Processes for preparation of kinase inhibitor

Abstract

To provide processes for preparation of a kinase inhibitor.SOLUTION: The present invention relates to processes for the synthetic preparation of c-Met inhibitors of Formula I, or pharmaceutically acceptable salts thereof. The present invention further relates to processes for the synthetic preparation of the c-Met inhibitor, Compound 1, or a pharmaceutically acceptable salt thereof. The present invention also relates to processes for the synthetic preparation of Compound 1 hemifumarate. The invention further relates to large scale processes for the synthetic preparation of the c-Met inhibitor, Compound 1 and Compound 1 hemifumarate.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application Serial No. 63 / 017,739, filed April 30, 2020. The entire contents of the foregoing application are incorporated herein by reference.

[0002] The present invention relates to a process for preparing a c-Met inhibitor of Formula I, or a pharmaceutically acceptable salt thereof. The present invention further relates to a process for preparing the c-Met inhibitor, Compound 1, or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for synthetically preparing Compound 1 hemifumarate. The present invention further relates to a large-scale process for synthetically preparing the c-Met inhibitor, Compound 1, and Compound 1 hemifumarate. [Background technology]

[0003] 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 several tumor cell types and was originally cloned from a patient with chronic myeloid leukemia. When overexpressed, Axl exhibits transforming potential. Axl signaling is thought to initiate tumor growth through activation of 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 confers a poor prognosis for patients with the indicated cancers.

[0004] Activation of Mer, like Axl, transduces downstream signaling pathways that initiate tumor growth and activation. Mer binds to ligands such as the soluble protein Gas-6. Gas-6 binding to Mer triggers autophosphorylation of Mer at its intracellular domain, resulting in downstream signal activation. Overexpression of Mer in cancer cells leads to increased metastasis, likely due to the generation of soluble Mer extracellular domain proteins as decoy receptors. Tumor cells secrete a soluble form of the extracellular Mer receptor, which reduces the ability of soluble Gas-6 ligand to activate Mer on endothelial cells, leading to cancer progression.

[0005] Therefore, there is a need for compounds that inhibit TAM receptor tyrosine kinases, such as Axl and Mer, to treat selected cancers, as well as processes for producing such compounds in high yield and purity. Summary of the Invention [Means for solving the problem]

[0006] In one aspect, the present invention provides a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, comprising: [ka] with a compound of formula III [ka] in the presence of a solvent and a base, the process optionally further comprising contacting the compound of formula I with an acid to form a pharmaceutically acceptable salt of the compound of formula I, wherein LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and organotriphosphate compounds; R1 is halo, C 1~6 Alkyl, C1~6 Alkoxy, and C 3~6 cycloalkyl; R2 and R3 are each independently halo and C 1~6 alkyl, R4 is halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, phenyl, and C 3~6 heteroaryl; R 5a are H, -NH2, -OH, C 1~8 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, phenyl, and C 3~6 heteroaryl; C 1~8 Up to three methylene units of the alkyl are optionally and independently replaced by -O-, -NR'-, -C(O)-, -C(O)O-, and -C(O)NR'-; R 5a is optional The options are 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 substituted with up to three substituents selected from heteroaryl; R 5b is H or C 1~6 alkyl, or R 5a and R 5b together with the nitrogen to which they are attached, optionally halo, CN, OH, NO, NH, SH, OR, C(O)OR, C(O)R, C(O)NR, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl or C 3~6 C substituted with heteroaryl 3~6 forming a heterocycloalkyl, R 5cis H or C optionally substituted with halo, CN, OH, NH, or OR' 1~6 is alkyl, R' is H or C 1~6 is alkyl, w, x, y, and z are each independently an integer of 0 to 4.

[0007] In another aspect, the present invention provides compound 1 (N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide) [ka] or a pharmaceutically acceptable salt thereof, comprising reacting compound 4 [ka] with a compound of formula III' [ka] 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 the process optionally further comprises contacting the compound of Compound 1 with an acid to produce a pharmaceutically acceptable salt of the compound of Compound 1.

[0008] Small molecule compounds that specifically inhibit, regulate, and / or modulate the signal transduction of TAM kinases, such as Axl and Mer, as described above, are particularly desirable as a means for treating or preventing conditions 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 incorporated herein by reference. PCT / US2019 / 015297 also discloses a separate and unrelated synthetic process for Compound 1 (see Example 4). A separate and unrelated process for 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 incorporated herein by reference. The present disclosure provides improved processes for preparing Compound 1 and Compound 1·hemifumarate salt, which are obtained in surprisingly high yields and purities. DETAILED DESCRIPTION OF THE INVENTION

[0009] Definitions and Abbreviations

[0010] solvent [Table 1]

[0011] As used herein, the following definitions shall apply unless otherwise indicated.

[0012] For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 95th Ed. Additionally, the general principles of organic chemistry are set forth in "Organic Chemistry," 2 nd Ed., Thomas Sorrell,University Science Books,Sausal ito: 2006 and “March's Advanced Organic Chemistry,” 7th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2013, the entire contents of which are incorporated herein by reference.

[0013] As used herein, the term "about," or "approximately," or "approximately" includes (and describes) embodiments that relate to the value or parameter itself. In certain embodiments, the term "about," or "approximately," or "approximately" includes ±10% of the stated amount. In other embodiments, the term "about," or "approximately," or "approximately" includes ±5% of the stated amount. In certain embodiments, the term "about," or "approximately," or "approximately" includes ±1% of the stated amount.

[0014] As used herein, the term "slurry" refers to a suspension prepared by adding sufficient solids to a given solvent at ambient conditions so that undissolved solids are present. A typical slurry involves agitation (typically by stirring or shaking) in a sealed vial at a given temperature for an extended period of time, an operation also known as "slurrying." Typically, the solids are recovered after a given period of time using the methods described herein.

[0015] The phrase "pharmaceutically acceptable" is used herein to refer to 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 human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0016] As used herein, the term "catalytic amount" refers to an amount of the limiting reagent that is less than a stoichiometric equivalent. In some embodiments, the catalytic amount is much less than the stoichiometric equivalent of the limiting reagent, such as 0-5%, 0-4%, 0-3%, 0-2%, 0-1%, 0-0.9%, 0-0.8%, 0-0.7%, 0-0.6%, 0-0.5%, 0-0.4%, 0-0.3%, 0-0.2%, 0-0.1%, 0-0.05%, and 0-0.01% by weight of the stoichiometric amount of the limiting reagent.

[0017] In general, the nomenclature used in this application is based on the naming conventions adopted by the International Union of Pure and Applied Chemistry (IUPAC). The chemical structures shown herein were prepared using CHEMDRAW®. Any open valency appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.

[0018] The symbol "-" means a single bond and "=" means a double bond.

[0019] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0020] Where a variable is generically defined with several possible substituents, each individual radical may be defined with or without a bond. For example, R z can be hydrogen, this means that R z In the definition of, it may be shown as "-H" or "H".

[0021] When chemical structures are depicted or described, all carbons are assumed to have hydrogen substitutions in accordance with a valence of four unless expressly stated otherwise. For example, in the structure on the left in the diagram below, nine hydrogens are meant to be present. The nine hydrogens are depicted in the structure on the right. Sometimes, specific atoms in a structure are described in the text formula as having one hydrogen or multiple hydrogens (well-defined hydrogens) as substitutions, e.g., -CHCH-. Those skilled in the art will appreciate that the above-described descriptive techniques are common in the chemical arts to simplify and simplify the description of otherwise complex structures. [ka]

[0022] The group "R" may, for example, be of the formula: [ka] When depicted as "floating" on a ring system, as in, unless otherwise defined, the substituent "R" may be located on any atom of the ring system, and replacement of a shown, implied, or explicitly defined hydrogen from one of the ring atoms is assumed so long as a stable structure is created.

[0023] For example, the expression: [ka] When the group "R" is depicted as floating on a fused ring system, as in, unless otherwise defined, the substituent "R" may be present on any atom of the fused ring system, and replacement of a depicted hydrogen (e.g., -NH- in the formula above), an implied hydrogen (e.g., in the formula above, a hydrogen is not shown but is understood to be present), or an explicitly defined hydrogen (e.g., in the formula above, "Z" equals =CH-) from one of the ring atoms is assumed so long as a stable structure is formed. In the depicted example, the "R" group may be present on either the 5- or 6-membered ring of the fused ring system. When the group "R" is present, for example, in the formula: [ka] When depicted as occurring on a ring system containing saturated carbons, such as in the formula: [where in this example, "v" can be more than one], each is assumed to replace a currently depicted, implied, or explicitly defined hydrogen on the ring, and unless otherwise defined, two "R"s can occur on the same carbon if the resulting structure is stable. A simple example is when R is a methyl group, and a geminal dimethyl can occur on the depicted ring carbon (an "annular" carbon). In another example, two Rs on the same carbon, including that carbon, can form a ring, thus, for example, in the formula: [ka] As in, a spirocyclic ring ("spirocyclyl" group) structure is created that includes the ring shown.

[0024] Unless otherwise stated, a bifunctional group can have the orientation as depicted or the reverse orientation. For example, for the bifunctional group "-C(O)NH-", the present disclosure also includes the reverse orientation "-NHC(O)-".

[0025] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0026] "C n ~ m " or "C n ~C m The term "n" denotes an inclusive range where n and m are integers and indicate the number of carbons. Examples include C1-4, C1-C4, C1-6, C1-C6, etc.

[0027] "Alkyl" refers to a branched or straight hydrocarbon chain, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, and heptyl. In some embodiments, an alkyl group can have 1 to 8 carbon atoms. (C1-C6) alkyl is preferred. "C n ~ m alkyl" or (C n ~C m The term alkyl refers to an alkyl group having n to m carbon atoms. When optionally substituted, one or more (e.g., 1 to 4, 1 to 2, or 1) hydrogen atoms of the alkyl group can be replaced with a moiety as described below under "optionally substituted." In some embodiments, the alkyl group is unsubstituted or not optionally substituted.

[0028] "Alkylene" refers to an optionally substituted divalent saturated aliphatic radical 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. When optionally substituted, one or more (e.g., 1 to 4, 1 to 2, or 1) hydrogen atoms of the alkylene group can be replaced with a moiety as described below under "optionally substituted." In some embodiments, an alkylene group is unsubstituted or not optionally substituted. "C n ~ m The term "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, and the like.

[0029] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound.n ~ m alkenyl" or (C n ~C m The term alkenyl refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0030] The term "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. "C" refers to a straight-chain or branched hydrocarbon group corresponding to the alkyl group. An alkynyl group formally corresponds to an alkyne with one C-H bond replaced by the point of attachment of the alkyl group to the rest of the compound. n ~ m alkynyl" or (C n ~C m The term alkynyl refers to an alkynyl group having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0031] "Alkoxy" means a group of the formula -OR i In this case, R i is a (C1-C6) alkyl moiety as defined herein. n ~ m Alkoxy" or (C n ~C m The term alkoxy refers to an alkoxy group whose alkyl group has n to m carbons. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0032] An alkoxy group can be unsubstituted or optionally substituted. When optionally substituted, one or more (e.g., 1 to 4, 1 to 2, or 1) hydrogen atoms of the alkoxy group can be replaced with a moiety as described below under "optionally substituted," provided that the hydrogen atom alpha to the ether oxygen is not replaced with a hydroxy, amino, or thio group. In some embodiments, an alkoxy group is unsubstituted or not optionally substituted.

[0033] "Alkoxycarbonyl" refers to the group -C(O)-R i In this case, R i is (C1-C6)alkoxy as defined herein.

[0034] The term "amino" refers to a group of formula -NH2.

[0035] The term "carbamyl" refers to a group of formula -C(O)NH2.

[0036] The term "carbonyl," used alone or in combination with other terms, refers to a -C(=O)- group, which may also be written as C(O).

[0037] The term "cyano" or "nitrile" refers to a group of formula -C≡N, which may also be written as -CN or CN.

[0038] The term "oxo" refers to an oxygen atom as a divalent substituent, which when attached to carbon forms a carbonyl group, or when attached to a heteroatom forms a sulfoxide or sulfone group, or an N-oxide group. In some embodiments, heterocyclic groups can be optionally substituted with one or two oxo (=O) substituents.

[0039] The term "sulfide" refers to a sulfur atom as a divalent substituent, which when attached to carbon forms a thiocarbonyl group (C=S).

[0040] As used herein, the term "heteroatom" is intended to include boron, phosphorus, sulfur, oxygen, and nitrogen.

[0041] The term "haloalkyl," as used herein, refers to an alkyl group in which one or more of the hydrogen atoms is replaced by one or more halogen atoms. n ~ m haloalkyl" or (C n ~C m The term haloalkyl refers to a C alkyl group having n to m carbon atoms and at least 1 to {2(n to m)+1} halogen atoms, which may be the same or different. n ~ m In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the haloalkyl group is a 1-6 or 1-4 carbon atom. Examples of haloalkyl groups include CF, C2F5, CHF2, CCl3, CHCl2, C2Cl5, etc. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0042] The term "haloalkoxy", used alone or in combination with other terms, refers to a radical of the formula -O-haloalkyl, where the haloalkyl radical is as defined above. n ~ m haloalkoxy" or (C n ~C m The term haloalkoxy refers to a haloalkoxy group where the haloalkyl group has n to m carbon atoms. Examples of 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.

[0043] "Aryl" means a monovalent 6- to 14-membered monocyclic, bicyclic, or tricyclic carbocyclic ring (e.g., having two fused rings), in which the monocyclic ring is aromatic and at least one of the rings of a bicyclic ring is aromatic. n ~ maryl" or "(C n ~C m The term "aryl" refers to an aryl group having n to m ring carbon atoms. In some embodiments, an aryl group has from 6 to about 10 carbon atoms. In some embodiments, an aryl group has 6 ring carbon atoms. In some embodiments, an aryl group has 10 ring carbon atoms. Unless otherwise stated, the valency of the group may be located on any atom of any ring within the radical, valence rules permitting. Representative examples include phenyl, naphthyl, indanyl, and the like.

[0044] An aryl group can be unsubstituted or optionally substituted. When optionally substituted, one or more (e.g., 1 to 5, 1 to 2, or 1) hydrogen atoms of the aryl group can be replaced with a moiety as described below under "optionally substituted." In some embodiments, an alkoxy group is unsubstituted or not optionally substituted.

[0045] "Arylene" means a divalent 6- to 14-membered monocyclic, bicyclic, or tricyclic carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings of the bicyclic or tricyclic ring is aromatic. Representative examples include phenylene, naphthylene, and indanylene.

[0046] "Cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic) including cyclized alkyl and alkenyl groups. n ~ m cycloalkyl" or "(C n ~C m The term "cycloalkyl" refers to a cycloalkyl having n to m ring carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms (C 3~14In some embodiments, the cycloalkyl group has 3 to 14 ring members, 3 to 10 ring 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 It is a monocyclic cycloalkyl group. The ring-forming carbon atoms of a cycloalkyl group may be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidene. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In some embodiments, cycloalkyl groups are cyclopropyl, cyclobutyl, In some embodiments, cycloalkyl includes a single saturated carbocyclic ring of 3 to 8 ring carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl can be optionally substituted with one or more substituents, such as 1, 2, or 3 substituents. In some embodiments, cycloalkyl substituents are selected from the group consisting of (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.

[0047] A cycloalkyl group can be unsubstituted or optionally substituted. When optionally substituted, one or more (e.g., 1 to 4, 1 to 2, or 1) hydrogen atoms of the cycloalkyl group can be replaced with a moiety as described below under "optionally substituted." In some embodiments, a substituted cycloalkyl group can incorporate an exo- or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some embodiments, a cycloalkyl group is unsubstituted or not optionally substituted.

[0048] "Cycloalkyloxycarbonyl" refers to the group -C(O)-OR i In this case, R i is (C3-C6)cycloalkyl as defined herein.

[0049] "Phenyloxycarbonyl" refers to the group -C(O)-O-phenyl.

[0050] "Heteroaryl" refers to -O-, -S(O) n -(n is 0, 1, or 2), -N-, and -N(R i )-, and the remaining ring atoms are carbon, where the ring containing the monocyclic radical is aromatic and at least one of the fused rings containing the bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any non-aromatic ring containing the bicyclic or tricyclic radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R iis hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Unless otherwise stated, valence may be located on any atom of any ring of the heteroaryl group, valence rules permitting. In particular, when the point of valence is located on nitrogen, no additional nitrogen substituents are present. More specifically, the term heteroaryl includes, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1H-indolyl (including, for example, 2,3-dihydro-1H-indol-2-yl or 2,3-dihydro-1H-indol-5-yl), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl, cinnolinyl, indolizinyl, naphthyridin-3-yl, phthalazin-3-yl, phthalazin-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and derivatives thereof, and N-oxides or protected derivatives thereof.

[0051] A 5-membered heteroaryl ring can have one or more (e.g., 1, 2, 3, or 4) ring atoms. and heteroaryl groups having 5 ring atoms, each ring independently selected from N, O, and S. Exemplary 5-membered heteroaryls include thienyl, furyl, 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.

[0052] A 6-membered heteroaryl ring is a heteroaryl group having 6 ring atoms, where one or more (e.g., 1, 2, 3, or 4) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0053] "Heteroarylene" refers to -O-, -S(O) n -(n is 0, 1, or 2), -N-, and -N(R 19 )-, and the remaining ring atoms are carbon, where the ring containing the monocyclic radical is aromatic and at least one of the fused rings containing the bicyclic or tricyclic radical is aromatic. One or two ring carbon atoms of any non-aromatic ring containing the bicyclic or tricyclic radical may be replaced by a -C(O)-, -C(S)-, or -C(=NH)- group. R 19is hydrogen, alkyl, or alkenyl. Unless otherwise stated, valence may be located on any atom of any ring of the heteroarylene group, if valence rules permit. In particular, when the point of valence is located on nitrogen, there are no additional nitrogen substituents. More specifically, the term heteroaryl includes, but is not limited to, thien-diyl, benzo[d]isoxazole-diyl, benzo[d]isothiazole-diyl, 1H-indazole-diyl (at the N1 position, R 19 benzo[d]oxazole-diyl, benzo[d]thiazole-diyl, 1H-benzo[d]imidazole-diyl (optionally substituted at N1 position with R 19 1H-benzo[d][1,2,3]triazole-diyl (optionally substituted at N1 position with R 19 optionally substituted with), imidazo[1,2-a]pyridine-diyl, cinnoline-diyl, quinoline-diyl, pyridine-diyl, 1-oxide-pyridine-diyl, [1,2,4]triazolo[4,3-a]pyridine-diyl, and 2,3-dihydroimidazo[1,2-a]pyridine-diyl.

[0054] As used herein, "heterocycloalkyl" or "heterocyclo" refers to a non-aromatic ring or ring system having 4 to 14 ring members, 4 to 10 ring members, 4 to 7 ring members, or 4 to 6 ring members, which may optionally contain one or more alkenylene groups as part of the ring structure and have at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include monocyclic, bicyclic, or polycyclic (e.g., having 2 or 3 fused or bridged rings) ring systems or spirocycles. In some embodiments, heterocycloalkyl groups are monocyclic groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group may be optionally oxidized to form oxo or sulfido groups or other oxidized bonds (e.g., C(O), S(O), C(S), S(O), N-oxide, etc.), or the nitrogen atom may be quaternized. A heterocycloalkyl group may be bonded through a ring-forming carbon atom or 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. The definition of heterocycloalkyl includes heterocycloalkyl groups. Also included are moieties having one or more aromatic rings fused to (i.e., having a bond in common with) an alkyl ring, e.g., a benzo or thienyl derivative, such as piperidine, morpholine, azepine, etc. Heterocycloalkyl groups containing fused aromatic rings may be bonded through any ring-forming atom, including a ring-forming atom of the fused aromatic ring. Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, 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-tetrahydrothiazolo[5,4-c]pyridinyl, and thiomorpholino.

[0055] A "heterocycloalkyl" or "heterocyclo" can be unsubstituted or optionally substituted. If optionally substituted, one or more (e.g., 1 to 4, 1 to 2, or 1) hydrogen atoms of the group can be replaced with a moiety independently selected from fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some aspects, a substituted heterocyclo group can incorporate an exo- or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some aspects, a heterocyclo group is unsubstituted or not optionally substituted.

[0056] Embodiment In one aspect, the present invention provides a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, comprising: [ka] with a compound of formula III [ka] in the presence of a solvent and a base, said process optionally further comprising contacting the compound of formula I with an acid to form a pharmaceutically acceptable salt of the compound of formula I, wherein LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and organotriphosphate compounds; R1 is halo, C 1~6 Alkyl, C 1~6 Alkoxy, and C 3~6 cycloalkyl; R2 and R3 are each independently halo and C 1~6 alkyl, R4 is halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, phenyl, and C 3~6 heteroaryl; R 5a are H, OH, NH2, C 1~8 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, phenyl, and C 3~6 heteroaryl, C 1~8 Up to three methylene units of the alkyl are optionally and independently replaced by -O-, -NR'-, -C(O)-, -C(O)O-, and -C(O)NR'-; R 5a is optional and includes 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 substituted with up to three substituents selected from heteroaryl; R 5b is H or C 1~6 alkyl, or R5a and R 5b together with the nitrogen to which they are attached, optionally halo, CN, OH, NO, NH, SH, OR, C(O)OR, C(O)R, C(O)NR, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 heterocycloalkyl, or C 3~6 C substituted with heteroaryl 3~6 forming a heterocycloalkyl, R 5c is H or C optionally substituted with halo, CN, OH, NH, or OR' 1~6 is alkyl, R' is H or C 1~6 is alkyl, w, x, y, and z are each independently an integer of 0 to 4. In some embodiments, the acid is fumaric acid.

[0057] In one embodiment of this aspect, LG has the structure [ka] and organotriphosphate coupling agents such as T3P® (2,4,6-tripropyl-1,3,5,2,4,6-trioxatritosphinan-2,4,6-trioxide; propylphosphonic anhydride), having the formula:

[0058] 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.

[0059] In one embodiment, the solvent is a mixture of water and an organic solvent.

[0060] In one embodiment, the organic solvent is selected from polar protic and aprotic polar solvents. In one embodiment, the polar protic or aprotic polar 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 an aprotic polar solvent selected from the group consisting of acetone, acetonitrile, dimethylformamide, 1,4-dioxane, and tetrahydrofuran. In yet a further embodiment, the organic solvent is a mixture of water and tetrahydrofuran. In still further embodiments, the mixture is from about 2:1 to about 8:1 tetrahydrofuran:water, or from about 2:1 to about 6:1 tetrahydrofuran:water, or from about 2:1 to about 4:1 tetrahydrofuran:water. In still further embodiments, the mixture is from about 2:1 tetrahydrofuran:water to about 3:1 tetrahydrofuran:water.

[0061] In one embodiment, a solution of a compound of Formula III dissolved in a first solvent is added to a solution of a compound of Formula II dissolved in a second solvent to contact the compound of Formula II with the compound of Formula III to form a reaction mixture.

[0062] In one embodiment, the first solvent is an organic solvent. In a further embodiment, the first solvent is an aprotic polar solvent. In a further embodiment, the first solvent is tetrahydrofuran.

[0063] 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 to about 8:1 tetrahydrofuran:water, or about 2:1 to about 6:1 tetrahydrofuran:water, or about 2:1 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.

[0064] In one embodiment, the compound of Formula III dissolved in a first solvent is added to a solution of a compound of Formula II dissolved in a second solvent over a period 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 a compound of Formula II dissolved in a second solvent over a period of 30 minutes or more.

[0065] In one embodiment, the temperature of the reaction mixture is maintained below about 27°C. In another embodiment, the reaction temperature is maintained between approximately 20-27°C. In another embodiment, the reaction temperature is maintained between approximately 25-27°C. In another embodiment, the reaction temperature is maintained between approximately 20-25°C.

[0066] In one embodiment, the reaction mixture is heated to approximately 35-40° C. and allowed to settle, allowing the organic and aqueous phases to separate.

[0067] In one embodiment, the process further comprises discarding the aqueous phase and heating the organic phase to 45-50°C, and then filtering the organic phase at 45-50°C.

[0068] In another embodiment, the process further comprises discarding the aqueous phase and heating the organic phase to 55-60°C, and then filtering the organic phase at 55-60°C.

[0069] In another embodiment, the process further comprises cooling the organic phase to 20-25°C and adding water to the organic phase to form a second mixture, wherein the volume of water added is about 1.5 to about 2.5 times the volume of the organic phase. In another embodiment, the process further comprises adding water to the organic phase to form a second mixture while maintaining the temperature at 50-55°C.

[0070] In one embodiment, water is added to the organic phase over a period of at least 1 hour, hi another embodiment, water is added to the organic phase over a period of approximately 4 to 4.5 hours.

[0071] 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.

[0072] In one embodiment, LG is Cl.

[0073] In one embodiment, the process comprises providing a compound of formula IV [ka] with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride to produce a compound of formula III [ka] The method further comprises producing [Wherein LG is chlorine.]

[0074] In one embodiment, the reagent is oxalyl chloride.

[0075] In another embodiment, the reaction is carried out in the presence of a catalytic amount of dimethylformamide.

[0076] 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.

[0077] In one embodiment, the reaction is carried out at a temperature of about -5°C to 25°C. In one embodiment, the reaction is carried out at a temperature of about 0° C. to 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° C. to 15° C. In a further embodiment, the reaction is carried out at a temperature of about 10° C. to 15° C. In a further embodiment, the reaction is carried out at a temperature of about 10° C. to 15° C. for 2 to 3 hours.

[0078] In one embodiment, the process comprises providing a compound of formula V [ka] with a compound of formula VI [ka] to form a compound of formula II [ka]

[0023] Further comprising: [Wherein LG' is F, Cl, Br, I, [ka] and -N2 + Selected from.]

[0079] 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 an aprotic polar solvent. In another embodiment, the organic solvent is an aprotic polar solvent selected from acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide (HMPT), tetrahydrofuran, 1,4-dioxane, and dichloromethane. In a further embodiment, the organic solvent is dimethylacetamide.

[0080] 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 hexamethyldisilazide, In a further embodiment, the base is sodium t-pentoxide.

[0081] In one embodiment, the reaction is carried out at a temperature of about 70-90° C. In another embodiment, the reaction is carried out at a temperature of about 75-80° C.

[0082] In one embodiment, the product is isolated by adding water to the reaction mixture and isolating the solid product, such as by filtration.

[0083] In one embodiment, LG' is selected from the group consisting of F, Cl, Br, and [ka] In a further embodiment, LG' is Cl.

[0084] In some embodiments, the compound of Formula I is a compound of Formula Ia, Formula Ib, Formula Ic, or Formula Id [ka] is. [In the formula, R1, R2, R3, R4, R 5a , R 5b , R 5c , w, x, y, and z are as defined herein.]

[0085] In one embodiment of Formula Ia, Ib, Ic, or Id, R is selected from halo, methyl, methoxy, isopropoxy, and cyclopropyl. In one embodiment, w is 0, 1, or 2. In a further embodiment, w is 0.

[0086] In one embodiment of Formula Ia, Ib, Ic, or Id, x is 0.

[0087] In another embodiment of Formula Ia, Ib, Ic, or Id, R3 is F or Cl. In one embodiment, y is 0, 1, or 2. In a further embodiment, y is 0.

[0088] In one embodiment of Formula Ia, Ib, Ic, or Id, R4 is halo or C 1~6 In one embodiment, z is 0 or 1. In a further embodiment, z is 0.

[0089] In one embodiment of Formula Ia, Ib, Ic, or Id, R 5b is H.

[0090] In one embodiment of Formula Ia, Ib, Ic, or Id, R 5a are H, -NH2, -OH, C 1~6 Alkyl, and C 3~6 heterocycloalkyl, C 1~6 Up to three methylene units of the alkyl are optionally and independently replaced by -O- or NR'-; R 5a are optional, OH, C 1~4 Alkyl, and C 3~6 Heterocycloalkyl is substituted with up to three substituents selected from:

[0091] In further embodiments of Formula Ia, Ib, Ic, or Id, R 5ais selected from H, —NH, —OH, methoxy, methyl, ethyl, N-methylazetidin-2-yl, pyrrolidin-2-yl-methyl, oxetan-2-yl-oxy, 2-hydroxyethyloxy, 2,3-dihydroxypropyloxy, oxetan-2-yl, 2-(N-piperidyl)ethyl, 2-(N-morpholino)ethyl, and 2-dimethylaminoethyl. 5a is methyl.

[0092] In one embodiment of Formula Ia, Ib, Ic, or Id, R 5c is H or C optionally substituted with OH or OR' 1~6 In a further embodiment, R 5c is methyl, 2-hydroxyethyl, 2-methoxyethyl, or 2-hydroxypropyl. 5c is methyl.

[0093] In another embodiment of Formula Ia, Ib, Ic, or Id, R 5a and R 5b are, together with the nitrogen to which they are attached, optionally substituted with OH, C 3~6 In a further embodiment, R 5a and R 5b together with the nitrogen to which they are attached to form azetidine or 2-hydroxyazetidine.

[0094] In one embodiment of Formula Ia, Ib, Ic, or Id, R' is H. In another embodiment, R' is C 1~6 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.

[0095] In one aspect, the present invention provides compound 1 [ka] or a pharmaceutically acceptable salt thereof, comprising reacting compound 4 [ka] with a compound of formula III' [ka] in the presence of a solvent and a base, wherein LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and an organotriphosphate compound, and optionally further comprising contacting the compound of Compound 1 with an acid to produce a pharmaceutically acceptable salt of the compound of Compound 1.

[0096] In one embodiment, the base is an inorganic base. In a further embodiment, the base is selected from NaOH, Na2CO3, K2CO3, NaHCO3, and KHCO3. In a still further embodiment, the base is Na2CO3. In a still further embodiment, the base is K2CO3.

[0097] 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 aprotic polar solvent. In one embodiment, the polar protic or aprotic polar solvent is selected from 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 acetone, acetonitrile, dimethylformamide, 1,4-dioxane, and tetrahydrofuran. In a further embodiment, the solvent is a mixture of water and tetrahydrofuran. In yet a further embodiment, the mixture is from approximately 2:1 tetrahydrofuran:water to approximately 3:1 tetrahydrofuran:water.

[0098] In one embodiment, a solution of the compound of formula III' dissolved in a first solvent is added to a solution of compound 4 dissolved in a second solvent to contact compound 4 with the compound of formula III' to form a reaction mixture.

[0099] In one embodiment, the first solvent is an organic solvent. In a further embodiment, the first solvent is an aprotic polar solvent. In a further embodiment, the first solvent is tetrahydrofuran.

[0100] In one embodiment, the second solvent is approximately 2:1 tetrahydrofuran:water.

[0101] In one embodiment, the compound of formula III' dissolved in the first solvent is added to a solution of compound 4 dissolved in the second solvent over a period of about 30 minutes to about 1 hour. 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 30 minutes or more.

[0102] In one embodiment, the temperature of the reaction mixture is maintained at about 20-27°C. In one embodiment, the reaction mixture is maintained at about 25-27°C. In one embodiment, the reaction mixture is maintained below about 27°C. In another embodiment, the reaction temperature is maintained at approximately 20-25°C.

[0103] In another embodiment, the reaction mixture is heated to 35-40° C. and allowed to settle, allowing the reaction mixture to separate into organic and aqueous phases.

[0104] In one embodiment, the process further comprises discarding the aqueous phase and heating the organic phase to 45-50°C, and then filtering the organic phase at 45-50°C.

[0105] In one embodiment, the process further comprises discarding the aqueous phase and heating the organic phase to 55-60°C, and then filtering the organic phase at 55-60°C.

[0106] In another embodiment, the process further comprises cooling the organic phase to 20-25°C and adding water to the organic phase to form a second mixture, wherein the volume of the added water is about 1.5 to about 2.5 times the volume of the organic phase.

[0107] In another embodiment, the process further comprises adding water to the organic phase while maintaining the temperature at 50-55°C to form a second mixture.

[0108] In one embodiment, water is added to the organic phase over a period of at least 1 hour, hi another embodiment, water is added to the organic phase over a period of approximately 4 to 4.5 hours.

[0109] In one embodiment, the second mixture is stirred for at least 12 hours and the product is a solid and is collected, such as by filtration. In another embodiment, the second mixture is stirred for at least 2 hours and the product is collected, such as by filtration.

[0110] In one embodiment, LG is Cl.

[0111] In one embodiment, the process comprises reacting compound 6 [ka] with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride to give compound 7 [ka] The method further comprises producing

[0112] In one embodiment, the reagent is oxalyl chloride.

[0113] In another embodiment, the reaction is carried out in the presence of a catalytic amount of dimethylformamide. .

[0114] In one embodiment, the reaction is carried out in the presence of an organic solvent. In a further embodiment, the organic solvent is tetrahydrofuran.

[0115] 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 approximately 10-15° C. In a further embodiment, the reaction is carried out for 2-3 hours at a temperature of approximately 10-15° C.

[0116] In one embodiment, the process comprises the step of: [ka] is reacted with 4-aminophenol (5) to give compound 4 [ka] The method further comprises producing

[0117] 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 acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide (HMPT), tetrahydrofuran, 1,4-dioxane, and dichloromethane. In yet a further embodiment, the organic solvent is dimethylacetamide.

[0118] 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 hexamethyldisilazide, sodium hexamethyldisilazide, sodium hydroxide, sodium methoxide, sodium t-butoxide, sodium t-pentoxide, lithium hydroxide, lithium methoxide, lithium t-butoxide, lithium t-pentoxide, potassium hydroxide, potassium methoxide, potassium t-butoxide, potassium t-pentoxide, cesium hydroxide, cesium methoxide, cesium t-butoxide, or cesium t-pentoxide.

[0119] In one embodiment, the reaction is carried out at a temperature of 75-80°C.

[0120] In one embodiment, the product is isolated by adding water to the reaction mixture and isolating the solid product.

[0121] In one embodiment, the process comprises reacting compound 1 with fumaric acid to form compound 1-hemifumaric acid. Malate [ka]

[0023] Further comprising:

[0122] In one 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.

[0123] In one embodiment, the alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, pentanol, hexanol, heptanol, and octanol.

[0124] In a further embodiment, the solvent is a 20% solution of ethanol in water.

[0125] In one embodiment, the volume of the 20% aqueous ethanol solution used in the reaction is about 2 to 3 times the weight of Compound 1. In another embodiment, the volume (mL) of the 20% aqueous ethanol solution used in the reaction is about 3 times the weight (grams) of Compound 1.

[0126] In one embodiment, the amount of fumaric acid used is about 0.5 to 1.0 equivalents relative to Compound 1. In another embodiment, the amount of fumaric acid used is about 0.75 to 1.0 equivalents relative to Compound 1. In another embodiment, the amount of fumaric acid used is about 0.8 to 0.82 equivalents relative to Compound 1.

[0127] In one embodiment, compound 1 is reacted with fumaric acid by adding a mixture of fumaric acid dissolved in a 20% aqueous solution of ethanol to compound 1 at 45-50°C to form a reaction mixture.

[0128] In one embodiment, the volume (mL) of the 20% aqueous ethanol solution used to dissolve fumaric acid is about 2 to 3 times the weight (grams) of Compound 1. In another embodiment, the volume of the 20% aqueous ethanol solution used to dissolve fumaric acid is about 2.2 to 2.8 times the weight of Compound 1. In another embodiment, the volume of the 20% aqueous ethanol solution used to dissolve fumaric acid is about 2.4 to 2.6 times the weight of Compound 1.

[0129] In one embodiment, the process further comprises heating the reaction mixture to reflux temperature and stirring. In another embodiment, the refluxing reaction mixture is stirred for 4 to 6 hours.

[0130] In one embodiment, the process further comprises cooling the reaction mixture and separating the solid product from the solvent.

[0131] In another aspect, the present invention provides compound 1 [ka] or a pharmaceutically acceptable salt thereof, comprising reacting compound 3 [ka] is reacted with 4-aminophenol (5) to give compound 4 [ka] and compound 6 [ka] is reacted with thionyl chloride or oxalyl chloride in the presence of a solvent to give compound 7 [ka] and reacting compound 4 with compound 7 to produce compound 1; and optionally further comprising contacting Compound 1 with an acid to produce a pharmaceutically acceptable salt of the compound of Compound 1.

[0132] In another aspect, the present invention provides compound 1 [ka] or a pharmaceutically acceptable salt thereof, comprising reacting compound 3 [ka] is reacted with 4-aminophenol (5) in the presence of a solvent of dimethylacetamide and a base of sodium t-pentoxide at a temperature of 75-80°C to give compound 4 [ka] providing a first reaction mixture comprising: adding water to the first reaction mixture to precipitate and isolate a solid product, Compound 4; compound 6 [ka] is reacted with oxalyl chloride in the presence of tetrahydrofuran as a solvent and dimethylformamide as a catalyst at a temperature of 5-15°C to give compound 7. [ka] forming a second reaction mixture comprising: adding the second reaction mixture to a third reaction mixture comprising a solvent which is approximately 2:1 tetrahydrofuran:water, a base which is NaCO or KCO (preferably KCO), and compound 4 over a period of at least 30 minutes to form a fourth reaction mixture, wherein the temperature of the fourth reaction mixture is maintained below about 27° C. during the addition; heating the fourth reaction mixture to 35-40°C and allowing it to stand to separate the organic and aqueous phases; Discarding the aqueous phase and heating the organic phase to 55-60°C, then filtering the organic phase at 55-60°C; adding water to the organic phase over approximately 4 to 4.5 hours while maintaining a temperature of 50 to 55°C to form a fifth reaction mixture; stirring the fifth reaction mixture for at least 2 hours; and isolating the solid product, which is Compound 1, optionally further comprising contacting Compound 1 with an acid to produce a pharmaceutically acceptable salt of the compound of Compound 1.

[0133] In one embodiment of this aspect, dimethylformamide is present in a catalytic amount.

[0134] In some embodiments of this aspect, the molar ratio of dimethylformamide to 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 volumetric ratio of dimethylformamide to 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 to oxalyl chloride is about 0.001 to about 0.005. In some embodiments, the volume ratio of dimethylformamide to oxalyl chloride is from about 0.001 to about 0.005.

[0135] In other embodiments of this aspect, the molar ratio of dimethylformamide to 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 volumetric ratio of dimethylformamide to 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 to Compound 6 is about 0.001 to about 0.005. In some embodiments, the volume ratio of dimethylformamide to compound 6 is about 0.001 to about 0.005.

[0136] In another aspect, the present invention provides compound 1-hemifumarate. [ka] 1. A process for preparing preparing a reaction mixture by adding a mixture of fumaric acid dissolved in a 20% aqueous solution of ethanol to Compound 1 at 45-50°C; heating the reaction mixture to reflux; stirring the reaction mixture at reflux for 4 to 6 hours; cooling the reaction mixture and isolating the solid product, Compound 1 hemifumarate, from the solvent; and The process includes the above.

[0137] In another aspect, the present invention provides compound 1-hemifumarate. [ka] 1. A process for preparing compound 3 [ka] is reacted with 4-aminophenol (5) to give compound 4 [ka] and compound 6 [ka] is reacted with thionyl chloride or oxalyl chloride in the presence of a solvent to give compound 7 [ka] and reacting compound 4 with compound 7 to produce compound 1; combining Compound 1 with fumaric acid dissolved in a 20% aqueous solution of ethanol to provide Compound 1-hemifumarate; The process includes the above.

[0138] In one embodiment, Compound 1 is reacted with fumaric acid by adding a mixture of fumaric acid dissolved in a 20% aqueous solution of ethanol to Compound 1 at 45-50° C. to form a slurry.

[0139] In one embodiment, the amount of fumaric acid used is about 0.5 to 1.0 equivalents relative to Compound 1. In another embodiment, the amount of fumaric acid used is about 0.75 to 1.0 equivalents relative to Compound 1. In another embodiment, the amount of fumaric acid used is about 0.8 to 0.82 equivalents relative to Compound 1.

[0140] In one embodiment, the volume (mL) of the 20% aqueous ethanol solution used to dissolve fumaric acid is about 2 to 3 times the weight (grams) of Compound 1. In another embodiment, the volume of the 20% aqueous ethanol solution used to dissolve fumaric acid is about 2.2 to 2.8 times the weight of Compound 1. In another embodiment, the volume of the 20% aqueous ethanol solution used to dissolve fumaric acid is about 2.4 to 2.6 times the weight of Compound 1.

[0141] In another aspect, the present invention provides compound 1-hemifumarate. [ka] 1. A process for preparing combining a fumaric acid solution with Compound 1 to form a reaction mixture comprising a slurry; heating the reaction mixture to reflux for a predetermined period of time; Isolating compound 1 hemifumarate as a solid, The process includes the above.

[0142] In one embodiment of this aspect, the combining comprises adding the fumaric acid solution to Compound 1.

[0143] In a further embodiment, fumaric acid is dissolved in a mixture of EtOH and acetone at about 45-50° C. to form a solution.

[0144] In another embodiment, the predetermined period of time is about 1 to 6 hours.

[0145] In another embodiment, the isolating comprises cooling the reaction mixture comprising the slurry, filtering the reaction mixture to obtain a solid, and washing the solid.

[0146] In one aspect, the invention includes a compound having the structure: [ka]

[0147] Consideration The synthetic transformation to produce compound 1 involves two parallel reactions: the formation of compound 7 as an acid chloride, and the formation of compound 1 via an amidation reaction. The formation of acid chloride 7 was found to be rapid and complete after approximately 15 minutes when carried out at ambient temperature. However, at ambient temperature, inconsistencies between batches were found, with some batches containing higher levels of impurities than others. It was further discovered that the production of unwanted by-products was avoided by running the reaction at 10-15°C. At this temperature, the reaction was slower and usually went to completion. This took approximately 2-3 hours, but the impurity levels were controlled and kept to a minimum.

[0148] During the amidation reaction to produce compound 1, the majority of impurities were found to be unreacted compound 4 and various reaction products from side reactions with the acid chloride. It was discovered that using a slightly less than stoichiometric amount of acid chloride in the reaction generally reduced the amount of impurities from the acid chloride side reactions.

[0149] As provided herein, compound 1 was reacted with fumaric acid to produce compound 1-hemifumarate. Due to the low solubility of hemifumarate, polishing filtration, which is typically performed at the API stage to remove any contaminants, was performed in the free base step. To achieve this, a large amount of solvent (50 v / w relative to compound 4) was used. Even with this large amount, product precipitation during aqueous phase removal was observed during scale-up. To resolve this issue, the organic phase was heated to 55-60°C before polishing filtration.

[0150] Salt formation of compound 1 hemifumarate was previously performed in a mixture of THF and water. After polishing and filtration, the THF was exchanged for IPA. However, the crystalline product was found to still contain high levels of THF. Attempts to remove the THF by high-temperature trituration in solvent and vacuum drying at elevated temperatures were unsuccessful. To attempt to correct this problem, MEK and IPA were used as solvents for salt formation, respectively. These attempts were unsuccessful because MEK and IPA replaced THF in the crystal lattice and formed the corresponding solvates.

[0151] It was recognized that when the salt was formed in solution, a solvate was obtained when THF was incorporated into the crystalline product, which could not be removed by drying under vacuum, even at 60-80° C. Attempts to remove residual THF by suspending the salt in refluxing IPA were also unsuccessful.

[0152] Our studies suggested that salts could be formed from slurries of the free base of compound 1. We further discovered that suspension salt formation could be carried out using ACN, IPA, or EtOH, provided the reaction temperature was above 70°C. The conversion under these slurry conditions was slow (more than 10 hours), likely due to the low solubility of the free base in the medium. An advantage of the suspension reaction was that the crystalline product contained minimal amounts of solvent (no solvate formation was observed). By observing the integral ratio of the fumaric acid peak at δ 6.64 ppm (corresponding to two protons) compared to the aromatic peak of compound 1 at δ 6.47 ppm (corresponding to one proton), 1 H NMR (dDMSO) was used to monitor the conversion of the free base to the hemifumarate salt, with complete conversion showing these two signals in a 1:1 ratio.

[0153] It was discovered that the conversion was faster in the presence of an aqueous solution of EtOH. Thus, in an alternative example, the reaction in 10% aqueous EtOH was complete after 5 hours at 62-65°C. The yields obtained were 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 and allow for polishing filtration 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. Higher temperatures (40-45°C) were also used to dissolve the fumaric acid, which allowed the acid to dissolve in a 20% aqueous solution of EtOH (2.48 volumes) compared to compound 1. Therefore, by using a 20% aqueous solution of EtOH in a volume 2-3 times (or 2.2-2.8 times, or 2.4-2.6 times) the weight of compound 1 to dissolve compound 1, the yield of compound 1 hemifumarate was approximately 58% (using pure ethanol) or 60% (using pure ethanol). It was surprising to discover that the purity of the product was greater than 99% by UPLC, with the yield improving significantly from 0.01% to over 95% (97%). No solvate formation was observed. The table below summarizes the solvents used to dissolve fumaric acid and the corresponding yields. [Table 2]

[0154] The invention will now be illustrated by the following non-limiting examples. [Example]

[0155] [Table 3]

[0156] Scheme 1: Process for preparing Compound 1 and Compound 1 hemifumarate [ka]

[0157] Example 1: Synthesis of 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide (3) [ka]

[0158] To a suspension of methyl 4-chloro-7-methoxyquinoline-6-carboxylate 2 (2 g, 8 mmol) in THF (20 mL) was added a solution of methylamine in EtOH (33% w / w, 8 M, 20 mL, 160 mmol) and HO (10 mL). The resulting mixture was stirred at room temperature. The mixture became a clear solution in approximately 10 minutes and remained a clear solution throughout the reaction. Stirring was continued until the starting material was completely consumed as determined by LCMS and HPLC, which took approximately 3 hours. The mixture was then concentrated, and the residue was slurried in 20 mL of water and filtered. Some EtOAc was used to transfer the material from the flask to a filter funnel. 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%).

[0159] Example 2: 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6- Synthesis of carboxamide (4) [ka]

[0160] A 5 L three-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 equiv.), 4-aminophenol (5; 195.9 g, 1.5 equiv.), and DMA (1500 mL). The resulting solution was stirred at room temperature, and a solution of sodium tert-pentoxide (184.52 g, 1.4 equiv.) dissolved in anhydrous THF (313 mL) was added with stirring for 5 minutes. 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, charged with water (3 L), and stirred for at least an additional hour. The product was filtered and washed twice with 600 mL of 1:1 DMA / water, followed by one 1200 mL water wash. The product was transferred to a crystallizing dish and dried in a vacuum oven at 40-45°C for a minimum of 18 hours to give a light brown glossy solid (370-377g, 96-97%).

[0161] Example 3A: Synthesis of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (7) [ka]

[0162] A 250 mL three-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 equiv.), 75 mL of anhydrous THF, and 0.25 mL of DMF (catalyst). The mixture was stirred and cooled to 5-10 °C until all solids dissolved, after which oxalyl chloride (7.13 mL, 1.28 equiv.) was charged. The resulting mixture was aged at 10-15 °C for 2-3 hours, and completion of the reaction was confirmed by IPC (in process control). Upon completion of the reaction, the resulting product mixture was used in the next step without further purification.

[0163] Example 3B: Synthesis of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (7) [Alternative Method] [ka]

[0164] A 250 mL three-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 equiv.), 75 mL of anhydrous THF, and 0.25 mL of DMF (catalyst). The mixture was stirred until all solids dissolved and cooled to 5-15 °C, after which oxalyl chloride (7.13 mL, 1.28 equiv.) was charged. The resulting mixture was allowed to warm to room temperature and stirred for 2-4 h. The resulting product mixture was used in the next step without further purification.

[0165] Example 4A: Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1) [ka]

[0166] A 500 mL three-neck 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 consisting of potassium carbonate (27.32 g, 3 equiv.) and 100 mL of water. The added aqueous K2CO3 solution was washed down with an additional 6.4 mL of water. With vigorous agitation, the reaction mixture containing compound 7 from the previous example was transferred to this reaction mixture over 30 min, maintaining the internal temperature at 20–25 °C. The transfer apparatus was rinsed with 32 mL of anhydrous THF. The reaction mixture was agitated at ambient temperature for 0.5–1 h. 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 55-60°C, then polish-filtered and rinsed with 21 mL of THF. The filtered organic phase was transferred to a 1 L three-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and mechanical stirring and charged with water at 55-60°C. Compound 1 was added to the resulting solution, and water was added as an antisolvent to the resulting seed bed over 4-4.5 hours, maintaining the temperature at 50-55°C. The resulting slurry was cooled to 20-25°C and aged for at least 2 hours. The product was then filtered, washed with water / THF, and dried.

[0167] Example 4B: Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1) [Alternative Method] [ka]

[0168] A 500 mL three-neck 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 consisting of potassium carbonate (27.32 g, 3 equiv.) and 100 mL of water. The added aqueous K2CO3 solution was washed down with an additional 6.4 mL of water. With vigorous agitation, the reaction mixture containing compound 7 from the previous example was transferred to this reaction mixture over 0.5–1 h, maintaining the internal temperature below 27 °C. The transfer apparatus was rinsed with 32 mL of anhydrous THF. The reaction mixture was agitated at ambient temperature for 0.5–1 h. 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, then filtered through a filter paper, rinsing with 21 mL of THF. The filtered organic phase was transferred to a 1 L, three-necked, round-bottom flask equipped with a thermometer, nitrogen inlet, and mechanical stirring, and charged with 694 mL of filtrate over a minimum of 1 hour. The resulting mixture was stirred at 20-25°C for a minimum of 12 hours, after which the product was filtered and rinsed twice with 42 mL of a 2:1 water:THF mixture. The product was then dried on the 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%).

[0169] 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 [ka]

[0170] A 2000 mL three-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with fumaric acid (80 g; 0.82 equiv.) and 1.2 L of a 20% aqueous solution of ethanol. The mixture was heated to 45-50 °C and stirred until all solids dissolved. A separate 3 L three-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 equiv.). The fumaric acid solution was clarified through a filter paper at 40-45 °C and transferred to the flask containing compound 1 at 40-45 °C. A 100 mL round-bottom flask was rinsed with 300 mL of 20% aqueous ethanol 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, the product was filtered, and the filter cake was washed twice with 300 mL of 20% aqueous ethanol. The product was then dried on the 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%).

[0171] 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 [ka]

[0172] Fumaric acid (2.68 g, 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 one-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. Seeds were added (2% seed, 0.244 g), and the vessel was heated to reflux (-65 °C). After 1 h, 0.5 mL of the slurry was filtered, washed with EtOH (6 × 1.5 mL), and analyzed by HPLC to determine the fumaric acid content (the result should be approximately 10%). The slurry was then cooled to 25 °C over 1 h and stirred for an additional 1 h. The solid was then filtered, washed with 1:1 EtOH / acetone (2 x 3V) and dried under vacuum at 25°C over the 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 2.840 (d, 3H, 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 19F NMR 700 MHz (DMSO-d6; reference trifluorotoluene at -63.72 ppm) δ -121.460. 13 13C 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 15N 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 ( 15 N).

[0173] Other embodiments The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the invention. It will be apparent to those skilled in the art that changes and modifications can be practiced within the scope of the appended claims. It is therefore to be understood that the foregoing is intended to be illustrative and not restrictive.

[0174] Therefore, the scope of the invention should be determined not with reference to the above, but rather should be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. The present invention provides, for example, the following items. (Item 1) Compounds of Formula I [ka] or a pharmaceutically acceptable salt thereof, comprising: [ka] with a compound of formula III [ka] in the presence of a solvent and a base, said process optionally further comprising contacting the compound of formula I with an acid to form a pharmaceutically acceptable salt of the compound of formula I, wherein LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and organotriphosphate compounds; R1 is halo, C 1~6 Alkyl, C 1~6 Alkoxy, and C 3~6 cycloalkyl; R2 and R3 are each independently halo and C 1~6 alkyl, R4 is halo, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, phenyl, and C 3~6 heteroaryl; R 5a are H, OH, NH2, C 1~8 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, phenyl, and C 3~6 heteroaryl, wherein C 1~8 Up to three methylene units of the alkyl are optionally and independently replaced by -O-, -NR'-, -C(O)-, -C(O)O-, and -C(O)NR'-; R 5a is optional and includes halo, CN, 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 substituted with up to three substituents selected from heteroaryl; R 5b is H or C 1~6 alkyl, or R 5a and R 5b together with the nitrogen to which they are attached, optionally halo, CN, OH, NO, NH, SH, OR, C(O)OR, C(O)R, C(O)NR, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 heterocycloalkyl, or C 3~6 C substituted with heteroaryl 3~6 forming a heterocycloalkyl, R 5c is H or C optionally substituted with halo, CN, OH, NH, or OR' 1~6 is alkyl, R' is H or C 1~6 is alkyl, w, x, y, and z are each independently an integer of 0 to 4. (Item 2) 2. The process according to item 1, wherein the base is an inorganic base. (Item 3) 3. The process of claim 1 or 2, wherein the base is selected from NaOH, Na2CO3, K2CO3, NaHCO3, and KHCO3. (Item 4) 4. The process according to any one of items 1 to 3, wherein the base is K2CO3. (Item 5) 5. The process according to any one of items 1 to 4, wherein the solvent is a mixture of water and an organic solvent. (Item 6) The organic solvent may be acetone, acetonitrile, butanediol, dimethylformamide, dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethylene 6. The process according to item 5, wherein the alkyl group is selected from the group consisting of 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. (Item 7) 7. The process according to item 6, wherein the organic solvent is selected from acetone, acetonitrile, dimethylformamide, 1,4-dioxane, and tetrahydrofuran. (Item 8) 8. The process according to any one of items 5 to 7, wherein the solvent is a mixture of water and tetrahydrofuran. (Item 9) 9. The process of any one of items 8, wherein the mixture is from about 2:1 tetrahydrofuran:water to about 3:1 tetrahydrofuran:water. (Item 10) 10. The process of any one of items 1 to 9, wherein contacting the compound of formula II with the compound of formula III comprises 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 form a reaction mixture. (Item 11) 11. The process of claim 10, wherein the first solvent is an organic solvent. (Item 12) Item 12. The process of item 11, wherein the first solvent is tetrahydrofuran. (Item 13) 11. The process of claim 10, wherein the second solvent is approximately 2:1 tetrahydrofuran:water. (Item 14) Item 11. The process according to item 10, wherein 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 at least 30 minutes. (Item 15) Item 11. The process of item 10, wherein the reaction mixture is maintained at a temperature of approximately 20 to 25°C. (Item 16) Item 11. The process according to item 10, wherein the reaction mixture is heated to 35-40°C and allowed to stand to separate into an organic phase and an aqueous phase. (Item 17) 17. The process of claim 16, further comprising discarding the aqueous phase and heating the organic phase to 55-60°C, and then filtering the organic phase at 55-60°C. (Item 18) 18. The process of claim 17, further comprising adding water to the organic phase while maintaining the temperature at 50-55°C to form a second mixture. (Item 19) 19. The process of claim 18, wherein the water is added to the organic phase over a period of at least 1 hour. (Item 20) 20. The process of claim 19, wherein the second mixture is stirred for at least 12 hours to obtain a solid product. (Item 21) 21. The process of any one of items 1 to 20, wherein LG is Cl. (Item 22) Compound of Formula IV [ka] with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride to obtain the compound of formula III [ka] 23. The process of claim 21, further comprising forming a compound of formula (I) wherein LG is Cl. 23. The process of claim 22, wherein the reagent is oxalyl chloride. (Item 24) 24. The process according to item 23, wherein reacting the compound of formula IV with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride is carried out in the presence of a catalytic amount of dimethylformamide. (Item 25) 25. The process according to any one of items 22 to 24, wherein reacting the compound of formula IV with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride is carried out in the presence of an organic solvent. (Item 26) 26. The process of claim 25, wherein the organic solvent is tetrahydrofuran. (Item 27) 27. The process according to any one of items 22 to 26, wherein reacting the compound of formula IV with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride is carried out at a temperature of 15°C or less. (Item 28) 28. The process according to any one of items 22 to 27, wherein reacting the compound of formula IV with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride is carried out at a temperature of 5 to 15°C. (Item 29) Compound of Formula V [ka] with a compound of formula VI [ka] By reacting with the compound of formula II [ka] wherein LG′ is F, Cl, Br, I, [ka] and -N2 + 29. The process according to any one of items 1 to 28, wherein the process is selected from the group consisting of (Item 30) 30. The process of claim 29, wherein reacting the compound of formula V with the compound of formula VI is carried out in the presence of a solvent. (Item 31) 31. The process of claim 30, wherein the solvent is an organic solvent. (Item 32) 32. The process according to item 31, wherein the organic solvent is selected from acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide (HMPT), tetrahydrofuran, 1,4-dioxane, and dichloromethane. (Item 33) 33. The process of claim 32, wherein the organic solvent is dimethylacetamide. (Item 34) 34. The process according to any one of items 29 to 33, wherein the reaction is carried out in the presence of a base. (Item 35) 35. The process of claim 34, wherein the base is n-BuLi, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, sodium hydroxide, sodium methoxide, sodium t-butoxide, sodium t-pentoxide, lithium hydroxide, lithium methoxide, lithium t-butoxide, lithium t-pentoxide, potassium hydroxide, potassium methoxide, potassium t-butoxide, potassium t-pentoxide, cesium hydroxide, cesium methoxide, cesium t-butoxide, or cesium t-pentoxide. (Item 36) 36. The process of claim 35, wherein the base is sodium t-pentoxide. (Item 37) 37. The process of any one of items 29 to 36, wherein reacting the compound of formula V with the compound of formula VI is carried out at a temperature of 75 to 80°C. (Item 38) 38. The process of any one of items 29 to 37, wherein the compound of formula II is isolated by adding water to the reaction mixture and isolating the solid compound of formula II. (Item 39) LG' is F, Cl, Br, and [ka] 39. The process according to any one of items 29 to 38, wherein the process is selected from the group consisting of: (Item 40) Item 39. The process of item 39, wherein LG′ is Cl. (Item 41) 41. The process according to any one of items 1 to 40, wherein R1 is selected from halo, methyl, methoxy, isopropoxy, and cyclopropyl. (Item 42) 42. The process of any one of items 1 to 41, wherein w is 0, 1, or 2. (Item 43) Item 43. The process of item 42, wherein w is 0. (Item 44) 44. The process according to any one of items 1 to 43, wherein x is 0. (Item 45) 45. The process according to any one of items 1 to 44, wherein R3 is F or Cl. (Item 46) 46. ​​The process of any one of items 1 to 45, wherein y is 0, 1, or 2. (Item 47) Item 47. The process of item 46, wherein y is 0. (Item 48) R4 is halo or C 1~648. The process according to any one of items 1 to 47, wherein the alkyl is alkyl. (Item 49) 49. The process according to any one of items 1 to 48, wherein z is 0 or 1. (Item 50) Item 49. The process of item 49, wherein z is 0. (Item 51) R 5b 51. The process according to any one of items 1 to 50, wherein (Item 52) R 5a H, -NH2, -OH, C 1~6 Alkyl, and C 3~6 heterocycloalkyl, wherein C 1~6 Up to three methylene units of the alkyl are optionally and independently replaced by -O- or NR'-; R 5a are optional, OH, C 1~4 Alkyl, and C 3~6 52. The process according to any one of items 1 to 51, wherein the heterocycloalkyl is substituted with up to three substituents selected from heterocycloalkyl. (Item 53) R 5a is selected from H, -NH2, -OH, methoxy, methyl, ethyl, N-methylazetidin-2-yl, pyrrolidin-2-yl-methyl, oxetan-2-yl-oxy, 2-hydroxyethyloxy, 2,3-dihydroxypropyloxy, oxetan-2-yl, 2-(N-piperidyl)ethyl, 2-(N-morpholino)ethyl, and 2-dimethylaminoethyl. (Item 54) R 5a Item 54. The process of item 53, wherein is methyl. (Item 55) R 5c is H or C optionally substituted with OR' 1~6 55. The process according to any one of items 1 to 54, wherein the alkyl is alkyl. (Item 56) R 5c56. The process of claim 55, wherein is methyl, 2-hydroxyethyl, 2-methoxyethyl, or 2-hydroxypropyl. (Item 57) R 5c 57. The process of claim 56, wherein is methyl. (Item 58) R 5a and R 5b together with the nitrogen to which they are attached, optionally substituted with OH, C 3~6 51. The process according to any one of items 1 to 50, wherein a heterocycloalkyl is formed. (Item 59) R 5a and R 5b together with the nitrogen to which they are attached to form azetidine or 2-hydroxyazetidine. (Item 60) compound 1 [ka] or a pharmaceutically acceptable salt thereof, comprising reacting compound 4 [ka] with a compound of formula III' [ka] in the presence of a solvent and a base, wherein LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and an organotriphosphate compound, and the process optionally further comprises contacting the compound of Compound 1 with an acid to produce a pharmaceutically acceptable salt of the compound of Compound 1. (Item 61) 61. The process according to item 60, wherein the base is an inorganic base. (Item 62) 62. The process according to item 60 or 61, wherein the base is selected from NaOH, Na2CO3, K2CO3, NaHCO3, and KHCO3. (Item 63) 63. The process of any one of items 60 to 62, wherein the base is K2CO3. (Item 64) 64. The process according to any one of items 60 to 63, wherein the solvent is a mixture of water and an organic solvent. (Item 65) The organic solvent is acetone, acetonitrile, butanediol, dimethylformamide 65. The process according to item 64, wherein the solvent is selected from the group consisting of 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. (Item 66) Item 66. The process according to item 65, wherein the organic solvent is selected from acetone, acetonitrile, dimethylformamide, 1,4-dioxane, and tetrahydrofuran. (Item 67) 67. The process of any one of items 64 to 66, wherein the solvent is a mixture of water and tetrahydrofuran. (Item 68) 68. The process of any one of items 64 to 67, wherein the mixture is from about 2:1 tetrahydrofuran:water to about 3:1 tetrahydrofuran:water. (Item 69) 69. The process of any one of items 60 to 68, wherein contacting compound 4 with the compound of formula III' comprises 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 form a reaction mixture. (Item 70) 70. The process of claim 69, wherein the first solvent is an organic solvent. (Item 71) 71. The process of claim 70, wherein the first solvent is tetrahydrofuran. (Item 72) 70. The process of claim 69, wherein the second solvent is approximately 2:1 tetrahydrofuran:water. (Item 73) 70. The process of claim 69, wherein the compound of formula III' dissolved in a first solvent is added to a solution of compound 4 dissolved in a second solvent over a period of at least 30 minutes. (Item 74) 70. The process of claim 69, wherein the temperature of the reaction mixture is maintained at approximately 20-25°C. (Item 75) 70. The process according to item 69, wherein the reaction mixture is heated to 35-40°C and allowed to stand to separate into an organic phase and an aqueous phase. (Item 76) 76. The process of claim 75, further comprising discarding the aqueous phase and heating the organic phase to 55-60°C, and then filtering the organic phase at 55-60°C. (Item 77) 77. The process of claim 76, wherein water is further added to the organic phase while maintaining the temperature at 50-55°C to form a second mixture. (Item 78) 78. The process of claim 77, wherein the water is added to the organic phase over a period of at least 1 hour. (Item 79) 79. The process of claim 78, wherein the second mixture is stirred for at least 2 hours to obtain a solid product. (Item 80) 80. The process of any one of items 60 to 79, wherein LG is Cl. (Item 81) compound 6 [ka] with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride to give compound 7 [ka] 81. The process of claim 80, further comprising making (Item 82) 82. The process of claim 81, wherein the reagent is oxalyl chloride. (Item 83) 83. The process of claim 82, wherein the reaction is carried out in the presence of a catalytic amount of dimethylformamide. (Item 84) 84. The process according to any one of items 81 to 83, wherein reacting compound 6 with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride is carried out in the presence of an organic solvent. (Item 85) 85. The process of claim 84, wherein the organic solvent is tetrahydrofuran. (Item 86) 86. The process according to any one of items 81 to 85, wherein the reacting of compound 6 with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride is carried out at a temperature of 15°C or less. (Item 87) 87. The process according to any one of items 81 to 86, wherein the reacting of compound 6 with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride is carried out at a temperature of 5 to 15°C. (Item 88) compound 3 [ka] is reacted with 4-aminophenol (5) to give compound 4 [ka] 88. The process of any one of items 60 to 87, further comprising providing: (Item 89) 89. The process according to item 88, wherein reacting compound 3 with 4-aminophenol (5) is carried out in the presence of a solvent. (Item 90) Item 89. The process of item 89, wherein the solvent is an organic solvent. (Item 91) 91. The process of claim 90, wherein the organic solvent is selected from acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide (HMPT), tetrahydrofuran, 1,4-dioxane, and dichloromethane. (Item 92) 92. The process of claim 91, wherein the organic solvent is dimethylacetamide. (Item 93) 93. The process according to any one of items 88 to 92, wherein reacting compound 3 with 4-aminophenol (5) is carried out in the presence of a base. (Item 94) Item 94. The process of item 93, wherein the base is n-BuLi, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, sodium hydroxide, sodium methoxide, sodium t-butoxide, sodium t-pentoxide, lithium hydroxide, lithium methoxide, lithium t-butoxide, lithium t-pentoxide, potassium hydroxide, potassium methoxide, potassium t-butoxide, potassium t-pentoxide, cesium hydroxide, cesium methoxide, cesium t-butoxide, or cesium t-pentoxide. (Item 95) Item 95. The process of item 94, wherein the base is sodium t-pentoxide. (Item 96) The reaction of compound 3 with 4-aminophenol (5) can be carried out at a temperature of 75-80°C. 96. The process according to any one of items 88 to 95, (Item 97) 97. The process of any one of items 88 to 96, further comprising adding water to the reaction mixture and isolating compound 4 as a solid. (Item 98) Compound 1 was reacted with fumaric acid to give compound 1-hemifumarate [ka] 98. The process of any one of items 60 to 97, further comprising: (Item 99) Item 99. The process according to item 98, wherein reacting compound 1 with fumaric acid is carried out in the presence of a solvent. (Item 100) Item 99. The process of item 99, wherein the solvent is selected from water, alcohol solvents, THF, DMF, MEK, acetonitrile, 1,4-dioxane, and MTBE, or any combination thereof. (Item 101) Item 102. The process of item 100, wherein the solvent is a mixture of water and an alcohol solvent. 102. The process of claim 101, wherein the alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, pentanol, hexanol, heptanol, and octanol. (Item 103) 102. The process of claim 101, wherein the solvent is a 20% aqueous solution of ethanol. (Item 104) 104. The process according to any one of items 98 to 103, wherein reacting compound 1 with fumaric acid comprises adding a mixture of fumaric acid dissolved in a solvent of 20% aqueous ethanol to compound 1 at 45 to 50°C to form a reaction mixture. (Item 105) Item 105. The process of item 104, further comprising heating the reaction mixture to reflux and stirring the reaction mixture. (Item 106) Item 107. The process according to Item 105, wherein the reaction mixture is stirred at reflux for 4 to 6 hours. 107. The process of claim 106, further comprising cooling the reaction mixture and isolating compound 1-hemifumarate from the solvent. (Item 108) compound 1 [ka] or a pharmaceutically acceptable salt thereof, comprising reacting compound 3 [ka] is reacted with 4-aminophenol (5) in the presence of dimethylacetamide and sodium t-pentoxide at a temperature of 75-80°C to give compound 4 [ka] providing a first reaction mixture comprising: adding water to the first reaction mixture to precipitate and isolate compound 4 as a solid; compound 6 [ka] is reacted with oxalyl chloride in the presence of tetrahydrofuran and a catalytic amount of dimethylformamide at a temperature of 5 to 15°C to give compound 7. [ka] forming a second reaction mixture comprising: adding the second reaction mixture to a third reaction mixture comprising a solvent of approximately 2:1 tetrahydrofuran:water, a base of KCO, and Compound 4 over a period of at least 30 minutes to form a fourth reaction mixture, wherein the temperature of the fourth reaction mixture is maintained below about 27° C. during the addition; heating the fourth reaction mixture to 35-40°C and allowing it to stand to separate into an organic phase and an aqueous phase; discarding the aqueous phase and heating the organic phase to 55-60°C, and then filtering the organic phase at 55-60°C; adding water to the organic phase over a period of at least one hour to form a fifth reaction mixture; stirring the fifth reaction mixture for at least 2 hours; and isolating Compound 1 as a solid product, the process optionally further comprising contacting the compound of Compound 1 with an acid to produce a pharmaceutically acceptable salt of the compound of Compound 1. (Item 109) Compound 1-hemifumarate [ka] A process for preparing preparing a reaction mixture by adding a mixture of fumaric acid dissolved in a solvent of 20% aqueous ethanol to Compound 1 at 45-50°C; heating the reaction mixture to reflux; stirring the reaction mixture at reflux for 4 to 6 hours; cooling the reaction mixture; filtering the reaction mixture to obtain Compound 1 hemifumarate as a solid; The process comprising: (Item 110) Compound 1-hemifumarate [ka] 1. A process for preparing combining a fumaric acid solution with Compound 1 to form a reaction mixture comprising a slurry; heating the reaction mixture to reflux for a predetermined period of time; Isolating compound 1 hemifumarate as a solid, The process comprising: (Item 111) 111. The process of claim 110, wherein combining comprises adding the fumaric acid solution to compound 1. (Item 112) Item 111. The process according to item 110, wherein fumaric acid is dissolved in a mixed solvent of EtOH and acetone at about 45-50°C to form the fumaric acid solution. (Item 113) Item 111. The process according to item 110, wherein the predetermined time is about 1 to 6 hours. (Item 114) Item 111. The process of item 110, wherein isolating comprises cooling the reaction mixture containing the slurry, filtering the reaction mixture to obtain a solid, and washing the solid.

Claims

[Claim 1] The invention described in the specification.

Images