0.5 mg to 125 mg, 0.5 mg to 100 mg, 0.5 mg to 75 mg, 0.5 mg to 50 mg, 0.5 mg to 30 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 mg to 15 mg, 0.5 mg to 10 mg, 0.5 mg to 5 mg, 0.5 mg to 1 mg, 1 mg to 500 mg, 1 mg to 450 mg, 1 mg to 300 mg, 1 mg to 250 mg, 1 mg to 200 mg, 1 mg to 175 mg, 1 mg to 150 mg, 1 mg to 125 mg, 1 mg to 100 mg, 1 mg to 75 mg, 1 mg to 50 mg, 1 mg to 30mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 10 mg, 1 mg to 5 mg, 1 mg to 4 mg, 1 mg to 3 mg, 1 mg to 2 mg, 2 mg to 500 mg, 2 mg to 450 mg, 2 mg to 300 mg, 2 mg to 250 mg, 2 mg to 200 mg, 2 mg to 175 mg, 2 mg to 150 mg, 2 mg to 125 mg, 2 mg to 100 mg, 2 mg to 75 mg, 2 mg to 50 mg, 2 mg to 30 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2 mg to 10 mg, 2 mg to 5 mg, 3 mg to 500 mg, 3 mg to 450 mg, 3 mg to 300 mg, 3 mg to 250 mg, 3 mg to 200 mg, 3 mg to 175 mg, 3 mg to 150 mg, 3 mg to 125 mg, 3 mg to 100 mg, 3 mg to 75 mg, 3 mg to 50 mg, 3 mg to 30 mg, 3 mg to 25 mg, 3 mg to 20 mg, 3 mg to 15 mg, 3 mg to 10 mg, 3 mg to 5 mg, 4 mg to 500 mg, 4 mg to 450 mg, 4 mg to 300 mg, 4 mg to 250 mg, 4 mg to 200 mg, 4 mg to 175 mg, 4 mg to 150 mg, 4 mg to 125 mg, 4 mg to 100 mg, 4 mg to 75 mg, 4 mg to 50 mg, 4 mg to 30 mg, 4 mg to 25 mg, 4 mg to 20 mg, 4 mg to 15 mg, 4 mg to 10 mg, 4 mg to 5 mg, 5 mg to 500 mg, 5 mg to 450 mg, 5 mg to 300 mg, 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 175 mg, 5 mg to 150 mg, 5 mg to 125 mg, 5 mg to 100 mg, 5 mg to 75 mg, 5 mg to 50 mg, 5 mg to 30 mg, 5 mg to 25 mg, 5 mg to 20 mg, 5 mg to 15 mg, 5 mg to 10 mg, 10 mg to 500 mg, 10 mg to 450 mg, 10 mg to 300 mg, 10 mg to 250 mg, 10 mg to 200 mg, 10 mg to 175 mg, 10 mg to 150 mg, 10 mg to 125 mg, 10 mg to 100 mg, 10 mg to 75 mg, 10 mg to 50 mg, 10 mg to 30 mg, 10mg to 500 mg, 10 mg to 450 mg, 10 mg to 300 mg, 10 mg to 250 mg, 10 mg to 200 mg, 10 mg to 175 mg, 10 mg to 150 mg, 10 mg to 125 mg, 10 mg to 100 mg, 10 mg to 75 mg, 10 mg to 50 mg, 10 mg to 30 mg, 10 mg to 25 mg, 10 mg to 20 mg, 20 mg to 500 mg, 20 mg to 450 mg, 20 mg to 300 mg, 20 mg to 250 mg, 20 mg to 200 mg, 20 mg to 175 mg, 20 mg to 150 mg, 20 mg to 125 mg, 20 mg to 100 mg, 20 mg to 75 mg, 20 mg to 50 mg, 20 mg to 30 mg, 20 mg to 25 mg, 25 mg to 500 mg, 25 mg to 450 mg, 25 mg to 300 mg, 25 mg to 250 mg, 25 mg to 200 mg, 25 mg to 175 mg, 25 mg to 150 mg, 25 mg to 125 mg, 25 mg to 100 mg, 25 mg to 80 mg, 25 mg to 75 mg, 25 mg to 50 mg, 25 mg to 30 mg, 30 mg to 500 mg, 30 mg to 450 mg, 30 mg to 300 mg, 30 mg to 250 mg, 30 mg to 200 mg, 30 mg to 175 mg, 30 mg to 150 mg, 30 mg to 125 mg, 30 mg to 100 mg, 30 mg to 75 mg, 30 mg to 50 mg, 40 mg to 500 mg, 40 mg to 450 mg, 40 mg to 400 mg, 40 mg to 250 mg, 40 mg to 200 mg, 40 mg to 175 mg, 40 mg to 150 mg, 40 mg to 125 mg, 40 mg to 100 mg, 40 mg to 75 mg, 40 mg to 50 mg, 50 mg to 500 mg, 50 mg to 450 mg, 50 mg to 300 mg, 50 mg to 250 mg, 50 mg to 200 mg, 50 mg to 175 mg, 50 mg to 150 mg, 50 mg to 125 mg, 50 mg to 100 mg, 50 mg to 75 mg, 75 mg to 500 mg, 75 mg to 450 mg, 75 mg to 300 mg, 75 mg to 250 mg, 75 mg to 200mg, 75 mg to 175 mg, 75 mg to 150 mg, 75 mg to 125 mg, 75 mg to 100 mg, 100 mg to 500 mg, 100 mg to 450 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 200 mg, 100 mg to 175 mg, 100 mg to 150 mg, 100 mg to 125 mg, 125 mg to 500 mg, 125 mg to 450 mg, 125 mg to 300 mg, 125 mg to 250 mg, 125 mg to 200 mg, 125 mg to 175 mg, 125 mg to 150 mg, 150 mg to 500 mg, 150 mg to 450 mg, 150 mg to 300 mg, 150 mg to 250 mg, 150 mg to 200 mg, 200 mg to 500 mg, 200 mg to 450 mg, 200 mg to 300 mg, 200 mg to 250 mg, 250 mg to 500 mg, 250 mg to 450 mg, 250 mg to 300 mg, 300 mg to 500 mg, 300 mg to 450 mg, 300 mg to 400 mg, 300 mg to 350 mg, 350 mg to 500 mg, 350 mg to 450 mg, 350 mg to 400 mg, 400 mg to 500 mg, 400 mg to 450 mg, wherein 0.01 mg, 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg are examples.

[0127] In embodiments, there is provided a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-1 -en-1 -carboxylic acid (1) and one or more of the following: (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3), (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4), (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5), (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6), (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-azabicyclo[2.2.1]heptan-3-one (7), (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8), or (S)-methyl 3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-1 -en-1 -carboxylate (9).

[0128] In embodiments, there is provided a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-1 -en-1 -carboxylic acid (1) and one or more of the following: cyclopent-3-ene-carboxylic acid ethyl ester (10), (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11), (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentane carboxylic acid ethyl ester (12), (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13), (S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14), or (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-1 -en-1 -carboxylic acid ethyl ester (15).

[0129] In embodiments, (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l-ene- 1 -carboxylic acid can be provided as an acid addition salt, a zwitterion hydrate, a zwitterion anhydrate, a hydrochloride salt, or a hydrobromide salt, or as a zwitterion monohydrate. Acid addition salts include, but are not limited to, addition salts of maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, pantothenic, p-aminobenzoic, glutamic, benzenesulfonic or theophylline acetic acids, as well as 8-halotheophyllines, for example 8-bromo-theophylline. In embodiments, addition salts of inorganic acids can be used, including, but not limited to, addition salts of hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric or nitric acids.

[0130] In embodiments, (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-ene-3- one (3), (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6- yl acetate (4), (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6- dione (5), (1R,4R,7R)-7-bromo-6-(difluoromethylenyl)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6), (1R,4R,7R)-7-bromo-6-(difluoromethylenyl)-2- azabicyclo[2.2.1]heptan-3-one (7), (1R,4R,7R)-7-bromo-6-(difluoromethylenyl)-2-(tert- butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8), or (S)-methyl 3-((tert- butoxycarbonyl)amino)-4-(difluoromethylenyl)cyclopent-l-ene-l-carboxylate (9) can be provided as an acid addition salt, a zwitterion hydrate, a zwitterion anhydrate, a hydrochloride salt, or a hydrobromide salt, or as a zwitterion monohydrate. Acid addition salts include, but are not limited to, addition salts of maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, pantothenic, p-aminobenzoic, glutamic, benzenesulfonic or theophylline acetic acids, as well as 8-halotheophyllines, for example 8-bromo-theophylline. In embodiments, addition salts of inorganic acids can be used, including, but not limited to, addition salts of hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric or nitric acids.

[0131] In embodiments, cyclopent-3-ene-carboxylic acid ethyl ester (10), (3R,4S)-3- ((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11), (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentane carboxylic acid ethyl ester (12), (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13), (S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14), or (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl)cyclopent-1-ene-1- carboxylic acid ethyl ester (15) can be provided as an acid addition salt, a zwitterionic hydrate, a zwitterionic anhydrate, a hydrochloride salt, or a hydrobromide salt or in the form of a zwitterionic monohydrate. Acid addition salts include, but are not limited to, addition salts of maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, pantothenic, p-aminobenzoic, glutamic, benzenesulfonic or theophylline acetic acids, as well as 8-halotheophyllines, for example 8-bromo-theophylline. In embodiments, addition salts of inorganic acids can be used, including but not limited to, addition salts of hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric or nitric acids.

[0132] In embodiments, the pharmaceutical compositions include a variety of dosage forms, including conventional formulations and modified release formulations. Such pharmaceutical compositions can be suitable for any suitable route of administration, for example, oral, rectal, nasal, ocular, pulmonary, vaginal, sublingual, transdermal, intravenous, intra-arterial, intramuscular, intraperitoneal, and subcutaneous routes of administration. Suitable dosage forms include tablets, capsules, oral liquids, eye drops, eye ointments, eye gels, powders, aerosols, transdermal forms such as topical liquids, patches, creams, and ointments, parenteral formulations, and suppositories.

[0133] In embodiments, as previously mentioned, the pharmaceutical compositions herein can be provided in a conventional release profile or a modified release profile. The pharmaceutical compositions can be prepared using a pharmaceutically acceptable "carrier" comprising materials believed to be safe and effective. "Carriers" include all components other than the active ingredient or ingredients present in a pharmaceutical formulation. The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, and coating compositions. Those of skill in the art are familiar with such pharmaceutical carriers and methods of compounding pharmaceutical compositions using such carriers.

[0134] In embodiments, the pharmaceutical compositions herein are modified release dosage forms that provide a modified release profile. The modified release profile can exhibit an immediate release profile, a delayed release profile, or an extended release profile. Conventional (or unmodified) release oral dosage forms such as tablets, capsules, suppositories, syrups, solutions, and suspensions generally release the drug into the mouth, stomach, or intestines as the tablet, capsule shell, or suppository dissolves, or in the case of syrups, solutions, and suspensions, as they are swallowed, releasing the drug into the mouth, stomach, or intestines. The pattern of drug release from a modified release (MR) dosage form is deliberately altered from that of a conventional dosage form to achieve a desired therapeutic goal and / or better patient compliance. Types of MR drug products include oral dissolving dosage forms (ODDFs) that provide immediate release, extended release dosage forms, delayed release dosage forms (e.g., enteric coated), and pulsatile release dosage forms.

[0135] ODDFs are solid dosage forms that contain a medicinal substance or active ingredient that generally disintegrate rapidly within a few seconds when placed on the tongue. The disintegration time of an ODDF is generally in the range of from one or two seconds to about one minute. ODDFs are designed to disintegrate or dissolve rapidly upon contact with saliva. This mode of administration can be beneficial for people who can have problems swallowing tablets, whether the problem is due to physical infirmity or mental illness in nature. Some subjects with ocular disorders can exhibit such behavior. ODDFs can provide rapid delivery of a drug through the mucosa to the bloodstream, resulting in rapid onset of action. Examples of ODDFs include oral disintegrating tablets, capsules, and fast-dissolving films and wafers.

[0136] Extended release dosage forms (ERDFs) have an extended release profile and are those that allow for a reduction in dosing frequency as compared to that exhibited by conventional dosage forms, e.g., solutions or unmodified release dosage forms. ERDFs provide a sustained duration of drug action. Suitable formulations that provide an extended release profile are well known in the art. For example, coated slow release beads or granules (“beads” and “granules” are used interchangeably herein), in which any of the compounds described herein are applied to beads, e.g., confectioners nonpareil beads, and then coated with conventional release retarding materials such as waxes, enteric coatings, and the like. In embodiments, beads can be formed in which any of the compounds described herein are mixed with a material to provide a mass from which the compound leaches. In embodiments, the beads can be engineered to provide different release rates by varying the properties of the coating or mass, e.g., thickness, porosity, using different materials, etc. Beads with different release rates can be combined into a single dosage form to provide variable or continuous release. The beads can be contained in a capsule, or compressed into a tablet.

[0137] In embodiments, the modified dosage forms herein include delayed release dosage forms having a delayed release profile. Delayed release dosage forms can include delayed release tablets or delayed release capsules. Delayed release tablets are solid dosage forms that release one compound (or more compounds) described herein at a time different from immediate release after administration. Delayed release capsules are solid dosage forms in which the drug is enclosed within either a hard or soft soluble container made of a suitable form of gelatin, and which release one drug (or more drugs) at a time different from immediate release after administration. For example, enteric-coated tablets, capsules, granules, and beads are well-known examples of delayed release dosage forms. Enteric-coated tablets, capsules, and granules, and beads pass through the stomach and release the drug in the intestine. In embodiments, delayed release tablets are solid dosage forms that comprise a conglomerate of pharmaceutical granules that release one drug (or more drugs) at a time different from immediate release after administration. In embodiments, the conglomerate of pharmaceutical granules is covered with a coating that delays drug release. In embodiments, delayed release capsules are solid dosage forms that comprise a conglomerate of pharmaceutical granules that release one drug (or more drugs) at a time different from immediate release after administration. In embodiments, the conglomerate of pharmaceutical granules is covered with a coating that delays drug release.

[0138] Delayed release dosage forms are known to those of skill in the art. For example, coated delayed release beads or granules in which any compound described herein is applied to a bead, such as confectioners nonpareil beads, and then coated with a conventional release delaying material such as wax, enteric coating, and the like. In embodiments, beads can be formed in which any compound described herein is mixed with a material to provide a mass from which the drug leaches. In embodiments, beads can be engineered to provide different release rates by varying the properties of the coating or mass, such as thickness, porosity, using different materials, and the like. In embodiments, enteric coated granules of any compound described herein can be contained in an enteric coated capsule or tablet that releases the granules in the small intestine. In embodiments, the granules have a coating that remains intact until the coated granules reach at least the ileum, and thereafter provide delayed release of the drug in the colon. Suitable enteric coating materials are well known in the art, for example, Coatings such as methacrylic acid and methyl methacrylate polymers, and others. The granules can be contained in a capsule, or compressed into a tablet.

[0139] In embodiments, any of the compounds described herein are incorporated into a porous inert carrier that provides a delayed release profile. In embodiments, the porous inert carrier includes channels or passageways through which the drug diffuses into the surrounding fluid. In embodiments, any of the compounds described herein are incorporated into an ion exchange resin to provide a delayed release profile. When the drug-resin complex is exposed to the gastrointestinal fluid and ion constituents dissolved therein, the pre-determined release rate of the drug from the resin can result in a delayed effect. In embodiments, a membrane is used to control the rate of release from a reservoir containing the drug. In embodiments, a liquid preparation can also be used to provide a delayed release profile. For example, a liquid preparation consisting of solid particles dispersed throughout a liquid phase, the particles being insoluble in the liquid phase. The suspension is formulated to allow at least a reduction in the frequency of dosing as compared to the frequency of dosing presented by the drug as a conventional dosage form (e.g., as a solution or a conventional solid dosage form of immediate release drug). For example, a suspension of ion exchange resin constituents or microbeads.

[0140] In embodiments, the pharmaceutical compositions described herein are suitable for ocular or parenteral administration, including, for example, intramuscular (i.m.), intravenous (i.v.), subcutaneous (s.c.), intraperitoneal (i.p.), or intrathecal (i.t.). Parenteral or ophthalmic compositions must be sterile and must be fluid to the extent that easy syringability exists, and can be packaged in unit- or multi-dose containers. In embodiments, a liquid pharmaceutical composition for ocular or parenteral administration to a subject comprises an active substance, such as any of the compounds described herein, in any of the corresponding amounts described above. In embodiments, a pharmaceutical composition for ocular or parenteral administration is formulated to a total volume of about, for example, 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 7.5 ml, 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. In embodiments, the composition is contained in a bag, glass vial, plastic vial, or bottle.

[0141] In embodiments, a pharmaceutical composition for ophthalmic or parenteral administration comprises the respective amounts described above in relation to any compound described herein. In embodiments, a pharmaceutical composition for ophthalmic or parenteral administration comprises about 0.0001 mg to about 500 mg of any compound described herein. In embodiments, a pharmaceutical composition for ophthalmic or parenteral administration to a subject can comprise any compound described herein at a respective concentration of about 0.005 mg / ml to about 500 mg / ml. In embodiments, a pharmaceutical composition for ophthalmic or parenteral administration comprises any compound described herein at a respective concentration of, e.g., about 0.05 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 10 mg / ml, about 0.05 mg / ml to about 25 mg / ml, about 0.05 mg / ml to about 10 mg / ml, about 0.05 mg / ml to about 5 mg / ml, or about 0.05 mg / ml to about 1 mg / ml. In embodiments, a pharmaceutical composition for ophthalmic or parenteral administration comprises any compound described herein at a respective concentration of, e.g., about 0.05 mg / ml to about 15 mg / ml, about 0.5 mg / ml to about 10 mg / ml, about 0.25 mg / ml to about 5 mg / ml, about 0.5 mg / ml to about 7 mg / ml, about 1 mg / ml to about 10 mg / ml, about 5 mg / ml to about 10 mg / ml, or about 5 mg / ml to about 15 mg / ml.

[0142] In embodiments, a pharmaceutical composition for ophthalmic or parenteral administration is provided, wherein the pharmaceutical composition is stable for at least six months. In embodiments, a pharmaceutical composition for ophthalmic or parenteral administration exhibits no more than about 5% reduction of active, e.g., (S)-3-amino-4-(difluoromethylidene)cyclopent-l-en- 1 -carboxylic acid or a pharmaceutically acceptable salt thereof, over, e.g., 3 months or 6 months. In embodiments, the amount of (S)-3-amino-4-(difluoromethylidene)cyclopent-l-en- 1 -carboxylic acid or a pharmaceutically acceptable salt thereof degrades no more than about, e.g., 2.5%, 1%, 0.5%, or 0.1%. In embodiments, the degradation is less than about, e.g., 5%, 2.5%, 1%, 0.5%, 0.25%, 0.1% over at least six months.

[0143] In embodiments, provided are pharmaceutical compositions for ophthalmic or parenteral administration, wherein the pharmaceutical compositions remain soluble. In embodiments, provided are pharmaceutical compositions for ophthalmic or parenteral administration that are stable, soluble, locally site compatible, and / or ready-to-use. In embodiments, the pharmaceutical compositions herein are ready-to-use for direct administration to a subject in need thereof.

[0144] The pharmaceutical compositions for ophthalmic or parenteral administration provided herein can include one or more excipients, such as a solvent, a solubility enhancer, a suspending agent, a buffering agent, an isotonic agent, a stabilizing agent, or an antimicrobial preservative. When used, the excipients of the ophthalmic or parenteral compositions will not adversely affect the stability, bioavailability, safety, and / or efficacy of any of the compounds described herein used in the compositions. Thus, provided are ophthalmic or parenteral compositions in which there is no incompatibility among any components of the dosage form.

[0145] In embodiments, the ophthalmic or parenteral compositions comprising any of the compounds described herein include a stabilizing amount of at least one excipient. For example, the excipient can be selected from the group consisting of a buffering agent, a solubilizing agent, a tonicity agent, an antioxidant, a chelating agent, an antimicrobial agent, and a preservative. It will be understood by those skilled in the art that an excipient can have more than one function and be classified into one or more defined groups.

[0146] In embodiments, the ophthalmic or parenteral compositions comprise any of the compounds described herein and an excipient, wherein the excipient is present in a weight percent (w / v) of less than about, for example, 10%, 5%, 2.5%, 1%, or 0.5%. In embodiments, the excipient is present in a weight percent between about, for example, 1.0% to 10%, 10% to 25%, 15% to 35%, 0.5% to 5%, 0.001% to 1%, 0.01% to 1%, 0.1% to 1%, or 0.5% to 1%. In embodiments, the excipient is present in a weight percent between about, for example, 0.001% to 1%, 0.01% to 1%, 1.0% to 5%, 10% to 15%, or 1% to 15%.

[0147] In embodiments, an ophthalmic or parenteral composition of any of the compounds described herein is provided, wherein the pH of the composition is between about 4.0 to about 8.0. In embodiments, the pH of the composition is, for example, between about 5.0 to about 8.0, about 6.0 to about 8.0, about 6.5 to about 8.0. In embodiments, the pH of the composition is, for example, between about 6.5 to about 7.5, about 7.0 to about 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6. In embodiments, the pH of the aqueous solution is, for example, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0, about 8.2, about 8.4, or about 8.6.

[0148] In embodiments, a pharmaceutical composition comprising (S)-3-amino-4- (difluoromethylidenyl)cyclopent-l-en-1 -carboxylic acid or a pharmaceutically acceptable salt thereof provides an in vivo plasma profile of (S)-3-amino-4-(difluoromethylidenyl)cyclopent- 1 -en- 1 -carboxylic acid having a Cmaxof less than about, for example, 2000 ng / ml, 1000 ng / ml, 850 ng / ml, 800 ng / ml, 750 ng / ml, 700 ng / ml, 650 ng / ml, 600 ng / ml, 550 ng / ml, 450 ng / ml, 400 ng / ml, 350 ng / ml, or 300 ng / ml. 最大 In embodiments, a pharmaceutical composition provides an in vivo plasma profile of (S)-3-amino-4-(difluoromethylidenyl)cyclopent-1-en-1-carboxylic acid having a Cmaxof less than about, for example, 250 ng / ml, 200 ng / ml, 150 ng / ml, or 100 ng / ml. 最大 In embodiments, a pharmaceutical composition provides an in vivo plasma profile of (S)-3-amino-4-(difluoromethylidenyl)cyclopent-1-en-1-carboxylic acid having a Cmaxof less than about, for example, 250 ng / ml, 200 ng / ml, 150 ng / ml, or 100 ng / ml.

[0149] In embodiments, a pharmaceutical composition comprising (S)-3-amino-4- (difluoromethylidenyl)cyclopent-l-en-1 -carboxylic acid or a pharmaceutically acceptable salt thereof and one or more of any of the compounds described herein is provided, wherein the composition provides a constant in vivo plasma profile of (S)-3-amino-4-(difluoromethylidenyl)cyclopent- 1 -en- 1 -carboxylic acid having an AUC 0-∞ of less than about 900 ng·hr / ml.

[0150] In embodiments, a pharmaceutical composition comprising (S)-3-amino-4- (difluoromethylidenyl)cyclopent-l-en-1 -carboxylic acid or a pharmaceutically acceptable salt thereof and one or more of any of the compounds described herein has a T 最大 of less than 3 hours. In embodiments, a pharmaceutical composition has a T 最大 of less than 2.5 hours. In embodiments, a pharmaceutical composition has a T 最大 of less than 2 hours. In embodiments, a pharmaceutical composition has a T 最大less than 1.5 hours. In embodiments, the Tmax of the pharmaceutical composition is less than 1.5 hours. 最大 less than 1 hour. In embodiments, the Tmax of the pharmaceutical composition is less than 1 hour. 最大 less than 0.5 hours. In embodiments, the Tmax of the pharmaceutical composition is less than 0.5 hours. 最大 less than 0.25 hours.

[0151] In embodiments, a pharmaceutical composition comprising (S)-3-amino-4- (difluoromethylidenyl)cyclopent-l-en-1 -carboxylic acid or a pharmaceutically acceptable salt thereof and one or more of any of the compounds described herein provides at least about 80% dissolution within the first 20 minutes of administration to a subject in need thereof. In embodiments, a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l-en-1 -carboxylic acid or a pharmaceutically acceptable salt thereof and one or more of any of the compounds described herein provides at least about, e.g., 85%, 90%, or 95% dissolution within the first 20 minutes of administration to a subject in need thereof. In embodiments, a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l-en-1 -carboxylic acid or a pharmaceutically acceptable salt thereof and one or more of any of the compounds described herein provides at least 80% dissolution within the first 10 minutes of administration to a subject in need thereof.

[0152] It will be appreciated that respective amounts of (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l-en-1 -carboxylic acid or a pharmaceutically acceptable salt thereof and one or more of any of the compounds described herein are suitable for use in all of the dosage forms described herein, including conventional dosage forms, modified dosage forms, and the ophthalmic and parenteral formulations described herein. The skilled artisan will determine the appropriate amount based on criteria such as dosage form, route of administration, subject tolerance, potency, therapeutic goals and benefits, and other pharmaceutically acceptable criteria.

[0153] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the disclosure herein belongs.

[0154] The term "about" or "approximately," as used herein, means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, "about" can mean ranges approximately 20%, approximately 10%, approximately 5%, and / or approximately 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold and more preferably within 2-fold, of a value.

[0155] "PK" refers to pharmacokinetic profile. 最大 defined as the highest plasma drug concentration (ng / ml) estimated during the experiment. 最大 defined as when C 最大 the time (min) when it is estimated. 0-∞ is the total area under the plasma drug concentration-time curve (ng-hr / ml) from drug administration until the drug is eliminated. The area under the curve is determined by the clearance rate. Clearance rate is defined as the volume of blood or plasma completely cleared of its drug content per unit time (ml / min).

[0156] "Pharmaceutically acceptable" refers to molecular entities and compositions that are "generally regarded as safe", e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset and the like, when administered to a human. In embodiments, the term refers to molecular entities and compositions approved by a regulatory agency of the Federal or a state government, as GRAS listed under Sections 204(s) and 409 of the Federal Food, Drug and Cosmetic Act, as an FDA approved drug, or as listed in the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0157] "Effective amount" or "therapeutically effective amount" means the amount of a drug that is sufficient to reduce one or more symptoms of the disorder, disease, or condition being treated.

[0158] “Administered with,”“co-therapy,”“in combination with,”“combination of,”“combined with,” or“administered with” can be used interchangeably and mean that two or more agents are administered in the course of therapy. The agents can be administered together simultaneously or separately at spaced-apart intervals. The agents can be administered in a single dosage form or in separate dosage forms.

[0159] A“patient in need thereof’ includes an individual who has been diagnosed with a disease, condition, or disorder for which treatment with (S)-3-amino-4-(difluoromethylidene)cyclopent-l-en- 1 -carboxylic acid or a pharmaceutically acceptable salt thereof is indicated. “Patient” and“subject” are used interchangeably herein. Examples

[0160] The examples provided herein are included merely for purposes of illustration and should not be construed as limiting in any way.

[0161] General Methods

[0162] (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (2) was purchased from Acella Chembio, San Diego, CA 92121 or AK Scientific, Inc., Union City, CA 94587. 4- methoxybenzyl chloride was purchased from AK Scientific, Inc., Union City, CA 94587. 2-(Difluoromethyl)sulfinyl)pyridine (20) was purchased from Enamine Chemicals, Monmouth Jct., NJ 08852, Sigma-Aldrich Corp, St Louis, MO or synthesized from bromodifluoromethylphosphonic acid diethyl ester and 2-mercaptopyridine. See, Zhou, Q.; Ruffoni, A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S. Angew. Chem. Int. Ed. 2013, 52, 3949-3952. 1,3-Dibromo-5,5-dimethylhydantoin was purchased from Acros Organics division of Thermo Fisher Scientific, Waltham, MA 02451. TPAP was purchased from Combi Blocks, Inc. San Diego, CA 92126. Cerium ammonium nitrate was purchased from Alfa Aesar, Ward Hill, MA 01835. All other reagents were purchased from Sigma-Aldrich, Fisher Scientific or Acros Organics and used without further purification. Anhydrous solvents (THF, CH2Cl2, DMF) were purified by passing through columns containing activated alumina and copper-loaded redox catalysts prior to use. Yields refer to chromatographically and spectroscopically (1H-NMR) homogeneous material. 1 Analytical thin layer chromatography (TLC) was performed using Merck silica gel F-254 pre-coated plates (0.25 mm thick) and components were visualized by ultraviolet light (254 nm) and / or cerium ammonium molybdate staining. Flash column chromatography was performed on a Teledyne Combiflash Rf Plus automated flash purification system with various Teledyne cartridges (4 g - 80 g, 40 pm - 63 pm, ). Purifications were performed with hexanes and ethyl acetate unless otherwise noted. 1 H NMR and 13CNMR spectra were recorded on a Bruker Avance-III NMR spectrometer at 500 MHz and 126 MHz in CDC13or D20, respectively. Chemical shifts are reported in ppm, multiplicities are indicated by the following: s = singlet, d = doublet, t = triplet, q = quartet, sep = septet, dd = doublet of doublets, dt = doublet of triplets, m = multiplet, br = broad resonance. Coupling constants are reported in Hz. High resolution mass spectrometry data were obtained at the Integrated Molecular Structure Education and Research Center (IMSERC), Northwestern University, on an Agilent 6210 LC-TOF spectrometer with an Agilent G1312A HPLC pump and an Agilent G1367B autoinjector, using electrospray ionization in positive mode. Analytical HPLC was performed by using a reversed-phase Agilent Infinity 1260 HPLC with UV absorbance detection at 254 nm with a Phenomenex Kintex C-18 column (50 x 2.1 mm, 2.6 pm).

[0163] Example 1

[0164] Preparation of (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-ene-3-one (3)

[0165] Method A

[0166] To a 2 L 3 -necked round bottom flask equipped with an overhead stirrer was added (1R,4S)-2-azabicyclo[2.2.1]heptan-5-one (21.00 g, 0.19 mol), DMF (600 mL) and THF (600 mL) and the flask was cooled to 0 °C. NaH (8.45 g, 0.21 mol, 1.1 eq, 60% dispersion in mineral oil) was added in portions. The flask was placed under N2and stirred for 30 min. The Et2O / PMBCl solution was transferred to an addition funnel and added dropwise at 0 °C. The reaction was stirred at room temperature for 6 h. After completion, the THF was removed in vacuo and diethyl ether and water were added. Any solids were filtered and the layers were separated. The aqueous layer was extracted with diethyl ether (3 x 100 mL) and the organic layers were combined and washed with brine (2 x 200 mL). After drying over Na2SO4and concentration, a yellow oil was obtained. The crude oil was purified by flash chromatography to yield 32.2 g (0.14 mol, 73% yield) of protected (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (3). The spectra matched those in the literature. See Qiu, J.; Silverman, R. B. J. Med. Chem. 2000, 43, 706-720.

[0167] Method B

[0168] A dry 2 L 3 -necked round bottom flask equipped with an overhead stirrer Paddle, 500 ml dropping funnel and serum cap / K-type thermocouple / N2 needle. (1R,4S)-(-)-2-Aza-bicyclo[2.2.1]hept-5-en-3-one (25 g, 229 mmol, 1 equiv) was dissolved in anhydrous THF (600 ml) in a flask and the dropping funnel was loaded with a solution of LiHMDS (1 M in toluene). The contents of the flask were cooled to -40 °C and the LiHMDS solution (252 ml, 252 mmol, 1.2 equiv) was added dropwise to the flask, keeping the temperature at about -35 °C to 40 °C. The contents of the flask started to thicken and became a thin gel at the end of the base addition. After all the LiHMDS had been added, the reaction mixture was stirred for an additional 1 hour and then the 500 ml dropping funnel was removed and replaced with a smaller 125 ml dropping funnel loaded with 4-methoxybenzyl chloride (37.2 g, 240.5 mmol, 1.05 equiv). The halide was added dropwise to the reaction flask. When about ¼ of the chloride had been added, powdered tetrabutylammonium iodide (1.3 g, 3.44 mmol, 0.015 equiv) was added in a single portion. When all of the 4-methoxybenzyl chloride had been added, the flask was initially warmed to room temperature and then warmed to 60 °C in a heating mantle. Over time, the progress of the benzylation reaction was tracked by HPLC and LCMS. After 2 days at 60 °C, when the reaction had reached ~85% conversion to the lactam (-)(1R,4S)-2-aza-bicyclo[2.2.1]hept-5-en-3-one (3), the reaction was worked up. The fine solid precipitate in the reaction solution was removed by filtration through a 17 cm large Buchner funnel / filter paper under vacuum. The residue was washed with THF (200 ml) and also the original filtrate was collected and the combined golden yellow filtrate was concentrated (rotary evaporator / vacuum / water bath at 40 °C). The residual golden oil was dissolved in EtOAc (350 ml) and washed with water (250 ml). After phase separation, the water layer was back-extracted with EtOAc (2 x 100 ml). The EtOAc layers were combined and dried over anhydrous Na2SO4 powder, filtered and concentrated (rotary evaporator / vacuum / water bath at 40 °C) to a golden yellow liquid. This crude product was purified by chromatography on a Biotage with a 340 g silica column and an EtOAc-hexane gradient [15% (2 CV) 15%-75% (8 CV) 100% (3 CV)] with fraction collection in 25 x 150 mm tubes. Fractions containing product were combined and concentrated (rotary evaporator / vacuum / water bath at 40 °C) to a golden yellow liquid which was pumped on a vacuum line for several hours.

[0169] Method C

[0170] NaH (40.3 g, 1.01 mol, 60% purity, 1.1 eq) and Bu4NI (16.9 g, 45.8 mmol, 0.05 eq) were added to THF (300 mL), then a solution of (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (100.0 g, 916.3 mmol, 1 eq) in DMF (900 mL) was added dropwise to the mixture at 0 °C. The mixture was stirred for 0.5 h, and p-methoxybenzyl chloride (215.2 g, 1.37 mol, 186.5 mL, 1.50 eq) was added dropwise to the above mixture at 0 °C. The mixture was stirred at 25 °C for 1 h. TLC (petroleum ether: ethyl acetate = 1:1, Rf = 0.20) showed the reactants were completely consumed. The mixture was diluted with MTBE (2 L) and water (3.5 L) was added. Any solids were filtered and the layers were separated. The aqueous layer was extracted with MTBE (800 mL x 2) and the organic layers were combined and washed with brine (1 L x 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give a residue as a yellow oil. The residue was purified by column chromatography on silica gel with petroleum ether: ethyl acetate (10:1 ~ 1:1) to give a yellow oil. Crude (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3) was obtained as a yellow oil (89.5 g, 390.3 mmol, 42.6% yield), which was used in the next step without further purification. f

[0171] Example 2

[0172] Preparation of (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2- azabicyclo[2.2.1]heptan-6-yl acetate (4)

[0173] Method A

[0174] ​To a solution of (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-5- en-3-one (3) (10.00 g, 43.62 mmol) in AcOH (110.0 mL) was added 1,3-dibromo-5,5- dimethylhydantoin (7.48 g, 26.17 mmol, 0.6 equiv). The reaction was stirred for 6 h and upon completion, water was added. The aqueous layer was extracted with diethyl ether (3 x 200 mL) and the organic layers were combined, washed with 1 M NaOH, dried over Na2SO4and concentrated. Purification by flash chromatography yielded (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4) (14.40 g, 39.25 mmol, 90% yield) as a thick oil. Spectra matched those in the literature. See Qiu, J.; Silverman, R. B. J. Med. Chem. 2000, 43, 706-720.

[0175] Method B

[0176] (1R, 4R)-(-)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-ene-3-one (15.5 g, 67.60 mmol, 1 equiv) was dissolved in glacial acetic acid (125 ml) in a 250 ml round bottom flask with a stir bar. 1,3-Dibromo-5,5-dimethylhydantoin (9.7 g, 33.43 mmol, 0.5 equiv) was added in multiple batches to the acidic solution over 10 minutes at room temperature. A serum cap / nitrogen needle was placed in the neck of the flask and the reaction mixture was stirred at room temperature overnight. The initially hazy yellow solution turned clear golden yellow after all the dibromide was added over 20 minutes. The progress of the reaction was monitored by HPLC and LCMS. After stirring overnight, the reaction solvent was removed (rotary evaporator / vacuum / water bath at 55 °C) to give a deep golden yellow liquid which was then dissolved in dichloromethane (200 ml). Water (100 ml) was added and the mixture was transferred to a 1 L conical flask. 10% sodium sulfite solution (75 ml) was added and stirred vigorously in the conical flask for ½ hour to destroy unreacted dibromo hydantoin. More water (100 ml) was added and then 3M sodium hydroxide was added slowly and swirled rapidly in the conical flask to bring the aqueous layer to pH = 7 (pH paper). The contents of the flask were transferred to a 1 L separatory funnel; the conical flask was rinsed with dichloromethane (100 ml) and the rinse was combined in the funnel. The dichloromethane layer from the phase separation was saved, the aqueous layer was back extracted with dichloromethane (2 x 100 ml) and combined with the originally saved extract, washed with saturated NaHC03(250 ml), water (250 ml) and brine (250 ml). The organic phase was dried over anhydrous Na2S04powder, filtered and concentrated (rotary evaporator / vacuum / water bath at 40 °C) to a golden yellow liquid. This crude product was purified by chromatography on a Biotage with a 340 g silica column and an EtOAc-hexanes gradient [15% (1 CV) 15%-75% (7.5 CV) 100% (3 CV)] fraction collection in 25 x 150 mm tubes. Fractions containing product were combined and concentrated (rotary evaporator / vacuum / water bath at 40 °C) to give a golden yellow liquid which was further pumped on a vacuum line for several hours to yield purified (1R, 4R, 6S, 7R)-(+)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]-hept-6-yl acetate (4) (23 g; 82%).

[0177] Example 3

[0178] Preparation of (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5)

[0179] Method A

[0180] (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4) (12.8 g, 34.7 mmol) was dissolved in MeOH (270 mL) and K2CO3 (14.40 g, 104.28 mmol, 3.0 eq) was added. The reaction was stirred for 1 h, filtered and then concentrated. Ethyl acetate and water were added and the layers were separated. The organic layer was dried over Na2SO4 and concentrated to yield an off-white solid ((1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one) (25) which was used directly in the next step.

[0181] The compound was placed in a 500 mL flask and purged with argon. Dichloromethane (170 mL) was added followed by Molecular sieves (10 g). TPAP (122.2 mg, 0.35 mmol, 0.01 eq) and NMO (8.14 g, 69.52 mmol, 2.0 eq) were then added and the reaction mixture was stirred overnight. The reaction mixture was then filtered and concentrated to a volume of 20 mL and loaded directly onto a flash chromatography column. The resulting yellow solid could be recrystallized from hexanes / ethyl acetate to yield a white powder (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) (5.96 g, 18.38 mmol, 52% yield). The spectra matched those in the literature. See Qiu, J.; Silverman, R. B. J. Med. Chem. 2000, 43, 706-720.

[0182] Method B

[0183] (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6-yl acetate (4) (25.5 g, 69.2 mmol) was dissolved in MeOH (300 mL) and K2CO3 (30 g, 0.23 mol, 3 equiv) was added. The reaction was stirred for 1 h, filtered and then concentrated. Ethyl acetate and water were added and the layers were separated. The organic layer was dried over Na2SO4 and concentrated to yield an off-white solid ((1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one) which was used directly in the next step. A three necked flask was equipped with an exhaust line to a gas bulb, a dropping funnel with a nitrogen inlet and a septum. Dichloromethane (160 mL) was added and the flask was purged with nitrogen. Oxalyl chloride (8.40 mL, 98.0 mmol, 1.4 equiv) was added and the reaction was cooled to -78 °C. DMSO (11.60 mL, 0.16 mol, 2.3 equiv) was added to the addition funnel and then added slowly dropwise at a rate to control the vigorous gas evolution. After the addition, the reaction was stirred at -78 °C for 10 min. The deacylated material was dissolved in dichloromethane (160 mL) and added slowly to the reaction via the addition funnel. The reaction was stirred at -78 °C for 10 min. Then triethylamine (68.3 mL, 0.49 mol, 7 equiv) was added dropwise via the addition funnel. After completion, the reaction was stirred at -78 °C for 10 min, warmed to room temperature and quenched with 1 M HCl. After separation, the organic layer was dried over Na2SO4 and concentrated in the hood. Purification via flash chromatography yielded (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) as a beige solid (13.5 g, 41.7 mmol, 60% yield).

[0184] Method C

[0185] To (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6-yl acetate (4) (96.5 g, 262.0 mmol, 1 equiv) in MeOH (680 mL) was added K2CO3 (108.6 g, 786.2 mmol, 3 equiv). The mixture was stirred at 25 °C for 1 h. TLC (petroleum ether: ethyl acetate = 1:1, R f= 0.65) showed completion of the reaction. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a black brown solid. MTBE (500 mL) was added to the brown solid and the mixture was stirred for 3 h, then filtered to give a filtrate which was concentrated under reduced pressure to give the crude product. The crude compound (76.5 g, 234.5 mmol, 89.5% yield) was obtained as off-white solid which was used for the next step without further purification.

[0186] The above crude compound (76.5 g, 234.5 mmol, 1 eq) was added to MeCN (400 mL). IBX (65.6 g, 234.5 mmol, 1.0 eq) was added to the above mixture in one portion at 20-30 °C for 0.5 h. The reaction mixture was stirred at 75-80 °C for 2 h, after which time TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.65) showed completion of the reaction. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a black brown solid. MTBE (500 mL) was added to the brown solid and the mixture was stirred for 3 h, then filtered to give a filtrate which was concentrated under reduced pressure to give the crude product. The crude compound (76.5 g, 234.5 mmol, 89.5% yield) was obtained as off-white solid which was used for the next step without further purification. f = 0.23) showed completion of the reaction. The mixture was concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel with petroleum ether: ethyl acetate (20:1 to 1:1) to give (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptane-3,6-dione (5) (48.5 g, 149.6 mmol, 63.7% yield) as off-white solid.

[0187] Example 3(a)

[0188] Preparation of (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (25)

[0189] (1R,4R,6S,7R)-(+)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo-[2.2.1]- heptan-6-yl acetate (4) (22.25 g, 60.42 mmol, 1 eq) was dissolved in a solvent mixture of methanol (120 ml) and water (15 ml) in a 500 mL round bottom flask. Potassium carbonate powder (12.5 g, 90.45 mmol, 1.5 eq) was added to the golden yellow solution and the resulting turbid reaction mixture was sealed with a serum cap / N2 needle and stirred at room temperature overnight. The progress of the reaction was monitored by LCMS and HPLC. The reaction was worked up by evaporating the volatiles (rotary evaporator / vacuum / water bath at 40 °C). Distilled water (200 ml) was added to the dark golden yellow oil obtained from evaporation. The pH of the aqueous layer was adjusted to pH = 7 with 1 M hydrochloric acid and the product was extracted into dichloromethane (200 ml, then 2 x 150 ml). The dichloromethane extracts were combined and washed with water (200 ml), brine (250 ml), dried over Na2S04 powder. The dried extracts were filtered and the spent drying agent was rinsed with dichloromethane (2 x 50 ml) and the combined extracts were concentrated (rotary evaporator / vacuum / water bath at 40 °C) to a golden yellow oil. The golden yellow product was split into two roughly equal portions and each portion was purified by chromatography on a 100 g silica column on a Biotage with an EtOAc-hexanes gradient [20% (1 CV) 20%-100% (7 CV) 100% (5 CV)] fraction collection in 25 x 150 mm tubes. The product fractions were combined and concentrated (rotary evaporator / vacuum / water bath at 40 °C) to a golden yellow liquid which was pumped on a vacuum line for several hours. The two chromatography purified samples (20 g) were combined and crystallized from hexanes-EtOAc. The first crop of crystals (17 g) was collected. The mother liquor was concentrated and crystallized from hexanes-EtOAc to provide the second crop of crystals (2 g). (1R,4R,6S,7R)-(+)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-aza- bicyclo[2.2.1]heptan-3-one (25) was obtained as a white crystalline powder (15 g total; 75%).

[0190] Example 3(b)

[0191] Preparation of (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane- 3,6-dione (5) by Swern oxidation

[0192] A 1 L 3 necked round bottom flask equipped with an overhead stirrer, a 50 ml dropping funnel and a serum cap / thermocouple / N2 needle was loaded with a solution of oxalyl chloride (3.4 g (2.3 ml), 1.25 eq) and dichloromethane (90 ml) and the stirred acid chloride solution was cooled to -60 °C in an acetone / CO2 cooling bath. The dropping funnel was loaded with a solution of DMSO (2.6 g (2.35 ml), 1.5 eq) in dichloromethane (18 ml) and this solution was added to the cold acid chloride solution over 3 minutes. The resulting mixture was stirred at -60 °C for 7 minutes and then (1R,4R,6S,7R)-(+)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]-heptan-3-one (25) (7.2 g, 22.1 mmol, 1 eq) was added to the solution over 10 minutes. The reaction mixture was kept at -60 °C for 25 minutes and then neat trimethylamine (21.5 ml, 7 eq) was placed in the dropping funnel and added to the flask. The resulting milky white solution was kept cold for 1 hour, the reaction was checked by HPLC / LCMS and then allowed to warm to room temperature over 2.5 hours before workup. Saturated brine (125 ml) was added to the flask and then diethyl ether (125 ml) was added to the workup. The quenched reaction was transferred to a 1 L separatory funnel. The upper layer was saved and the lower aqueous layer was extracted with diethyl ether (2 x 125 ml). These ether extracts were combined with the original extract and then it was washed with 1 M hydrochloric acid (125 ml), brine (125 ml) and water (50 ml). The organic phase was dried over anhydrous Na2S04 powder, filtered and the filter cake was washed with dichloromethane (2 x 50 ml) and the washings were combined with the filtrate. The volatiles were removed (rotary evaporator / vacuum / water bath at 40 °C) to give a yellow liquid which solidified upon standing. The solid was crystallized from EtOAc-hexane and a first crop (5.31 g) was obtained. The mother liquor was concentrated and crystallized to give a second crop (1.36 g). The mother liquor from the second crystallization was purified on a 25 g silica column with an EtOAc-hexane gradient [20% (2 CV), 20%-100% (8 CV), 100% (2 Cv)] eluting into 16 x 150 mm tubes. 250 mg of product was obtained by chromatography. The combined yield of (1R,4R,7R)-(+)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) was 6.8 g (94% yield).

[0193] Example 3(c)

[0194] Preparation of (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-3,6-dione (5) by TPAP oxidation

[0195] A 2-liter, three-necked round-bottom flask equipped with a top-mounted stirrer and a serum cap / thermocouple / N2 needle was loaded with (1R,4R,6S,7R)-(+)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]-hepta-3-one (25) (12 g, 36.8 mmol, 1 equivalent), 4-morpholine-N-oxide (12.9 g, 110 mmol, 3 equivalent), and 4A molecular sieve powder in dichloromethane (400 ml). Then, a catalytic amount of TPAP (25 mg, 0.07 mmol, 0.002 equivalent) was added. The solution was stirred at room temperature under nitrogen, resulting in a darkening green solution over time. The reaction was monitored daily by LC-MS. On day 2, the reaction stalled, and the solution was filtered through a flask and a vacuum source. The reaction was filtered. The solution was returned to a 2-liter, three-necked, round-bottom reaction flask, and fresh 4-morpholine-N-oxide (5.5 g), 4A molecular sieve powder (10 g), and TPAP (25 mg) were added. The reaction stalled late on day 3, and the reaction was filtered and restarted with fresh NMO (5.5 g), 4A sieve (10 g), and TPAP (25 mg). By the end of day 4, ~7% of the bromoalcohol remained, and the TPAP oxidation reaction was thus resolved. Using a Buchner flask and a vacuum source, the solids in the reaction solution were removed by filtration through a sintered plastic funnel filled with 1 / 2-cm of sand, 1 / 2-cm of anhydrous Na2SO4 powder, and 1-cm of diatomaceous earth. The filter cake was washed with dichloromethane (2 × 100 ml and 50 ml) until the filtrate stream was colorless. The filtrate was concentrated to a dark gold oil (rotary evaporator / vacuum / water bath at 40°C), which showed signs of solidification on the glass surface. The crude product was divided into two halves, and each half was subjected to chromatography on a Biotage silica gel (100 g) with an EtOAc-hexane gradient of 20% (1 CV), 20%-100% (7.5 CV), and 100% (4 CV). The fractions were collected in 25 × 150 mm tubes. The product fractions from the two chromatographys were combined and concentrated (rotary evaporator / vacuum / water bath at 40 °C) to obtain a white powder.

[0196] The powder was crystallized from EtOAc-hexane to obtain the first batch of crystals (8.5 g). The mother liquor was concentrated and crystallized to give the second batch (1.5 g). The combined yield of (1R,4R,7R)-(+)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-3,6-dione (5) was 10 g (80%).

[0197] Example 4

[0198] Preparation of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6)

[0199] Method A

[0200] (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6- dione (5) (1.00 g, 3.09 mmol) and 2-((difluoromethyl)sulfinyl)pyridine (20) (715.10 mg, 3.70 mmol, 1.2 equiv) were added to a round bottom flask and purged with argon. DMF (15 mL) was added and the reaction was cooled to between -55 °C and -65 °C. KO t Bu (623.0 mg, 5.55 mmol, 1.8 equiv in DMF 0.5 M) was added via syringe pump over 1 h. The temperature was maintained between -55 °C and -65 °C. After the addition was complete, the reaction was stirred at -60 °C for an additional 30 min. Saturated NH4CI (5.00 mL) was added and the reaction was stirred at -60 °C for 5 min before the addition of 6 M HCI (5.00 mL). After stirring at -60 °C for 5 min, the reaction mixture was warmed to room temperature and then warmed to 65 °C for 1 h. After cooling, the reaction was diluted with brine, extracted with ethyl acetate (2 x 20 mL), and washed with brine (10 mL). Dried over Na2S04and concentrated to yield a yellow oil which was purified via flash chromatography to yield a white solid (620.0 mg, 1.73 mmol, 58% yield). (c 0.80, CHCI3); m.p. 85-87 °C; 1 H NMR (500 MHz, CDCI3) δ 7.14 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 4.60 (d, J = 14.6 Hz, 1 H), 4.19 (s, 0 H), 4.14 (s, 0 H), 3.90 (d, J = 14.7 Hz, 1 H), 3.79 (s, 1 H), 3.00 (s, 0 H), 2.83 (dq, J = 14.6, 3.0 Hz, 1 H), 2.27 (d, J = 15.2 Hz, 1 H). See Figure 1 . 13C NMR (126 MHz, CDC13) δ 173.0, 159.5, 153.9 (dd, J = 287.5, 283.8 Hz), 129.7, 127.5, 114.3, 87.1 (dd, J = 24.9, 23.5 Hz), 63.4, 63.3, 55.3, 50.8 (d, J = 17.1 Hz), 44.6, 24.8. See Figure 2 . 19 F NMR (376 MHz, CDC13) δ -88.15 (dp, J = 55.1, 2.7 Hz), -88.88 (dq, J = 54.8, 2.8 Hz). See Figure 3 . IR (film, cm -1 ) 3013, 1785, 1683, 1551; for C 15 H 14 BrF2NO2 + Na + of HMRS (ESI + ) calculated: 380.0074; found: 380.0075.

[0201] Method B

[0202] (1R,4R,7R)-(+)-7-bromo-2-(4-methoxy-benzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) (3.5 g, 10.8 mmol, 1 equiv) and 2-(difluoromethylsulfonyl)pyridine (20) (2.5 g, 12.94 mmol, 1.2 equiv) were combined in a round bottom flask with a stir bar, to which was added dimethylformamide (32 ml). The resulting yellow solution was sealed with a serum cap / N2 needle / thermocouple and cooled to -40 °C. A solution of potassium bis(trimethylsilyl)amide (KHMDS) (15.1 ml, 15.1 mmol, 1.4 equiv) was added, keeping the temperature between -40 °C and -35 °C. As the base was added, the reaction solution turned a deep orange color. The resulting reaction mixture was stirred at -40 °C for 1 hour, and then allowed to gradually warm to room temperature. The reaction was quenched with saturated NH4Cl solution (10 ml), stirred for 10 minutes, 3 M hydrochloric acid (40 ml) was added, stirred for 10 minutes, and then the flask contents were heated in a heating bath at 60 °C for 1.5 hours, and then cooled to room temperature. Water (35 ml) was added, and the reaction was extracted with tert-butyl methyl ether (MTBE) (3 x 75 ml). The ether extracts were combined into one portion, washed with brine, dried over anhydrous Na2SO4 powder, and filtered through a Chem-R-Us plastic frit funnel to remove the spent drying agent. The filtrate was concentrated (rotary evaporator / vacuum / water bath at 40 °C) to give a light brown oil. The crude product was purified by chromatography on a Biotage on a 100 g silica column with an EtOAc-hexanes gradient [15% (1 CV) 15%-75% (7.5 CV) 100% (3 CV)], and fractions were collected in 16 x 100 mm tubes. The product fractions were combined and concentrated (rotatory evaporator / vacuum / water bath at 40 °C) to a golden yellow liquid, which was pumped on a vacuum line for several hours to give (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) (2.5 g; 63%).

[0203] Method C

[0204] To a solution of (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) (48.5 g, 149.6 mmol, 1 equiv) and 2-((difluoromethyl)sulfinyl)pyridine (20) (31.8 g, 164.6 mmol, 1.1 equiv) in DMF (800 mL) was added t-BuOK (30.2 g, 269.3 mmol, 1.8 equiv) in DMF (800 mL) very slowly dropwise at -57 °C to -52 °C. The reaction was stirred at -55 °C for 0.5 h, then a saturated NH4Cl solution (400 mL) was added slowly dropwise to the reaction mixture at a temperature below -30 °C. After the addition, a 6 N HC1 solution (360 mL) was added to the above mixture at below -20 °C. The mixture was warmed to 10 °C and stirred at 65 °C for 1 h. TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.50) showed a new spot. The mixture was added to water (4 L) and extracted with MTBE (2 L x 2). The organic layer was separated and washed with brine (2 L), then dried over Na2S04, concentrated under reduced pressure to give a residue as a red oil. The crude product was purified by column chromatography on silica gel with petroleum ether: ethyl acetate (20:1 ~ 1:1) to give (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) (32.5 g, 90.7 mmol, 60.6% yield) as a white solid. f = 0.50) showed a new spot. The mixture was added to water (4 L) and extracted with MTBE (2 L x 2). The organic layer was separated and washed with brine (2 L), then dried over Na2S04, concentrated under reduced pressure to give a residue as a red oil. The crude product was purified by column chromatography on silica gel with petroleum ether: ethyl acetate (20:1 ~ 1:1) to give (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) (32.5 g, 90.7 mmol, 60.6% yield) as a white solid.

[0205] Example 5

[0206] Preparation of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7)

[0207] Method A

[0208] (1R,4R,7R)-7-bromo-6-(difluoromethyl enyl)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6) (140 mg, 0.39 mmol) was added to MeCN (2.0 mL) and cooled to 0 °C. Cerium ammonium nitrate (643.5 mg, 1.17 mmol, 3 equiv) in H2O (0.75 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 h. Upon completion, water was added and the solution was extracted with ethyl acetate (2 x 15 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. Flash chromatography yielded (1R,4R,7R)-7-bromo-6-(difluoromethyl enyl)-2-azabicyclo[2.2.1]heptan-3-one (7) (75 mg, 0.315 mmol, 80% yield) as a white solid. (c 0.90, CHCl3); m.p. 139-141 °C; 1 H NMR (500 MHz, CDCl3) δ 5.87 (s, 1H), 4.41 (s, 1H), 4.32 (s, 1H), 2.96 (s, 1H), 2.87 (dq, J = 15.4, 3.4 Hz, 1H), 2.32 (d, J = 15.2 Hz, 1H). See Figure 4 . 13 C NMR (126 MHz, CDCl3) δ 174.9, 153.5 (t, J = 287.5 Hz), 88.7 (t, J = 24.1 Hz), 60.6, 51.5, 50.3, 24.3. See Figure 5 . 19 F NMR (376 MHz, CDCl3) δ -88.60 (dq, J = 55.1, 2.8 Hz), -88.88 (dp, J = 54.6, 2.5 Hz). See Figure 6 . IR (film, cm-1) 3249.1788, 1678, 1397; HMRS (ESI+) calculated for C7H6BrF2NO + H + 237.9679; found 237.9678.

[0209] Method B

[0210] An aqueous solution of cerium(IV) ammonium nitrate (CAN) (6.4 g, 11.67 mmol, 2.94 eq) in 20 ml of distilled water was prepared 10 minutes prior to performing the oxidative cleavage reaction. (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-aza-bicyclo[2.2.1]heptan-3-one (1.4 g, 3.91 mmol, 1 eq) was dissolved in acetonitrile (70 ml) and stirred in a round bottom flask with a stir bar. The aqueous solution of CAN was added dropwise to the flask and the resulting mixture was stirred at room temperature for several hours, monitoring the progress of the reaction by HPLC and LCMS. The reaction was worked up by pouring the reaction into a 500 ml separatory funnel and then adding EtOAc (300 ml), shaking, and saving the upper layer. The lower aqueous layer was extracted with more EtOAc (2 x 50 mL). The ethyl acetate extracts were combined into one portion and washed with water (4 x 10 ml) and saturated brine (25 ml) and then dried over anhydrous Na2S04. After filtration through a plastic frit funnel to remove the spent drying agent, the filtrate was concentrated (rotary evaporator / vacuum / water bath at 40 °C) to obtain a light brown oil. The crude product was purified by chromatography on a Biotage on a 25 g silica column with an EtOAc-hexanes gradient [15% (1 CV) 15%-75% (7.5 CV) 100% (3 CV)] and fractions were collected in 16 x 100 mm tubes. Fractions containing product were combined and concentrated (rotary evaporator / vacuum / water bath at 40 °C) to a golden yellow liquid which was pumped on a vacuum line for several hours to yield purified (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]heptan-3-one (7) (0.65 g; 70%).

[0211] Example 6

[0212] Preparation of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert- butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) and (S)-3-((tert- butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1-en-1-carboxylic acid methyl ester (9)

[0213] Method A

[0214] (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7) (890.0 mg, 3.74 mmol) was added to dichloromethane (18.0 mL) followed by Boc20 (978.8 mg, 4.49 mmol, 1.2 equiv), DMAP (45.7 mg, 0.37 mmol, 0.1 equiv) and Et3N (0.78 mL, 5.61 mmol, 1.5 equiv) sequentially. The reaction was stirred for 1 h and then washed with 1 M HC1 (10 mL), dried over Na2S04and concentrated. The resulting oil containing (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) was dissolved in methanol (18.0 mL), then K2C03(1.55 g, 11.21 mmol, 3.0 equiv) was added and the reaction stirred for 6 h. After completion, as indicated by LC / MS (methanolysis of the lactam occurs within the first 10 min), the reaction was diluted with brine and extracted with ethyl acetate (3 x 200 mL). After drying over Na2S04, concentration and purification by flash chromatography, (S)-methyl 3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1-en-1-carboxylate (9) was obtained as a white solid (570 mg, 1.97 mmol, 52% yield). (c 0.50, CHCl3); m.p. 95-97 °C; 1 H NMR (500 MHz, CDCl3) δ 6.58 (s, 1H), 5.50 (d, J = 9.1 Hz, 1H), 4.63 (d, J = 8.7 Hz, 1H), 3.75 (s, 3H), 3.33 (d, J = 20.4 Hz, 1H), 3.21 (dd, J = 20.3, 2.7 Hz, 1H), 1.42 (s, 9H). See Figure 7 . 13 C NMR (126 MHz, CDCl3) δ 164.3, 154.7, 154.6, 152.4 (t, J = 288.5 Hz), 150.1, 140.6, 135.5, 88.9 (dd, J = 21.8, 20.2 Hz), 80.1, 55.3, 51.9, 31.1, 28.3. See Figure 8 . 19F NMR (376 MHz, CDCl3) δ -84.49 (d, J = 43.6 Hz), -85.91 (d, J = 43.4 Hz). See Figure 9 IR (film, cm -1 ) 3347, 2987, 1773, 1681; for C 13 H 17 F2NO4+Na + The HMRS (ESI + ) calculated for C

[0215] Method B

[0216] To a solution of (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]heptan-3-one (7) (14.4 g, 60.5 mmol, 1 equiv) in DCM (150 mL) was added DMAP (739.0 mg, 6.05 mmol, 0.1 equiv) and TEA (9.18 g, 90.7 mmol, 12.6 mL, 1.5 equiv). Then (Boc)20 (15.8 g, 72.6 mmol, 16.6 mL, 1.2 equiv) was added slowly. After the addition, the mixture was stirred at 25 °C for 1 h. TLC (petroleum ether: ethyl acetate = 1:1, R f = 0.20) showed the reaction was completed. The mixture was adjusted to pH = 3-4 with 1 N HC1 solution, then the organic layer was separated and washed with brine (100 mL), dried over Na2S04, and concentrated under reduced pressure to give (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) (7.50 g, crude) as a black brown solid, which was used in the next step without further purification. (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) (7.50 g, 22.1 mmol, 1 equiv) was dissolved in MeOH (55 mL), then CH3ONa (1.44 g, 26.6 mmol, 1.2 equiv) was added. The mixture was stirred at 0 °C for 1 h. TLC (petroleum ether: ethyl acetate = 1:1, R f= 0.70) showed that the reaction was complete. Water (100 mL) was added to the reaction mixture and the mixture was extracted with MTBE (200 mL x 2), washed with brine (150 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to give a residue (crude) as a red solid. The crude product was purified by column chromatography on silica gel with petroleum ether: ethyl acetate (20: 1 ~ 1 : 1) to give (S)-methyl 3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidene)cyclopent-l -en- 1 -carboxylate (9) as a white solid (5.20 g, 17.9 mmol, 81.0% yield).

[0217] Example 7

[0218] Preparation of (1R,4R,7R)-(+)-tert-butyl 7-bromo-6-(difluoromethylidene)-3-oxo-2- azabicyclo[2.2.1]heptane-2-carboxylate (8)

[0219] Methylene chloride (30 ml) to be used in this reaction was deoxygenated with a gas dispersion tube and nitrogen prior to use in the reaction. (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]-heptan-3-one (7) (1.4 g, 5.88 mmol, 1 equiv) and di-tert- butyl dicarbonate (2.56 g, 11.73 mmol, 2 equiv) were dissolved in methylene chloride (30 ml) in a 100 ml round bottom flask. 4-(dimethylamino)-pyridine (DMAP) (0.3 g, 2.46 mmol, 7.3 equiv) was dissolved in triethylamine (6 ml, 43 mmol, 0.4 equiv) and then the amine was added dropwise to the reaction under a nitrogen atmosphere blanket. The resulting reaction mixture in the flask was sealed with a serum cap / N2 needle and the contents were stirred at room temperature for 1 hour. A small aliquot was removed and the reaction progress was checked by HPLC and LCMS. In workup, the volatiles were removed (rotary evaporator / vacuum / water bath at ambient temperature) to obtain a deep golden yellow liquid. This liquid was dissolved in methylene chloride (50 ml) and partitioned with 1 M hydrochloric acid (25 ml), washed with brine (50 ml). The extracts were dried over anhydrous Na2S04 powder, filtered and the filtrate was concentrated (rotary evaporator / vacuum / water bath at ambient temperature) to provide a brown oil. The crude product was purified by chromatography on a Biotage on a 25 g silica column with an EtOAc-hexanes gradient [15% (1 CV) 15%-75% (7.5 CV) 100% (3 CV)] and fractions were collected in 16 x 100 mm tubes. Fractions containing product were combined and concentrated (rotary evaporator / vacuum / water bath at 40 °C) to a golden yellow liquid which was pumped on a vacuum line for several hours to yield purified (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.65 g; 82%).

[0220] Example 8

[0221] Preparation of (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1- ene-1-carboxylic acid (19)

[0222] The solvent methanol-water (3:1 v / v) to be used in this reaction was deoxygenated with a gas sparge and nitrogen just prior to use in the reaction. (1R,4R,7R)-tert-Butyl 7-bromo-6-(difluoromethylidene)-3-oxo-2- azabicyclo[2.2.1]-heptane-2-carboxylate (8) (1.6 g, 4.73 mmol, 1 equiv) was dissolved in aqueous methanol (35 ml) and stirred with a stir bar under a nitrogen atmosphere and potassium carbonate powder (1.96 g, 14.18 mmol, 3 equiv) was added to the solution in a single portion. The reaction flask was sealed with a serum cap and nitrogen needle and the internal mixture was stirred for 12 hours. Dichloromethane (50 ml) was added and then the biphasic crude reaction mixture was acidified with 1 M hydrochloric acid to destroy excess potassium carbonate and bring the pH to 7 (pH paper). The phases were separated and then the volatiles were removed from the dichloromethane layer. The crude product was purified by chromatography on a Biotage on a 25 g silica column with a methanol-CH2Cl2gradient [1% (1 CV) 1%-20% (7.5 CV) 20% (3 CV)] and fractions were collected in 16 x 100 mm tubes. Fractions containing product were combined and concentrated (rotary evaporator / vacuum / water bath at 40 °C) into a golden yellow solid which was pumped on a vacuum line for several hours to yield purified (S)-3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidene)cyclopenta-1 -ene-1 -carboxylic acid (19) (0.733 g, 56%).

[0223] Example 9

[0224] Preparation of (S)-3-amino-4-(difluoromethylidene)cyclopenta-1 -ene-1 - carboxylic acid hydrochloride (1)

[0225] Method A

[0226] (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopenta-1 - ene-1 -carboxylic acid methyl ester (9) (570.0 mg, 1.97 mmol) was dissolved in dioxane (1.00 mL) and 6M HC1 (9 mL) was added. After heating at 80 °C for 2 h, the reaction was concentrated to yield (S)-3-amino-4- (difluoromethylidene)cyclopenta-1 -ene-1 -carboxylic acid hydrochloride (1) as a light brown powder (403.0 mg, 1.90 mmol, 97% yield). Crystallization from ethanol / ethyl ether improved the purity to >99%. (c 0.90, H20); m.p. 207 °C (decomposition); 1¹H NMR (500MHz, D₂O) δ 6.59 (s, ¹H), 4.70 (s, ¹³H), 3.39 (d, J = 20.5Hz, ¹H), 3.33 (d, J = 20.8Hz, ¹H). See also Figure 10 . 13 C NMR (126MHz, D₂O) δ 167.2, 153.0 (dd, J = 290.1, 288.4Hz), 141.8, 134.3, 86.1 (dd, J = 26.6, 21.2Hz), 54.8 (d, J = 5.7Hz), 31.1. See also Figure 11 . 19 F NMR (470MHz, D₂O) δ -83.1 (dq, J = 40.8, 2.8Hz), -83.5 (dq, J = 40.4, 2.1Hz). See also Figure 12 IR (membrane, cm) -1 )3348,3075,2981,2883,2829,2600,2434,1771,1686; The calculated HMRS (ESI-) value for C7H7F2NO2-H is 174.0372; the measured value is 174.0369.

[0227] Method B

[0228] (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylate (9) (5.20 g, 17.9 mmol, 1 equivalent) was added to 4 M HCl (g) / EtOAc (100 mL), and the mixture was stirred at 20-30 °C for 2 h. TLC (petroleum ether:ethyl acetate = 5:1, R f =0) indicates that the starting material was completely consumed. The mixture was concentrated under reduced pressure to give (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid methyl ester hydrochloride (3.00 g, crude, HCl salt) as a yellow solid, which was used in the next step without further purification. The above compound (3.00 g, 13.3 mmol, 1.0 equivalent) was added to MeOH (15 mL), and a solution of LiOH·H2O (1.39 g, 33.2 mmol, 2.5 equivalent) in H2O (10 mL) was slowly added to the above mixture at 20-30 °C. The mixture was stirred at 20-30 °C for 3 h. TLC (dichloromethane:methanol = 5:1, R f= 0.40) indicated that the starting material was completely consumed. The mixture was adjusted to pH = 2-3 with 6 M HCI solution and concentrated to give the crude product which was purified by reverse phase HPLC (Agela C18 330 g; mobile phase: [water (0.1% HCI) - MeOH]; B%: 10% - 20%, 20 min, 70 mL / min) to give (S)-3-amino-4-(difluoromethylidene)cyclopent-1 - ene-1 -carboxylic acid hydrochloride (1) (1.80 g, 8.46 mmol, 63.7% yield, 99.5% purity) as a white solid.

[0229] Example 10

[0230] Preparation of (S)-3-amino-4-(difluoromethylidene)cyclopent-1 - ene-1 -carboxylic acid hydrochloride (1)

[0231] 6M hydrochloric acid was prepared by mixing concentrated hydrochloric acid (10 ml) and water (10 ml). THF used in this reaction was deoxygenated with a gas dispersion tube and nitrogen gas just before use in the reaction. (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)- cyclopent-1 -en-1 -carboxylic acid (19) was dissolved in THF (2 ml) and stirred in a 10 ml round bottom flask with a stir bar. 6M hydrochloric acid (2 ml) was added. The reaction mixture was stirred at room temperature for 2 hours and then THF and water were removed with a stream of active nitrogen overnight. The pink solid residue was pumped on a vacuum line for several hours to remove any residual solvent to give (S)-3-amino-4-(difluoromethylidene)-1 -cyclopenten-1 -carboxylic acid hydrochloride (1) as a pink solid (~ 100 mg; 86%).

[0232] It is understood that the examples and embodiments provided herein are exemplary examples and embodiments. Those of skill in the art will envision various modifications to the examples and embodiments consistent with the scope of the disclosure herein. Such modifications are intended to be encompassed by the claims.

[0233] The present application is also directed to the following items:

[0234] 1. A process for preparing (S)-3-amino-4-(difluoromethylidene)cyclopent-1 - ene-1 -carboxylic acid (1) or a salt thereof, comprising:

[0235] converting (1R,4S)-2-azabicyclo[2.2.1]heptan-5-one (2) to (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4);

[0236] converting (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2- azabicyclo[2.2.1]heptan-3-one (7);

[0237] converting (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2- azabicyclo[2.2.1]heptan-3-one (7);

[0238] converting (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2- azabicyclo[2.2.1]heptan-3-one (7);

[0239] converting (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2- azabicyclo[2.2.1]heptan-3-one (7);

[0240] converting (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2- azabicyclo[2.2.1]heptan-3-one (7);

[0241] converting (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-7-bromo-6-(difluoromethyl)-2- azabicyclo[2.2.1]heptan-3-one (7);

[0242] 2. The process according to item 1, wherein (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (2) is converted to (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3); and (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3) is converted to (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4).

[0243] 3. The process according to item 1, wherein (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (2) is reacted with a. PMBOH, HC1, NaH, THF / DMF; and b. DBDMH, AcOH to produce (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4).

[0244] 4. The process according to item 1, wherein (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4) is reacted with a. K2CO3, alcohol; and b. 2-iodoxybenzoic acid (IBX), MeCN to produce (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5).

[0245] 5. The process according to item 1, wherein (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4) is reacted with a. K2CO3, alcohol; and b. TPAP, NMO to produce (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5).

[0246] 6. The process according to item 1, wherein (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) is reacted with 2-((difluoromethyl)sulfinyl)pyridine (20), KO t Bu, DMF, NH4CI, HC1 to produce (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6).

[0247] 7. The process of item 1, wherein (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptane-3,6-dione (5) is reacted with tert-butyllithium and F2CHP(O)(OEt)2 to produce (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6).

[0248] 8. The process of item 1, wherein (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- (4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) is reacted with CAN, MeCN, H2O to produce (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan- 3-one (7).

[0249] 9. The process of item 1, wherein (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]heptan-3-one (7) is reacted with Boc2O, DMAP, Et3N, CH2Cl2 to produce (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(tert-butoxycarbonyl)-2- azabicyclo[2.2.1]heptan-3-one (8).

[0250] 10. The process of item 1, wherein (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- (tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) is reacted with K2CO3, methanol or ethanol to produce (S)-3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidene)cyclopent-1-en-1-carboxylate.

[0251] 11. The process of item 1, wherein (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2- (tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) is reacted with K2CO3, methanol, CH3ONa to produce (S)-3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidene)cyclopent-1-en-1-carboxylate (9).

[0252] 12. The process of item 10, wherein (S)-methyl 3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidenyl)cyclopent-1 -en-1 -carboxylate or (S)-ethyl 3-((tert- butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-1 -en-1 -carboxylate is reacted with HC1 to produce (S)-3-amino-4-(difluoromethylidenyl)cyclopent-1 -en-1 - carboxylic acid (1) or a pharmaceutically acceptable salt thereof.

[0253] 13. (S)-3-amino-4-(difluoromethylidenyl)cyclopent-1 -en-1 -carboxylic acid (1) or a pharmaceutically acceptable salt thereof, prepared by the process of item 1.

[0254] 14. A process for preparing (S)-3-amino-4-(difluoromethylidenyl)cyclopent-1 -en-1 - carboxylic acid (1) or a salt thereof, comprising:

[0255] converting (1R,4S)-(-)-2-azabicyclo[2.2.1]heptan-5-one (2) to (1R,4S)-(-)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-5-one (3);

[0256] converting (1R,4S)-(-)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-5-one (3) to (1R,4R,6S,7R)-(+)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6- yl acetate (4);

[0257] converting (1R,4R,6S,7R)-(+)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4) to (1R,4R,6S,7R)-(+)-7-bromo-6-hydroxy-2-(4- methoxybenzyl)-2-aza-bicyclo[2.2.1]heptan-3-one (25);

[0258] converting (1R,4R,6S,7R)-(+)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-aza- bicyclo[2.2.1]heptan-3-one (25) to (1R,4R,7R)-(+)-7-bromo-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptane-3,6-dione (5);

[0259] converting (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-(+)-7-bromo-6- (difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7);

[0260] converting (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-(+)-7-bromo-6- (difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7);

[0261] converting (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-(+)-7-bromo-6- (difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7);

[0262] converting (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-(+)-7-bromo-6- (difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7);

[0263] converting (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) to (1R,4R,7R)-(+)-7-bromo-6- (difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7);

[0264] 15. The process of item 14, wherein (1R,4S)-(-)-2-azabicyclo[2.2.1]hept-5-en-3-one (2) is reacted with 4-methoxybenzyl chloride, tetrabutylammonium iodide, and lithium bis(trimethylsilyl)amide to produce (1R,4S)-(-)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3).

[0265] 16. The process of item 14, wherein (1R,4S)-(-)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]hept-5-en-3-one (3) is reacted with 1,3-dibromo-5,5- dimethylhydantoin to produce (1R,4R,6S,7R)-(+)-7-bromo-2-(4-methoxybenzyl)-3- oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4).

[0266] 17. The process of item 14, wherein (1R,4R,6S,7R)-(+)-7-bromo-2-(4- methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4) is reacted with potassium carbonate in methanol to produce (1R,4R,6S,7R)-(+)-7-bromo-6- hydroxy-2-(4-methoxybenzyl)-2-aza-bicyclo[2.2.1]heptan-3-one (25).

[0267] 18. The process of item 14, wherein (1R,4R,6S,7R)-(+)-7-bromo-6-hydroxy-2-(4- methoxybenzyl)-2-aza-bicyclo[2.2.1]heptan-3-one (25) is reacted with oxalyl chloride in dichloromethane, DMSO and triethylamine to produce (1R,4R,7R)-(+)-7- bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5).

[0268] 19. The process of item 14, wherein (1R,4R,6S,7R)-(+)-7-bromo-6-hydroxy-2-(4- methoxybenzyl)-2-aza-bicyclo[2.2.1]heptan-3-one (25) is reacted with 4- methylmorpholine-N-oxide in dichloromethane, and tetrapropylammonium perruthenate to produce (1R,4R,7R)-(+)-7-bromo-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptane-3,6-dione (5).

[0269] 20. The process of item 14, wherein (1R,4R,7R)-(+)-7-bromo-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) is reacted with 2- ((difluoromethyl)sulfinyl)pyridine (20) and potassium bis(trimethylsilyl)amide in DMF, quenched with NH4Cl to produce (1R,4R,7R)-(+)-7-bromo-6- (difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6).

[0270] 21. The process of item 14, wherein (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2- (4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6) is reacted with cerium (IV) ammonium nitrate, MeCN, H2O to produce (1R,4R,7R)-(+)-7-bromo-6- (difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7) in acetonitrile.

[0271] 22. The process of item 14, wherein (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2- azabicyclo[2.2.1]heptan-3-one (7) is reacted with Boc2O, DMAP, Et3N, CH2Cl2 to produce (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2-(tert-butoxycarbonyl)-2- azabicyclo[2.2.1]heptan-3-one (8).

[0272] 23. The process of item 14, wherein (1R,4R,7R)-(+)-7-bromo-6-(difluoromethylidene)-2- (tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8) is reacted with K2CO3, methanol or ethanol to produce (S)-3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidene)cyclopent-1-en-1-carboxylic acid (19).

[0273] 24. The process of item 14, wherein (S)-3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidene)cyclopent-1-en-1-carboxylic acid (19) is reacted with HCl to produce (S)-3-amino-4-(difluoromethylidene)cyclopent-1-en-1-carboxylic acid (1) or a pharmaceutically acceptable salt thereof.

[0274] 25. (S)-3-amino-4-(difluoromethylidene)cyclopent-1-en-1-carboxylic acid (1) or a pharmaceutically acceptable salt thereof, prepared by the process of item 1.

[0275] 26. (S)-3-amino-4-(difluoromethylidene)cyclopent-1-en-1-carboxylic acid (1) or a pharmaceutically acceptable salt thereof, prepared by the process of item 12.

[0276] 27. (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6) or a pharmaceutically acceptable salt thereof.

[0277] 28. (1R,4R,7R)-7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7), or a pharmaceutically acceptable salt thereof.

[0278] 29. (S)-methyl 3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1- ene-1-carboxylate (8), or a pharmaceutically acceptable salt thereof.

[0279] 30. (S)-methyl 3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1- ene-1-carboxylate (9), or a pharmaceutically acceptable salt thereof.

[0280] 31. (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1-ene-1- carboxylic acid (19), or a pharmaceutically acceptable salt thereof.

[0281] 32. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidene)cyclopent-1- ene-1-carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and one or more of the following compounds: (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (2), (1R,4S)-2-(4- methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3), (1R,4R,6S,7R)-7-bromo-2-(4- methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4), (1R,4R,6S,7R)-7-bromo- 6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25), (1R,4R,7R)-7-bromo- 2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5), (1R,4R,7R)-7-bromo-6- (difluoromethylidene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6), (1R,4R,7R)- 7-bromo-6-(difluoromethylidene)-2-azabicyclo[2.2.1]heptan-3-one (7), (1R,4R,7R)-7-bromo- 6-(difluoromethylidene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8), or (S)- 3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1-ene-1-carboxylate (9), (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1-ene-1- carboxylic acid (19), or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0282] 33. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1) or a pharmaceutically acceptable salt thereof and from 0.0001 mg to 1 mg of (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (2) or a pharmaceutically acceptable salt thereof.

[0283] 34. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1) or a pharmaceutically acceptable salt thereof and from 0.0001 mg to 1 mg of (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3) or a pharmaceutically acceptable salt thereof.

[0284] 35. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1) or a pharmaceutically acceptable salt thereof and from 0.0001 mg to 1 mg of (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]hept-6- yl acetate (4) or a pharmaceutically acceptable salt thereof.

[0285] 36. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1) or a pharmaceutically acceptable salt thereof and from 0.0001 mg to 1 mg of (1R,4R,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3- one (25) or a pharmaceutically acceptable salt thereof.

[0286] 37. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1) or a pharmaceutically acceptable salt thereof and from 0.0001 mg to 1 mg of (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5) or a pharmaceutically acceptable salt thereof.

[0287] 38. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1) or a pharmaceutically acceptable salt thereof and from 0.0001 mg to 1 mg of (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-(4-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (6) or a pharmaceutically acceptable salt thereof.

[0288] 39. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1) or a pharmaceutically acceptable salt thereof and from 0.0001 mg to 1 mg of (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-azabicyclo[2.2.1]heptan-3-one (7) or a pharmaceutically acceptable salt thereof.

[0289] 40. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1) or a pharmaceutically acceptable salt thereof and from 0.0001 mg to 1 mg of (1R,4R,7R)-7-bromo-6-(difluoromethylidenyl)-2-(tert-butoxycarbonyl)-2- azabicyclo[2.2.1]heptan-3-one (8) or a pharmaceutically acceptable salt thereof.

[0290] 41. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1) or a pharmaceutically acceptable salt thereof and from 0.0001 mg to 1 mg of (S)-methyl 3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylate (9) or a pharmaceutically acceptable salt thereof.

[0291] 42. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1) or a pharmaceutically acceptable salt thereof and from 0.0001 mg to 1 mg of (S)-ethyl 3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylate or a pharmaceutically acceptable salt thereof.

[0292] 43. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1) or a pharmaceutically acceptable salt thereof and from 0.0001 mg to 1 mg of (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid or a pharmaceutically acceptable salt thereof.

[0293] 44. A process for preparing (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l-enel-carboxylic acid (1) or a salt thereof, comprising:

[0294] converting cyclopent-3-ene-carboxylic acid ethyl ester (10) to (3R,4S)-3-((tert- butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11);

[0295] Ethyl (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentanecarboxylate (11) is converted into ethyl (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentanecarboxylate (12);

[0296] Ethyl (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentanecarboxylate was converted to ethyl (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonanecarboxylate (13);

[0297] Ethyl (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonanecarboxylate (13) was converted to ethyl (S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7-carboxylate (14);

[0298] (S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7-carboxylate ethyl ester (14) was converted to (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylate ethyl ester (15); and

[0299] Ethyl (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid (15) was converted to (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid (1).

[0300] 45. According to the process described in Project 44, ethyl cyclopent-3-ene carboxylate (10) is converted to ethyl (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentanecarboxylate (11) by Sharpless amino hydroxylation and Boc protection.

[0301] 46. ​​According to the process described in Project 44, ethyl (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentanecarboxylate (11) is converted into ethyl (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentanecarboxylate (12) by oxidation.

[0302] 47. According to the process described in Project 44, ethyl (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentanecarboxylate (12) is protected and converted to ethyl (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonanecarboxylate (13).

[0303] 48. The process of item 44, wherein (9S)-Ethyl 9-(tert-butoxycarbonylamino)- 1,4-dioxa-7-spiro[4.4]nonanecarboxylate (13) is subjected to phenyl selenyl bromide, a base, and H2O2 to produce (S)-Ethyl 9-(tert-butoxycarbonylamino)- 1,4-dioxa-7-spiro[4.4]nonene-7-carboxylate (14).

[0304] 49. The process of item 44, wherein (S)-Ethyl 9-(tert-butoxycarbonylamino)- 1,4-dioxa-7-spiro[4.4]nonene-7-carboxylate (14) is deprotected and subjected to a Horner- Wittig reaction to produce (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidene)cyclopenta-1-en-1-carboxylate (15).

[0305] 50. The process of item 44, wherein (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-4- (difluoromethylidene)cyclopenta-1-en-1-carboxylate (15) is converted to (S)-3- Amino-4-(difluoromethylidene)cyclopenta-1-en-1-carboxylic acid (1) with trifluoroacetic acid (TFA), dichloromethane (DCM), and saturated NaHCO3.

[0306] 51. (S)-3-Amino-4-(difluoromethylidene)cyclopenta-1-en-1-carboxylic acid (1) or a pharmaceutically acceptable salt thereof, prepared by the process of item 44.

[0307] 52. (9S)-Ethyl 9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonanecarboxylate (13) or a pharmaceutically acceptable salt thereof.

[0308] 53. (S)-Ethyl 9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7- carboxylate (14) or a pharmaceutically acceptable salt thereof.

[0309] 54. (S)-Ethyl 3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopenta-1- en-1-carboxylate (15) or a pharmaceutically acceptable salt thereof.

[0310] 55. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and one or more of the following compounds: cyclopent-3-ene-carboxylic acid ethyl ester (10), (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11), (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentane carboxylic acid ethyl ester (12), (9S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13), (S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14), (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-l-en- l-carboxylic acid ethyl ester (15), or a pharmaceutically acceptable salt of any of the foregoing.

[0311] 56. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and from 0.0001 mg to 1 mg of cyclopent-3-ene-carboxylic acid ethyl ester (10), or a pharmaceutically acceptable salt thereof.

[0312] 57. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and from 0.0001 mg to 1 mg of cyclopent-3-ene-carboxylic acid ethyl ester (10), (3R,4S)-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11), or a pharmaceutically acceptable salt thereof.

[0313] 58. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and from 0.0001 mg to 1 mg of (3R)-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentane carboxylic acid ethyl ester (12), or a pharmaceutically acceptable salt thereof.

[0314] 59. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-l- ene- 1 -carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and from 0.0001 mg to 1 mg of (9S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13), or a pharmaceutically acceptable salt thereof.

[0315] 60. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-1 - ene-1 -carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and from 0.0001 mg to 1 mg of (S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonene-7- carboxylic acid ethyl ester (14), or a pharmaceutically acceptable salt thereof.

[0316] 61. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylidenyl)cyclopent-1 - ene-1 -carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and from 0.0001 mg to 1 mg of (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidenyl)cyclopent-1 - ene-1 -carboxylic acid ethyl ester (15), or a pharmaceutically acceptable salt thereof.

Claims

1. A process for preparing (S)-3-amino-4-(difluoromethylidene)cyclopent-l-en- 1 -carboxylic acid ethyl ester or a salt thereof, comprising: Ethyl cyclopent-3-ene-carboxylate (10) was converted to (3 S ,4 R )-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11); (3 S ,4 R )-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentanecarboxylic acid ethyl ester (11) to (3 S )-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentanecarboxylic acid ethyl ester (12); (3 S )-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentanecarboxylic acid ethyl ester to (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13); converting (9S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13) to (S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7- spiro[4.4]nonene-7-carboxylic acid ethyl ester (14); (S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7-spiro[4.4]nonene-7-carboxylic acid ethyl ester (14) was converted to S ethyl -3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-l- ene-l-carboxylate (15); and Will( S )-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid ethyl ester (15) is converted to (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid ethyl ester.

2. Process according to claim 1, wherein cyclopent-3-ene-carboxylic acid ethyl ester (10) is converted to (3 S ,4 R )-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentane carboxylic acid ethyl ester (11) by Sharpless aminohydroxylation and Boc protection.

3. The process of claim 1, wherein (3 S ,4 R )-3-((tert-butoxycarbonyl)amino)-4-(hydroxy)cyclopentanecarboxylic acid ethyl ester (11) is converted to (3 S )-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentanecarboxylic acid ethyl ester (12) by oxidation.

4. The process of claim 1, wherein (3 S )-3-((tert-butoxycarbonyl)amino)-4-oxo-cyclopentane carboxylic acid ethyl ester (12) is protected and converted to (9S)-9-(tert-butoxycarbonylamino)-1,4-dioxa-7-spiro[4.4]nonane carboxylic acid ethyl ester (13).

5. The process of claim 1, wherein (9S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7- spiro[4.4]nonane carboxylic acid ethyl ester (13) is subjected to bromobenzene selenide, a base, and H2O2 to produce (S)-9-(tert-butoxycarbonylamino)-l,4-dioxa-7- spiro[4.4]nonene-7-carboxylic acid ethyl ester (14).

6. The process of claim 1, wherein (S)-ethyl 9-(tert-butoxycarbonylamino)-1,4- dioxa-7-spiro[4.4]nonene-7-carboxylate (14) is deprotected and subjected to a Horner- Wittig reaction to produce S ethyl (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylidene)cyclopent-1- ene-1-carboxylate (15).

7. The process of claim 1, wherein the conversion of (E)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl) cyclopent-1 -en-1 -carboxylic acid ethyl ester (15) to (E)-3-amino-4-(difluoromethyl)cyclopent-1 -en-1 -carboxylic acid ethyl ester is performed with trifluoroacetic acid (TFA), dichloromethane (DCM), and saturated NaHC03. S (E)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl) cyclopent-1 -en-1 -carboxylic acid ethyl ester (15) to (E)-3-amino-4-(difluoromethyl)cyclopent-1 -en-1 -carboxylic acid ethyl ester. S (E)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethyl) cyclopent-1 -en-1 -carboxylic acid ethyl ester (15

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