Intermediates, formulations, syntheses, polymorphs, and salt forms of CRS3123

Abstract

Various salt forms, syntheses, intermediates, polymorphs, and formulations for CRS3123 are disclosed. CRS3123 is a narrow spectrum antibiotic that may be useful in treatment of C. difficile infections and other indications.

Description

INTERMEDIATES, FORMULATIONS, SYNTHESES, POLYMORPHS, AND SALT FORMS OF CRS3123CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a PCT application claims priority to US provisional patent application number: 63 / 691 ,870, filed to the US Patent Office on September 6, 2024, and entitled “Formulations, Syntheses, Polymorphs, and Salt Forms of CRS3123", which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure generally relates to a composition for oral care comprising various hydrophobic constituents.BACKGROUND

[0003] Bicyclic heteroaromatic compounds having a left hand side chromane and right hand side thienopyridone are inhibitors of bacterial methionyl tRNA synthetases (MetRS). This class has uses in therapy as antibacterial agents. In particular, this class has uses in therapy of Clostridium difficile based infections, as well as other therapeutic uses in mammals including humans.

[0004] Clostridium difficile infection (GDI) is a gastrointestinal condition caused by toxinproducing strains of C. difficile bacteria. CDI symptoms range from severe diarrhea to toxic megacolon. C. difficile forms spores that are very difficult to eliminate from the hospital environment, which may lead to infection of hospitalized patients. Emergence of hypervirulent and drug-resistant strains of C. difficile has resulted in an alarming increase in the incidence and mortality of CDI in the past 15 years, especially among elderly patients. C. difficile is found in abundance in the environment, so exposure to this resilient, spore-forming pathogen can be presumed to be both continuous and unavoidable. Under normal circumstances, healthy gut microbiota keeps C. difficile growth in check. However, the disruption of gut microbiota due, for example, to exposure to broad spectrum antibiotics or chemotherapy predisposes the patient to CDI. Vancomycin and fidaxomicin are the only approved antibiotics for C. difficile treatment. Paradoxically, vancomycin is also one of the broad-spectrum antibiotics that is known to induce CDI due to disruption of normal gut microbiota.

[0005] According to the U.S. Centers for Disease Control, there are an estimated 223,900 CDI infections per year in the U.S. that require hospitalization, and at least 12,800 people die from the disease annually. A key unmet need in the CDI market is C. difficile treatment or prevention of relapse which is associated with additional antibiotic treatment and often re-hospitalization. Recurrence rates range from 15-30%, and result from re-infection by spores. Recurrence rates in 1Attorney Docket CU-76504-Crestone-PCT-FYGGDI patients treated with vancomycin exceed 20%. Recurrence following fidaxomicin treatment is somewhat lower, with the notable exception of those infected with the recently emerging epidemic strains (BI / NAP1). Those patients suffer recurrence rates above 20% with either vancomycin or fidaxomicin treatment.

[0006] Despite extensive optimization of methodologies over many years for CRS3123 preparation, difficulties and issues remain in the syntheses of CRS3123, with respect to low yields and product stability and isolation from polar solvents. The current methodologies are also plagued by atom and energy inefficiency due, for example, to the use of large solvent excesses and the need for temperature-controlled reaction conditions.

[0007] The reported syntheses of CRS3123 are becoming more scalable, but use corrosive and expensive reagents, and lengthy deprotection steps, and thus still display batch-to-batch quality variation, thereby presenting difficulties in maintaining good standards.

[0008] Synthetically, the preparation of CRS3132 remains time-consuming, atom-inefficient, and costly, due to the need for numerous protection and deprotection steps.

[0009] Crystalline forms of useful molecules can have advantageous properties relative to the respective amorphous forms of such molecules. For example, crystal forms are often easier to handle and process, for example, when preparing compositions that include the crystal forms. Crystalline forms typically have greater storage stability and are more amenable to purification. The use of a crystalline form of a pharmaceutically useful compound can also improve the performance characteristics of a pharmaceutical product that includes the compound. Obtaining the crystalline form also serves to enlarge the repertoire of materials that formulation scientists have available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life.

[0010] US20080227808 A1 , incorporated by reference herein in its entirety, describes bicyclic heteroaromatic compounds having a left hand side phenylether and right hand side thienopyridone, and in particular to the use of these compounds as inhibitors of bacterial methionyl tRNA synthetases (MetRS), to processes for their preparation and to their uses in therapy as antibacterial agents, and in particular to their uses in therapy of Clostridium difficile based infections..

[0011] In view of the above, there is a need for processes that are atom-efficient in terms of reagent and solvent equivalency, that bypass the need for polar, non-GRAS (“generally recognized as safe”) solvents, that are versatile in terms of limitations associated with solubility2Attorney Docket CU-76504-Crestone-PCT-FYGand reagent mixing, that are time- and energy-efficient, and that provide efficient, practical, and scalable methods for the preparation of CRS3132 and analogs thereof.

[0012] In view of the above, there is a need for novel crystalline forms and method of making CRS3132 and analogs thereof.SUMMARY

[0013] In accordance with various aspects, syntheses of CRS3123 are provided, along with characterizations of polymorphs, salt forms, and formulations of the same.

[0014] In one embodiment, the disclosure provides compounds of formula (I), or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof:

[0015] I

[0016] in which: X is selected from the group consisting of NH, O, S, SO, SO2. or CH2; n is 1 , 2 or 3; 0 is 1 , 2, or 3; * indicates an asymmetric carbon atom, wherein when n is 2 or 3, then * is R configuration; wherein when n is 1 and X is CH2, then * is R configuration; and wherein when n is 1 and X is selected from the group consisting of NH, O, S, SO, or SO2, then * is S configuration;

[0017] R1is independently selected from halo, cyano, hydroxyl, (Ci-s)alkyl (optionally substituted by halo, hydroxyl, amino, carboxy, or (Ci-6)alkoxycarbonyl), (C^cycloalkyl, C1-6 alkoxy, amino, mono- or di-(Ci-6)alkylamino, acylamino, carboxy, (Ci-6)alkoxycarbonyl, carboxy(Ci-6)alkyloxy, (Ci-e)alkylthio, (Ci-6)alkylsulphinyl, (Ci-6)alkylsulphonyl, sulphamoyl, mono- and di-(Ci-6)alkylsulphamoyl, carbamoyl, mono- and di-(Ci-6)alkylcarbamoyl and heterocyclic;

[0018] m is 0, 1 , 2, 3 or 4;

[0019] R2is independently selected from hydrogen, halo, cyano, hydroxyl, (Ci-e)alkyl (optionally substituted by halo, hydroxyl, amino, carboxy), or (Ci-6)alkoxycarbonyl), (C3-7)cycloalkyl, C1-6 alkoxy, amino, mono- or di-(Ci-6)alkylamino, acylamino, carboxy, (Ci-6)alkoxycarbonyl, 3Attorney Docket CU-76504-Crestone-PCT-FYGcarboxy(Ci-6)alkyloxy, (Ci-s)alkylthio, (Ci-6)alkylsulphinyl, (Ci-6)alkylsulphonyl, sulphamoyl, mono- and di-(Ci-6)alkylsulphamoyl, carbamoyl, mono- and di-(Ci-6)alkylcarbamoyl and heterocyclic;

[0020] R3is independently selected from (Ci-e)alkyl (optionally substituted by halo, hydroxyl, amino, carboxy), or (Ci-6)alkoxycarbonyl), (C3-7)cycloalkyl, C1-6 alkoxy, amino, mono- or di-(Ci-6)alkylamino, acylamino, carboxy, (Ci-6)alkoxycarbonyl, carboxy(Ci-6)alkyloxy, (Ci-e)alkylthio, (Ci-6)alkylsulphinyl, (Ci-6)alkylsulphonyl, sulphamoyl, mono- and di-(Ci-6)alkylsulphamoyl, carbamoyl, mono- and di-(Ci-6)alkylcarbamoyl and heterocyclic; and when Zi is S, Z2and Z3are CH; when Z2is S, Zi and Z3are CH; and when Z3is S, Zi and Z2are CH.

[0021] Optionally in any embodiment, the disclosure provides pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof, characterized in that: said compound has a structure of formula, wherein the compounds have a formula (II):II

[0022] Optionally in any embodiment, the disclosure provides pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof, characterized in that: said compound has a structure of formula, wherein (R1)mis a 6, 8 substitution and can be the same or different substituents, wherein the substituents are selected from the group consisting of bromine, chlorine, iodine and sulfone.

[0023] Optionally in any embodiment, the disclosure provides pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof, characterized in that said compound has a structure of formula, wherein the compound is:4Attorney Docket CU-76504-Crestone-PCT-FYG

[0024]

[0025] In yet another embodiment, the disclosure provides compounds of formula (III), or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof:

[0026] III o is 1 , 2, or 3;R1, R2, R4, R5are independently selected from hydrogen, (Ci-e)alkyl (optionally substituted by halo, hydroxyl, amino, carboxy, or (Ci-e)alkoxycarbonyl), (C37)cycloalkyl, C1-6 alkoxy, amino, mono- or di-(Ci-6)alkylamino, acylamino, carboxy, (Ci-6)alkoxycarbonyl, carboxy(Ci-6)alkyloxy, (Ci-e)alkylthio, (Ci-6)alkylsulphinyl, (Ci-6)alkylsulphonyl, sulphamoyl, mono- and di-(Ci- 6)alkylsulphamoyl, carbamoyl, mono- and di-(Ci-6)alkylcarbamoyl and heterocyclic, when R1and R4are both hydrogen at the same time, one end carbon connecting two OH group becomes aldehyde;

[0027] R3is independently selected from (Ci-e)alkyl (optionally substituted by halo, hydroxyl, amino, carboxy), or (Ci-e)alkoxycarbonyl), (C3-?)cycloalkyl, C1-6 alkoxy, amino, mono- or di-(Ci-6)alkylamino, acylamino, carboxy, (Ci-6)alkoxycarbonyl, carboxy(Ci-6)alkyloxy, (Ci-s)alkylthio, (Ci-5Attorney Docket CU-76504-Crestone-PCT-FYG6)alkylsulphinyl, (Ci-e)alkylsulphonyl, sulphamoyl, mono- and di-(Ci-6)alkylsulphamoyl, carbamoyl, mono- and di-(Ci-6)alkylcarbamoyl, sodium (Na), and heterocyclic.

[0028] Optionally in any embodiment, the disclosure provides pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof, characterized in that: said compound has a structure of formula, wherein the compound is at least one of:

[0030] Further in another embodiment, the disclosure provides a polymorph of a compound having the structure represented by formula (IV)IV

[0031] Optionally in any embodiment, the polymorph is characterized by at least one of the following powder x-ray diffraction pattern peak expressed in terms of diffraction angles (20) (±0.3°) as measured with copper Ka radiation chosen from: 6°, 10.8°, 13.3°, 14.5°, 15.4°, 16.1 °, 17°, 18.2°, 20.1 °, 21.3°, 23.7°, 25.1 °, 25.4°, 26.5°, 27.2°, 30.8°, 32°, and 37.8°.

[0032] Optionally in any embodiment, a pharmaceutical formulation comprising the polymorph of a compound having a structure represented by formula (IV), and a pharmaceutically acceptable excipient.

[0033] Optionally in any embodiment, a method of treating a disease, comprising administering to a subject in need of such treatment a therapeutically effective amount of the polymorph of a compound having a structure represented by formula (IV).

[0034] Further in another embodiment, a disclosure directs to a process for preparing a compound having formula (IV):6Attorney Docket CU-76504-Crestone-PCT-FYG

[0036] The method comprises the following steps: (a) providing a compound having formula (II):

[0037]

[0038] wherein X is Oxygen; O is 1 ; R3is Me; R1is Br at 6, 8 positions; R2is hydrogen;

[0039] (b) treating the compound having formula (II) or a salt thereof with NMP and pyridine-HCI solution;

[0040] (c) isolating the compound of formula (IV).

[0041] Optionally in any embodiment, the method further comprises providing a compound with the formula (V);

[0043] treating compound with the formula (V) with 6,8-dibromo-chroman-4(R)-ylamine hydrochloride in TEA, then STAB to form the compound having formula (II):7Attorney Docket CU-76504-Crestone-PCT-FYG

[0044]

[0045] wherein X is oxygen; O is 1 ; R3is Me; R1is Br at 6, 8 positions; R2is hydrogen.

[0046] Optionally in any embodiment, the process further comprises treating compound having the formula (VI) in dioxane HCI solution to form the compound with formula (V)

[0048] In yet further another embodiment, the disclosure further discloses a process for preparing a compound having formula (IV):

[0050] The process comprises the following steps:

[0051] (a) providing a compound having formula (II):8Attorney Docket CU-76504-Crestone-PCT-FYG

[0052] wherein X is Oxygen; O is 1 ; R3is Me; R1is Br at 6, 8 positions; R2is hydrogen.

[0053] (b) treating the compound having formula (II) or a salt thereof with a base solution.

[0054] (c) converting the compound having formula (II) to 2HCI salt in HCI solution and isolating the compound of formula (IV).

[0055] Optionally in any embodiment, the process further comprises reacting 5-(3- Oxopropylamino) thieno[3,2-b]pyridin-7-yl benzoate HCI salt with the 6,8-dibromo-chroman-4(R)- ylamine hydrochloride and triethylamine to yield 5-[3-(6,8-Dibromo-chroman-4-ylamino) propylamino]-thieno[3,2-b]pyridin-7-yl benzoate (the compound having formula (II): wherein X is Oxygen; O is 1 ; R3is OCOPh; R1is Br at 6, 8 positions; R2is hydrogen).

[0056] Optionally in any embodiment, the process further comprises dissolving 5-(3,3- Diethoxypropylamino) thieno[3,2-b]pyridin-7-yl benzoate HCI to yield 5-(3-oxopropylamino) thieno[3,2-b]pyridin-7-yl benzoate HCI salt.

[0057] Optionally in any embodiment, the process further comprises reacting Sodium 5-(3,3- diethoxypropylamino) thieno[3,2-b]pyridin-7-olate with Benzoic anhydride to yield 5-(3,3- Diethoxypropylamino) thieno[3,2-b]pyridin-7-yl benzoate.

[0058] Optionally in any embodiment, the process further comprises reacting 5-(3,3- Diethoxypropylamino)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylic acid with a base to yield Sodium 5-(3,3-diethoxypropylamino) thieno[3,2-b]pyridin-7-olate.

[0059] Optionally in any embodiment, the process further comprises suspending 5-((3,3- Diethoxypropylamino)(thiophene-3-ylamino)methylene)-2,2-dimethyl-1 ,3-dioxane-4, 6-dione (1.62 mol) in a solution to yield 5-(3,3-Diethoxypropylamino)-7-oxo-4,7-dihydrothieno[3,2- b]pyridine-6-carboxylic acid.

[0060] Optionally in any embodiment, the process further comprises reacting 2,2-dimethyl-5- (methylsulfanyl-thiophene-3-ylamino-methylene)-[1 ,3]dioxane-4, 6-dione with 3,3-9Attorney Docket CU-76504-Crestone-PCT-FYGDiethoxypropylamine to yield 5-((3,3-Diethoxypropylamino)(thiophene-3-ylamino)methylene)-2,2- dimethyl-1 ,3-dioxane-4, 6-dione.BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0061] FIG. 1 is a graph illustrating various X ray diffraction patterns, in accordance with various embodiments;

[0062] FIG. 2 is a graph illustrating various X ray diffraction patterns, in accordance with various embodiments;

[0063] FIG. 3 illustrates a moisture sorption-desorption of CRS3123 in the Form A solid form, according to various embodiments;

[0064] FIG. 4 illustrates a proposed ionization scheme, according to various embodiments;

[0065] FIG. 5 illustrates various polymorph screens in various solvent systems, according to various embodiments;

[0066] FIG. 5A illustrates various polymorph screens in various solvent systems, according to various embodiments;

[0067] FIG. 5B illustrates various polymorph screens in various solvent systems, according to various embodiments;

[0068] FIG. 6 illustrates various microplate polymorph screens in various solvent systems, according to various embodiments.

[0069] FIG. 6A illustrates various microplate polymorph screens in various solvent systems, according to various embodiments.

[0070] FIG. 6B illustrates various microplate polymorph screens in various solvent systems, according to various embodiments.

[0071] FIG. 7 illustrates various in situ generated polymorph screens in various solvent systems, according to various embodiments.

[0072] FIG. 8 illustrates an NMR result of CRS3123»2HCI, according to various embodiments.

[0073] FIG. 9 illustrates an XRPD result of CRS3123.2HCI as made by Synthetic Pathway 2, as described below, according to various embodiments.

[0074] FIG. 10 illustrates an XRPD result of CRS3123.2HCI as made by Synthetic Pathway 2, according to various embodiments.

[0075] FIG. 11 A illustrates the peaks produced using XRPD of CRS3123.2HCI as made by Synthetic Pathway 2, according to various embodiments.10Attorney Docket CU-76504-Crestone-PCT-FYG

[0076] FIG. 11 B illustrates the peaks produced using XRPD of CRS3123.2HCI as made by Synthetic Pathway 2, according to various embodiments.DETAILED DESCRIPTION

[0077] Definitions

[0078] The following is a list of definitions for terms used herein. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. Generally, the nomenclature used herein and the laboratory procedures in cytopathicity analysis, microbial analysis, organic, physical and inorganic chemistry, and clinical research are those well-known and commonly employed in the art.

[0079] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it can be used. Generally, “about” encompasses a range of values that are plus / minus 10% of a reference value, unless specifically defined. For instance, “about 25%” encompasses values from 22.5% to 27.5%.

[0080] As used herein, “pharmaceutically acceptable” is set forth broadly and refers without limitation to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment suitable for contact with the tissues of and / or for consumption by human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable risk / benefit ratio.

[0081] As used herein, the term “polymorph” refers to the different crystal structures (of solvated or unsolvated forms) in which a compound can crystallize.

[0082] As used herein, the term “solvate” refers to a solid form with either a stoichiometric or non- stoichiometric amount of solvent (e.g., a channel solvate). For polymorphs, the solvent is incorporated into the crystal structure. Similarly, the term “hydrate” refers to a solid form with either a stoichiometric or non-stoichiometric amount of water. For polymorphs, the water is incorporated into the crystal structure.

[0083] As used herein, the term “about”, when used in reference to a degree 2-theta value refers to the stated value±0.3 degree 2-theta. In various embodiments, “about” refers to ±0.2 degree 2- theta or ±0.1 degree 2-theta. In certain embodiments, “about” refers to ±0.2 degree 2-theta.

[0084] All percentages and ratios used herein are by weight of a multi-component composition and not of the overall topical formulation that is delivered, unless otherwise specified. All11Attorney Docket CU-76504-Crestone-PCT-FYGmeasurements are made at room temperature i.e. 20-25 °C, unless otherwise specified. Heat and humidity, under normal circumstances, may cause such a composition to degrade from liquid to gas, changing its weight and rendering common assay calculations inaccurate.[0085J CRS3123 inhibits type 1 methionyl-tRNA synthetase (MetRS), an essential component of protein translation. CRS3123 is active only in bacteria that express type 1 MetRS, which include C. difficile, Clostridium perfringens, and many aerobic Gram-positive bacteria, such as staphylococci, enterococci, and streptococci. Bacterial strains that express type 2 MetRS show virtually no susceptibility to CRS3123 and include most Gram-negative bacteria and many constituents of the normal intestinal microbiota such as Bacteroides, bifidobacteria, actinobacteria, and lactobacilli. In addition, CRS3123 has exhibited low systemic absorption following oral dosing in preclinical testing. Thus, CRS3123 is a good candidate for treating such infections. However, there is a need for a synthesis of CRS3123, such as a commercially viable synthesis. Moreover, the various polymorphs of CRS3123 have not been adequately studied. Further various formulations of CRS3123 are needed to develop effective therapeutic treatments.

[0086] CRS3123[0087J CRS3123 is a small molecule protein synthesis inhibitor that acts on the novel target methionyl-tRNA synthetase (MetRS). CRS3123 has numerous potential advantages over current CDI therapies. CRS3123 is highly potent against all clinical isolates of C. difficile. CRS3123 is narrow spectrum for C. difficile, which may substantially reduce the disruption of normal intestinal microbiota compared to current therapies. CRS3123 inhibits toxin production, potentially leading to lower morbidity and mortality, and faster resolution of symptoms. CRS3123 inhibits sporulation, potentially leading to lower rates of transmission and recurrence. CRS3123’s novel mechanism of action means that its use will not compromise the utility of systemic, broad spectrum antibiotics (eg. vancomycin).[0088J CRS3123 has the below structure

[0089] 12Attorney Docket CU-76504-Crestone-PCT-FYG[0090J CRS3123 has the chemical formula CigHigBr2N3O2S with a molecular weight of 513.25 g / mol. CRS3123 may be referred to as (4R)-5-(3-(6,8-Dibromochroman-4- ylamino)propylamino)thieno[3,2-b]pyridin-7(7aH)-one.

[0091] One salt form of CRS3123 may be referred to as (4R)-5-(3-(6,8-Dibromochroman-4- ylamino)propylamino)thieno[3,2-b]pyridin-7(7aH)-one dihydrochloride or simply as CRS3123*2HCL.

[0092] Detailed Description of Embodiments

[0093] Disclosed herein, in various embodiments, are various formulations, salt forms, polymorphs, and syntheses for CRS3123.

[0094] Synthesis of CRS3123

[0095] Synthetic pathway 1

[0096] Provided herein is a synthesis of CRS 3123, starting with a recitation of a starting material prior to each step. This synthesis is hereinafter referred to as “Synthetic Pathway 1

[0097] 6,8 -Dibromo-chroman-4(R)-ylamine hydrochloride salt (5)

[0098] 3-(2,4-Dibromo-phenoxy) propionic acid (1 )

[0099] To a 2 L round bottom flask equipped with thermometer, stir bar and nitrogen inlet was added 100.00 g (396.95 mmol) of 2,4-dibromophenol and 500 ml of anhydrous tetrahydrofuran (THF). The mixture was cooled with an ice-bath and 45 g (401.00 mmol) of potassium tert- butoxide added in portions over 3 minutes while maintaining the reaction temperature below 30 13Attorney Docket CU-76504-Crestone-PCT-FYG°C. The cold bath was removed and the clear yellow solution stirred at room temperature for 30 minutes, followed by the addition of 27.5 ml (437.34 mmol) of beta-propiolactone. The reaction was stirred at room temperature overnight while monitoring by high-performance liquid chromatography (HPLC). The mixture was acidified with 37% hydrochloric acid to pH 2 and 1 L of ethylacetate added followed by 1 L of water. The organic phase was extracted with 1 L of saturated sodium bicarbonate. The aqueous phase was acidified to pH 2 with 37% hydrochloric acid and extracted with 1 .2 L of ethylacetate. The organic phase was concentrated under reduced pressure to afford 97.1 g (75.5%) of product as a white solid.

[0100] 6,8 -Dibromo-chroman-4-one (2)

[0101] To a 250 ml round bottom flask equipped with stir bar was added 25.4 g (78.40 mmol) of 3-(2,4-dibromo-phenoxy)propionic acid followed by 28 ml (316.44 mmol) of trifluoromethanesulfonic acid. The mixture was heated to 50 °C with stirring. After 2 h, HPLC analysis of reaction mixture indicated 93% conversion. The reaction mixture was poured into 300 ml of water and extracted with 500 ml of dichloromethane. The organic phase was washed with 300 ml of saturated sodium bicarbonate. The organic phase was concentrated under reduced pressure to afford 19.80 g (82.6%) of product as a tan solid.

[0102] 6,8 -Dibromo-chroman-4(S)-ol (3)

[0103] To a 22 L reactor equipped with mechanical stirrer, nitrogen inlet, and temperature probe was added 600 g (1961 .1 mmol) of 6,8-dibromochroman-4-one and 6 L of acetonitrile followed by 1690 ml of 5 / 2 formic acid / triethylamine, 7.03 g (19.18 mmol) of (1S,2S)-(+)-N-p-tosyl-1 ,2- diphenylethylene diamine and 6.27 g (10.24 mmol) of dichloro(p-cymene)-ruthenium (II) dimer. The brown solution was stirred at room temperature while monitoring by HPLC. The reaction was diluted with 6.3 L of ethylacetate and washed with 6.5 L of brine followed by 6.5 L of 1 :1 brine / saturated sodium bicarbonate. The organic phase was concentrated under reduced pressure to afford 612 g (101 .3%) of product a rust color solid. (>98% ee).

[0104] Preparation of 5 / 2 formic acid / triethylamine solution

[0105] To a 5 L round bottom flask was added 780 ml (20.68 mol) of 99% formic acid. The flask was cooled in an ice-bath and 1 120 ml (8.04 mol) of triethylamine added over 15 minutes. The solution was stored at room temperature.

[0106] 4(R) -Azido-6,8-dibromo-chroman (4)

[0107] To a solution containing 312 g (1013.1 mmol) of 6,8-dibromo-chroman-4(S)-ol in 6.2 L of anhydrous THF under a nitrogen atmosphere was added 263 ml (1216.6 mmol) of diphenylphosphorylazide (DPPA). After stirring the rust color solution for 15 minutes at room temperature, the solution was cooled with an ice-bath to 10 °C and 195 ml (1294.5 mmol) of 1 ,8- 14Attorney Docket CU-76504-Crestone-PCT-FYGdiazabicyclo[5.4.0]undec-7-ene (DBll) were added. The reaction mixture was allowed to stir with gradual warming to room temperature over 5 hours and maintained for 48 h. The reaction was diluted with 6.2 L of ethylacetate and washed with 4.6 L of brine followed by 6.2 L of water containing 1 L of brine. The organic phase was concentrated under reduced pressure to afford 409 g (121.2 %) of product as a brown oil. The material is carried forward without further purification.

[0108] 6,8 -Dibromo-chroman-4(R)-ylamine hydrochloride salt (5)

[0109] To a 12 L round bottom flask equipped with stir bar, nitrogen inlet and thermometer was added 409 g (1013.1 mmol) of crude 4(R)-azido-6,8-dibromo-chroman and 6.5 L of anhydrous THF. The dark brown solution was cooled to 9 °C and 109 ml (1232.1 mmol) of trimethylphosphine added over 25 minutes. The reaction temperature increased to 14 °C. The cold bath was removed and the reaction mixture stirred at room temperature for 16 h. The reaction was monitored for completion by HPLC. The reaction was concentrated under reduced pressure to afford 480 g of a dark brown, viscous oil. Proton NMR and HPLC analysis indicated the intermediate iminophosphorane and desired amine.

[0110] The crude product was dissolved in 5.2 L of acetonitrile and 172 ml (2064 mmol) of concentrated hydrochloric acid added dropwise over 30 min. with stirring. The resultant mixture was stirred at room temperature for 16 h. The solids were filtered through a coarse glass fritted funnel, washed with 2 x 900 ml of acetonitrile and dried under vacuum to yield 302.3 g (86.9%) of product as a tan solid. (> 98% ee)

[0111] Recrystallization of 6,8-Dibromo-chroman-4(R)-ylamine hydrochloride salt (5)

[0112] To a 12 L reactor equipped with mechanical stirrer, condenser, nitrogen inlet, heating mantle and thermometer was added 300 g of crude 6,8-Dibromo-chroman-4(R)-ylamine hydrochloride salt followed by 1150 ml of dimethyl sulfoxide (DMSO). The mixture was heated to 80 °C to afford a clear brown solution. Acetonitrile (3.6 L) were added and the resultant mixture heated at reflux for 30 min. The solution was allowed to cool to room temperature over 3 h and the reactor then chilled in an ice-bath for 1 h. The solids were filtered through a coarse glass fritted funnel, washed with 2 x 1 L of acetonitrile and dried under vacuum to afford 249 g (71 .6%) of product as an off-white crystalline solid.

[0113] Preparation of 5-(3,3-diethoxypropylamino) thieno[3,2-b]pyridin-7-yl benzoate (12)15Attorney Docket CU-76504-Crestone-PCT-FYG(11) (12)

[0114] 3-Thiophene isothiocyanate (7)

[0115] Methyl 3-aminothiophene-2-carboxylic ester 1 (545.4 g, 3.47 mol) was suspended in an aqueous NaOH solution, prepared by mixing NaOH (277.6 g, 6.94 mol) and water (1 .8 L). The resultant mixture was stirred at 80 °C for 1 h to afford a clear brown solution. The resultant solution was cooled below 20 °C and carefully acidified with 37% hydrochloric acid (0.6 L) to pH 1 or 2 while maintaining the reaction temperature below 20 °C using an ice-water bath to afford a heavy slurry. Dichloromethane (3.0 L) was added to the reaction vessel and the mixture heated gently at reflux and stirred for 2 h until all solids were dissolved. After complete decarboxylation to the intermediate 3-amino-thiophene (6), the reaction was chilled in an ice-water bath and thiophosgene (400g, 3.47 mol) was added over 30 minutes while maintaining the reaction temperature below 15 °C. To the mixture was then added 6 N sodium hydroxide (1.15 L, 6.9 mol) over 50 minutes to pH 7 to 8. After stirring for 5 min., HPLC analysis of reaction mixture indicated mostly desired product. The organic layer was separated, and the aqueous layer was extracted 16Attorney Docket CU-76504-Crestone-PCT-FYGwith dichloromethane (0.8 L). The combined organic phase was dried over magnesium sulfate. Filtration and removal of solvent gave 472.5 g (96%) of product as a dark brown oil (7).

[0116] 2,2-Dimethyl-5-(methylsulfanyl-thiophene-3-ylamino-methylene)-[1 ,3]dioxane-4, 6-dione (8)[O117] 3-Thiophene isothiocyanate (472.5 g, 3.34 mol) was mixed with 2,2-dimethyl-1 ,3-dioxane- 4, 6-dione (433.2 g, 3.006 mol) in dimethylsulfoxide (1 .9 L). Triethylamine (516 mL, 3.67 mol) was added dropwise over 130 min. while maintaining the reaction temperature below 20 °C. After the addition, the resultant mixture was stirred at room temperature for 16 h. lodomethane (426.7 g, 3.006 mol) was added slowly over 70 min while the reaction temperature was maintained below 20 °C. After complete addition, the mixture was stirred at room temperature for 1 h. A dilute aqueous hydrochloric acid solution (4.8 L of water containing 46 mL of 37% HCI) was slowly added to precipitate the product while the temperature was kept below 30 °C. The formed precipitates were stirred for 2h. The solids were filtered and rinsed with water. The resultant wet solids of crude (8) were suspended in ethanol (EtOH) (6 L) and then the solvents were removed under reduced pressure. The resultant slurry was dissolved in boiling methanol (4.0 L) and treated with decolorizing charcoal (130 g) and maintained at reflux for 40 min. The hot solution was filtered through a pad of flux-calcined diatomaceous earth (CELITE 543) and the filter cake rinsed with boiling methanol (1 L). The filtrate was allowed to stand at room temperature for 24 h. The solids were filtered and dried to afford 408.4 g (45%) of product as light brown crystals 8. The filtrate was concentrated under reduced pressure to about 1.5 L to afford additional 71 g (7.9%) of product.

[0118] 5-((3,3-Diethoxypropylamino)(thiophene-3-ylamino)methylene)-2,2-dimethyl-1 ,3- dioxane-4, 6-dione (9)

[0119] 3,3-Diethoxypropylamine (210.7 g, 1.43 mol) was added in portions to the solution of 2,2- dimethyl-5-(methylsulfanyl-thiophene-3-ylamino-methylene)-[1 ,3]dioxane-4, 6-dione (407.3 g, 1.36 mol) in dichloromethane (1.7 L) and methanol (0.36 L) over 60 min, while the reaction temperature was kept under 25 °C with a water bath. After stirring for 1 .5 h at room temperature, the reaction mixture was diluted with dichloromethane (0.8 L). The organic layer was separated and washed with aqueous ammonium chloride solution (400 mL, made of 200 mL of sat. NH4CI and 200 mL of water), brine (300 mL) and dried over magnesium sulfate. Concentration of the reaction mixture under reduced pressure afforded a dark oil (645.7 g, 119%).

[0120] Xylenes (500 ml) were added and the mixture concentrated under reduced pressure. The resultant dark oil was used directly in next step without further purification.17Attorney Docket CU-76504-Crestone-PCT-FYG

[0121] 5-(3,3-Diethoxypropylamino)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylic acid (10)

[0122] 5-((3,3-Diethoxypropylamino)(thiophene-3-ylamino)methylene)-2,2-dimethyl-1 ,3- dioxane-4, 6-dione (1 .62 mol) was suspended in a solution of hexamethyldisilazane (1 .08 L, 5.18 mol) in xylenes (2.4 L) and was heated at reflux for 24 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to afford a dark oil. The dark oil was carefully treated with methanol (0.5 L) to form brown solids and suspended in ethyl ether (1.6 L). The resultant solids were filtered and washed with methanol (MeOH)Zdiethyl ether (1 :3) (0.8 L). The solids were dried under vacuum to afford 432.2 g (78 %) of product as beige solid.

[0123] Sodium 5-(3,3-diethoxypropylamino) thieno[3,2-b]pyridin-7-olate (11 )

[0124] 5-(3,3-Diethoxypropylamino)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylic acid (432 g, 1 .27 mol) was mixed with sodium methoxide (95% pure, 75.8 g, 1 .33 mol) and suspended in xylenes (2 L). The resultant mixture was heated at reflux for 2 h. The reaction mixture was gradually cooled to room temperature with stirring to afford light brown solids. The solids were collected by filtration and washed with toluene and dried under vacuum at 50-60 °C for 48 h to yield 446.8 g (1 11%) of product. This crude product was used in the next step without further purification.

[0125] 5-(3,3-Diethoxypropylamino) thieno[3,2-b]pyridin-7-yl benzoate (12)

[0126] Sodium 5-(3,3-diethoxypropylamino) thieno[3,2-b]pyridin-7-olate (445.7 g, 1.40 mol) was suspended in DMSO (2.8 L). Benzoic anhydride (332.9 g, 1.47 mol) was added in portions at room temperature. After the addition, the reaction mixture was stirred for 3 h at room temperature. The mixture was diluted with ethyl acetate (6 L). The resultant organic solution was washed with water (6 L). The separated aqueous layer was extracted with ethyl acetate (2 L). The combined organic layers were dried over magnesium sulfate. Removal of solvent under reduced pressure and drying under high vacuum afforded the desired product as a dark oil (677.3 g, 120%). This product was contaminated with excess benzoic anhydride, benzoic acid and ethyl acetate, and was used in the next step without further purification.

[0127] Preparation of CRS323118Attorney Docket CU-76504-Crestone-PCT-FYG

[0129] 5-(3-oxopropylamino) thieno[3,2-b]pyridin-7-yl benzoate HCI salt (13)

[0130] The crude 5-(3,3-diethoxypropylamino) thieno[3,2-b]pyridin-7-yl benzoate from above (677.3 g, 1 .68 mol) was dissolved in 3.0 L of THF. Then, 12N HCI (1.68 mol, 0.14 L) was added dropwise while the reaction temperature was maintained below 20 °C with an ice-water batch. After stirring for 5 minutes, solids precipitated. The resultant mixture was stirred at room temperature for 1 h, followed by the addition of ethyl acetate (2.0 L). The mixture was stirred for 30 min. The solids were filtered, rinsed with ethyl acetate (250 ml X 2), and then dried under reduced pressure at 55 °C to afford light brown solids (465 g, 90%).

[0131] 5-[3-(6,8-Dibromo-chroman-4-ylamino) propylamino]-thieno[3,2-b]pyridin-7-yl benzoate (14)

[0132] 5-(3-Oxopropylamino) thieno[3,2-b]pyridin-7-yl benzoate HCI salt (146.42 g, 0.4 mol) was mixed with 6,8-dibromo-chroman-4(R)-ylamine hydrochloride (145.5 g, 0.424 mol) in anhydrous THF (2.4 L) to afford a suspended solution. Triethylamine (168.7 mL, 1.2 mol) was added in 10 min. After the reaction mixture was stirred for 1 h, sodium triacetoxyborohydride (95% pure, 116 g, 0.52 mol) was added in portions over 30 min while maintaining the reaction temperature below 30 °C with an ice-water bath. After the addition, the reaction mixture was stirred for 100 min at room temperature, then diluted with ethyl acetate (500 mL). The resultant organic solution was washed with half saturated NaHCOs (1 .2 L). After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (EtOAc) (400 mL). The combined organic layers were washed with brine (300 mL), and dried over magnesium sulfate. Removal of solvent under reduced pressure afforded the desired product (271 .5 g, 110%) as a sticky tan solid.19Attorney Docket CU-76504-Crestone-PCT-FYG

[0133] 5-[3-(6,8-Dibromo-chroman-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one (CRS3123)

[0134] 5-[3-(6,8-Dibromo-chroman-4-ylamino) propylamino]-thieno[3,2-b]pyridin-7-yl benzoate (271 g) was dissolved in THF (700 mL) and MeOH (270 mL). Then, 7 N ammonium in MeOH (240 mL) was added to the above solution. After stirring 2 to 3 h, solids precipitated. The mixture was continually stirred over 12h. The resultant solid mixture was diluted with EtOAc (1.3 L) and stirred for 30 min. The solids were filtered, rinsed with ethyl acetate (300 mL X 2) and dried under reduced pressure at 55 °C to afford 185.6 g (90%) of REP3123 free base as colorless solids.

[0135] 5-[3-(6,8-Dibromo-chroman-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one HCI salt (CRS3123 2HCI)

[0136] 5-[3-(6,8-Dibromo-chroman-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridin-7-one free base (5.625 g) was dissolved EtOH (28 mL) and 4N HCI (10 mL) at 75 °C. The solution was filtered through a pad of Celite (545). The filtrate was stirred over 3 h at room temperature until crystals formed, then chilled in an ice-bath for 1 h. The solids were filtered and dried under vacuum at 95-100 °C (to remove the residual solvent-EtOH) over 3 days to afford 5.77 g (90%) of CRS3123*2HCL as colorless solids.

[0137] FIG. 7 illustrates an NMR analysis of the final product.

[0138] Synthetic pathway 2

[0139] Also provided herein is a further synthesis of CRS3123.2HCI, starting with a recitation of a starting material prior to each step. This synthesis is hereinafter referred to as “Synthetic Pathway 2.” The overall Synthetic Pathway 2 is below:20Attorney Docket CU-76504-Crestone-PCT-FYG

[0140] Step 1 (Preparation of Compound 1 )

[0142] Representative Procedure

[0143] To a reactor equipped with thermometer and stirrer, 2,4-dibromophenol (1200.0 g, 1 .0 eq.) and THF (6000 mL, 5 V) were added. The mixture was cooled to 0-10 °C and potassium tert- butoxide (539.89 g, 1.01 eq.) was added in portions while maintaining the reaction temperature below 30 °C. Raised the inner temperature to 20-30 °C (clear yellow solution) and stirred at 20-30 °C for 30 minutes, followed by the addition of beta-propiolactone (377.62 g, 1 .1 eq.). The reaction was stirred at room temperature 15-20 h while monitoring by HPLC. The mixture was acidified with 37% hydrochloric acid to pH 2 and ethyl acetate (12000 mL, 10 V) added followed by water (12000 mL, 10 V). The organic phase was extracted with saturated sodium bicarbonate (12000 mL, 10 V). The aqueous phase was acidified to pH 2 with 37% hydrochloric acid and extracted with ethyl acetate (14400 mL, 12V). The organic phase was concentrated under reduced pressure to afford the product (1 ) as an off-white solid (compound 1 ) (1212.59 g, purity: 79.37%, QNMR: 89.2%, yield: 78.57%).

[0144] Step 2 (Preparation of Compound 2)

[0146] Representative Procedure

[0147] To a reactor equipped with a thermometer and stirrer, compound (1) (1180.0 g, 1.0 eq) and TFA (11800 mL, 10 V) were added. TFAA (2295.0 g, 3.0 eq.) was then added dropwise at 20-30°C. After the addition was complete, the mixture was heated to 45-50°C and stirred at this temperature for 20 hours while monitoring by HPLC. Once the reaction was complete, the mixture was cooled to 20-30°C and quenched into 10% NaHCO3 aqueous solution (11800 mL, 10 V) slowly at 0-20°C. DCM (11800 mL, 10 V) was then added, and the mixture was filtered to collect the organic phase of the filtrate. The aqueous phase was extracted with DCM (11800 mL, 10 V).21Attorney Docket CU-76504-Crestone-PCT-FYGThe organic phase was concentrated under reduced pressure to afford a tan solid (2) (1031.90 g, purity: 84.45%, isolation yield: 92.60%).

[0148] Step 3 (Preparation of Compound 15)

[0149]

[0150] Representative Procedure

[0151] To a reactor equipped with thermometer and stirrer, compound (2) (1000.0 g, 1 .0 eq) and THF (10000 mL, 10 V) were added, then Ti (0Et)4 (1566.0 g, 2.10 eq.) and (S)-2-methylpropane- 2-sulfinamide (475.37 g, 1.2eq.) was added at 20-30 °C. After the charge finished, the mixture was heated to 45-50 °C and stirred at 45-50 °C for 10- 20 h while monitoring by HPLC. After the reaction is completely transformed, the mixture was cooled to 20-30 °C and poured into 10% NaHCOs aq. (10000 mL, 10 V) at 20-30°C. Then filter and wash the cake with EtOAc (4000 mL, 2 V *2). The filtrate was separated and collected the organic phase. The aqueous phase was extracted with EtOAc (20000 mL, 10 V *2) and combined with organic phase. The organic phase was concentrated under reduced pressure to afford a brown oil (15) (1372.61 g, purity: 87.48%, yield: 102.6%).

[0152] Step 4 (Preparation of Compound 16)

[0154] Representative Procedure

[0155] To a reactor equipped with thermometer and stirrer, compound (15) (1372.0 g, 1.0 eq) and THF (13720 mL, 10 V) were added. The solution was cooled to -40—20 °C, then L-selectride (4024.0 mL, 1 .2eq.) was added dropwise quickly at the temperature below -10 °C and stirred at - 20—10 °C for 1 h while monitoring by HPLC. After the reaction is completely transformed, the reaction mixture was quenched with 10% citric acid aq. (13720 mL, 10 V) and stirred at 20~30°C. Separation and aqueous phase were extracted with EA (6860 mL, 5 V), then combined with the22Attorney Docket CU-76504-Crestone-PCT-FYGorganic phase. The organic phase was concentrated under reduced pressure to afford a tan solid (16) (1035.30 g, purity: 79.80%, isolation yield: 75.20%).

[0156] Step 5 (Preparation of compound 5)

[0158] Representative Procedure

[0159] To a reactor equipped with thermometer and stirrer, compound (16) (952.7 g, 1 .0 eq) and CPME (4764 mL, 5 V) were added, then 3M HCI / CPME solution (5716 mL, 6 V) was added dropwise at 20-30 °C. After the drip finished, the mixture was stirred at 20-30 °C for 1 ~3 h while monitoring by HPLC. After the reaction is completely transformed, the mixture was filtered, and the wet cake was washed with dioxane (3811 mL, 2 V*2). The wet cake was dried at 40-50 °C for 8-16 h to afford an off-white solid (5) (493.12 g, purity: 99.85%, chiral purity: 99.94%, QNMR: 91.4%, yield: 62.0%).

[0160] Step 6 (Preparation of compound 18)

[0162] Representative Procedure

[0163] Charged compound (17) (500.0 g, 1.00 eq) to a reactor with MeOH (5000 mL, 10 V), and MeONa (198.53 g, 1 .50 eq) was added to the mixture in batches, then the mixture was heated to 40-50 °C and stirred for 20-25 hrs. Cooled the suspension to room temperature, then quenched with NH4CI (393.15g, 3.0 eq) until pH was about 7-8. The mixture was concentrated under reduced pressure until about 2 V MeOH was left, followed by H2O (5000 mL, 5 V) added and stirred at room temperature. Filter and wash the cake with H2O (4000 mL, 2 V*2), obtained compound (18) as off-white solid (470.2 g, purity:97.95%, assay yield:96.10%).

[0164] Step 7 (Preparation of Compound 20)23Attorney Docket CU-76504-Crestone-PCT-FYGPd(OAc)2(0.2 eq.) . t-Bu-X-phos(04 eq ) t-BuOK(2.0 eq.)Dioxane(10 V) 70-80 °C, 12-16 h

[0165] (18) (19)

[0166] Representative Procedure

[0167] Charged toluene (8000 mL, 20 V), compound (18) (400.0 g, 1 .00 eq), t-Bu-Xphos (340.30 g, 0.20 eq), Pd(OAc)2 (89.96 g, 0.10 eq) and t-BuOK (449.61 g, 2.00 eq) in succession to fournecked reaction flasks. Heated to 40-50 °C after replacing nitrogen three times, and compound (19) (353.92 g, 1 .20 eq) solution of toluene (800 mL, 2 V) was added dropwise to the mixture and stirred for 15-20 h. After the reaction was completely cooled to 20-30 oC, filter through diatomaceous earth and mother liquor was washed with saturated NaHC03(4000 mL, 5 V*2). Organic phase was concentrated and added heptane (4000 mL, 5 V*2) then concentrated. The residue was slurry with heptane (2000 mL, 5 V) and filter to obtain gray solid (20) (266.0 g, purity: 95.56%, Yield:42.8%).

[0168] Step 8 (Preparation of compound 21)oxane( ) H20~30°C HCI

[0169] (20)<21’

[0170] Representative Procedure

[0171] Charged dioxane (1150 mL, 5 V), Compound (20) (230.0 g, 1.00 eq) and H2O (80 mL, 5.00 eq) in succession to a four-necked reaction flasks, 4 N HCI in dioxane(1150 mL, 5 V) was added dropwise to the mixture at 20-30 oC, sample for IPC, concentrated the mixture and added ACN(460 mL, 2 V), then concentrated again. The residues were slurried with ACN (1150 mL, 5 V) at 20-30 °C, filter and washed the cake with ACN (460 mL, 1 V*2), the cake obtained was dried at 45-55 °C for overnight, obtained brown solid (21 ) with 99.10% assay purity and 98.70% assay yield. (203.5 g, purity: 96.08%, isolated yield: 97.2%).

[0172] Step 9 (Preparation of Compound 22)24Attorney Docket CU-76504-Crestone-PCT-FYG

[0173]

[0174] Representative Procedure

[0175] Charged THF (3232 mL, 16 V), compound (21 ) (202.0 g, 1.00 eq) and compound (5) (269.62 g, 1 .06 eq) in succession to a four-necked reaction flasks, TEA (224.82 g, 3.00 eq) was added dropwise to the mixture at 20-30 °C, then STAB (204.05 g, 1 .30 eq) was added in batches at 20-30 °C ( There was warming up in here). Sample for IPC, then added EA (808 mL, 4 V) and 5wt% NaHCO3aq. (1616 mL, 8 V) and stirred for 0.5-1 h. Separated and organic phase was stirred with activated carbon (40.4 g, 20wt%) for 0.5 h, then filter and concentrated to get residues. Then slurried with EA (2020 mL, 10 V) for 2-3 h and filtered and washed the cake with EA (202 mL, 0.5 V*2). Concentrated the mother liquor at 35-45°C. Obtained brown oil (compound 22) with 86.29% purity and 112.67% isolated yield and went directly to the next step (440.0 g, purity: 82.69%, isolated yield: 1 12.67%).

[0176] Step 10 (Preparation of CRS3123)

[0177] Representative Procedure

[0178] Charged NMP (808 mL, 2 V), compound (22) (404.0 g, 1.00 eq) to a four-necked reaction flasks, pyridine-HCI (832.13 g, 10.00 eq) was added in batches to the mixture then heated to 100-110 °C and stirred for 10-14 h. Sample for IPC, then cooled to 30-40 °C, followed by adding 2-Me-THF (6060 mL, 15 V) and H2O (4040 mL, 10 V), then adjusted pH to 7-8 with NH3.H2O and separated. The aqueous phase was extracted with 2-Me-THF (2020 mL, 5V-1), The organic phase was washed with saturated NaCI aq. (2020 mL*2, 5V*2). The organic phase was decolored with activated carbon (80.8 g *2, 20% wt*2) two times. Concentrated and added EtOH (404 mL*2, 1 V-2) and concentrated again, then slurry with EtOH (4040 mL, 10 V) at 60-70 °C, cooled to 20-30°C25Attorney Docket CU-76504-Crestone-PCT-FYGand filter then dried at 45-55 °C for overnight. Obtained light orange solid (CRS31323) (226.0 g, purity: 92.97%, yield for two steps: 52.10%, QNMR: 90.10%).

[0179] Step 1 1 (Preparation of CRS3123.2HCI)

[0181] Representative Procedure

[0182] Preparation of CRS3123.2HCI: charged CRS3123 (150.0 g, 1.00 eq), EtOH (750 mL, 5 V), 4 N HCI in EtOH (300 mL, 2 V) and H2O (150 mL, 1 V), then heated to 60-70 °C, filter, added H2O (150 mL, 1 V) and 0.05 g crystal seed. Cooled to 20-30 °C slowly and stirred overnight. Stirred at 0-10 °C for 5-6 h. Filter and dry at 40-50 °C, dried at 100 °C under N2for 48 h. Obtained Off-white solid with 99.15% purity and 78.50% assay yield. (121.2 g, Cl: 12.0%, QNMR for freebase: 86.1 %, note: the wrong crystal form was obtained).

[0183] Re-production of CRS3123.2HCI: charged CRS3123.2HCI (wrong crystal form:1 18.5 g, 1 .0 eq.) to a reactor, added H2O (230 mL 1 .94 V) and EtOH (240 mL, 2 V), followed by added 12 M HCI (14.76 g, 2.00 eq) to stirred at 65-75 °C to afford a dissolved solution, then cooled to 50-55 °C and stirred at 50-55 °C for 2~3h (solid precipitate out). Cooled to 20-30 °C and stirred at 20-30 °C for 8-10 h, water(730 mL 6 V) was added dropwise at 20-30 °C and stirred at 20-30 °C for 3-5h, filter, wet cake was washed with EtOH: H2O=1 :4(120 mL 1 V) and dried at 45-50°C for 10-14 h. Obtained off-white solid with 99.42% purity. (120.2 g, assay yield: 95.7%, QNMR for free base: 81 .2%, assay of Cl: 1 1 .6%).

[0184] In that regard, Synthetic Pathway 2 yields CRS3123. X-ray powder diffraction (XRPD) was used to create patterns to identify CRS3123 made via Synthetic Pathway 2. With reference to FIGs. 9 and 10, XRPD data is illustrated. The XRPD Peak List is illustrated in Figures 11 A and 11 B.

[0185] Formulations

[0186] In various embodiments, formulations of the present disclosure include formulations suitable for administration orally, intravenously, intrathecally, subcutaneously, topically, transdermally, and sublingually, among other routes. In various embodiments, formulations intended for oral administration may be produced in a capsule. In various embodiments, formulations intended for oral administration include CRS3123*2HCL.26Attorney Docket CU-76504-Crestone-PCT-FYG

[0187] In various embodiments, formulations intended for oral administration include a filler. Any suitable filler may be used. For example, in various embodiments, fillers may include one or more of cellulose, microcrystalline cellulose lactose, sucrose, maize-starch, calcium phosphate, sorbitol or glycine.

[0188] In various embodiments, formulations intended for oral administration include a disintegrant. Any suitable disintegrant may be used. For example, in various embodiments, disintegrants may include one or more of sodium starch glycolate, potato starch.

[0189] In various embodiments, formulations intended for oral administration include a lubricant. Any suitable lubricant may be used. For example, in various embodiments, lubricants may include one or more of magnesium stearate, talc, polyethylene glycol or silica.

[0190] In various embodiments, formulations intended for oral administration are packaged in a gelatin capsule. For example, any size gelatin capsule may be used, including a size 0 capsule.

[0191] In various embodiments, CRS3123*2HCL is formulated with an excipient of microcrystalline cellulose (Avicel® PH-302), a disintegrant of sodium starch glycolate (Explotab®), and a lubricant of magnesium stearate and filled in a size 0 gelatin capsule.

[0192] In various embodiments, formulations intended for oral administration include from 1%- 70% w / w CRS3123»2HCL, from 30%-80% w / w filler, from 1% to 4% w / w / disintegrant, and from 0.1 % to 2% w / w lubricant.

[0193] TABLE 1 contains formulations in accordance with various embodiments:

[0194] TABLE 127Attorney Docket CU-76504-Crestone-PCT-FYG

[0195] It should be noted that 121 .1 mg CRS3123*2HCL is equivalent to 100mg CRS3123*2HCL anhydrous base.

[0196] TABLE 2 contains formulations in accordance with various embodiments: fO1971 TABLE 2

[0198] It should be noted that 242.2 mg CRS3123*2HCL is equivalent to 200mg CRS3123*2HCL anhydrous base.

[0199] Solid Forms

[0200] CRS3123*2HCL can exist in a variety of solid forms. Such forms include polymorphs and amorphous forms. The solid forms can be solvated, hydrates and un-solvated forms CRS3123*2HCL. All such forms are contemplated by the present disclosure. In various embodiments, CRS3123«2HCL as a mixture of one or more solid forms of CRS3123*2HCL, though in various embodiments CRS3123*2HCL is provided in a single solid form substantially free of other solid forms.

[0201] In various embodiments, CRS3123*2HCL is a crystalline solid. In various embodiments, CRS3123*2HCL is a crystalline solid substantially free of amorphous CRS3123*2HCL. As used herein, the term “substantially free of amorphous CRS3123*2HCL” means that the material contains no significant amount of amorphous CRS3123*2HCL, meaning not more than 2% by weight amorphous CRS3123*2HCL. In various embodiments, at least about 90% by weight of crystalline CRS3123*2HCL is present, or at least about 95% by weight of CRS3123*2HCL is present. In still further embodiments, at least about 97%, 98% or 99% by weight of crystalline CRS3123*2HCL is present.28Attorney Docket CU-76504-Crestone-PCT-FYG

[0202] In various embodiments, CRS3123*2HCL is a hydrate polymorphic form. In various embodiments, CRS3123«2HCL occurs in a dihydrate polymorphic form of referred to herein as Form A. In various embodiments, CRS3123*2HCL is provided as at least one of an acetonitrile solvate (ACN solvate), a tetrahydrofuran solvate (THF solvate), an isopropyl alcohol solvate (IPA solvate), a monohydrate, and an anhydrate. The ACN solvate is referred to herein as Pattern B. The THF solvate is referred to herein as Pattern D. The IPA solvate is referred to herein as Pattern E.

[0203] In various embodiments, CRS3123*2HCL is a neat or unsolvated crystal form and thus does not have any water or solvent incorporated into the crystal structure. In various embodiments, the anhydrous polymorphic form of CRS3123*2HCL is referred to herein as Pattern J.

[0204] In various embodiments, CRS3123*2HCL is formed in the presence of excess HCL, treated with charcoal, and vacuum dried, resulting solids containing >5% EtOH. Further vacuum treatment at elevated temperatures (~100°C) over several days yields an amorphous material. Recrystallization of the dihydrochloride salt from EtOH-water causes formation of the monohydrochloride salt, which is less soluble in EtOH-water. It appears that excess hydrochloric acid is needed for formation of the dihydrochloride salt.

[0205] As described below, X-ray powder diffraction (XRPD) was used to create patterns to identify polymorphs CRS3123 in different preparations. An abbreviated polymorph screen of CRS3123 dihydrochloride salt was carried out using vials and a microplate. Most experiments were set up using excess hydrochloric acid to avoid generation of monohydrochloride salt. Crystalline solids with nine unique XRPD patterns were generated from the screen and were labeled Form A and Pattern B-J materials (FIG. 1 ). Form A is the topmost pattern, followed by Patterns B, C, D, E and F, from top to bottom of the graph. In FIG. 2, Patterns G, H, I J, K and L are shown, from top to bottom.

[0206] Solids that were known to be physically pure were designated as 'Form X', otherwise XRPD patterns of solids were labeled 'Pattern X'. Form A was generated from a wide variety of solvents and conditions including both vial and microplate experiments. However, the formation of Form A appeared to be pH dependent, as experiments did not yield Form A in the absence of excess HCI. This suggests Form A is associated with CRS3123 dihydrochloride salt. The pattern B material was generated from an aqueous slurry in the absence of excess HCI and exhibited a XRPD pattern that matched that of solids from the preparation of the monohydrochloride salt29Attorney Docket CU-76504-Crestone-PCT-FYG(Table 3). Pattern D and E materials were generated from THE and isopropyl alcohol (IPA) solvent systems respectively, in both vial and well-plate experiments.

[0207] TABLE 3

[0208] Highly disordered CRS3123 dihydrochloride salt was stressed at high relative humidity, elevated temperature, and by compression. An elevated temperature relative humidity stress experiment (85%RH / 60°C) produced crystalline solids corresponding to Form A material. All other stress experiments resulted in amorphous material.

[0209] Attempts were made to crystallize CRS3123 dihydrochloride salt from constituent components in solution. Gels or amorphous solids were initially generated but crystalline material was collected from methanol-water mixtures and was composed of either Form A or a unique form, designated Pattern J material.

[0210] Equimolar amounts of CRS3123 free base and aqueous HOI were slurred for one day in an EtOH:water mixture in order to prepare the monohydrochloride salt of CRS3123. The resulting solids exhibited a unique XRPD pattern designated Pattern B material. Several peaks in the powder pattern of pattern B material matched peak positions for the XRPD pattern of a mixture of mono and dihydrochloride material. These results suggest that the formation of monohydrochloride had occurred.

[0211] CRS3123 dihydrochloride salt Form A is a crystalline, slightly hygroscopic hydrate or solvate. Form A exhibited a powder pattern characteristic of crystalline material (FIG. 1 ). Thermal analysis of Form A solids exhibited 1 % weight loss from 25-68°C, probably due to loss of volatile components, followed by a further 5% loss from 68-121 °C (FIG. 2). The second weight loss was accompanied by a large endotherm in the corresponding DSC thermogram at 146°C and is probably due to desolvation and / or loss of HCI. No melt was observed for Form A, although the sample darkened in color above 2 I 5°C. Form A was slightly hygroscopic at high relative humidity during moisture sorption-desorption analysis, gaining 1 .5% weight at 95%RH (FIG. 3). All gained weight was lost during desorption. The post moisture balance XRPD pattern matched Form A.

[0212] Figure 1 shows XRPD of CRS3123 dihydrochloride salt forms. Form A is characterized by one or more peaks in its powder X-ray diffraction pattern selected from those at about 2-theta. Form A is characterized by one or more peaks in its powder X-ray diffraction pattern as shown in FIG. 1. For example, peaks appear at about degree 2-theta values of 6, 10.8, 13.3, 14.5, 15.4, 16.1 , 17, 18.2, 20.1 , 21.3, 23.7, 25.1 , 25.4, 26.5, 27.2, 30.8, 32, and 37.8. The term about in this 30Attorney Docket CU-76504-Crestone-PCT-FYGcontext only means ±0.3, and / or ±0.2, and / or ±0.1 . In other words, Form A of FIG. 1 illustrates the crystalline compound CRS3123*2HCL characterized by peaks in powder x-ray diffraction pattern at 2D values of 6±0.3, 10.8±0.3, 13.3±0.3, 14.5±0.3, 15.4±0.3, 16.1 ±0.3, 17±0.3, 18.2±0.3, 20.1±0.3, 21.3±0.3, 23.7±0.3, 25.1 ±0.3, 25.4±0.3, 26.5±0.3, 27.2±0.3, 30.8±0.3, 32±0.3, and 37.8±0.3. Form A of FIG. 1 illustrates the crystalline compound CRS3123*2HCL characterized by peaks in powder x-ray diffraction pattern at 2D values of 6±0.2, 10.8±0.2, 13.3±0.2, 14.5±0.2, 15.4±0.2, 16.1 ±0.2, 17±0.2, 18.2±0.2, 20.1±0.2, 21.3±0.2, 23.7±0.2, 25.1±0.2, 25.4±0.2, 26.5±0.2, 27.2±0.2, 30.8±0.2, 32±0.2, and 37.8±0.2. Form A of FIG. 1 illustrates the crystalline compound CRS3123*2HCL characterized by peaks in powder x-ray diffraction pattern at 2D values of 6±0.1 , 10.8±0.1 , 13.3±0.1 , 14.5±0.1 , 15.4±0.1 , 16.1 ±0.1 , 17±0.1 , 18.2 =0.1 , 20.1±0.1 , 21.3±0.1 , 23.7±0.1 , 25.1±0.1 , 25.4±0.1 , 26.5±0.1 , 27.2±0.1 , 30.8±0.1 , 32±0.1 , and 37.8±0.1 .

[0213] Pattern C-E materials were analyzed by elemental analysis for chlorine content and by 1 H-NMR spectroscopy for solvent content. Pattern B material was not further characterized as it was determined to be the monohydrochloride salt according to XRPD analysis. Chlorine content was between 1 1-13 % for Pattern C-E materials, which is in good agreement with the calculated value of 12% for the dihydrochloride salt. Acetonitrile, tetrahydrofuran and isoproylalcohol were detected in proton NMR spectra of Pattern C-E materials respectively, suggesting that each solid is solvated. All samples were washed with diethylether prior to NMR analysis to remove residual crystallization solvents. Figure 8 shows NMR results of CRS3123 dihydrochloride salt.

[0214] Figure 1 further shows XRPD of CRS3123 dihydrochloride salt forms of Patterns B-F. XRPD of CRS3123 dihydrochloride salt forms.

[0215] Thus, Form A (CRS3123 dihydrochloride salt) appears to be most stable form of CRS3123. CRS3123 dihydrochloride salt stability was affected by solvent and pH conditions. A proposed ionization scheme is shown in FIG. 4. Further solvent systems and XRPD results are contained in FIGs. 5, 5A and 5B. FIG. 7, 7A, 7B, and 7C show further solvent systems and the solid forms obtained therefrom.

[0216] Various formulations of CRS3123 may comprise an enteric coating. The enteric coating, as described above, is resistant to dissolution in the gastric juices and may thus protect the CRS3123 from absorption in the stomach. The enteric coating is then degraded in the intestines so that the CRS3123 may be absorbed systemically. Suitable coating materials are commercially available, e.g. under the trademarks Opadry® and Eudragit®. Examples of suitable coating materials include cellulose esters and cellulose ethers, such as methylcellulose (MC), 31Attorney Docket CU-76504-Crestone-PCT-FYGhydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), poly(meth)acrylates, such as aminoalkylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers, methacrylic acid methylmethacrylate copolymers; vinyl polymers, such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinylacetate; and natural film formers. In a various embodiment, the coating is water-soluble. In various embodiments, the coating is based on polyvinyl alcohol, such as polyvinyl alcohol-partially hydrolyzed, and may additionally contain polyethylene glycol, such as macrogol 3350, and / or pigments. In various embodiments, the coating is based on hydroxypropylmethyl cellulose, such as hypromellose type 2910. The coating can be resistant to gastric juices and dissolve as a function of the pH value of the release environment. By means of this coating, it is possible to ensure that the tablet or capsule according to the disclosure in various embodiments passes through the stomach undissolved and the active compound is only, or substantially, released in the intestines. The coating which is resistant to gastric juices dissolves at a pH value of between 5 and 7.5. In various embodiments, the enteric coating are comprised of one or more compositions comprising copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid and ethyl acrylate to which a monomer of methylacrylate has been added during polymerization.

[0217] The detailed description shows embodiments by way of illustration, including the best mode. While these embodiments are described in sufficient detail to enable those skilled in the art to practice the principles of the present disclosure, it should be understood that other embodiments may be realized and that chemical changes may be made without departing from the spirit and scope of principles of the present disclosure. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. With regard to procedures, methods, techniques, and workflows that are in accordance with some embodiments, some operations in the procedures, methods, techniques, and workflows disclosed herein may be combined and / or the order of some operations may be changed. For example, the steps recited in any of the method descriptions may be executed in any suitable order and are not limited to the order presented.

[0218] In the above description, all cited references are incorporated herein by reference in their entireties. The citing of any reference is not an admission that such a reference is relevant prior art; rather, citations are to reference the novelty of the invention and discoveries described herein relative to known scientific literature, practices and prior art. In the description of the present disclosure, all ratios are weight ratios unless specifically stated otherwise. Unless otherwise32Attorney Docket CU-76504-Crestone-PCT-FYGindicated or evident from context, preferences indicated above and herein apply to the entirety of the embodiments discussed herein.

[0219] In describing the present disclosure, the following terminology will be used: The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to an item includes reference to one or more items. The term “ones” refers to one, two, or more, and generally applies to the selection of some or all of a quantity. The term “plurality” refers to two or more of items. The term “about” means quantities, dimensions, sizes, formulations, parameters, shapes and other characteristics need not be exact, but may be approximated and / or larger or smaller, as desired, reflecting acceptable tolerances, conversion factors, rounding off, measurement error and the like and other factors known to those of skill in the art. The term “substantially” means that the recited characteristic, parameter, or value need not be achieved exactly, but that deviations or variations, including for example, tolerances, measurement error, measurement accuracy limitations and other factors known to those of skill in the art, may occur in amounts that do not preclude the effect the characteristic was intended to provide.

[0220] Numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also interpreted to include all of the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of “about 1 to 5” should be interpreted to include not only the explicitly recited values of about 1 to about 5 but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3 and 4 and sub-ranges such as 1 -3, 2-4 and 3-5, etc.

[0221] This same principle applies to ranges reciting only one numerical value (e.g., “greater than about 1”) and should apply regardless of the breadth of the range or the characteristics being described. A plurality of items may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary. Furthermore, where the terms “and” and “or” are used in conjunction with a list of items, they are to be interpreted broadly, in that any one or more of the listed items may be used alone or in combination with other listed items. The term “alternatively” refers to selection of one of two or more alternatives and is not intended to limit the 33Attorney Docket CU-76504-Crestone-PCT-FYGselection to only those listed alternatives or to only one of the listed alternatives at a time, unless the context clearly indicates otherwise.

[0222] The scope should be determined by the appended claims and their legal equivalents, rather than by the examples given above. For example, the operations recited in any method claims may be executed in any order and are not limited to the order presented in the claims. Moreover, no element is essential unless specifically described herein as “critical” or “essential.”

[0223] Moreover, where a phrase similar to ‘at least one of A, B, and C’ or ‘at least one of A, B, or C’ is used in the claims or specification, it is intended that the phrase be interpreted to mean that A alone may be present in an embodiment, B alone may be present in an embodiment, C alone may be present in an embodiment, or that any combination of the elements A, B and C may be present in a single embodiment; for example, A and B, A and C, B and C, or A and B and C.34Attorney Docket CU-76504-Crestone-PCT-FYG

Claims

CLAIMS1 . Compounds of formula (I), or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof:I in which: X is selected from the group consisting of NH, O, S, SO, SO2. or CH2; n is 1 , 2 or 3;0 is 1 , 2, or 3;* indicates an asymmetric carbon atom, wherein when n is 2 or 3, then * is R configuration; wherein when n is 1 and X is CH2, then * is R configuration; and wherein when n is 1 and X is selected from the group consisting of NH, O, S, SO, or SO2, then * is S configuration;R1is independently selected from halo, cyano, hydroxyl, (Ci-e)alkyl (optionally substituted by halo, hydroxyl, amino, carboxy, or (Ci-6)alkoxycarbonyl), (C3 7)cycloalkyl, C1-6 alkoxy, amino, mono- or di-(Ci-6)alkylamino, acylamino, carboxy, (Ci-6)alkoxycarbonyl, carboxy(Ci-6)alkyloxy, (C1-6)alkylthio, (Ci-6)alkylsulphinyl, (Ci-©)alkylsulphonyl, sulphamoyl, mono- and di-(Ci-6)alkylsulphamoyl, carbamoyl, mono- and di-(Ci-6)alkylcarbamoyl and heterocyclic; m is 0, 1 , 2, 3 or 4;R2is independently selected from hydrogen, halo, cyano, hydroxyl, (Ci-e)alkyl (optionally substituted by halo, hydroxyl, amino, carboxy), or (Ci-e)alkoxycarbonyl), (C3-7)cycloalkyl, C1-6 alkoxy, amino, mono- or di-(Ci-6)alkylamino, acylamino, carboxy, (Ci-e)alkoxycarbonyl, carboxy(Ci-e)alkyloxy, (Ci-e)alkylthio, (Ci-e)alkylsulphinyl, (Ci-e)alkylsulphonyl, sulphamoyl, mono- and di-(Ci-6)alkylsulphamoyl, carbamoyl, mono- and di-(Ci-6)alkylcarbamoyl and heterocyclic;35Attorney Docket CU-76504-Crestone-PCT-FYGR3is independently selected from (Ci-e)alkyl (optionally substituted by halo, hydroxyl, amino, carboxy), or (Ci-6)alkoxycarbonyl), (C37)cycloalkyl, Ci-6alkoxy, amino, mono- or di-(Ci 6)alkylamino, acylamino, carboxy, (Ci-e)alkoxycarbonyl, carboxy(Ci-6)alkyloxy, (Ci-e)alkylthio, (Ci- e)alkylsulphinyl, (Ci-6)alkylsulphonyl, sulphamoyl, mono- and di-(Ci-6)alkylsulphamoyl, carbamoyl, mono- and di-(Ci-6)alkylcarbamoyl and heterocyclic; and when Zi is S, Z2 and Z3are CH; when Z2is S, Z1 and Z3are CH; and when Z3is S, Z1 and Z2are CH.

2. The compounds of claim 1 , pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof, characterized in that: said compound has a structure of formula, wherein the compounds have a formula (II):II3. The compounds of claim 1 or 2, pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof, characterized in that: said compound has a structure of formula, wherein (R1)mis a 6, 8 substitution and can be the same or different substituents, wherein the substituents are selected from the group consisting of bromine, chlorine, iodine and sulfone.

4. The compounds of any one of claims 1 -3, pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof, characterized in that: said compound has a structure of formula, wherein the compound is36Attorney Docket CU-76504-Crestone-PCT-FYG5. Compounds of formula (III), or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof:o is 1 , 2, or 3;R1, R2, R4, R5are independently selected from hydrogen, (Ci-e)alkyl (optionally substituted by halo, hydroxyl, amino, carboxy, or (Ci-e)alkoxycarbonyl), (C^cycloalkyl, Ci-6alkoxy, amino, mono- or di-(Ci-6)alkylamino, acylamino, carboxy, (Ci-6)alkoxycarbonyl, carboxy(Ci-6)alkyloxy, (Ci-e)alkylthio, (Ci-6)alkylsulphinyl, (Ci-6)alkylsulphonyl, sulphamoyl, mono- and di-(Ci- 6)alkylsulphamoyl, carbamoyl, mono- and di-(Ci-6)alkylcarbamoyl and heterocyclic, when R1and R4are both hydrogen at the same time, one end carbon connecting two OH group becomes aldehyde ;R3is independently selected from (Ci-e)alkyl (optionally substituted by halo, hydroxyl, amino, carboxy), or (Ci-e)alkoxycarbonyl), (C3-7)cycloalkyl, C1-6 alkoxy, amino, mono- or di-(Ci- 6)alkylamino, acylamino, carboxy, (Ci-6)alkoxycarbonyl, carboxy(Ci-6)alkyloxy, (Ci-e)alkylthio, (Ci-37Attorney Docket CU-76504-Crestone-PCT-FYGe)alkylsulphinyl, (Ci-e)alkylsulphonyl, sulphamoyl, mono- and di-(Ci-6)alkylsulphamoyl, carbamoyl, mono- and di-(Ci-6)alkylcarbamoyl, sodium (Na), and heterocyclic.

6. The compound of claim 5, pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, or metabolites thereof, or deuterated derivatives thereof, characterized in that: said compound has a structure of formula, wherein the compound is at least one of7. A polymorph of a compound having the structure represented by formula (IV)8. The polymorph of claim 7, which is characterized by at least one of the following powder x-ray diffraction pattern peak expressed in terms of diffraction angles (20) (±0.3°) as measured with copper Ka radiation chosen from: about 6°, about 10.8°, about 13.3°, about 14.5°, about 15.4°, about 16.1 °, about 17°, about 18.2°, about 20.1 °, about 21.3°, about 23.7°, about 25.1 °, about 25.4°, about 26.5°, about 27.2°, about 30.8°, about 32°, and about 37.8°.

9. A pharmaceutical formulation comprising the polymorph of a compound having a structure represented by formula (IV), as defined in claim 7 or 8, and a pharmaceutically acceptable excipient.38Attorney Docket CU-76504-Crestone-PCT-FYG10. A method of treating a disease, comprising administering to a subject in need of such treatment a therapeutically effective amount of the polymorph of the compound having a structure represented by formula (IV), as defined in any one of claims 7-9.11 . A process for preparing a compound having formula (IV), comprising:(a) providing a compound having formula (II):II wherein X is Oxygen; O is 1 ; R3is Me; R1is Br at 6, 8 positions; R2is hydrogen;(b) treating the compound having formula (II) or a salt thereof with NMP and pyridine-HCI solution;(c) isolating the compound of formula (IV).

12. The process of claim 1 1 , further comprising:39Attorney Docket CU-76504-Crestone-PCT-FYGproviding a compound with the formula (V);treating compound with the formula (V) with 6,8-dibromo-chroman-4(R)-ylamine hydrochloride inTEA, then STAB to form the compound having formula (II):II wherein X is Oxygen; O is 1 ; R3is Me; R1is Br at 6, 8 positions; R2is hydrogen.

13. The process of claim 12, further comprising: treating compound having the formula (VI) in dioxane HCI solution to form the compound with formula (V)14. A process for preparing a compound having formula (IV):40Attorney Docket CU-76504-Crestone-PCT-FYGthe method comprises the following steps:(a) providing a compound having formula (II):II wherein X is Oxygen; O is 1 ; R3is OCOPh; R1is Br at 6, 8 positions; R2is hydrogen;(b) treating the compound having formula (II) or a salt thereof with a base solution.(c) Converting compound having formula (II) to 2HCI salt in HCI solution and isolating the compound of formula (IV).

15. The process of claim 14, further comprising: reacting 5-(3-Oxopropylamino) thieno[3,2-b]pyridin-7-yl benzoate HCI salt with the 6,8-dibromo- chroman-4(R)-ylamine hydrochloride and triethylamine to yield 5-[3-(6,8-Dibromo-chroman-4- ylamino) propylamino]-thieno[3,2-b]pyridin-7-yl benzoate (the compound having formula (II): wherein X is Oxygen; O is 1 ; R3is OCOPh; R1is Br at 6, 8 positions; R2is hydrogen).41Attorney Docket CU-76504-Crestone-PCT-FYG16. The process of claim 15, further comprising: dissolving 5-(3,3-Diethoxypropylamino) thieno[3,2-b]pyridin-7-yl benzoate HCI to yield 5-(3- oxopropylamino) thieno[3,2-b]pyridin-7-yl benzoate HCI salt.

17. The process of claim 16, further comprising: reacting Sodium 5-(3,3-diethoxypropylamino) thieno[3,2-b]pyridin-7-olate with Benzoic anhydride to yield 5-(3,3-Diethoxypropylamino) thieno[3,2-b]pyridin-7-yl benzoate.

18. The process of claim 17, further comprising: reacting 5-(3,3-Diethoxypropylamino)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylic acid with a base to yield Sodium 5-(3,3-diethoxypropylamino) thieno[3,2-b]pyridin-7-olate.

19. The process of claim 18, further comprising: suspending 5-((3,3-Diethoxypropylamino)(thiophene-3-ylamino)methylene)-2,2-dimethyl-1 ,3- dioxane-4, 6-dione (1.62 mol) in a solution to yield 5-(3,3-Diethoxypropylamino)-7-oxo-4,7- dihydrothieno[3,2-b]pyridine-6-carboxylic acid.

20. The process of claim 19, further comprising: reacting 2,2-dimethyl-5-(methylsulfanyl- thiophene-3-ylamino-methylene)-[1 ,3]dioxane-4, 6-dione with 3,3-Diethoxypropylamine to yield 5-((3,3-Diethoxypropylamino)(thiophene-3-ylamino)methylene)-2,2-dimethyl-1 ,3-dioxane-4,6- dione.42Attorney Docket CU-76504-Crestone-PCT-FYG

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