Methods for preparing kinase inhibitors

Abstract

The present invention relates to a process for the synthetic preparation of a c-Met inhibitor of Formula I or a pharmaceutically acceptable salt thereof. The present invention further relates to a process for the synthetic preparation of a c-Met inhibitor, Compound 1, or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for the synthetic preparation of Compound 1 · hemifumarate salt. The present invention further relates to a process for the synthetic preparation of a c-Met inhibitor, Compound 1, and Compound 1 · hemifumarate salt on a large scale.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Application Serial No. 63 / 017,739, filed April 30, 2020. The entire contents of the above application are incorporated herein by reference. Technical Field

[0003] This invention relates to a method for preparing a c-Met inhibitor of formula I or a pharmaceutically acceptable salt thereof. The invention further relates to a method for preparing a c-Met inhibitor, compound 1, or a pharmaceutically acceptable salt thereof. The invention also relates to a method for synthesizing compound 1 hemifumarate. The invention further relates to a large-scale method for synthesizing the c-Met inhibitor, compound 1, and compound 1 hemifumarate. Background Technology

[0004] Human Axl belongs to the Tyro3, ​​Axl, and Mer (TAM) subfamily of receptor tyrosine kinases. TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Axl is overexpressed in many tumor cell types and was initially cloned from patients with chronic myeloid leukemia. When overexpressed, Axl exhibits transformative potential. Axl signaling is believed to induce tumor growth by activating proliferative and anti-apoptotic signaling pathways. Axl has been associated with cancers such as lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, glioma, melanoma, thyroid cancer, renal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer. Overexpression of Axl leads to poor prognosis in patients with the indicated cancers.

[0005] Like Axl, Mer activation leads to downstream signaling pathways in tumor growth and activation. Mer binds to ligands such as the soluble protein Gas-6. Gas-6 binding to Mer induces autophosphorylation of Mer in its intracellular domain, resulting in downstream signal activation. Overexpression of Mer in cancer cells leads to increased metastasis, most likely through the generation of soluble Mer extracellular domain proteins as decoy receptors. Tumor cells secrete soluble forms of extracellular Mer receptors, which reduce the ability of soluble Gas-6 ligands to activate Mer on endothelial cells, thereby contributing to cancer progression.

[0006] Therefore, there is a need for compounds that inhibit TAM receptor tyrosine kinases (such as Axl and Mer) and methods for producing said compounds in high yield and high purity for the treatment of selected cancers. Summary of the Invention

[0007] In one aspect, the present application includes a process for preparing a compound of Formula I

[0008]

[0009] comprising contacting a compound of Formula II

[0010]

[0011] with a compound of Formula III

[0012]

[0013] in the presence of a solvent and a base, wherein

[0014] LG is a leaving group selected from the group consisting of CI, Br, I, HOAt, HOBt, and an organic triphosphate compound;

[0015] R1is selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl;

[0016] R2and R3are each independently selected from the group consisting of halo and C 1-6 alkyl;

[0017] R4is selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl, and C 3-6 heteroaryl;

[0018] R 5a is selected from the group consisting of H, -NH2, -OH, C 1-8 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl, and C 3-6 heteroaryl, wherein said C 1-8 alkyl is optionally and independently substituted with up to three substituents selected from the group consisting of -O-, NR'-, -C(O)-, -C(O)O-, and -C(O)NR'- wherein R 5a is optionally substituted with up to three substituents selected from the group consisting of halo, CN, OH, NO2, NH2, SH, OR', C(O)OR', C(O)R', C(O)NR'2, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, and C 3-6 heteroaryl;

[0019] R 5b is H or C1-6 Alkyl; or

[0020] R 5a and R 5b Together with the nitrogen to which it is attached, it can optionally be halogenated, CN, OH, NO2, NH2, SH, OR', C(O)OR', C(O)R', C(O)NR'2, C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl or C 3-6 heteroaryl-substituted C 3-6 Heterocyclic alkyl groups;

[0021] R 5c It is H or C that is optionally substituted with a halogenated group, CN, OH, NH2 or OR'. 1-6 alkyl;

[0022] R' is H or C 1-6 Alkyl, and

[0023] w, x, y, and z are each an independent integer from 0 to 4;

[0024] Furthermore, the method optionally includes contacting the compound of formula I with an acid to produce a pharmaceutically acceptable salt of the compound of formula I.

[0025] In another aspect, the present invention includes a method for preparing compound 1 (N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide) or a pharmaceutically acceptable salt thereof:

[0026]

[0027] The method includes making compound 4

[0028]

[0029] Compounds of Formula III'

[0030]

[0031] The contact is carried out in the presence of a solvent and a base, wherein LG is a leaving group selected from Cl, Br, I, HOAt, HOBt and organotriphosphate compounds, and wherein the method optionally further comprises contacting the compound of compound 1 with an acid to produce a pharmaceutically acceptable salt of the compound of compound 1.

[0032] Small molecule compounds that specifically inhibit, modulate, and / or regulate the signal transduction of TAM kinases, such as Axl and Mer described above, are particularly desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis. Compound 1 is one such small molecule compound. The biological activity of Compound 1 is disclosed in PCT / US2019 / 015297, filed January 25, 2019, the entire contents of which are hereby incorporated by reference. An independent and unrelated method of synthesis of Compound 1 is also disclosed in PCT / US2019 / 015297 (see Example 4). A separate and unrelated method of preparing Compound 1 hemifumarate is disclosed in USSN 62 / 779430, filed December 13, 2018 (see Example 2 and paragraphs 360-375), the entire contents of which are also hereby incorporated by reference. The present disclosure provides improved methods of preparing Compound 1 and Compound 1 hemifumarate, which are obtained in surprisingly high yield and purity. DETAILED DESCRIPTION

[0033] Definitions and Abbreviations

[0034] Solvents

[0035]

[0036]

[0037] As used herein, the following definitions shall apply unless otherwise indicated.

[0038] For purposes of the present application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 95th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, 2ndEd., Thomas Sorrell, University Science Books, Sausalito: 2006, and “March’s Advanced Organic Chemistry”, 7thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2013, the entire contents of which are hereby incorporated by reference.

[0039] As used herein, the term "about" or "approximately" includes (and describes) embodiments that are within a range of values or parameters that are plus or minus ten percent (10%) of the value or parameter itself. In other embodiments, the term "about" or "approximately" includes values or parameters that are plus or minus five percent (5%) of the value or parameter itself. In certain other embodiments, the term "about" or "approximately" includes values or parameters that are plus or minus one percent (1%) of the value or parameter itself.

[0040] As used herein, the term "slurry" refers to a suspension prepared by adding sufficient solids to a given solvent under ambient conditions such that there is unsolved solids present. A typical slurry includes agitation (usually by stirring or shaking), this action is also referred to as "slurrying", in a sealed vial at a given temperature for an extended period of time. Typically, the solids are recovered after a given period of time using the methods described herein.

[0041] The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0042] As used herein, the term "catalytic amount" means an amount less than the stoichiometric equivalent of the limiting reagent. In some embodiments, the catalytic amount is much less than the stoichiometric equivalent of the limiting reagent, for example between 0wt% and 5wt%, 0wt% and 4wt%, 0wt% and 3wt%, 0wt% and 2wt%, 0wt% and 1wt%, 0wt% and 0.9wt%, 0wt% and 0.8wt%, 0wt% and 0.7wt%, 0wt% and 0.6wt%, 0wt% and 0.5wt%, 0wt% and 0.4wt%, 0wt% and 0.3wt%, 0wt% and 0.2wt%, 0wt% and 0.1wt%, 0wt% and 0.05wt%, and 0wt% and 0.01wt% of the stoichiometric amount of the limiting reagent.

[0043] Generally, the nomenclature used in this application is based on the nomenclature adopted by the International Union of Pure and Applied Chemistry (IUPAC). The chemical structures shown herein are drawn using ChemDraw® Any open valence bond appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.

[0044] The symbol "-" represents a single bond, and "=" represents a double bond.

[0045] As used herein, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” include plural references.

[0046] When a variable is defined generally, it has many possible substituents, and each individual group can be defined as having or not having a bond. For example, if R z It could be hydrogen, then in R z In the definition, this can be indicated as "-H" or "H".

[0047] When depicting or describing chemical structures, unless otherwise explicitly stated, it is assumed that all carbon atoms have tetravalent hydrogen substitutions. For example, in the structure on the left of the following diagram, nine hydrogen atoms are implied. Nine hydrogen atoms are depicted in the structure on the right. Sometimes, specific atoms in a structure are described in the textual formula as having one or more hydrogen atoms as substituents (explicitly defined as hydrogen), such as -CH2CH2-. Those skilled in the art will understand that the above descriptive techniques are common in the field of chemistry to provide a concise and simple description of other complex structures.

[0048]

[0049] If the group "R" is described as "floating" on the ring system, such as in the following formula:

[0050]

[0051] Unless otherwise defined, the substituent “R” can be located on any atom of the ring system, assuming that a hydrogen atom described, implicit or explicitly defined is replaced from one of the ring atoms, as long as a stable structure is formed.

[0052] If the group "R" is described as floating on a fused ring system, such as in the following formula:

[0053]

[0054] Unless otherwise defined, the substituent “R” can be located on any atom in a fused ring system, assuming substitution from one of the ring atoms for a hydrogen atom described (e.g., -NH- in the above formula), an implicit hydrogen atom (e.g., hydrogen not shown in the above formula but to be understood as present), or an explicitly defined hydrogen atom (e.g., “Z” equals =CH- in the above formula), as long as a stable structure is formed. In the example shown, the “R” group can be located on a 5-membered or 6-membered ring in the fused ring system. When the group “R” is described as being present on a ring system containing saturated carbon, for example in the following formula:

[0055]

[0056] wherein, in this example, "v" can be one or more, provided each replaces a currently depicted, implied, or explicitly defined hydrogen on the ring; then, unless otherwise defined, two "R"s can be on the same carbon, in the event the resulting structure is stable. A simple example is when R is a methyl group, gem- dimethyl groups can be present on the carbon of the ring shown ("cyclic" carbon). In another example, two R's on the same carbon (including the carbon atom) can form a ring, resulting in a spirocyclic ("spirocyclic group") structure with a ring as shown, for example, in the following formula:

[0057]

[0058] Unless otherwise indicated, a bifunctional group can have the written orientation, or the opposite orientation. For example, for the bifunctional group "-C(O)NH-", the disclosure also includes the reverse "-NHC(O)-".

[0059] "Halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

[0060] The term "C n-m " or "C n -C m " denotes a range inclusive of the endpoints, where n and m are integers and represent the number of carbons. Examples include C 1-4 , C1-C4, C 1-6 , C1-C6, and the like.

[0061] "Alkyl" means a branched or straight chain hydrocarbon chain, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl, and heptyl. In some embodiments, an alkyl group can have one to eight carbon atoms. (C1-C6)alkyl is preferred. The term "C n-m alkyl" or "(C n -C m )alkyl" means an alkyl group having n to m carbon atoms. When optionally substituted, one or more hydrogen atoms of the alkyl group (e.g., 1 to 4, 1 to 2, or 1) can be replaced with moieties described below under "optionally substituted." In some aspects, the alkyl group is unsubstituted or unoptionally substituted.

[0062] "alkylene" refers to a divalent saturated aliphatic group having 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms with optional substitution. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the alkylene group may be partially substituted as described in "Optional Substitution" below. In some aspects, the alkylene group is unsubstituted or not optionally substituted. The term "Cn-m alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, etc.

[0063] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. An alkenyl group formally corresponds to an alkene in which one of the CH bonds is replaced by the alkenyl group at the junction with the rest of the compound. The term "C..." n-m "alkenyl" or "(C n -C m "Alkenyl" refers to an alkenyl group having n to m carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc.

[0064] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. Formally, an alkynyl group corresponds to an alkyne in which one of the CH bonds is replaced by an alkyl group at the junction with the rest of the compound. The term "C..." n-m "acetylenic" or "(C n -C m "Alynyl" refers to an alkynyl group having n to m carbon atoms. Exemplary alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0065] "Alkoxy" refers to the formula –OR i The part where R i The (C1-C6) alkyl moiety as defined herein. The term "C" refers to... n-m "alkoxy" or (C n -C m Alkoxy refers to an alkoxy group whose alkyl group has n to m carbons. Examples of alkoxy moiety include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

[0066] An alkoxy group can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms (e.g., 1 to 4, 1 to 2, or 1) of the alkoxy group can be replaced with moieties described below under “optionally substituted,” with the proviso that the alpha hydrogen atoms of the ether oxygen are not replaced with hydroxyl, amino, or thio groups. In some aspects, the alkoxy group is unsubstituted or unoptionally substituted.

[0067] “Alkoxycarbonyl” refers to a group -C(O)-R i where R i is (C1-C6)alkoxy as defined herein.

[0068] The term “amino” refers to a group of formula -NH2.

[0069] The term “carbamoyl” refers to a group of formula -C(O)NH2.

[0070] The term “carbonyl,” used alone or in combination with other terms, refers to a -C(=O)- group, which can also be written as C(O).

[0071] The term “cyano” or “nitrile” refers to a group of formula -C≡N, which can also be written as -CN or CN.

[0072] The term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or a sulfoxide or sulfone group or N-oxide group when attached to a heteroatom. In some embodiments, a heterocyclyl group can be optionally substituted with 1 or 2 oxo (=O) substituents.

[0073] The term “sulfide” refers to a sulfur atom as a divalent substituent, forming a thiocarbonyl group (C=S) when attached to carbon.

[0074] The term “heteroatom” as used herein is intended to include boron, phosphorus, sulfur, oxygen, and nitrogen.

[0075] As used herein, the term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms have been replaced with one or more halogen atoms. The term “C n-m haloalkyl” or (C n -C m )haloalkyl refers to a C n-m alkyl group having n to m carbon atoms and at least one to a maximum of {2(n-m)+1} halogen atoms which can be the same or different. In some embodiments, the halogen atoms are fluorine atoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0076] The term "haloalkoxy," used alone or in combination with other terms, refers to a group of the formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term "C n-m haloalkoxy" or (C n -C m )haloalkoxy refers to a haloalkoxy group having n to m carbons in its haloalkyl group. Exemplary haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0077] "Aryl" means a monovalent, six- to fourteen-membered, monocyclic or bicyclic or tricyclic (e.g., having two fused rings) ring carbocyclic group in which the monocyclic ring is aromatic and at least one ring in the bicyclic ring is aromatic. The term "C n-m aryl" or "(C n -C m )aryl" refers to an aryl group having n to m ring carbon atoms. In some embodiments, the aryl group has 6 to about 10 carbon atoms. In some embodiments, the aryl group has 6 ring carbon atoms. In some embodiments, the aryl group has 10 ring carbon atoms. Unless otherwise specified, valences of a group can be located on any atom within any ring of the group, to the extent that valence rules permit. Representative examples include phenyl, naphthyl, and indanyl, and the like.

[0078] An aryl group can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the aryl group (e.g., 1 to 5, 1 to 2, or 1) can be replaced with a moiety as described below under "optionally substituted." In some aspects, the alkoxy group is unsubstituted or not optionally substituted.

[0079] "Arylene" means a divalent, six- to fourteen-membered, monocyclic or bicyclic or tricyclic ring carbocyclic group in which the monocyclic ring is aromatic and at least one ring in the bicyclic ring is aromatic. Representative examples include phenylene, naphthylene, and indanylene, and the like.

[0080] "Cycloalkyl" refers to non-aromatic hydrocarbon ring systems (monocyclic, bicyclic, or polycyclic), including cyclized alkyl and alkenyl groups. The term "C n-m cycloalkyl" or "(C n -C m )cycloalkyl" refers to a cycloalkyl group having n to m ring member carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbon (C 3-14). In some embodiments, the cycloalkyl group has 3 to 14 members, 3 to 10 members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C 3-6 monocyclic cycloalkyl group. The ring-forming carbon atoms of a cycloalkyl group can optionally be oxidized to form oxo or thio groups. Cycloalkyl groups also include cycloalkenyl groups. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, bicyclopentenyl, bicyclohexenyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, cycloalkyl includes a single saturated carbocyclic ring having three to eight ring carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be optionally substituted with one or more substituents, such as one, two, or three substituents. In some embodiments, the cycloalkyl substituents are selected from (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, halo, amino, mono- and di(C1-C6)alkylamino, hetero(C1-C6)alkyl, acyl, aryl, and heteroaryl.

[0081] A cycloalkyl group can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the cycloalkyl group (e.g., 1 to 4, 1 to 2, or 1) can be replaced with a moiety as described below under “optionally substituted.” In some aspects, a substituted cycloalkyl group can be incorporated into an exo or endo cycloalkene (e.g., cyclohex-2-ene-1-yl). In some aspects, a cycloalkyl group is unsubstituted or unoptionally substituted.

[0082] “Cycloalkoxy” means a group -OR i where R i is (C3-C6)cycloalkyl as defined herein.

[0083] “Phenoxycarbonyl” means a group -C(O)-Ophenyl.

[0084] “Heteroaryl” means a monocyclic, fused-bicyclic, or fused-tricyclic, monovalent radical of 5 to 14 ring atoms which contains one or more (preferably one, two, three, or four) ring atoms independently selected from the group consisting of -O-, -S(O) n -(n is 0, 1, or 2), -N-, and -N(R i) and the remaining ring atoms are carbon, wherein the ring comprising the monocyclic group is aromatic, and wherein at least one of the fused rings comprising the bicyclic or tricyclic group is aromatic. One or two of the ring carbon atoms of any non-aromatic ring comprising the bicyclic or tricyclic group can be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R i is hydrogen, alkyl, hydroxyl, alkoxy, acyl, or alkylsulfonyl. Unless otherwise indicated, valence bonds can be located on any atom of any ring of a heteroaryl group, where valence rules permit. In particular, when a valence bond is located on a nitrogen, there is no additional nitrogen substituent. More particularly, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-lH-indolyl (including, e.g., 2,3-dihydro-lH-indol-2-yl or 2,3-dihydro-lH-indol-5-yl, etc.), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzobenzofuran-4-yl, benzofuranyl, cinnolinyl, indolizinyl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, e.g., tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, etc.), pyrrolopyridinyl (including, e.g., pyrrolopyridin-2-yl or pyrrolopyridin-7-yl, etc.), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and derivatives thereof, as well as N-oxides or protected derivatives thereof.

[0085] A five-membered heteroaromatic ring is a heteroaryl group having five ring atoms, wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls include thienyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0086] A six-membered heteroaryl ring is a heteroaryl group having six ring atoms, wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0087] "Heteroarylene" refers to a divalent group of 5 to 14 ring atoms in a monocyclic, fused bicyclic, or fused tricyclic ring, containing one or more (preferably one, two, three, or four) independently selected from -O- and -S(O). n -(n is 0, 1, or 2), -N-, and -N(R) 19 The ring contains a heteroatom of the cyclic group ⇌ ... 19 It is hydrogen, alkyl, or alkenyl. Unless otherwise specified, the valence bond may be located on any atom of any ring of the heteroaryl group, where permitted by the valence bond rules. In particular, when the valence bond is located on nitrogen, there is no additional nitrogen substituent. More specifically, the term heteroaryl includes, but is not limited to, thiophene-diyl, benzo[d]isoxazole-diyl, benzo[d]isothiazol-diyl, 1H-indazole-diyl (optionally with R at the N1 position). 19 Substitution), benzo[d]oxazol-diyl, benzo[d]thiazole-diyl, 1H-benzo[d]imidazol-diyl (optionally R at the N1 position) 19 Substitution), 1H-benzo[d]triazole-diyl (optionally R at the N1 position) 19 Substitutes), imidazopyridine-diyl, cyclophosphine-diyl, quinoline-diyl, pyridine-diyl, 1-oxo-pyridine-diyl, triazolopyridine-diyl and 2,3-dihydroimidazopyridine-diyl, etc.

[0088] As used herein, "heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic ring or ring system, which can optionally contain one or more alkylene groups as part of the ring structure, which has at least one ring member that is a heteroatom independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus, and which has 4-14 ring members, 4-10 ring members, 4-7 ring members, or 4-6 ring members. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include monocyclic or bicyclic or polycyclic (e.g., having two or three fused or bridged rings) ring systems or spirocyclic rings. In some embodiments, a heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can optionally be oxidized to form oxo or thia groups or other oxidized linkages (e.g., C(O), S(O), C(S), S(O)2, N-oxide, etc.), or a nitrogen atom can be quaternized. A heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, a heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, a heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (i.e., having a bond in common with) the heterocycloalkyl ring, such as benzene or thiophene derivatives of piperidine, morpholine, azepine, and the like. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom, including ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazolopyridinyl, and thiomorpholino.

[0089] A "heterocycloalkyl" or "heterocyclyl" can be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the group (e.g., 1 to 4, 1 to 2, or 1) can be replaced by a moiety independently selected from fluorine, hydroxyl, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some aspects, a substituted heterocyclyl group can be incorporated into an exo or endocyclic alkene (e.g., cyclohex-2-ene-1-yl). In some aspects, a heterocyclyl group is unsubstituted or not optionally substituted.

[0090] Embodiments

[0091] In one aspect, the application includes a method for preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof

[0092]

[0093] The method comprises contacting a compound of formula II

[0094]

[0095] with a compound of formula III

[0096]

[0097] in the presence of a solvent and a base, wherein

[0098] LG is a leaving group selected from the group consisting of CI, Br, I, HOAt, HOBt and an organic triphosphate compound;

[0099] R1is selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl;

[0100] R2and R3are each independently selected from the group consisting of halo and C 1-6 alkyl;

[0101] R4is selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl and C 3-6 heteroaryl;

[0102] R 5a is selected from the group consisting of H, OH, NH2, C 1-8 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl and C 3-6 heteroaryl, wherein up to three methylene units of the C 1-8 alkyl groups are optionally and independently replaced with -0-, NR'-, -C(O)-, -C(O)O-, and -C(O)NR'- wherein R 5a is optionally substituted with up to three substituents selected from the group consisting of halo, CN, OH, NO2, NH2, SH, OR', C(O)OR', C(O)R', C(O)NR'2, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl and C 3-6 heteroaryl;

[0103] R 5b is H or C 1-6 alkyl; or

[0104] R 5a and R 5bhalo, CN, OH, NO2, NH2, SH, OR', C(O)OR', C(O)R', C(O)NR'2, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, or C 3-6 heteroaryl-substituted C 3-6 heterocycloalkyl;

[0105] R 5c is H or C 1-6 alkyl optionally substituted with halo, CN, OH, NH2, or OR';

[0106] R' is H or C 1-6 alkyl, and

[0107] w, x, y, and z are each independently an integer from 0 to 4;

[0108] and wherein the method optionally further comprises contacting the compound of Formula I with an acid to produce a pharmaceutically acceptable salt of the compound of Formula I. In some embodiments, the acid is fumaric acid.

[0109] In one embodiment of this aspect, the LG is an organic triphosphate coupling agent, such as (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4,6-trioxide; propyl phosphonic anhydride), which has the structure

[0110] In one embodiment of this aspect, the base is an inorganic base. In one embodiment, the base is selected from NaOH, Na2CO3, K2CO3, NaHCO3, and KHCO3. In a further embodiment, the base is Na2CO3. In a further embodiment, the base is K2CO3.

[0111] In one embodiment, the solvent is a mixture of water and an organic solvent.

[0112] In one embodiment, the organic solvent is selected from polar protic and polar aprotic solvents. In one embodiment, the polar protic or polar aprotic solvent is selected from the group consisting of acetone, acetonitrile, butanediol, dimethylformamide, dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethylene glycol, furfuryl alcohol, glycerol, methanol, methyl isocyanide, N-methyl-2-pyrrolidone, 1-propanol, 1,3-propanediol, 1,5-pentanediol, 2-propanol, propylene glycol, tetrahydrofuran, and triethylene glycol. In a further embodiment, the organic solvent is a polar aprotic solvent selected from the group consisting of acetone, acetonitrile, dimethylformamide, 1,4-dioxane, and tetrahydrofuran. In yet another embodiment, the organic solvent is a mixture of water and tetrahydrofuran. In yet another embodiment, the mixture is about 2: 1 tetrahydrofuran:water to about 8: 1 tetrahydrofuran:water, or about 2: 1 tetrahydrofuran:water to about 6: 1 tetrahydrofuran:water, or about 2: 1 tetrahydrofuran:water to about 4: 1 tetrahydrofuran:water. In yet another embodiment, the mixture is about 2: 1 tetrahydrofuran:water to about 3: 1 tetrahydrofuran:water.

[0113] In one embodiment, the compound of Formula II is contacted with the compound of Formula III by adding a solution of the compound of Formula III dissolved in a first solvent to a solution of the compound of Formula II dissolved in a second solvent to produce a reaction mixture.

[0114] In one embodiment, the first solvent is an organic solvent. In a further embodiment, the first solvent is a polar aprotic solvent. In a further embodiment, the first solvent is tetrahydrofuran.

[0115] In one embodiment, the second solvent is a mixture of water and tetrahydrofuran. In one embodiment, the second solvent is a mixture of about 2: 1 tetrahydrofuran:water to about 8: 1, or about 2: 1 tetrahydrofuran:water to about 6: 1 tetrahydrofuran:water, or about 2: 1 tetrahydrofuran:water to about 4: 1 tetrahydrofuran:water. In a further embodiment, the second solvent is a mixture of about 3: 1 to about 2: 1 tetrahydrofuran:water. In a further embodiment, the second solvent is a mixture of about 2: 1 tetrahydrofuran:water.

[0116] In one embodiment, the compound of Formula III dissolved in a first solvent is added to a solution of the compound of Formula II dissolved in a second solvent over a period of time of about 30 minutes to about 1 hour. In another embodiment, the compound of Formula III dissolved in a first solvent is added to a solution of the compound of Formula II dissolved in a second solvent over a period of time of no less than 30 minutes.

[0117] In one embodiment, the temperature of the reaction mixture is maintained below about 27°C. In another embodiment, the reaction temperature is maintained at about 20°C to 27°C. In another embodiment, the reaction temperature is maintained at about 25°C to 27°C. In another embodiment, the reaction temperature is maintained at about 20°C to 25°C.

[0118] In one embodiment, the reaction mixture is heated to about 35-40°C and allowed to settle to separate into an organic phase and an aqueous phase.

[0119] In one embodiment, the method further comprises discarding the aqueous phase, heating the organic phase to 45-50°C, and then filtering the organic phase at 45-50°C.

[0120] In another embodiment, the method further comprises discarding the aqueous phase, heating the organic phase to 55-60°C, and then filtering the organic phase at 55-60°C.

[0121] In another embodiment, the method further comprises cooling the organic phase to 20-25°C and adding water to the organic phase to produce a second mixture, wherein the volume of water added is about 1.5 times to about 2.5 times the volume of the organic phase. In another embodiment, the method further comprises adding water to the organic phase to produce a second mixture while maintaining the temperature at 50-55°C.

[0122] In one embodiment, the water is added to the organic phase over a period of at least one hour. In another embodiment, the water is added to the organic phase over a period of about 4 hours to 4.5 hours.

[0123] In one embodiment, the second mixture is stirred for at least 12 hours, and the product is a solid. In another embodiment, the second mixture is stirred for at least 2 hours.

[0124] In one embodiment, LG is Cl.

[0125] In one embodiment, the method further comprises reacting a compound of Formula IV

[0126]

[0127] with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride to produce a compound of Formula III

[0128]

[0129] wherein LG is chloride.

[0130] In one embodiment, the reagent is oxalyl chloride.

[0131] In another embodiment, the reaction is carried out in the presence of a catalytic amount of dimethylformamide.

[0132] In another embodiment, the reaction is carried out in the presence of an organic solvent. In a further embodiment, the organic solvent is a polar aprotic solvent. In a further embodiment, the polar aprotic solvent is tetrahydrofuran.

[0133] In one embodiment, the reaction is carried out at a temperature between about -5 °C and 25 °C. In a further embodiment, the reaction is carried out at a temperature of about 0 °C and 20 °C. In a further embodiment, the reaction is carried out at a temperature of about 15 °C or less. In a further embodiment, the reaction is carried out at a temperature of about 5-15 °C. In a further embodiment, the reaction is carried out at a temperature of about 10-15 °C. In a further embodiment, the reaction is carried out at a temperature of about 10-15 °C for 2-3 hours.

[0134] In one embodiment, the method further comprises reacting a compound of Formula V

[0135]

[0136] with a compound of Formula VI

[0137]

[0138] to provide a compound of Formula II

[0139]

[0140] wherein LG' is selected from the group consisting of F, Cl, Br, I, and -N2 + .

[0141] In one embodiment, the reaction is carried out in the presence of a solvent. In another embodiment, the solvent is an organic solvent. In another embodiment, the solvent is a polar aprotic solvent. In another embodiment, the organic solvent is a polar aprotic solvent selected from the group consisting of acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HMPT), tetrahydrofuran, 1,4-dioxane, and dichloromethane. In a further embodiment, the organic solvent is dimethylacetamide.

[0142] In one embodiment, the reaction is carried out in the presence of a base. In another embodiment, the base is n-BuLi, lithium diisopropylamide, lithium hexamethyldisilylamide, sodium hexamethyldisilylamide, sodium hydroxide, sodium methoxide, sodium tert-butoxide, sodium tert-pentoxide, lithium hydroxide, lithium methoxide, lithium tert-butoxide, lithium tert-pentoxide, potassium hydroxide, potassium methoxide, potassium tert-butoxide, potassium tert-pentoxide, cesium hydroxide, cesium methoxide, cesium tert-butoxide, or cesium tert-pentoxide. In a further embodiment, the base is sodium tert-pentoxide.

[0143] In one embodiment, the reaction is carried out at a temperature of about 70 °C to 90 °C. In another embodiment, the reaction is carried out at a temperature of about 75-80 °C.

[0144] In one embodiment, the product is isolated by adding water to the reaction mixture and isolating the solid product by filtration or the like.

[0145] In one embodiment, LG' is selected from the group consisting of F, Cl, Br, and In a further embodiment, LG' is Cl.

[0146] In some embodiments, the compound of Formula I is a compound of Formula la, Formula lb, Formula lc, or Formula Id:

[0147]

[0148] wherein R1, R2, R3, R4, R 5a , R 5b , R 5c , w, x, y, and z are as defined herein.

[0149] In one embodiment of Formula la, lb, lc, or Id, R1is selected from the group consisting of halo, methyl, methoxy, isopropoxy, and cyclopropyl. In one embodiment, w is 0, 1, or 2. In a further embodiment, w is 0.

[0150] In one embodiment of Formula la, lb, lc, or Id, x is 0.

[0151] In another embodiment of Formula la, lb, lc, or Id, R3is F or Cl. In one embodiment, y is 0, 1, or 2. In a further embodiment, y is 0.

[0152] In one embodiment of Formula la, lb, lc, or Id, R4is halo or C 1-6 alkyl. In one embodiment, z is 0 or 1. In a further embodiment, z is 0.

[0153] In one embodiment of Formula la, lb, lc, or Id, R 5b is H.

[0154] In one embodiment of Formula Ia, Ib, Ic, or Id, R 5a is selected from H, -NH2, -OH, C 1-6 alkyl, and C 3-6 heterocycloalkyl, wherein up to three substituents of the C 1-6 alkyl groups are optionally and independently replaced with -O- or NR'-; 5a is optionally substituted with up to three substituents selected from OH, C 1-4 alkyl, and C 3-6 heterocycloalkyl.

[0155] In another embodiment of Formula Ia, Ib, Ic, or Id, R 5a is selected from H, -NH2, -OH, methoxy, methyl, ethyl, N-methylazetidin-2-yl, pyrrolidin-2-yl-methyl, oxetan-2-yl-oxy, 2-hydroxyethoxy, 2,3-dihydroxypropoxy, oxetan-2-yl, 2-(N-piperidinyl)ethyl, 2-(N-morpholino)ethyl, and 2-dimethylaminoethyl. In yet another embodiment, R 5a is methyl.

[0156] In one embodiment of Formula Ia, Ib, Ic, or Id, R 5c is H or C 1-6 alkyl optionally substituted with OH or OR'. In a further embodiment, R 5c is methyl, 2-hydroxyethyl, 2-methoxyethyl, or 2-hydroxypropyl. In yet another embodiment, R 5c is methyl.

[0157] In another embodiment of Formula Ia, Ib, Ic, or Id, R 5a and R 5b together with the nitrogen to which they are attached form C 3-6 heterocycloalkyl optionally substituted with OH. In a further embodiment, R 5a and R 5b together with the nitrogen to which they are attached form azetidine or 2-hydroxyazetidine.

[0158] In one embodiment of Formula Ia, Ib, Ic, or Id, R' is H. In another embodiment, R' is C 1-6 alkyl. In some embodiments, R' is selected from H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl. In one embodiment, R' is H or methyl. In one embodiment, R' is methyl.

[0159] In one aspect, the application includes a method for preparing Compound 1, or a pharmaceutically acceptable salt thereof

[0160]

[0161] The method comprises contacting Compound 4

[0162]

[0163] with a compound of Formula III’

[0164]

[0165] in the presence of a solvent and a base, wherein LG is a leaving group selected from the group consisting of CI, Br, I, HOAt, HOBt, and an organic triphosphate compound, and wherein the method optionally further comprises contacting the compound of Compound 1 with an acid to produce a pharmaceutically acceptable salt of the compound of Compound 1.

[0166] In one embodiment, the base is an inorganic base. In a further embodiment, the base is selected from the group consisting of NaOH, Na2C03, K2C03, NaHC03, and KHCO3. In yet another embodiment, the base is Na2C03. In yet another embodiment, the base is K2C03.

[0167] In one embodiment, the solvent is a mixture of water and an organic solvent. In one embodiment, the organic solvent is a polar protic or polar aprotic solvent. In one embodiment, the polar protic or polar aprotic solvent is selected from the group consisting of acetone, acetonitrile, butanediol, dimethylformamide, dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethylene glycol, furfuryl alcohol, glycerol, methanol, methyl isocyanide, N-methyl-2-pyrrolidone, 1-propanol, 1,3-propanediol, 1,5-pentanediol, 2-propanol, propylene glycol, tetrahydrofuran, and triethylene glycol. In another embodiment, the organic solvent is selected from the group consisting of acetone, acetonitrile, dimethylformamide, 1,4-dioxane, and tetrahydrofuran. In a further embodiment, the solvent is a mixture of water and tetrahydrofuran. In yet another embodiment, the mixture is about 2: 1 tetrahydrofuran:water to about 3: 1 tetrahydrofuran:water.

[0168] In one embodiment, Compound 4 is contacted with a compound of Formula III’ by adding a solution of the compound of Formula III’ dissolved in a first solvent to a solution of Compound 4 dissolved in a second solvent to produce a reaction mixture.

[0169] In one embodiment, the first solvent is an organic solvent. In a further embodiment, the first solvent is a polar aprotic solvent. In a further embodiment, the first solvent is tetrahydrofuran.

[0170] In one embodiment, the second solvent is about 2: 1 tetrahydrofuran: water.

[0171] In one embodiment, the compound of Formula III' dissolved in the first solvent is added to the solution of compound 4 dissolved in the second solvent over a period of about 30 minutes to about 1 hour. In another embodiment, the compound of Formula III' dissolved in the first solvent is added to the solution of compound 4 dissolved in the second solvent over a period of no less than 30 minutes.

[0172] In one embodiment, the temperature of the reaction mixture is maintained between about 20 °C and 27 °C. In one embodiment, the reaction mixture is maintained between about 25 °C and 27 °C. In one embodiment, the reaction mixture is maintained below about 27 °C. In another embodiment, the reaction temperature is maintained at about 20 °C to 25 °C.

[0173] In another embodiment, the reaction mixture is heated to 35-40 °C and allowed to sit to separate into an organic phase and an aqueous phase.

[0174] In one embodiment, the method further comprises discarding the aqueous phase, heating the organic phase to 45-50 °C, and then filtering the organic phase at 45-50 °C.

[0175] In one embodiment, the method further comprises discarding the aqueous phase, heating the organic phase to 55-60 °C, and then filtering the organic phase at 55-60 °C.

[0176] In another embodiment, the method further comprises cooling the organic phase to 20-25 °C and adding water to the organic phase to produce a second mixture, wherein the volume of water added is about 1.5 times to about 2.5 times the volume of the organic phase.

[0177] In another embodiment, the method further comprises adding water to the organic phase to produce a second mixture while maintaining the temperature at 50-55 °C.

[0178] In one embodiment, the water is added to the organic phase over a period of at least one hour. In another embodiment, the water is added to the organic phase over a period of about 4 hours to 4.5 hours.

[0179] In one embodiment, the second mixture is stirred for at least 12 hours, and the product is a solid, which is collected by filtration or the like. In another embodiment, the second mixture is stirred for at least 2 hours, and the product is collected by filtration or the like.

[0180] In one embodiment, LG is Cl.

[0181] In one embodiment, the method further comprises reacting compound 6

[0182]

[0183] with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride to produce compound 7

[0184]

[0185] In one embodiment, the reagent is oxalyl chloride.

[0186] In another embodiment, the reaction is carried out in the presence of a catalytic amount of dimethylformamide.

[0187] In one embodiment, the reaction is carried out in the presence of an organic solvent. In a further embodiment, the organic solvent is tetrahydrofuran.

[0188] In one embodiment, the reaction is carried out at a temperature of 15 °C or less. In a further embodiment, the reaction is carried out at a temperature of 5-15 °C. In a further embodiment, the reaction is carried out at a temperature of about 10-15 °C. In a further embodiment, the reaction is carried out at a temperature of about 10-15 °C for 2-3 hours.

[0189] In one embodiment, the method further comprises reacting compound 3

[0190]

[0191] with 4-aminophenol (5) to provide compound 4

[0192]

[0193] In one embodiment, the reaction is carried out in the presence of a solvent. In a further embodiment, the solvent is an organic solvent. In a further embodiment, the organic solvent is selected from the group consisting of acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, hexamethylphosphoramide (HMPT), tetrahydrofuran, 1,4-dioxane, and dichloromethane. In yet another embodiment, the organic solvent is dimethylacetamide.

[0194] In one embodiment, the reaction is carried out in the presence of a base. In a further embodiment, the base is n-BuLi, lithium diisopropylamide, lithium hexamethyldisilylamide, sodium hexamethyldisilylamide, sodium hydroxide, sodium methoxide, sodium tert-butoxide, sodium tert-pentoxide, lithium hydroxide, lithium methoxide, lithium tert-butoxide, lithium tert-pentoxide, potassium hydroxide, potassium methoxide, potassium tert-butoxide, potassium tert-pentoxide, cesium hydroxide, cesium methoxide, cesium tert-butoxide, or cesium tert-pentoxide.

[0195] In an embodiment, the reaction is carried out at a temperature of 75-80 °C.

[0196] In an embodiment, the product is isolated by adding water to the reaction mixture and isolating the solid product.

[0197] In an embodiment, the method further comprises reacting Compound 1 with fumaric acid to provide Compound 1 - hemi-fumarate

[0198]

[0199] In an embodiment, the reaction is carried out in the presence of a solvent. In a further embodiment, the solvent is selected from water, an alcoholic solvent, THF, DMF, MEK, acetonitrile, 1,4-dioxane, and MTBE, or any combination thereof. In a further embodiment, the solvent is a mixture of water and an alcoholic solvent.

[0200] In an embodiment, the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, pentanol, hexanol, heptanol, and octanol.

[0201] In a further embodiment, the solvent is a 20% aqueous solution of ethanol.

[0202] In an embodiment, the volume of the 20% aqueous solution of ethanol used in the reaction is about 2-3 times the weight of Compound 1. In another embodiment, the volume (mL) of the 20% aqueous solution of ethanol used in the reaction is about 3 times the weight (grams) of Compound 1.

[0203] In an embodiment, the amount of fumaric acid used is about 0.5-1.0 equivalents relative to Compound 1. In another embodiment, the amount of fumaric acid used is about 0.75-1.0 equivalents relative to Compound 1. In another embodiment, the amount of fumaric acid used is about 0.8-0.82 equivalents relative to Compound 1.

[0204] In an embodiment, Compound 1 is reacted with fumaric acid by adding a fumaric acid mixture dissolved in a 20% aqueous solution of ethanol at 45-50 °C to Compound 1 to produce a reaction mixture.

[0205] In an embodiment, the volume (mL) of the 20% aqueous solution of ethanol used to dissolve fumaric acid is about 2-3 times the weight (grams) of Compound 1. In another embodiment, the volume of the 20% aqueous solution of ethanol used to dissolve fumaric acid is about 2.2-2.8 times the weight of Compound 1. In another embodiment, the volume of the 20% aqueous solution of ethanol used to dissolve fumaric acid is about 2.4-2.6 times the weight of Compound 1.

[0206] In one embodiment, the method further comprises heating the reaction mixture to reflux temperature and stirring. In another embodiment, the refluxing reaction mixture is stirred for 4-6 hours.

[0207] In one embodiment, the method further comprises cooling the reaction mixture and isolating the solid product from the solvent.

[0208] In another aspect, the application includes a method for preparing Compound 1, or a pharmaceutically acceptable salt thereof

[0209]

[0210] The method comprises:

[0211] reacting Compound 3

[0212]

[0213] with 4-aminophenol (5) to provide Compound 4

[0214]

[0215] reacting Compound 6

[0216]

[0217] with thionyl chloride or oxalyl chloride in the presence of a solvent to produce Compound 7,

[0218]

[0219] reacting Compound 4 and Compound 7 to produce Compound 1,

[0220] wherein the method optionally further comprises contacting Compound 1 with an acid to produce a pharmaceutically acceptable salt of the compound of Compound 1.

[0221] In another aspect, the application includes a method for preparing Compound 1, or a pharmaceutically acceptable salt thereof

[0222]

[0223] The method comprises:

[0224] reacting Compound 3

[0225]

[0226] with 4-aminophenol (5) in the presence of dimethylacetamide solvent and sodium tert-pentoxide base at a temperature of 75-80 °C to provide a first reaction mixture comprising Compound 4

[0227]

[0228] precipitating and isolating the solid product, compound 4, by adding water to the first reaction mixture;

[0229] reacting compound 6

[0230]

[0231] with oxalyl chloride in the presence of tetrahydrofuran solvent and dimethylformamide catalyst at a temperature of 5-15 °C to produce a second reaction mixture comprising compound 7,

[0232]

[0233] adding the second reaction mixture to a third reaction mixture comprising a solvent of about 2: 1 tetrahydrofuran: water, Na2CO3 or K2CO3 (preferably K2CO3) base, and compound 4 over a period of at least 30 minutes to produce a fourth reaction mixture, wherein the temperature of the fourth reaction mixture is maintained below about 27 °C during the addition;

[0234] heating the fourth reaction mixture to 35-40 °C and allowing to stand to separate into an organic phase and an aqueous phase;

[0235] discarding the aqueous phase, heating the organic phase to 55-60 °C, and then filtering the organic phase at 55-60 °C;

[0236] adding water to the organic phase over a period of about 4 hours to 4.5 hours while maintaining the temperature at 50-55 °C to produce a fifth reaction mixture;

[0237] stirring the fifth reaction mixture for at least 2 hours; and

[0238] isolating the solid product, compound 1, and wherein the method optionally further comprises contacting compound 1 with an acid to produce a pharmaceutically acceptable salt of the compound of compound 1.

[0239] In one embodiment of this aspect, dimethylformamide is present in a catalytic amount.

[0240] In some embodiments of this aspect, the molar ratio between dimethylformamide and oxalyl chloride is about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, or 0.05. In some embodiments, the volume ratio between dimethylformamide and oxalyl chloride is about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, or 0.05. In some embodiments, the molar ratio of dimethylformamide / oxalyl chloride is between about 0.001 and about 0.005. In some embodiments, the volume ratio of dimethylformamide / oxalyl chloride is between about 0.001 and about 0.005.

[0241] In other embodiments of this aspect, the molar ratio between dimethylformamide and compound 6 is about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, or 0.05. In some embodiments, the volume ratio between dimethylformamide and compound 6 is about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, or 0.05. In some embodiments, the molar ratio of dimethylformamide / compound 6 is between about 0.001 and about 0.005. In some embodiments, the volume ratio of dimethylformamide / compound 6 is between about 0.001 and about 0.005.

[0242] In another aspect, the present application includes a process for preparing compound 1-hemi-fumarate salt

[0243]

[0244] Compound 1-hemi-fumarate salt

[0245] The process comprises:

[0246] adding a fumaric acid mixture dissolved in a 20% aqueous ethanol solution at 45-50 °C to compound 1 to produce a reaction mixture;

[0247] heating the reaction mixture to reflux;

[0248] stirring the reaction mixture at reflux for 4-6 hours; and

[0249] cooling the reaction mixture and isolating the solid product, compound 1 - hemifumarate salt, from the solvent.

[0250] In another aspect, the present application includes a process for preparing compound 1 - hemifumarate salt

[0251]

[0252] compound 1 - hemifumarate salt

[0253] The process comprises:

[0254] reacting compound 3

[0255]

[0256] with 4-aminophenol (5) to provide compound 4

[0257]

[0258] reacting compound 6

[0259]

[0260] with thionyl chloride or oxalyl chloride in the presence of a solvent to produce compound 7,

[0261]

[0262] reacting compound 4 and compound 7 to produce compound 1; and

[0263] combining fumaric acid dissolved in a 20% aqueous ethanol solution with compound 1 to provide compound 1 - hemifumarate salt.

[0264] In one embodiment, compound 1 is reacted with fumaric acid to produce a slurry by adding a mixture of fumaric acid dissolved in a 20% aqueous ethanol solution at 45-50 °C to compound 1.

[0265] In one embodiment, the amount of fumaric acid used is about 0.5-1.0 equivalents relative to compound 1. In another embodiment, the amount of fumaric acid used is about 0.75-1.0 equivalents relative to compound 1. In another embodiment, the amount of fumaric acid used is about 0.8-0.82 equivalents relative to compound 1.

[0266] In one embodiment, the volume (mL) of 20% aqueous ethanol solution used to dissolve the fumaric acid is about 2-3 times the weight (grams) of Compound 1. In another embodiment, the volume of 20% aqueous ethanol solution used to dissolve the fumaric acid is about 2.2-2.8 times the weight of Compound 1. In another embodiment, the volume of 20% aqueous ethanol solution used to dissolve the fumaric acid is about 2.4-2.6 times the weight of Compound 1.

[0267] In another aspect, the present application includes a method for preparing Compound 1 - hemifumarate salt

[0268]

[0269] Compound 1 - hemifumarate salt

[0270] The method comprises:

[0271] combining a fumaric acid solution with Compound 1 to produce a reaction mixture comprising a slurry;

[0272] heating the reaction mixture to reflux for a predetermined amount of time; and

[0273] isolating Compound 1 · hemifumarate salt in solid form.

[0274] In one embodiment of this aspect, the combining comprises adding the fumaric acid solution to Compound 1.

[0275] In further embodiments, the fumaric acid is dissolved in a mixed solvent of EtOH and acetone to form a solution at about 45-50 °C.

[0276] In another embodiment, the predetermined amount of time is between about 1 hour and 6 hours.

[0277] In another embodiment, the isolating comprises cooling the reaction mixture comprising a slurry; filtering the reaction mixture to obtain a solid; and washing the solid.

[0278] In one aspect, the present application includes a compound having the following structure:

[0279]

[0280] Discussion

[0281] The synthetic transformation to produce Compound 1 includes two parallel reactions: the generation of the acid chloride 7 and the amidation reaction to produce Compound 1. When performed at ambient temperature, the generation of the acid chloride 7 was found to be fast and complete after approximately 15 minutes. However, at ambient temperature, batch to batch inconsistencies were observed and some batches contained higher levels of impurities than others. It was also found that by performing the reaction at 10-15 °C, the production of unwanted side products was avoided. At this temperature, the reaction was slower and typically took 2-3 hours to complete, but the impurity levels could be controlled and minimized.

[0282] During the amidation reaction to produce Compound 1, the major impurities were found to be unreacted Compound 4 and various reaction products due to side reactions with the acid chloride. It was found that using slightly less than the stoichiometric amount of acid chloride in the reaction greatly reduced the amount of impurities from acid chloride side reactions.

[0283] As provided herein, Compound 1 is reacted with fumaric acid to produce Compound 1 - hemifumarate. Due to the low solubility of the hemifumarate, the polishing filtration to remove any adventitious material, typically performed at the API stage, was performed at the free base stage. As a result, a high volume of solvent was used (50 v / w relative to Compound 4). Even at such a high volume, product precipitation was observed during the scaled up aqueous phase removal. To address this issue, the organic phase was heated to 55-60 °C prior to polishing filtration.

[0284] The salt formation of Compound 1 · hemifumarate was previously performed in a mixture of THF and water. After polishing filtration, the THF was exchanged to IPA. However, it was found that the crystalline product still contained high levels of THF. Attempts to remove the THF by hot trituration in solvent and vacuum drying at high temperature were unsuccessful. In an attempt to correct this issue, MEK and IPA were each used as solvents for the salt formation. These attempts were unsuccessful as the MEK and IPA replaced the THF in the crystal lattice, forming respective solvates.

[0285] It was recognized that when the salt was formed in solution, a solvate was produced in which THF was incorporated into the crystalline product and could not be removed by vacuum drying even at 60-80 °C. Attempts to remove the residual THF by suspending the salt in refluxing IPA were also unsuccessful.

[0286] Our studies showed that the salt can be formed from a slurry of the free base of Compound 1. It was also found that ACN, IPA or EtOH can be used for the slurry salt formation as long as the reaction temperature is above 70 °C. The transformation under these slurry conditions was slower (>10 hours) possibly due to the low solubility of the free base in the medium. The benefit of the slurry reaction is that the crystalline product contains minimal amounts of solvent (no solvate formation was observed). Using 1H NMR (d6 DMSO) monitored the conversion of free base to hemifumarate by observing the integral ratio of the fumaric acid peak at δ 6.64 ppm (corresponding to 2 protons) compared to the aromatic peak of compound 1 at δ 6.47 ppm (corresponding to 1 proton). Full conversion would show a 1 : 1 ratio of these two signals.

[0287] It was found that the conversion was faster in the presence of water in EtOH. Thus, in another example, the reaction in 10% aqueous EtOH solution was completed after 5 hours at 62-65 °C. The yield obtained was moderate, but higher yields were generally obtained when the solvent volume was reduced. However, a large amount of solvent was required to dissolve the fumaric acid in order to be able to fine filter at ambient temperature. To reduce the reaction volume, the amount of fumaric acid used was reduced to 0.8-0.82 equivalents relative to compound 1. A higher temperature was also used to dissolve the fumaric acid (40-45 °C), which enabled the acid to be dissolved with 2.48 volumes of 20% aqueous EtOH relative to compound 1. Thus, it was surprisingly found that by using 2-3 times (or 2.2-2.8 times, or 2.4-2.6 times) the weight of compound 1 in 20% aqueous EtOH to dissolve compound 1, the yield of compound 1 hemifumarate had been greatly improved from about 58% (by using pure ethanol) to >95% (97%), with the purity of the product being greater than 99% (determined by UPLC). No solvate formation was observed. The following table summarizes the solvents used to dissolve the fumaric acid and the corresponding yields.

[0288]

[0289] The application will now be illustrated by the following non-limiting examples.

[0290] Example

[0291] Materials and sources

[0292] Material Compound No. 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide 3 4-aminophenol 5 sodium tert-pentoxide N / A N,N-dimethylacetamide N / A tetrahydrofuran N / A 1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxylic acid 6 oxalyl chloride N / A DMA N / A DMF N / A THF N / A potassium carbonate N / A fumaric acid N / A ethanol N / A

[0293] Scheme 1: Process for preparing compound 1 and compound 1 hemifumarate

[0294]

[0295] Example 1: Synthesis of 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide (3)

[0296]

[0297] To a suspension of methyl 4-chloro-7-methoxyquinoline-6-carboxylate 2 (2 g, 8 mmol) in THF (20 mL) was added methylamine in EtOH (33% w / w, 8 M, 20 mL, 160 mmol) and H2O (10 mL). The resulting mixture was stirred at room temperature. The mixture turned into a clear solution within about 10 minutes and remained a clear solution during the reaction. Stirring was continued until complete consumption of the starting material was confirmed by LCMS and HPLC. This took about 3 hours. The mixture was then concentrated and the residue was slurried in 20 mL of water and filtered. The material was transferred from the flask to the filter funnel using some EtOAc. The product was dried to give 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide as a white solid (yield 1.8 g, 90%, HPLC purity >97%).

[0298] Example 2: Synthesis of 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6- carboxamide (4)

[0299]

[0300] A 5 L 3 -necked round bottom flask, equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with 4-chloro-7-methoxy-N-methylquinoline-6- carboxamide (3; 300 g; 1 eq), 4-aminophenol (5; 195.9 g; 1.5 eq), and DMA (1500 mL). The resulting solution was stirred at room temperature and a solution of sodium tert- pentoxide (184.52 g; 1.4 eq) dissolved in anhydrous THF (313 mL) was added over a 5 minute period with stirring. The reaction mixture was then heated to 75-80 °C and stirred for an additional 2-6 hours. The reaction mixture was then cooled to room temperature and charged with water (3 L) and stirred for at least an additional 1 hour. The product was filtered and washed twice with 600 mL of 1 : 1 DMA / water and then once with 1200 mL of water. The product was transferred to a crystallization dish and dried in a vacuum oven at 40-45 °C for a minimum of 18 hours to give a light brown shiny solid (370-377 g; 96-97%).

[0301] Example 3A: Synthesis of l-((4-fluorophenyl)carbamoyl)cyclopropane-l-carbonyl chloride (7)

[0302]

[0303] A 250 mL 3 necked round bottom flask, equipped with a thermometer, nitrogen inlet and magnetic stirrer was charged with 1-((4-fluorophenyl)carbamoyl)cyclopropane-1- carboxylic acid (6; 19.11 g; 1.3 eq), 75 mL of dry THF and 0.25 mL of DMF (catalyst). The mixture was stirred until all the solids were dissolved, cooled to 5-10 °C and then charged with oxalyl chloride (7.13 mL; 1.28 eq). The resulting mixture was aged at 10-15 °C for 2-3 hours and the completion of the reaction was confirmed by IPC (in process control). After completion of the reaction, the resulting product mixture was used in the next step without further purification.

[0304] Example 3B: Synthesis of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (7) [Alternate method]

[0305]

[0306] A 250 mL 3 necked round bottom flask, equipped with a thermometer, nitrogen inlet and magnetic stirrer was charged with 1-((4-fluorophenyl)carbamoyl)cyclopropane-1- carboxylic acid (6; 19.11 g; 1.3 eq), 75 mL of dry THF and 0.25 mL of DMF (catalyst). The mixture was stirred until all the solids were dissolved, cooled to 5-15 °C and then charged with oxalyl chloride (7.13 mL; 1.28 eq). The resulting mixture was warmed to room temperature and then stirred for 2-4 hours. The resulting product mixture was used in the next step without further purification.

[0307] Example 4A: Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1)

[0308]

[0309] A 500 mL 3 -necked round bottom flask, equipped with a thermometer, nitrogen inlet, and magnetic stirrer, was charged with 4-(4-aminophenoxy)-7-methoxy-N- methylquinoline-6-carboxamide (4, 21.3 g; 1.0 equiv), 210 mL of anhydrous THF, and a solution of potassium carbonate (27.32 g; 3 equiv) and 100 mL of water. The aqueous K2CO3 solution was flushed forward with an additional 6.4 mL of water. The reaction mixture from the previous example containing compound 7 was transferred to the reaction mixture of the invention over a period of no less than 30 minutes with vigorous stirring while maintaining the internal temperature between 20 °C and 25 °C. The transfer apparatus was flushed with 32 mL of anhydrous THF. The reaction mixture was stirred at ambient temperature for 0.5-1 hour. The resulting mixture was warmed to 35-40 °C and the phases were allowed to separate. The lower aqueous layer was discarded and the upper organic layer was warmed to 55-60 °C and then filtered dry against the frit with 21 mL of THF. The filtered organic phase was transferred to a 1 L 3 -necked round bottom flask, equipped with a thermometer, nitrogen inlet, and mechanical stirring, and charged with water at 55-60 °C. The resulting solution was seeded with compound 1 and water was added to the resulting seed bed as antisolvent over 4-4.5 hours while maintaining the temperature at 50-55 °C. The resulting slurry was cooled to 20-25 °C and aged for no less than 2 hours. The product was then filtered, washed with water / THF, and dried.

[0310] Example 4B: Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1 -dicarboxamide (1) [Alternate Method]

[0311]

[0312] A 500 mL 3 -necked round bottom flask, equipped with a thermometer, nitrogen inlet, and magnetic stirrer, was charged with 4-(4-aminophenoxy)-7-methoxy-N- methylquinoline-6-carboxamide (4, 21.3 g; 1.0 equiv), 210 mL of anhydrous THF, and a solution of potassium carbonate (27.32 g; 3 equiv) and 100 mL of water. The aqueous K2CO3 addition was flushed forward with an additional 6.4 mL of water. The reaction mixture from the previous example containing compound 7 was transferred to the reaction mixture of the invention over a period of 0.5-1 hour with vigorous stirring while maintaining an internal temperature below 27 °C. The transfer apparatus was flushed with 32 mL of anhydrous THF. The reaction mixture was stirred at ambient temperature for 0.5-1 hour. The resulting mixture was warmed to 35-40 °C and the phases were allowed to separate. The lower aqueous layer was discarded and the upper organic phase was warmed to 45-50 °C and then filtered through filter paper and flushed with 21 mL of THF. The filtered organic phase was transferred to a 1 L 3 -necked round bottom flask, equipped with a thermometer, nitrogen inlet, and mechanical stirrer, and charged with 694 mL of filtered water over a minimum of 1 hour. The resulting mixture was stirred at 20-25 °C for a minimum of 12 hours, then the product was filtered and flushed twice with 42 mL of a 2: 1 water:THF mixture. The product was then dried on filter paper at room temperature or in a vacuum oven at 40-45 °C to yield a white to beige solid (31.36 g; 90%).

[0313] Example 5: Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1 -dicarboxamide 1 / 2 fumaric acid (1 · hemifumarate) - Method 1

[0314]

[0315] A 2000 mL 3 necked round bottom flask, equipped with a thermometer, nitrogen inlet and magnetic stirrer was charged with fumaric acid (80 g; 0.82 eq) and 1.2 L of 20% aqueous ethanol solution. The mixture was heated to 45-50 °C and stirred until all the solid dissolved. Into a separate 3 L 3 necked round bottom flask, equipped with a thermometer, nitrogen inlet and mechanical stirrer was charged with N-(4-fluorophenyl)-N-(4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1 -dicarboxamide (1 ; 500 g; 1.0 eq). The fumaric acid solution was clarified through filter paper at 40-45 °C and transferred to the flask with compound 1 at 40-45 °C. The 2000 mL round bottom flask was flushed forward with 300 mL of 20% aqueous ethanol solution at 45-50 °C. The resulting mixture was heated to reflux (75-80 °C) and stirred for 4-6 hours. The reaction mixture was then cooled to room temperature and the product was filtered and the filter cake was washed twice with 300 mL of 20% aqueous ethanol solution. The product was then dried on filter paper at room temperature or in a vacuum oven at 40-45 °C to yield a white to beige solid (472-474 g; 97%).

[0316] Example 6: Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6- (methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1 -dicarboxamide · 1 / 2 fumaric acid (1 · hemifumarate) - Method 2

[0317]

[0318] Fumaric acid (2.68 grams, 1 eq) and 1 : 1 EtOH / acetone (48 mL) were added to a two-piece EasyMax (EM) reaction vessel and heated to a reaction temperature of 50 °C to dissolve all materials. In an adjacent EM pot, a 1 -piece EM vessel containing Compound 1 (12.0 g, 1 eq) was set to a jacket temperature of 50 °C. The fumaric acid solution was transferred to the vessel containing Compound 1. Seed crystals were charged (2% seed, 0.244 g) and the vessel was heated to reflux (-65 °C). After 1 hour, 0.5 mL of slurry was filtered, washed with EtOH (6 x 1.5 mL) and analyzed by HPLC to determine fumaric acid content (results should be about 10%). The slurry was then allowed to cool to 25 °C over 1 hour and stirred for an additional 1 hour. The solids were then filtered, washed with 1 : 1 EtOH / acetone (2 x 3 V), and dried under vacuum at 25 °C for one weekend. 1 H NMR 700MHz (DMSO-d6) δ 1.473 (s, 4H), δ 4.009 (s, 3H), δ 2.839 (d, 3H, 3 J 1H-1H= 4.7 Hz), δ 6.450 (d, 1H, 3 J 1H-1H = 4.7 Hz), δ 6.450 (d, 1H, 3 J 1H-1H = 5.2 Hz), δ 6.632 (s, 2H), δ 6.635 (s, 2H), δ 7.137 (m, 2H), δ 7.244 (d, 2H, 3 J 1H-1H = 8.6 Hz), δ 7.494 (s, 1H), δ 7.642 (m, 2H), δ 7.776 (d, 2H, 3 J 1H-1H = 8.6 Hz), δ 8.361 (q, 1H, 3 J 1H-1H = 4.7 Hz), δ 8.618 (s, 1H), 8.615 (s, 1H), δ 8.638 (d, 1H, 3 J 1H-1H = 5.2 Hz), δ 10.070 (s, 1H), δ 10.216 (s, 1H), δ 13.164 (s, 1H). 19 F NMR 700 MHz (DMSO-d6; reference trifluoromethylbenzene at -63.72 ppm) δ -121.460. 13 C NMR 700 MHz (DMSO-d6) δ 15.46, δ 26.47, δ 31.60, δ 56.15, δ 102.91, δ 107.83, δ 114.55, δ 115.05 (d, 2 J 19F-13C = 22.2 Hz), δ 121.15, δ 122.23, δ 122.43 (d, 3 J 19F-13C = 7.6 Hz), δ 124.35, δ 125.24, δ 134.03, δ 135.22 (d, 4 J 19F-13C = 2.4 Hz), δ 136.73, δ 149.08, δ 151.46, δ 153.18, δ 157.94, δ 158.30 (d, 1 J 19F-13C = 240.2 Hz), δ 161.76, δ 164.89, δ 168.16 and δ 168.16. 15 N NMR 700 MHz (DMSO-d6) δ 106.25 ( 15 N), δ 127.79 ( 15 N), δ 128.86 ( 15 N), δ 166.04, δ 289.56 ( 15N).

[0319] Other embodiments

[0320] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The application has been described with reference to various specific and preferred embodiments and techniques. However, it is clear that many variations and modifications of the application can be made and will be apparent to those skilled in the art. It is the applicant's intention to cover all such changes and modifications that fall within the scope and spirit of the application. Changes and modifications can be made by those skilled in the art in going from the described embodiments to practices of the application. Therefore, it is manifestly intended that the application be limited only by the following claims and equivalents thereof.

[0321] The scope of the application should therefore not be determined with reference to the above description, but instead should be determined with reference to the pending claims along with their full scope of equivalents.

Claims

1. A process for preparing Compound 1 - hemi-fumarate salt said process comprising reacting Compound 1 with fumaric acid in the presence of 20% aqueous ethanol solvent to obtain Compound 1 - hemi-fumarate salt.

2. The process as claimed in claim 1, wherein reacting Compound 1 with fumaric acid comprises adding a mixture of fumaric acid dissolved in 20% aqueous ethanol solution solvent at 45-50 °C to Compound 1 to produce a reaction mixture.

3. The process as claimed in claim 2, further comprising heating the reaction mixture to reflux and stirring the reaction mixture.

4. The process as claimed in claim 3, wherein the reaction mixture is stirred at reflux for 4-6 hours.

5. The process as claimed in claim 4, further comprising cooling the reaction mixture and isolating the Compound 1 - hemi-fumarate salt from the solvent.

6. A process for preparing Compound 1 - hemi-fumarate salt said process comprising: adding a mixture of fumaric acid dissolved in 20% aqueous ethanol solution solvent at 45-50 °C to Compound 1 to produce a reaction mixture; heating the reaction mixture to reflux; stirring the reaction mixture at reflux for 4-6 hours; cooling the reaction mixture; and filtering the reaction mixture to obtain Compound 1 · hemi-fumarate salt as a solid.

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