Process for preparation of modulators of eukaryotic initiation factor 2B

Abstract

The present disclosure relates generally to processes for the preparation of Compound (I-1): # imgabs0 # or a stereoisomer or mixture of stereoisomers thereof, or respective salts thereof, as well as compounds and salts useful in their synthesis.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 355,072, filed on June 23, 2022, under 35 U.S.C. §119(e), the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present application relates to a synthesis method of a small molecule regulator of eukaryotic initiation factor 2B which can be used as a therapeutic agent, a novel intermediate and a synthesis method thereof. Summary of the invention

[0004] The multi-subunit protein complexes eukaryotic initiation factor 2B (eIF2B) and eukaryotic initiation factor 2 (eIF2) are required for the initiation and regulation of protein synthesis in eukaryotic cells. The interaction of eIF2B with eIF2 plays an important role in the integrated stress response (ISR) pathway. Activation of this pathway leads in part to ATF4 (activating transcription factor 4) expression and stress granule formation. Abnormal ISR activation is found in a variety of neurodegenerative diseases, which has a strong functional connection with the pathology characterized by RNA binding / stress granule protein TAR DNA binding protein (TARDBP) (also known as TDP43). Impairment of eIF2B activity is associated with activation of the ISR pathway involved in a variety of neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and frontotemporal dementia and vanishing white matter disease. On the other hand, activation of eIF2B inhibits the formation of ISR and ISR-dependent stress granules, and has been found to be neuroprotective in these disease models. Small molecule modulators of eIF2B are expected to treat these conditions.

[0005] Disclosed herein are improved methods for synthesizing small molecule modulators of eukaryotic initiation factor 2B. In certain embodiments, provided herein are improved methods for preparing compounds of formula I-1:

[0006]

[0007] where p, t, x, y, z, X 1 , R 1 , R 3 , R 4 , R 5 , R 10 and R 11 As described in this article.

[0008] In certain embodiments, the methods described herein are directed to preparing compounds of Formula I:

[0009]

[0010] In some embodiments, the methods described herein avoid malodorous reactions or intermediates, improve purity, or provide salt or solid (e.g., crystalline) forms that allow the methods to avoid oil or other liquid forms that may make subsequent purification methods or handling difficult. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 is an X-ray powder diffraction (XRPD) pattern of the tert-butylamine (TBA) salt of the compound of Formula VIa-1a, Form A (also known as Formula VII-1a, Form A).

[0012] Figure 2 Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) of the TBA salt of the compound of Formula VIa-1a which is Form A.

[0013] Figure 3 is the XRPD pattern of the dicyclohexylamine (DCHA) salt of the compound of Formula VIa-1a, Form A (also known as Formula VII-1b, Form A).

[0014] Figure 4 TGA and DSC of the DCHA salt of the compound of Formula VIa-1a which is Form A.

[0015] Figure 5 is the XRPD of the L-arginine salt of the compound of Formula VIa-1a, Form A (also known as Formula VII-1c, Form A).

[0016] Figure 6 TGA and DSC of the L-arginine salt of the compound of Formula VIa-1a which is Form A.

[0017] Figure 7 XRPD of the tromethamine (TMA) salt of the compound of Formula VIa-1a in Form A (also known as Formula VII-1d, Form A).

[0018] Figure 8 TGA and DSC of the TMA salt of the compound of Formula VIa-1a, which is Form A (also known as Formula VII-1d, Form A).

[0019] Fig. 9 DSC of the 4-chlorophenoxyacetic acid salt of the compound of Formula XI-1a in Form A.

[0020] Fig.10 is the XRPD of Form A of the 4-chlorophenoxyacetic acid salt of the compound of Formula XI-1a.

[0021] Fig.11 is the XRPD of the compound of Formula XI-1a, free base Form A.

[0022] Fig.12 DSC of the free base Form A of the compound of Formula XI-1a.

[0023] Fig.13 is the XRPD of the hydrogen oxalate salt Form A of the compound of Formula XI-1a.

[0024] Fig.14 is the DSC of the hydrogen oxalate salt Form A of the compound of Formula XI-1a.

[0025] Fig.15 is the crystal structure of the 4-chlorophenoxyacetic acid salt of the compound of formula XI-1a determined by microED.

[0026] Fig.16 is the unit cell structure of 4-chlorophenoxyacetic acid salt of the compound of formula XI-1a determined by microED.

[0027] Fig.17 is the single crystal X-ray structure of the compound of formula VII-1a.

[0028] Fig.18 is the unit cell structure of the compound of formula VII-1a.

[0029] 1. Definition

[0030] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below unless otherwise indicated by the context in which they are used.

[0031] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH 2 Attachment is through a carbon atom. A dash at the front or end of a chemical group is convenient; a chemical group may be depicted with or without one or more dashes without losing its ordinary meaning. A wavy or dotted line drawn through a line in a structure indicates a specific point of attachment for a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality or stereochemistry.

[0032] The prefix "C u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0033] References to "about" values ​​or parameters herein include (and describe) embodiments for the value or parameter itself. In certain embodiments, the term "about" includes an indication of ±10%. In other embodiments, the term "about" includes an indication of ±5%. In certain other embodiments, the term "about" includes an indication of ±1%. In addition, the term "about X" includes a description of "X". In addition, the singular forms "a" and "the / said" include plural references unless the context clearly indicates otherwise. Therefore, for example, reference to "the compound" includes a variety of such compounds, and reference to "the assay" includes reference to one or more assays known to those skilled in the art and their equivalents.

[0034] "Alkyl" refers to a straight or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbon atoms is designated by chemical name or identified by molecular formula, all positional isomers having that number of carbon atoms are contemplated; thus, for example, "butyl" includes n-butyl (i.e., -(CH 2 ) 3 CH 3 ), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e., -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e., -C(CH 3 ) 3 ); and "propyl" includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ) and isopropyl (i.e., -CH(CH 3 ) 2 ).

[0035] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" groups or "alkylenyl" groups, "arylene" groups or "arylenyl" groups, respectively. Furthermore, unless otherwise expressly stated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last-mentioned group contains the atoms by which the moiety is attached to the rest of the molecule.

[0036] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C 2-4 Examples of the alkenyl group include, for example, vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0037] "Alkynyl" refers to a group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0038] “Alkoxy” refers to the group “alkyl-O—.” Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0039] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl".

[0040] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S(O)-". "Alkylsulfonyl" refers to the group "alkyl-S(O)-". 2 -". "Alkylsulfonylalkyl" refers to -alkyl-S(O) 2 -alkyl.

[0041] "Acyl" refers to the group -C(O)R y , where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of acyl include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.

[0042] "Acylamino" refers to a "C-acylamino" group (which refers to the group -C(O)NR y R z ) and "N-amido" groups (which refers to the group -NR y C(O)R z ) Both, where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein, or R y and R z taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted as defined herein.

[0043] "Amino" refers to the group -NR y R z , where R y and R z R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0044] "Aminoalkyl" refers to the group "-alkyl-NR y R z ”, where R y and R z R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0045] "Amidino" refers to -C(NR y )(NR z 2 ), where R y and R z R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0046] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 The term "aryl" refers to a group consisting of a phenyl group, a naphthyl group, a fluorenyl group, and an anthracenyl group. The term "aryl" refers to a group consisting of a phenyl group, a naphthyl group, a fluorenyl group, and an anthracenyl group. However, an aryl group does not encompass a heteroaryl group as defined below or overlap in any way with a heteroaryl group as defined below. If one or more aryl groups are fused to a heteroaryl group, the resulting ring system is a heteroaryl group. If one or more aryl groups are fused to a heterocyclyl group, the resulting ring system is a heterocyclyl group.

[0047] "Arylalkyl" or "aralkyl" refers to the radical "aryl-alkyl-".

[0048] "Carbamoyl" refers to an "O-carbamoyl" group (which refers to the group -OC(O)NR y R z ) and "N-carbamoyl" groups (which refers to the group -NR y C(O)OR z ) Both, where R y and R z R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0049] "Carboxyl ester" or "ester" refers to -OC(O)R x He-C(O)OR x Both, of which R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0050] "Cyanoalkyl" means an alkyl group as defined above in which one or more hydrogen atoms are replaced by a cyano (-CN) group.

[0051] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused rings, bridged rings, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and cycloalkenyl groups having at least one sp 3 As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6Cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. In addition, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring, regardless of attachment to the rest of the molecule. In addition, when there are two substitution positions on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl.

[0052] "Cycloalkoxy" refers to a "-O-cycloalkyl" group.

[0053] "Cycloalkylalkyl" refers to the radical "cycloalkyl-alkyl-".

[0054] "Cycloalkylalkoxy" refers to "-O-alkyl-cycloalkyl".

[0055] "Guanidyl" refers to -NR y C(=NR z )(NR y R z ), where each R y and R z R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0056] "Hydrazino" refers to -NHNH 2 .

[0057] "Imino" refers to the group -C(NR y )R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0058] "Imino" refers to the group -C(O)NR y C(O)R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0059] "Halogen" or "halo" refers to an atom occupying Group VIIA of the Periodic Table, such as fluorine, chlorine, bromine or iodine.

[0060] "Haloalkyl" refers to a straight or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by a halogen. For example, when a residue is substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to an alkyl group substituted by two ("two") or three ("three") halo groups, which can be, but are not necessarily, identical halogens. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0061] "Haloalkoxy" means an alkoxy group as defined above wherein one or more hydrogen atoms are replaced by a halogen.

[0062] "Hydroxyalkyl" means an alkyl group as defined above wherein one or more hydrogen atoms are replaced by a hydroxy group.

[0063] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups, provided that the point of attachment to the rest of the molecule is through a carbon atom. The term "heteroalkyl" includes straight or branched saturated chains having carbon and heteroatoms. For example, 1, 2, or 3 carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O) 2 - etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CH 2 OCH 3 、-CH(CH 3 )OCH 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 2 OCH 3 etc.), thioethers (e.g., -CH 2 SCH 3 、-CH(CH 3 )SCH 3 、-CH 2 CH 2 SCH 3 、-CH 2 CH 2SCH 2 CH 2 SCH 3 etc.), sulfones (e.g., -CH 2 S(O) 2 CH 3 、-CH(CH 3 )S(O) 2 CH 3 、-CH 2 CH 2 S(O) 2 CH 3 、-CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 3 etc.) and amines (e.g., -CH 2 NR y CH 3 、-CH(CH 3 )NR y CH 3 、-CH 2 CH 2 NR y CH 3 、-CH 2 CH 2 NR y CH 2 CH 2 NR y CH 3 etc.), where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted (as defined herein). As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0064] "Heteroalkylene" refers to a divalent alkyl group (i.e., alkylene) in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkylene" includes straight or branched saturated chains having carbon and heteroatoms. For example, 1, 2, or 3 carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O) 2 - etc., where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of heteroalkylene groups include, for example, -CH 2 OCH 2 -、-CH(CH 3 )OCH 2 -、-CH 2 CH 2 OCH 2 -、-CH 2 CH 2 OCH 2 CH 2 OCH 2 -、-CH 2 SCH 2 -、-CH(CH 3 )SCH 2 -、-CH 2 CH 2 SCH 2 -、-CH 2 CH 2 SCH 2 CH 2 SCH 2 -、-CH 2 S(O) 2 CH 2 -、-CH(CH 3 )S(O) 2 CH 2 -、-CH 2 CH 2 S(O) 2 CH 2 -、-CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 2 -、-CH 2 NR y CH 2 -、-CH(CH 3 )NR y CH 2 -、-CH 2 CH 2 NR y CH 2 -、-CH 2 CH 2 NR y CH 2 CH 2 NR y CH 2- etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0065] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group includes 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. In some cases, heteroaryl includes a 5-10 ring system, a 5-7 ring system or a 5-6 ring system, each independently having 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothiophenyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, , indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidized pyridinyl, 1-oxidized pyrimidinyl, 1-oxidized pyrazinyl, 1-oxidized pyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolyl, quinuclidinyl, isoquinolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolyl, isoquinolyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and imidazo[1,5-a]pyridinyl, wherein the heteroaryl may be attached via either ring of the fused system. Any aromatic ring containing at least one heteroatom, with single or multiple fused rings, is considered a heteroaryl group, regardless of how it is attached to the rest of the molecule (i.e., through any of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0066] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0067] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups and spiral-heterocyclyl groups. The heterocyclyl group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged or spiral, and can contain one or more oxo (=O) or N-oxide (-O - ) moiety. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., bonding may be through a carbon atom or a heteroatom). In addition, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the rest of the molecule. As used herein, a heterocyclyl group has from 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclic) or 3 to 6 ring carbon atoms (i.e., C 3-6heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepine, benzodioxol, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithienyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl The term "heterocyclyl" also includes spiroheterocyclyl, oxazolidinyl, oxirane, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. When there are two substitution positions on the same carbon atom, the term "heterocyclyl" also includes "spiroheterocyclyl". Examples of spiroheterocyclyl rings include, for example, bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, wherein the heterocyclyl may be attached via either ring of the fused system.

[0068] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0069] "Oxime" refers to the group -CR y (=NOH), where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0070] "Closed-shell metals" refer to metal elements in which all of the valence electrons of the metal element are paired. Such metals can be used as cations (or ions) M W+ , where W represents the charge and can be, for example, 1, 2, or 3. The metal cation can be, for example, a monovalent ion (e.g., having a charge of +1), a divalent ion (e.g., having a charge of +2), or a trivalent ion (e.g., having a charge of +3). For example, the ion M W+ It can be sodium ion (Na +), lithium ion (Li + ), zinc ion (Zn 2+ ), calcium ions (Ca 2+ ), manganese ion (Mg 2 + ), aluminum ions (Al 3+ ) etc. In other words, the closed shell metal can be Na, Li, Zn, Ca, Mn, Al, etc.

[0071] "Sulfonyl" refers to the group -S(O) 2 R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0072] "Sulfinyl" refers to the group -S(O)R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

[0073] "Sulfonamide" refers to the group -SO 2 NR y R z and-NR y SO 2 R z Both, of which R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0074] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. In addition, the term "optionally substituted" means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced with a moiety other than hydrogen.

[0075] The term "substituted" refers to any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups, wherein one or more hydrogen atoms are independently replaced by deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h、-NR g C(=O)R h 、-NR g C(=O)NR g R h 、-NR g C(=O)OR h 、-NR g S(=O) 1-2 R h 、-C(=O)R g 、-C(=O)OR g 、-OC(=O)OR g 、-OC(=O)R g 、-(=O)NR g R h 、-OC(=O)NR g R h 、-OR g 、-SR g 、-S(=O)R g 、-S(=O) 2 R g 、-OS(=O) 1-2 R g 、-S(=O) 1-2 OR g 、-NR g S(=O) 1-2 NR g R h , =NSO 2 R g , =NOR g 、-S(=O) 1-2 NR g R h 、-SF 5 、-SCF 3 、-OCF 3 , N-oxide or -Si(R y ) 3 Replace, where each R y In some embodiments, "substituted" also means any of the above groups, wherein one or more hydrogen atoms are replaced by -C(=O)R g 、-C(=O)OR g 、-C(=O)NR g R h 、-CH 2 SO 2 R g 、-CH 2 SO 2 NRg R h Replace. In the above, R g and R h R is the same or different and is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl. In certain embodiments, "substituted" also means any of the above groups, wherein one or more hydrogen atoms are replaced by a bond to amino, cyano, hydroxy, imino, nitro, oxo, thio, halo, alkyl, alkoxy, alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl, or R is the same or different and is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl. g and R h and R i The two of the are taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0076] By defining substituents and infinitely attaching more substituents (e.g., substituted aryl has substituted alkyl, which itself is substituted by substituted aryl groups, which are further substituted by substituted heteroalkyl groups, etc.) polymers or similar indefinite structures obtained are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, the aryl substituted with two other substituted aryls is limited to the aryl substituted by ((substituted aryl) substituted aryl). Similarly, the above definition is not intended to include unallowed substitution patterns (e.g., methyl substituted by 5 fluorine or heteroaryl groups with two adjacent oxygen ring atoms). Such unallowed substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" can describe other chemical groups defined herein.

[0077] Any compound or structure given herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. These forms of the compound may also be referred to as "isotopically enriched analogs." Isotopically labeled compounds have structures described herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as , respectively. 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Various isotopically labeled compounds of the present disclosure, for example, compounds into which radioactive isotopes such as 3 H. 13 C and 14 Such isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy of patients.

[0078] The term "isotopically enriched analogs" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogens are replaced by deuterium, such as hydrogens on carbon atoms. Such compounds exhibit resistance to increased metabolism and are therefore useful for increasing the half-life of any compound when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0079] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes (such as deuterium) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements and / or improvements in therapeutic index. 18 F. 3 H. 11 C-labeled compounds can be used for PET or SPECT or other imaging studies. Isotope-labeled compounds and prodrugs thereof disclosed herein can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents by following the procedures disclosed in the schemes or examples and preparations described below. It should be understood that deuterium herein is considered as a substituent in the compounds described herein.

[0080] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen at its natural abundance isotopic composition. Therefore, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0081] In many cases, the compounds described in this disclosure or prepared by the methods of this disclosure include amino and / or carboxyl groups or groups similar thereto and, therefore, can be prepared as acid and / or base salts.

[0082] As used herein, the term "salt" means an acidic salt formed with an inorganic and / or organic acid, or a basic salt formed with an inorganic and / or organic base. In addition, when a compound contains both a basic moiety (such as, but not limited to, pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid), zwitterions ("inner salts") may be formed and are included in the term "salt" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is not a pharmaceutically acceptable salt. Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthylsulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), etc. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamine, tert-butylamine, choline, and salts with amino acids such as arginine, lysine, etc. In certain embodiments, the salt comprises an amine such as, but not limited to, tert-butylamine, L-lysine, arginine, piperazine, dicyclohexylamine, tromethamine, ethanolamine, diethanolamine, N,N,N',N'-tetramethylethylenediamine, triisobutylamine, 4-methylmorpholine, dibutylamine, tromethamine, dehydroabietylamine, N-methyldicyclohexylamine, diethylamine, diisopropylethylamine, diisopropylamine, imidazole, 1,4-diazabicyclo[2.2.2]octane (DABCO), ammonia, or dibenzylamine. In some embodiments, the salt comprises a cation such as, but not limited to, magnesium, sodium, potassium, calcium, zinc, lithium, cesium, tetramethylammonium, or ammonium. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0083] Acid salts and base salts may be pharmaceutically acceptable salts or physiologically acceptable salts as defined below.

[0084] Also provided are pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein, and methods for making the same. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0085] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of a given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared according to conventional procedures for preparing acid addition salts from base compounds, by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. By way of example only, salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium and magnesium salts. Salts derived from organic bases (e.g., amines) include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkylamines (i.e., NH 2 (alkyl)), dialkylamine (i.e., HN(alkyl) 2 ), trialkylamine (i.e., N(alkyl) 3 ), substituted alkylamines (i.e., NH 2 (substituted alkyl)), di(substituted alkyl)amine (i.e., HN(substituted alkyl) 2 ), tri(substituted alkyl)amine (i.e., N(substituted alkyl) 3 ), alkenylamine (i.e., NH 2 (alkenyl)), dienylamine (i.e., HN(alkenyl) 2 ), trienylamine (i.e., N(enyl) 3 ), substituted alkenylamines (i.e., NH 2 (substituted alkenyl)), di(substituted alkenyl)amine (i.e., HN(substituted alkenyl) 2 ), tri(substituted alkenyl)amine (i.e., N(substituted alkenyl) 3 , mono-, di- or tri-cycloalkylamines (i.e., NH 2 (cycloalkyl), HN(cycloalkyl) 2 、N(cycloalkyl) 3 ), mono-, di-, or tri-arylamines (i.e., NH 2(aryl), HN(aryl) 2 、N(aryl) 3 ) or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0086] The term "hydrate" refers to a complex formed by the combination of a compound described herein and water.

[0087] "Solvate" refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. Thus, the term "solvate" encompasses "hydrates"

[0088] As used herein, the term "solid form" refers to a type of solid state material including amorphous and crystalline forms. The term "crystalline form" refers to polymorphs as well as solvates, hydrates, etc. The term "polymorph" refers to a specific crystal structure with specific physical properties such as X-ray diffraction, melting point, etc.

[0089] Some compounds exist as tautomers. Tautomers are in balance with each other. For example, compounds containing amides can exist in balance with imidic acid tautomers. No matter which tautomer is shown and no matter how the nature of the balance between the tautomers is, it is understood by those of ordinary skill in the art that compounds contain amides and imidic acid tautomers. Therefore, compounds containing amides are understood to include their imidic acid tautomers. Likewise, compounds containing imidic acids are understood to include their amide tautomers.

[0090] The compounds described herein or provided by the methods described herein, or pharmaceutically acceptable salts thereof, may include asymmetric centers and may therefore produce enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as (R)- or (S)-, or as (D)- or (L)- for amino acids, based on absolute stereochemistry. The disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise indicated, the compounds are intended to include E and Z geometric isomers.

[0091] "Stereoisomers" refer to compounds made up of the same atoms bound by the same bonds but with different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0092] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0093] Relative centers of compounds as depicted herein are illustrated with a "thick bond" style (bold or parallel lines), and absolute stereochemistry is depicted with wedge-shaped bonds (bold or parallel lines).

[0094] "Prodrug" refers to any compound that releases an active parent drug according to the structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of compounds described herein are prepared by modifying the functional groups present in the compounds described herein in such a way that the modification can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying the functional groups present in the compounds in such a way that the modification is cleaved into the parent compound in conventional operations or in vivo. Prodrugs include compounds described herein, wherein the hydroxyl, amino, carboxyl or sulfhydryl groups in the compounds described herein are combined with any group that can be cleaved in vivo to regenerate free hydroxyl, amino or sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate derivatives) of hydroxyl functional groups in compounds described herein, amides, guanidines, carbamates (e.g., N, N-dimethylaminocarbonyl), etc. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," ACSSymposium Series Vol. 14; "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is hereby incorporated by reference in its entirety.

[0095] The phrase "substantially as shown" when applied to a DSC thermogram is meant to include variations of ± 3°C, and when applied to a TGA is meant to include variations of ± 2% weight loss.

[0096] For the compounds described herein, radicals and substituents may be chosen based on the allowed valences of atoms and substituents such that selection and substitution results in stable compounds, e.g., which do not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, or the like.

[0097] Where a range of values ​​is provided, it is understood that unless the context clearly indicates otherwise, each intervening value between the upper and lower limits of the range to one-tenth of the unit of the lower limit and any other stated or intermediate values ​​in the stated range are included in the disclosure. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are also included in the disclosure, subject to any specific exclusions in the stated range. When the stated range includes one or two limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0098] For the recitation of numerical ranges herein, each intervening number with the same degree of precision is expressly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range of 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated.

[0099] It should be understood that, for the sake of clarity, some features of the disclosure described in the context of a separate embodiment may also be provided in combination in a single embodiment. On the contrary, for the sake of brevity, the various features of the disclosure described in the context of a single embodiment may also be provided individually or in any suitable sub-combination. All combinations belonging to the embodiments of the present disclosure are specifically encompassed by the disclosure and disclosed herein, to the extent that each and every combination is individually and clearly disclosed, i.e. such combinations include subject matter, i.e., compounds such as stable compounds (i.e., compounds that can be prepared, separated, characterized and tested for biological activity). In addition, all sub-combinations of various embodiments and elements thereof (e.g., elements of chemical groups listed in the embodiments describing such variables) are also specifically encompassed by the disclosure and disclosed herein, as each and every such sub-combination is individually and clearly disclosed herein.

[0100] 2. Methods

[0101] The methods described herein provide improved manufacturability for compounds useful for treating various diseases. The methods described herein are performed using appropriate reaction conditions and optionally one or more protecting groups as desired.

[0102] The term "reaction conditions" is intended to refer to the physical and / or environmental conditions for carrying out a chemical reaction. Examples of reaction conditions include, but are not limited to, one or more of the following: temperature of reaction, solvent, pH, pressure, reaction time, the molar ratio of reactants, the presence of alkali or acid, one or more protecting groups, or catalysts, radiation, etc. Reaction conditions can be named according to the specific chemical reaction using these conditions, such as coupling conditions, hydrogenation conditions, acylation conditions, reduction conditions, etc. The reaction conditions of most reactions are usually known to those skilled in the art, or can be easily obtained from the literature. Exemplary reaction conditions sufficient to carry out the chemical transformation provided herein can be found in the full text, particularly in the following embodiments. It is also contemplated that reaction conditions may include reagents other than those listed in the specific reaction.

[0103] The term "protecting group" refers to those groups intended to protect a given atom or functional group from undesirable reactions during a synthetic procedure, and includes, but is not limited to, silyl ethers, such as 2-(trimethylsilyl)ethoxymethyl (SEM) ether, or alkoxymethyl ethers, such as methoxymethyl (MOM) ether, tert-butoxymethyl (BUM) ether, benzyloxymethyl (BOM) ether, or methoxyethoxymethyl (MEM) ether. Additional protecting groups include tert-butyl, acetyl, benzyl, benzyloxycarbonyl (benzyloxycarbonyl, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), trifluoroacetyl, and the like. Certain protecting groups may be preferred over other protecting groups because they are convenient or relatively easy to remove, or because of their stereospecific effects in subsequent steps of the process. Additional suitable amino protecting groups are taught in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, 5th ed., Wiley, New York, 2014, and references cited therein, all of which are incorporated by reference in their entirety.

[0104] The term "contacting" or "contact" refers to the process of bringing at least two different substances into contact so that they can interact with each other, such as in a non-covalent or covalent binding interaction or binding reaction. However, it should be understood that the resulting complex or reaction product can be directly produced by the interaction or reaction between the added reagents, or by an intermediate product of one or more added reagents or moieties, which can be produced in the contact mixture.

[0105] The term "leaving group" refers to an atom (or group of atoms) with electron-withdrawing ability that can be replaced by a stable species while it serves as a bonding electron. Examples of suitable leaving groups include halides (e.g., Br, Cl, I), sulfonates (e.g., triflate, mesylate, tosylate, and brosylate), and nitrophenols.

[0106] 3. Abbreviations

[0107] Abbreviation meaning

[0108] ACN or MeCN Acetonitrile

[0109] ℃ Celsius

[0110] DBDMH 1,3-Dibromo-5,5-dimethylhydantoin

[0111] DCHA Dicyclohexylamine

[0112] DCM Dichloromethane

[0113] DMF Dimethylformamide

[0114] DIPEA Diisopropylethylamine

[0115] DSC Differential Scanning Calorimetry

[0116] aq. water-based

[0117] Eq equivalent

[0118] g

[0119] h hour

[0120] M Moore

[0121] Me Methyl (CH 3 )

[0122] MHz Megahertz

[0123] MicroED Microcrystal Electron Diffraction

[0124] NBS N-Bromosuccinimide

[0125] MTBE Methyl tert-butyl ether

[0126] nm nanometer

[0127] μM micromolar

[0128] RT Room temperature

[0129] TBA tert-butylamine

[0130] TGA Thermogravimetric Analysis

[0131] THF Tetrahydrofuran

[0132] TMA Tromethamine

[0133] XRPD X-ray powder diffraction

[0134] 4. Methods

[0135] Provided herein is a method for preparing a compound of formula I-1 according to Scheme 1:

[0136]

[0137] or its stereoisomers or mixtures of stereoisomers or their respective salts:

[0138] in

[0139] x is 1 or 2;

[0140] p is 0, 1, 2, 3, 4, 5, 6 or 7;

[0141] t is 0, 1, 2, 3, 4, or 5;

[0142] z is 0 or 1, provided that when z is 0 and X 1 When it is 0, R 3 Not an alkyl group; X 1 O, NR 9 or key;

[0143] R 1 For hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl or heterocyclyl, each of which except hydrogen is optionally substituted by one or more halo, oxo, acetyl, amino, hydroxyl, or C 1-12 Alkyl or R 1 and R 5 together form a heterocyclyl ring;

[0144] R 3 For hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which except hydrogen is optionally replaced by one or more R 11 replace;

[0145] R 4 and R 5 Each of which is independently hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl or C2-12 alkynyl, each of which except hydrogen is independently optionally substituted with one or more halo, oxo, acetyl, amino or hydroxy;

[0146] or R 3 and R 4 join together with the atoms to which they are attached to form C 3-10 Cycloalkyl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more R 11 replace;

[0147] or R 4 and R 5 join together with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R 11 replace;

[0148] R 6 , R 7 and R 8 Each of which is independently hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 、-C(O)OR 20 、-C(O)NR 20 R 21 、-S(O) 1-2 R 20 or -S(O) 1-2 NR 20 , where R 6 , R 7 and R 8 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group of 12 replace; or

[0149] R 6 , R 7 and R 8 The two of them are taken together with the atoms to which they are attached to form C which is independently optionally substituted with one or more halo, oxo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group;

[0150] R 9 For hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10Cycloalkyl or heterocyclic groups, each of which, except hydrogen, is optionally substituted by one or more halo, oxo, acetyl, amino, hydroxyl or C 1-12 Alkyl substitution;

[0151] Each R 10 are independently halo, C 1-12 Alkyl or C 1-12 Haloalkyl;

[0152] y is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0153] Each R 11 are independently halo, cyano, nitro, oxo, -OR 6 、-SR 6 、-SF 5 、-NR 6 R 7 , C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 6 、-C(O)OR 6 、-OC(O)OR 6 、-OC(O)R 6 、-C(O)NR 6 R 7 、-OC(O)NR 6 R 7 、-NR 6 C(O)NR 7 R 8 、-S(O) 1-2 R 6 、-S(O) 1-2 NR 6 、-NR 6 S(O) 1-2 R 7 、-NR 6 S(O) 1-2 NR 7 R 8 、-NR 6 C(O)R 7 or –NR 6 C(O)OR 7 , where R 11 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group of 12 replace;

[0154] Each R 12are independently halo, cyano, nitro, oxo, -OR 30 、-SR 30 、-SF 5 、-NR 30 R 31 , C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 30 、-C(O)OR 30 、-OC(O)OR 30 、-OC(O)R 30 、-C(O)NR 30 R 31 、-OC(O)NR 30 R 31 、-NR 30 C(O)NR 30 R 31 、-S(O) 1-2 R 30 、-S(O) 1-2 NR 30 、-NR 30 S(O) 1-2 R 31 、-NR 30 S(O) 1-2 NR 30 R 31 、-NR 30 C(O)R 31 or -NR 30 C(=O)OR 31 , where R 12 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 Alkyl substitution;

[0155] Each R 20 and R 21 is independently hydrogen or independently optionally substituted with one or more oxo, halo, hydroxyl or amino groups. 1-12 Alkyl; or

[0156] R 20 and R 21 Together with the atoms to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group; and

[0157] Each R 30 and R 31 is independently hydrogen or independently optionally substituted with one or more oxo, halo, hydroxyl or amino groups. 1-12 Alkyl; or

[0158] R 30 and R 31 Together with the atoms to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 Alkyl substituted heterocyclic group.

[0159] Solution 1

[0160]

[0161] in:

[0162] x is 1 or 2;

[0163] p is 0, 1, 2, 3, 4, 5, 6 or 7;

[0164] t is 0, 1, 2, 3, 4, or 5;

[0165] z is 0 or 1, provided that when z is 0 and X 1 When it is 0, R 3 Not an alkyl group;

[0166] X 1 O, NR 9 or key;

[0167] X 2 O or NR 53 ;

[0168] R 1 For hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl or heterocyclyl, each of which except hydrogen is optionally substituted by one or more halo, oxo, acetyl, amino, hydroxyl, or C 1-12 Alkyl or R 1 and R 5 together form a heterocyclyl ring;

[0169] R 3 For hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which except hydrogen is optionally replaced by one or more R11 replace;

[0170] R 4 and R 5 Each of which is independently hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 alkynyl, each of which except hydrogen is independently optionally substituted with one or more halo, oxo, acetyl, amino or hydroxy;

[0171] or R 3 and R 4 join together with the atoms to which they are attached to form C 3-10 Cycloalkyl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more R 11 replace;

[0172] or R 4 and R 5 join together with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R 11 replace;

[0173] R 6 , R 7 and R 8 Each of which is independently hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 20 、-C(O)OR 20 、-C(O)NR 20 R 21 、-S(O) 1-2 R 20 or -S(O) 1-2 NR 20 , where R 6 , R 7 and R 8 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group of 12 replace; or

[0174] R 6 , R 7 and R 8 The two of them are taken together with the atoms to which they are attached to form C which is independently optionally substituted with one or more halo, oxo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group;

[0175] R 9 For hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl or heterocyclic groups, each of which, except hydrogen, is optionally substituted by one or more halo, oxo, acetyl, amino, hydroxyl or C 1-12 Alkyl substitution;

[0176] Each R 10 are independently halo, C 1-12 Alkyl or C 1-12 Haloalkyl;

[0177] y is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0178] Each R 11 are independently halo, cyano, nitro, oxo, -OR 6 、-SR 6 、-SF 5 、-NR 6 R 7 , C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 6 、-C(O)OR 6 、-OC(O)OR 6 、-OC(O)R 6 、-C(O)NR 6 R 7 、-OC(O)NR 6 R 7 、-NR 6 C(O)NR 7 R 8 、-S(O) 1-2 R 6 、-S(O) 1-2 NR 6 、-NR 6 S(O) 1-2 R 7 、-NR 6 S(O) 1-2 NR 7 R 8 、-NR 6 C(O)R 7 or –NR 6 C(O)OR 7 , where R 11Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group of 12 replace;

[0179] Each R 12 are independently halo, cyano, nitro, oxo, -OR 30 、-SR 30 、-SF 5 、-NR 30 R 31 , C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 30 、-C(O)OR 30 、-OC(O)OR 30 、-OC(O)R 30 、-C(O)NR 30 R 31 、-OC(O)NR 30 R 31 、-NR 30 C(O)NR 30 R 31 、-S(O) 1-2 R 30 、-S(O) 1-2 NR 30 、-NR 30 S(O) 1-2 R 31 、-NR 30 S(O) 1-2 NR 30 R 31 、-NR 30 C(O)R 31 or -NR 30 C(=O)OR 31 , where R 12 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 Alkyl substitution;

[0180] Each R 20 and R 21 is independently hydrogen or independently optionally substituted with one or more oxo, halo, hydroxyl or amino groups. 1-12 Alkyl; or

[0181] R 20 and R 21Together with the atoms to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group;

[0182] Each R 30 and R 31 is independently hydrogen or independently optionally substituted with one or more oxo, halo, hydroxyl or amino groups. 1-12 Alkyl; or

[0183] R 30 and R 31 Together with the atoms to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group;

[0184] R 51 C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution;

[0185] R 53 For hydrogen, C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution; or

[0186] R 51 and R 53 Together with the nitrogen atom to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group; and

[0187] R 73 is hydrogen, a protecting group or

[0188] As shown in Scheme 1 above, in some embodiments, a compound of formula XIII or a salt thereof is converted into a carboxylic acid VI or a salt thereof. Carboxylic acid VI or a salt thereof reacts with a hydrazide or a salt thereof of formula VIII under condensation conditions to provide a compound of formula IX or a salt thereof. The compound of formula IX or a salt thereof is then subjected to an intramolecular ring closure reaction to provide a compound of formula XI or a salt thereof. Finally, the compound of formula XI or a salt thereof is further condensed with a compound of formula XII or a salt thereof to form a product compound of formula I-1. These methods are described in more detail below.

[0189] Solution 2

[0190]

[0191] Where p, t and R 11 As defined herein;

[0192] n is 0 or 1;

[0193] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0194] X 2 O or NR 53 ;

[0195] R 51 C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution;

[0196] R 52 C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution;

[0197] R 53 C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution; or

[0198] R 51 and R 53Together with the nitrogen atom to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group; and

[0199] R 55 is selected from -Cl, -O-pyridyl, 1-imidazolyl, -N(alkyl)(alkyl), 1-pyridonyl and 1-benzotriazolyl.

[0200] In some embodiments, at least one of the above R 11 OR 6 In some embodiments, at least one R 11 OCF 3 .

[0201] In some embodiments, R 51 For hydrogen, C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 In some embodiments, R 51 C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 In some embodiments, R 51 In some embodiments, R 51 Not hydrogen.

[0202] In some embodiments, X 2 NR 53 , and R 51 and R 53 Together with the nitrogen atom to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 In some embodiments, X 2 -R 51 N-morpholino.

[0203] Referring to Scheme 2 above, in some embodiments, the compound of Formula VIa or a salt thereof is prepared from the compound of Formula XIII or a salt thereof according to a series of steps. The compound of Formula VIa or a salt thereof is an intermediate for preparing the compound of Formula I-1.

[0204] In some embodiments, a method for providing a compound of formula II or its stereoisomer or a mixture of stereoisomers or its salt is provided herein. The method includes contacting a compound of formula XIII or its stereoisomer or a mixture of stereoisomers or its salt with a reducing agent under conditions suitable for providing a compound of formula II or its stereoisomer or a mixture of stereoisomers or its salt. In some embodiments, the conditions include a temperature below 0°C, such as about -25°C to about -55°C, or about -35°C to about -45°C. In some embodiments, the reducing agent is a chemical reducing agent. In some embodiments, the chemical reducing agent is selected from the group consisting of molecular hydrogen, elemental metals, metal hydrides, transition metal complexes of metals with reduced valence states, boranes, borohydrides, hydrazines, thiols, phosphites, etc. In some embodiments, the chemical reducing agent is sodium borohydride or lithium aluminum hydride.

[0205] In some embodiments, the compound of formula II is provided as a racemic mixture. In some embodiments, an enantiomer of a compound of formula II is provided herein. In some embodiments, the compound of formula II has formula IIa:

[0206]

[0207] wherein the substituents are as defined above for Scheme 2.

[0208] In some embodiments, the compound of Formula II has Formula IIa-1:

[0209]

[0210] wherein the substituents are as defined above for Scheme 2.

[0211] In some embodiments, the compound of Formula II or IIa-1 has Formula II-1:

[0212]

[0213] In some embodiments, the compound is not ethyl 3-[(methylthio)thiomethoxy]cyclobutanecarboxylate. In some embodiments, the compound is not cis-ethyl 3-[(methylthio)thiomethoxy]cyclobutanecarboxylate.

[0214] In some embodiments, a method for providing a compound of formula III, or a stereoisomer or a mixture of stereoisomers, or a salt thereof, is provided herein. The method comprises contacting a compound of formula II, IIa-1, II-1, or a stereoisomer or a mixture of stereoisomers, or a salt thereof, with an activator under reaction conditions sufficient to provide a compound of formula III, or a stereoisomer or a mixture of stereoisomers, or a salt thereof.

[0215] Any suitable activating agent may be used. In some embodiments, the activating agent is selected from the group consisting of thiophosgene, 1,1'-thiocarbonyldiimidazole, thiram, 1,1'-thiocarbonyldi-2(1H)-pyridone, 1,1'-(thiocarbonyl)bis-1H-benzotriazole, and di-2-pyridylthiocarbonate. In some embodiments, the activating agent is 1,1'-thiocarbonyldiimidazole.

[0216] In some embodiments, the contact of the compound of formula II, IIa-1, II-1, or its stereoisomer or mixture of stereoisomers, or its respective salt with the activator includes a) optionally a reaction temperature of about 0°C to about 60°C; and / or b) optionally a reaction duration of about 3 hours to about 48 hours. In some embodiments, the reaction temperature is about 15°C to about 30°C. In some embodiments, the reaction time is about 3 hours to about 4 hours. In some embodiments, the reaction can be carried out in any suitable solvent. In some embodiments, the solvent can be diethyl ether, methyl tert-butyl ether, etc.

[0217] In some embodiments, the activating agent is carbon disulfide. In some embodiments, the contacting of the compound of Formula II, IIa-1, II-1, or its stereoisomer or mixture of stereoisomers, or its respective salt with the activating agent comprises a) optionally a solvent of DMSO, b) optionally contacting the compound of Formula II, IIa-1, II-1, or its stereoisomer or mixture of stereoisomers, or its respective salt with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at a temperature of about 0°C to about 50°C, such as about 10°C to about 15°C, c) further contacting the mixture with carbon disulfide at a temperature of about 0°C to about 50°C, such as about 10°C to about 15°C, d) optionally further contacting the mixture with methyl iodide at a temperature of about 0°C to about 50°C, such as about 10°C to about 30°C.

[0218] In some embodiments, provided herein is a method for providing a compound of formula V, or a stereoisomer or mixture of stereoisomers, or a salt thereof. The method comprises contacting a compound of formula III, or a stereoisomer or mixture of stereoisomers, or a salt thereof, with a compound of formula IV under reaction conditions sufficient to provide a compound of formula V, or a stereoisomer or mixture of stereoisomers, or a salt thereof.

[0219] In some embodiments, the compound of Formula IV has Formula IV-1:

[0220]

[0221] In some embodiments, provided herein is a compound of Formula V, wherein the substituents are as defined above with respect to Scheme 2.

[0222] In some embodiments, provided herein are compounds of Formula V as racemic mixtures. In some embodiments, provided herein are enantiomers of compounds of Formula V. In some embodiments, compounds of Formula V have Formula V-1:

[0223]

[0224] wherein the substituents are as defined above.

[0225] In some embodiments, the compound of Formula V is of Formula V-2:

[0226]

[0227] wherein the substituents are as defined above.

[0228] In some embodiments, a method of preparing a compound of formula V-2 is provided:

[0229]

[0230] or a salt thereof, which comprises making a compound of formula IIa-1:

[0231]

[0232] contacting with an activating agent and then with a compound of formula IV:

[0233]

[0234] contacting under reaction conditions sufficient to provide a compound of formula V-2, wherein:

[0235] n is 0 or 1;

[0236] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0237] X 2 O or NR 53 ;

[0238] R 51 For hydrogen, C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution;

[0239] R 52 For hydrogen, C 1-12 alkyl or silyl, wherein the C 1-12C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substituted; and

[0240] R 53 For hydrogen, C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution; or

[0241] R 51 and R 53 Together with the nitrogen atom to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group;

[0242] Provided that the compound is not cis-ethyl 3-[(methylthio)thiomethoxy]cyclobutanecarboxylate.

[0243] In some embodiments, X 2 is O.

[0244] In some embodiments, X 2 NR 53 .

[0245] In some embodiments, X 2 NR 53 , and R 51 and R 53 Together with the nitrogen atom to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 Alkyl substituted heterocyclic group.

[0246] In some embodiments, R 51 and R 53 Together with the nitrogen atom it joins to form an α-morpholino.

[0247] In some embodiments, R 51 C 1-12 alkyl.

[0248] In some embodiments, X 2 is O and R 51 C 1-12 alkyl.

[0249] In some embodiments, R 52C 1-12 alkyl.

[0250] In some embodiments, n is 1. In some embodiments, n is 0.

[0251] In some embodiments, q is 1.

[0252] In some embodiments, R 52 is substituted or unsubstituted C 4 -C 12 alkyl.

[0253] In some embodiments, a compound selected from the group consisting of:

[0254] or their respective salts.

[0255] In some embodiments, the compound of Formula V or the compound of Formula V-1 is Formula V-1a or a salt thereof:

[0256]

[0257] In some embodiments, the compound of Formula V or the compound of Formula V-1 is Formula V-1b or a salt thereof:

[0258]

[0259] In some embodiments, the compound of Formula V or the compound of Formula V-1 is Formula V-1b or a salt thereof:

[0260]

[0261] In some embodiments, the compound of Formula V or the compound of Formula V-1 is Formula V-1b or a salt thereof:

[0262]

[0263] In some embodiments, contacting with a compound of formula IV includes contacting under reaction conditions including: a) optionally a reaction temperature of about 20°C to about 80°C; and / or b) optionally a reaction duration of about 1 hour to about 48 hours. In some embodiments, the reaction temperature is about 40°C to about 45°C. In some embodiments, the reaction time is about 1 hour to about 18 hours. In some embodiments, the reaction can be carried out in any suitable solvent. In some embodiments, the solvent can be diethyl ether, methyl tert-butyl ether, etc.

[0264] Thus, as described above, there is provided a method for preparing a compound of formula V, V-1 or V-2. The method comprises contacting a compound of formula II, IIa-1, II-1, or a stereoisomer or mixture of stereoisomers, or a salt thereof, with an activating agent, and then contacting with a compound of formula IV or IV-1 under reaction conditions sufficient to provide a compound of formula V, V-1 or V-2, wherein the substituents and parameters are according to those defined above with respect to Scheme 2.

[0265] In some embodiments, provided herein is a method for preparing a compound of formula V-1a. The method comprises contacting a compound of formula II-1 with an activating agent and then with a compound of formula IV-1 under reaction conditions sufficient to provide a compound of formula V-1a, wherein the substituents and parameters are as defined above with respect to Scheme 2.

[0266] In some embodiments, for the methods described herein with respect to any of the above methods, R 51 It is a branched chain alkyl.

[0267] In some embodiments, for the methods described herein with respect to any of the above methods, t is 0, and X 2 is O.

[0268] In some embodiments, for the methods described herein with respect to any of the above methods, at least one R 11 OR 6 Therefore, the compound of formula VI can be described as formula VIa-1:

[0269]

[0270] wherein the substituents are as defined above.

[0271] In some embodiments, a method for providing a compound of formula VIa-1 or a stereoisomer or a mixture of stereoisomers or a salt thereof is provided herein. The method comprises contacting a compound of formula V, V-1, V-2 or V1-a or a mixture of stereoisomers or a salt thereof with a brominating agent and a fluoride source under reaction conditions sufficient to provide a compound of formula VIa or VIa-1.

[0272] In some embodiments, the compound of Formula V, V-1, V-2, or V1-a, or its respective stereoisomer or mixture of stereoisomers, or its respective salt, has been prepared using any of the methods described above.

[0273] In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R6 is trifluoromethyl (-CF 3 In some embodiments, provided herein is a (1s, 3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid or a compound of Formula VIa-1a or a salt thereof:

[0274]

[0275] In some embodiments, provided herein is a method for providing a compound of Formula VIa-1a. In some embodiments, the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).

[0276] In some embodiments, the fluoride source is hydrogen fluoride (HF).In some embodiments, the fluoride source is HF-pyridine.

[0277] In some embodiments, the contact with the brominating agent and the fluoride source includes introducing the compound of formula V, V-1, V-2 or V1-a into a solution of the brominating agent and the fluoride source at a temperature of less than about -25°C. In some embodiments, the contact further includes aging the resulting reaction mixture at room temperature. In some embodiments, the reaction can be carried out in any suitable solvent. In some embodiments, the solvent can be DCM or the like.

[0278] In some embodiments, provided herein is a salt of a compound of Formula VIa, such as a salt of a compound of Formula VIa-1a, wherein the salt comprises an amine selected from the group consisting of tert-butylamine, L-lysine, arginine, piperazine, dicyclohexylamine, tromethamine, ethanolamine, diethanolamine, N,N,N',N'-tetramethylethylenediamine, triisobutylamine, 4-methylmorpholine, dibutylamine, tromethamine, dehydroabietylamine, N-methyldicyclohexylamine, diethylamine, diisopropylethylamine, diisopropylamine, imidazole, 1,4-diazabicyclo[2.2.2]octane (DABCO), ammonia and dibenzylamine, or a cation selected from magnesium, sodium, potassium, calcium, zinc, lithium, cesium, tetramethylammonium and ammonium.

[0279] In some embodiments, provided herein is a method for preparing a salt of a compound of Formula VIa-1a:

[0280]

[0281] The method comprises making a compound of formula V-2:

[0282]

[0283] or a salt thereof with an electrophilic bromine source and a fluorinating agent to provide a compound of Formula VIa-1a; and

[0284] contacting a compound of formula VIa-1a with an amine selected from the group consisting of tert-butylamine, L-lysine, arginine, piperazine, dicyclohexylamine, tromethamine, ethanolamine, diethanolamine, N,N,N',N'-tetramethylethylenediamine, triisobutylamine, 4-methylmorpholine, dibutylamine, tromethamine, dehydroabietylamine, N-methyldicyclohexylamine, diethylamine, diisopropylethylamine, diisopropylamine, imidazole, 1,4-diazabicyclo[2.2.2]octane (DABCO), ammonia and dibenzylamine, or a base containing a cation selected from magnesium, sodium, potassium, calcium, zinc, lithium, cesium, tetramethylammonium and ammonium under reaction conditions sufficient to provide a compound of formula V-2,

[0285] in:

[0286] n is 0 or 1;

[0287] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0288] X 2 O or NR 53 ;

[0289] R 51 For hydrogen, C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution;

[0290] R 52 For hydrogen, C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substituted; and

[0291] R 53 For hydrogen, C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution; or

[0292] R 51 and R 53 Together with the nitrogen atom to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group;

[0293] The condition is that when R 51 C 1-12 alkyl or silyl, or when X 2 NR 53 When the method comprises a hydrolysis step prior to salt formation.

[0294] In some embodiments, the electrophilic bromine source includes DBDMH (1,3-dibromo-5,5-dimethylhydantoin) or NBS (n-bromosuccinimide).

[0295] In some embodiments, the fluorinating agent is HF . Pyridine.

[0296] In some embodiments, the hydrolysis step comprises a strong acid (ie, HCl) at an elevated temperature.

[0297] In some embodiments, X 2 is O.

[0298] In some embodiments, X 2 NR 53 .

[0299] In some embodiments, provided herein is a method for preparing a salt of a compound of Formula VIa-1a:

[0300]

[0301] The method comprises making a compound of formula V-2:

[0302]

[0303] or a salt thereof is contacted with an electrophilic bromine source and a fluorinating agent, followed by hydrolysis to form VIa-1a; and

[0304] Contacting VIa-1a with an amine selected from the group consisting of tert-butylamine, L-lysine, arginine, piperazine, dicyclohexylamine, tromethamine, ethanolamine, diethanolamine, N,N,N',N'-tetramethylethylenediamine, triisobutylamine, 4-methylmorpholine, dibutylamine, tromethamine, dehydroabietylamine, N-methyldicyclohexylamine, diethylamine, diisopropylethylamine, diisopropylamine, imidazole, 1,4-diazabicyclo[2.2.2]octane (DABCO), ammonia and dibenzylamine, or a base containing a cation selected from magnesium, sodium, potassium, calcium, zinc, lithium, cesium, tetramethylammonium and ammonium under reaction conditions sufficient to provide a salt of VIa-1a:

[0305] n is 0 or 1;

[0306] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0307] X 2 NR 53 ;

[0308] R 51 For hydrogen, C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution;

[0309] R 52 For hydrogen, C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substituted; and

[0310] R 53 For hydrogen, C 1-12 alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution; or

[0311] R 51 and R 53 Together with the nitrogen atom to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group;

[0312] Provided that the compound is not cis-ethyl 3-[(methylthio)thiomethoxy]cyclobutanecarboxylate.

[0313] In some embodiments, the cation-containing base is Mg(OH) 2 or NaOH.

[0314] In some embodiments, the salt of the compound of Formula VIa or VIa-1a is an amine salt (e.g., a salt comprising an amine (ie, nitrogen) as described herein). In some embodiments, provided herein is a compound of Formula VIIa:

[0315]

[0316] or a stereoisomer or a mixture of stereoisomers thereof, wherein:

[0317] t is 0, 1, 2, 3, or 4;

[0318] Each R 46 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-20 Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein R 46 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group of 12 replace; and

[0319] The other substituents are as defined above for Scheme 2.

[0320] In some embodiments, p is 1, at least one R 11 is a halogen, and R 46 None of them is H.

[0321] In some embodiments, p is 1, at least one R 11 is a halogen, and R 46 One of them is H.

[0322] In some embodiments, p is 1, at least one R 11 is a halogen, and R 46 Both of them are H.

[0323] In some embodiments, N(R 46 ) 3 The moiety is selected from the group consisting of tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine and dibenzylamine.

[0324] In some embodiments, provided herein is a composition comprising a compound of formula VIIa as a racemic mixture. In some embodiments, provided herein is a composition comprising a compound of formula VIIa as a single diastereomer. In some embodiments, provided herein is a composition comprising a trans isomer (e.g., >90%de, or >95%de, or >98%de, or greater than 99%de) of a compound of formula VIIa. In some embodiments, provided herein is a composition comprising a cis isomer (e.g., >90%de, or >95%de, or >98%de, or greater than 99%de) of a compound of formula VIIa.

[0325] In some embodiments, the compound of Formula VIIa is Formula VII-1:

[0326]

[0327] wherein the substituents are as defined above.

[0328] In some embodiments, the compound of Formula VII-1 is Formula VII-2a:

[0329]

[0330] wherein the substituents are as defined above.

[0331] In some embodiments, provided herein is a method for preparing a compound of formula VII-2a:

[0332]

[0333] The method comprises treating a compound of formula VIa-1a:

[0334]

[0335] With an amine of formula VIb:

[0336]

[0337] contacting under reaction conditions sufficient to provide a compound of Formula Vila,

[0338] Where N(R 46 ) 3 The moiety is selected from the group consisting of tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine and dibenzylamine.

[0339] In some embodiments, provided herein is the tert-butylamine salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid, or a compound having the structure of Formula VII-1a:

[0340]

[0341] In some embodiments, provided herein is a dicyclohexylamine salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid, or a compound having the structure of Formula VII-1b:

[0342]

[0343] In some embodiments, provided herein is an L-arginine salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid, or a compound having the structure of Formula VII-1c:

[0344]

[0345] In some embodiments, provided herein is the tromethamine salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid, or a compound having the structure of Formula VII-1d:

[0346]

[0347] In some embodiments, the salt of the compound of formula VIa is a metal salt. In some embodiments, a compound of formula VIIb is provided herein:

[0348]

[0349] or a stereoisomer or a mixture of stereoisomers thereof, wherein:

[0350] t is 0, 1, 2, 3, or 4;

[0351] w is 1, 2, or 3;

[0352] v is 1 or 2;

[0353] j is wv and is 0, 1, or 2;

[0354] M w+ It is a cation;

[0355] Each R 47 C 1-6 Alkyl; and

[0356] The other substituents and parameters are as defined above for Scheme 2.

[0357] Thus, the compound of Formula VIIb is a metal salt of the compound of Formula VIa, and includes anionic forms of the compound of Formula VIa, such as a monovalent anion of the compound of Formula VIa. In some embodiments, j is 0.

[0358] In some embodiments, the compound of Formula VIIb may further comprise another anion. In other words, j may be non-zero. For example, the compound of Formula VIIb may further comprise a carboxylate anion. In some embodiments, R 47 is a substituted or unsubstituted alkyl. 47 In some embodiments, j is 0 or 1.

[0359] In some embodiments, M is a closed shell metal. In some embodiments, M is selected from the group consisting of Mg, Ca, Zn, Na, and Li. In some embodiments, the anion of Formula VIa and the additional anion together balance the charge of the metal ion.

[0360] In some embodiments, provided herein are compounds of Formula VIIb as racemic mixtures. In some embodiments, provided herein are enantiomers of compounds of Formula VIIb. In some embodiments, compounds of Formula VIIb are of Formula VIIb-1:

[0361]

[0362] wherein the substituents are as defined above.

[0363] In some embodiments, the compound of Formula VIIb-1 is Formula VII-2b:

[0364]

[0365] wherein the substituents are as defined above.

[0366] In some embodiments, with respect to the salts of compounds of Formula VIa, such as compounds of Formula VIIa or VIIb, at least one R 11 OR 6 .

[0367] Solution 3

[0368]

[0369] Referring to Scheme 3, in some embodiments, there is provided a method for preparing a compound of Formula IX or its stereoisomer or mixture of stereoisomers from a compound of Formula VI or its stereoisomer or mixture of stereoisomers according to a series of steps, wherein:

[0370] R 1 For hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl or trialkylsilyl, each of which except hydrogen is optionally substituted by one or more halo, oxo, acetyl, amino, hydroxyl or C 1-12 Alkyl substituted, or R 1 and R 5 together form a heterocyclyl ring; and

[0371] R 73 is hydrogen, a protecting group or part of; and

[0372] The other substituents and parameters are as defined above for Scheme 2.

[0373] In some embodiments, j is 0.

[0374] In some embodiments, the formula The part is

[0375] In some embodiments, provided herein is a method for preparing a compound of formula VIIa or a stereoisomer or a mixture of stereoisomers thereof, the method comprising reacting a compound of formula VIa or a stereoisomer or a mixture of stereoisomers thereof with an amine of formula VIb:

[0376]

[0377] The contacting is under reaction conditions sufficient to provide a compound of Formula Vila.

[0378] In some embodiments, contacting comprises contacting the compound of Formula VIa with the amine of Formula VIb in a stoichiometric ratio of about 1:0.8 to about 1:1.3. In some embodiments, contacting comprises contacting the compound of Formula VIa with a slight excess of the amine of Formula VIb in a stoichiometric ratio of about 1:1.05 to about 1:1.3.

[0379] In some embodiments, a method for preparing a compound of formula IX or a mixture of its stereoisomers or stereoisomers or their respective solvates from a compound of formula VIIa or its stereoisomers or mixture of stereoisomers is provided herein. In some embodiments, the method includes purifying a compound of formula VIIa or its stereoisomers or mixture of stereoisomers to sufficient purity (e.g., >95%, or >96%, or >97%, or >98%, or >99%, or between 95%-100%). In some embodiments, the method includes contacting the purified compound of formula VIIa or its stereoisomers or mixture of stereoisomers with an acid under reaction conditions sufficient to provide a compound of formula VI or its stereoisomers or mixture of stereoisomers; and contacting a compound of formula VI or its stereoisomers or mixture of stereoisomers with a compound of VIII under conditions sufficient to provide a compound of formula IX or its stereoisomers or mixture of stereoisomers.

[0380] Therefore, the compound of formula VI is generated by the compound of formula VIIa before reacting with the compound of formula VIII. In some embodiments, the generation of the compound of formula VI is carried out in situ before the compound of formula VIII is introduced. In some embodiments, the generation step ensures that the compound of formula VI is provided with sufficient purity before the subsequent reaction. As discussed above, the compound of formula VI is usually present in oil form, which may make it difficult to purify, thereby converting into low yield or low purity in subsequent conversions. Here, using the compound of formula VIIa as a starting material and then regenerating the compound of formula VI when needed alleviates the above-mentioned purity challenge. In some embodiments, the purity of the compound of formula VIIa is about 95%. In some embodiments, the purity of the compound of formula VIIa is about 98%. In some embodiments, the purity of the compound of formula VIIa is about 99%. In some embodiments, the purity of the compound of formula VIIa is about 99.5%. In some embodiments, the purity of the compound of formula VIIa is about 99.9%.

[0381] In some embodiments, the acid is a mineral acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the reaction conditions for contacting the purified compound of Formula Vila or its stereoisomer or mixture of stereoisomers with the acid include contacting at a temperature of about 20-25°C.

[0382] In some embodiments, the reaction conditions for providing a compound of formula IX or a stereoisomer thereof or a mixture of stereoisomers include introducing a compound of formula VIII into a mixture of carbonyl diimidazole and a regenerated compound of formula VI. In some embodiments, the reaction conditions include reacting at a temperature of about -10°C to about 60°C. In some embodiments, the reaction conditions include reacting at a temperature of about 0°C to about 30°C. The reaction may be carried out in any suitable solvent. In some embodiments, the reaction conditions include reacting in DMF. In some embodiments, the reaction conditions include a reaction time of about 10 minutes to about 18 hours. In some embodiments, the reaction time is about 0.5 hours to about 4 hours.

[0383] In some embodiments, the step of producing a compound of Formula VI, or a stereoisomer or mixture of stereoisomers thereof, is omitted such that the process instead involves contacting a purified compound of Formula VIIa, or a stereoisomer or mixture of stereoisomers thereof, with a compound of VIII under conditions sufficient to provide a compound of Formula IX, or a stereoisomer or mixture of stereoisomers thereof.

[0384] In some embodiments, there is provided herein a method for preparing a compound of formula IX or a mixture of its stereoisomers or stereoisomers or their respective solvates by a compound of formula VIIb or its stereoisomers or a mixture of stereoisomers. In some embodiments, the method includes contacting a compound of formula VI with a suitable metal salt (such as magnesium acetate tetrahydrate, sodium hydroxide, calcium acetate, zinc acetate, lithium hydroxide or similar metal salt) in a stoichiometric ratio of about 1:1 in a suitable organic solvent (such as ethyl acetate or toluene). In some embodiments, the method includes purifying a compound of formula VIIb or its stereoisomers or a mixture of stereoisomers to sufficient purity. In some embodiments, the purity of the compound of formula VIIb is about 95%. In some embodiments, the purity of the compound of formula VIIb is about 98%. In some embodiments, the purity of the compound of formula VIIb is about 99%. In some embodiments, the purity of the compound of formula VIIb is about 99.5%. In some embodiments, the purity of the compound of formula VIIb is about 99.9%. Any suitable purification method is contemplated, including but not limited to recrystallization and chromatography.

[0385] In some embodiments, the method includes contacting the purified compound of formula VIIb, or its stereoisomer, or a mixture of stereoisomers, with an acid under reaction conditions sufficient to provide a compound of formula VI, or its stereoisomer, or a mixture of stereoisomers; and contacting the compound of formula VI, or its stereoisomer, or a mixture of stereoisomers, with a compound of formula VIII under conditions sufficient to provide a compound of formula IX, or its stereoisomer, or a mixture of stereoisomers. Similar to the above-mentioned alternative approach, the purification of the compound of formula VIIb alleviates the challenges associated with purifying the compound of formula VI.

[0386] In some embodiments, the step of producing a compound of Formula VI, or a stereoisomer or mixture of stereoisomers thereof, is omitted such that the process instead involves contacting a purified compound of Formula VIIb, or a stereoisomer or mixture of stereoisomers thereof, with a compound of VIII under conditions sufficient to provide a compound of Formula IX, or a stereoisomer or mixture of stereoisomers thereof.

[0387] In some embodiments, the acid is a mineral acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the reaction conditions for contacting the purified compound of Formula VIIb, or a stereoisomer or mixture of stereoisomers thereof, with the acid include contacting at a temperature of about 20°C to 25°C.

[0388] In some embodiments, the reaction conditions for providing a compound of formula IX or a stereoisomer thereof or a mixture of stereoisomers include introducing a compound of formula VIII into a mixture of carbonyl diimidazole and a regenerated compound of formula VI. In some embodiments, the reaction conditions include reacting at a temperature of about -10°C to about 60°C. In some embodiments, the reaction conditions include reacting at a temperature of about 0°C to about 30°C. The reaction may be carried out in any suitable solvent. In some embodiments, the reaction conditions include reacting in DMF. In some embodiments, the reaction conditions include a reaction time of about 10 minutes to about 18 hours. In some embodiments, the reaction time is about 0.5 hours to about 4 hours.

[0389] In some embodiments, the compound of Formula VIII is Formula VIIIa:

[0390]

[0391] The substituent R 73 As defined above.

[0392] In some embodiments, provided herein are compounds of Formula IX as racemic mixtures. In some embodiments, provided herein are enantiomers of compounds of Formula IX. In some embodiments, compounds of Formula IX are of Formula IX-1:

[0393]

[0394] wherein the substituents are as defined above.

[0395] In some embodiments, the compound of Formula IX or IX-1 is Formula IX-2:

[0396]

[0397] wherein the substituents are as defined above.

[0398] In some embodiments, a method for preparing a compound of formula IX-2 or a solvate thereof (e.g., hydrate) from a compound of formula VII-2a is provided herein. In some embodiments, the method includes contacting a salt of a compound of formula VIa-1a, i.e., a compound of formula VII-2a, with an acid under reaction conditions sufficient to provide a compound of formula VIa-1a, and contacting a compound of formula VIa-1a with a compound of formula VIIIa or its salt under conditions sufficient to provide a compound of formula IX-2. In some embodiments, the method includes purifying the compound of formula VII-2a to sufficient purity. In some embodiments, the purity of the compound of formula VII-2a is about 95%. In some embodiments, the purity of the compound of formula VII-2a is about 98%. In some embodiments, the purity of the compound of formula VII-2a is about 99%. In some embodiments, the purity of the compound of formula VII-2a is about 99.5%. In some embodiments, the purity of the compound of formula VII-2a is about 99.9%. Any suitable purification method is contemplated, including but not limited to recrystallization and chromatography.

[0399] In some embodiments, the compound of Formula IX or IX-1 is Formula IX-1a:

[0400]

[0401] In some embodiments, a solvate of a compound of Formula IX-1a is provided herein. In some embodiments, a solvate of a compound of Formula IX-1a is provided herein, such as a hydrate. In some embodiments, a hydrate of a compound of Formula IX-1a is provided herein, such as a monohydrate. In other words, the hydrate of the compound of Formula IX-1a comprises a compound of Formula IX-1a and water in a stoichiometric ratio of about 1:1. In some embodiments, the monohydrate of the compound of Formula IX-1a provides excellent stability in the preparation method compared to, for example, an anhydrous form of the compound of Formula IX-1a.

[0402] Solution 4

[0403]

[0404] With respect to Scheme 4, wherein the substituents are as defined above, in some embodiments, there is provided herein a method for preparing a compound of formula XI or its stereoisomer or mixture of stereoisomers or its respective salt by a two-step reaction from a compound of formula IX or its stereoisomer or mixture of stereoisomers or its respective solvate. In some embodiments, the reaction is initiated by a solvate of a compound of formula IX or its stereoisomer or mixture of stereoisomers. In some embodiments, the solvate is a hydrate. In some embodiments, the solvate is a polar aprotic solvent, optionally N,N-dimethylformamide, N-methylpyrrolidone or dimethylacetamide.

[0405] In some embodiments, provided herein is a method for preparing a compound of formula X, or a stereoisomer or a mixture of stereoisomers, or a salt thereof, from a compound of formula IX, or a stereoisomer or a mixture of stereoisomers, or a solvate thereof. In some embodiments, the method comprises contacting a compound of formula IX, or a stereoisomer or a mixture of stereoisomers, or a solvate thereof, with a dehydrating agent and a base under reaction conditions sufficient to provide a compound of formula X, or a stereoisomer or a mixture of stereoisomers, or a salt thereof.

[0406] Alternatively, in some embodiments, provided herein is a method of preparing a compound of formula X, or a stereoisomer or a mixture of stereoisomers, or a respective salt thereof, by contacting a compound of formula XIV, or a stereoisomer or a mixture of stereoisomers, or a solvate thereof, with a compound of formula XV under reaction conditions sufficient to provide a compound of formula X, or a stereoisomer or a mixture of stereoisomers, or a respective salt thereof. In some embodiments, the method includes a dehydrating agent and a base.

[0407] In some embodiments, the dehydrating agent is selected from the group consisting of sulfonyl chloride, sulfonic anhydride, phosphonic anhydride, carbonic anhydride with an electron withdrawing group, and a mixture of triphenylphosphine and carbon tetrachloride.

[0408] In some embodiments, the dehydrating agent is selected from the group consisting of: 4-toluenesulfonyl chloride, methanesulfonyl chloride, toluenesulfonic anhydride, methanesulfonic anhydride, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine 2,4,6-trioxide (or referred to herein as tri-n-propylphosphonic anhydride), trifluoroacetic anhydride, and a mixture of triphenylphosphine and carbon tetrachloride.

[0409] In some embodiments, the acid is 4-toluenesulfonyl chloride.

[0410] In some embodiments, the base is potassium carbonate. In some embodiments, the base is an amine. In some embodiments, the base is N, N-diisopropylethylamine (DIPEA) or triethylamine (TEA). In some embodiments, the base is DIPEA. In some embodiments, the reaction conditions for providing a compound of formula X or a mixture of its stereoisomers or stereoisomers or their respective salts include reacting in an ACN solvent. In some embodiments, the reaction conditions include a reaction temperature of about 0°C to about 40°C. In some embodiments, the reaction conditions include a reaction temperature of about 20°C to about 25°C. In some embodiments, ACN is anhydrous. For example, ACN may have a water content of less than about 2%, or about 1%, or about 0.5%, or about 0.1%, or about 0.01%, or about 10ppm, or about 1ppm. In some embodiments, other solvents, such as other organic solvents, including but not limited to DMF, N-methylpyrrolidone (NMP), THF, methyltetrahydrofuran (MeTHF), MTBE, isopropyl acetate (IPAc), do not produce satisfactory yields for the reaction.

[0411] In some embodiments, the compound of formula IX or its stereoisomer or mixture of stereoisomers or their respective solvates used to synthesize the compound of formula X or its stereoisomer or mixture of stereoisomers or their respective solvates is formed via a compound of formula VIIa. In some embodiments, the compound of formula IX or its stereoisomer or mixture of stereoisomers or their respective solvates used to synthesize the compound of formula X or its stereoisomer or mixture of stereoisomers or their respective solvates is formed via a compound of formula VIIb.

[0412] Therefore, in some embodiments, provided herein is a method for preparing a compound of formula X or a stereoisomer or a mixture of stereoisomers or a salt thereof, the method comprising:

[0413] a) contacting a compound of formula VIIa, or a stereoisomer or mixture of stereoisomers thereof, with a first acid under reaction conditions sufficient to provide a compound of formula VI, or a stereoisomer or mixture of stereoisomers thereof; and contacting a compound of formula VI, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIII under reaction conditions sufficient to provide a compound of formula IX, or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof;

[0414] b) contacting a compound of formula VIIa, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIII under conditions sufficient to provide a compound of formula IX, or a stereoisomer or mixture of stereoisomers thereof, or a respective solvate thereof;

[0415] c) contacting a compound of formula VIIb, or a stereoisomer or mixture of stereoisomers thereof, with a first acid under reaction conditions sufficient to provide a compound of formula VI, or a stereoisomer or mixture of stereoisomers thereof; and contacting a compound of formula VI, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIII under reaction conditions sufficient to provide a compound of formula IX, or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof; or

[0416] d) contacting a compound of formula VIIb, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIII under conditions sufficient to provide a compound of formula IX, or a stereoisomer or mixture of stereoisomers thereof, or a solvate thereof; and

[0417] The compound of formula IX or its stereoisomer or mixture of stereoisomers or their respective solvates is contacted with a dehydrating agent and a base under reaction conditions sufficient to provide the compound of formula X or its stereoisomer or mixture of stereoisomers or their respective salts.

[0418] In some embodiments, R 73 is a protecting group for an amine functional group. 73 In some embodiments, R 1 In some embodiments, R 73 for

[0419] In some embodiments, the methods described with respect to Schemes 3 and 4 are performed in the same reaction vessel without removing the reaction mixture. In some embodiments, the preparation of the compound of Formula IX, IX-1 or IX-1a and the preparation of the compound of Formula X are performed in the same reaction vessel without removing the reaction mixture. In some embodiments, the method described in Scheme 4 is performed in the same reaction vessel without removing the reaction mixture.

[0420] In some embodiments, the preparation of the compound of Formula XIV, XV, IX, X or IX-1a is carried out in the same reaction vessel without removing the reaction mixture or isolating the compound of Formula IX or any intermediate provided by the process described in Schemes 3 or 4.

[0421] In some embodiments, provided herein are compounds of formula X as racemic mixtures. In some embodiments, provided herein are enantiomers of compounds of formula X. In some embodiments, compounds of formula X are of formula X-1:

[0422]

[0423] wherein the substituents are as defined above.

[0424] In some embodiments, the compound of formula X-1 is of formula X-2:

[0425]

[0426] wherein the substituents are as defined above.

[0427] In some embodiments, a method for preparing a compound of formula X-2 from a compound of formula VII-2a is provided herein. In some embodiments, the method includes contacting a compound of formula VII-2a with an acid under reaction conditions sufficient to provide a compound of formula VIa-1a, contacting a compound of formula VIa-1a with a compound of formula VIIIa or a salt thereof under conditions sufficient to provide a compound of formula IX-2 or its respective solvate (e.g., hydrate), and contacting a compound of formula IX-2 with a dehydrating agent and a base under reaction conditions sufficient to provide a compound of formula X-2 or a salt thereof. In some embodiments, the method includes purifying a compound of formula VII-2a to sufficient purity. In some embodiments, the purity of the compound of formula VII-2a is about 95%. In some embodiments, the purity of the compound of formula VII-2a is about 98%. In some embodiments, the purity of the compound of formula VII-2a is about 99%. In some embodiments, the purity of the compound of formula VII-2a is about 99.5%. In some embodiments, the purity of the compound of formula VII-2a is about 99.9%. Any suitable purification method is contemplated, including, but not limited to, recrystallization and chromatography.

[0428] In some embodiments, provided herein is a compound of formula X-1a:

[0429]

[0430] In some embodiments, provided herein is a method of preparing a compound of formula XI, or a stereoisomer, or a mixture of stereoisomers, or a salt thereof, from a compound of formula X, or a stereoisomer, or a mixture of stereoisomers, or a salt thereof. In some embodiments, the method comprises contacting a compound of formula X, or a stereoisomer, or a mixture of stereoisomers, or a salt thereof, under deprotection conditions sufficient to provide a compound of formula XI, or a stereoisomer, or a mixture of stereoisomers, or a salt thereof.

[0431] In some embodiments, the deprotection conditions described for the preparation of the compound of formula IX include contacting the compound of formula X with an acid. In some embodiments, the acid is generated in situ from an acid precursor in the presence of a protic compound. In some embodiments, the acid precursor is acetyl chloride. In some embodiments, the protic compound is an alcohol. In some embodiments, the generation of the acid includes generation at a temperature of about -30°C to about 100°C. In some embodiments, the temperature is about -30°C to about 60°C. In some embodiments, the generation of the acid includes lowering the temperature to about 0°C to about 5°C and warming the reaction to a temperature of about 15°C to about 25°C. In some embodiments, the temperature of the reaction mixture is raised to about 30°C to about 60°C, such as about 40°C to about 45°C, and stirred for a duration of at least about 2 hours. In some embodiments, the latter reaction step at a higher temperature (such as at about 40°C to about 45°C) provides significantly improved yields and / or reduced impurity content compared to other methods (e.g., maintaining the temperature below about 30°C).

[0432] In some embodiments, the deprotection conditions include generating hydrogen chloride in situ. In some embodiments, the deprotection conditions also include neutralizing the residual acid generated immediately after the reaction is completed and separating the compound of formula X or its salt. Other deprotection conditions, such as contacting the intermediate X-1a with aqueous hydrochloric acid to remove the BOC group, usually lead to the decomposition of the oxadiazole ring, thereby resulting in a low yield of the intermediate XI. In contrast, by implementing the deprotection and neutralization conditions described herein, ring decomposition is avoided, and the yield and / or purity of the compound of formula XI can be significantly improved. Therefore, the deprotection conditions described herein enable large-scale industrial production that was previously unimaginable.

[0433] In some embodiments, the contact of a compound of formula X or its stereoisomer or mixture of stereoisomers or its respective salt under deprotection conditions provides a free base form of a compound of formula XI or its stereoisomer or mixture of stereoisomers. In some embodiments, the contact of a compound of formula X or its stereoisomer or mixture of stereoisomers or its respective salt under deprotection conditions provides a salt of a compound of formula XI or its stereoisomer or mixture of stereoisomers. In some embodiments, the salt is hydrochloride, oxalate and 4-chlorophenoxyacetic acid salt. In some embodiments, each equivalent of hydrochloride includes two equivalents of chloride ions. In some embodiments, each equivalent of oxalate includes two equivalents of oxalate anions. In some embodiments, each equivalent of 4-chlorophenoxyacetic acid salt includes one equivalent of 4-chlorophenoxyacetic acid anions.

[0434] Thus, in some embodiments, provided herein is a method for preparing a compound of formula XI or a stereoisomer or a mixture of stereoisomers or a salt thereof, the method comprising:

[0435] a) contacting a compound of formula VIIa, or a stereoisomer or mixture of stereoisomers thereof, with a first acid under reaction conditions sufficient to provide a compound of formula VI, or a stereoisomer or mixture of stereoisomers thereof; and contacting a compound of formula VI, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIII under reaction conditions sufficient to provide a compound of formula IX, or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof;

[0436] b) contacting a compound of formula VIIa, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIII under conditions sufficient to provide a compound of formula IX, or a stereoisomer or mixture of stereoisomers thereof, or a respective solvate thereof;

[0437] c) contacting a compound of formula VIIb, or a stereoisomer or mixture of stereoisomers thereof, with a first acid under reaction conditions sufficient to provide a compound of formula VI, or a stereoisomer or mixture of stereoisomers thereof; and contacting a compound of formula VI, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIII under reaction conditions sufficient to provide a compound of formula IX, or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof; or

[0438] d) contacting a compound of formula VIIb, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIII under conditions sufficient to provide a compound of formula IX, or a stereoisomer or mixture of stereoisomers thereof, or a solvate thereof;

[0439] contacting a compound of formula IX, or a stereoisomer or mixture of stereoisomers, or a respective solvate thereof, with a dehydrating agent and a base under reaction conditions sufficient to provide a compound of formula X, or a stereoisomer or mixture of stereoisomers, or a respective salt thereof; and

[0440] The compound of formula X, or its stereoisomer or mixture of stereoisomers, or its respective salt, is contacted under deprotection conditions sufficient to provide the compound of formula XI, or its stereoisomer or mixture of stereoisomers, or its respective salt.

[0441] In some embodiments, provided herein are compounds of formula XI as racemic mixtures. In some embodiments, provided herein are enantiomers of compounds of formula XI. In some embodiments, compounds of formula XI are of formula XI-1:

[0442]

[0443] wherein the substituents are as defined above.

[0444] In some embodiments, provided herein is a compound of formula XI-1a:

[0445]

[0446] In some embodiments, with respect to any of the above methods for preparing a salt of a compound of formula XI, formula XI-1, or formula XI-1a, the salt is a hydrochloride, an oxalate, and a 4-chlorophenoxyacetic acid salt. In some embodiments, the salt is a 4-chlorophenoxyacetic acid salt. In some embodiments, the compound of formula XI, formula XI-1, or formula XI-1a is present in the salt at a ratio of about 1:1 relative to its counterion. In some embodiments, the compound of formula XI, formula XI-1, or formula XI-1a is present in the salt at a ratio of about 1:2 relative to its counterion.

[0447] In some embodiments, a method for preparing a compound of formula XI-1a from a compound of formula VII-2a is provided herein. In some embodiments, the method includes contacting a compound of formula VII-2a with an acid under reaction conditions sufficient to provide a compound of formula VIa-1a, contacting a compound of formula VIa-1a with a compound of formula VIIIa or a salt thereof under conditions sufficient to provide a compound of formula IX-2 or its respective solvate (e.g., hydrate), contacting a compound of formula IX-2 with a dehydrating agent and a base under reaction conditions sufficient to provide a compound of formula X-2 or a salt thereof, and contacting a compound of formula X-2 or a salt thereof under deprotection conditions sufficient to provide a compound of formula XI-1a or a salt thereof. In some embodiments, the method includes purifying a compound of formula VII-2a to sufficient purity. In some embodiments, the purity of the compound of formula VII-2a is about 95%. In some embodiments, the purity of the compound of formula VII-2a is about 98%. In some embodiments, the purity of the compound of formula VII-2a is about 99%. In some embodiments, the compound of Formula VII-2a has a purity of about 99.5%.In some embodiments, the compound of Formula VII-2a has a purity of about 99.9%.Any suitable purification method is contemplated, including but not limited to recrystallization and chromatography.

[0448] In some embodiments, R 73 For the style wherein the substituents are as defined above. Thus, the compound of formula X above has formula I-1.

[0449] Solution 5

[0450]

[0451] Referring to Scheme 5, in some embodiments, provided herein is a method for preparing a compound of formula I-1 or its stereoisomer or mixture of stereoisomers or their respective salts from a compound of formula XI or its stereoisomer or mixture of stereoisomers, wherein:

[0452] R 3 For hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which except hydrogen is optionally replaced by one or more R 11 replace;

[0453] R 4 and R 5 Each of which is independently hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 alkynyl, each of which except hydrogen is independently optionally substituted with one or more halo, oxo, acetyl, amino or hydroxy;

[0454] or R 3 and R 4 join together with the atoms to which they are attached to form C 3-10 Cycloalkyl or heterocyclyl, each of which is optionally substituted by one or more R 11 replace;

[0455] or R 4 and R 5 join together with the atoms to which they are attached to form C 3-10 Cycloalkyl, heterocyclyl or heteroaryl, each of which is optionally substituted by one or more R 11 replace;

[0456] X 1 O, NR 9 or key;

[0457] z is 0 or 1, provided that when z is 0 and X 1 When it is 0, R 3 is not an alkyl group; and

[0458] Other substituents and parameters are as defined for Scheme 2.

[0459] In some embodiments, the compound of Formula XII is Formula XII-1:

[0460]

[0461] In some embodiments, if the compound of Formula XI is used in the form of a salt, for example, a salt of an acid with a compound of Formula XII-1, then no additional compound of Formula XII is required in the reaction shown in Scheme 5.

[0462] In some embodiments, the method comprises contacting a compound of Formula XI, or a stereoisomer or mixture of stereoisomers thereof, with a compound of Formula XII under reaction conditions sufficient to provide a compound of Formula 1-1, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof.

[0463] In some embodiments, X 1 is O. In some embodiments, R 3 is aryl substituted with 0-3 halo, hydroxyl or alkoxy groups. 3 It is 4-chlorophenyl.

[0464] In some embodiments, the reaction conditions for providing a compound of Formula 1-1 include:

[0465] a) optionally a first reaction step at a temperature of about 0°C to about 5°C;

[0466] b) optionally a second reaction step at a temperature of about 15°C to about 30°C; and / or

[0467] c) optionally in the presence of a base and diphenylphosphinic chloride.

[0468] In some embodiments, the second reacting step is carried out at a temperature of about 20°C to about 30°C.

[0469] In some embodiments, the reaction conditions to provide a compound of Formula 1-1 further comprise contacting the reaction mixture with a base such as a carbonate, and then contacting with a mixture of isopropanol and heptane.

[0470] In some embodiments, the preparation of the compound of Formula 1-1 further comprises isolating the compound of Formula XI or its stereoisomer or mixture of stereoisomers or their respective salts using heptane, IPAc and / or IPA.

[0471] Therefore, in some embodiments, provided herein is a method for preparing a compound of formula I-1 or a stereoisomer or a mixture of stereoisomers or a salt thereof, the method comprising:

[0472] a) contacting a compound of formula VIIa, or a stereoisomer or mixture of stereoisomers thereof, with a first acid under reaction conditions sufficient to provide a compound of formula VI, or a stereoisomer or mixture of stereoisomers thereof; and contacting a compound of formula VI, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIII under reaction conditions sufficient to provide a compound of formula IX, or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof;

[0473] b) contacting a compound of formula VIIa, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIII under conditions sufficient to provide a compound of formula IX, or a stereoisomer or mixture of stereoisomers thereof, or a respective solvate thereof;

[0474] c) contacting a compound of formula VIIb, or a stereoisomer or mixture of stereoisomers thereof, with a first acid under reaction conditions sufficient to provide a compound of formula VI, or a stereoisomer or mixture of stereoisomers thereof; and contacting a compound of formula VI, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIII under reaction conditions sufficient to provide a compound of formula IX, or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof; or

[0475] d) contacting a compound of formula VIIb, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIII under conditions sufficient to provide a compound of formula IX, or a stereoisomer or mixture of stereoisomers thereof, or a solvate thereof;

[0476] contacting a compound of formula IX with a dehydrating agent and a base under reaction conditions sufficient to provide a compound of formula X or a stereoisomer or mixture of stereoisomers thereof or a salt thereof;

[0477] contacting a compound of formula X, or a stereoisomer or mixture of stereoisomers, or a respective salt thereof, under deprotection conditions sufficient to provide a compound of formula XI, or a stereoisomer or mixture of stereoisomers, or a respective salt thereof; and

[0478] The compound of formula XI, or its stereoisomer or mixture of stereoisomers, is contacted with the compound of formula XII under reaction conditions sufficient to provide the compound of formula 1-1, or its stereoisomer or mixture of stereoisomers, or their respective salts.

[0479] In some embodiments, provided herein are compounds of formula I-1 as racemic mixtures. In some embodiments, provided herein are enantiomers of compounds of formula I-1. In some embodiments, the compound of formula I-1 is formula I-1a:

[0480]

[0481] wherein the substituents are as defined above.

[0482] In some embodiments, provided herein is a method for preparing a compound of formula I-1a or a stereoisomer or a mixture of stereoisomers or a salt thereof, the method comprising:

[0483] a) contacting a compound of formula VII-2a, or a stereoisomer or mixture of stereoisomers thereof, with a first acid under reaction conditions sufficient to provide a compound of formula VIa-1a, or a stereoisomer or mixture of stereoisomers thereof; and

[0484] contacting a compound of formula VIa-1a, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIIIa under conditions sufficient to provide a compound of formula IX-2, or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof; or

[0485] b) contacting a compound of formula VII-2b, or a stereoisomer or mixture of stereoisomers thereof, with a compound of formula VIIIa under conditions sufficient to provide a compound of formula IX-2, or a stereoisomer or mixture of stereoisomers thereof, or a solvate thereof; and

[0486] contacting a compound of formula IX-2, or a stereoisomer or mixture of stereoisomers, or a respective solvate thereof, with a dehydrating agent and a base under reaction conditions sufficient to provide a compound of formula X-2, or a stereoisomer or mixture of stereoisomers, or a respective salt thereof;

[0487] contacting a compound of formula X-2, or a stereoisomer or mixture of stereoisomers, or a respective salt thereof, under deprotection conditions sufficient to provide a compound of formula XI-1a, or a stereoisomer or mixture of stereoisomers, or a respective salt thereof; and

[0488] The compound of formula XI-1a, or a stereoisomer or mixture of stereoisomers thereof, is contacted with a compound of formula XII-1 under reaction conditions sufficient to provide the compound of formula I-1a, or a stereoisomer or mixture of stereoisomers thereof, or their respective salts.

[0489] In some embodiments, the compound of formula I-1a is of formula I:

[0490]

[0491] In some embodiments, a method for preparing a compound of formula I or a salt thereof from a compound of formula VII-2a is provided herein. In some embodiments, the method includes contacting a compound of formula VII-2a with an acid under reaction conditions sufficient to provide a compound of formula VIa-1a, contacting a compound of formula VIa-1a with a compound of formula VIIIa or a salt thereof under conditions sufficient to provide a compound of formula IX-2 or its respective solvate (e.g., hydrate), contacting a compound of formula IX-2 with a dehydrating agent and a base under reaction conditions sufficient to provide a compound of formula X-2 or a salt thereof, contacting a compound of formula X-2 or a salt thereof under deprotection conditions sufficient to provide a compound of formula XI-1a or a salt thereof, and optionally contacting a compound of formula XI-1a or a salt thereof with a compound of formula XII-1 under reaction conditions sufficient to provide a compound of formula I or a salt thereof. In some embodiments, the method includes purifying a compound of formula VII-2a to sufficient purity. In some embodiments, the purity of the compound of formula VII-2a is about 95%. In some embodiments, the purity of the compound of formula VII-2a is about 98%. In some embodiments, the purity of the compound of Formula VII-2a is about 99%. In some embodiments, the purity of the compound of Formula VII-2a is about 99.5%. In some embodiments, the purity of the compound of Formula VII-2a is about 99.9%. Any suitable purification method is contemplated, including but not limited to recrystallization and chromatography.

[0492] Any combination of the above steps can be used to prepare the compounds described herein, including any of the procedures described in the Examples section.

[0493] The compounds disclosed herein can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that, given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise indicated. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art.

[0494] In addition, as will be apparent to those skilled in the art, conventional blocking groups may be required to prevent some functional groups from experiencing undesirable reactions. Suitable blocking groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many blocking groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, the 3rd edition, Wiley, New York and the references cited therein.

[0495] As mentioned above, the compounds of the present disclosure may contain one or more chiral centers. In addition, the present disclosure contemplates other chiral centers that are not clearly described. Therefore, if necessary, these compounds can be prepared or separated into pure stereoisomers, that is, single enantiomers or diastereomers or mixtures enriched in stereoisomers. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included in the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, the racemic mixture of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0496] 5. Salt and solid forms

[0497] Also provided herein are salts of compounds of Formula VIa-1a:

[0498]

[0499] In some embodiments, the salt is selected from tert-butylamine, L-lysine, arginine, piperazine, dicyclohexylamine, tromethamine, ethanolamine, diethanolamine, N,N,N',N'-tetramethylethylenediamine, triisobutylamine, 4-methylmorpholine, dibutylamine, tromethamine, dehydroabietylamine, N-methyldicyclohexylamine, diethylamine, diisopropylethylamine, diisopropylamine, imidazole, 1,4-diazabicyclo[2.2.2]octane (DABCO), ammonia, dibenzylamine, magnesium, sodium, potassium, calcium, zinc, lithium, cesium, tetramethylammonium, and ammonium.

[0500] In some embodiments, provided herein is a crystalline form of a salt of a compound of Formula VIa-1a. In some embodiments, the solid form is a crystalline form of a salt comprising an amine selected from the group consisting of tert-butylamine, L-lysine, arginine, piperazine, dicyclohexylamine, tromethamine, ethanolamine, diethanolamine, N,N,N',N'-tetramethylethylenediamine, triisobutylamine, 4-methylmorpholine, dibutylamine, tromethamine, dehydroabietylamine, N-methyldicyclohexylamine, diethylamine, diisopropylethylamine, diisopropylamine, imidazole, 1,4-diazabicyclo[2.2.2]octane (DABCO), ammonia and dibenzylamine or a cation selected from magnesium, sodium, potassium, calcium, zinc, lithium, cesium, tetramethylammonium and ammonium.

[0501] In some embodiments, the solid form is a crystalline form of a compound of Formula VII-2a:

[0502]

[0503] Each R 46 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-20 Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein R 46 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group of 12 replace;

[0504] Each R 12 are independently halo, cyano, nitro, oxo, -OR 30 、-SR 30 、-SF 5 、-NR 30 R 31 , C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R 30 、-C(O)OR 30 、-OC(O)OR 30 、-OC(O)R 30 、-C(O)NR 30 R 31 、-OC(O)NR 30 R 31 、-NR 30 C(O)NR 30 R 31 、-S(O) 1-2 R 30 、-S(O) 1-2 NR 30 、-S(O) 1- 2 NR 30 R 31 、-NR 30 S(O) 1-2 R 31 、-NR 30 S(O) 1-2 NR 30 R 31 、-NR 30 C(O)R 31 or -NR 30 C(=O)OR 31 , where R 12 Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 Alkyl substituted; and

[0505] Each R 30 and R31 is independently hydrogen or independently optionally substituted with one or more oxo, halo, hydroxyl or amino groups. 1-12 Alkyl; or

[0506] R 30 and R 31 Together with the atoms to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 Alkyl substituted heterocyclic group.

[0507] In some embodiments, N(R 46 ) 3 The moiety is selected from the group consisting of tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine and dibenzylamine.

[0508] In some embodiments, the solid form is a crystalline form of a compound of Formula VII-2b:

[0509]

[0510] Where w is 1, 2 or 3; v is 1 or 2; j is wv and is 0, 1 or 2; M w+ is a cation; and each R 47 C 1-6 alkyl.

[0511] In some embodiments, the salt comprises a cation selected from the group consisting of magnesium, sodium, potassium, calcium, zinc, lithium, and cesium.

[0512] In some embodiments, as described above, preparing the salt form of the compound of Formula VIa-1a significantly improves the purity of the compound of Formula VIa-1a. In some embodiments, the salt is tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine, or dibenzylamine. In some embodiments, the salt is tert-butylamine, wherein the salt formation improves the purity from 96.9% to 99.8% compared to the free base starting material.

[0513] In some embodiments, provided herein is a polymorph (or crystalline) form of the tert-butylamine (TBA) salt of a compound of Formula VIa-1a, which is also a crystalline form of a compound of Formula VII-1a (referred to as "Compound VIa-1a, TBA Salt Form A").

[0514] In some embodiments, Compound VIa-1a, TBA Salt Form a is characterized by an X-ray powder diffraction pattern comprising one or more, or two, or three, or four, or five, or six, or seven, or eight peaks selected from 6.6, 11.6, 12.1, 15.6, 19.8, 20.8, 26.5, and 27.3 ° 2θ ± 0.2 ° 2θ, as measured on a diffractometer using Cu-K radiation In some embodiments, the diffraction pattern further comprises one, two, three, four, five, six, seven, eight, nine or ten additional peaks selected from 13.2, 14.4, 15.8, 17.2, 22.0, 23.2, 24.3, 32.9, 33.2 and 36.7 ° 2θ ± 0.2 ° 2θ. In some embodiments, Compound VIa-1a, TBA Salt Form A is further characterized in that its total X-ray powder diffraction pattern is substantially as follows Figure 1 shown.

[0515] In some embodiments, Compound VIa-1a, TBA Salt Form A is characterized in that the TGA comprises substantially Figure 2 In some embodiments, Compound VIa-1a, TBA Salt Form A is further characterized by a DSC curve comprising an endotherm at about 171°C. In another embodiment, the DSC curve is substantially as shown in Figure 2 shown.

[0516] In some embodiments, provided herein is a crystalline form of the dicyclohexylamine (DCHA) salt of a compound of Formula VIa-1a, which is also a crystalline form of a compound of Formula VII-1b (referred to as "Compound VIa-1a, DCHA Salt Form A").

[0517] In some embodiments, Compound VIa-1a, DCHA Salt Form A is characterized by an X-ray powder diffraction pattern comprising one or more, or two, or three, or four, or five peaks selected from 6.7, 10.6, 17.2, 19.0, and 19.6 ° 2θ ± 0.2 ° 2θ, as measured on a diffractometer using Cu-K radiation In some embodiments, the diffraction pattern further comprises one, two, three, four, five, six, seven, eight, nine or ten additional peaks selected from 13.5, 15.1, 20.3, 21.4, 27.2, 28.0, 28.8, 35.4, 36.8 and 39.0 ° 2θ ± 0.2 ° 2θ. In some embodiments, Compound VIa-1a, DCHA Salt Form A is further characterized in that its complete X-ray powder diffraction pattern is substantially as follows Figure 3 shown.

[0518] In some embodiments, Compound VIa-1a, DCHA Salt Form A is characterized by TGA comprising substantially Figure 4 In some embodiments, Compound VIa-1a, DCHA Salt Form A is further characterized by a DSC curve comprising an endotherm at about 139°C. In another embodiment, the DSC curve is substantially as shown in Figure 4 shown.

[0519] In some embodiments, provided herein is a crystalline form of an L-arginine salt of a compound of Formula VIa-1a that is also a crystalline form of a compound of Formula VII-1c (referred to as "Compound VIa-1a, L-arginine salt Form A").

[0520] In some embodiments, Compound VIa-1a, L-arginine Form A is characterized by an X-ray powder diffraction pattern comprising one or more, or two, or three, or four, or five, or six, or seven peaks selected from 17.8, 19.0, 20.3, 21.1, 22.4, 23.2, and 24.2 ° 2θ ± 0.2 ° 2θ, as measured on a diffractometer using a Cu-K radiation In some embodiments, the diffraction pattern further comprises one, two, three, four, five, six, seven, eight, nine or ten additional peaks selected from 12.0, 15.3, 16.1, 19.9, 23.9, 26.0, 29.2, 30.7, 32.2 and 38.0 ° 2θ ± 0.2 ° 2θ. In some embodiments, the diffraction pattern further comprises one, two, three, four, five, six or seven additional peaks selected from 14.9, 27.8, 29.9, 33.8, 34.7, 35.2 and 37.7 ° 2θ ± 0.2 ° 2θ. In some embodiments, Compound VIa-1a, L-arginine salt Form A is further characterized in that its complete X-ray powder diffraction pattern is substantially as follows Figure 5 shown.

[0521] In some embodiments, Compound VIa-1a, L-arginine salt Form A is further characterized by TGA comprising substantially Figure 6 In some embodiments, Compound VIa-1a, L-arginine salt Form A is further characterized by a DSC curve comprising an endotherm at about 167°C. In another embodiment, the DSC curve is substantially as shown in Figure 6 shown.

[0522] In some embodiments, provided herein is a crystalline form of the tromethamine (TMA) salt of a compound of Formula VIa-1a, which is also a crystalline form of a compound of Formula VII-1d (referred to as "Compound VIa-1a, TMA Salt Form A").

[0523] In some embodiments, Compound VIa-1a, TMA Salt Form A is characterized by an X-ray powder diffraction pattern comprising one or more, or two, or three, or four, or five, or six peaks selected from 6.6, 13.2, 19.9, 20.1, 21.8, and 26.7 ° 2θ ± 0.2 ° 2θ, as measured on a diffractometer using Cu-K radiation In some embodiments, the diffraction pattern further comprises one, two, three, four, five, six, seven, eight, nine, ten or eleven additional peaks selected from 15.9, 17.8, 18.9, 19.5, 20.9, 22.5, 28.4, 29.8, 33.5, 34.3 and 34.8 ° 2θ ± 0.2 ° 2θ. In some embodiments, Compound VIa-1a, TMA Salt Form A is further characterized in that its complete X-ray powder diffraction pattern is substantially as follows Figure 7 shown.

[0524] In some embodiments, Compound VIa-1a, TMA Salt Form A is further characterized by TGA comprising substantially Figure 8 In some embodiments, Compound VIa-1a, TMA Salt Form A is further characterized by a DSC curve comprising endotherms at about 123°C and about 136°C. In another embodiment, the DSC curve is substantially as shown in Figure 8 shown.

[0525] Also provided herein are compounds of formula XI-1a:

[0526]

[0527] and solid forms and their respective salts.

[0528] In some embodiments, provided herein is a crystalline form of a 4-chlorophenoxyacetic acid salt of a compound of Formula XI-1a (also referred to as "Compound XI-1a, 4-chlorophenoxyacetic acid salt Form A").

[0529] In some embodiments, Compound XI-1a, 4-chlorophenoxyacetic acid salt Form A is characterized by an X-ray powder diffraction pattern comprising one or more, or two, or three, or four peaks selected from 15.7, 16.4, 22.7, and 23.8 ° 2θ ± 0.2 ° 2θ, as measured on a diffractometer using Cu-K radiation In some embodiments, the diffraction pattern further comprises one, two, three, four or five additional peaks selected from 20.0, 20.7, 21.9, 25.8 and 31.0 ° 2θ ± 0.2 ° 2θ. In some embodiments, Compound XI-1a, 4-chlorophenoxyacetic acid salt Form A is further characterized in that its complete X-ray powder diffraction pattern is substantially as follows Fig.10 shown.

[0530] In some embodiments, Compound XI-1a, 4-chlorophenoxyacetic acid salt Form A is further characterized by a DSC curve comprising an endotherm at about 162° C. (onset). In another embodiment, the DSC curve is substantially as follows Fig. 9 shown.

[0531] In some embodiments, provided herein is a crystalline form of the free base of a compound of Formula XI-1a.

[0532] In some embodiments, Compound XI-1a, free base Form A is characterized by an X-ray powder diffraction pattern comprising one or more, or two, or three, or four, or five, or six, or seven peaks selected from 6.6, 10.9, 14.5, 19.9, 21.9, 25.0, 25.9 ° 2θ ± 0.2 ° 2θ, as measured on a diffractometer using Cu-K radiation In some embodiments, the crystalline Compound XI-1a, free base is further characterized by a total X-ray powder diffraction pattern substantially as Fig.11 shown.

[0533] In some embodiments, Compound XI-1a, free base Form A is further characterized by a DSC curve comprising an endotherm at about 98° C. (onset). In another embodiment, the DSC curve is substantially as follows Fig.12 shown.

[0534] In some embodiments, provided herein is a crystalline form of a hydrogen oxalate salt of a compound of Formula XI-1a (also referred to as "Compound XI-1a, hydrogen oxalate Form A").

[0535] In some embodiments, Compound XI-1a, hydrogen oxalate salt Form A is characterized by an X-ray powder diffraction pattern comprising one or more, or two, or three, or four, or five peaks selected from 5.9, 19.2, 20.9, 22.0, and 23.7 ° 2θ ± 0.2 ° 2θ, as measured on a diffractometer using Cu-K radiation In some embodiments, the diffraction pattern further comprises one, two, three, four or five additional peaks selected from 14.9, 18.9, 23.1, 23.9 and 30.7° 2θ ± 0.2° 2θ. In some embodiments, Compound XI-1a, hydrogen oxalate salt Form A is further characterized in that its complete X-ray powder diffraction pattern is substantially as follows Fig.13 shown.

[0536] In some embodiments, Compound XI-1a, hydrogen oxalate salt Form A is further characterized by a DSC curve comprising an endotherm at about 163.0°C (onset). In another embodiment, the DSC curve is substantially as follows Fig.14 shown.

[0537] Therefore, the present disclosure provides the following numbered embodiments:

[0538] Embodiment 1. A method for preparing the following: a compound of formula V-2:

[0539]

[0540] or a salt thereof, which comprises making a compound of formula IIa-1:

[0541]

[0542] contacting with an activating agent and then with a compound of formula IV:

[0543]

[0544] contacting under reaction conditions sufficient to provide a compound of formula V-2, wherein:

[0545] n is 0 or 1;

[0546] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0547] X 2 O or NR 53 ;

[0548] R 51 For hydrogen, C 1-12 Alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution;

[0549] R 52 For hydrogen, C 1-12 Alkyl or silyl, wherein the C 1-12C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substituted; and

[0550] R 53 For hydrogen, C 1-12 Alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution; or

[0551] R 51 and R 53 Together with the nitrogen atom to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group;

[0552] Provided that the compound is not cis-ethyl 3-[(methylthio)thiomethoxy]cyclobutanecarboxylate.

[0553] Embodiment 2. The method according to embodiment 1, wherein X 2 is O.

[0554] Embodiment 3. The method according to embodiment 1, wherein X 2 NR 53 .

[0555] Embodiment 4. The method according to embodiment 1, wherein X 2 NR 53 , and R 51 and R 53 Together with the nitrogen atom, they form a heterocyclic group.

[0556] Embodiment 5. The method according to embodiment 4, wherein R 51 and R 53 Together with the nitrogen atom it joins to form an α-morpholino.

[0557] Embodiment 6. A method as described in Embodiment 1, wherein n is 0.

[0558] Embodiment 7. The method according to embodiment 1, wherein R 52 C 1-12 alkyl.

[0559] Embodiment 8. A method as described in any of Embodiments 1-7, wherein the activation reagent is selected from the group consisting of: 1,1'-thiocarbonyldiimidazole, thiram, 1,1'-thiocarbonyldi-2(1H)-pyridone, 1,1'-(thiocarbonyl)bis-1H-benzotriazole and di-2-pyridylthiocarbonate.

[0560] Embodiment 9. The method of embodiment 8, wherein the activation reagent is 1,1'-thiocarbonyldiimidazole.

[0561] Embodiment 10. The method of any one of Embodiments 1-9, wherein the contacting of the compound of Formula IIa-1 with the activating agent comprises:

[0562] a) optionally a reaction temperature of about 0°C to about 60°C; and / or

[0563] b) optionally a reaction duration of about 3 hours to about 72 hours.

[0564] Embodiment 11. The method of any one of Embodiments 1-10, wherein the contacting with the compound of Formula IV comprises contacting under reaction conditions comprising:

[0565] a) optionally a reaction temperature of about 20°C to about 80°C; and / or

[0566] b) optionally a reaction duration of about 1 hour to about 48 hours.

[0567] Embodiment 12. A compound selected from the group consisting of:

[0568]

[0569] or their respective salts.

[0570] Embodiment 13. A salt of a compound of formula VIa-1a:

[0571]

[0572] wherein the salt comprises an amine selected from the group consisting of tert-butylamine, L-lysine, arginine, piperazine, dicyclohexylamine, tromethamine, ethanolamine, diethanolamine, N,N,N',N'-tetramethylethylenediamine, triisobutylamine, 4-methylmorpholine, dibutylamine, tromethamine, dehydroabietylamine, N-methyldicyclohexylamine, diethylamine, diisopropylethylamine, diisopropylamine, imidazole, 1,4-diazabicyclo[2.2.2]octane (DABCO), ammonia and dibenzylamine, or a cation selected from the group consisting of magnesium, sodium, potassium, calcium, zinc, lithium, cesium, tetramethylammonium and ammonium.

[0573] Embodiment 14. A method for preparing a salt of a compound of formula VIa-1a:

[0574]

[0575] The method comprises making a compound of formula V-2:

[0576]

[0577] or a salt thereof is contacted with an electrophilic bromine source and a fluorinating agent to provide the compound of formula VIa-1a; and

[0578] contacting the compound of formula VIa-1a with an amine selected from the group consisting of tert-butylamine, L-lysine, arginine, piperazine, dicyclohexylamine, tromethamine, ethanolamine, diethanolamine, N,N,N',N'-tetramethylethylenediamine, triisobutylamine, 4-methylmorpholine, dibutylamine, tromethamine, dehydroabietylamine, N-methyldicyclohexylamine, diethylamine, diisopropylethylamine, diisopropylamine, imidazole, 1,4-diazabicyclo[2.2.2]octane (DABCO), ammonia and dibenzylamine, or a base containing a cation selected from magnesium, sodium, potassium, calcium, zinc, lithium, cesium, tetramethylammonium and ammonium under reaction conditions sufficient to provide the compound of formula V-2,

[0579] in:

[0580] n is 0 or 1;

[0581] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0582] X 2 O or NR 53 ;

[0583] R 51 For hydrogen, C 1-12 Alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution;

[0584] R 52 For hydrogen, C 1-12 Alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substituted; and

[0585] R 53 For hydrogen, C 1-12 Alkyl or silyl, wherein the C1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution; or

[0586] R 51 and R 53 Together with the nitrogen atom to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group;

[0587] The condition is that when R 51 C 1-12 alkyl or silyl, or when X 2 NR 53 When the method comprises a hydrolysis step prior to salt formation.

[0588] Embodiment 15. The method of embodiment 14, wherein the electrophilic bromine source comprises DBDMH (1,3-dibromo-5,5-dimethylhydantoin) or NBS (n-bromosuccinimide).

[0589] Embodiment 16. The method according to embodiment 14, wherein X 2 is O.

[0590] Embodiment 17. The method according to embodiment 14, wherein R 51 is hydrogen or C 1-12 alkyl.

[0591] Embodiment 18. The method according to embodiment 14, wherein X 2 NR 53 .

[0592] Embodiment 19. A method for preparing a salt of a compound of formula VIa-1a:

[0593]

[0594] The method comprises making a compound of formula V-2:

[0595]

[0596] or a salt thereof is contacted with an electrophilic bromine source and a fluorinating agent, followed by hydrolysis to form VIa-1a; and

[0597] Contacting VIa-1a with an amine selected from the group consisting of tert-butylamine, L-lysine, arginine, piperazine, dicyclohexylamine, tromethamine, ethanolamine, diethanolamine, N,N,N',N'-tetramethylethylenediamine, triisobutylamine, 4-methylmorpholine, dibutylamine, tromethamine, dehydroabietylamine, N-methyldicyclohexylamine, diethylamine, diisopropylethylamine, diisopropylamine, imidazole, 1,4-diazabicyclo[2.2.2]octane (DABCO), ammonia and dibenzylamine, or a base containing a cation selected from magnesium, sodium, potassium, calcium, zinc, lithium, cesium, tetramethylammonium and ammonium under reaction conditions sufficient to provide a salt of said VIa-1a:

[0598] n is 0 or 1;

[0599] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0600] X 2 NR 53 ;

[0601] R 51 For hydrogen, C 1-12 Alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution;

[0602] R 52 For hydrogen, C 1-12 Alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substituted; and

[0603] R 53 For hydrogen, C 1-12 Alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution; or

[0604] R 51 and R 53 Together with the nitrogen atom to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group;

[0605] Provided that the compound is not cis-ethyl 3-[(methylthio)thiomethoxy]cyclobutanecarboxylate.

[0606] Embodiment 20. The salt of Embodiment 13, which has the formula VII-2a:

[0607]

[0608] Wherein the N(R 46 ) 3 The moiety is selected from the group consisting of tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine and dibenzylamine.

[0609] Embodiment 21. The salt according to Embodiment 13, which has the formula VII-1a:

[0610]

[0611] Embodiment 22. The salt according to Embodiment 13, which has the formula VII-1b

[0612]

[0613] Embodiment 23. The salt according to Embodiment 13, which has the formula VII-1c:

[0614]

[0615] Embodiment 24. The salt according to Embodiment 13, which has the formula VII-1d:

[0616]

[0617] Embodiment 25. Form A polymorph of the tert-butylamine (TBA) salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (Compound VIa-1a, TBA Salt Form A), which exhibits an X-ray powder diffraction pattern having one or more peaks selected from 6.6, 11.6, 12.1, 15.6, 19.8, 20.8, 26.5 and 27.3°2q±0.2°2q, wherein the X-ray powder diffraction pattern is prepared using Cu-Kα radiation.

[0618] Embodiment 26. Compound VIa-1a, TBA Salt Form A polymorph as described in Embodiment 25, is further characterized in that:

[0619] i) the X-ray powder diffraction pattern further comprises one or more peaks selected from 13.2, 14.4, 15.8, 17.2, 22.0, 23.2, 24.3, 32.9, 33.2 and 36.7°2q±0.2°2q;

[0620] ii) The diffraction pattern is basically Figure 1 As shown;

[0621] iii) differential scanning calorimetry (DSC) includes an endotherm at about 171°C; or

[0622] iv) Thermogravimetric analysis (TGA) includes essentially Figure 2 Thermoanalysis diagram shown.

[0623] Embodiment 27. Form A polymorph of the dicyclohexylamine (DCHA) salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (Compound VIa-1a, DCHA salt Form A), which exhibits an X-ray powder diffraction pattern having one or more peaks selected from 6.7, 10.6, 17.2, 19.0 and 19.6°2q±0.2°2q, wherein the X-ray powder diffraction pattern is prepared using Cu-Kα radiation.

[0624] Embodiment 28. Compound VIa-1a, DCHA Salt Form A polymorph as described in Embodiment 27, further characterized in that:

[0625] i) the X-ray powder diffraction pattern further comprises one or more peaks selected from 13.5, 15.1, 20.3, 21.4, 27.2, 28.0, 28.8, 35.4, 36.8 and 39.0°2q±0.2°2q;

[0626] ii) The diffraction pattern is basically Figure 3 As shown;

[0627] iii) differential scanning calorimetry (DSC) includes an endotherm at about 139°C; or

[0628] iv) Thermogravimetric analysis (TGA) includes essentially Figure 4 Thermoanalysis diagram shown.

[0629] Embodiment 29. Form A polymorph of the L-arginine salt of (1s, 3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (Compound VIa-1a, L-arginine salt Form A), which exhibits an X-ray powder diffraction pattern having one or more peaks selected from 17.8, 19.0, 20.3, 21.1, 22.4, 23.2 and 24.2°2q±0.2°2q, wherein the X-ray powder diffraction pattern is prepared using Cu-Kα radiation.

[0630] Embodiment 30. Compound VIa-1a, L-arginine salt form A polymorph as described in Embodiment 29, characterized in that:

[0631] i) the X-ray powder diffraction pattern further comprises one or more peaks selected from 12.0, 15.3, 16.1, 19.9, 23.9, 26.0, 29.2, 30.7, 32.2 and 38.0°2q±0.2°2q;

[0632] ii) The diffraction pattern is basically Figure 5 As shown;

[0633] iii) differential scanning calorimetry (DSC) includes an endotherm at about 167°C; or

[0634] iv) Thermogravimetric analysis (TGA) includes essentially Figure 6 Thermoanalysis diagram shown.

[0635] Embodiment 31. Form A polymorph of the tromethamine (TMA) salt of (1s, 3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (Compound VIa-1a, TMA salt Form A), which exhibits an X-ray powder diffraction pattern having one or more peaks selected from 6.6, 13.2, 19.9, 20.1, 21.8 and 26.7°2q±0.2°2q, wherein the X-ray powder diffraction pattern is prepared using Cu-Kα radiation.

[0636] Embodiment 32. Compound VIa-1a, TMA Salt Form A polymorph as described in Embodiment 31, is further characterized in that:

[0637] i) the X-ray powder diffraction pattern further comprises one or more peaks selected from 15.9, 17.8, 18.9, 19.5, 20.9, 22.5, 28.4, 29.8, 33.5, 34.3 and 34.8°2q±0.2°2q;

[0638] ii) The diffraction pattern is basically Figure 7 As shown;

[0639] iii) differential scanning calorimetry (DSC) includes endotherms at about 123°C and about 136°C; or

[0640] iv) Thermogravimetric analysis (TGA) includes essentially Figure 8 Thermoanalysis diagram shown.

[0641] Embodiment 33. A method for preparing the following: a compound of formula IX-2:

[0642]

[0643] or a solvate thereof, comprising:

[0644] Make a salt of the compound of formula VIa-1a:

[0645]

[0646] contacting with an acid under reaction conditions sufficient to provide the compound of Formula VIa-1a; and

[0647] The compound of formula VIa-1a is reacted with a compound of formula VIIIa or a salt thereof:

[0648]

[0649] contacting under conditions sufficient to provide said compound of formula IX-2 or a solvate thereof,

[0650] Where R 73 is hydrogen or a protecting group.

[0651] Embodiment 34. A method as described in Embodiment 33, wherein the protecting group is tert-butyloxycarbonyl or has the formula

[0652] Embodiment 35. A method according to embodiment 33 or 34, wherein the salt is of formula VII-2a:

[0653]

[0654] Wherein the N(R 46 ) 3 The moiety is selected from the group consisting of tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine and dibenzylamine.

[0655] Embodiment 36. The method of embodiment 34 or 35, wherein the compound of formula IX-2 is prepared by contacting the compound of formula V-2 with a fluorinating agent and DBDMH (1,3-dibromo-5,5-dimethylhydantoin) or NBS (n-bromosuccinimide).

[0656] Embodiment 37. The method of Embodiment 36, wherein the fluorinating agent is HF·pyridine.

[0657] Embodiment 38. A method for preparing the following: a compound of formula X-2:

[0658]

[0659] or a salt thereof, comprising:

[0660] Make a salt of the compound of formula VIa-1a:

[0661]

[0662] contacting with a first acid under reaction conditions sufficient to provide the compound of formula VIa-1a; and

[0663] The compound of formula VIa-1a is reacted with a compound of formula VIIIa or a salt thereof:

[0664]

[0665] In sufficient amount to provide a compound of formula IX-2:

[0666]

[0667] or a solvate thereof; and

[0668] The compound of formula IX-2 or a solvate thereof is contacted with a dehydrating agent and a base under reaction conditions sufficient to provide the compound of formula X-2 or a salt thereof, wherein R 73 is hydrogen or a protecting group.

[0669] Embodiment 39. The method of embodiment 38, wherein the salt of the compound of formula VIa-1a is of formula VII-2a:

[0670]

[0671] Wherein the N(R 46 ) 3 The moiety is selected from the group consisting of tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine and dibenzylamine.

[0672] Embodiment 40. The method of embodiment 38 or 39, wherein R 73 For the protecting group.

[0673] Embodiment 41. A method as described in any one of embodiments 38-40, wherein R 73 It is tert-butoxycarbonyl.

[0674] Embodiment 42. A method as described in any one of embodiments 38-40, wherein the protecting group is tert-butyloxycarbonyl or has the formula

[0675] Embodiment 43. A method for preparing the following: a compound of formula XI-1a:

[0676]

[0677] or a salt thereof, comprising:

[0678] Make a salt of the compound of formula VIa-1a:

[0679]

[0680] contacting with a first acid under reaction conditions sufficient to provide the compound of formula VIa-1a; and

[0681] The compound of formula VIa-1a is reacted with a compound of formula VIIIa or a salt thereof:

[0682]

[0683] In sufficient amount to provide a compound of formula IX-2:

[0684]

[0685] or its solvate;

[0686] The compound of formula IX-2 or a solvate thereof is treated with a dehydrating agent and a base in an amount sufficient to provide a compound of formula X-2:

[0687]

[0688] or a salt thereof under reaction conditions; and

[0689] The compound of formula X-2 or a salt thereof is contacted under deprotection conditions sufficient to provide the compound of formula XI-1a or a salt thereof, wherein R 73 is hydrogen or a protecting group.

[0690] Embodiment 44. A method as described in Embodiment 43, wherein the protecting group is tert-butyloxycarbonyl or has the formula

[0691] Embodiment 45. The method of embodiment 43 or 44, wherein the salt of the compound of formula VIa-1a is of formula VII-2a:

[0692]

[0693] Wherein the N(R 46 ) 3 The moiety is selected from the group consisting of tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine and dibenzylamine.

[0694] Embodiment 46. A method for preparing the following: a compound of formula I:

[0695]

[0696] or a salt thereof, comprising:

[0697] Make a salt of the compound of formula VIa-1a:

[0698]

[0699] contacting with a first acid under reaction conditions sufficient to provide the compound of formula VIa-1a; and

[0700] The compound of formula VIa-1a is reacted with a compound of formula VIIIa or a salt thereof:

[0701]

[0702] In sufficient amount to provide a compound of formula IX-2:

[0703]

[0704] or its solvate;

[0705] The compound of formula IX-2 or a solvate thereof is treated with a dehydrating agent and a base in an amount sufficient to provide a compound of formula X-2:

[0706]

[0707] or a salt thereof under reaction conditions; and

[0708] The compound of formula X-2 or a salt thereof is subjected to an incubation sufficient to provide a compound of formula XI-1a:

[0709]

[0710] or a salt thereof under deprotection conditions, and

[0711] Optionally, the compound of formula XI-1a or a salt thereof is reacted with a compound of formula XII-1:

[0712]

[0713] under reaction conditions sufficient to provide a compound of Formula I or a salt thereof, wherein R 73 is hydrogen or a protecting group.

[0714] Embodiment 47. The method of embodiment 46, wherein the salt of the compound of formula VIa-1a is of formula VII-2a:

[0715]

[0716] Wherein the N(R 46 ) 3 The moiety is selected from the group consisting of tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine and dibenzylamine.

[0717] Embodiment 48. The method of embodiment 46 or 47, wherein the salt of the compound of formula X-2 is hydrochloride, oxalate and 4-chlorophenoxyacetate.

[0718] Embodiment 49. The method of any one of Embodiments 46-48, wherein the deprotection conditions comprise contacting the compound of Formula X-2 with a second acid.

[0719] Embodiment 50. The method of Embodiment 49, wherein the second acid is generated in situ from an acid precursor in the presence of a protic compound, optionally at a temperature of about 10°C to about 100°C.

[0720] Embodiment 51. A method as described in any of Embodiments 46-50, wherein the deprotection conditions include in situ generation of hydrogen chloride.

[0721] Embodiment 52. The method of any one of Embodiments 46-51, further comprising isolating the compound of Formula XI-1a or a salt thereof using heptane, IPAc and / or IPA.

[0722] Embodiment 53. The method of embodiment 46, wherein the reaction conditions for providing the compound of formula I comprise:

[0723] a) temperatures from about 0°C to about 5°C, and elevated temperatures from about 20°C to about 25°C; and / or

[0724] b) optionally in the presence of a base and diphenylphosphinic chloride.

[0725] Embodiment 54. The method of Embodiment 53, wherein the reaction conditions for providing the compound of Formula I further comprise contacting the reaction mixture of Embodiment 53 with a base and further contacting with a mixture of isopropanol and heptane.

[0726] Embodiment 55. A method as described in Embodiment 38, 46 or 47, wherein the dehydrating agent is selected from the group consisting of sulfonyl chloride, sulfonic anhydride, phosphonic anhydride, carbonic anhydride with an electron withdrawing group, and a mixture of triphenylphosphine and carbon tetrachloride.

[0727] Embodiment 56. A method as described in Embodiment 55, wherein the dehydrating agent is selected from the group consisting of: 4-toluenesulfonyl chloride, methanesulfonyl chloride, toluenesulfonic anhydride, methanesulfonic anhydride, tri-n-propylphosphonic anhydride, trifluoroacetic anhydride, and a mixture of triphenylphosphine and carbon tetrachloride.

[0728] Embodiment 57. The method of any one of Embodiments 35-56, wherein the solvate is a polar aprotic solvent.

[0729] Embodiment 58. The method of any one of Embodiments 35-56, wherein the solvate is a hydrate.

[0730] Embodiment 59. The method of Embodiment 49, wherein the polar aprotic solvent is selected from the group consisting of: N,N-dimethylformamide, N-methylpyrrolidone, and dimethylacetamide.

[0731] Embodiment 60. The method of any one of Embodiments 38-59, wherein the base is N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), or potassium carbonate.

[0732] Embodiment 61. The method of any one of Embodiments 38-60, wherein the reaction conditions sufficient to provide the compound of Formula X-2 or a salt thereof include acetonitrile as a solvent.

[0733] Embodiment 62. The method of any one of embodiments 43-61, preparing the salt of the compound of formula XI-1a, wherein the salt of the compound of formula XI-1a is hydrochloride, oxalate or 4-chlorophenoxyacetate.

[0734] Embodiment 63. The method of embodiment 62, wherein the salt of the compound of formula XI-1a is 4-chlorophenoxyacetic acid salt.

[0735] Embodiment 64. A hydrate of a compound of formula IX-1a:

[0736]

[0737] Embodiment 65. The hydrate of Embodiment 64, wherein the stoichiometric ratio of the compound of Formula IX-1a to water in the hydrate is about 1:1.

[0738] Embodiment 66. A hydrogen oxalate salt of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine:

[0739]

[0740] Embodiment 67. A 4-chlorophenoxyacetic acid salt of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine:

[0741]

[0742] Embodiment 68. A crystalline 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine (Compound XI-1a) free base Form A:

[0743]

[0744] Characterized in that the X-ray powder diffraction pattern includes one or more, or two, or three, or four, or five, or six, or seven peaks selected from 6.6, 10.9, 14.5, 19.9, 21.9, 25.0, 25.9°2θ±0.2°2θ, as measured on a diffractometer using Cu-Kα radiation Sure.

[0745] Embodiment 69. Compound XI-1a free base Form A as described in Embodiment 68 is further characterized in that the DSC curve includes an endotherm at about 98°C (onset). Example

[0746] X-ray powder diffraction (XRPD)

[0747] Standard XRPD patterns were collected using a Bruker D8 Advance diffractometer (Bruker, GER). The X-ray source was a copper (Cu) tube operated at 40 kV and 40 mA. Powder samples were prepared using manual light pressure on a zero background silicon (Si) holder to keep the sample surface flat. Each sample was analyzed from 3 to 45 ° 2θ with an effective step length of 0.02 ° 2θ and an exposure time of 0.08 s.

[0748] In-situ high temperature XRPD patterns were collected using a Malvern Panalytical Aeris diffractometer (Malvern Panalytical, UK) connected to a BTS500 online hot stage (Anton Paar, AT). The X-ray source was operated at 40 kV and 7.5 mA, and powder samples were prepared on a zero background Si holder. Each sample was analyzed from 8 to 45 ° 2θ with an effective step length of 0.02 ° 2θ. The measurement time for each sample was 20 minutes.

[0749] Thermogravimetric analysis (TGA)

[0750] Thermogravimetric analysis (TGA) was performed on a TA Instruments Discovery 550 (TA, US). Each sample was placed in a pre-tared platinum pan and heated from 25°C to the target temperature at a heating rate of 10°C / min under a nitrogen atmosphere. The nitrogen purge at the balance was 40 mL / min, and the nitrogen purge at the furnace was 60 mL / min.

[0751] Differential Scanning Calorimetry (DSC)

[0752] DSC analysis was performed on a TA Instruments Discovery 250 (TA, US). Indium was used to calibrate the instrument temperature and unit cell constant. During each analysis, the DSC cell was kept under a nitrogen purge of 50 mL / min. The sample was placed in a Tzero sealed pan with a pinhole and heated from 25°C to the target temperature at a rate of 10°C / min. Several DSC analyses were performed using a Tzero sealed pan without a pinhole because the sample may sublime at high temperatures.

[0753] Dynamic Vapor Sorption (DVS) Analysis

[0754] DVS analysis was performed using a surface measurement system DVS Intrinsic analyzer (SMS, UK). The instrument balance was calibrated with standard weights. Approximately 15-20 mg of sample was loaded into a pan for analysis. Samples were analyzed at 25°C in 10% relative humidity (RH) steps from 50% to 95% RH (adsorption cycle), 95% to 0% RH (desorption cycle), and 0% to 50% RH (adsorption cycle). Movement from one step to the next occurred after the equilibrium criterion of 0.002% weight change (dm / dt) was met, or after six hours if the equilibrium criterion was not met.

[0755] Polarized Light Microscopy (PLM)

[0756] Microscopic images of the crystals were captured on a Nikon Ci-POL445 polarizing microscope (Nikon, Japan) under a suitable objective.

[0757] Gas chromatography (GC)

[0758] Shimadzu GC-2104 (Shimadzu, Japan) was used for chemical purity characterization. The detailed chromatographic conditions are listed in Table 1.

[0759] Table 1

[0760]

[0761] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and supplementary material (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0762] The following examples are included to illustrate specific embodiments of the present disclosure. It will be appreciated by those skilled in the art that the techniques disclosed in the following examples represent techniques that work well in the practice of the present disclosure and therefore can be considered to constitute specific modes of its practice. However, it will be appreciated by those skilled in the art that, in light of the present disclosure, many changes may be made to the disclosed specific embodiments without departing from the spirit and scope of the present disclosure and still obtaining the same or similar results.

[0763] Example 1: Preparation of (1s, 3s)-3-hydroxycyclobutane-1-carboxylic acid (II-1)

[0764]

[0765] Ethyl acetate (EtOAc) (277.2 kg) and EtOH (120.0 kg) were charged into a 1000 L stainless steel (SS) reactor at about 15° C. to 25° C. Sodium borohydride (NaBH 4, 9.36kg, 247mol, 0.35 equivalents) was added to the reactor at about 15°C to 25°C under nitrogen. The 1000L reactor was cooled to about -35°C to -45°C. EtOAc (68.4kg) and tert-butyl 3-oxo-cyclobutanecarboxylate (XIII-1) (120.0kg, 705mol, 1.0 equivalents) were charged into a 500L container. The solution was stirred at about 10°C to 30°C for about 0.5 hours. The XIII-1 solution in the 500L container was charged with NaBH at about -35°C to -45°C. 4 The reaction mixture was stirred at about -35°C to -45°C for about 3 hours until the reaction was considered complete.

[0766] Deionized water (336.0 kg) and ammonium chloride (24.0 kg) were added to a 2000L glass-lined (GL) reactor. The solution was stirred at about 10°C to 30°C. The ammonium chloride solution in the 2000L GL reactor was cooled to about -3°C to 5°C. The reaction mixture in the 1000L SS reactor was charged into the 2000L GL reactor. During the addition, the temperature was controlled within the range of about -3°C to 5°C to control the exotherm. The reaction mixture of the 2000L GL reactor was heated to about 5°C to 15°C and stirred for about 6 hours. The reaction mixture in the 2000L GL reactor was filtered at about 5°C to 15°C, and the filter cake was then washed with EtOAc (54.0 kg). The filtrate was transferred to the 1000L GL reactor at about 5°C to 15°C, settled and phase separated. The aqueous phase and EtOAc (216 kg) were added to a 1000L GL reactor at about 5°C to 15°C, stirred for about 1 hour, and settled for about 1 hour. The aqueous phase was discarded. The combined organic phase was washed once with water (120 kg) at about 5°C to 15°C, and the aqueous layer was discarded. The organic solution in the 1000L GL reactor was concentrated at a pressure (P) of less than or equal to about -0.8 mPa at gradually increasing temperatures until the temperature reached about 60°C. Heptane (81.6 kg) was added to the 1000L GL reactor and concentrated at P≤-0.08 mPa until the temperature reached about 60°C. Then, another portion of heptane (81.6 kg) was added to the 1000L GL reactor and concentrated at P≤-0.08 mPa until the temperature reached about 60°C. The removal of EtOAc and EtOH was confirmed. Heptane (120 kg) was added to the solution and heated to about 50°C to 60°C to dissolve the solid. The solution in the 1000L GL reactor was cooled to about 8°C to 12°C and stirred at about 10°C to 15°C for about 1 hour. The mixture was centrifuged in a centrifuge at about 8°C to 12°C. The centrifuged solid was washed with heptane (81.6 kg) and the solid was weighed. Heptane (96.8 kg) and the centrifuged solid were charged into a 1000L GL reactor and heated to about 50-60°C until the solid was completely dissolved. The solution in the 1000L GL reactor was cooled to about 8°C to 12°C and stirred at about 8°C to 12°C for about 1 hour. The product was separated by centrifugation at about 8°C to 12°C, washed with heptane (66.0 kg), and dried at about 35°C to 40°C to obtain II-1. Yield: 83.38 kg (68.7% yield).

[0767] 1 H NMR (DMSO-d 6,400MHz)δ=5.14(d,J=6.8Hz,1H),3.88-3.97(m,1H),2.32-2.42(m,3H),1.88-1.91(m,2H),1.39(s,9H)ppm.

[0768] Example 2: Preparation of tert-butyl (1s,3s)-3-((((2-((2-ethylhexyl)oxy)-2-oxoethyl)thio)thiocarbonyl)oxy)cyclobutane-1-carboxylate (V-1a)

[0769]

[0770] Methyl tert-butyl ether (MTBE) (310.8 kg) was charged into a 1000 L GL reactor and stirred at about 15-30° C. for 0.5 hour. II-1 (42 kg, 244 mol, 1.0 eq.) was charged into a 1000 L GL reactor and stirred at about 15-30° C. for about 0.5 hour. Thiocarbonyldiimidazole (47.88 kg, 269 mol, 1.1 eq.) was charged into a 1000 L GL reactor at about 20-25° C. and stirred at about 20-25° C. for 4 hours until the reaction was deemed complete.

[0771] 2-Ethylhexyl thioglycolate (55 kg, 269 mol, 1.1 equiv) was charged to a 1000 L GL reactor at about 20-25 °C and heated to about 40-45 °C for about 2 hours until the reaction was deemed complete. The reaction mixture was then cooled to about 10-20 °C. Deionized (DI) water (420.0 kg) was charged to a 1000 L GL reactor at about 10-20 °C, stirred for about 1 hour, and allowed to settle for about 4 hours. The layers were separated, and the aqueous layer was extracted with MTBE (155.4 kg) at about 10-20 °C. The combined organic phases were charged to a 1000 L GL reactor at about 10-20 °C with 5 wt % sodium bicarbonate solution (420 kg), stirred for about 1 hour, and allowed to settle for about 4 hours. The layers were separated. Anhydrous sodium sulfate (63 kg) was charged to a 1000 L GL reactor at about 10-20° C., stirred for about 12 hours and sampled to confirm that the water content was less than about 2%. The reaction mixture was filtered at about 10-20° C., and the filter cake was rinsed with MTBE (63 kg). The filtrate was charged to a 1000 L GL reactor at about 15-30° C. The organic solution was concentrated at P≤-0.8 mPa at gradually increasing temperatures until the temperature reached about 50° C. Dichloromethane (DCM) (223.44 kg) was charged to a 1000 L GL reactor and concentrated at P≤-0.08 mPa at gradually increasing temperatures until the temperature reached about 40° C. The distillation process of DCM was repeated until the DCM content was less than or equal to about 5.0%, the MTBE content was less than or equal to about 2.0%, each as a percentage of the integrated area under the gas chromatographic curve, and the water content was less than or equal to about 500 ppm (by Karl Fischer method). The mixture was cooled to 15-30° C. The liquid was used as it was in the next step.

[0772] 1 H NMR (CDCl 3 ,400MHz)δ=5.43-5.36(m,1H),4.11-4.05(m,2H),3.92(s,2H),2.75-2.63(m,3H),2.48 -2.37(m,2H),1.68-1.56(m,1H),1.45(s,9H),1.39-1.25(m,8H),0.92-0.87(m,6H)ppm.

[0773] Example 3: Preparation of tert-butyl (1s, 3s)-3-(dithiocarboxyloxy)cyclobutane-1-carboxylate (III-1b)

[0774]

[0775] Compound II-1 (9.67 kg, 56.2 mol, 1.0 eq) was dissolved in DMSO (29 L) at 25 °C to give a colorless solution. The mixture was cooled to 10 °C over 0.5 hours. DBU (9.40 kg, 61.8 mol, 1.10 eq) was added dropwise to the reaction mixture over 0.5 hours to maintain the internal temperature between 10-15 °C. The reaction mixture was stirred at 10 °C for 0.5 hours. CS 2 4-(4-(4-(4-(4-(4-piperidin-2-yl)-2-yl)-1,4-dihydro-1,4-dihydro-2 ...2,4-dihydro-1,4-dihydro-2,4-dihydro-2,4-dihydro-2,4-dihydro-1,4-dihydro-2,4-dihydro-2,4-dihydro-2,4-dihydro-1,4-dihydro-2,4-dihydro-2,4-dihydro-2,4-dihydro-1,4-dihydro-2,4-dihydro-2,4-dihydro-2,4-dihydro- 2 PO 4 (29L) was added dropwise to the reaction mixture to keep the internal temperature between 10-15°C. The mixture was extracted with n-heptane (20L x 3). The combined organic layer was washed with water (10L x 2) and brine (10L x 2). The organic layer was concentrated in vacuo at 45°C to obtain a yellow solution (30L). Activated carbon (3.0kg) was added to the solution at 20°C in one go. The mixture was stirred at 20°C for 12 hours. The mixture was filtered through a diatomaceous earth pad at 25°C. The filter cake was washed with n-heptane (10L). The eluent becomes colorless. The filtrate was concentrated in vacuo at 45°C to provide compound III-1b (5.1kg, 19.2mol, 66.6% yield, 98.5% purity). 1 H NMR (d6-DMSO, 400MHz) δ = 5.37-5.44 (m, 1H), 2.76-2.78 (m, 1H), 2.65-2.68 (m, 2H), 2.55 (s, 3H), 2.23-2.26 (m, 2H), 1.40 (s, 9H) ppm.

[0776] In the preparation of compound V-1a as in Example 2 above, the title compound can be used as a substitute for compound III-1.

[0777] Example 4: Preparation of (1s, 3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (VIa-1a)

[0778]

[0779] DCM (235 kg) and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (75.2 kg, 263 mol, 3.5 equiv) were charged into a 500 L perfluoroalkoxyalkane (PFA) coated reactor at about 15 to 30 ° C, and the container was cooled to about -75 ° C to -50 ° C. Hydrogen fluoride pyridine (130.2 kg, 1.31 kmol, 61 equiv) was charged into the container via a drop tank at about -75 ° C to -50 ° C, and the tank was then rinsed with about 10-20 kg DCM. After the addition was complete, the mixture was aged at the same temperature for about 1 hour. Separately, V-1a (38.2 kg, 78 mol, 1.0 equiv) and DCM (18.3 kg) were mixed and transferred to the container via a drop tank, maintaining about -75 ° C to -50 ° C at an addition rate of about 10 to 30 kg / h. After the addition was complete, the reaction mixture was warmed to about 15°C to 25°C and aged for about 2 hours until the reaction was considered complete. Water (286.5 kg) and ice (95.5 kg) were added to a separate 1000LPTFE reactor at about 15°C to 30°C. While controlling the temperature to about -5°C to 15°C, the reaction mixture was transferred to an ice-water mixture via a pump and stirred for 4 hours. The mixture was stirred for another about 2 hours at about 0°C to 20°C, and then the phases were separated. The aqueous phase was extracted three times with DCM (191 kg). The combined organic phases were washed twice with water (355.3 kg). The organic layer was transferred to a GL reactor and distilled at a temperature of less than or equal to about 50°C until no distillate was observed, and the contents were cooled to about 20°C to 30°C. Water (68.8 kg) and potassium carbonate (22.9 kg) were mixed separately and then combined with the DCM product mixture at no more than about 30°C. The mixture was stirred for about 2 hours, and then the layers were separated. The aqueous phase was washed three times with DCM (38 kg). At about 0-30° C., HCl was added dropwise to adjust the pH to about 1-2. The phases were separated and the aqueous layer was extracted once with DCM (68.8 kg). The DCM product stream was transferred to a 1000L GL reactor and concentrated at no more than about 50° C., P≤-0.08 MPa, until no fractions were observed. VIa-1a was obtained as an oil after separation by vacuum distillation until about 110° C., P≤5 mmHg. Three batches were combined for vacuum distillation to obtain a yield of 99.1 kg (based on the assay, 55% yield based on the input assay of V-1a). 1 H NMR (DMSO-d 6 ,400MHz)δ=12.42(br s,1H),4.78-4.70(m,1H),2.74-2.65(m,1H),2.59-2.56(m,2H),2.28-2.25(m,2H)ppm. 19F NMR (DMSO-d 6 ,400MHz)δ=-57.9ppm.

[0780] Example 5. Alternative preparation of (1s, 3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (VIa-1a):

[0781]

[0782] Step-1: T3P (1.5 equivalents, 50% solution in EtOAc) was added to a stirred solution of 3-oxocyclobutanecarboxylic acid (XIII) (300 g, 1 equivalent) in anhydrous DCM (3 L, 10 volumes) at 0 ° C under an inert atmosphere, followed by morpholine (1.1 equivalents), and the reaction mixture was stirred at RT for 30 minutes. The reaction mass was then cooled to 0 ° C, and TEA (3 equivalents) was added. The reaction mixture was then stirred at RT for 8 hours. After the reaction was completed as monitored by TLC, the reaction mass was quenched with water (1.5 L). The layers were separated, and the organic layer was washed with 10% NaHCO 3 The combined organic layers were washed with anhydrous Na 2 SO 4 Drying and evaporation of the solvent to dryness gave the product (2) as a yellow viscous liquid which solidified after standing in a refrigerator at -20°C. The crude product was used in the next step without further purification (410 g, 85% yield). Melting point: 36.0°C-45.0°C. 1 H NMR (CDCl 3 ,400MHz)δ=3.70-3.62(m,6H),3.55-3.47(m,4H),3.36-3.28(m,1H),3.24-3.15(m,2H)ppm.

[0783] Step-2: To a stirred solution of XIII-a (100 g, 1 eq.) in anhydrous methanol (70 vols) at 0 °C under inert atmosphere was added NaBH in portions (over a period of 60 min). 4 (0.5 equivalent). The reaction mass was then stirred at RT for 2 hours. At this stage, the progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice water (1 volume), and the solvent was evaporated to dryness. The obtained residue was diluted with water (2 volumes) and acidified to pH = 1 to 2 with 1.5N HCl aqueous solution at 0°C and stirred for 1 hour at RT. Extracted in 15% to 20% methanol in dichloromethane (5x 2L). The combined extracts were dried (Na 2 SO 4 ) and purified by HPLC. 2 SO 4), and the solvent was evaporated to dryness to obtain crude II-2 as a light yellow gum, which slowly solidified after standing (96 g, 95% yield). The crude product obtained was mainly cis isomer (>96%). Melting point: 86.1°C-89.1°C. 1 H NMR (CDCl 3 ,400MHz)δ=4.20(p,J=7.2Hz,1H),3.67-3.62(m,4H),3.60-3.45(m,4H),2.79-2.70(m,1H),2.60-2.53(m,2H),2.27-2.18(m,2H)ppm.

[0784] Step-3: Compound II-2 (50 g, 1 eq.) was dissolved in anhydrous DMSO (75 mL, 1.5 vols) and DBU (1.1 eq.) was added at 0°C and allowed to stir at RT for 1 hour under inert atmosphere. Carbon disulfide (1.5 eq.) was then added dropwise to the reaction mixture at 0°C and stirred at RT for 2 hours. Methyl iodide (1.1 eq.) was then added to the reaction mixture at 0°C and the reaction was stirred at RT for 2 hours. The reaction mass was washed with 10% NaHCO 3 4 OH. 2 PO 4 The product was treated with aqueous solution (500 mL) and EtOAc (1000 mL). The organic layer was separated and washed with water (2 x 250 mL). The aqueous layer was extracted again in EtOAc (2 x 200 mL). The combined extracts were dried and the solvent was removed in vacuo. The crude product V-1c obtained slowly solidified to orange-brown (63 g, 85% yield) after standing overnight at -20 ° C. Melting point: 50.5 ° C-60.1 ° C. 1 H NMR (CDCl 3 ,400MHz)δ=5.51(p,1H,J=7.2Hz),3.70-3.64(m,6H),3.42-3.40(m,2H),2.92-2.86(m,1H),2.78-2.72(m,2H),2.64-2.58(m,5H)ppm.

[0785] Step-4: To a solution of DBH (3 eq.) in DCM (1250 mL, 25 vol.) was added HF-pyridine (22 eq.) in a polyethylene bottle at -78 °C under open air and allowed to stir at the same temperature for 30 min. Then a solution of V-1c (50 g, 1 eq.) in DCM (250 mL, 5 vol.) was added dropwise at -78 °C (reaction mass turned reddish brown) and the reaction mass was stirred at the same temperature for 30 min. Then the reaction mass was stirred at RT for 6 h. The progress of the reaction was monitored by TLC and HPLC. The reaction mixture was slowly poured into NaHSO 3(10 vol, 10% solution), NaOH (40 vol, 10% solution), and NaHCO 3 The mixture of VIa-1b and VIa-2 (200 g) was added to a mixture of 4-nitropropene (200 g) to a pH of about 10 to 11. The layers were separated and the aqueous layer was further extracted in dichloromethane (2 x 1000 mL). The combined extracts were washed with 1.5 N HCl solution (750 mL), water (2 x 750 mL) and the solvent was evaporated to dryness to give a crude product. The crude product VIa-1b was triturated with petroleum ether to remove non-polar impurities (35 g, 76% yield). Melting point: 45.8°C-56.9°C. 1 H NMR (CDCl 3 ,300MHz)=4.58(p,J=7.6Hz,1H),3.67–3.60(m,4H),3.51(bs,4H),2.83-2.73(m,1H),2.59-2.53(m,4H)ppm.

[0786] Step-5: Method-1: 4N HCl in dioxane (50 mL) was added dropwise to VIa-1b (5 g, 1 eq.) at 0°C, followed by addition of water (10 mL). The reaction mass was heated to 100°C for 5 hours. The reaction progress was monitored by TLC. TLC showed that the reaction was complete. The solvent was concentrated in vacuo and the reaction mass was diluted with water (10 mL). The aqueous layer was alkalized with 5% NaOH aqueous solution (pH~10 to 11) and washed with MTBE (3x 50 mL) to remove non-polar impurities. The reaction mass was acidified with 1.5N HCl (pH~1 to 2) and the aqueous layer was further extracted in EtOAc (3x75 mL). The combined extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give product VI (2.9 g, 80% yield).

[0787] Step-5: Method-2: Compound VIa-1b (10 g, 1 eq.) was suspended in concentrated HCl (375 mL, 37.5 volumes) at RT. The reaction mixture was heated to 120 ° C for 4 hours. At this stage, TLC showed that the reaction was complete. The reaction mass was cooled to RT and diluted with water (100 mL). It was extracted in EtOAc (3x 250 mL). The combined extracts were concentrated in vacuo. The obtained residue was suspended in water (50 mL) and basified to pH = 10 to 12 using 5% NaOH solution at 0 ° C. The aqueous layer was washed with MTBE (4x 100 mL). The aqueous layer was cooled to 0 ° C, and acidified to pH = 1 to 2, and extracted in EtOAc (3x 150 mL). The solvent was dried (Na 2 SO 4 ) and concentrated in vacuo to afford the acid to give product VI (4.7 g, 64% yield).

[0788] Example 6: Preparation of methyl 2-((((1s,3s)-3-(morpholine-4-carbonyl)cyclobutyloxy)thiocarbonyl)thio)acetate

[0789]

[0790] 1,1'-thiocarbonyldiimidazole (TCDI) (1424g, 8.0mol, 1.2 equivalents) was added to a stirred mixture of (3-hydroxycyclobutyl)-morpholino-methanone (1225g, 6.7mol, 1.0 equivalents) in DMF (1.85L, 1.5V) at 0-5°C. The reaction mixture was stirred at this temperature for 30 minutes, then heated to 20-30°C and stirred for 4 hours. Subsequently, methyl thioglycolate (711g, 6.7mol, 1.0 equivalents) was charged at 20-30°C, and the reaction mass was stirred at this temperature for 2 hours. The reaction mixture was quenched with ice-cold water (12.4L, 10.0V) and stirred for 30 minutes. The resulting precipitate was filtered and the solid was washed with water (1.2L, 1.0V). The solid was added to MTBE (3.7 L, 3.0 V) and stirred at 40-45 ° C for 1 hour, then cooled to 20-25 ° C and stirred for 30 minutes. The material was then filtered and the filter cake was washed with MTBE (1.2 L, 1.0 V) and then vacuum dried at 40-50 ° C. A mixture of the crude product in 60% methanol in water (3.7 L, 3.0 V) was heated at 55-60 ° C for 1 hour. The material was then cooled to 20-30 ° C and stirred for about 30 minutes, then cooled to 0-5 ° C and stirred for 1 hour. The mixture was then filtered and the solid was washed with a cooled solution of 60% methanol in water (1.2 L, 1.0 V) and then vacuum dried at 45-50 ° C. Yield: 1320 g (63%). Mass spectrum: calculated value MH + = 334.08, found value = 334.19. 1 H NMR (CDCl 3 ,400MHz)δ=5.45(p,J=7.2Hz,1H),3.91(s,2H),3.76(s,3H),3.70-3.57(bs,6H), 3.40-3.33(bs,2H),2.93-2.82(m,1H),2.75-2.67(m,2H),2.62-2.53(m,2H)ppm.

[0791] Example 7: Preparation of morpholino ((1s, 3s)-3-(trifluoromethoxy)cyclobutyl)methanone (VIa-1b)

[0792]

[0793] To a solution of DBDMH (3.5 kg, 12.3 mol, 3.0 equiv) in dichloromethane (6.9 L, 5.0 rel vol) stirred in a Teflon flask at -78°C was added a solution of HF-pyridine (70%, 5.9 kg, 205 mol, 50.0 equiv). The mixture was stirred at this temperature for 1 hour and then a solution of methyl 2-[3-(morpholine-4-carbonyl)cyclobutyloxy]thiocarbonylsulfanyl acetate (1370 g, 4.1 mol, 1.0 equiv) in dichloromethane (5.5 L, 4.0 rel vol) was added dropwise at -78°C. The reaction mixture was stirred at this temperature for 30 minutes and then the reaction mass was allowed to warm to 20-30°C and the mixture was subsequently stirred at this temperature for 2 hours when HPLC showed no starting material remaining. (When the reaction was complete, this was kept overnight). The reaction mixture was then quenched by slowly adding to ice-cold water (13.7L, 10 volumes) and sodium thiosulfate solution (10%, 9.6L, 7.0 volumes). The obtained layer was separated, and the aqueous layer was extracted with dichloromethane (2x 2.7L, 2x 2 volumes). The organic layer was neutralized to about pH 10 with a solution of saturated sodium bicarbonate (4.1L, about 3.0 volumes). The solution was then washed with hydrochloric acid solution (1.5N, 3.4L, 2.5 volumes) and water (2x 3.4L, 2x 2.5 volumes), and then concentrated in vacuo. The heptane solution (3.8L, 3.0 relative volumes) of 10% MTBE was then added to the obtained crude product (1255g, 1.0 equivalents) and cooled to 0-5°C. The mixture was then stirred for 1 hour, then filtered. The solid on the filter was washed with pre-cooled 10% MTBE / heptane (1.3 L, 1.0 volume) and then the resulting solid was dried under vacuum at 40°C. Yield: 975 g (94%)

[0794] Example 8: Preparation of (1s, 3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid tert-butylamine complex (VII-1a)

[0795]

[0796] EtOAc (55.6 kg) and VIa-1a (55.6 kg, 292 mol, 1.0 equiv) were combined in a bucket and then charged to a reactor via a filter. EtOAc (222.4 kg) was then charged to a container via a filter and the contents were mixed for about 0.5 hours. Tert-butylamine (24.5 kg, 335 mol, 1.15 equiv) was charged to the reactor via a pump at about 15-35°C and stirred at about 15-35°C for about 2 hours. The reaction mixture was warmed to about 75-78°C, stirred for about 1 hour, and then cooled to about 20-25°C. VII-1a was separated by centrifugation and washed with EtOAc (55.6 kg). The product was dried at no more than about 55°C to give solid VII-1a. Yield: 70.5 kg (93.5% yield).

[0797] 1 H NMR (DMSO-d 6 ,400MHz)δ=6.05(s,1H),4.57-4.53(m,1H),2.42-2.25(m,3H),2.20-2.11(m,2H),1.21(s,9H)ppm. 19 F NMR (DMSO-d 6 ,376MHz)δ=-57.8ppm.

[0798] Example 9: Preparation of tert-butyl (3-(2-((1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carbonyl)hydrazine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)carbamate monohydrate (IX-1a)

[0799]

[0800] Purified water is charged to the reactor and cooled to about 0-5°C. Sulfuric acid is charged slowly while maintaining the internal temperature at no more than about 35°C and then cooled to about 0-5°C. VII-1a and MTBE are charged and then adjusted at about 20-25°C. The contents are stirred at about 20-25°C for not less than about 1.5 hours to provide a solution containing in situ generated VIa-1a. The layers are settled and then separated. The organic layer is concentrated in vacuo until no distillate is observed while maintaining the jacket temperature at no more than about 50°C (water content no more than 0.5 w / w%).

[0801] 1,1'-Carbonyldiimidazole (CDI) and N,N-dimethylformamide (DMF) are charged to another reactor and cooled to about 0-5°C. The solution containing the in situ generated VIa-1a is transferred to the CDI slurry for not less than about 0.5 hours and then rinsed with DMF. The contents are stirred at about 0-5°C for not less than about 2 hours to form activated VI-1a Once the reaction is complete, VIII-1 is loaded into VI-1 a The mixture was stirred at about 0-5°C and then rinsed with DMF at about 0-5°C. The contents were stirred at about 0-5°C and then adjusted to about 20-25°C for not less than about 0.5 hours. The contents were stirred at about 20-25°C for not less than about 3 hours until the reaction was complete. Potassium carbonate (K 2 CO 3 ) and purified water were charged into another reactor and heated to about 40-45°C. Once the reaction was complete, the reaction mixture was slowly transferred to K 2 CO 3 The mixture was stirred in an aqueous solution for no less than about 1 hour while maintaining the internal temperature at about 40-45°C. The contents were adjusted to about 20-25°C and then stirred at about 20-25°C for no less than about 1 hour. The slurry was filtered and then washed twice with purified water. The wet cake was vacuum dried at no more than about 80°C (target 50°C) until the water content did not exceed about 5.0 w / w%. 1 H NMR (d 6 -DMSO,600MHz):9.74(s,2H),7.58-7.32(m,1H),4.79(p,1H,J=7.5Hz),2.68(p,1H, J=7.5Hz),2.53-2.49(m,2H),2.29-2.24(m,2H),2.12-2.00(m,6H),1.28(s,9H)ppm.

[0802] Optional purification

[0803] The IX-1a dry cake and purified water are loaded into a reactor. The contents are stirred at about 20-25°C for not less than about 6 hours. The slurry is filtered and then washed twice with purified water. The wet cake is vacuum dried at no more than about 80°C (target 50°C) until the water content does not exceed 5.0 w / w%. If the purity of the dry cake is less than 96.0 a / a% by HPLC, the optional purification is repeated.

[0804] Example 10: Preparation of tert-butyl (3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (X-1a)

[0805]

[0806] IX-1a, 4-toluenesulfonyl chloride (TsCl) and acetonitrile (ACN) are charged into a reactor. The contents are stirred and adjusted to about 20-25°C. N,N-diisopropylethylamine (DIPEA) is added and rinsed with ACN. The contents are adjusted to about 20-25°C and stirred at about 20-25°C for not less than about 12 hours. Once the reaction is complete, potassium hydroxide (KOH) solution (6% aqueous solution) is added to the reaction mixture while keeping the internal temperature at no more than about 30°C (target 20-25°C). The resulting slurry is adjusted to about 20-25°C and then stirred at about 20-25°C for not less than about 2 hours until the TsCl content does not exceed about 10ppm. The slurry is filtered and then washed with ACN aqueous solution and purified water. The wet cake is vacuum dried at no more than about 60°C (target 50°C) until the water content is no more than about 0.2w / w% by Karl Fischer method. 1 H NMR (CDCl 3 , 600MHz): 5.12 (s, 1H), 4.68 (p, 1H, J = 8Hz), 3.30 (p, 1H, J = 9Hz), 2.86-2.82 (m, 2H), 2.68-1.63 (m, 2H), 2.58 (s, 6H), 1.45 (s, 9H) ppm.

[0807] Example 11: Preparation of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine (XI-1a)

[0808]

[0809] Acetyl chloride (AcCl) and isopropyl acetate (IPAc) were charged into a reactor and cooled to about 0-5°C. Isopropyl alcohol (IPA) in IPAc was added to the AcCl solution for no less than about 1 hour while nitrogen (N 2 ) atmosphere to maintain the internal temperature not exceeding about 20°C. Adjust the contents to about 20-25°C and then stir at about 20-25°C for not less than about 2 hours to provide an in-situ generated hydrogen chloride (HCl) solution. Charge X-1a and IPAc to another reactor and cool to about 0-5°C. Add the HCl solution to the X-1a / IPAc slurry while stirring under N 2 The internal temperature was maintained at no more than about 15°C under an atmosphere, and then flushed with IPAc. The contents were adjusted to about 40-45°C and then stirred at about 40-45°C for not less than about 2 hours. Once the reaction was complete, the reaction mixture was adjusted to about 20-25°C and slowly added to pre-cooled (0-5°C) potassium phosphate (K 3 PO 4) aqueous solution while maintaining the internal temperature at no more than about 20°C, followed by two rinses with IPAc. The mixture is adjusted to about 20-25°C and stirred for not less than about 1 hour. The layers are allowed to settle and separate. The aqueous layer is extracted with IPAc. If the 3-amino-N'-(cis-3-(trifluoromethoxy)cyclobutane-1-carbonyl)bicyclo[1.1.1]pentane-1-carbohydrazide content is greater than 1.0%, the combined organic layers are additionally washed with aqueous KOH. The combined organic layers are concentrated in vacuo to a target volume of 3V at no more than about 50°C. The resulting concentrate is diluted with IPAc. The contents are adjusted to about 20-25°C, then filtered through a 1 μm disc filter and a 1 μm cartridge filter, followed by rinses with IPAc. The filtrate is concentrated to a target volume of 1.6V while maintaining the jacket temperature at no more than about 50°C. The contents are heated to about 40-50°C, followed by stirring for not less than about 1 hour. The n-heptane is slowly added to the contents and then cooled to about 20-25°C for not less than about 1 hour. The n-heptane is slowly added for not less than about 1 hour, and then the slurry is stirred at about 20-25°C for not less than about 2 hours. The slurry is cooled to about 0-5°C and then stirred at about 0-5°C for not less than about 3 hours. The slurry is filtered and then washed with a pre-cooled n-heptane / IPAc (16:1, v / v) mixture. The wet cake is vacuum dried at no more than about 50°C (target 25°C) until the water content is no more than 0.6w / w% by Karl Fischer method and the sum of the residual solvents (ethyl chloride, 2-chloropropane, tert-butylamine, IPAc, n-heptane, DIPEA) does not exceed 5,000ppm. 1 HNMR (CDCl 3 , 600MHz):4.69(quint,1H,J=8Hz),3.29(quint,1H,J=9Hz),2.85-2.80(m,2H),2.68-2.63(m,2H),2.28(s,6H)ppm. The DSC of the free base is shown in Fig.12 middle.

[0810] Example 12: Preparation of 4-chlorophenoxyacetic acid salt of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine

[0811]

[0812] Acetyl chloride (AcCl) and isopropyl acetate (IPAc) were charged into a reactor and cooled to about 0-5°C. Isopropyl alcohol (IPA) in IPAc was added to the AcCl solution for no less than about 1 hour while nitrogen (N 2) atmosphere to maintain the internal temperature not exceeding about 20°C. Adjust the contents to about 20-25°C and then stir at about 20-25°C for not less than about 2 hours to provide an in-situ generated hydrogen chloride (HCl) solution. Charge X-1a and IPAc to another reactor and cool to about 0-5°C. Add the HCl solution to the X-1a / IPAc slurry while stirring under N 2 The internal temperature was maintained at no more than about 15°C under an atmosphere, and then flushed with IPAc. The contents were adjusted to about 40-45°C and then stirred at about 40-45°C for not less than about 2 hours. Once the reaction was complete, the reaction mixture was adjusted to about 20-25°C and slowly added to pre-cooled (0-5°C) potassium phosphate (K 3 PO 4 ) aqueous solution while maintaining the internal temperature at no more than about 20°C, followed by two rinses with IPAc. The mixture was adjusted to about 20-25°C and stirred for not less than about 1 hour. The layers were settled and separated. The aqueous layer was extracted with IPAc. The combined organic layers were concentrated to a target volume of 3V under vacuum at no more than about 50°C until the water content did not exceed 0.3% w / w. The resulting concentrate was diluted with IPAc. The contents were adjusted to about 20-25°C and then filtered through a 1 μm disc filter and a 1 μm cartridge filter, followed by rinsing with IPAc. The filtrate was concentrated to a target volume of 2.5V while maintaining the jacket temperature at no more than about 50°C. The contents were adjusted to about 20-25°C. An IPA solution of 4-chlorophenoxyacetic acid was prepared separately and then slowly added to the concentrated XI-1a / IPAc mixture at 20-25°C over not less than 2 hours and rinsed with IPA. The contents were then adjusted to 0-5°C over 1 hour and mixed for not less than 1 hour. The slurry was vacuum filtered and deliquated. The container was rinsed with pre-cooled IPA and the filter cake was dried under vacuum at no more than 50°C. 1 H NMR (600MHz, d 6 -DMSO)=7.32-7.30(m,2H),6.93-6.91(m,2H),4.88(quint,1H,J=7.2Hz),4.61(s, 2H), 3.39 (quint, 1H, J = 6.0Hz), 2.85-2.82 (m, 2H), 2.50-2.45 (m, 2H), 2.12 (s, 6H).

[0813] refer to Fig. 9 The DSC of 4-chlorophenoxyacetic acid salt of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine includes an endothermic peak with an onset temperature of about 162°C.

[0814] Example 13: Preparation of the Hydrogen Oxalate Salt of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine

[0815]

[0816] To a 3-neck 100 mL round-bottom flask, 5 g of compound XI-1a, 11.56 g (10 equivalents) of oxalic acid and 50 mL (10 V) of MeCN were added. The contents were heated to 40-45 ° C and stirred for 19 hours. The contents were cooled to 20-25 ° C and stirred for about 1 hour. The contents were filtered and rinsed with 20 mL (4 V) of MeCN. The wet cake was vacuum dried in a 30 ° C oven to obtain the title compound (97% yield). 1 H NMR (d 6 -DMSO, 600MHz): 4.89 (quint, 1H, J = 7.8Hz), 3.41 (quint, 1H, J = 8.4Hz), 2.85-2.81 (m, 2H), 2.51-2.46 (m, 2H), 2.43 (s, 6H) ppm. The DSC of the salt is shown in Fig.14 middle.

[0817] Example 14: 2-(4-chlorophenoxy)-N-(3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-

[0818] Preparation of 1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)acetamide (I)

[0819]

[0820] In N 2 XI-1a, 2-(4-chlorophenoxy)acetic acid (XII-1a) and 2-MeTHF were charged into a reactor and cooled to 0-5°C. TEA was added while N 2 Keep the internal temperature no higher than about 10°C and rinse with 2-methyltetrahydrofuran (2-MeTHF). Stir the contents at about 0-5°C for not less than about 20 minutes. Slowly add a solution of diphenylphosphinyl chloride in 2-MeTHF while stirring under N 2 Keep the internal temperature no higher than about 10°C and rinse with 2-MeTHF. Warm the contents to about 20-25°C and stir for not less than about 1 hour until the reaction is complete. Cool the contents to about 0-5°C and then add 10% K 2 CO 3 aqueous solution while maintaining the internal temperature at no more than about 10°C. After phase separation, the organic layer was washed with 10% K2 CO 3 aqueous solution and 5% K 2 CO 3 Aqueous solution washing. The organic layer is concentrated to a target volume of 3V. 2-MeTHF is added, and the contents are then concentrated to a target volume of 3V to control the water content to be no more than about 0.3w / w%. IPA is added, and the contents are then heated to about 60-70°C to dissolve all solids. The contents are filtered through a cartridge filter at about 60-70°C and rinsed with preheated IPA (60-70°C). The filtrate is concentrated to a target volume of 4V. IPA is added and concentrated to a target volume of 4V to control the residual 2-MeTHF to be no more than 1% by GC relative to IPA. The contents are adjusted to about 20-25°C. n-heptane is added, and then heated to about 60-80°C to dissolve all solids. The contents are adjusted to about 62-70°C. Seed crystals are loaded and stirred for no less than about 0.5 hours. n-heptane is added while maintaining an internal temperature of about 60-65°C. The contents are cooled to about 0-5°C (5°C per hour) within 12 hours. The slurry is stirred for no less than 2 hours. The slurry was filtered and washed with a pre-cooled IPA / n-heptane mixture. The wet cake was dried under vacuum at 25° C. If any individual impurity other than 2-(4-chlorophenoxy)-N-(3-(5-(trans-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)acetamide was greater than 0.12%, recrystallization was performed.

[0821] 1 H NMR (600 MHz, MeCN-d 3 ):7.65(s,1H),7.31(d,2H,J=9Hz),6.96(d,2H,J=9Hz),4.79(m,1H),4.40(s,2H),3.3 4-3.29(m,1H),2.96-2.82(q,2H,J=9Hz),2.59-2.54(q,2H,J=10Hz),2.53(s,6H)ppm.

[0822] Example 15: Alternative Preparation of 2-(4-chlorophenoxy)-N-(3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-yl)acetamide (I)

[0823]

[0824] In N 24-Chlorophenoxyacetic acid salt of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine (XI-1a) and 2-MeTHF were charged into a reactor and cooled to 0-5°C. TEA was added and the mixture was stirred under N 2 Keep the internal temperature no higher than about 10°C and rinse with 2-methyltetrahydrofuran (2-MeTHF). Stir the contents at about 0-5°C for not less than about 20 minutes. Slowly add a solution of diphenylphosphinyl chloride in 2-MeTHF while stirring under N 2 Keep the internal temperature no more than about 10°C under the conditions and rinse with 2-MeTHF. Warm the contents to about 20-25°C and then stir for not less than about 1 hour until the reaction is complete. Cool the mixture to about 0-5°C and add 10% potassium carbonate aqueous solution at no more than 10°C for no less than 1 hour. Raise the temperature to about 45-50°C and stir for no less than 1 hour. Separate the layers and charge the organic phase with 10% potassium carbonate aqueous solution again and stir for no less than 0.5 hour at about 45-50°C. Separate the layers and charge the organic phase with 5% potassium carbonate aqueous solution and stir for no less than 0.5 hour at about 45-50°C. Separate the layers and concentrate the organic layer in vacuo at no more than 50°C to about 3.6V. Charge MeTHF and concentrate the mixture in vacuo at no more than 50°C to about 3.6V until the water content does not exceed 1% w / w. Charge MeTHF into a container and cool the mixture to 20-25°C. The solution is filtered through a cartridge filter, and the filtrate is vacuum concentrated to about 2.4V at no more than 50°C. The solvent is exchanged with IPA until the MeTHF:IPA ratio does not exceed 20% by weight. The mixture temperature is adjusted to about 45-50°C. Heptane is loaded, and the contents are adjusted to 60-70°C to generate a uniform solution. The temperature is then adjusted to 50-55°C and stirred for no less than 2 hours. Additional heptane is loaded, and the temperature is then adjusted to about 0-5°C and stirred for no less than 2 hours. The solid is separated by filtration and washed with a pre-cooled IPA / heptane solution, and thoroughly deliquified. The solid is vacuum dried at no more than 25°C.

[0825] Example 16: Salt Screening of Compounds of Formula VIa-1a

[0826] The selected solvent (ethyl acetate (EtOAc) or toluene) is added to a vial containing about 22 mg of the compound of Formula VIa-1a and an equimolar amount of the selected base to prepare a slurry, as described in Table 2. The slurry is stirred at room temperature (RT) for 2 to 3 days. If a solid precipitates out, the solid is recovered by centrifugation and then vacuum dried at RT for XRPD analysis. The sample without precipitation after the solution-mediated reaction is cooled in a -15°C refrigerator for 1 day. If a solid precipitates out at this time, the solid is recovered by centrifugation and then vacuum dried at RT for XRPD analysis. If no solid is obtained after cooling, n-heptane is added and the mixture is further stirred for 2 days. The solution that has not precipitated after the addition of n-heptane is then uncapped to slowly evaporate at ambient temperature until a solid is formed. The results are summarized in Table 2 below:

[0827] Table 2

[0828]

[0829] Example 17: Expansion of Certain Salts of Compounds of Formula VIa-1a

[0830] Compound VIa-1a, DCHA Salt Form A

[0831] About 2.5 mmol of the compound of Formula VIa-1a and DCHA (1.1 eq.) were added to 20 mL of EtOAc and stirred at RT for 2 days. The solid was recovered by centrifugation and dried under vacuum at 40° C. for about 1 day. The solid was identified as the compound of Formula VIa-1a, DCHA Salt Form A.

[0832] Compound VIa-1a, L-arginine salt form A

[0833] About 2.5mmol of the compound of formula VIa-1a and L-arginine (1.1 equivalents) were added to 20mL EtOAc and stirred at RT for about 5 days. After stirring at RT for 2 days, the wet cake was characterized by XRPD and identified as the compound of formula VIa-1a, L-arginine salt form B. After stirring at RT for about 3 more days, the wet cake was characterized by XRPD and identified as the compound of formula VIa-1a, L-arginine salt form A. The solid was recovered by centrifugation and vacuum dried at 40°C for 2 days. The obtained solid was then further vacuum dried at 60°C for 2 days. The solid was identified as the compound of formula VIa-1a, L-arginine salt form A.

[0834] Compound VIa-1a, TMA Salt Form A

[0835] About 2.5 mmol of the compound of formula VIa-1a and tromethamine (TMA) (1.1 equivalents) were added to 20 mL of EtOAc and stirred at RT for about 2 days. The solid was recovered by centrifugation and dried under vacuum at 40°C for about 1 day. The solid was identified as the compound of formula VIa-1a, TMA salt form A. However, compared to compound VIa-1a, TMA salt form A prepared by Example 15, the XRPD pattern included an additional peak at 18.1°.

[0836] Example 18: Characterization of Salt Forms

[0837] As illustrated in Table 2, eighteen salts were obtained from the above experiments. These salts were characterized by XRPD, TGA and DSC. The data for the selected salts are presented above. Additional results are summarized in Table 3.

[0838] Table 3

[0839]

[0840] The hygroscopicity, purity and solid form stability of several salts were further investigated. To determine the solid form stability, glass weigh bottles containing approximately 20 mg of sample were maintained at (1) 60°C, (2) 25°C / 60% RH and (3) 40°C / 75% RH. After 1 week and 2 weeks, XRPD and GC analyses were performed to investigate the physical and chemical stability of the selected forms under the corresponding conditions. The results are summarized in Table 4 below.

[0841] Table 4

[0842]

[0843] # Based on DSC results, the mixture contains TMA salt form A and unidentified forms

[0844] & Complete sublimation by pressing at 60°C for 1 day

[0845] Compound VIa-1a TBA Salt Form A

[0846] Compound VIa-1a TBA salt form A is obtained by reaction mediated by an equimolar amount of tert-butylamine in ethyl acetate (EtOAc) or toluene. Figure 1 The XRPD pattern of Compound VIa-1a TBA Salt Form A is depicted. Figure 2 As shown, no weight loss was observed in the TGA curve until 70° C. The sample can sublime above 100° C. The DSC curve shows an endothermic peak at about 171° C. The DSC analysis was performed using a Tzero sealed pan without a pinhole. 1H NMR indicated that in the absence of organic solvents, the compound of Formula VIa-1a formed a salt with tert-butylamine in a ratio of about 1:1. Form A is an anhydrate.

[0847] Compound VIa-1a DCHA Salt Form A

[0848] Compound VIa-1a DCHA salt form A was obtained by reaction mediated by an equimolar amount of dicyclohexylamine (DCHA) in EtOAc. Figure 3 The XRPD pattern of Compound VIa-1a DCHA Salt Form A is depicted. Figure 4 As shown, a weight loss of 0.8% was observed in the TGA curve up to 100°C, and the sample may sublime above 110°C. DSC analysis was performed by using a Tzero sealed pan without a pinhole. The DSC curve showed an endothermic peak at about 139°C corresponding to melting. 1 H NMR results show that in the absence of organic solvents, a salt is formed between the compound of Formula VIa-1a and DCHA at a ratio of about 1:1. Compound VIa-1a DCHA Salt Form A is an anhydrous substance. DVS analysis shows that Compound VIa-1a DCHA Salt Form A is non-hygroscopic; and no form conversion is detected after the DVS test. PLM images show that Compound VIa-1a DCHA Salt Form A crystals are needle-shaped. Form B is an anhydrous substance.

[0849] Compound VIa-1a, L-arginine salt form A

[0850] Compound VIa-1a, L-arginine salt form A is obtained by reaction mediated by an equimolar amount of L-arginine in EtOAc or toluene. Figure 5 The XRPD pattern of Compound VIa-1a, L-arginine salt Form A is depicted. Figure 6 As shown, a weight loss of 1.0% is observed in the TGA curve up to 150° C., and the sample can be decomposed by heating above 170° C. The DSC curve shows an endothermic peak at about 161° C. corresponding to melting. 1 H NMR results show that in the absence of an organic solvent, a salt is formed between the compound of Formula VIa-1a and L-arginine at a ratio of about 1:1. Compound VIa-1a, L-arginine salt Form A may be an anhydrous substance. DVS analysis of Compound VIa-1a, L-arginine salt Form A showed a weight increase of about 28% at 80% RH and a weight increase of about 74% at 95% RH, indicating high hygroscopicity. Compound VIa-1a, L-arginine salt Form A deliquesces at high humidity. PLM images show that Compound VIa-1a, L-arginine salt Form A crystals are small particles aggregated together.

[0851] Compound VIa-1a, TMA Salt Form A

[0852] Compound VIa-1a, tromethamine (TMA) salt form A is obtained by reaction mediated by an equimolar amount of TMA in EtOAc or toluene. Figure 7 The XRPD pattern of Compound VIa-1a, TMA Salt Form A is depicted. Figure 8 As shown, no weight loss was observed in the TGA curve until 100°C, and the sample may have decomposed above 135°C. DSC analysis was performed by using a Tzero sealed pan without a pinhole. The DSC curve showed endothermic peaks at about 123°C and 136°C. 1 H NMR shows that in the absence of organic solvents, the compound of Formula VIa-1a forms a salt with TMA at a ratio of about 1:1. Compound VIa-1a, TMA Salt Form A may be an anhydrous substance. DVS analysis of Compound VIa-1a, TMA Salt Form A shows a weight increase of about 0.1% at 80% RH, a weight increase of about 47% at 95% RH, and a weight increase of about 7% at 0% RH. Compound VIa-1a, TMA Salt Form A is non-hygroscopic, but can be deliquesced at high humidity (>90% RH). PLM images of Compound VIa-1a, TMA Salt Form A show plate-like crystals.

[0853] Example 19: Determination of the crystal structure of the 4-chlorophenoxyacetic acid salt of the compound of formula XI-1a by microED

[0854]

[0855] Thermo Scientific Glacios 200 kV cryo-TEM with a Thermo Scientific Ceta-D detector was used at 200 kV, 98(2) K, and 10 -7 MicroED data were collected under high vacuum at 1000 psi. The sample was prepared by adding 4-chlorophenoxyacetic acid salt powder of the compound of formula XI-1a to the electron microscope grid and rapidly freezing the grid in liquid ethane using a Thermo Scientific Vitrobot cryo-EM sample preparation system. Data collection was performed using a ThermoScientific EPU-D. Data were processed using XDS, SHELXT, and SHELXL. Twenty-six diffraction frames were collected from 30 different particles. They were indexed and integrated by XDS. The unit cell parameters were α=90°, β=108.3(2)°, γ=90°, volume Twenty-two datasets produced the best quality and were merged using XSCALE. The merged dataset has 47570 total reflections, of which 3003 are independent. The resolution of the reflections was cut off at The Rint value was 0.3625. The crystal system was determined to be a monoclinic system, the space group was C2 / c (No. 15), and Z' was 1.

[0856] Example 20: Single crystal structure X-ray determination of the compound of formula VII-1a

[0857]

[0858] Crystals of the compound of formula VII-1a were obtained by liquid evaporation from EtOAc solution at room temperature. Suitable single crystals with dimensions of 0.35×0.08×0.06 mm were mounted on glass fiber for SCXRD measurements. SCXRD was collected using SuperNova (Rigaku JPN). The X-ray source was a Cu tube The crystal was kept at a stable temperature of 150.0 K during data collection. Preliminary checks and data collection were performed and analyzed using the CrysAlisPro software package. The unit cell parameters and orientation matrix for data collection were retrieved and corrected by CrysAlisPro using a set angle of 1547 reflections in the range 3.235° < θ < 74.111°. The final data integrity was 99.7% (θ = 66.97°). The structure was solved in space group P-1 with the XT (Sheldrick, 2015) structure solver using the intrinsic phasing method and by using Olex2 as a graphical interface. The F-based 2 The model was refined using the full matrix least squares method minimized using the XL version (Sheldrick, 2015). All non-hydrogen atoms were anisotropically corrected. The positions of all hydrogen atoms were calculated using geometry and refined using the riding model. The crystal structure representation and thermal ellipsoids were generated by Diamond. The crystal system of the single crystal of VII-1a is triclinic and the space group is P-1. The unit cell parameters are: α=101.253(6)°, β=91.442(6)°, γ=100.968(6)°,

[0859] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0860] The disclosure illustratively described herein is appropriately practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," and the like are to be understood expansively and without limitation. In addition, the terms and expressions employed herein have been used as descriptive and non-limiting terms, and when such terms and expressions are used, it is not intended to exclude any equivalents of the features shown and described, or portions thereof, but it should be recognized that various modifications are possible within the scope of the disclosure claimed.

[0861] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each were individually incorporated by reference. In the event of a conflict, the present specification, including definitions, will control.

[0862] It should be understood that although the present disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate rather than limit the scope of the present disclosure. Other aspects, advantages and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure belongs.

Claims

1. A salt of a compound of formula VIa-1a: wherein the salt comprises an amine selected from the group consisting of tert-butylamine, L-lysine, arginine, piperazine, dicyclohexylamine, tromethamine, ethanolamine, diethanolamine, N,N,N',N'-tetramethylethylenediamine, triisobutylamine, 4-methylmorpholine, dibutylamine, tromethamine, dehydroabietylamine, N-methyldicyclohexylamine, diethylamine, diisopropylethylamine, diisopropylamine, imidazole, 1,4-diazabicyclo[2.2.2]octane (DABCO), ammonia and dibenzylamine, or a cation selected from the group consisting of magnesium, sodium, potassium, calcium, zinc, lithium, cesium, tetramethylammonium and ammonium.

2. The salt of claim 1 having the formula VII-2a: Wherein the N(R 46 )3 part is selected from the group consisting of tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine and dibenzylamine.

3. The salt of claim 1, which has the formula VII-1a:

4. The salt of claim 1 having the formula VII-1b:

5. The salt of claim 1, which has the formula VII-1c:

6. The salt of claim 1, which has the formula VII-1d:

7. Form A polymorph of the tert-butylamine (TBA) salt of (1s, 3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (Compound VIa-1a, TBA Salt Form A), which exhibits an X-ray powder diffraction pattern having one or more peaks selected from 6.6, 11.6, 12.1, 15.6, 19.8, 20.8, 26.5 and 27.3°2q±0.2°2q, wherein the X-ray powder diffraction pattern is prepared using Cu-Kα radiation.

8. The compound VIa-1a TBA salt form A polymorph according to claim 7, further characterized by: i) the X-ray powder diffraction pattern further comprises one or more peaks selected from 13.2, 14.4, 15.8, 17.2, 22.0, 23.2, 24.3, 32.9, 33.2 and 36.7°2q±0.2°2q; ii) the diffraction pattern is substantially as shown in Figure 1; iii) differential scanning calorimetry (DSC) includes an endotherm at about 171°C; or iv) Thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG2.

9. Form A polymorph of the dicyclohexylamine (DCHA) salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (Compound VIa-1a, DCHA salt Form A), which exhibits an X-ray powder diffraction pattern having one or more peaks selected from 6.7, 10.6, 17.2, 19.0 and 19.6°2q±0.2°2q, wherein the X-ray powder diffraction pattern is prepared using Cu-Kα radiation.

10. The DCHA salt form A polymorph of compound VIa-1a according to claim 9, further characterized by: i) the X-ray powder diffraction pattern further comprises one or more peaks selected from 13.5, 15.1, 20.3, 21.4, 27.2, 28.0, 28.8, 35.4, 36.8 and 39.0°2q±0.2°2q; ii) the diffraction pattern is substantially as shown in FIG3 ; iii) differential scanning calorimetry (DSC) includes an endotherm at about 139°C; or iv) Thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG4.

11. Form A polymorph of the tromethamine (TMA) salt of (1s, 3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (Compound VIa-1d, TMA salt Form A), which exhibits an X-ray powder diffraction pattern having one or more peaks selected from 6.6, 13.2, 19.9, 20.1, 21.8 and 26.7°2q±0.2°2q, wherein the X-ray powder diffraction pattern is prepared using Cu-Kα radiation.

12. The Form A polymorph of claim 11, further characterized by: i) the X-ray powder diffraction pattern further comprises one or more peaks selected from 15.9, 17.8, 18.9, 19.5, 20.9, 22.5, 28.4, 29.8, 33.5, 34.3 and 34.8°2q±0.2°2q; ii) the diffraction pattern is substantially as shown in FIG7 ; iii) differential scanning calorimetry (DSC) includes endotherms at about 123°C and about 136°C; or iv) Thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG8.

13. A hydrate of a compound of formula IX-1a:

14. A hydrogen oxalate salt of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine having the following structure:

15. A 4-chlorophenoxyacetic acid salt of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine having the following structure:

16. A crystalline 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine (Compound XI-1a) free base Form A: Features The X-ray powder diffraction pattern includes one or more, or two, or three, or four, or five, or six, or seven peaks selected from 6.6, 10.9, 14.5, 19.9, 21.9, 25.0, 25.9° 2θ ± 0.2° 2θ, as measured on a diffractometer using Cu-Kα radiation. Sure.

17. A compound selected from the group consisting of: or their respective salts.

18. A method for preparing a compound of formula V-2: or a salt thereof, which comprises making a compound of formula IIa-1: contacting with an activating agent and then with a compound of formula IV: contacting under reaction conditions sufficient to provide a compound of formula V-2, wherein: n is 0 or 1; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; X 2 O or NR 53 ; R 51 For hydrogen, C 1-12 Alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution; R 52 For hydrogen, C 1-12 Alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substituted; and R 53 For hydrogen, C 1-12 Alkyl or silyl, wherein the C 1-12 C alkyl or silyl optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino 1-12 Alkyl substitution; or R 51 and R 53 Together with the nitrogen atom to which they are attached, they form a C which is independently optionally substituted with one or more halo, or independently optionally substituted with one or more oxo, halo, hydroxyl or amino. 1-12 an alkyl-substituted heterocyclic group; Provided that the compound is not cis-ethyl 3-[(methylthio)thiomethoxy]cyclobutanecarboxylate.

19. A method for preparing the following: a compound of formula IX-2: or a solvate thereof, comprising: Make a salt of the compound of formula VIa-1a: contacting with an acid under reaction conditions sufficient to provide the compound of formula VIa-1a; as well as The compound of formula VIa-1a is reacted with a compound of formula VIIIa or a salt thereof: contacting under conditions sufficient to provide said compound of formula IX-2 or a solvate thereof, Where R 73 is hydrogen, a protecting group or 20. The method of claim 19, wherein R 73 is tert-butyloxycarbonyl or has the formula 21. The method of claim 19 or 20, wherein the salt is of formula VII-2a: Wherein the N(R 46 )3 part is selected from the group consisting of tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine and dibenzylamine.

22. A method for preparing the following: a compound of formula X-2: or a salt thereof, comprising: Make a salt of the compound of formula VIa-1a: contacting with a first acid under reaction conditions sufficient to provide the compound of formula VIa-1a; as well as The compound of formula VIa-1a is reacted with a compound of formula VIIIa or a salt thereof: In sufficient amount to provide a compound of formula IX-2: or a solvate thereof; and The compound of formula IX-2 or a solvate thereof is contacted with a dehydrating agent and a base under reaction conditions sufficient to provide the compound of formula X-2 or a salt thereof, wherein R 73 is hydrogen, a protecting group or 23. The method of claim 22, wherein the salt of the compound of formula VIa-1a is of formula VII-2a: Wherein the N(R 46 )3 part is selected from the group consisting of tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine and dibenzylamine.

24. The method of claim 22 or 23, wherein R 73 is tert-butyloxycarbonyl or has the formula 25. A method for preparing a compound of formula I: or a salt thereof, comprising: Make a salt of the compound of formula VIa-1a: contacting with a first acid under reaction conditions sufficient to provide the compound of formula VIa-1a; as well as The compound of formula VIa-1a is reacted with a compound of formula VIIIa or a salt thereof: In sufficient amount to provide a compound of formula IX-2: or its solvate; The compound of formula IX-2 or a solvate thereof is treated with a dehydrating agent and a base in an amount sufficient to provide a compound of formula X-2: or a salt thereof; and The compound of formula X-2 or a salt thereof is subjected to an incubation sufficient to provide a compound of formula XI-1a: or a salt thereof under deprotection conditions, and Optionally, the compound of formula XI-1a or a salt thereof is reacted with a compound of formula XII-1: under reaction conditions sufficient to provide a compound of Formula I or a salt thereof, wherein R 73 is hydrogen, a protecting group or 26. The method of claim 25, wherein the salt of the compound of formula VIa-1a is of formula VII-2a: Wherein the N(R 46 )3 part is selected from the group consisting of tert-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine and dibenzylamine.

27. The method of claim 25 or 26, wherein the salt of the compound of formula X-2 is hydrochloride, oxalate and 4-chlorophenoxyacetate.

28. The method of any one of claims 25-27, wherein the deprotection conditions comprise contacting the compound of Formula X-2 with a second acid.

29. The method of claim 25, wherein the reaction conditions for providing the compound of Formula I comprise: a) temperatures from about 0°C to about 5°C, and elevated temperatures from about 20°C to about 25°C; and / or b) optionally in the presence of a base and diphenylphosphinic chloride.

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