Preparation process of a modulator of eukaryotic initiation factor 2B

Abstract

The present disclosure as a whole relates to compound (I-1): JPEG2025523444000168.jpg37164 or its stereoisomers or mixtures of stereoisomers, or salts of each of them, and methods for the preparation of compounds and salts useful in their synthesis. The present application relates to small molecule modulators of eukaryotic initiation factor 2B useful as therapeutic agents, synthetic processes for novel intermediates, and methods for their synthesis. The processes described herein avoid malodorous reactants or intermediates, improve purity, or provide salts or solid (e.g., crystalline) forms such that the process can avoid oil or other liquid forms that can make subsequent purification processes or handling difficult.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of U.S. Provisional Application No. 63 / 355,072, filed on June 23, 2022, under 35 U.S.C. § 119(e), the content of which is hereby incorporated by reference in its entirety.

[0002] This application relates to small - molecule modulators of eukaryotic initiation factor 2B (eIF2B) that are useful as therapeutic agents, synthetic processes for novel intermediates, and methods for their synthesis.

Summary of the Invention

Means for Solving the Problems

[0003] The eukaryotic initiation factor 2B (eIF2B) and eukaryotic initiation factor 2 (eIF2), which are multi - subunit protein complexes, are required for the initiation and regulation of protein synthesis in eukaryotic cells. The interaction between eIF2B and eIF2 plays an important role in the integrated stress response (ISR) pathway. Activation of this pathway results, in part, in the expression of ATF4 (activating transcription factor 4) and the formation of stress granules. Abnormal ISR activation is seen in multiple neurodegenerative diseases and is strongly functionally associated with the pathology characterized by the RNA - binding / stress granule protein TAR DNA - binding protein (TARDBP), also known as TDP43. Impairment of eIF2B activity correlates with activation of the ISR pathway, which is implicated in a variety of neurodegenerative diseases including Parkinson's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease and frontotemporal dementia, and leukoencephalopathy. In contrast, activation of eIF2B inhibits the ISR and ISR - dependent stress granule formation and has been found to be neuroprotective in these disease models. Small - molecule modulators of eIF2B are desirable for treating these pathologies.

[0004] Improved synthetic methods of low molecular weight modulators of eukaryotic initiation factor 2B are disclosed herein. In certain embodiments, herein, Formula I-1:

Chemical formula

[0005] In certain embodiments, the process described herein is directed to the preparation of a compound of Formula I:

Chemical formula

[0006] In some embodiments, the process described herein avoids malodorous reactants or intermediates, improves purity, or provides a salt or solid (e.g., crystalline) form such that the process can avoid an oil or other liquid form that can make subsequent purification processes or handling difficult.

Brief Description of the Drawings

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[0025] 1. Definitions As used herein, the following words, phrases, and symbols are generally intended to have the meanings as defined below, unless otherwise indicated by the context in which they are used.

[0026] A dash symbol ("-") that is not between two characters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached via a carbon atom. Dash symbols before or after a chemical group are a matter of convenience, and the chemical groups may be represented with or without one or more dash symbols without losing their customary meaning. A wavy or broken line drawn as a line in a structure indicates the specified point of attachment of a group. Unless otherwise required chemically or structurally, no directionality or stereochemistry is indicated or implied by the order in which chemical groups are described or named.

[0027] The prefix "C u-v " indicates that the group that follows has u to v carbon atoms. For example, "C 1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0028] References to "about" values or parameters herein include (and describe) embodiments that are directed to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. Also, the term "about X" includes the description of "X". Also, the singular forms "a" and "the" include the plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "(the) compound" includes a plurality of such compounds, and a reference to "(the) assay" includes references to one or more assays and their equivalents known to those of skill in the art.

[0029] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl 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 has (alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons may be included. Thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), iso-butyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0030] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups may also be referred to as "alkylene" groups or "alkylenyl" groups, "arylene" groups or "arylenyl" groups, respectively. Also, unless otherwise explicitly indicated, when a combination of groups is referred to in this specification as one moiety, for example, as arylalkyl or aralkyl, the last-mentioned group contains the atom that attaches that moiety to the rest of the molecule.

[0031] "Alkenyl" refers to an alkyl group that contains at least one carbon-carbon double bond and has 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 alkenyl). Examples of alkenyl groups include, for example, ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0032] "Alkynyl" contains at least one carbon-carbon triple bond and has 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 alkynyl), and refers to an alkyl group. The term "alkynyl" also includes a group having one triple bond and one double bond.

[0033] "Alkoxy" refers to a group of the formula "alkyl-O-". Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0034] "Alkoxyalkyl" refers to a group of the formula "alkyl-O-alkyl".

[0035] "Alkylthio" refers to a group of the formula "alkyl-S-". "Alkylsulfinyl" refers to a group of the formula "alkyl-S(O)-". "Alkylsulfonyl" refers to a group of the formula "alkyl-S(O)2-". "Alkylsulfonylalkyl" refers to -alkyl-S(O)2-alkyl.

[0036] "Acyl" refers to a group of the formula -C(O)R y wherein 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 acyl groups include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0037] "Amide" refers to a group of the formula -C(O)NRy R z The term "C-amide" group referring to a group of the formula -C(O)R, and -NR y C(O)R z The term "N-amide" group referring to a group of the formula -NR-C(O)R, wherein R y and R z are 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 together form cycloalkyl or heterocyclyl, each of which may be optionally substituted as defined herein.

[0038] "Amino" refers to a group of the formula -NR y R z wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0039] "Aminoalkyl" refers to a group of the formula "-alkyl-NR y R z " wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0040] "Amidino" refers to -C(NR y )(NR z 2), wherein R y and R zis independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may optionally be substituted as defined herein.

[0041] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings including fused systems (e.g., bicyclic or tricyclic). As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbocyclic atoms (i.e., C 6-12 aryl), or 6 to 10 carbocyclic atoms (i.e., C 6-10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl never includes nor overlaps with heteroaryl as defined below. When one or more aryl groups are fused to heteroaryl, the resulting ring system is heteroaryl. When one or more aryl groups are fused to heterocyclyl, the resulting ring system is heterocyclyl.

[0042] "Arylalkyl" or "aralkyl" refers to a group of the form "aryl-alkyl-".

[0043] "Carbamoyl" refers to both an "O-carbamoyl" group of the form -OC(O)NR y R z and an "N-carbamoyl" group of the form -NR y C(O)OR z wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may optionally be substituted as defined herein.

[0044] "Carboxyl ester" or "ester" refers to both -OC(O)R x and -C(O)OR x wherein R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0045] "Cyanoalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by a cyano (-CN) group.

[0046] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused ring systems, bridged ring systems, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and carbocyclic fused ring systems having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl 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 3-6It has (cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, etc. Further, the term cycloalkyl is intended to include any non-aromatic ring that can be fused to an aryl ring, regardless of the bond to the rest of the molecule. Still further, cycloalkyl also includes "spirocycloalkyl" when there are two positions with respect to substitution on the same carbon atom, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0047] "Cycloalkoxy" refers to "-O-cycloalkyl".

[0048] "Cycloalkyl" refers to the group "cycloalkyl-alkyl-".

[0049] "Cycloalkylalkoxy" refers to "-O-alkyl-cycloalkyl".

[0050] "Guanidino" is -NR y C(=NR z )(NR y R z ) and in the formula, each R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, and each of these may be optionally substituted as defined herein.

[0051] "Hydrazino" refers to -NHNH2.

[0052] "Imino" refers to the group -C(NR y )R z and in the formula, R y and Rz is, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0053] "Imide" refers to a -C(O)NR y C(O)R z group, where R y and R z are, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0054] "Halogen" or "halo" refers to an atom occupying Group VIIA of the periodic table, for example, fluoro, chloro, bromo, or iodo.

[0055] "Haloalkyl" refers to a non-branched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by halogen. For example, if the residue is substituted with more than one halogen, it may be referred to by the use of a prefix corresponding to the number of attached halogen moieties. Dihaloalkyl and trihaloalkyl refer to an alkyl substituted with two ("di") or three ("tri") halo groups, and these halo groups may, but not necessarily, be the same halogen. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0056] "Haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms are replaced by halogen.

[0057] "Hydroxyalkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms are replaced by hydroxy groups.

[0058] "Heteroalkyl" refers to an alkyl group in which one or more of the 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 remainder of the molecule is via a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, 1, 2, or 3 carbon atoms may each independently be 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 optionally be substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.), and amines (e.g., -CH2NR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3, etc. (wherein R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein). As used herein, heteroalkyl contains from 1 to 10 carbon atoms, from 1 to 8 carbon atoms, or from 1 to 4 carbon atoms and from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom.

[0059] “Heteroalkylene” refers to a divalent alkyl group (i.e., alkylene) in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term “heteroalkylene” includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, 1, 2, or 3 carbon atoms may each independently be 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 heteroalkylene groups include, for example, -CH2OCH2-, -CH(CH3)OCH2-, -CH2CH2OCH2-, -CH2CH2OCH2CH2OCH2-, -CH2SCH2-, -CH(CH3)SCH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2SCH2-, -CH2S(O)2CH2-, -CH(CH3)S(O)2CH2-, -CH2CH2S(O)2CH2-, -CH2CH2S(O)2CH2CH2OCH2-, -CH2NR y CH2-, -CH(CH3)NR y CH2-, -CH2CH2NR y CH2-, -CH2CH2NR y CH2CH2NR y CH2-, etc. (where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein). As used herein, heteroalkyl contains from 1 to 10 carbon atoms, from 1 to 8 carbon atoms, or from 1 to 4 carbon atoms and from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom.

[0060] "Heteroaryl" refers to an aromatic group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, and having a monocyclic, polycyclic, or polycondensed ring structure. As used herein, heteroaryl has from 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), from 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or from 3 to 8 ring carbon atoms (i.e., C 3-8a heteroaryl) 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 certain cases, the heteroaryl includes a 5- to 10-membered ring system, a 5- to 7-membered ring system, or a 5- to 6-membered ring system, each independently having 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. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzothiazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, indazolyl, benzimidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be attached via either ring of the fused system. Any aromatic ring having a single ring or multiple fused rings and containing at least one heteroatom is considered a heteroaryl regardless of the bond to the rest of the molecule (i.e., via any one of the fused rings).Heteroaryl includes, but is not overlapping with, aryl as defined above.

[0061] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0062] "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 spiroheterocyclyl groups. Heterocyclyl may be a monocyclic or multiple rings (where the multiple rings may be fused, bridged, or spiro), and may contain one or more oxo (=O) or N-oxide (-O - ) moieties. Any non-aromatic ring containing at least one heteroatom, regardless of the bond (i.e., it can be bonded through a carbon atom or a heteroatom), is considered heterocyclyl. Further, the term heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, and the ring thereof can be fused to an aryl or heteroaryl ring regardless of the bond to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6having a (heterocyclyl), and 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 the heterocyclyl group include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl" when there are two positions with respect to substitution on the same carbon atom. Examples of the spiroheterocyclyl ring include 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 the fused heterocyclyl ring include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be attached through either ring of the fused system.

[0063] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0064] "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.

[0065] "Closed-shell metal" refers to a metal element in which all valence electrons of the metal element are paired. Such a metal may exist as a cation (or ion) M W+ , where W represents a 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+ can be a sodium ion (Na + ), a lithium ion (Li + ), a zinc ion (Zn 2+ ), a calcium ion (Ca 2+ ), a manganese ion (Mg 2+ ), an aluminum ion (Al 3+ ), etc. In other words, the closed-shell metal can be Na, Li, Zn, Ca, Mn, Al, etc.

[0066] "Sulfonyl" refers to the group -S(O)2R 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.

[0067] "Sulfinyl" refers to the group -S(O)R yrefers to the group, where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may optionally be substituted as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0068] "Sulfonamide" refers to the groups -SO2NR y R z and -NR y SO2R z wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may optionally be substituted as defined herein.

[0069] The terms "optional" or "optionally" mean that the event or circumstance described thereafter may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. Also, the term "optionally substituted" refers to the possibility that any one or more hydrogen atoms on the specified atom or group may or may not be replaced by a moiety other than hydrogen.

[0070] The term "substituted" means that in any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, one or more hydrogen atoms are independently deuterium, halo, cyano, nitro, azide, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h , -NR g C(=O)R h , -NR g C(=O)NRg 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)2R g 、 -OS(=O) 1-2 R g 、 -S(=O) 1-2 OR g 、 -NR g S(=O) 1-2 NR g R h 、 =NSO2R g 、 =NOR g 、 -S(=O) 1-2 NR g R h 、 -SF5, -SCF3, -OCF3, N-oxide, or -Si(R y )3 that is replaced, where each R y is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl. In certain embodiments, "substituted" also means that in any of the above groups, one or more hydrogen atoms are replaced by -C(=O)R g 、 -C(=O)OR g 、 -C(=O)NR g R h 、 -CH2SO2R g 、 -CH2SO2NR g R h In the foregoing, R g and R his the same as or different and independently is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" also means that in any of the above groups, one or more hydrogen atoms are replaced by a bond to amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkyl, haloalkyl, heterocyclyl, N - heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or R g and R h and R i also means that two of R

[0071] and R together with the atoms to which they are attached form a heterocyclyl ring optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy. Polymers or similar infinite structures reached by defining substituents by further substituents added ad infinitum (e.g., a substituted aryl having a substituted alkyl, this substituted alkyl itself being substituted with a substituted aryl group, this substituted aryl group being further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise noted, the maximum number of consecutive substitutions in the compounds described herein is 3. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may also describe other chemical groups defined herein.

[0072] Any compound or structure provided herein is also intended to represent, simultaneously with the unlabeled form of the compound, an isotopically labeled form. These forms of the compound may also be referred to as "isotope-enriched analogs". An isotopically labeled compound has the structure depicted herein, except that one or more atoms are replaced by an atom 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, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 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, 3 H, 13 C, and 14 C and other isotopically labeled compounds incorporating radioactive isotopes such as these. Such isotopically labeled compounds can be useful in metabolic studies, reaction rate 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 the radiotherapy of patients.

[0073] The term "isotopically enriched analogs" includes "deuterated analogs" of the compounds described herein in which one or more hydrogens, such as hydrogens on a carbon atom, are replaced by deuterium. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens are replaced by deuterium.

[0074] The therapeutic compounds of the disclosure labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope such as deuterium can result in certain therapeutic advantages arising from greater metabolic stability, such as an increase in in vivo half-life, a reduction in required dosage, and / or an improvement in the therapeutic index. 18 F, 3 H, 11 C-labeled compounds may be useful in PET or SPECT or other imaging studies. The isotopically labeled compounds of the disclosure and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents and carrying out the procedures disclosed in the schemes or in the Examples and Preparation Examples described below. Deuterium in this context is understood to be regarded as a substituent in the compounds described herein.

[0075] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotope 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 specified, when a position is specifically designated as "H" or "hydrogen", it is understood that the position has hydrogen in its naturally occurring isotope composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0076] Often, the compounds described in the present disclosure or prepared by the processes of the present disclosure contain amino groups and / or carboxyl groups, or groups similar thereto, and thus may be prepared as acid salts and / or base salts.

[0077] As used herein, the term "salt" refers to acidic salts formed with inorganic and / or organic acids, or basic salts formed with inorganic and / or organic bases. Further, 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, carboxylic acid, zwitterions ("inner salts") may be formed, and these are included within the term "salt(s)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salt. In another embodiment, the salt is other than 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"), naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like. 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, t-butylamine, choline, and salts with amino acids such as arginine, lysine, and the like. In certain embodiments, the salt includes amines such as, but not limited to, t-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 includes, but is not limited to, cations such as magnesium, sodium, potassium, calcium, zinc, lithium, cesium, tetramethylammonium, or ammonium. The basic nitrogen-containing group may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chloride, bromide, and iodide), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long-chain halides (e.g., decyl, lauryl, and stearyl chloride, bromide, and iodide), aralkyl halides (e.g., benzyl bromide and phenethyl), and others.

[0078] The acid salts and base salts may be pharmaceutically acceptable salts or physiologically acceptable salts as defined below.

[0079] Also provided are pharmaceutically acceptable salts, isotope-enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein, as well as processes for their preparation. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0080] The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Further, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying the solution of the acid salt. Conversely, when the product is a free base, addition salts, particularly pharmaceutically acceptable addition salts, can be generated by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize the various synthetic techniques that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic acids 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-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.Salts derived from organic bases (e.g., amines) include primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-, di-, or tricycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc., but are not limited thereto. Specific examples of suitable amines include, but are not limited to, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0081] The term "hydrate" refers to a complex formed by combining the compounds described herein with water.

[0082] "Solvate" refers to an association or complex of one or more solvent molecules with the compounds 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 "hydrate".

[0083] As used herein, the term "solid form" refers to a solid-like material, including both amorphous and crystalline forms. The term "crystalline form" refers to polymorphs, as well as solvates, hydrates, etc. "Polymorph" refers to a specific crystal structure having specific physical properties such as X-ray diffraction, melting point, etc.

[0084] Some of the compounds exist as tautomers. The tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with its imidic acid tautomer. It is understood by those skilled in the art that a compound includes both the amide tautomer and the imidic acid tautomer, regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers. Thus, it is understood that amide-containing compounds include their imidic acid tautomers. Similarly, it is understood that imidic acid-containing compounds include their amide tautomers.

[0085] Compounds described herein, or obtained by the processes described herein, or pharmaceutically acceptable salts thereof, may contain asymmetric centers and, thus, may give rise to enantiomers, diastereomers, and other stereoisomers, which can be defined as (R)- or (S)- in terms of absolute stereochemistry, or (D)- or (L)- in the case of amino acids. This disclosure is intended to cover all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (−), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using a chiral synthon or chiral reagent or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from an optically pure suitable precursor or resolution of a racemate (or a racemate of a salt or derivative), for example using chiral high pressure liquid chromatography (HPLC). Where the compounds described herein contain an olefinic double bond or other geometrically asymmetric center and are not otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0086] "Stereoisomers" refer to compounds that consist of the same atoms bonded by the same bonds but have different three-dimensional structures that are not interchangeable. This disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0087] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0088] The relative configuration of the compounds illustrated herein is shown schematically using the "thick bond" style (bold or parallel lines), and the absolute stereochemistry is shown using the wedge bond (bold or parallel lines).

[0089] "Prodrug" means any compound that, when administered to a mammalian subject, releases an active parent drug having the structure described herein in vivo. Prodrugs of the 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 may be prepared by modifying the functional groups present in the compound in such a way that the modification is cleaved to the parent compound either by conventional manipulation or in vivo. Prodrugs include the compounds described herein, where a hydroxy, amino, carboxyl, or sulfhydryl group in the compounds described herein is attached to any group that can be cleaved in vivo to regenerate a free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives) of hydroxy functional groups in the 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," Vol. 14 of the A.C.S. Symposium Series, "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.

[0090] The phrase "substantially as shown in the figure" is intended to include variations of ±3 °C when applied to a DSC thermogram and variations of ±2% in weight loss when applied to a TGA.

[0091] For the compounds described in this specification, the groups and their substituents may be selected according to the allowed valences of the atoms and substituents such that, by selection and substitution, stable compounds are provided that do not spontaneously undergo conversion, for example, by rearrangement, cyclization, elimination, etc.

[0092] Where a range of values is provided, each intervening value, to one tenth of the unit of the lower limit, between the upper and lower limits of that range, as well as any other stated value or intervening value of the stated range, is understood to be included within the present disclosure, unless a clear indication to the contrary is given by the context. The upper and lower limits of these smaller ranges may independently be included within the smaller ranges, and also within the present disclosure, subject to any specifically excluded limit values within the stated range. Where the stated range includes one or both of the limit values, ranges excluding one or both of those included limit values are also included within the present disclosure.

[0093] When numerical ranges are recited herein, each numerical value therebetween having the same degree of precision is explicitly contemplated. For example, in the case of the range 6-9, the numerical values 7 and 8 are contemplated in addition to 6 and 9, and in the case of the range 6.0-7.0, the numerical values 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0094] It is understood that certain features of the present disclosure that are described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure that are described in the context of a single embodiment for brevity may also be provided separately or in any suitable partial combination. All combinations of embodiments related to the present disclosure are specifically encompassed by and disclosed herein by the present disclosure to the extent such combinations include the subject matter of the invention, such as a compound that is, for example, a stable compound (i.e., a compound that can be made, isolated, characterized, and tested for biological activity). Further, all partial combinations of various embodiments and their elements (e.g., elements of chemical groups recited in embodiments that describe such variable elements) are also specifically encompassed by and disclosed herein by the present disclosure as if every such partial combination were individually and explicitly disclosed herein.

[0095] 2. Process The processes described herein provide improved manufacturability of compounds useful in treating various diseases. The processes described herein are carried out using suitable reaction conditions and optionally one or more protecting groups as needed.

[0096] The term "reaction conditions" is intended to refer to the physical and / or environmental conditions under which a chemical reaction proceeds. Examples of reaction conditions include, but are not limited to, one or more of the following: reaction temperature, solvent, pH, pressure, reaction time, molar ratio of reactants, base or acid, one or more protecting groups, or catalyst, presence of radiation, etc. Reaction conditions may be named according to the particular chemical reaction in which they are used, such as coupling conditions, hydrogenation conditions, acylation conditions, reduction conditions, etc. Reaction conditions for most reactions are generally known to those skilled in the art or can be readily obtained from the literature. Exemplary reaction conditions sufficient to effect the chemical transformations provided herein can be found throughout, and in particular in the examples below. It is also contemplated that reaction conditions may include reagents in addition to those recited for a particular reaction.

[0097] The term "protecting group" refers to a group that is intended to protect a given atom or functional group against unwanted 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 (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), trifluoroacetyl, and the like. Certain protecting groups may be preferred over others due to their convenience or relative ease of removal, or due to their stereospecific effects in subsequent steps of the process. Additional suitable amino protecting groups are taught in T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, Fifth Edition, Wiley, New York, 2014, and the references cited therein, which are hereby incorporated by reference in their entirety.

[0098] The term "contacting" or "contact" refers to the process of bringing at least two separate species into contact with each other such that they can interact with each other, for example, in non-covalent or covalent binding interactions or binding reactions. However, it should be understood that the resulting complex or reaction product can be formed directly from the interaction or reaction between the added reagents, or from intermediates from one or more of the added reagents or moieties that are generated in the contacting mixture.

[0099] The term "leaving group" refers to an atom (or group of atoms) having an electron-withdrawing ability that can leave as a stable species with the bonded electrons. Examples of suitable leaving groups include halides (e.g., Br, Cl, I), sulfonic acid esters (e.g., triflate, mesylate, tosylate, and brosylate), and nitrophenol.

Table 5

[0100] 4. Method As used herein, Formula I-1:

Chemical Formula

Chemical formula

[0101] As illustrated in Scheme 1 above, in some embodiments, the compound of formula XIII or a salt thereof is converted to a carboxylic acid VI or a salt thereof. The carboxylic acid VI or a salt thereof reacts with a hydrazide of formula VIII or a salt thereof under condensation conditions to afford a compound of formula IX or a salt thereof. The compound of formula IX or a salt thereof then undergoes an intramolecular ring closure reaction to afford 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 the product compound of formula I-1. These processes are described in further detail below. [Chemistry] (wherein p, t, and R 11 are as defined herein, n is 0 or 1, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, X 2 is O or NR 53 and R 51 is C 1-12 alkyl or silyl, and the C 1-12 alkyl or the silyl is optionally substituted with one or more C 1-12 alkyl independently optionally substituted with one or more halo, or one or more oxo, halo, hydroxyl, or amino, R 52 is C 1-12 alkyl or silyl, and the C 1-12 alkyl or the silyl is optionally substituted with one or more C 1-12 alkyl independently optionally substituted with one or more halo, or one or more oxo, halo, hydroxyl, or amino, R 53 is C 1-12is alkyl or silyl, and the C 1-12 alkyl or the silyl is optionally independently substituted by one or more halo, or one or more oxo, halo, hydroxyl, or amino on one or more C 1-12 alkyl optionally substituted with, or R 51 and R 53 together with the nitrogen atom to which they are attached form a heterocyclyl optionally independently substituted by one or more halo, or one or more oxo, halo, hydroxyl, or amino on one or more C 1-12 alkyl optionally independently substituted with, R 55 is selected from -Cl, -O-pyridyl, 1-imidazolyl, -N(alkyl)(alkyl), 1-pyridonyl, and 1-benzotriazolyl.)

[0102] In some embodiments, at least one of the above R 11 is OR 6 In some embodiments, at least one of the R 11 is -OCF3.

[0103] In some embodiments, R 51 is hydrogen, C 1-12 alkyl, or silyl, and the C 1-12 alkyl or the silyl is optionally independently substituted by one or more halo, or one or more oxo, halo, hydroxyl, or amino on one or more C 1-12 alkyl optionally substituted with. In some embodiments, R 51 is C 1-12 alkyl or silyl, and the C 1-12 alkyl or the silyl is optionally independently substituted by one or more halo, or one or more oxo, halo, hydroxyl, or amino on one or more C 1-12 alkyl optionally substituted with. In some embodiments, R 51 is hydrogen. In some embodiments, R 51 is not hydrogen.

[0104] In some embodiments, X 2 is NR 53 wherein R 51 and R 53 together with the nitrogen atom to which they are attached, independently optionally substituted by one or more halo, or one or more oxo, halo, hydroxyl, or amino, form one or more C 1-12 alkyl independently optionally substituted by, form a heterocyclyl. In some embodiments, X 2 -R 51 is N-morpholino.

[0105] Referring to Scheme 2 above, in some embodiments, a compound of formula VIa or a salt thereof is prepared from a 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 the preparation of a compound of formula I-1.

[0106] In some embodiments, provided herein is a process for obtaining a compound of formula II, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof. The process comprises contacting a compound of formula XIII, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof with a reducing agent under conditions suitable for obtaining a compound of formula II, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof. In some embodiments, the conditions include a temperature below 0 °C, such as from about -25 °C to about -55 °C, or from 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, metal elements, metal hydrides, transition metal complexes having a metal in a low valence state, boranes, borohydrides, hydrazine, thiols, phosphites, etc. In some embodiments, the chemical reducing agent is sodium borohydride or lithium aluminum hydride.

[0107] In some embodiments, the compound of Formula II is obtained as a racemic mixture. In some embodiments, enantiomers of the compound of Formula II are provided herein. In some embodiments, the compound of Formula II is of Formula IIa: [Chemical formula] wherein the substituents are as defined above with respect to Scheme 2.

[0108] In some embodiments, the compound of Formula II is of Formula IIa-1: [Chemical formula] wherein the substituents are as defined above with respect to Scheme 2.

[0109] In some embodiments, the compound of Formula II or IIa-1 is of Formula II-1: [Chemical formula] as such.

[0110] In some embodiments, the compound is not ethyl 3-[(methylthio)thioxomethoxy]cyclobutanecarboxylate. In some embodiments, the compound is not cis-ethyl 3-[(methylthio)thioxomethoxy]cyclobutanecarboxylate.

[0111] In some embodiments, a process for obtaining a compound of Formula III, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof, is provided herein. The process comprises contacting a compound of Formula II, IIa-1, II-1, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof, with an activator under reaction conditions sufficient to obtain a compound of Formula III, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof.

[0112] Any suitable activating reagent may be implemented. In some embodiments, the activating reagent 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-pyridyl-thionocarbonate. In some embodiments, the activating reagent is 1,1'-thiocarbonyldiimidazole.

[0113] In some embodiments, the contacting of the compound of Formula II, IIa-1, II-1 or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, with an activator comprises a) optionally a reaction temperature of from about 0 °C to about 60 °C, and / or b) optionally a reaction duration of from about 3 hours to about 48 hours. In some embodiments, the reaction temperature is from about 15 °C to about 30 °C. In some embodiments, the reaction time is from about 3 hours to about 4 hours. In some embodiments, the reaction may proceed in any suitable solvent. In some embodiments, the solvent may be diethyl ether, methyl t-butyl ether, etc.

[0114] In some embodiments, the activating reagent is carbon disulfide. In some embodiments, the contacting of the compound of Formula II, IIa-1, II-1 or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, with an activator comprises a) optionally a DMSO solvent, b) optionally contacting the compound of Formula II, IIa-1, II-1 or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at a temperature of from about 0 °C to about 50 °C, for example from about 10 °C to about 15 °C, c) further contacting the mixture with a mixture of carbon disulfide at a temperature of from about 0 °C to about 50 °C, for example from about 10 °C to about 15 °C, d) optionally further contacting the mixture with methyl iodide at a temperature of from about 0 °C to about 50 °C, for example from about 10 °C to about 30 °C.

[0115] In some embodiments, provided herein is a process for obtaining a compound of formula V, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof. The process comprises contacting a compound of formula III, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof, with a compound of formula IV under reaction conditions sufficient to obtain a compound of formula V or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof.

[0116] In some embodiments, the compound of formula IV is of formula IV-1:

Chemical formula

[0117] In some embodiments, provided herein is a compound of formula V, wherein the substituents are as defined above with respect to Scheme 2.

[0118] In some embodiments, provided herein is a compound of formula V as a racemic mixture. In some embodiments, provided herein is an enantiomer of a compound of formula V. In some embodiments, the compound of formula V is of formula V-1:

Chemical formula

[0119] In some embodiments, the compound of formula V is of formula V-2:

Chemical formula

[0120] In some embodiments, for formula V-2:

Chemical formula

[0121] In some embodiments, X 2 is O.

[0122] In some embodiments, X 2 is NR 53 .

[0123] In some embodiments, X 2 is NR 53 and R 51 and R 53 together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted independently by one or more halo, or one or more oxo, halo, hydroxyl, or amino, or one or more C 1-12 alkyl optionally substituted independently by alkyl.

[0124] In some embodiments, R 51 and R 53 are linked together with the nitrogen atom to form -morpholino.

[0125] In some embodiments, R 51 is C 1-12 alkyl.

[0126] In some embodiments, X 2 is O and R 51 is C 1-12 alkyl.

[0127] In some embodiments, R 52 is C 1-12 alkyl.

[0128] In some embodiments, n is 1. In some embodiments, n is 0.

[0129] In some embodiments, q is 1.

[0130] In some embodiments, R 52 is a substituted or unsubstituted C4-C 12 alkyl.

[0131] In some embodiments,

Chemical formula

[0132] In some embodiments, the compound of formula V or the compound of formula V-1 is the compound of formula V-1a or a salt thereof:

Chemical formula

[0133] In some embodiments, the compound of formula V or the compound of formula V-1 is the compound of formula V-1b or a salt thereof:

Chemical formula

[0134] In some embodiments, the compound of formula V or the compound of formula V-1 is the compound of formula V-1b or a salt thereof:

Chemical formula

[0135] In some embodiments, the compound of formula V or the compound of formula V-1 is the compound of formula V-1b or a salt thereof:

Chemical formula

[0136] In some embodiments, contacting with the compound of formula IV comprises contacting under reaction conditions that include 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 may proceed in any suitable solvent. In some embodiments, the solvent may be diethyl ether, methyl t-butyl ether, etc.

[0137] Accordingly, as described above, provided herein is a process for preparing a compound of formula V, V-1, or V-2. The process comprises contacting a compound of formula II, IIa-1, II-1, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof, with an activator, and then contacting with a compound of formula IV or IV-1 under reaction conditions sufficient to obtain a compound of formula V, V-1, or V-2, wherein the substituents and parameters follow those defined above with respect to Scheme 2.

[0138] In some embodiments, provided herein is a process for preparing a compound of formula V-1a. The process comprises contacting a compound of formula II-1 with an activator, and then contacting with a compound of formula IV-1 under reaction conditions sufficient to obtain a compound of formula V-1a, wherein the substituents and parameters follow those defined above with respect to Scheme 2.

[0139] In some embodiments, for the methods described herein with respect to any of the above processes, R 51 is a branched alkyl.

[0140] In some embodiments, for the methods described herein with respect to any of the above processes, t is 0 and X 2 is O.

[0141] In some embodiments, for the methods described herein with respect to any of the above processes, at least one R11 is OR 6 Therefore, the compound of formula VI is of formula VIa-1:

Chemical formula

[0142] In some embodiments, provided herein is a process for obtaining a compound of formula VIa-1, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof. The process comprises contacting a compound of formula V, V-1, V-2, or V1-a, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof, with a brominating reagent and a fluoride source under reaction conditions sufficient to obtain a compound of formula VIa or VIa-1.

[0143] In some embodiments, the compound of formula V, V-1, V-2, or V1-a, or a stereoisomer or mixture of stereoisomers thereof, or a salt thereof, is prepared using any of the methods described above.

[0144] In some embodiments, R 6 is substituted alkyl. In some embodiments, R 6 is haloalkyl. In some embodiments, R 6 is trifluoromethyl (-CF3). In some embodiments, provided herein is a compound of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid, i.e., a compound of formula VIa-1a or a salt thereof:

Chemical formula

[0145] In some embodiments, provided herein is a process for obtaining a compound of formula VIa-1a. In some embodiments, the brominating reagent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).

[0146] In some embodiments, the fluoride source is hydrogen fluoride (HF). In some embodiments, the fluoride source is HF-pyridine.

[0147] In some embodiments, contacting the brominating reagent and the fluoride source comprises introducing a compound of Formula V, V-1, V-2, or V1-a into a solution of the brominating reagent and the fluoride source at a temperature of less than about -25 °C. In some embodiments, the contacting further comprises aging the resulting reaction mixture at room temperature. In some embodiments, the reaction may proceed in any suitable solvent. In some embodiments, the solvent may be DCM or the like.

[0148] In some embodiments, provided herein are salts of a compound of Formula VIa, such as a salt of a compound of Formula VIa-1a, the salt comprising an amine selected from the group consisting of t-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.

[0149] In some embodiments, provided herein is a method for preparing a salt of a compound of Formula VIa-1a:

Chemical formula

Chemical formula

[0150] In some embodiments, the electrophilic bromine source includes DBDMH (1,3-dibromo-5,5-dimethylhydantoin) or NBS (n-bromosuccinimide).

[0151] In some embodiments, the fluorinating agent is HF·pyridine.

[0152] In some embodiments, the hydrolysis step includes a strong acid (i.e., HCl) at high temperature.

[0153] In some embodiments, X 2 is O.

[0154] In some embodiments, X 2 is NR 53 .

[0155] In some embodiments herein, formula VIa-1a:

Chemical formula

Chemical formula

[0156] In some embodiments, the base containing the cation is Mg(OH)2 or NaOH.

[0157] In some embodiments, the salt of the compound of formula VIa or VIa-1a is an amine salt (e.g., a salt containing an amine (i.e., nitrogen) as described herein). In some embodiments, herein, formula VIIa:

Chemical formula

[0158] In some embodiments, p is 1 and at least one R 11 is halogen and none of the R 46 is H.

[0159] In some embodiments, p is 1 and at least one R 11 is halogen and one of the R 46 is H.

[0160] In some embodiments, p is 1 and at least one R 11 is halogen and two of the R 46 are H.

[0161] In some embodiments, the N(R 46 )3 moiety in Formula VIIa is selected from the group consisting of t-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine, and dibenzylamine.

[0162] 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 predominantly comprising the trans isomer of the compound of formula VIIa (e.g., diastereomeric excess > 90%, or diastereomeric excess > 95%, or diastereomeric excess > 98%, or diastereomeric excess > 99%). In some embodiments, provided herein is a composition predominantly comprising the cis isomer of the compound of formula VIIa (e.g., diastereomeric excess > 90%, or diastereomeric excess > 95%, or diastereomeric excess > 98%, or diastereomeric excess > 99%).

[0163] In some embodiments, the compound of formula VIIa is of formula VII-1:

Chemical formula

[0164] In some embodiments, the compound of formula VII-1 is of formula VII-2a:

Chemical formula

[0165] In some embodiments, provided herein is a method for preparing a compound of formula VII-2a:

Chemical formula

Chemical formula

Chemical formula

[0166] In some embodiments herein, the t-butylamine salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid, i.e., formula VII-1a:

Chemical formula

[0167] In some embodiments herein, the dicyclohexylamine salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid, i.e., formula VII-1b:

Chemical formula

[0168] In some embodiments herein, the L-arginine salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid, i.e., formula VII-1c:

Chemical formula

[0169] In some embodiments herein, the tromethamine salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid, i.e., formula VII-1d:

Chemical formula

[0170] In some embodiments, the salts of the compounds of formula VIa are metal salts. In some embodiments herein, formula VIIb:

Chemical formula

[0171] Accordingly, the compounds of formula VIIb are metal salts of the compounds of formula VIa and include the anionic form of the compounds of formula VIa, for example, the monovalent anion of the compounds of formula VIa. In some embodiments, j is 0.

[0172] In some embodiments, the compounds of formula VIIb may further include another anion. In other words, j may be other than zero. For example, the compounds of formula VIIb may further include a carboxylic acid anion. In some embodiments, R 47 is substituted or unsubstituted alkyl. In some embodiments, R 47 is methyl. In some embodiments, j is 0 or 1.

[0173] 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 anions of formula VIa and the additional anion together balance the charge of the metal ion.

[0174] In some embodiments, provided herein is a compound of Formula VIIb as a racemic mixture. In some embodiments, provided herein are enantiomers of the compound of Formula VIIb. In some embodiments, the compound of Formula VIIb is of Formula VIIb-1: [Chemical formula] wherein the substituents are as defined above.

[0175] In some embodiments, the compound-1 of Formula VIIb is of Formula VII-2b: [Chemical formula] wherein the substituents are as defined above.

[0176] In some embodiments, for a salt of a compound of Formula VIa, for example a compound of Formula VIIa or VIIb, at least one R 11 is OR 6 as such. [Chemical formula]

[0177] Referring to Scheme 3, in some embodiments, provided herein is a method for preparing a compound of Formula IX or a stereoisomer or mixture of stereoisomers thereof from a compound of Formula VI or a stereoisomer or mixture of stereoisomers thereof according to a series of steps, wherein R 1 is hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, heterocyclyl, or trialkylsilyl, each of which other than hydrogen is optionally substituted with one or more halo, oxo, acetyl, amino, hydroxyl, or C 1-12 alkyl, or R 1 and R 5 together form a heterocyclyl ring, R 73 is hydrogen, a protecting group, or a moiety of the formula

Chem.

[0178] In some embodiments, the moiety of the formula

[0179] is

Chem.

Chem.

[0180] In some embodiments, the contacting comprises contacting the compound of formula VIa with the amine of formula VIb in a stoichiometric ratio of from about 1:0.8 to about 1:1.3. In some embodiments, the contacting comprises contacting the compound of formula VIa with a slightly excess amine of formula VIb in a stoichiometric ratio of from about 1:1.05 to about 1:1.3.

Chem.

[0181] In some embodiments, the contacting comprises contacting the compound of formula VIa with the amine of formula VIb in a stoichiometric ratio of from about 1:0.8 to about 1:1.3. In some embodiments, the contacting comprises contacting the compound of formula VIa with a slightly excess amine of formula VIb in a stoichiometric ratio of from about 1:1.05 to about 1:1.3.

[0182] In some embodiments, provided herein is a process for preparing a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, from a compound of formula VIIa or a stereoisomer or mixture of stereoisomers thereof. In some embodiments, the process comprises purifying the compound of formula VIIa or a stereoisomer or mixture of stereoisomers thereof to a sufficient purity (e.g., >95%, or >96%, or >97%, or >98%, or >99%, or 95-100%). In some embodiments, the process comprises contacting the purified compound of formula VIIa or a stereoisomer or mixture of stereoisomers thereof with an acid under reaction conditions sufficient to obtain a compound of formula VI or a stereoisomer or mixture of stereoisomers thereof, and contacting the compound of formula VI or a stereoisomer or mixture of stereoisomers thereof with a compound of formula VIII under conditions sufficient to obtain a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof.

[0183] Accordingly, the compound of formula VI is formed from the compound of formula VIIa prior to its reaction with the compound of formula VIII. In some embodiments, the formation of the compound of formula VI is carried out in situ prior to the introduction of the compound of formula VIII. In some embodiments, this formation step ensures that the compound of formula VI is obtained in sufficient purity prior to the subsequent reaction. As discussed above, the compound of formula VI generally exists in the form of an oil, which makes its purification difficult, which in turn can lead to low yields or low purity in subsequent conversions. Herein, the use of the compound of formula VIIa as a starting material and subsequent regeneration of the compound of formula VI when needed alleviates the above-mentioned purity problems. 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%.

[0184] 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 VIIa or a stereoisomer or mixture of stereoisomers thereof with the acid include contacting at a temperature of about 20 to 25 °C.

[0185] In some embodiments, the reaction conditions for obtaining the compound of formula IX or a stereoisomer or mixture of stereoisomers thereof include introducing the compound of formula VIII into a mixture of carbonyldiimidazole and the 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 proceed 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.

[0186] In some embodiments, the step of forming the compound of formula VI or a stereoisomer or mixture of stereoisomers thereof is omitted, whereby the process instead comprises contacting the purified compound of formula VIIa or a stereoisomer or mixture of stereoisomers thereof with the compound of VIII under conditions sufficient to obtain the compound of formula IX or a stereoisomer or mixture of stereoisomers thereof.

[0187] In some embodiments, provided herein is a process for preparing a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, from a compound of formula VIIb or a stereoisomer or mixture of stereoisomers thereof. In some embodiments, the process comprises 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 a similar metal salt in a suitable organic solvent such as ethyl acetate or toluene in a stoichiometric ratio of about 1:1. In some embodiments, the process comprises purifying the compound of formula VIIb or a stereoisomer or mixture of stereoisomers thereof to a 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.

[0188] In some embodiments, the process comprises contacting the purified compound of formula VIIb or a stereoisomer or mixture of stereoisomers thereof with an acid under reaction conditions sufficient to obtain a compound of formula VI or a stereoisomer or mixture of stereoisomers thereof, and contacting the compound of formula VI or a stereoisomer or mixture of stereoisomers thereof with a compound of formula VIII and then with a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof under conditions sufficient to obtain the compound of formula IX or a stereoisomer or mixture of stereoisomers thereof. Similar to the alternative route described above, purification of the compound of formula VIIb reduces problems associated with purification of the compound of formula VI.

[0189] In some embodiments, the step of forming the compound of formula VI or a stereoisomer or mixture of stereoisomers thereof is omitted, whereby the process instead comprises contacting the purified compound of formula VIIb or a stereoisomer or mixture of stereoisomers thereof with the compound of VIII under conditions sufficient to obtain the compound of formula IX or a stereoisomer or mixture of stereoisomers thereof.

[0190] In some embodiments, the acid is a mineral acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the reaction conditions under which the purified compound of formula VIIb or a stereoisomer or mixture of stereoisomers thereof is contacted with the acid include contacting at a temperature of about 20-25 °C.

[0191] In some embodiments, the reaction conditions for obtaining the compound of formula IX or a stereoisomer or mixture of stereoisomers thereof include introducing the compound of formula VIII into a mixture of carbonyldiimidazole and the 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 proceed 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.

[0192] In some embodiments, the compound of formula VIII is of formula VIIIa:

Chemical formula

[0193] In some embodiments, provided herein is the compound of formula IX as a racemic mixture. In some embodiments, provided herein is an enantiomer of the compound of formula IX. In some embodiments, the compound of formula IX is of formula IX-1: [Chemical formula] wherein the substituents are as defined above.

[0194] In some embodiments, the compound of formula IX or IX-1 is of formula IX-2: [Chemical formula] wherein the substituents are as defined above.

[0195] In some embodiments, provided herein is a method for preparing a compound of formula IX-2 or a solvate (e.g., hydrate) thereof from a compound of formula VII-2a. In some embodiments, the method comprises contacting a compound of formula VII-2a, which is a salt of a compound of formula VIa-1a, with an acid under reaction conditions sufficient to obtain a compound of formula VIa-1a, and contacting the compound of formula VIa-1a with formula VIIIa under conditions sufficient to obtain a compound of formula IX-2 or a salt thereof. In some embodiments, the process comprises purifying the compound of formula VII-2a to a 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.

[0196] In some embodiments, the compound of formula IX or IX-1 is of formula IX-1a: [Chemical formula] which is as follows.

[0197] In some embodiments, provided herein is a solvate of a compound of formula IX-1a. In some embodiments, provided herein is a solvate of a compound of formula IX-1a, such as a hydrate. In some embodiments, provided herein is a hydrate of a compound of formula IX-1a, such as a monohydrate. In other words, the hydrate of the compound of formula IX-1a comprises the 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, for example, better stability in the manufacturing process as compared to the anhydrous form of the compound of formula IX-1a. [Chemical formula]

[0198] Referring to Scheme 4 (wherein the substituents are as defined above), in some embodiments, provided herein is a method for preparing a compound of formula XI or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, from a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, via a two-step reaction. In some embodiments, the reaction starts from a solvate of a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof. 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.

[0199] In some embodiments, provided herein is a method for preparing a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, from a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof. In some embodiments, the method comprises contacting a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, with a dehydrating agent and a base under reaction conditions sufficient to obtain a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof.

[0200] Alternatively, in some embodiments, provided herein is a process for preparing a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, by contacting a compound of formula XIV or a stereoisomer or mixture of stereoisomers thereof, or a solvate thereof, with a compound of formula XV under reaction conditions sufficient to obtain a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof. In some embodiments, the process comprises a dehydrating agent and a base.

[0201] In some embodiments, the dehydrating agent described above is selected from the group consisting of sulfonyl chlorides having an electron-withdrawing group, sulfonic anhydrides, phosphonic anhydrides, carbonic anhydrides, and mixtures of triphenylphosphine and carbon tetrachloride.

[0202] In some embodiments, the dehydrating agent described above 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-trioxatriphosphinan 2,4,6-trioxide (or referred to herein as tri-n-propylphosphonic anhydride), trifluoroacetic anhydride, and mixtures of triphenylphosphine and carbon tetrachloride.

[0203] In some embodiments, the acid is 4-toluenesulfonyl chloride.

[0204] 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 obtaining the compound of formula X or its stereoisomers or a mixture of stereoisomers, or salts thereof, include reacting in a solvent of ACN. 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 about 2%, or about 1%, or about 0.5%, or about 0.1%, or about 0.01%, or about 10 ppm, or less than about 1 ppm. 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 provide satisfactory yields for this reaction.

[0205] In some embodiments, the compound of formula IX or its stereoisomers or a mixture of stereoisomers, or solvates thereof, used in the synthesis of the compound of formula X or its stereoisomers or a mixture of stereoisomers, or solvates thereof, is formed via a compound of formula VIIa. In some embodiments, the compound of formula IX or its stereoisomers or a mixture of stereoisomers, or solvates thereof, used in the synthesis of the compound of formula X or its stereoisomers or a mixture of stereoisomers, or solvates thereof, is formed via a compound of formula VIIb.

[0206] Accordingly, in some embodiments, provided herein is a method for preparing a compound of formula X or its stereoisomers or a mixture of stereoisomers, or salts thereof, the method comprising a) contacting a compound of formula VIIa or a stereoisomer or mixture of stereoisomers thereof with a first acid under reaction conditions sufficient to obtain a compound of formula VI or a stereoisomer or mixture of stereoisomers thereof, and contacting the compound of formula VI or a stereoisomer or mixture of stereoisomers thereof with a compound of VIII and a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, under conditions sufficient to obtain the same, b) contacting a compound of formula VIIa or a stereoisomer or mixture of stereoisomers thereof with a compound of VIII and a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, under conditions sufficient to obtain the same, c) contacting a compound of formula VIIb or a stereoisomer or mixture of stereoisomers thereof with a first acid under reaction conditions sufficient to obtain a compound of formula VI or a stereoisomer or mixture of stereoisomers thereof, and contacting the compound of formula VI or a stereoisomer or mixture of stereoisomers thereof with a compound of VIII and a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, under conditions sufficient to obtain the same, or d) contacting a compound of formula VIIb or a stereoisomer or mixture of stereoisomers thereof with a compound of VIII and a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, under conditions sufficient to obtain the same, and contacting a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, with a dehydrating agent and a base under reaction conditions sufficient to obtain a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof.

[0207] In some embodiments, R 73 is a protecting group for an amine functional group. In some embodiments, R 73 is tert-butoxycarbonyl (BOC). In some embodiments, R 1 is hydrogen. In some embodiments, R 73 is [Chemistry] is.

[0208] In some embodiments, the processes described with respect to Schemes 3 and 4 are carried out 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 carried out in the same reaction vessel without removing the reaction mixture. In some embodiments, the process described in Scheme 4 is carried out in the same reaction vessel without removing the reaction mixture.

[0209] 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 obtained by the method described in Scheme 3 or 4.

[0210] In some embodiments, as used herein, a compound of Formula X is provided as a racemic mixture. In some embodiments, as used herein, an enantiomer of the compound of Formula X is provided. In some embodiments, the compound of Formula X is of Formula X-1: [Chemistry] wherein the substituents are as defined above.

[0211] In some embodiments, the compound of Formula X-1 is of Formula X-2: [Chemistry] wherein the substituents are as defined above.

[0212] In some embodiments, provided herein is a method for preparing a compound of formula X-2 from a compound of formula VII-2a. In some embodiments, the method comprises contacting a compound of formula VII-2a with an acid under reaction conditions sufficient to obtain a compound of formula VIa-1a, contacting the compound of formula VIa-1a with a compound of formula VIIIa or a salt thereof and a compound of formula IX-2, or a solvate (e.g., hydrate) of each thereof, under conditions sufficient to obtain a compound of formula IX-2, and contacting the compound of formula IX-2 with a dehydrating agent and a base under reaction conditions sufficient to obtain a compound of formula X-2 or a salt thereof. In some embodiments, the process comprises purifying the compound of formula VII-2a to a 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.

[0213] In some embodiments, provided herein is a compound of formula X-1a:

Chemical formula

[0214] In some embodiments, provided herein is a method for preparing a compound of formula XI or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, from a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof. In some embodiments, the method comprises contacting a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, under deprotection conditions sufficient to obtain a compound of formula XI or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof.

[0215] 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 generating at a temperature of about -30 °C to about 100 °C. In some embodiments, the temperature is from 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 raising the temperature of the reactants to a temperature of about 15 °C to about 25 °C. In some embodiments, the temperature of the reaction mixture is increased to about 30 °C to about 60 °C, for example, 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 about 40 °C to about 45 °C, results in a significantly improved yield and / or a reduced impurity content compared to other techniques, for example, maintaining the temperature below about 30 °C.

[0216] In some embodiments, the deprotection conditions include generating hydrogen chloride in situ. In some embodiments, the deprotection conditions further include immediately neutralizing the remaining generated acid and isolating the compound of formula X or a salt thereof upon completion of the reaction. Other deprotection conditions, such as contacting intermediate X-1a with an aqueous hydrochloric acid solution to remove the BOC group, often result in the decomposition of the oxadiazole ring, leading to a low yield of intermediate XI. In contrast, by implementing the deprotection and neutralization conditions described herein, ring decomposition can be avoided and the yield and / or purity of the compound of formula XI can be substantially improved. In this way, the deprotection conditions described herein enable large-scale industrial production that was not previously possible.

[0217] In some embodiments, contacting a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, under deprotection conditions results in the free base form of a compound of formula XI or a stereoisomer or mixture of stereoisomers thereof. In some embodiments, contacting a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, under deprotection conditions results in a salt of a compound of formula XI or a stereoisomer or mixture of stereoisomers thereof. In some embodiments, the salts are hydrochloride, oxalate, and 4-chlorophenoxyacetate. In some embodiments, 2 equivalents of chloride anions are included per 1 equivalent of hydrochloride. In some embodiments, 2 equivalents of oxalate anions are included per 1 equivalent of oxalate. In some embodiments, 1 equivalent of 4-chlorophenoxyacetate anion is included per 1 equivalent of 4-chlorophenoxyacetate.

[0218] Accordingly, in some embodiments, provided herein is a method for preparing a compound of formula XI or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, the method comprising a) contacting a compound of formula VIIa or a stereoisomer or mixture of stereoisomers thereof with a first acid under reaction conditions sufficient to obtain a compound of formula VI or a stereoisomer or mixture of stereoisomers thereof, and contacting the compound of formula VI or a stereoisomer or mixture of stereoisomers thereof with a compound of VIII and a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, under conditions sufficient to obtain the compound of VIII and the compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof; b) contacting a compound of formula VIIa or a stereoisomer or mixture of stereoisomers thereof with a compound of VIII and a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, under conditions sufficient to obtain the compound of VIII and the compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof; c) contacting a compound of formula VIIb or a stereoisomer or mixture of stereoisomers thereof with a first acid under reaction conditions sufficient to obtain a compound of formula VI or a stereoisomer or mixture of stereoisomers thereof, and contacting the compound of formula VI or a stereoisomer or mixture of stereoisomers thereof with a compound of VIII and a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, under conditions sufficient to obtain a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, or d) contacting a compound of formula VIIb or a stereoisomer or mixture of stereoisomers thereof with a compound of VIII and a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, under conditions sufficient to obtain a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, contacting a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, with a dehydrating agent and a base under reaction conditions sufficient to obtain a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, and contacting a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, with a compound of formula XI or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, under deprotection conditions sufficient to obtain a compound of formula XI or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof,

[0219] In some embodiments, provided herein is a compound of formula XI as a racemic mixture. In some embodiments, provided herein is an enantiomer of a compound of formula XI. In some embodiments, the compound of formula XI is of formula XI-1:

Chemical formula

[0220] In some embodiments, provided herein is a compound of formula XI-1a:

Chemical formula

[0221] In some embodiments, with respect to any of the above methods for preparing salts of the compounds of Formula XI, Formula XI-1, or Formula XI-1a, the salts are hydrochloride, oxalate, and 4-chlorophenoxyacetate. In some embodiments, the salt is 4-chlorophenoxyacetate. In some embodiments, the compound of Formula XI, Formula XI-1, or Formula XI-1a is present as a salt in a ratio of about 1:1 with respect to its counterion. In some embodiments, the compound of Formula XI, Formula XI-1, or Formula XI-1a is present as a salt in a ratio of about 1:2 with respect to its counterion.

[0222] In some embodiments, provided herein is a method for preparing a compound of Formula XI-1a from a compound of Formula VII-2a. In some embodiments, the method comprises contacting a compound of Formula VII-2a with an acid under reaction conditions sufficient to obtain a compound of Formula VIa-1a, contacting the compound of Formula VIa-1a with a compound of Formula VIIIa or a salt thereof and a compound of Formula IX-2, or a solvate (e.g., hydrate) of each thereof, under conditions sufficient to obtain a compound of Formula IX-2, contacting the compound of Formula IX-2 with a dehydrating agent and a base under reaction conditions sufficient to obtain a compound of Formula X-2 or a salt thereof, and contacting the compound of Formula X-2 or a salt thereof under deprotection conditions sufficient to obtain a compound of Formula XI-1a or a salt thereof. In some embodiments, the process comprises purifying the compound of Formula VII-2a to a 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.

[0223] In some embodiments, R 73 is of the formula

Chemical formula

Chemical formula

[0224] Referring to Scheme 5, in some embodiments, provided herein is a method for preparing a compound of formula I-1 or a stereoisomer or mixture of stereoisomers thereof, or a salt of each of them, from a compound of formula XI or a stereoisomer or mixture of stereoisomers thereof, wherein R 3 is hydrogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which other than hydrogen is optionally substituted with one or more R 11 ; R 4 and each of R 5 is independently hydrogen, C 1-12 alkyl, C 2-12 alkenyl, or C 2-12 alkynyl, each of which other than hydrogen is independently optionally substituted with one or more halo, oxo, acetyl, amino, or hydroxyl, or alternatively, R 3 and R 4 together with the atoms to which they are attached are linked to form C 3-10 cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more R 11 ; or alternatively, R 4 and R 5 together with the atoms to which they are attached are linked to form C 3-10 cycloalkyl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more R 11 ; X 1 is O, NR 9or a bond, z is 0 or 1, provided that when z is 0 and X 1 is O, R 3 is not alkyl, and the other substituents and parameters are as defined with respect to Scheme 2.

[0225] In some embodiments, the compound of formula XII is of formula XII-1:

Chemical formula

[0226] In some embodiments, when the compound of formula XI used is in salt form, for example, a salt with an acid of the compound of formula XII-1, no additional compound of formula XII is required in the reaction shown in Scheme 5.

[0227] 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 obtain a compound of formula I-1 or a stereoisomer or mixture of stereoisomers thereof, or a salt of each of them.

[0228] In some embodiments, X 1 is O. In some embodiments, R 3 is aryl substituted with 0 to 3 halo, hydroxy, or alkoxy. In some embodiments, R 3 is 4-chlorophenyl.

[0229] In some embodiments, the reaction conditions for obtaining the compound of formula I-1 are a) an optional first reaction step at a temperature of about 0 °C to about 5 °C, b) an optional second reaction step at a temperature of about 15 °C to about 30 °C, and / or c) optionally in the presence of a base and diphenylphosphinic acid chloride.

[0230] In some embodiments, the second reaction step is carried out at a temperature of about 20 °C to about 30 °C.

[0231] In some embodiments, the reaction conditions for obtaining the compound of formula I-1 further include contacting the reaction mixture with a base such as a carbonate and then with a mixture of isopropyl alcohol and heptane.

[0232] In some embodiments, the preparation of the compound of formula I-1 further includes isolating the compound of formula XI or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, using heptane, IPAc, and / or IPA.

[0233] Accordingly, in some embodiments, provided herein is a method for preparing a compound of formula I-1 or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, the method comprising a) contacting a compound of formula VIIa or a stereoisomer or mixture of stereoisomers thereof with a first acid under reaction conditions sufficient to obtain a compound of formula VI or a stereoisomer or mixture of stereoisomers thereof, and contacting the compound of formula VI or a stereoisomer or mixture of stereoisomers thereof with a compound of VIII and a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, under conditions sufficient to obtain the same; b) contacting a compound of formula VIIa or a stereoisomer or mixture of stereoisomers thereof with a compound of VIII and a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, under conditions sufficient to obtain the same; c) contacting a compound of formula VIIb or a stereoisomer or mixture of stereoisomers thereof with a first acid under reaction conditions sufficient to obtain a compound of formula VI or a stereoisomer or mixture of stereoisomers thereof, and contacting the compound of formula VI or a stereoisomer or mixture of stereoisomers thereof with a compound of VIII and a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, under conditions sufficient to obtain the same, or d) contacting a compound of formula VIIb or a stereoisomer or mixture of stereoisomers thereof with a compound of VIII under conditions sufficient to obtain a compound of formula IX or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof; contacting a compound of formula IX with a dehydrating agent and a base under reaction conditions sufficient to obtain a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof; contacting a compound of formula X or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, under deprotection conditions sufficient to obtain a compound of formula XI or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof; and 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 obtain a compound of formula I-1 or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof.

[0234] In some embodiments, provided herein is a compound of formula I-1 as a racemic mixture. In some embodiments, provided herein is an enantiomer of a compound of formula I-1. In some embodiments, the compound of formula I-1 is of formula I-1a: [Chemical formula] wherein the substituents are as defined above.

[0235] In some embodiments, provided herein is a process for preparing a compound of formula I-1a or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, the process comprising: 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 obtain a compound of formula VIa-1a or a stereoisomer or mixture of stereoisomers thereof; and 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 obtain a compound of formula IX-2 or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, or 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 obtain a compound of formula IX-2 or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, and Contacting a compound of formula IX-2 or a stereoisomer or mixture of stereoisomers thereof, or a solvate of each thereof, with a dehydrating agent and a base under reaction conditions sufficient to obtain a compound of formula X-2 or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, Contacting a compound of formula X-2 or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, under deprotection conditions sufficient to obtain a compound of formula XI-1a or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, and Contacting a compound of formula XI-1a or a stereoisomer or mixture of stereoisomers thereof with a compound of formula XII-1 under reaction conditions sufficient to obtain a compound of formula I-1a or a stereoisomer or mixture of stereoisomers thereof, or a salt of each thereof, is included.

[0236] In some embodiments, the compound of formula I-1a has the formula I:

Chemical formula

[0237] Any combination of the above steps may be used in the preparation of the compounds described herein, including any procedures described in the Examples section.

[0238] The compounds of the present disclosure can be prepared from readily available starting materials, for example, using the following general methods and procedures. It will be understood that other process conditions can also be used, unless otherwise specified, when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. The optimal reaction conditions can vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art by conventional optimization procedures.

[0239] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. Protecting groups suitable for various functional groups, as well as conditions suitable for the protection and deprotection of specific functional groups, are well known in the art. For example, numerous protecting groups are described in T.W. Greene and G.M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0240] As described above, the compounds of the present disclosure may contain one or more chiral centers. Furthermore, the present disclosure contemplates other chiral centers not explicitly described. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched in stereoisomers. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0241] 5. Salts and Solid Forms Further provided herein are compounds of formula VIa-1a: [Chemical formula] A salt thereof is provided.

[0242] In some embodiments, the salt is selected from t-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.

[0243] In some embodiments, provided herein are crystalline forms of salts of the compounds 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 t-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.

[0244] In some embodiments, the solid form is a compound of Formula VII-2a: [Chemical formula] is a crystalline form, where each R 46 is, independently, hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-20 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R 46 is independently optionally substituted with one or more R 12 ; each R 12 is, independently, halo, cyano, nitro, oxo, -OR 30 , -SR 30 , -SF5, -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 R12 each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently one or more C optionally substituted with one or more halo, or one or more oxo, halo, hydroxyl, or amino 1-12 optionally substituted with alkyl, each R 30 and R 31 is independently hydrogen, or C optionally substituted with one or more oxo, halo, hydroxyl, or amino 1-12 alkyl, or R 30 and R 31 together with the atom to which they are attached form a heterocyclyl optionally substituted with one or more halo, or one or more oxo, halo, hydroxyl, or amino 1-12 optionally substituted with alkyl.

[0245] 46 In some embodiments, the N(R

[0246] )3 moiety is selected from the group consisting of t-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine, and dibenzylamine. In some embodiments, the solid form is a compound of Formula VII-2b:

Chemical formula

[0247] In some embodiments, the salt comprises a cation selected from the group consisting of magnesium, sodium, potassium, calcium, zinc, lithium, and cesium.

[0248] In some embodiments, as described above, by preparing a salt form of the compound of formula VIa-1a, the purity of the compound of formula VIa-1a is substantially improved. In some embodiments, the salt is t-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine, or dibenzylamine. In some embodiments, the salt is t-butylamine, and this salt formation results in an increase in purity from 96.9% to 99.8% compared to the starting material which is the free base.

[0249] In some embodiments, provided herein is a polymorphic (or crystalline) form of the t-butylamine (TBA) salt of the compound of formula VIa-1a, which is also a crystalline form of the compound of formula VII-1a (referred to as "Form A of the TBA salt of Compound VIa-1a").

[0250] In some embodiments, Form A of the TBA salt of Compound VIa-1a 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 when determined with a diffractometer using Cu-Kα radiation (λ = 1.54059 Å). In some embodiments, the diffractogram further comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 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, Form A of the TBA salt of Compound VIa-1a can also be characterized by its overall X-ray powder diffraction pattern substantially as shown in FIG. 1.

[0251] In some embodiments, Form A of the TBA salt of compound VIa-1a is characterized by TGA that substantially includes a thermogram as shown in FIG. 2. In some embodiments, Form A of the TBA salt of compound VIa-1a is also characterized by a DSC curve that includes an endotherm at about 171 °C. In another embodiment, the DSC curve is substantially as shown in FIG. 2.

[0252] In some embodiments, provided herein is a crystalline form of the dicyclohexylamine (DCHA) salt of the compound of formula VIa-1a, which is also a crystalline form of the compound of formula VII-1b (referred to as "Form A of the DCHA salt of compound VIa-1a").

[0253] In some embodiments, Form A of the DCHA salt of compound VIa-1a is characterized by an X-ray powder diffraction pattern that includes 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 when determined with a diffractometer using Cu-Kα radiation (λ = 1.54059 Å). In some embodiments, the diffractogram further includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 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, Form A of the DCHA salt of compound VIa-1a can also be characterized by its overall X-ray powder diffraction pattern substantially as shown in FIG. 3.

[0254] In some embodiments, Form A of the DCHA salt of compound VIa-1a is characterized by TGA that substantially includes a thermogram as shown in FIG. 4. In some embodiments, Form A of the DCHA salt of compound VIa-1a is also characterized by a DSC curve that includes an endotherm at about 139 °C. In another embodiment, the DSC curve is substantially as shown in FIG. 4.

[0255] In some embodiments, provided herein is a crystalline form of the L-arginine salt of the compound of formula VIa-1a, which is also a crystalline form of the compound of formula VII-1c (referred to as "Form A of the L-arginine salt of compound VIa-1a").

[0256] In some embodiments, Form A of the L-arginine salt of compound VIa-1a 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 determined with a diffractometer using Cu-Kα radiation (λ = 1.54059 Å). In some embodiments, the diffractogram further comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 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 diffractogram further comprises 1, 2, 3, 4, 5, 6, or 7 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, Form A of the L-arginine salt of compound VIa-1a can also be characterized by its overall X-ray powder diffraction pattern substantially as shown in FIG. 5.

[0257] In some embodiments, Form A of the L-arginine salt of compound VIa-1a can also be characterized by TGA comprising a thermogram substantially as shown in FIG. 6. In some embodiments, Form A of the L-arginine salt of compound VIa-1a can also be characterized by a DSC curve comprising an endotherm at about 167°C. In another embodiment, the DSC curve is substantially as shown in FIG. 6.

[0258] In some embodiments, provided herein is a crystalline form of the tromethamine (TMA) salt of the compound of formula VIa-1a, which is also a crystalline form of the compound of formula VII-1d (referred to as "Form A of the TMA salt of compound VIa-1a").

[0259] In some embodiments, Form A of the TMA salt of compound VIa-1a 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 determined with a diffractometer using Cu-Kα radiation (λ = 1.54059 Å). In some embodiments, the diffractogram further comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 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, Form A of the TMA salt of compound VIa-1a may also be characterized by its overall X-ray powder diffraction pattern substantially as shown in FIG. 7.

[0260] In some embodiments, Form A of the TMA salt of compound VIa-1a may also be characterized by TGA comprising a thermogram substantially as shown in FIG. 8. In some embodiments, Form A of the TMA salt of compound VIa-1a may also be 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 FIG. 8.

[0261] Further provided herein is a compound of formula XI-1a:

Chemical formula

[0262] In some embodiments, provided herein is a crystalline form of the 4-chlorophenoxyacetate of the compound of Formula XI-1a (alternatively, “Form A of the 4-chlorophenoxyacetate of Compound XI-1a”).

[0263] In some embodiments, Form A of the 4-chlorophenoxyacetate of Compound XI-1a 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 when determined with a diffractometer using Cu-Kα radiation (λ = 1.54059 Å). In some embodiments, the diffractogram further comprises 1, 2, 3, 4, or 5 additional peaks selected from 20.0, 20.7, 21.9, 25.8, and 31.0° 2θ ± 0.2° 2θ. In some embodiments, Form A of the 4-chlorophenoxyacetate of Compound XI-1a may also be characterized by its overall X-ray powder diffraction pattern substantially as shown in FIG. 10.

[0264] In some embodiments, Form A of the 4-chlorophenoxyacetate of Compound XI-1a is also characterized by a DSC curve comprising an endotherm at about 162 °C (onset). In another embodiment, the DSC curve is substantially as shown in FIG. 9.

[0265] In some embodiments, provided herein is a crystalline form of the free base of the compound of Formula XI-1a.

[0266] In some embodiments, Form A of the free base of Compound XI-1a 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 when determined with a diffractometer using Cu-Kα radiation (λ = 1.54059 Å). In some embodiments, the crystalline free base of Compound XI-1a may also be characterized by its overall X-ray powder diffraction pattern substantially as shown in FIG. 11.

[0267] In some embodiments, Form A of the free base of Compound XI-1a is also characterized by a DSC curve that includes an endotherm at about 98 °C (onset). In another embodiment, the DSC curve is substantially as shown in Figure 12.

[0268] In some embodiments, provided herein is a crystalline form of the disuccinate salt of the compound of formula XI-1a (alternatively referred to as "Form A of the disuccinate salt of Compound XI-1a").

[0269] In some embodiments, Form A of the disuccinate salt of Compound XI-1a is characterized by an X-ray powder diffraction pattern that includes 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 when determined with a diffractometer using Cu-Kα radiation (λ = 1.54059 Å). In some embodiments, the diffractogram further includes 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, Form A of the disuccinate salt of Compound XI-1a can also be characterized by its overall X-ray powder diffraction pattern that is substantially as shown in Figure 13.

[0270] In some embodiments, Form A of the disuccinate salt of Compound XI-1a is also characterized by a DSC curve that includes an endotherm at about 163.0 °C (onset). In another embodiment, the DSC curve is substantially as shown in Figure 14.

[0271] Accordingly, the present disclosure provides the following numbered embodiments.

[0272] Embodiment 1. A method for preparing a compound of formula V-2:

Chemical formula

[0273] Embodiment 2.X 2 which is O, the method according to Embodiment 1.

[0274] Embodiment 3.X 2 which is NR 53 the method according to Embodiment 1.

[0275] Embodiment 4.X 2 which is NR 53 and R 51 and R 53 which are linked together with the nitrogen atom to form a heterocyclyl, the method according to Embodiment 1.

[0276] Embodiment 5.R 51 and R 53 which are linked together with the nitrogen atom to form -morpholino, the method according to Embodiment 4.

[0277] Embodiment 6. where n is 0, the method according to Embodiment 1.

[0278] Embodiment 7.R 52 which is C 1-12 alkyl, the method according to Embodiment 1.

[0279] Embodiment 8. The activating 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-pyridyl thiocarbonate, the method according to any one of Embodiments 1 to 7.

[0280] Embodiment 9. The activating reagent is 1,1'-thiocarbonyldiimidazole, the method according to Embodiment 8.

[0281] Embodiment 10. The contact of the compound of formula IIa-1 with the activator is a) optionally at a reaction temperature of about 0 °C to about 60 °C, and / or b) optionally for a reaction duration of about 3 hours to about 72 hours, The method according to any one of Embodiments 1 to 9, comprising.

[0282] Embodiment 11. The contact with the compound of formula IV is a) optionally at a reaction temperature of about 20 °C to about 80 °C, and / or b) optionally for a reaction duration of about 1 hour to about 48 hours, The method according to any one of Embodiments 1 to 10, comprising contacting under reaction conditions including.

[0283] Embodiment 12.

Chemical formula

[0284] Embodiment 13. Formula VIa-1a:

Chemical formula

[0285] Embodiment 14. Formula VIa-1a:

Chem.

Chem.

[0286] Embodiment 15. The method according to embodiment 14, wherein the electrophilic bromine source comprises DBDMH (1,3-dibromo-5,5-dimethylhydantoin) or NBS (n-bromosuccinimide).

[0287] Embodiment 16. The method according to embodiment 14, wherein X 2 is O.

[0288] Embodiment 17. The method according to embodiment 14, wherein R 51 is hydrogen or C 1-12 alkyl.

[0289] Embodiment 18.X 2 is NR 53 The method according to Embodiment 14, wherein

[0290] Embodiment 19. Formula VIa-1a:

Chemical formula

Chemical formula

[0291] Embodiment 20.VII-2a: [Chemical formula] having the formula: wherein the N(R 46 )3 moiety is selected from the group consisting of t-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine, and dibenzylamine, the salt according to embodiment 13.

[0292] Embodiment 21. Formula VII-1a: [Chemical formula] The salt according to Embodiment 13, having

[0293] Embodiment 22. Formula VII-1b [Chemical formula] The salt according to Embodiment 13, having

[0294] Embodiment 23. Formula VII-1c: [Chemical formula] The salt according to Embodiment 13, having

[0295] Embodiment 24. Formula VII-1d: [Chemical formula] The salt according to Embodiment 13, having

[0296] Embodiment 25. 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° 2θ ± 0.2° 2θ, wherein the X-ray powder diffraction pattern is prepared using Cu-Kα radiation, polymorph A of the t-butylamine (TBA) salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (polymorph A of the TBA salt of Compound VIa-1a).

[0297] Embodiment 26. i) said X-ray powder diffraction pattern further comprising 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° 2θ ± 0.2° 2θ, ii) a diffractogram substantially as shown in FIG. 1, iii) a differential scanning calorimetry (DSC) including an endotherm at about 171 °C, or iv) a thermogravimetric analysis (TGA) including a thermogram substantially as shown in FIG. 2, Polymorph A of the TBA salt of compound VIa-1a according to embodiment 25, further characterized thereby.

[0298] Embodiment 27.6.7, 10.6, 17.2, 19.0, and 19.6° 2θ ± 0.2° 2θ showing an X-ray powder diffraction pattern having one or more peaks selected therefrom, said X-ray powder diffraction pattern being created using Cu-Kα radiation, polymorph A of the dicyclohexylamine (DCHA) salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (polymorph A of the DCHA salt of compound VIa-1a).

[0299] Embodiment 28. i) said X-ray powder diffraction pattern further comprising 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° 2θ ± 0.2° 2θ, ii) a diffractogram substantially as shown in Figure 3, iii) differential scanning calorimetry (DSC) including an endotherm at about 139°C, or iv) a thermogram including thermogravimetric analysis (TGA) substantially as shown in Figure 4, Polymorph A of the DCHA salt of compound VIa-1a according to embodiment 27, further characterized thereby.

[0300] Embodiment 29.17.8, 19.0, 20.3, 21.1, 22.4, 23.2, and 24.2° 2θ ± 0.2° 2θ showing an X-ray powder diffraction pattern having one or more peaks selected therefrom, said X-ray powder diffraction pattern being created using Cu-Kα radiation, polymorph A of the L-arginine salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (polymorph A of the L-arginine salt of compound VIa-1a).

[0301] Embodiment 30. i) The X-ray powder diffraction pattern further comprising 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° 2θ ± 0.2° 2θ, ii) A diffractogram substantially as shown in Figure 5, iii) Differential scanning calorimetry (DSC) including an endotherm at about 167 °C, or iv) A thermogram including thermogravimetric analysis (TGA) substantially as shown in Figure 6, The Form A polymorph of the L-arginine salt of compound VIa-1a according to embodiment 29, further characterized by

[0302] Embodiment 31. An X-ray powder diffraction pattern having one or more peaks selected from 31.6, 6.6, 13.2, 19.9, 20.1, 21.8, and 26.7° 2θ ± 0.2° 2θ, the X-ray powder diffraction pattern being prepared using Cu-Kα radiation, the Form A polymorph of the tromethamine (TMA) salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (Form A of the TMA salt of compound VIa-1a).

[0303] Embodiment 32. i) The X-ray powder diffraction pattern further comprising 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° 2θ ± 0.2° 2θ, ii) A diffractogram substantially as shown in Figure 7, iii) Differential scanning calorimetry (DSC) including endotherms at about 123 °C and about 136 °C, or iv) A thermogram including thermogravimetric analysis (TGA) substantially as shown in Figure 8, The Form A polymorph of the TMA salt of compound VIa-1a according to embodiment 31, further characterized by

[0304] Embodiment 33. Formula IX-2:

Chemical formula

Chem.

Chem.

[0305] Embodiment 34. The method according to Embodiment 33, wherein the protecting group is tert-butoxycarbonyl or of the formula

Chem.

[0306]

Chem.

[0307] Embodiment 36. The method according to 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).

[0308] Method according to Embodiment 36, wherein the fluorinating agent is HF·pyridine.

[0309] Embodiment 38. Formula X-2:

Chem.

Chem.

Chem.

Chem.

[0310] Embodiment 39. The salt of the compound of Formula VIa-1a is Formula VII-2a:

Chem.

[0311] Embodiment 40. R73 The method according to embodiment 38 or 39, wherein the protecting group is

[0312] Embodiment 41.R 73 The method according to any one of embodiments 38 to 40, wherein R is tert-butoxycarbonyl

[0313] Embodiment 42. The protecting group is tert-butoxycarbonyl or a group of the formula

Chemical formula

[0314] Embodiment 43. A method for preparing a compound of formula XI-1a:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0315] Embodiment 44. The method according to embodiment 43, wherein the protecting group is tert-butoxycarbonyl or of the formula

Chemical formula

[0316]

Chemical formula

Chemical formula

[0317] Embodiment 46. A process for preparing a compound of formula I:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0318] Embodiment 47. The salt of the compound of formula VIa-1a is of formula VII-2a:

Chemical formula

[0319] Embodiment 48. The salt of the compound of formula X-2 is hydrochloride, oxalate, and 4-chlorophenoxyacetate, the method according to Embodiment 46 or 47.

[0320] Embodiment 49. The method according to any one of Embodiments 46 to 48, wherein the deprotection conditions include contacting the compound of Formula X-2 with a second acid.

[0321] Embodiment 50. The method according to 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.

[0322] Embodiment 51. The method according to any one of Embodiments 46 to 50, wherein the deprotection conditions include generating hydrogen chloride in situ.

[0323] Embodiment 52. The method according to any one of Embodiments 46 to 51, further comprising isolating the compound of Formula XI-1a or a salt thereof using heptane, IPAc, and / or IPA.

[0324] Embodiment 53. The reaction conditions for obtaining the compound of Formula I are a) a temperature of about 0°C to about 5°C, and a temperature increase to about 20°C to about 25°C, and / or b) optionally in the presence of a base and diphenylphosphinic acid chloride, The method according to Embodiment 46.

[0325] Embodiment 54. The reaction conditions for obtaining the compound of Formula I further include contacting the reaction mixture of Embodiment 53 with a base and further contacting it with a mixture of isopropyl alcohol and heptane. The method according to Embodiment 53.

[0326] Embodiment 55. The dehydrating agent is selected from the group consisting of sulfonyl chloride having an electron-withdrawing group, sulfonic anhydride, phosphonic anhydride, carbonic anhydride, and a mixture of triphenylphosphine and carbon tetrachloride. The method according to Embodiment 38, 46, or 47.

[0327] Embodiment 56. The method according to 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 the mixture of triphenylphosphine and carbon tetrachloride.

[0328] Embodiment 57. The method according to any one of embodiments 35 to 56, wherein the solvate is a polar aprotic solvent.

[0329] Embodiment 58. The method according to any one of embodiments 35 to 56, wherein the solvate is a hydrate.

[0330] Embodiment 59. The method according to embodiment 49, wherein the polar aprotic solvent is selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidone, and dimethylacetamide.

[0331] Embodiment 60. The method according to any one of embodiments 38 to 59, wherein the base is N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), or potassium carbonate.

[0332] Embodiment 61. The method according to any one of embodiments 38 to 60, wherein the reaction conditions sufficient to obtain the compound of formula X-2 or a salt thereof include acetonitrile as a solvent.

[0333] Embodiment 62. The salt of the compound of formula XI-1a is prepared, and the salt of the compound of formula XI-1a is a hydrochloride, oxalate, or 4-chlorophenoxyacetate. The method according to any one of embodiments 43 to 61.

[0334] Embodiment 63. The method according to embodiment 62, wherein the salt of the compound of formula XI-1a is 4-chlorophenoxyacetate.

[0335] Embodiment 64. Formula IX-1a:

Chemical formula

[0336] Embodiment 65. The hydrate according to embodiment 64, wherein the stoichiometric ratio of the compound of formula IX-1a to water in the hydrate is about 1:1.

[0337] Embodiment 66. The disuccinate of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine: [Chemical formula]

[0338] Embodiment 67. The 4-chlorophenoxyacetate of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine: [Chemical formula]

[0339] Embodiment 68. Form A of 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: [Chemical formula] The 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, 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 when determined by a diffractometer using Cu-Kα radiation (λ = 1.54059 Å).

[0340] Form A of the free base of Compound XI-1a according to Embodiment 68, further characterized by a DSC curve comprising an endotherm at about 98 °C (onset).

Examples

[0341] X-ray powder diffraction (XRPD) 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 on zero-background silicon (Si) holders using light manual pressure to keep the sample surface flat. Each sample was analyzed from 3 - 45° 2θ using an effective step size of 0.02° 2θ and an exposure time of 0.08 seconds.

[0342] In-situ high-temperature XRPD patterns were collected using a Malvern PANalytical Aeris diffractometer (Malvern Panalytical, UK) coupled 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 zero-background Si holders. Each sample was analyzed from 8 - 45° 2θ using an effective step size of 0.02° 2θ. The measurement time for each sample was 20 minutes.

[0343] Thermogravimetric analysis (TGA) Thermogravimetric analysis (TGA) was carried out on a TA Instruments Discovery 550 (TA, US). Each sample was placed in a pre-weighed 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 was 40 mL / min at the balance and 60 mL / min in the furnace.

[0344] Differential scanning calorimetry (DSC) DSC analysis was performed on a TA Instruments Discovery 250 (TA, US). Calibration of the instrument temperature and cell constant was carried out using indium. The DSC cell was maintained under a nitrogen purge of 50 mL / min during each analysis. 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. Some DSC analyses were carried out by using a Tzero sealed pan without a pinhole because the sample might sublime at high temperatures.

[0345] Dynamic vapor sorption (DVS) analysis DVS analysis was carried out using a Surface Measurement System DVS Intrinsic analyzer (SMS, UK). The balance of the instrument was calibrated using a standard weight. A sample of approximately 15 - 20 mg was loaded into the pan for analysis. The sample was 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). The transition from one step to the next was made either after meeting the equilibrium criterion of a weight change of 0.002% (dm / dt) or after 6 hours if the equilibrium criterion was not met.

[0346] Polarizing microscopy (PLM) Microscopic images of the crystals were obtained under a suitable objective lens on a Nikon Ci-POL445 polarizing microscope (Nikon, Japan).

[0347] Gas chromatography (GC) Shimadzu GC-2104 (Shimadzu, Japan) was used for the characterization of chemical purity. The detailed chromatographic conditions are listed in Table 1. [Table 1]

[0348] 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 of the 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 may be prepared by procedures described in standard reference textbooks 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 Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 5 th Edition, 2001), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989) or obvious modifications thereof.

[0349] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that function well in the implementation of the present disclosure, and thus, can be considered to constitute specific modes for its implementation. However, those skilled in the art should understand that, in light of the present disclosure, many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of the present disclosure, and still obtain the same or similar results.

[0350] Example 1: Preparation of (1s,3s)-3-hydroxycyclobutane-1-carboxylic acid (II-1) [Chemical formula] 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 (NaBH4, 9.36 kg, 247 mol, 0.35 equivalent) was added to the reactor at about 15°C to 25°C under nitrogen. The 1000 L reactor was cooled to about -35°C to -45°C. EtOAc (68.4 kg) and tert-butyl 3-oxocyclobutanecarboxylate (XIII-1) (120.0 kg, 705 mol, 1.0 equivalent) were charged into a 500 L reaction tank. The solution was stirred at about 10°C to 30°C for about 0.5 hour. The XIII-1 solution in the 500 L reaction tank was charged into the 1000 L reactor of NaBH4 at about -35°C to -45°C. The reaction mixture was stirred at about -35°C to -45°C for about 3 hours until the reaction was considered complete.

[0351] Deionized water (336.0 kg) and ammonium chloride (24.0 kg) were added to a 2000 L glass-lined (GL) reactor. The solution was stirred at about 10 °C to 30 °C. The ammonium chloride solution in the 2000 L GL reactor was cooled to about -3 °C to 5 °C. The reaction mixture in a 1000 L SS reactor was charged into the 2000 L GL reactor. During the addition, the temperature was controlled in the range of about -3 °C to 5 °C to control the exotherm. The reaction mixture in the 2000 L GL reactor was heated to about 5 °C to 15 °C and stirred for about 6 hours. The reaction mixture in the 2000 L GL reactor was filtered at about 5 °C to 15 °C, and then the cake was washed with EtOAc (54.0 kg). The filtrate was transferred to a 1000 L GL reactor at about 5 °C to 15 °C, precipitated, and phase-separated. An aqueous phase and EtOAc (216 kg) were added to the 1000 L GL reactor at about 5 °C to 15 °C, stirred for about 1 hour, and precipitated for about 1 hour. The aqueous phase was discarded. The combined organic phases were washed once with water (120 kg) at about 5 °C to 15 °C, and the aqueous layer was discarded. The organic solution in the 1000 L GL reactor was concentrated at a gradually increasing temperature under a pressure (P) of about -0.8 mPa or less until the temperature reached about 60 °C. Heptane (81.6 kg) was added to the 1000 L GL reactor and concentrated under P ≤ -0.08 mPa until the temperature reached about 60 °C. Then, another portion of heptane (81.6 kg) was added to the 1000 L GL reactor and concentrated under 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, heated to about 50 °C to 60 °C to dissolve the solid. The solution in the 1000 L 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 the 1000 L GL reactor and heated to about 50 to 60 °C until the solid was completely dissolved. The solution in the 1000 L 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 isolated by a centrifuge 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 (yield 68.7%).

[0352] 1 1H NMR (DMSO-d6, 400 MHz) δ = 5.14 (d, J = 6.8 Hz, 1H), 3.88 - 3.97 (m, 1H), 2.32 - 2.42 (m, 3H), 1.88 - 1.91 (m, 2H), 1.39 (s, 9H) ppm.

[0353] Example 2: Preparation of tert-Butyl (1S,3S)-3-((((2-((2-Ethylhexyl)oxy)-2-oxoethyl)thio)carbonothioyl)oxy)cyclobutane-1-carboxylate (V-1a)

Chemical Structure

[0354] 2-Ethylhexyl thioglycolate (55 kg, 269 mol, 1.1 eq) was charged into a 1000 L GL reactor at about 20 - 25 °C and heated to about 40 - 45 °C over about 2 hours until the reaction was considered complete. The reaction mixture was then cooled to about 10 - 20 °C. Deionized (DI) water (420.0 kg) was charged into the 1000 L GL reactor at about 10 - 20 °C, stirred for about 1 hour, and allowed to precipitate 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 into a 1000 L GL reactor at about 10 - 20 °C together with a 5 wt% sodium bicarbonate solution (420 kg), stirred for about 1 hour, and allowed to precipitate for about 4 hours. The layers were separated. Anhydrous sodium sulfate (63 kg) was charged into the 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 into a 1000 L GL reactor at about 15 - 30 °C. The organic solution was concentrated at a gradually increasing temperature until the temperature reached about 50 °C under P ≤ -0.8 mPa. Dichloromethane (DCM) (223.44 kg) was charged into the 1000 L GL reactor and concentrated at a gradually increasing temperature until the temperature reached about 40 °C under P ≤ -0.08 mPa. The DCM distillation process was repeated until the DCM content was about 5.0% or less and the MTBE content was about 2.0% or less (each by percentage of the integrated area under the gas chromatography curve), and the water content was about 500 ppm or less (by the Karl Fischer method). The mixture was cooled to 15 - 30 °C. The liquid was used directly in the next step.

[0355] 1 H NMR (CDCl3, 400 MHz) 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.

[0356] Example 3: Preparation of (III-1b) of tert-butyl (1s,3s)-3-(dithiocarboxyoxy)cyclobutane-1-carboxylate [Chemical formula] Compound II-1 (9.67 kg, 56.2 mol, 1.0 eq) was dissolved in DMSO (29 L) at 25 °C to obtain a colorless solution. The mixture was cooled to 10 °C within 0.5 h. DBU (9.40 kg, 61.8 mol, 1.10 eq) was added dropwise to the reaction mixture over 0.5 h while maintaining the internal temperature at 10 - 15 °C. The reaction mixture was stirred at 10 °C for 0.5 h. CS2 (6.41 kg, 84.2 mol, 1.50 eq) was added dropwise to the reaction mixture over 1 h while maintaining the internal temperature at 10 - 15 °C, and the solution changed from colorless to yellow. The reaction mixture was stirred at 10 °C for 0.5 h. MeI (8.77 kg, 61.8 mol, 1.10 eq) was added dropwise to the reaction mixture over 1.5 h while maintaining the internal temperature at 10 - 15 °C. The mixture was warmed to 25 °C within 0.5 h and stirred for 12 h. HPLC_IPC (Rt-SM = 2.226, Rt-product = 3.918) indicated that the starting material had been completely consumed. The reaction mixture was cooled to 10 °C. 10% NaH2PO4 (29 L) was added dropwise to the reaction mixture over 2 h while maintaining the internal temperature at 10 - 15 °C. The mixture was extracted with n-heptane (20 L × 3). The combined organic layers were washed with water (10 L × 2) and brine (10 L × 2). The organic layer was concentrated in vacuo at 45 °C to obtain a yellow solution (30 L). Activated carbon (3.0 kg) was added to the solution at 20 °C all at once. The mixture was stirred at 20 °C for 12 h. The mixture was filtered through a Celite pad at 25 °C. The filter cake was washed with n-heptane (10 L). The eluate changed to colorless. The filtrate was concentrated in vacuo at 45 °C to obtain Compound III-1b (5.1 kg, 19.2 mol, yield 66.6%, purity 98.5%). 11H NMR (d6-DMSO, 400 MHz) 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.

[0357] The title compound can be used as a substitute for compound III-1 in the preparation of compound V-1a as in Example 2 above.

[0358] Example 4: Preparation of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (VIa-1a) [Chemical formula] DCM (235 kg) and 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (75.2 kg, 263 mol, 3.5 equivalents) were charged into a 500 L perfluoroalkoxyalkane (PFA) coated reactor at about 15 - 30 °C, and the reaction tank was cooled to about -75 °C to -50 °C. Hydrogen fluoride pyridine (130.2 kg, 1.31 kmol, 61 equivalents) was charged into the reaction tank via a dropping tank at about -75 °C to -50 °C, and then the tank was rinsed with about 10 - 20 kg of 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 equivalent) and DCM (18.3 kg) were mixed and transferred into the reaction tank via a dropping tank at an addition rate of about 10 - 30 kg / h while maintaining at about -75 °C to -50 °C. When 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 1000 L PTFE 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 the ice-water mixture via a pump and stirred for 4 hours. The mixture was further stirred for an additional about 2 hours at about 0 °C to 20 °C, and then the phases were separated. The aqueous phase was extracted 3 times with DCM (191 kg). The combined organic phase was washed 2 times with water (355.3 kg). The organic layer was transferred to a GL reactor and distilled at a temperature of about 50 °C or less 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 a temperature of about 30 °C or less. The mixture was stirred for about 2 hours and then the layers were separated. The aqueous phase was washed 3 times with DCM (38 kg). At about 0 - 30 °C, HCl was added dropwise to adjust the pH to about 1 - 2. The phases separated, and the aqueous layer was extracted 1 time with DCM (68.8 kg). The DCM product stream was transferred to a 1000 L GL reactor and concentrated at a temperature of about 50 °C or less and P ≤ -0.08 MPa until no fraction was observed. After isolation by vacuum distillation at a maximum of about 110 °C and P ≤ 5 mmHg, VIa-1a was obtained as an oil. Combining three batches of vacuum distillation, a yield of 99.1 kg (55% yield based on the input assay of V-1a based on the assay) was obtained. 11H NMR (DMSO-d6, 400 MHz) 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. 19 19F NMR (DMSO-d6, 400 MHz) δ = -57.9 ppm.

[0359] Example 5. Alternative preparation of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (VIa-1a):

Chemical Structure

[0360] Step - 2: To a stirred solution of XIII - a (100 g, 1 equivalent) in anhydrous methanol (70 volumes), NaBH4 (0.5 equivalent) was added portionwise at 0 °C under an inert atmosphere over a period of 60 minutes. The reaction product was then stirred at room temperature 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 then the solvent was evaporated to dryness. The resulting residue was diluted with water (2 volumes), acidified to pH = 1 - 2 with 1.5 N aqueous HCl at 0 °C, and stirred at room temperature for 1 hour. It was extracted in dichloromethane with 15 - 20% methanol (5 × 2 L). The combined extracts were dried (Na2SO4), and the solvent was evaporated to dryness to obtain crude II - 2 as a pale - yellow gum, which slowly solidified on standing (96 g, 95% yield). The crude product obtained was predominantly the cis - isomer (>96%). Melting point: 86.1 ° - 89.1 °C. 1 1H NMR (CDCl3, 400 MHz) δ = 4.20 (p, J = 7.2 Hz, 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.

[0361] Step - 3: Compound II - 2 (50 g, 1 equivalent) was dissolved in anhydrous DMSO (75 mL, 1.5 volumes), DBU (1.1 equivalent) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour under an inert atmosphere. Then, carbon disulfide (1.5 equivalents) was added dropwise to the reaction mixture at 0 °C, and the mixture was stirred at room temperature for 2 hours. Then, methyl iodide (1.1 equivalents) was added to the reaction mixture at 0 °C, and the reaction was stirred at room temperature for 2 hours. The reaction product was treated with 10% aqueous NaH2PO4 (500 mL) and EtOAc (1000 mL). The organic layer was separated and washed with water (2 × 250 mL). The aqueous layer was extracted again with EtOAc (2 × 200 mL). The combined extracts were dried, and the solvent was removed under vacuum. The resulting crude product V - 1c slowly solidified as an orange - tinged brown color on standing at - 20 °C overnight (63 g, 85% yield). Melting point: 50.5 ° - 60.1 °C. 11H NMR (CDCl3, 400 MHz) δ = 5.51 (p, 1H, J = 7.2 Hz), 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.

[0362] Step - 4: In a polyethene bottle, HF - pyridine (22 equivalents) was added outdoors to a solution of DBH (3 equivalents) in DCM (1250 mL, 25 volumes) at - 78 °C, and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of V - 1c (50 g, 1 equivalent) in DCM (250 mL, 5 volumes) was added dropwise at - 78 °C (the reaction product changed to a reddish - brown color), and the reaction product was stirred at the same temperature for 30 minutes. Then, the reaction product was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC and HPLC. The reaction mixture was slowly poured onto a mixture of NaHSO3 (10 volumes, 10% solution), NaOH (40 volumes, 10% solution), and NaHCO3 (200 g) such that the pH was approximately 10 - 11. The layers were separated, and the aqueous layer was further extracted with dichloromethane (2 × 1000 mL). The combined extracts were washed with 1.5 N HCl solution (750 mL) and water (2 × 750 mL), and the solvent was evaporated to dryness to obtain the 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 ° - 56.9 °C. 1 1H NMR (CDCl3, 300 MHz) = 4.58 (p, J = 7.6 Hz, 1 H), 3.67 - 3.60 (m, 4 H), 3.51 (bs, 4 H), 2.83 - 2.73 (m, 1 H), 2.59 - 2.53 (m, 4 H) ppm.

[0363] Step - 5: Method - 1: 4N HCl (50 mL) in dioxane was added dropwise to VIa - 1b (5 g, 1 equivalent) at 0 °C, followed by the addition of water (10 mL). The reaction product was heated to 100 °C for 5 hours. The progress of the reaction was monitored by TLC. A complete reaction was indicated by TLC. The solvent was concentrated in vacuo, and the reaction product was diluted with water (10 mL). The aqueous layer was basified with 5% aqueous NaOH (pH about 10 - 11) and washed with MTBE (3 × 50 mL) to remove non - polar impurities. The reaction product was acidified with 1.5N HCl (pH about 1 - 2), and the aqueous layer was further extracted in EtOAc (3 × 75 mL). The combined extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain product VI (2.9 g, 80% yield).

[0364] Step - 5: Method - 2: Compound VIa - 1b (10 g, 1 equivalent) was suspended in concentrated HCl (375 mL, 37.5 volumes) at room temperature. The reaction mixture was heated to 120 °C for 4 hours. At this stage, a complete reaction was indicated by TLC. The reaction product was cooled to room temperature and diluted with water (100 mL). It was extracted in EtOAc (3 × 250 mL). The combined extracts were concentrated in vacuo. The resulting residue was suspended in water (50 mL) and basified to pH = 10 - 12 using 5% NaOH solution at 0 °C. The aqueous layer was washed with MTBE (4 × 100 mL). The aqueous layer was cooled to 0 °C, acidified to pH = 1 - 2, and extracted in EtOAc (3 × 150 mL). The solvent was dried (Na2SO4) and concentrated in vacuo to obtain the acid and product VI (4.7 g, 64% yield).

[0365] Example 6: Preparation of Methyl 2 - ((((1s,3s) - 3 - (morpholine - 4 - carbonyl)cyclobutoxy)carbonothioyl)thio)acetate

Chemical Structure

[0366] Example 7: Preparation of morpholino((1s,3s)-3-(trifluoromethoxy)cyclobutyl)methanone (VIa-1b)

Chemical formula

[0367] Example 8: Preparation of (1s,3s)-tert-butyl 3-(trifluoromethoxy)cyclobutane-1-carboxylate tert-butylamine complex (VII-1a) [Chemical formula] EtOAc (55.6 kg) and VIa-1a (55.6 kg, 292 mol, 1.0 eq) were combined in a drum and then charged into the reactor through a filter. Then, EtOAc (222.4 kg) was charged into the reaction tank through a filter, and the contents were mixed for about 0.5 h. At about 15 - 35 °C, tert-butylamine (24.5 kg, 335 mol, 1.15 eq) was charged into the reactor via a pump and stirred at about 15 - 35 °C for about 2 h. The reaction mixture was warmed to about 75 - 78 °C, stirred for about 1 h, and then cooled to about 20 - 25 °C. VII-1a was isolated by centrifugation and washed with EtOAc (55.6 kg). The product was dried at about 55 °C or below to obtain solid VII-1a. Yield: 70.5 kg (93.5% yield).

[0368] 1 H NMR (DMSO-d6, 400 MHz) 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-d6, 376 MHz) δ = -57.8 ppm.

[0369] 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)

Chemical Structure

[0370] 1,1'-Carbonyldiimidazole (CDI) and N,N-dimethylformamide (DMF) were charged into another reactor and cooled to about 0 - 5 °C. The solution containing in-situ generated VIa-1a was transferred to the CDI slurry over about 0.5 hours or more and then rinsed with DMF. The contents were stirred at about 0 - 5 °C for about 2 hours or more to form activated VI-1a. Once the reaction was complete, VIII-1 was charged into VI-1a 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 over about 0.5 hours or more. The contents were stirred at about 20 - 25 °C for about 3 hours or more until the reaction was complete. Potassium carbonate (K2CO3) 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 the K2CO3 aqueous solution over about 1 hour or more while maintaining an internal temperature of about 40 - 45 °C. The contents were adjusted to about 20 - 25 °C and then stirred at about 20 - 25 °C for about 1 hour or more. The slurry was filtered and then washed twice with purified water. The wet cake was vacuum dried at about 80 °C or lower (target 50 °C) until the water content was about 5.0 w / w% or less. 1 H NMR (d6-DMSO, 600 MHz): 9.74 (s, 2H), 7.58 - 7.32 (m, 1H), 4.79 (p, 1H, J = 7.5 Hz), 2.68 (p, 1H, J = 7.5 Hz), 2.53 - 2.49 (m, 2H), 2.29 - 2.24 (m, 2H), 2.12 - 2.00 (m, 6H), 1.28 (s, 9H) ppm.

[0371] Optional purification The dry cake of IX-1a and purified water were charged into a reactor. The contents were stirred at about 20 - 25 °C for about 6 hours or more. The slurry was filtered and then washed twice with purified water. The wet cake was vacuum dried at about 80 °C or lower (target 50 °C) until the water content was 5.0 w / w% or less. If the purity of the dry cake was less than 96.0 a / a% by HPLC, optional purification was repeated.

[0372] 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) [Chemical formula] IX-1a, 4-toluenesulfonyl chloride (TsCl), and acetonitrile (ACN) were charged into a reactor. The contents were stirred and adjusted to about 20 - 25 °C. N,N-Diisopropylethylamine (DIPEA) was added and rinsed with ACN. The contents were adjusted to about 20 - 25 °C and stirred at about 20 - 25 °C for about 12 hours or more. Once the reaction was complete, a potassium hydroxide (KOH) solution (6% aqueous solution) was added to the reaction mixture while maintaining an internal temperature of about 30 °C or lower (target 20 - 25 °C). The resulting slurry was adjusted to about 20 - 25 °C and then stirred at about 20 - 25 °C for about 2 hours or more until the TsCl content was about 10 ppm or less. The slurry was filtered and then washed with an aqueous ACN solution and purified water. The wet cake was vacuum dried at about 60 °C or lower (target 50 °C) until the water content was about 0.2 w / w% or less by the Karl Fischer method. 1 H NMR (CDCl3, 600 MHz): 5.12 (s, 1H), 4.68 (p, 1H, J = 8 Hz), 3.30 (p, 1H, J = 9 Hz), 2.86 - 2.82 (m, 2H), 2.68 - 1.63 (m, 2H), 2.58 (s, 6H), 1.45 (s, 9H) ppm.

[0373] 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) [Chemical formula] Acetyl chloride (AcCl) and isopropyl acetate (IPAc) were charged into a reactor and cooled to about 0 - 5 °C. An IPAc solution of isopropyl alcohol (IPA) was charged into the AcCl solution over about 1 hour or more while maintaining an internal temperature of about 20 °C or less under a nitrogen (N₂) atmosphere. The contents were adjusted to about 20 - 25 °C and then stirred at about 20 - 25 °C for about 2 hours or more to obtain an in-situ generated hydrogen chloride (HCl) solution. X-1a and IPAc were charged into another reactor and cooled to about 0 - 5 °C. The HCl solution was added to the X-1a / IPAc slurry while maintaining an internal temperature of about 15 °C or less under a N₂ atmosphere and then rinsed with IPAc. The contents were adjusted to about 40 - 45 °C and then stirred at about 40 - 45 °C for about 2 hours or more. Once the reaction was complete, the reaction mixture was adjusted to about 20 - 25 °C and slowly added to a pre-cooled (0 - 5 °C) aqueous potassium phosphate (K₃PO₄) solution while maintaining an internal temperature of about 20 °C or less and then rinsed twice with IPAc. The mixture was adjusted to about 20 - 25 °C and stirred for about 1 hour or more. The layers were allowed to precipitate and separated. The aqueous layer was extracted with IPAc. When the content of 3-amino-N'-(cis-3-(trifluoromethoxy)cyclobutane-1-carbonyl)bicyclo[1.1.1]pentane-1-carbohydrazide was more than 1.0%, the combined organic layer was additionally washed with an aqueous KOH solution. The combined organic layer was vacuum concentrated to the target volume to 3V at about 50 °C or less. The resulting concentrate was diluted with IPAc. The contents were adjusted to about 20 - 25 °C and then filtered through a 1 μm disk filter and a 1 μm cartridge filter and then rinsed with IPAc. The filtrate was concentrated to a target volume of 1.6V while maintaining a jacket temperature of about 50 °C or less. The contents were heated to about 40 - 50 °C and then stirred for about 1 hour or more. N-heptane was slowly added to the contents and then cooled to about 20 - 25 °C over about 1 hour or more. N-heptane was slowly added over about 1 hour or more and then the slurry was stirred at about 20 - 25 °C for about 2 hours or more. The slurry was cooled to about 0 - 5 °C and then stirred at about 0 - 5 °C for about 3 hours or more. The slurry was filtered and then washed with a pre-cooled mixture of n-heptane / IPAc (16:1, v / v).The wet cake was vacuum dried at about 50 °C or lower (target 25 °C) until the water content became 0.6 w / w% or less by the Karl Fischer method and the total of the residual solvents (chloroethane, 2-chloropropane, tert-butylamine, IPAc, n-heptane, DIPEA) became 5,000 ppm or less. 1 1H NMR (CDCl3, 600 MHz): 4.69 (quintet, 1H, J = 8 Hz), 3.29 (quintet, 1H, J = 9 Hz), 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 Figure 12.

[0374] Example 12: Preparation of 4-chlorophenoxyacetate of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine [Chemical formula] Acetyl chloride (AcCl) and isopropyl acetate (IPAc) were charged into a reactor and cooled to about 0 - 5°C. A solution of isopropyl alcohol (IPA) in IPAc was charged into the AcCl solution over about 1 hour or more while maintaining an internal temperature of about 20°C or less under a nitrogen (N2) atmosphere. The contents were adjusted to about 20 - 25°C and then stirred at about 20 - 25°C for about 2 hours or more to obtain an in-situ generated hydrogen chloride (HCl) solution. X-1a and IPAc were charged into another reactor and cooled to about 0 - 5°C. The HCl solution was added to the X-1a / IPAc slurry while maintaining an internal temperature of about 15°C or less under a N2 atmosphere and then rinsed with IPAc. The contents were adjusted to about 40 - 45°C and then stirred at about 40 - 45°C for about 2 hours or more. Once the reaction was complete, the reaction mixture was adjusted to about 20 - 25°C and slowly added to a pre-cooled (0 - 5°C) aqueous potassium phosphate (K3PO4) solution while maintaining an internal temperature of about 20°C or less and then rinsed twice with IPAc. The mixture was adjusted to about 20 - 25°C and stirred for about 1 hour or more. The layers were allowed to precipitate and separated. The aqueous layer was extracted with IPAc. The combined organic layers were vacuum concentrated to the target volume of 3V at about 50°C or less until the water content was 0.3% w / w or less. The resulting concentrate was diluted with IPAc. The contents were adjusted to about 20 - 25°C and then filtered through a 1 μm disk filter and a 1 μm cartridge filter and then rinsed with IPAc. The filtrate was concentrated to the target volume of 2.5V while maintaining a jacket temperature of about 50°C or less. The contents were adjusted to about 20 - 25°C. A solution of 4-chlorophenoxyacetic acid in IPA was prepared separately and then slowly added to the concentrated XI-1a / IPAc mixture at 20 - 25°C over 2 hours or more and rinsed with IPA. Then the contents were adjusted to 0 - 5°C over 1 hour and mixed for 1 hour or more. The slurry was filtered under vacuum to remove the liquid. The reaction vessel was rinsed with pre-cooled IPA and the cake was vacuum dried at 50°C or less. 11H NMR (600 MHz, d6-DMSO) = 7.32 - 7.30 (m, 2H), 6.93 - 6.91 (m, 2H), 4.88 (quintet, 1H, J = 7.2 Hz), 4.61 (s, 2H), 3.39 (quintet, 1H, J = 6.0 Hz), 2.85 - 2.82 (m, 2H), 2.50 - 2.45 (m, 2H), 2.12 (s, 6H).

[0375] Referring to Figure 9, the DSC of the 4-chlorophenoxyacetate of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine contains an endothermic peak with an onset temperature of about 162 °C.

[0376] Example 13: Preparation of the disuccinate salt of 3-(5-((1s,3s)-3-(trifluoromethoxy)cyclobutyl)-1,3,4-oxadiazol-2-yl)bicyclo[1.1.1]pentan-1-amine [Chemical formula] To a 100 mL three-necked round-bottom flask, 5 g of Compound XI-1a, 11.56 g (10 equivalents) of oxalic acid, and 50 mL (10 volumes) 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 washed with 20 mL (4 volumes) of MeCN. The wet cake was dried under vacuum in an oven at 30 °C to obtain the title compound (yield 97%). 1 1H NMR (d6-DMSO, 600 MHz): 4.89 (quintet, 1H, J = 7.8 Hz), 3.41 (quintet, 1H, J = 8.4 Hz), 2.85 - 2.81 (m, 2H), 2.51 - 2.46 (m, 2H), 2.43 (s, 6H) ppm. The DSC of this salt is shown in Figure 14.

[0377] Example 14: 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)

Chemical formula

[0378] 11H NMR (600 MHz, MeCN-d3): δ 7.65 (s, 1H), 7.31 (d, 2H, J = 9 Hz), 6.96 (d, 2H, J = 9 Hz), 4.79 (m, 1H), 4.40 (s, 2H), 3.34 - 3.29 (m, 1H), 2.96 - 2.82 (q, 2H, J = 9 Hz), 2.59 - 2.54 (q, 2H, J = 10 Hz), 2.53 (s, 6H) ppm.

[0379] 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) [Chemical Structure Diagram] The 4-chlorophenoxyacetate 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 under N2 conditions and cooled to 0 - 5 °C. While maintaining an internal temperature of about 10 °C or less under N2 conditions, TEA was added and rinsed with 2-methyltetrahydrofuran (2-MeTHF). The contents were stirred at about 0 - 5 °C for about 20 minutes or more. Diphenylphosphinic acid chloride in 2-MeTHF solution was slowly added while maintaining an internal temperature of about 10 °C or less under N2 conditions and rinsed with 2-MeTHF. The contents were warmed to about 20 - 25 °C and then stirred for about 1 hour or more until the reaction was complete. The mixture was cooled to about 0 - 5 °C and a 10% aqueous potassium carbonate solution was charged over 1 hour or more at 10 °C or less. The temperature was increased to about 45 - 50 °C and stirred for 1 hour or more. The layers were separated, the organic phase was charged again with a 10% aqueous potassium carbonate solution, and stirred at about 45 - 50 °C for 0.5 hour or more. The layers were separated, the organic phase was charged with a 5% aqueous potassium carbonate solution, and stirred at about 45 - 50 °C for 0.5 hour or more. The layers were separated and the organic layer was vacuum concentrated to about 3.6V at 50 °C or less. MeTHF was charged and the mixture was vacuum concentrated to about 3.6V at 50 °C or less until the water content was 1% w / w or less. MeTHF was charged into the reaction vessel and the mixture was cooled to 20 - 25 °C. The solution was filtered through a cartridge filter and the filtrate was vacuum concentrated to about 2.4V at 50 °C or less. The solvent was exchanged with IPA until the MeTHF:IPA ratio was 20 wt% or less. The temperature of the mixture was adjusted to about 45 - 50 °C. Heptane was charged and the contents were adjusted to 60 - 70 °C to form a homogeneous solution. Then the temperature was adjusted to 50 - 55 °C and stirred for 2 hours or more. Additional heptane was charged and then the temperature was adjusted to about 0 - 5 °C and stirred for 2 hours or more. The solid was isolated by filtration, washed with a pre-cooled IPA / heptane solution, and completely drained. The solid was vacuum dried at 25 °C or less.

[0380] Example 16: Screening of salts for the compound of formula VIa-1a As exemplified in Table 2, the selected solvent (ethyl acetate (EtOAc) or toluene) was added into 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. The slurry was stirred at room temperature (RT) for 2 - 3 days. If a solid precipitated, the solid was collected by centrifugation and then vacuum dried at room temperature for XRPD analysis. Samples that did not precipitate after the solution-mediated reaction were cooled at -15 °C in a refrigerator for 1 day. If a solid precipitated at that point, the solid was collected by centrifugation and then vacuum dried at room temperature for XRPD analysis. If no solid was obtained after cooling, n-heptane was added and the mixture was stirred for an additional 2 days. Solutions that did not precipitate after the addition of n-heptane were then unstoppered to slowly evaporate under the atmosphere until a solid formed. The results are summarized in Table 2 below.

Table 2

[0381] Example 17: Scale-up for a specific salt of the compound of formula VIa-1a Form A of the DCHA salt of compound VIa-1a About 2.5 mmol of the compound of formula VIa-1a and DCHA (1.1 equivalents) were added into 20 mL of EtOAc and stirred at room temperature for 2 days. The solid was collected by centrifugation and vacuum dried at 40 °C for about 1 day. The solid was identified as Form A of the DCHA salt of the compound of formula VIa-1a.

[0382] Form A of the L-arginine salt of compound VIa-1a Approximately 2.5 mmol of the compound of formula VIa-1a and L-arginine (1.1 equivalents) were added into 20 mL of EtOAc and stirred at room temperature for about 5 days. After stirring at room temperature for 2 days, the wet cake was characterized by XRPD and identified as Form B of the L-arginine salt of the compound of formula VIa-1a. After stirring at room temperature for an additional about 3 days, the wet cake was characterized by XRPD and identified as Form A of the L-arginine salt of the compound of formula VIa-1a. The solid was collected by centrifugation and dried in vacuo at 40 °C for 2 days. The resulting solid was then further dried in vacuo at 60 °C for 2 days. The solid was identified as Form A of the L-arginine salt of the compound of formula VIa-1a.

[0383] Form A of the TMA salt of compound VIa-1a Approximately 2.5 mmol of the compound of formula VIa-1a and tromethamine (TMA) (1.1 equivalents) were added into 20 mL of EtOAc and stirred at room temperature for about 2 days. The solid was collected by centrifugation and dried in vacuo at 40 °C for about 1 day. The solid was identified as Form A of the TMA salt of the compound of formula VIa-1a. However, the XRPD pattern contains an extrapolated peak at 18.1° as compared to that of Form A of the TMA salt of compound VIa-1a prepared from that of Example 15.

[0384] Example 18: Characterization of Salt Forms As illustrated in Table 2, 18 salts were obtained from the above experiments. These salts were characterized by XRPD, TGA, and DSC. The data for the selected salts were presented above. Additional results are summarized in Table 3.

Table 3

[0385] Several salts were further investigated with respect to hygroscopicity, purity, and stability of the solid form. To determine the stability of the solid form, glass weighing bottles containing approximately 20 mg of the sample were maintained under the conditions of (1) 60 °C, (2) 25 °C / 60% RH, and (3) 40 °C / 75% RH, respectively. After 1 week and 2 weeks, XRPD and GC analyses were performed to investigate the physical and chemical stability of the selected form under the corresponding conditions. The results are summarized in Table 4 below.

Table 4

[0386] Form A of the TBA salt of compound VIa-1a Form A of the TBA salt of compound VIa-1a was obtained by a solution-mediated reaction with an equimolar amount of t-butylamine in ethyl acetate (EtOAc) or toluene. The XRPD pattern of Form A of the TBA salt of compound VIa-1a was described above with respect to Figure 1. As shown in Figure 2, no weight loss was observed in the TGA curve up to 70 °C. The sample may sublime above 100 °C. The DSC profile showed an endothermic peak around 171 °C. The DSC analysis was performed using a Tzero sealed pan without a pinhole. 1 1H NMR indicated salt formation between the compound of formula VIa-1a and t-butylamine in a ratio of approximately 1:1 without an organic solvent. Form A is an anhydride.

[0387] Form A of the DCHA salt of compound VIa-1a Form A of the DCHA salt of compound VIa-1a was obtained by a solution-mediated reaction with an equimolar amount of dicyclohexylamine (DCHA) in EtOAc. The XRPD pattern of Form A of the DCHA salt of compound VIa-1a was described above with respect to Figure 3. As shown in Figure 4, a 0.8% weight loss was observed in the TGA curve up to 100 °C, and the sample may sublime above 110 °C. The DSC analysis was performed by using a Tzero sealed pan without a pinhole. The DSC curve showed an endothermic peak around 139 °C corresponding to melting. 1The \(^1\)H NMR results suggested salt formation between the compound of formula VIa-1a and DCHA in a ratio of approximately 1:1 without an organic solvent. Form A of the DCHA salt of compound VIa-1a is an anhydrate. DVS analysis suggested that form A of the DCHA salt of compound VIa-1a is non-hygroscopic, and no morphological transformation was detected after the DVS test. The PLM image showed that the crystals of form A of the DCHA salt of compound VIa-1a are needle-shaped. Form B is an anhydrate.

[0388] Form A of the L-arginine salt of compound VIa-1a Form A of the L-arginine salt of compound VIa-1a was obtained by a solution-mediated reaction with an equimolar amount of L-arginine in EtOAc or toluene. The XRPD pattern of form A of the L-arginine salt of compound VIa-1a was described above with respect to Figure 5. As shown in Figure 6, a 1.0% weight loss was observed up to 150 °C in the TGA curve, and the sample may decompose upon heating above 170 °C. The DSC curve showed an endothermic peak at around 161 °C corresponding to melting. 1 The \(^1\)H NMR results showed salt formation between the compound of formula VIa-1a and L-arginine in a ratio of approximately 1:1 without an organic solvent. Form A of the L-arginine salt of compound VIa-1a is likely to be an anhydrate. DVS analysis of form A of the L-arginine salt of compound VIa-1a showed a weight increase of approximately 28% at 80% RH and approximately 74% at 95% RH, indicating high hygroscopicity. Form A of the L-arginine salt of compound VIa-1a deliquesced at high humidity. The PLM image showed that the crystals of form A of the L-arginine salt of compound VIa-1a are aggregates of small particles.

[0389] Form A of the TMA salt of compound VIa-1a Form A of the tromethamine (TMA) salt of compound VIa-1a was obtained by a solution-mediated reaction with an equimolar amount of TMA in EtOAc or toluene. The XRPD pattern of Form A of the TMA salt of compound VIa-1a was described above with respect to Figure 7. As shown in Figure 8, no weight loss was observed in the TGA curve up to 100 °C, and the sample might decompose above 135 °C. DSC analysis was carried out by using a Tzero hermetic pan without pinholes. Endothermic peaks were shown at around 123 °C and 136 °C in the DSC curve. 1 1H NMR results indicated salt formation between the compound of formula VIa-1a and TMA in a ratio of approximately 1:1 without an organic solvent. Form A of the TMA salt of compound VIa-1a is likely to be an anhydrate. DVS analysis of Form A of the TMA salt of compound VIa-1a showed a weight gain of approximately 0.1% at 80% RH, approximately 47% at 95% RH, and approximately 7% at 0% RH. Form A of the TMA salt of compound VIa-1a was non-hygroscopic but might deliquesce at high humidity (>90% RH). Plate-like crystals were shown in the PLM image of Form A of the TMA salt of compound VIa-1a.

[0390] Example 19: Crystal Structure Determination of the 4-Chlorophenoxyacetate Salt of the Compound of Formula XI-1a by Micro-ED

Chemical formula

[0391] Example 20: X-ray measurement of the single crystal structure of the compound of formula VII-1a

Chemical formula

[0392] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this disclosure belongs.

[0393] The disclosure illustratively described herein may be suitably implemented in the absence of any element(s) or limitation(s) not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," "containing," etc. should be read expansively and without limitation. Further, these terms and expressions used herein are used as terms of explanation and not of limitation, and in the use of such terms and expressions, there is no intention to exclude any equivalents of the features described or portions thereof, but rather it is recognized that various modifications are possible within the scope of the claimed disclosure.

[0394] All publications, patent applications, patents, and other references mentioned herein are hereby expressly incorporated by reference in their entirety to the same extent as if each were individually incorporated by reference. In case of conflict, this specification, including definitions, will control.

[0395] Although the disclosure has been described in connection with the above embodiments, it should be understood that the above description and examples are intended to be illustrative and not limiting of the scope of the disclosure. Other aspects, advantages, and modifications of the disclosure will be apparent to those of ordinary skill in the art to which the disclosure pertains.

Claims

1. A salt of a compound of formula VIa-1a: 【Chemical 126】 wherein the salt is an amine selected from the group consisting of t-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, a salt of said compound.

2. VII-2a: 【Chemical 127】 having the formula, in which N(R ４６ ), ３ the part is selected from the group consisting of t-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine, and dibenzylamine, the salt according to claim 1.

3. A salt according to claim 1, having formula VII-1a: 【Chemical 128】

4. A salt according to claim 1, having formula VII-1b: 【Chemical 129】

5. A salt according to claim 1, having formula VII-1c: 【Chemical 130】

6. A salt according to claim 1, having formula VII-1d: 【Chemical 131】

7. An X-ray powder diffraction pattern showing one or more peaks selected from 6.6, 11.6, 12.1, 15.6, 19.8, 20.8, 26.5, and 27.3° 2θ ± 0.2° 2θ, said X-ray powder diffraction pattern being prepared using Cu-Kα radiation, polymorph A of the t-butylamine (TBA) salt of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (polymorph A of the TBA salt of compound VIa-1a).

8. i) said X-ray powder diffraction pattern further comprising 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° 2θ ± 0.2° 2θ, ii) a diffractogram substantially as shown in Figure 1, iii) a differential scanning calorimetry (DSC) including an endotherm at about 171 °C, or iv) a thermogravimetric analysis (TGA) including a thermogram substantially as shown in Figure 2, whereby the polymorph A of the TBA salt of compound VIa-1a according to claim 7 is further characterized.

9. 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° 2θ ± 0.2° 2θ, wherein the X-ray powder diffraction pattern is prepared using Cu-Kα radiation, polymorph Form A of the dicyclohexylamine (DCHA) salt of (1S,3S)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (Form A of the DCHA salt of Compound VIa-1a).

10. i) The X-ray powder diffraction pattern further comprising 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° 2θ ± 0.2° 2θ, ii) A diffractogram substantially as shown in Figure 3, iii) Differential scanning calorimetry (DSC) including an endotherm at about 139 °C, or iv) A thermogram including thermogravimetric analysis (TGA) substantially as shown in Figure 4, The polymorph Form A of the DCHA salt of Compound VIa-1a according to Claim 9, further characterized by.

11. 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° 2θ ± 0.2° 2θ, wherein the X-ray powder diffraction pattern is prepared using Cu-Kα radiation, polymorph Form A of the tromethamine (TMA) salt of (1S,3S)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (Form A of the TMA salt of Compound VIa-1d).

12. i) The X-ray powder diffraction pattern further comprising 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° 2θ ± 0.2° 2θ, ii) A diffractogram substantially as shown in Figure 7, iii) Differential scanning calorimetry (DSC) including endotherms at about 123 °C and about 136 °C, or iv) A thermogram including thermogravimetric analysis (TGA) substantially as shown in Figure 8, The polymorph Form A according to Claim 11, further characterized by.

13. A hydrate of the compound of formula IX-1a: 【Chemical 132】

14. The disuccinate 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: 【Chemical 133】

15. The following structure: 【Chemical 134】 The 4-chlorophenoxyacetate 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. Crystalline form A of 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: 【Chemical 135】 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 when determined with a diffractometer using Cu-Kα radiation (λ = 1.54059 Å), said crystalline form A of 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.

17. 【Fig. 136】 A compound selected from the group consisting of, or a salt of each thereof.

18. Formula V-2: 【Chemical 137】 A process for preparing a compound of formula V-2, or a salt thereof, comprising contacting a compound of formula IIa-1: 【Chemical 138】 with an activator, and then contacting with a compound of formula IV: 【Chemical 139】 under reaction conditions sufficient to obtain the 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 is O or NR ５３ and R ５１ is hydrogen, C １－１２ alkyl, or silyl, and the C １－１２ alkyl or the silyl is optionally substituted by one or more halo, or one or more oxo, halo, hydroxyl, or amino independently optionally substituted by one or more C １－１２ alkyl optionally substituted with, R ５２ is hydrogen, C １－１２ alkyl, or silyl, wherein said C １－１２ alkyl or said silyl is optionally substituted with one or more halos, or one or more oxo, halo, hydroxyl, or amino independently optionally substituted C １－１２ alkyl optionally substituted with, R ５３ is hydrogen, C １－１２ alkyl, or silyl, and said C １－１２ alkyl or said silyl is optionally substituted by one or more C １－１２ alkyl optionally substituted by one or more halo, or one or more oxo, halo, hydroxyl, or amino, or R ５１ and R ５３ together with the nitrogen atom(s) to which they are attached form one or more C １－１２ alkyl optionally independently substituted with one or more halo, or one or more oxo, halo, hydroxyl, or amino, to form a heterocyclyl, provided that said compound is not ethyl cis-3-[(methylthio)thioxomethoxy]cyclobutanecarboxylate, said process.

19. Formula IX-2: 【Chemical 140】 A process for preparing a compound of formula IX-2, or a solvate thereof, comprising contacting a salt of a compound of formula VIa-1a: 【Chemical Formula 141】 with an acid under reaction conditions sufficient to obtain the compound of formula VIa-1a, and contacting the compound of formula VIa-1a with a compound of formula VIIIa or a salt thereof: 【Chemical 142】 under conditions sufficient to obtain the compound of formula IX-2 or a solvate thereof, In the formula, R ７３ is hydrogen, a protecting group, or 【Chemical 143】 said process.

20. R ７３ is tert-butoxycarbonyl or a formula 【Chemical 144】 The process according to claim 19, which is as claimed in claim 20.

21. Said salt is of formula VII-2a: 【Chemical 145】 and in the formula, the N(R ４６ ), ３ wherein the part is selected from the group consisting of t-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine, and dibenzylamine, the method according to claim 19 or 20.

22. Formula X-2: 【Chemical 146】 A process for preparing a compound of formula X-2, or a salt thereof, comprising Formula VIa-1a: 【Chemical 147】 Contacting a salt of the compound with a first acid under reaction conditions sufficient to obtain the compound of formula VIa-1a; Contacting the compound of formula VIa-1a with a compound of formula VIIIa or a salt thereof: 【Chemical 148】 And formula IX-2: 【Chemical 149】 Contacting under conditions sufficient to obtain the compound or a solvate thereof; Contacting the compound of formula IX-2 or a solvate thereof with a dehydrating agent and a base under reaction conditions sufficient to obtain the compound of formula X-2 or a salt thereof, wherein R ７３ is hydrogen, a protecting group, or 【Chemical 150】 The method as described above.

23. The salt of the compound of formula VIa-1a is of formula VII-2a: 【Chemical 151】 and in the formula, N(R ４６ ), ３ wherein the portion is selected from the group consisting of t-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine, and dibenzylamine, the method according to claim 22.

24. R ７３ is tert-butoxycarbonyl or of the formula 【Chemical 152】 The method according to claim 22 or 23, wherein the salt of the compound of formula VIa-1a is as described above.

25. A process for preparing a compound of formula I or a salt thereof, comprising: 【Chemical 153】 Contacting a salt of a compound of formula VIa-1a with a first acid under reaction conditions sufficient to obtain the compound of formula VIa-1a; Contacting the compound of formula VIa-1a with a compound of formula VIIIa or a salt thereof: 【Chemical Formula 154】 And formula IX-2: Contacting under conditions sufficient to obtain the compound or a solvate thereof; 【Chemical 155】 Contacting the compound of formula IX-2 or a solvate thereof with a dehydrating agent and a base and a compound of formula X-2: 【Chemical 156】 Contacting under reaction conditions sufficient to obtain the compound or a salt thereof; Contacting the compound of formula X-2 or a salt thereof with the compound of formula XI-1a: 【Chemical 157】 Contacting under deprotection conditions sufficient to obtain the compound or a salt thereof; Optionally, contacting the compound of formula XI-1a or a salt thereof with a compound of formula XII-1: 【Chemical 158】 The method as described above.

26. 【Chemical 159】 and contacting under reaction conditions sufficient to obtain a compound of formula I or a salt thereof, wherein R ７３ is hydrogen, a protecting group, or 【Chemical 160】 The salt of the compound of formula VIa-1a is of formula VII-2a:

27. The salt of the compound of formula X-2 is hydrochloride, oxalate, and 4-chlorophenoxyacetate, the method according to claim 25 or 26. 【Chemical 161】 wherein N(R ４６ ), ３ the portion is selected from the group consisting of t-butylamine, L-lysine, piperazine, dicyclohexylamine, arginine, tromethamine, ethanolamine, dehydroabietylamine, and dibenzylamine, the method according to claim 25.

28. The deprotection conditions include contacting the compound of formula X-2 with a second acid, the method according to any one of claims 25 to 27.

29. The reaction conditions for obtaining the compound of formula I are a) a temperature of about 0 °C to about 5 °C, and a temperature increase to about 20 °C to about 25 °C, and / or b) optionally in the presence of a base and diphenylphosphinic acid chloride, The method according to claim 25. ​ ​

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