Thienyl compounds for treating schizophrenia

Abstract

Disclosed herein are thienyl compounds and salts, pharmaceutical compositions, and uses thereof.

Description

[0001] Attorney Docket No. CTX0016-401-PC THIENYL COMPOUNDS FOR TREATING SCHIZOPHRENIA BACKGROUND

[0001] This application claims the benefit of priority of United States provisional application no. 63 / 707,937, filed October 16, 2024, the contents of which are incorporated by reference as if written herein in their entirety.

[0002] Schizophrenia is a chronic, severe mental disorder characterized by significant impairments in the way reality is perceived. Schizophrenia is associated with considerable disability and may affect all areas of life including personal, family, social, educational, and occupational functioning. People with schizophrenia are 2 to 3 times more likely to die early than the general population (Laursen TM, Nordentoft M, Mortensen PB. Excess early mortality in schizophrenia. Annual Review of Clinical Psychology, 2014;10, 425-438). This is often due to physical illnesses, such as cardiovascular, metabolic, and infectious diseases.

[0003] Schizophrenia affects approximately 24 million people worldwide, about 1 in 300 people (0.32%) or 1 in 222 adults (0.45%) (Institute of health Metrics and Evaluation (IHME). Global Health Data Exchange (GHDx). http: / / ghdx.healthdata.org / gbd-results-tool?params=gbd-api-2019- permalink / 27a7644e8ad28e739382d31e77589dd7). Onset is most often during late adolescence and the twenties, and onset tends to happen earlier among men than among women. Although treatment options exist, about 75% of patients with schizophrenia discontinue their antipsychotic treatment within 18 months (Lieberman, J.A. et al., “Effectiveness of antipsychotic drugs in patients with chronic schizophrenia,” N Engl J Med. 2005, 353, 1209-23).

[0004] There remains a need for effective treatments for schizophrenia. The present invention provides treatments to meet this critical need. SUMMARY

[0005] Provided is a compound of Formula (I): (I) Attorney Docket No. CTX0016-401-PC or a pharmaceutically acceptable salt thereof, wherein R1and R2are independently chosen from H and C1-C3alkyl, or R1and R2, taken together with the intervening nitrogen atom, form a 4-6 membered saturated heterocyclic ring.

[0006] Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, enriched in the (S) enantiomer. Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, enriched in the (R) enantiomer.

[0007] Also provided is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] Also provided is a method for treating schizophrenia comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided is a method for treating schizophrenia comprising the step of administering to a patient in need thereof a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] These and other aspects of the invention will be apparent upon reference to the following description. References cited herein are hereby incorporated by reference in their entireties. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG.1 shows the ORTEP structure of compound 8a.

[0011] FIG.2 shows a photograph of single crystals of compound 8a. DETAILED DESCRIPTION

[0012] This description is intended to acquaint others skilled in the art with the present invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples are intended for purposes of illustration only. This invention is not limited to the embodiments or examples described herein. A. DEFINITIONS

[0013] The term “about” is intended to qualify a numerical value as including a margin of measurement accuracy, such as a standard error of a mean value. In some embodiments, “about” means the indicated numerical value ± 10%. Attorney Docket No. CTX0016-401-PC

[0014] The term “alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon radical containing the indicated number of carbon atoms. Examples of alkyl radicals include methyl, ethyl, n-propyl, and isopropyl.

[0015] The term “heterocycloalkyl” or “heterocycloalkyl group” or “heterocycle” or “heterocyclic” or “heterocyclic ring” or “heterocyclyl” refers to a monocyclic non- aromatic, saturated or partially unsaturated (if not defined as “saturated”) ring containing the indicated number of ring atoms, including at least one ring heteroatom, such as nitrogen, oxygen, or sulfur. Unless otherwise indicated, the ring is unsubstituted. Examples include, but are not limited to, azetidinyl, pyrrolidinyl, and piperidinyl.

[0016] The term “patient” refers to a human being with schizophrenia.

[0017] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound judgment, suitable for use in contact with the tissues of human beings with acceptable toxicity, irritation, allergic response, and other problems or complications commensurate with a reasonable benefit / risk ratio.

[0018] The term “pharmaceutical composition” refers to the combination of an active ingredient with a pharmaceutically acceptable excipient, in a form suitable for administration to a patient.

[0019] The term “safe and well tolerated” refers to a drug treatment method having an acceptable safety and tolerability profile in patients treated according to the method, as assessed by parameters such as AEs, ECGs, vital signs, safety laboratory parameters, and physical examinations, consistent with the safety and tolerability requirements of government agencies responsible for regulating drugs for human use, such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).

[0020] The term “stable” or “chemically stable” refers to a compound that is sufficiently robust to be isolated to a useful degree of purity from a reaction mixture. The present invention is directed to stable compounds.

[0021] The term “therapeutically effective” refers to effective to treat schizophrenia in a patient or patient population.

[0022] The term “treating” or “treatment” refers to any lessening, reducing, modulating, ameliorating, improving, stabilizing, inhibiting, slowing progression, or delaying onset of schizophrenia or a symptom thereof. For example, treatment may include diminishment of a troublesome symptom of schizophrenia. Attorney Docket No. CTX0016-401-PC

[0023] Compounds described herein may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including R- and S-enantiomers, the racemic mixtures thereof, and other mixtures thereof.

[0024] Chemical names and / or structural formulas described herein that do not specifically recite the isotope ratios of the constituent atoms are intended to include compounds in which the constituent atoms are present in any ratio of isotopes. For example, unless otherwise specified, a carbon atom may be present in any ratio of12C,13C, and14C, and a hydrogen atom may be present in any ratio of1H,2H, and3H. In some embodiments, the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotopes. In some embodiments, one or more of the constituent atoms in a compound of the present invention is enriched to contain a non-naturally occurring ratio of isotopes. B. COMPOUNDS

[0025] Provided is a compound of Formula (I): (I) or a pharmaceutically independently chosen from H and C1-C3alkyl, or R1and R2, taken together with the intervening nitrogen atom, form a 4-6 membered saturated heterocyclic ring.

[0026] In some embodiments, R1and R2are independently chosen from H and methyl, or R1and R2, taken together with the intervening nitrogen atom, form a 4-6 membered saturated heterocyclic ring.

[0027] In some embodiments, R1and R2are independently chosen from H and methyl, or R1and R2, taken together with the intervening nitrogen atom, form an azetidinyl, pyrrolidinyl, or piperidinyl ring.

[0028] In some embodiments, R1and R2are independently chosen from H and C1-C3 alkyl.

[0029] In some embodiments, R1and R2are independently chosen from H and methyl.

[0030] In some embodiments, R1is H and R2is chosen from H and C1-C3 alkyl. Attorney Docket No. CTX0016-401-PC

[0031] In some embodiments, R1is H and R2is chosen from H and methyl.

[0032] In some embodiments, R1is H and R2is chosen from C1-C3alkyl.

[0033] In some embodiments, R1is H and R2is methyl.

[0034] In some embodiments, R1and R2are H.

[0035] In some embodiments, R1and R2are C1-C3 alkyl.

[0036] In some embodiments, R1and R2are methyl.

[0037] In some embodiments, R1and R2, taken together with the intervening nitrogen atom, form an azetidinyl, pyrrolidinyl, or piperidinyl ring. In some embodiments, R1and R2, taken together with the intervening nitrogen atom, form an azetidinyl ring. In some embodiments, R1and R2, taken together with the intervening nitrogen atom, form a pyrrolidinyl ring. In some embodiments, R1and R2, taken together with the intervening nitrogen atom, form a piperidinyl ring.

[0038] Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, enriched in one enantiomer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 80% enriched in the (S) enantiomer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 80% enriched in the (R) enantiomer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 85% enriched in the (S) enantiomer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 85% enriched in the (R) enantiomer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 90% enriched in the (S) enantiomer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 90% enriched in the (R) enantiomer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 95% enriched in the (S) enantiomer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 95% enriched in the (R) enantiomer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least about 99% enriched in the (S) enantiomer. In some embodiments, the compound of Formula (I), is at least about 99% enriched in the (R) enantiomer. Attorney Docket No. CTX0016-401-PC

[0039] Also provided is N-Methyl-4-oxa-7-thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine ), or a pharmaceutically acceptable salt thereof,enriched in one the N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 80% enriched in the (S) enantiomer. In some embodiments, the N-Methyl-4-oxa-7-thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 80% enriched in the (R) enantiomer. In some embodiments, the N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 85% enriched in the (S) enantiomer. In some embodiments, the N-Methyl-4-oxa-7-thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 85% enriched in the (R) enantiomer. In some embodiments, the N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 90% enriched in the (S) enantiomer. In some embodiments, the N-Methyl-4-oxa-7-thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 90% enriched in the (R) enantiomer. In some embodiments, the N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 95% enriched in the (S) enantiomer. In some embodiments, the N-Methyl-4-oxa-7-thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 95% enriched in the (R) enantiomer. In some embodiments, the N-Methyl-4-oxa-7-thiatricyclo[6.3.0.02,6]undeca- 1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 99% enriched in the (S) enantiomer. In some embodiments, the N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 99% enriched in the (R) enantiomer.

[0040] Also provided is a pharmaceutically acceptable salt of a compound of Formula (I). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt. Attorney Docket No. CTX0016-401-PC C. PHARMACEUTICAL COMPOSITIONS

[0041] While it may be possible for the compounds and salts described herein to be administered to a patient as the raw chemical, they are preferably administered as a pharmaceutical composition. Accordingly, provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, enriched in one enantiomer. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at least about 80%, 85%, 90%, 95% or 99% enriched in the (R) enantiomer. In some embodiments, the pharmaceutical composition comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at least about 80%, 85%, 90%, 95% or 99% enriched in the (S) enantiomer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is N-Methyl-4-oxa-7-thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises N-Methyl-4-oxa-7-thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien- 10-amine, or a pharmaceutically acceptable salt thereof, enriched in one enantiomer. In some embodiments, the pharmaceutical composition comprises N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, at least about 80%, 85%, 90%, 95% or 99% enriched in the (R) enantiomer. In some embodiments, the pharmaceutical composition comprises N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, at least about 80%, 85%, 90%, 95% or 99% enriched in the (S) enantiomer.

[0042] Any of the well-known techniques and excipients may be used as suitable and as understood in the art (see, e.g., Remington: The Science and Practice of Pharmacy, 20th ed., Gennaro et al. Eds., Lippincott Williams and Wilkins, 2000). Pharmaceutically acceptable excipients include pharmaceutically acceptable binding agents, lubricants, wetting agents, disintegrants, and the like. Tablets, pills, capsules, troches and the like can contain any of the following excipients, or excipients of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a diluent such as starch or lactose, a dispersing agent such as alginic acid, sodium starch glycolate, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide. The amount of active ingredient that is combined with the pharmaceutically acceptable Attorney Docket No. CTX0016-401-PC excipient (s) to produce a single dosage form will vary depending upon the particular mode of administration and the identity of the dosage form.

[0043] In certain embodiments, the pharmaceutical composition contains about 0.1 mg to about 2000 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein. In certain embodiments, the pharmaceutical composition contains about 0.5 mg to about 1500 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein. In certain embodiments, the pharmaceutical composition contains about 1 mg to about 1000 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein. In certain embodiments, the pharmaceutical composition contains about 0.25 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 1000 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein. In certain embodiments, the pharmaceutical composition contains about 2 mg, 25 mg, 75 mg, or 150 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein.

[0044] Compressed oral tablets may comprise the following ingredients: Ingredient mg / tablet 00 0 0 1 nd granulate with purified water; then dry the granules, mill the dried granules to desired particle size, and finally add ingredient 5, mix thoroughly, and compress.

[0046] Powder filled oral capsules may comprise the following ingredients: Ingredient mg / capsule 0 Attorney Docket No. CTX0016-401-PC 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 0 3 a o es e pa c e s e; e a g e e s a , o oug y, a into capsules (e.g., hard gelatin capsules).

[0048] Sterile injection pharmaceutical composition may comprise the following ingredients: Ingredient mg / sterile injection composition ix ingredients 1 and 2 and a portion of ingredient 4 to dissolve ingredient 1; then adjust to pH 5 with ingredient 3 and add ingredient 4 to about 1 mL total volume; and finally filter, fill into vials, and sterilize. D. TREATMENT METHODS

[0050] Also provided is a method of treating schizophrenia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, enriched in one enantiomer. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at least about 80%, 85%, 90%, 95% or 99% enriched in the (R) enantiomer. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at least about 80%, 85%, 90%, 95% or 99% enriched in the (S) enantiomer. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of N-Methyl-4-oxa-7- Attorney Docket No. CTX0016-401-PCthiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10- ), or apharmaceutically acceptable salt thereof. In some effective amount of N-Methyl-4-oxa-7-thiatricyclo -dien-10- amine, or a pharmaceutically acceptable salt thereof, is at least about 80% enriched in the (S) enantiomer. In some embodiments, the therapeutically effective amount of N-Methyl- 4-oxa-7-thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 80% enriched in the (R) enantiomer. In some embodiments, the therapeutically effective amount of N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 85% enriched in the (S) enantiomer. In some embodiments, the therapeutically effective amount of N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 85% enriched in the (R) enantiomer. In some embodiments, the therapeutically effective amount of N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 90% enriched in the (S) enantiomer. In some embodiments, the therapeutically effective amount of N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 90% enriched in the (R) enantiomer. In some embodiments, the therapeutically effective amount of N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 95% enriched in the (S) enantiomer. In some embodiments, the therapeutically effective amount of N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 95% enriched in the (R) enantiomer. In some embodiments, the therapeutically effective amount of N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, or a pharmaceutically acceptable salt thereof, is at least about 99% enriched in the (S) enantiomer. In some embodiments, the therapeutically effective amount of N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine, is at least about 99% enriched in the (R) enantiomer. In some embodiments, the patient is an adult. Attorney Docket No. CTX0016-401-PC

[0051] A compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein may be administered at a dose of from about 0.01 to about 300 mg / kg per day, such as about 0.03 to about 100 mg / kg per day. The dose range for adult humans is generally from about 0.05 mg to about 2 g / day, such as for example about 0.1 mg to about 1 g / day, about 0.1 to about 500 mg / day, or about 0.5 to about 400 mg / day. Dosage forms provided in discrete units (e.g., tablets or capsules) may conveniently contain an amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, which is therapeutically effective at that amount or a multiple thereof, for instance, units containing about 0.1 mg to about 500 mg, such as about 0.25 mg to about 100 mg. E. EXAMPLES 1. Synthesis

[0052] The examples below provide exemplary synthetic methods for the preparation of compounds of Formula (I), and pharmaceutically acceptable salts thereof, described herein. One of ordinary skill in the art will understand that similar methods may be employed.

[0053] Synthetic Route to (R) N-Methyl-4-oxa-7-thiatricyclo[6.3.0.02,6]undeca- 1(8),2(6)-dien-10-amine Hydrochloride (8a) and (S) N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine Hydrochloride (8b) butoxycarbonylamino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate (2) Attorney Docket No. CTX0016-401-PC To a 1 eq) and ethyl g, was added S (7.14 g, 222.67 mmol, 1.2 eq) and morpholine (24.27 g, 278.55 mmol, 24.51 mL, 1.5 eq). The mixture was stirred at 10 °C for 16 hr. The reaction was filtered and concentrated under reduced pressure to remove EtOH. The residue was diluted with H2O (300 mL) and extracted with EtOAc (300 mL × 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). Compound ethyl 2-amino-5-(tert- butoxycarbonylamino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate (31 g, 94.97 mmol, 51.14% yield) was obtained as a brown oil. LC-MS: m / z [M +H]+= 327.1.

[0055] Procedure for the preparation of ethyl 2-bromo-5-(tert- butoxycarbonylamino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate (3) To a mL) was added t-BuONO (11.75 g, 113.97 mmol, 13.56 mL, 1.2 eq) at 0 °C for 15 mins, then ethyl 2-amino-5-(tert-butoxycarbonylamino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3- carboxylate (31 g, 94.97 mmol, 1 eq) in acetonitrile (100 mL) was added to it. The mixture was stirred at 20 °C for 16 hr. The reaction mixture was quenched by addition sat.NaHCO3200 mL at 0 °C, and then concentrated under reduced pressure to remove solvent. The residue was diluted with H2O 300 mL and extracted with EtOAc (300 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 65 mL / min). Compound ethyl 2-bromo-5-(tert-butoxycarbonylamino)-5,6-dihydro-4H- Attorney Docket No. CTX0016-401-PC cyclopenta[b]thiophene-3-carboxylate (4.7 g, 9.75 mmol, 10.3% yield, 81% purity) was obtained as a yellow oil. LC-MS: m / z [M+Na]+= 412.0 / 414.0.

[0056] Procedure for the preparation of diethyl 5-(tert-butoxycarbonylamino)-5,6- dihydro-4H-cyclopenta[b]thiophene-2,3-dicarboxylate (4) To a cyclopenta[b]thiophene-3-carboxylate (4.7 g, 12.04 mmol, 1 eq) and TEA (3.66 g, 36.13 mmol, 5.03 mL, 3 eq) in DMF (50 mL) was added Pd(dppf)Cl2(881.14 mg, 1.20 mmol, 0.1 eq) and EtOH (10 mL). The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50 psi) at 80°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, Eluent of 0~14% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound diethyl 5-(tert-butoxycarbonylamino)-5,6-dihydro-4H- cyclopenta[b]thiophene-2,3-dicarboxylate (2.3 g, 6.00 mmol, 49.8% yield) was obtained as a colorless oil. LC-MS: m / z [M+H]+= 384.1.

[0057] Procedure for the preparation of diethyl 5-[tert- butoxycarbonyl(methyl)amino]-5,6-dihydro-4H-cyclopenta[b]thiophene-2,3- dicarboxylate (5) To cyclopenta[b]thiophene-2,3-dicarboxylate (2.3 g, 6.00 mmol, 1 eq) in DMF (20 mL) was added NaH (359.85 mg, 9.00 mmol, 60% purity, 1.5 eq) at 0 °C. After addition, the mixture was stirred at 0°C for 0.5hr, and then methyl iodide (1.28 g, 9.00 mmol, 560.10 μL, 1.5 eq) was added dropwise at 0°C. The resulting mixture was stirred at 0 °C for 2hr. The reaction mixture was quenched with sat.NH4Cl 50 mL and extracted with EtOAc (30mL × 2). The combined organic layers were washed with sat.NaCl (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g Attorney Docket No. CTX0016-401-PC SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound diethyl 5-[tert-butoxycarbonyl(methyl)amino]-5,6- dihydro-4H-cyclopenta[b]thiophene-2,3-dicarboxylate (1.1 g, 2.77 mmol, 46.14% yield) was obtained as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 6.03 - 5.62 (m, 1H), 4.38 (qd, J = 7.2, 14.6 4H), 3.02 - 2.88 (m, 1H), 2.87 - 2.73 (m, 2H), 2.66 (br s, 3H), 2.37 - 2.23 (m, , (s, 9H), 1.39 (q, J = 7.2 Hz, 6H). LC-MS: m / z [M+H]+= 398.1.

[0058] Procedure for the preparation of tert-butyl N-[2,3-bis(hydroxymethyl)-5,6- dihydro-4H-cyclopenta[b]thiophen-5-yl]-N-methyl-carbamate (6) To cyclopenta[b]thiophene-2,3-dicarboxylate (1.1 g, 2.77 mmol, 1 eq) in THF (10 mL) was added dropwise LiBH4 (4 M, 30.53 mL, 44.12 eq) at 0°C. After addition, the mixture was stirred at 0°C for 10 min, and then MeOH (1 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2hr. The reaction mixture was quenched with sat.NH4Cl 20 mL and extracted with EtOAc (30mL * 2). The combined organic layers were washed with sat.NaCl (50mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound tert-butyl N- [2,3-bis(hydroxymethyl)-5,6-dihydro-4H-cyclopenta[b]thiophen-5-yl]-N-methyl- carbamate (550 mg, 1.75 mmol, 63.41% yield) was obtained as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 5.48 - 5.26 (m, 1H), 4.79 - 4.71 (m, 2H), 4.62 (s, 2H), 3.14 (br dd, J = 8.5, 16.1 Hz, 1H), 2.99 (br dd, J = 8.6, 15.3 Hz, 1H), 2.92 - 2.66 (m, 5H), 2.55 - 2.11 (m, 2H), 1.52 - 1.44 (m, 9H). LC-MS: m / z [M-OH]+= 296.1.

[0059] Procedure for the preparation of (R,S) tert-butyl N-methyl-N-(4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-yl)carbamate (7) Attorney Docket No. CTX0016-401-PC To a solution of tert-butyl N-[2,3-bis(hydroxymethyl)-5,6-dihydro-4H- cyclopenta[b]thiophen-5-yl]-N-methyl-carbamate (550 mg, 1.75 mmol, 1 eq) in dichloromethane (10 mL) was added MnO2 (762.82 mg, 8.77 mmol, 5 eq). The mixture was stirred at 25°C for 16h. The reaction mixture was filtered. The filtrate was cooled to 0 °C and TFA (3.00 g, 26.32 mmol, 1.96 mL, 15 eq) was added. Then Et3SiH (1.02 g, 8.77 mmol, 1.40 mL, 5 eq) was added drop-wise. The mixture was stirred at 0 °C for 0.5 h. To the reaction mixture was added NaHCO3 (589.69 mg, 7.02 mmol, 273.13 µL, 4 eq) and (Boc)2O (765.99 mg, 3.51 mmol, 806.31 µL, 2 eq) in EtOAc (10 mL) and H2O (10 mL). The mixture was stirred at 25°C for 2h. The reaction mixture was extracted with EtOAc (30mL x 2). The combined organic layers were washed with sat.NaCl (10mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 40 mL / min). Compound tert-butyl N-methyl-N-(4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-yl)carbamate (260 mg, 880.17 µmol, 50.2% yield) was obtained as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 5.56 - 5.04 (m, 1H), 4.96 (br d, J = 1.1 Hz, 2H), 4.85 - 4.76 (m, 2H), 3.09 (br dd, J = 8.9, 15.6 Hz, 1H), 2.82 (br dd, J = 7.9, 15.1 Hz, 2H), 2.76 - 2.67 (m, 3H), 2.56 (br dd, J = 4.9, 14.4 Hz, 1H), 1.40 (s, 9H). LC-MS: m / z [M-t-Bu]+= 240.0.

[0060] Procedure for the preparation of (R) tert-butyl N-methyl-N-(4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-yl)carbamate (7a) and (S) tert-butyl N-methyl-N-(4-oxa-7-thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-yl)carbamate (7b) Attorney Docket No. CTX0016-401-PC The residue was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm,10µm); mobile phase: [CO2-MeOH(0.1%NH3H2O)];B%:20%, isocratic elution mode ). Compound (R)-tert-butyl N-methyl-N-(4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-yl)carbamate (7a) (24 mg, 81.25 µmol, 9.23% yield) was obtained as a yellow oil. Compound (S)-tert-butyl N-methyl-N-(4-oxa- 7-thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-yl)carbamate (7b) (20 mg, 67.71 µmol, 7.69% yield) was obtained as a yellow oil.

[0061] Procedure for preparation of (R)-N-methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine Hydrochloride (8a) To a undeca- 1(8),2(6)-dien-10-yl)carbamate (24 mg, 81.25 µmol, 1 eq) in EtOAc (2 mL) was added HCl / EtOAc (2 M, 2 mL, 49.23 eq).The mixture was stirred at 25 °C for 1hr. The reaction mixture was concentrated. The product was triturated with EtOAc (2 mL) at 25°C for 10 min. The mixture was followed by filtration, the filter cake was dried. Compound (R)-N- methyl-4-oxa-7-thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine (9.78 mg, 41.45 µmol, 51.02% yield, 98.22% purity, HCl) was obtained as a yellow solid.1H NMR (400 MHz, METHANOL-d4) δ = 5.01 - 4.97 (m, 2H), 4.88 - 4.85 (m, 2H), 4.41 - 4.29 (m, 1H), 3.44 (dd, J = 7.9, 16.4 Hz, 1H), 3.19 (dd, J = 7.8, 16.1 Hz, 1H), 3.08 (br dd, J = 4.8, 16.3 Hz, 1H), 2.82 (dd, J = 4.7, 16.1 Hz, 1H), 2.76 (s, 3H). LC-MS: m / z [M+H]+= 196.1.

[0062] Procedure for preparation of (S)-N-methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine Hydrochloride (8b) To a solution of (S)-tert-butyl N-methyl-N-(4-oxa-7-thiatricyclo[6.3.0.02,6]undeca- 1(8),2(6)-dien-10-yl)carbamate (20 mg, 67.71 µmol, 1 eq) in EtOAc (2 mL) was added HCl / EtOAc (2 M, 2.35 mL, 69.51 eq). The mixture was stirred at 25 °C for 1hr. The reaction mixture was concentrated. The product was triturated with EtOAc (2 mL) at Attorney Docket No. CTX0016-401-PC 25°C for 10 min. The mixture was followed by filtration, the filter cake was dried. Compound (S)-N-methyl-4-oxa-7-thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10- amine (13.93 mg, 57.85 µmol, 85.44% yield, 96.24% purity, HCl) was obtained as a yellow solid.1H NMR (400 MHz, METHANOL-d4) δ = 5.01 - 4.96 (m, 2H), 4.87 (br d, J = 4.0 Hz, 2H), 4.40 - 4.30 (m, 1H), 3.44 (dd, J = 7.9, 16.3 Hz, 1H), 3.19 (dd, J = 7.9, 16.1 Hz, 1H), 3.08 (br dd, J = 4.8, 16.4 Hz, 1H), 2.82 (dd, J = 4.8, 16.0 Hz, 1H), 2.76 (s, 3H). LC-MS: m / z [M+H]+= 196.1. 2. X-Ray Crystallography

[0063] An X-ray crystallographic analysis was performed on the enantiomer 8a and the absolute stereochemistry was shown to be (R). The symmetry of the crystal structure was assigned the orthorhombic space group P21212 with the following parameters: a = 18.5682(3) Å, b = 8.48050(10) Å, c = 6.91230(10) Å, α = 90°, β = 90°, γ = 90°, V = 1088.46(3) Å3, Z = 4, Dc = 1.414 g / cm3, μ(Cu Kα) = 4.629 mm–1, and F(000) = 488.0. The absolute configuration structure is judged by the value of Flack parameter, and the structure of the tested crystal is as . The ORTEP structure is shown in FIG. 1. A picture of FIG. 2.

[0064] Description of equipment: • Rigaku Oxford Diffraction XtaLAB Synergy-S equipped with a HyPix-6000HE area detector • Cryogenic system: Oxford Cryostream 800 • Cu: λ=1.54184 Å, 50W • Distance from the crystal to the CCD detector: d = 35 mm • Tube Voltage: 50 kV; Tube Current: 1 mA

[0065] A suitable crystal 0.15×0.06×0.02 mm3was selected for testing. Data collection temperature: T = 149.99(10) K. A total of 29837 reflections were collected in the 2θ range from 9.526 to 133.188°. The limiting indices were: -22 ≤ h ≤ 22, -10 ≤ k ≤ 10, -8 ≤ l ≤ 8; which yielded 1920 unique reflections (Rint= 0.0779). The structure was solved using SHELXT (Sheldrick, G. M. 2015. Acta Cryst. A71, 3-8) and refined using SHELXL (against F2) (Sheldrick, G. M. 2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 128, compared with 1920 data. All reflections were included in the refinement. The goodness of fit on F2was 1.039 with a final R value for [I >= 2σ Attorney Docket No. CTX0016-401-PC (I)] R1= 0.0290 and wR2= 0.0715. The largest differential peak and hole were 0.32 and - 0.26 eÅ-3. Summary of X-ray Crystallographic Data. Temperature / K 149.99(10) Crystal system orthorhombic Atomic coordinates (×104) and equivalent isotropic displacement parameters (Å2×103). Atom x y z U(eq) Cl1 2901.2(3) 6339.6(6) 2446.7(9) 23.34(18) S1 5049.9(3) 2472.8(8) 10302.9(9) 26.51(19) Attorney Docket No. CTX0016-401-PC Atom x y z U(eq) O1 6420.4(10) 986(3) 6215(3) 32.5(5) N1 2787.7(11) 4485(2) 6264(3) 20.5(5) C5 4598.8(14) 2826(3) 6801(4) 20.7(5) C7 3567.6(13) 4455(3) 6795(4) 21.0(5) C6 4011.1(14) 3373(3) 5452(4) 24.3(6) C1 5571.0(14) 1783(3) 8430(4) 22.8(6) C8 3694.5(15) 3899(3) 8894(4) 24.4(6) C4 5277.6(14) 2047(3) 6667(4) 21.1(5) C9 4415.1(14) 3124(3) 8662(4) 21.7(6) C10 2363.5(13) 5639(3) 7410(5) 25.9(5) C2 6287.9(14) 969(3) 8277(4) 25.8(6) C3 5782.0(13) 1443(3) 5145(4) 24.7(6) Bond lengths [A]. Atom Atom Length / Å Atom Atom Length / Å S1 C1 1.719(3) C5 C9 1.355(4) S1 C9 1.727(3) C7 C6 1.543(4) O1 C2 1.447(3) C7 C8 1.543(4) O1 C3 1.450(3) C1 C4 1.354(4) N1 C7 1.494(3) C1 C2 1.503(4) N1 C10 1.485(3) C8 C9 1.499(4) C5 C6 1.508(4) C4 C3 1.499(4) C5 C4 1.426(4) Bond angles [deg]. Atom Atom Atom Angle / ˚ Atom Atom Atom Angle / ˚ C1 S1 C9 89.90(13) C4 C1 C2 111.7(2) C2 O1 C3 111.5(2) C2 C1 S1 135.0(2) C10 N1 C7 113.2(2) C9 C8 C7 99.8(2) C4 C5 C6 137.9(2) C5 C4 C3 139.1(3) C9 C5 C6 110.3(2) C1 C4 C5 112.0(2) C9 C5 C4 111.8(2) C1 C4 C3 108.9(2) N1 C7 C6 112.3(2) C5 C9 S1 113.10(19) N1 C7 C8 112.6(2) C5 C9 C8 114.1(2) C6 C7 C8 107.6(2) C8 C9 S1 132.8(2) C5 C6 C7 101.4(2) O1 C2 C1 102.4(2) C4 C1 S1 113.27(19) O1 C3 C4 104.1(2) Hydrogen Bonds. D H A d(D-H) / Å d(H-A) / Å d(D-A) / Å D-H-A / ° 11 / 2-X,-1 / 2+Y,1-Z Torsion angles [deg]. A B C D Angle / ˚ A B C D Angle / ˚ S1 C1 C4 C5 -0.6(3) C8 C7 C6 C5 -25.3(3) S1 C1 C4 C3 178.45(18) C4 C5 C6 C7 -166.7(3) Attorney Docket No. CTX0016-401-PC A B C D Angle / ˚ A B C D Angle / ˚ S1 C1 C2 O1 -171.4(2) C4 C5 C9 S1 -0.2(3) N1 C7 C6 C5 -149.7(2) C4 C5 C9 C8 -178.2(2) N1 C7 C8 C9 149.2(2) C4 C1 C2 O1 7.4(3) C5 C4 C3 O1 172.2(3) C9 S1 C1 C4 0.4(2) C7 C8 C9 S1 166.8(2) C9 S1 C1 C2 179.2(3) C7 C8 C9 C5 -15.7(3) C9 C5 C6 C7 15.7(3) C6 C5 C4 C1 -177.1(3) C9 C5 C4 C1 0.5(3) C6 C5 C4 C3 4.3(6) C9 C5 C4 C3 -178.1(3) C6 C5 C9 S1 178.05(17) C10 N1 C7 C6 -174.3(2) C6 C5 C9 C8 0.0(3) C10 N1 C7 C8 64.1(3) C6 C7 C8 C9 24.9(3) C2 O1 C3 C4 11.6(3) C1 S1 C9 C5 -0.1(2) C2 C1 C4 C5 -179.7(2) C1 S1 C9 C8 177.4(3) C2 C1 C4 C3 -0.6(3) C1 C4 C3 O1 -6.5(3) C3 O1 C2 C1 -11.7(3) 3. Biology

[0066] To demonstrate the utility of the provided compounds to treat neurological and psychiatric diseases and disorders, compounds are evaluated using the neuropharmacological screen described in S.L. Roberds et al. Front. Neurosci. 2011 Sep 9;5: 103 (doi: 10.3389 / fnins.2011.00103) (“Roberds”). As reported in Roberds, because psychiatric diseases generally result from disorders of cell-cell communication or circuitry, intact systems are useful in detecting improvement in disease-relevant endpoints. These endpoints are typically behavioral in nature, often requiring human observation and interpretation. To facilitate testing of multiple compounds for behavioral effects relevant to psychiatric disease, PsychoGenics, Inc. (Tarrytown, NY, "PGI") developed SmartCube™, an automated system in which behaviors of compound-treated mice are captured by digital video and analyzed with computer algorithms. (D. Brunner et al. Drug Discov. Today 2002, 7:S107-S112). PGI Analytical Systems uses data from SmartCube™ to compare the behavioral signature of a test compound to a database of behavioral signatures obtained using a large set of diverse reference compounds. (The composition of the database and validation of the method are further described in Roberds). In this way, the neuropharmacological effects of a test compound can be predicted by similarity to major classes of compounds, such as antipsychotics, anxiolytics and antidepressants.

[0067] The SmartCube™ system produces an activity signature indicating the probability that the activity of the test compound at the administered dose matches a given class of neuropharmacological agents (“Activity”). (See, e.g., Roberds, Figures 2 and 3). The test compound is simultaneously compared against multiple classes of Attorney Docket No. CTX0016-401-PC agents; thus, a separate probability is generated for each behavioral effect measured (e.g., anxiolytic activity, analgesic activity, etc.). In Table 2 below, these probabilities are reported for each behavioral effect measured as described in Table 1 below: Table 1 Code Class AD Antidepressant

[0068] Provided compounds were dissolved in a mixture of Pharmasolve™ (N- methyl-2-pyrrolidone), polyethylene glycol and propylene glycol, and were injected i.p. 15 min. before the behavioral test. Test compounds are routinely examined at dose levels of 0.3, 1, 3 and 10 mg / kg, although the dose range is increased or decreased, if necessary, to obtain a full dose response curve. For each behavioral effect measured, results for the 3.0 mg / kg dose are presented below. A compound’s minimal effective dose (MED) is a measure of the compound’s potency. The MED is defined as the dose (in mg / kg) having 45% or more total Activity across all tested classes. The potencies of the compounds are shown in Table 2. Table 2 Compound AD AX SH AP MS PS CE AN AG HL UK MED Attorney Docket No. CTX0016-401-PC INCORPORATION BY REFERENCE

[0069] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS

[0070] The foregoing embodiments are illustrative rather than limiting the invention described herein. The scope of the invention is thus indicated by the appended claims, and all embodiments that come within the meaning and range of equivalency of the claims are intended to be encompassed therein.

Claims

Attorney Docket No. CTX0016-401-PC CLAIMS What is claimed is:

1. A compound of Formula (I): (I) or a pharmaceutically independently chosenfrom H and C1-C3alkyl, or nitrogen atom, form a 4-6 membered saturated heterocyclic ring.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1and R2are independently chosen from H and methyl, or R1and R2, taken together with the intervening nitrogen atom, form a 4-6 membered saturated heterocyclic ring.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1and R2are independently chosen from H and C1-C3 alkyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is H and R2is chosen from H and C1-C3alkyl.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R2is chosen from C1-C3 alkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R2is methyl.

7. The compound of claim 1, wherein the compound is N-Methyl-4-oxa-7- thiatricyclo[6.3.0.02,6]undeca-1(8),2(6)-dien-10-amine or a pharmaceutically acceptable salt thereof.Attorney Docket No. CTX0016-401-PC 8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, at least about 80% enriched in the (R) enantiomer.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, at least about 80% enriched in the (S) enantiomer.

10. A pharmaceutical composition comprising a compound of any one of claims 1-9, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. A method of treating schizophrenia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 10.

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