Manufacturing process of kinase inhibitors

Abstract

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

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims priority to U.S. provisional application serial number 63 / 017,739 filed on April 30, 2020. The entire contents of said application are incorporated herein by reference.

[0003] Field of invention

[0004] The present invention relates to a process for manufacturing a c-Met inhibitor of Formula I, or a pharmaceutically acceptable salt thereof. The present invention further relates to a process for manufacturing a c-Met inhibitor, Compound 1, or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for the synthesis of Compound 1·hemifumarate. The present invention further relates to a large-scale synthesis process for manufacturing a c-Met inhibitor, Compound 1, and Compound 1·hemifumarate. Background Technology

[0005] 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 composed of two immunoglobulin-like domains and two fibronectin type III domains. Axl is overexpressed in numerous tumor cell types and was initially cloned from patients with chronic myeloid leukemia. When overexpressed, Axl exhibits transformability. Axl signaling is believed to induce tumor growth through the activation of proliferative and anti-apoptotic signaling pathways. Axl is associated with cancers such as lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, glioma, melanoma, thyroid cancer, renal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer. Overexpression of Axl leads to a poor prognosis in patients with the aforementioned cancers.

[0006] Activation of Mers, such as Axl, transmits downstream signaling pathways that induce tumor growth and activation. Mers bind to ligands such as the soluble protein Gas-6. Gas-6 binding to Mers induces autophosphorylation of Mers on their intracellular domains, leading to downstream signal activation. Overexpression of Mers in cancer cells increases metastasis, most potently through the production of soluble Mer extracellular domain proteins acting as attractant receptors. Tumor cells secrete soluble forms of extracellular Mer receptors, reducing the ability of soluble Gas-6 ligands to activate Mers in endothelial cells, thereby causing cancer progression.

[0007] Therefore, for the treatment of selected cancers, compounds that inhibit TAM receptor tyrosine kinases, such as Axl and Mer, and methods for producing compounds with high yield and purity are required.

[0008] Summary of the Invention

[0009] In one aspect, the present invention relates to a compound of Formula I.

[0010] ,

[0011] Formula I

[0012] or includes a process for manufacturing a pharmaceutically acceptable salt thereof, wherein the process comprises a compound of Formula II

[0013]

[0014] Formula II

[0015] compound of Formula III

[0016]

[0017] Formula III

[0018] It includes a step of contacting in the presence of a solvent and a base, wherein

[0019] LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and organotriphosphate compounds;

[0020] R1 is Halo, C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 Selected from cycloalkyl;

[0021] R2 and R3 are halo and C, respectively. 1-6 Independently selected from alkyls;

[0022] R4 is Halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, phenyl, and C 3-6 Selected from heteroaryls;

[0023] R 5a is H, -NH2, -OH, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, phenyl, and C 3-6 Selected from heteroaryls, where unit C 1-8 Up to three methylene groups of the alkyl group are optionally and independently replaced with -O-, NR'-, -C(O)-, -C(O)O-, and -C(O)NR'-, where R 5a is 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 Randomly substituted with up to three substituents selected from heteroaryls;

[0024] R 5b is H or C 1-6 alkyl; or

[0025] R 5a and R 5btogether with the nitrogen to which they are attached, 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, or C 3-6 C arbitrarily substituted with a heteroaryl 3-6 Forming a heterocycloalkyl;

[0026] R 5c is C arbitrarily substituted with H or halo, CN, OH, NH2, or OR' 1-6 Alkyl;

[0027] R' is H or C 1-6 alkyl, and

[0028] w, x, y, and z are each independently integers 0 to 4;

[0029] and the process optionally further includes the step of contacting the compound of Formula I with an acid to produce a pharmaceutically acceptable salt of the compound of Formula I.

[0030] In another aspect, the present invention relates to compound 1 (N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide):

[0031] ,

[0032] Compound 1

[0033] or includes a process for preparing a pharmaceutically acceptable salt thereof, wherein the process comprises compound 4

[0034]

[0035] compound of Formula III'

[0036]

[0037] Formula III'

[0038] The process comprises the step of contacting in the presence of a solvent and a base, wherein LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and organotriphosphate compounds, and wherein the process optionally further comprises the step of contacting a compound of compound 1 with an acid to prepare a pharmaceutically acceptable salt of compound 1.

[0039] Small molecule compounds that specifically inhibit, regulate, and / or modulate the signaling of TAM kinases such as the aforementioned Axl and Mer are particularly desirable as means for treating or preventing disease 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 full contents of which are incorporated herein by reference. Additionally, PCT / US2019 / 015297 discloses a separate, unrelated synthesis process for Compound 1 (see Example 4). A separate, 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 full contents of which are also incorporated herein by reference. The present disclosure provides an improved method for producing compound 1 and compound 1·hemifumarate obtained with surprisingly high yield and purity. Specific details for implementing the invention

[0040] Detailed description of the invention

[0041] Definitions and Abbreviations

[0042] menstruum

[0043]

[0044] As used in this specification, the following definitions apply unless otherwise indicated.

[0045] For the purposes of the present invention, chemical elements are identified from the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 95th Ed. Additionally, the general principles of organic chemistry are from "Organic Chemistry," 2 nd Ed., Thomas Sorrell, University Science Books, Sausalito: 2006, and described in "March's Advanced Organic Chemistry," 7th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2013, the full content of which is incorporated herein by reference.

[0046] As used herein, the term “about” or “approximately” or “approximately” includes (and describes) embodiments relating to the value or parameter itself. In certain embodiments, the term “about” or “approximately” or “approximately” includes the indicated amount ± 10%. In other embodiments, the term “about” or “approximately” or “approximately” includes the indicated amount ± 5%. In certain other embodiments, the term “about” or “approximately” or “approximately” includes the indicated amount ± 1%.

[0047] As used herein, the term “slurry” refers to a suspension prepared by adding a sufficient amount of solid to a given solvent under ambient conditions such that undissolved solid is present. A typical slurry involves stirring (typically by stirring or vibration), also known as “slurrying,” in a sealed vial at a given temperature for an extended period. Typically, the solid is recovered after a given period using the method described herein.

[0048] The phrase "pharmaceuticalally acceptable" is used herein to refer to compounds, substances, compositions, and / or preparations suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, within sound medical judgment and according to a reasonable benefit-risk ratio.

[0049] As used herein, the term “catalyst amount” means an amount less than the stoichiometric equivalent of the limiting reagent. In some embodiments, the catalyst amount is much less than the stoichiometric equivalent of the limiting reagent, for example, 0 to 5 wt%, 0 to 4 wt%, 0 to 3 wt%, 0 to 2 wt%, 0 to 1 wt%, 0 to 0.9 wt%, 0 to 0.8 wt%, 0 to 0.7 wt%, 0 to 0.6 wt%, 0 to 0.5 wt%, 0 to 0.4 wt% of the stoichiometric amount of the limiting reagent, 0 to 0.3 wt%, 0 to 0.2 wt%, 0 to 0.1 wt%, 0 to 0.05 wt%, and 0 to 0.01 wt% of the stoichiometric amount of the limiting reagent.

[0050] In general, the nomenclature used in this application is based on the nomenclature rules adopted by the International Union of Pure and Applied Chemistry (IUPAC). The chemical structures depicted herein were fabricated using CHEMDRAW®. Here, open valence appearing on carbon, oxygen, or nitrogen atoms within the structure indicates the presence of a hydrogen atom.

[0051] The symbol "-" signifies a single combination, and "=" signifies a double combination.

[0052] The single forms "a," "an," and "the" used herein include plural references unless the context clearly indicates otherwise.

[0053] When the variable is generally defined, with many possible substituents, each individual radical can be defined with or without bonding. For example, R z If this could be hydrogen, then this is R z of In the definition, it can be represented as "-H" or "H".

[0054] When a chemical structure is illustrated or described, it is assumed that all carbons have hydrogen substitutions to match a valence of 4, unless explicitly stated otherwise. For example, in the structure on the left side of the schematic diagram below, 9 hydrogens are implied. In the structure on the right, 9 hydrogens are illustrated. Often, specific atoms within a structure are described in the chemical formula in the text as having hydrogen or hydrogens (clearly defined hydrogens) as substitutions, for example, as -CH2CH2-. Those skilled in the field understand that the above descriptive descriptions are common in chemistry to provide brevity and simplicity to complex structures.

[0055]

[0056] For example, if the group "R" in the following chemical formula is plotted as a "floating" on a ring system:

[0057]

[0058] Then, unless otherwise defined, the substituent "R" may exist on any atom of the ring system as long as a stable structure is formed, and presumes the substitution of a hydrogen shown, implied, or explicitly defined from one of the ring constituent atoms.

[0059] For example, if the group "R" in the chemical formula is depicted as a "floating" on a fused ring system:

[0060] , , and

[0061] Then, unless otherwise defined, the substituent "R" may exist on any atom of the ring system as long as a stable structure is formed, and presumes the substitution of one of the ring constituent atoms of the illustrated hydrogen (e.g., -NH- in the above formula), implied hydrogen (e.g., in the above formula, where hydrogens are not illustrated but are understood to be present), or explicitly defined hydrogen (e.g., where "Z" in the formula is =CH-). In the illustrated examples, the "R" group may exist on the 5-membered or 6-membered ring of the fused ring system. For example, when the group "R" is illustrated as existing on a ring system containing saturated carbon in the following formula:

[0062]

[0063] In this example, if "v" can be more than one by presuming that it replaces the currently depicted, implied, or explicitly defined hydrogen on the ring; then, unless otherwise defined, the structure generated here is stable and two "R"s can exist on the same carbon. A simple example is that when R is a methyl group, a cosite dimethyl can exist on the depicted ring-shaped carbon ("cyclic" carbon). In another example, two Rs on the same carbon, including that carbon, form a ring and thus can form a spirocyclic ring ("spirocyclyl" group) structure having the depicted ring, for example, as in the following chemical formula:

[0064]

[0065] Unless otherwise noted, the difunctional group may have the described orientation or reverse orientation. For example, in the case of the difunctional group "-C(O)NH-", the present disclosure also includes the reverse orientation "-NHC(O)-".

[0066] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0067] Term "Cn-m " or "C n -C m " indicates the range including the terminal points, where n and m are integers representing the number of carbons. An example is C 1-4 , C1-C4, C 1-6 Includes , C1-C6, etc.

[0068] "Alkyl" refers to branched or straight-chain hydrocarbon chains, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, and heptyl. In some embodiments, the alkyl group may have 1 to 8 carbon atoms. (C1-C6)alkyl is preferred. The term "C n-m "alkyl" or (C n -C m ) Alkyl refers to an alkyl group having n to m carbon atoms. When optionally substituted, one or more hydrogen atoms of the alkyl group (e.g., 1 to 4, 1 to 2, or 1) may be replaced by a moiety as described under “Optional Substitution” below. In some aspects, the alkyl group is unsubstituted or optionally unsubstituted.

[0069] "Alkylene" refers to 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 having an optionally substituted divalent saturated aliphatic radical. When optionally substituted, one or more hydrogen atoms of the alkylene group (e.g., 1 to 4, 1 to 2, or 1) may be replaced by a moiety as described under "Optional Substitution" below. In some aspects, the alkylene group is unsubstituted or optionally unsubstituted. The term "Cn-m "Alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, etc.

[0070] 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. The alkenyl group formally corresponds to an alkene having one CH bond replaced by an attachment site of the alkenyl group in the remainder of the compound. The term "C n-m "Alkenyl" or (C n -C m ) 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. Example alkenyl groups are, but not limited to, ethenyl, n -propenyl, isopropenyl, n -Butenyl, sec - Includes butenyl, etc.

[0071] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. The alkynyl group formally corresponds to an alkyne having one CH bond replaced by an alkyl group attachment site in the remainder of the compound. The term "C n-m "Alkynyl" or (C n -C m ) Alkynyl refers to an alkynyl group having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethinyl, propin-1-yl, propin-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0072] "Alkoxy" is the chemical formula - OR i Refers to the moiety of, where Ri is a (C1-C6)alkyl moiety as defined herein. The term "C n-m "Alkoxy" or (C n -C m ) refers to an alkoxy group, and its alkyl group has n to m carbons. Examples of alkoxy moiety include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

[0073] The alkoxy group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the alkoxy group (e.g., 1 to 4, 1 to 2, or 1) may be replaced by a moiety as described under “Optional Substitution” below, provided that the hydrogen atom at the alpha position of the ether oxygen is not replaced by a hydroxyl, amino, or thio group. In some aspects, the alkoxy group is unsubstituted or optionally not substituted.

[0074] "Alkoxycarbonyl" is the -C(O)-R group i Refers to , and here R i is a (C1-C6)alkoxy as defined here.

[0075] The term "amino" refers to the group of the chemical formula -NH2.

[0076] The term "carbamyl" refers to the group of the chemical formula -C(O)NH2.

[0077] The term "carbonyl," used alone or in combination with other terms, refers to a -C(=O)- group, which can also be written as C(O).

[0078] The term "cyno" or "nitrile" refers to a group of the chemical formula -C≡N, which may also be written as -CN or CN.

[0079] The term "oxo" refers to a group that forms a carbonyl group when attached to a carbon, or a sulfoxide or sulfone group when attached to a heteroatom, or N- Refers to an oxygen atom as a divalent substituent forming an oxide group. In some embodiments, the heterocyclic group may be optionally substituted with a 1 or 2 oxo (=O) substituent.

[0080] The term "sulfide" refers to a sulfur atom as a divalent substituent that forms a thiocarbonyl group (C=S) when attached to a carbon.

[0081] The term "heteroatom" used here means including boron, phosphorus, sulfur, oxygen, and nitrogen.

[0082] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms. The term "C n-m "haloalkyl" or (C n -C m ) The haloalkyl group has n to m carbon atoms and at least one to {2(n to m)+1} halogen atom that may be the same or different. C n-m It refers to an alkyl group. In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, etc. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0083] The term "haloalkoxy," used alone or in combination with other terms, refers to a group of the chemical formula -O-haloalkyl, wherein the haloalkyl group is as defined above. The term "C n-m Haloalkoxy" or (C n -C m ) Haloalkoxy refers to a haloalkoxy group, and its haloalkyl group has n to m carbons. Examples of haloalkoxy groups include trifluoromethoxy, etc. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0084] "Aryl" means a monovalent 6- to 14-membered, mono- or bi-carbocyclic or tri-carbocyclic ring (e.g., having two fused rings), wherein the monocyclic ring is aromatic and at least one of the rings within the bicyclic ring is aromatic. The term "C n-m Aril" or "(C n -C m "Aryl" refers to an aryl group having n to m ring carbon atoms. In some embodiments, the aryl group has 6 to approximately 10 carbon atoms. In some embodiments, the aryl group has 6 ring carbon atoms. In some embodiments, the aryl group has 10 ring carbon atoms. Unless otherwise noted, the valence of the group may be located on any atom of any ring within the radical as permitted by the valence rule. Representative examples include phenyl, naphthyl, and indanyl, etc.

[0085] The aryl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the aryl group (e.g., 1 to 5, 1 to 2, or 1) may be replaced by a moiety as described under “optional substitution” below. In some aspects, the alkoxy group is unsubstituted or optionally substituted.

[0086] "Aryllene" means a divalent 6- to 14-membered, mono- or bi-carbocyclic or tri-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings within the bicyclic ring or tri-carbocyclic ring is aromatic. Representative examples include phenylene, naphthylene, and indanylene, etc.

[0087] "Cycloalkyl" refers to cyclic alkyl and alkenyl groups comprising non-aromatic hydrocarbon ring systems (monocyclic, bicyclic, or polycyclic). The term "C n-m "cycloalkyl" or "(C n -C m") Cycloalkyl" refers to a cycloalkyl having n to m ring member carbon atoms. The cycloalkyl group may include a mono- or polycyclic group (e.g., having 2, 3, or 4 fused rings) and a spirocycle. The cycloalkyl group has 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming carbons (C 3-14 It may have ). In some embodiments, the cycloalkyl group has 3 to 14 members, 3 to 10 members, 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C 3-6It is a monocyclic cycloalkyl group. The ring-forming carbon atom of the cycloalkyl group may optionally be oxidized to form an oxo or sulfido group. The cycloalkyl group also includes cycloalkylidene. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornelyl, norfinyl, norcarnyl, bicyclo[1.1.1]fentanyl, bicyclo[2.1.1]hexanyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl comprises a monosaturated carbocyclic ring of 3 to 8 ring carbons, e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl may optionally be substituted with one or more substituents, e.g., 1, 2, or 3 substituents. In some embodiments, the cycloalkyl substituent is 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.

[0088] The cycloalkyl group may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the cycloalkyl group (e.g., 1 to 4, 1 to 2, or 1) may be replaced by a moiety as described under “Optional Substitution” below. In some aspects, the substituted cycloalkyl group may comprise an exo- or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some aspects, the cycloalkyl group is unsubstituted or optionally unsubstituted.

[0089] "Cycloalkyloxycarbonyl" is a group -C(O)-OR i It means , and here R iIt is a (C3-C6) cycloalkyl as defined here.

[0090] "Phenyloxycarbonyl" refers to the -C(O)-O-phenyl group.

[0091] "Heteroaryl" is -O-, -S(O) n - (n is 0, 1, or 2), -N-, and -N(R i It means a monocyclic, fused bicyclic, or fused tricyclic, monovalent radical of 5 to 14 ring constituent atoms containing one or more, preferably 1, 2, 3, or 4 ring heteroatoms independently selected from ), and the remaining ring constituent atoms being carbon, wherein 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 with -C(O)-, -C(S)-, or -C(=NH)- groups. R i is hydrogen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Unless otherwise noted, the valence point may be located on any atom of any ring of the heteroaryl group as permitted by the valence rule. In particular, when the valence point is located on the nitrogen, no additional nitrogen substituents exist. In particular, the term heteroaryl is, but is not limited to, 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1 H -Indolyl (e.g., 2,3-dihydro-1 H -Indole-2-yl or 2,3-dihydro-1 H-Indole-5-yl, including etc.), isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzodioxo-1-4-yl, benzofuranyl, cinnolinyl, indolinil, naphthiridin-3-yl, phthalazine-3-yl, phthalazine-4-yl, pteridinyl, furinyl, quinazolinyl, quinoxalinyl, tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (e.g., tetrahydroisoquinoline-4-yl or tetrahydroisoquinoline-6-yl, including etc.), pyrrolo[3,2-c]pyridinyl (e.g., (including pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, etc.), benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothienyl, and derivatives thereof, and N - It includes oxide or a protected derivative thereof.

[0092] A 5-membered heteroaryl ring is a heteroaryl group having 5 ring members, wherein one or more (e.g., 1, 2, 3, or 4) ring members are 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.

[0093] A 6-membered heteroaryl ring is a heteroaryl group having 6 ring members, where one or more (e.g., 1, 2, 3, or 4) ring members are independently selected from N, O, and S. Exemplary 6-membered heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0094] "Heteroarylene" is -O-, -S(O) n - (n is 0, 1, or 2), -N-, and -N(R 19 )- means a monocyclic, fused bicyclic, or fused tricyclic, divalent radical of 5 to 14 ring constituents containing one or more, preferably 1, 2, 3, or 4 ring heteroatoms independently selected from ), and the remaining ring constituent atoms being carbon, wherein 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 with -C(O)-, -C(S)-, or -C(=NH)- groups. R 19 is hydrogen, alkyl, or alkenyl. Unless otherwise noted, the valence point may be located on any atom of any ring of the heteroarylene group permitted by the valence rule. In particular, when the valence point is located on nitrogen, no additional nitrogen substituents exist. In particular, the term heteroaryl is, but is not limited to, thiene-diyl, benzo[ d ]Isoksajol-Dil, Benjo[ d ]Isothiazol-diyl, 1 H -Indazole-diyl (R at the N1 position 19 Arbitrarily substituted as), benzo[ d ]Oxazole-diyl, benzo[ d ]Thiazol-Diyl, 1 H -Benzo[ d ]Imidazole-diyl (R at the N1 position 19 arbitrarily substituted as), 1 H -Benzo[ d ][1,2,3]triazole-diyl (R at N1 position 19 arbitrarily substituted as), imidazo[1,2- aIncludes ]pyridine-diyl, cinnoline-diyl, quinoline-diyl, pyridine-diyl, 1-oxide-pyridine-diyl, [1,2,4]triazolo[4,3-a]pyridine-diyl, and 2,3-dihydroimideazo[1,2-a]pyridine-diyl, etc.

[0095] As used herein, “heterocycloalkyl” or “heterocyclo” refers to a non-aromatic ring or ring system, which may optionally contain a ring structure as part of one or more alkenylene groups and has at least one heteroatom ring member independently selected from boron, nitrogen, sulfur, oxygen, and phosphorus, which has a 4-14 ring member, a 4-10 ring member, a 4-7 ring member, or a 4-6 ring member. Monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups are included within the term “heterocycloalkyl”. The heterocycloalkyl group may comprise a mono- or bicyclic or polycyclic (e.g., two or three fused or cross-linked rings having) ring system or a spirocycle. In some embodiments, the heterocycloalkyl group is a monocyclic group having one, two, or three heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may optionally be oxidized to form an oxo or sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S), S(O)2, N-oxide, etc.), or the nitrogen atom may be quaternized. The heterocycloalkyl group may be attached via the ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Moiety having one or more aromatic rings fused to the heterocycloalkyl ring (i.e., having a common bond), e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc., is also included within the definition of heterocycloalkyl. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom containing a ring-forming atom of the fused aromatic ring.Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azapiro[5.5]undecanyl, 1-oxa-8-azapiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperajinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, trophanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, and thiomophorino.

[0096] "Heterocycloalkyl" or "heterocyclo" may be unsubstituted or optionally substituted. When optionally substituted, one or more hydrogen atoms of the group (e.g., 1 to 4, 1 to 2, or 1) may be replaced with a moiety independently selected from fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio. In some aspects, the substituted heterocyclyl group may comprise an exo- or endocyclic alkene (e.g., cyclohex-2-en-1-yl). In some aspects, the heterocyclyl group is unsubstituted or optionally unsubstituted.

[0097] Mode of implementation

[0098] In one aspect, the present invention relates to a compound of Formula I.

[0099] ,

[0100] Formula I

[0101] or includes a process for manufacturing a pharmaceutically acceptable salt thereof, wherein the process comprises a compound of Formula II

[0102]

[0103] Formula II

[0104] Compound of Formula III

[0105]

[0106] Formula III

[0107] It includes a step of contacting in the presence of a solvent and a base, wherein

[0108] LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and organotriphosphate compounds;

[0109] R1 is Halo, C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-6 Selected from cycloalkyl;

[0110] R2 and R3 are halo and C, respectively. 1-6 Independently selected from alkyls;

[0111] R4 is Halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, phenyl, and C 3-6 Selected from heteroaryls;

[0112] R 5a is H, OH, NH2, C 1-8 Alkyl, C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, phenyl, and C 3-6 Selected from heteroaryls, where unit C 1-8 Up to three methylene groups of the alkyl group are optionally and independently replaced with -O-, NR'-, -C(O)-, -C(O)O-, and -C(O)NR'-, where R 5a is 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 Randomly substituted with up to three substituents selected from heteroaryls;

[0113] R 5b is H or C 1-6 alkyl; or

[0114] R 5a and R 5b together with the nitrogen to which they are attached, 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, or C 3-6 C arbitrarily substituted with a heteroaryl 3-6 Forming a heterocycloalkyl;

[0115] R 5c is C arbitrarily substituted with H or halo, CN, OH, NH2, or OR' 1-6 Alkyl;

[0116] R' is H or C 1-6 alkyl, and

[0117] w, x, y, and z are each independently integers 0 to 4;

[0118] and the process optionally further includes the step of contacting the compound of Formula I with an acid to prepare a pharmaceutically acceptable salt of the compound of Formula I. In some embodiments, the acid is fumaric acid.

[0119] In one embodiment of this aspect, LG is an organic triphosphate coupling agent, e.g., structure It is T3P® (2,4,6-tripropyl-1,3,5,2,4,6-trioxatrioxatriphosphinan 2,4,6-trioxide; propylphosphonic acid anhydride) having

[0120] 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.

[0121] In one embodiment, the solvent is a mixture of water and an organic solvent.

[0122] In one embodiment, the organic solvent is selected from polar protic and polar aprotic solvents. In one embodiment, the polar protic or polar aprotic solvent is selected from the group consisting of acetone, acetonitrile, butanediol, dimethylformamide, dimethoxyethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethylene glycol, furfuryl alcohol, glycerol, methanol, methyl isocyanide, N-methyl-2-pyrrolidone, 1-propanol, 1,3-propanediol, 1,5-pentanediol, 2-propanol, propylene glycol, tetrahydrofuran, and triethylene glycol. In a further embodiment, the organic solvent is a polar aprotic solvent selected from the group consisting of acetone, acetonitrile, dimethylformamide, 1,4-dioxane, and tetrahydrofuran. Also in an additional embodiment, the organic solvent is a mixture of water and tetrahydrofuran. Also in an additional embodiment, the mixture is approximately 2:1 tetrahydrofuran:water to approximately 8:1, or approximately 2:1 tetrahydrofuran:water to approximately 6:1, or approximately 2:1 tetrahydrofuran:water to approximately 4:1. Also in an additional embodiment, the mixture is approximately 2:1 tetrahydrofuran:water to approximately 3:1 tetrahydrofuran:water.

[0123] In one embodiment, the compound of Formula II is brought into contact with the compound of Formula III by adding a solution of the compound of Formula III dissolved in a first solvent to a solution of the compound of Formula II dissolved in a second solvent, thereby producing a reaction mixture.

[0124] In one embodiment, the first solvent is an organic solvent. In a further embodiment, the first solvent is a polar aprotic solvent. In a further embodiment, the first solvent is tetrahydrofuran.

[0125] In one embodiment, the second solvent is a mixture of water and tetrahydrofuran. In one embodiment, the second solvent is a mixture of approximately 2:1 tetrahydrofuran:water to approximately 8:1, or approximately 2:1 tetrahydrofuran:water to approximately 6:1, or approximately 2:1 tetrahydrofuran:water to approximately 4:1. In a further embodiment, the second solvent is a mixture of approximately 3:1 to approximately 2:1 tetrahydrofuran:water. In a further embodiment, the second solvent is a mixture of approximately 2:1 tetrahydrofuran:water.

[0126] In one embodiment, 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 over a period of about 30 minutes to about 1 hour. In another embodiment, 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 over a period of more than 30 minutes.

[0127] In one embodiment, the temperature of the reaction mixture is maintained at about 27°C or less. In another embodiment, the reaction temperature is maintained at approximately 20 to 27°C. In another embodiment, the reaction temperature is maintained at approximately 25 to 27°C. In another embodiment, the reaction temperature is maintained at approximately 20 to 25°C.

[0128] In one embodiment, the reaction mixture is heated to about 35-40°C and left to stand to separate into an organic phase and an aqueous phase.

[0129] In one embodiment, the process further comprises discarding the aqueous phase, heating the organic phase to 45-50°C, and then filtering the organic phase at 45-50°C.

[0130] In another embodiment, the process further comprises discarding the aqueous phase, heating the organic phase to 55-60°C, and then filtering the organic phase at 55-60°C.

[0131] In another embodiment, the process further comprises the step of cooling the organic phase to 20-25°C and adding water to the organic phase to produce a second mixture, wherein the volume of water added is approximately 1.5 to approximately 2.5 times the volume of the organic phase. In another embodiment, the process further comprises adding water to the organic phase to produce a second mixture while maintaining a temperature of 50-55°C.

[0132] In one embodiment, water is added to the organic phase over a period of at least one hour. In another embodiment, water is added to the organic phase over a period of approximately four to four.5 hours.

[0133] In one embodiment, the second mixture is stirred for at least 12 hours, and the product is solid. In another embodiment, the second mixture is stirred for more than 2 hours.

[0134] In one embodiment, LG is Cl.

[0135] In one embodiment, the process is a compound of Formula IV

[0136]

[0137] Formula IV

[0138] The method further includes the step of preparing the compound of Formula III by reacting it with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride.

[0139] ,

[0140] Formula III

[0141] Here, LG is chloride.

[0142] In one embodiment, the reagent is oxalyl chloride.

[0143] In another embodiment, the reaction is carried out in the presence of a catalytic amount of dimethylformamide.

[0144] 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.

[0145] In one embodiment, the reaction is carried out at a temperature approximately between -5°C and 25°C. In a further embodiment, the reaction is carried out at a temperature approximately between 0°C and 20°C. In a further embodiment, the reaction is carried out at a temperature approximately 15°C or lower. In a further embodiment, the reaction is carried out at a temperature approximately 5-15°C. In a further embodiment, the reaction is carried out at a temperature approximately 10-15°C. In a further embodiment, the reaction is carried out for 2-3 hours at a temperature approximately 10-15°C.

[0146] In one embodiment, the process is a compound of Formula V.

[0147]

[0148] Formula V

[0149] React with the compound of Formula VI

[0150]

[0151] Formula VI

[0152] The method further includes the step of providing a compound of Formula II.

[0153] ,

[0154] Formula II

[0155] Here, LG' is F, Cl, Br, I, , , , and -N2 + Selected from.

[0156] In one embodiment, the reaction is carried out in the presence of a solvent. In another embodiment, the solvent is an organic solvent. In another embodiment, the solvent is a polar aprotic solvent. In another embodiment, the organic solvent is a polar aprotic solvent selected from acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, hexamethylphosphate triamide (HMPT), tetrahydrofuran, 1,4-dioxane, and dichloromethane. In a further embodiment, the organic solvent is dimethylacetamide.

[0157] 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, 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 - It is pentoxide. In additional embodiments, the base is sodium t - It is pentoxide.

[0158] In one embodiment, the reaction is carried out at a temperature of about 70 to 90 °C. In another embodiment, the reaction is carried out at a temperature of about 75-80 °C.

[0159] In one embodiment, the product is isolated by adding water to the reaction mixture and isolating the solid product by filtration or the like.

[0160] In one embodiment, LG' is F, Cl, Br, and It is selected from. In an additional embodiment, LG' is Cl.

[0161] In some embodiments, the compound of Formula I is a compound of Formula Ia, Formula Ib, Formula Ic, or Formula Id:

[0162]

[0163] Formula Ia

[0164]

[0165] Formula Ib

[0166]

[0167] Formula Ic

[0168]

[0169] Formula Id

[0170] Here, R1, R2, R3, R4, R 5a , R 5b , R 5c , w, x, y, and z are as defined herein.

[0171] In one embodiment of formula Ia, Ib, Ic, or Id, R1 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.

[0172] In one embodiment of formula Ia, Ib, Ic, or Id, x is 0.

[0173] 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 an additional embodiment, y is 0.

[0174] In one embodiment of formula Ia, Ib, Ic, or Id, R4 is a halo or C 1-6 It is an alkyl. In one embodiment, z is 0 or 1. In a further embodiment, z is 0.

[0175] In one embodiment of formula Ia, Ib, Ic, or Id, R 5b is H.

[0176] In one embodiment of formula Ia, Ib, Ic, or Id, R 5a is H, -NH2, -OH, C 1-6 Alkyl, and C 3-6 Selected from heterocycloalkyl, where c 1-6 Up to three methylene units of the alkyl group are optionally and independently replaced with -O- or NR'-, where R 5a is OH, C 1-4 Alkyl, and C 3-6 It is optionally substituted with up to three substituents selected from heterocycloalkyls.

[0177] In additional embodiments of formulas Ia, Ib, Ic, or Id, R 5a is selected from H, -NH2, -OH, methoxy, methyl, ethyl, N-methylazetidin-2-yl, pyrrolidine-2-yl-methyl, oxetane-2-yl-oxy, 2-hydroxyethyloxy, 2,3-dihydroxypropyloxy, oxetane-2-yl, 2-(N-piperidyl)ethyl, 2-(N-morpholino)ethyl, and 2-dimethylaminoethyl. Also in additional embodiments, R 5a is methyl.

[0178] In one embodiment of formula Ia, Ib, Ic, or Id, R 5c is C arbitrarily substituted with H or OH or OR' 1-6 It is an alkyl. In additional embodiments, R 5c is methyl, 2-hydroxyethyl, 2-methoxyethyl, or 2-hydroxypropyl. Also in additional embodiments, R 5c is methyl.

[0179] In another embodiment of formula Ia, Ib, Ic, or Id, R 5a and R 5b C, arbitrarily substituted with OH along with the nitrogen to which they are attached 3-6 It forms a heterocycloalkyl group. In additional embodiments, R5a and R 5b They form azetidine or 2-hydroxyazetidine together with the nitrogen to which they are attached.

[0180] In one embodiment of formula Ia, Ib, Ic, or Id, R' is H. In another embodiment, R' is C 1-6 It is an alkyl. In some embodiments, R' is selected from H, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl. In one embodiment, R' is H or methyl. In one embodiment, R' is methyl.

[0181] In one aspect, the present invention relates to compound 1

[0182] ,

[0183] Compound 1

[0184] or includes a process for preparing a pharmaceutically acceptable salt thereof, wherein the process comprises compound 4

[0185]

[0186] compound of Formula III'

[0187]

[0188] Formula III'

[0189] The process comprises the step of contacting in the presence of a solvent and a base, wherein LG is a leaving group selected from Cl, Br, I, HOAt, HOBt, and organotriphosphate compounds, and wherein the process optionally further comprises the step of contacting a compound of compound 1 with an acid to prepare a pharmaceutically acceptable salt of compound 1.

[0190] In one embodiment, the base is an inorganic base. In a further embodiment, the base is selected from NaOH, Na2CO3, K2CO3, NaHCO3, and KHCO3. Also in a further embodiment, the base is Na2CO3. Also in a further embodiment, the base is K2CO3.

[0191] In one embodiment, the solvent is a mixture of water and an organic solvent. In one embodiment, the organic solvent is a polar protic or polar aprotic solvent. In one embodiment, the polar protic or polar aprotic solvent is selected from 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. Also in a further embodiment, the mixture is approximately 2:1 tetrahydrofuran:water to approximately 3:1 tetrahydrofuran:water.

[0192] In one embodiment, compound 4 is brought into contact with the compound of formula III by adding a solution of compound of formula III dissolved in a first solvent to a solution of compound 4 dissolved in a second solvent, thereby producing a reaction mixture.

[0193] In one embodiment, the first solvent is an organic solvent. In a further embodiment, the first solvent is a polar aprotic solvent. In a further embodiment, the first solvent is tetrahydrofuran.

[0194] In one embodiment, the second solvent is approximately 2:1 tetrahydrofuran:water.

[0195] In one embodiment, a 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 about 30 minutes to about 1 hour. In another embodiment, a 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 more than 30 minutes.

[0196] In one embodiment, the temperature of the reaction mixture is maintained between approximately 20 and 27°C. In one embodiment, the reaction mixture is maintained between approximately 25 and 27°C. In one embodiment, the reaction mixture is maintained below approximately 27°C. In another embodiment, the reaction temperature is maintained at approximately 20 to 25°C.

[0197] In another embodiment, the reaction mixture is heated to 35-40°C and left to stand to separate into an organic phase and an aqueous phase.

[0198] In one embodiment, the process further comprises discarding the aqueous phase, heating the organic phase to 45-50°C, and then filtering the organic phase at 45-50°C.

[0199] In one embodiment, the process further comprises discarding the aqueous phase, heating the organic phase to 55-60°C, and then filtering the organic phase at 55-60°C.

[0200] In another embodiment, the process further comprises the step of cooling the organic phase to 20-25°C and adding water to the organic phase to produce a second mixture, wherein the volume of water added is approximately 1.5 to approximately 2.5 times the volume of the organic phase.

[0201] In another embodiment, the process further includes adding water to the organic phase to produce a second mixture while maintaining a temperature of 50-55°C.

[0202] In one embodiment, water is added to the organic phase over a period of at least one hour. In another embodiment, water is added to the organic phase over a period of approximately four to four.5 hours.

[0203] In one embodiment, the second mixture is stirred for at least 12 hours, and the product is a solid collected by filtration, etc. In another embodiment, the second mixture is stirred for at least 2 hours, and the product is a solid collected by filtration, etc.

[0204] In one embodiment, LG is Cl.

[0205] In one embodiment, the process is compound 6

[0206]

[0207] The method further includes the step of preparing compound 7 by reacting with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride.

[0208] .

[0209] In one embodiment, the reagent is oxalyl chloride.

[0210] In another embodiment, the reaction is carried out in the presence of a catalytic amount of dimethylformamide.

[0211] In one embodiment, the reaction is carried out in the presence of an organic solvent. In a further embodiment, the organic solvent is tetrahydrofuran.

[0212] In one embodiment, the reaction is carried out at a temperature of 15°C or lower. 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.

[0213] In one embodiment, the process is compound 3

[0214]

[0215] The method further includes the step of reacting with 4-aminophenol (5) to provide compound 4.

[0216] .

[0217] 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, hexamethylphosphate triamide (HMPT), tetrahydrofuran, 1,4-dioxane, and dichloromethane. Also in a further embodiment, the organic solvent is dimethylacetamide.

[0218] In one embodiment, the reaction is carried out in the presence of a base. In further embodiments, 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 - It is pentoxide.

[0219] In one embodiment, the reaction is carried out at a temperature of 75-80°C.

[0220] In one embodiment, the product is isolated by adding water to the reaction mixture and isolating the solid product.

[0221] In one embodiment, the process further comprises the step of reacting compound 1 with fumaric acid to provide compound 1-hemifumarate.

[0222] .

[0223] 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 alcohol solvent, THF, DMF, MEK, acetonitrile, 1,4-dioxane, and MTBE, or a combination thereof. In a further embodiment, the solvent is a mixture of water and an alcoholic solvent.

[0224] In one embodiment, the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, pentanol, hexanol, heptanol, and octanol.

[0225] In an additional embodiment, the solvent is a 20% solution of water in ethanol.

[0226] In one embodiment, the volume of a 20% solution of water in the ethanol used in the reaction is about 2-3 times the weight of compound 1. In another embodiment, the volume of a 20% solution of water in the ethanol used in the reaction is about 3 times the weight (g) of compound 1.

[0227] In one embodiment, the amount of fumaric acid used is about 0.5-1.0 equivalents for compound 1. In another embodiment, the amount of fumaric acid used is about 0.75-1.0 equivalents for compound 1. In yet another embodiment, the amount of fumaric acid used is about 0.8-0.82 equivalents for compound 1.

[0228] In one embodiment, compound 1 reacts with fumaric acid by adding a mixture of fumaric acid dissolved in a 20% solution of water in ethanol at 45-50°C to compound 1 to produce a reaction mixture.

[0229] In one embodiment, the volume (mL) of a 20% solution of water in ethanol used to dissolve fumaric acid is about 2-3 times the weight (gram) of compound 1. In another embodiment, the volume of a 20% solution of water in ethanol used to dissolve fumaric acid is about 2.2-2.8 times the weight of compound 1. In yet another embodiment, the volume of a 20% solution of water in ethanol used to dissolve fumaric acid is about 2.4-2.6 times the weight of compound 1.

[0230] In one embodiment, the process further comprises heating the reaction mixture to a reflux temperature and stirring. In another embodiment, the reflux reaction mixture is stirred for 4 to 6 hours.

[0231] In one embodiment, the process further comprises cooling the reaction mixture and separating the solid product from the solvent.

[0232] In another aspect, the present invention relates to compound 1

[0233] ,

[0234] 1

[0235] or a process for manufacturing a pharmaceutically acceptable salt thereof, wherein the process comprises the following:

[0236] Compound 3

[0237]

[0238] Step of reacting with 4-aminophenol (5) to provide compound 4

[0239] ;

[0240] Compound 6

[0241]

[0242] A step of preparing compound 7 by reacting with thionyl chloride or oxalyl chloride in the presence of a solvent,

[0243] ;

[0244] A step of preparing compound 1 by reacting compound 4 and compound 7,

[0245] Here, the process optionally includes the step of additionally contacting compound 1 with an acid to produce a pharmaceutically acceptable salt of compound 1.

[0246] In another aspect, the present invention relates to compound 1

[0247] ,

[0248] 1

[0249] or a process for manufacturing a pharmaceutically acceptable salt thereof, wherein the process comprises the following:

[0250] Compound 3

[0251]

[0252] a solvent that is dimethylacetamide and sodium t - A step of reacting 4-aminophenol (5) with compound 4 at a temperature of 75 to 80 °C in the presence of a base that is pentoxide to provide a first reaction mixture containing compound 4.

[0253] ;

[0254] A step of adding water to the first reaction mixture to precipitate and isolate the solid product, compound 4;

[0255] Compound 6

[0256]

[0257] A step of preparing a second reaction mixture comprising compound 7 by reacting oxalyl chloride with a solvent of tetynhydrofuran and a catalyst of dimethylformamide at a temperature of 5 to 15 °C in the presence of the catalyst,

[0258] ;

[0259] A step of preparing a fourth reaction mixture by adding a second reaction mixture over a period of 30 minutes or more to a third reaction mixture comprising a solvent of approximately 2:1 tetrahydrofuran:water, a base of Na2CO3 or K2CO3 (preferably K2CO3), and compound 4, wherein the temperature of the fourth reaction mixture is maintained below approximately 27°C during addition;

[0260] Step 4: Heating the reaction mixture to 35-40℃ and letting it stand to separate it into an organic phase and an aqueous phase;

[0261] A step of discarding the aqueous phase, heating the organic phase to 55-60℃, and then filtering the organic phase at 55-60℃;

[0262] A step of adding water to the organic phase over a period of approximately 4 to 4.5 hours to produce a fifth reaction mixture while maintaining a temperature of 50 to 55°C;

[0263] A fifth step of stirring the reaction mixture for at least 2 hours; and

[0264] A step of isolating a solid product of compound 1, wherein the process optionally further comprises a step of contacting compound 1 with an acid to produce a pharmaceutically acceptable salt of compound 1.

[0265] In one embodiment of this aspect, dimethylformamide is present in a catalytic amount.

[0266] In some embodiments of this aspect, the molar ratio between dimethylformamide and oxalyl chloride is about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, or 0.05. In some embodiments, the volume ratio between dimethylformamide and oxalyl chloride is about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, or 0.05. In some embodiments, the molar ratio of dimethylformamide / oxalyl chloride is between about 0.001 and about 0.005. In some embodiments, the volume ratio of dimethylformamide / oxalyl chloride is between about 0.001 and about 0.005.

[0267] In another embodiment of this aspect, the molar ratio between dimethylformamide and compound 6 is about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, or 0.05. In some embodiments, the volume ratio between dimethylformamide and compound 6 is about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, or 0.05. In some embodiments, the molar ratio of dimethylformamide / compound 6 is between about 0.001 and about 0.005. In some embodiments, the volume ratio of dimethylformamide / compound 6 is between about 0.001 and about 0.005.

[0268] In another aspect, the present invention comprises a process for manufacturing compound 1-hemifumarate.

[0269]

[0270] Compound 1-hemifumarate

[0271] This process includes the following:

[0272] A step of producing a reaction mixture by adding a mixture of fumaric acid dissolved in a 20% solution of water in ethanol at 45-50℃ to compound 1;

[0273] Step of reflux heating the reaction mixture;

[0274] A step of stirring the reaction mixture under reflux for 4-6 hours; and

[0275] A step of cooling the reaction mixture and separating the solid product, compound 1·hemifumarate, from the solvent.

[0276] In another aspect, the present invention comprises a process for manufacturing compound 1-hemifumarate.

[0277] ,

[0278] Compound 1-hemifumarate

[0279] This process includes the following:

[0280] Compound 3

[0281]

[0282] Step of reacting with 4-aminophenol (5) to provide compound 4

[0283] ;

[0284] Compound 6

[0285]

[0286] A step of preparing compound 7 by reacting with thionyl chloride or oxalyl chloride in the presence of a solvent,

[0287] ;

[0288] A step of preparing compound 1 by reacting compound 4 and compound 7; and

[0289] A step of providing compound 1-hemifumarate by combining fumaric acid dissolved in a 20% solution of water in ethanol with compound 1.

[0290] In one embodiment, compound 1 is reacted with fumaric acid to produce a slurry by adding a mixture of fumaric acid dissolved in a 20% solution of water in ethanol at 45-50°C to compound 1.

[0291] In one embodiment, the amount of fumaric acid used is about 0.5-1.0 equivalents for compound 1. In another embodiment, the amount of fumaric acid used is about 0.75-1.0 equivalents for compound 1. In yet another embodiment, the amount of fumaric acid used is about 0.8-0.82 equivalents for compound 1.

[0292] In one embodiment, the volume (mL) of a 20% solution of water in ethanol used to dissolve fumaric acid is about 2-3 times the weight (gram) of compound 1. In another embodiment, the volume of a 20% solution of water in ethanol used to dissolve fumaric acid is about 2.2-2.8 times the weight of compound 1. In yet another embodiment, the volume of a 20% solution of water in ethanol used to dissolve fumaric acid is about 2.4-2.6 times the weight of compound 1.

[0293] In another aspect, the present invention comprises a process for manufacturing compound 1-hemifumarate.

[0294]

[0295] Compound 1-hemifumarate

[0296] This process includes the following:

[0297] A step of combining a fumaric acid solution with compound 1 to produce a reaction mixture containing a slurry;

[0298] A step of reflux heating the reaction mixture for a predetermined time; and

[0299] Step of isolating compound 1·hemifumarate as a solid.

[0300] In one embodiment of this aspect, the combination includes adding a fumar solution to compound 1.

[0301] In an additional embodiment, fumaric acid is dissolved in a mixed solvent of EtOH and acetone at about 45-50°C to form a solution.

[0302] In another embodiment, the predetermined time is about 1 to 6 hours.

[0303] In another embodiment, isolation includes the step of cooling a reaction mixture containing a slurry; the step of filtering the reaction mixture to obtain a solid; and the step of washing the solid.

[0304] In one aspect, the present invention comprises a compound having the following structure:

[0305] .

[0306] argument

[0307] The synthetic conversion to produce Compound 1 involves two parallel reactions: the formation of the acid chloride Compound 7 and the amidation reaction to produce Compound 1. The formation of the acid chloride 7 was found to be rapid and complete after about 15 minutes when performed at ambient temperature. However, batch-to-batch inconsistencies were observed at ambient temperature, with some batches containing higher levels of impurities than others. It was further found that proceeding the reaction at 10–15°C could avoid the formation of unwanted byproducts. At this temperature, the reaction was slower and generally took 2–3 hours to complete, but impurity levels could be controlled and minimized.

[0308] During the amidation reaction to produce Compound 1, the major impurities were found to be unreacted Compound 4 and various reaction products resulting from side reactions with acid chloride. It was found that using a slightly smaller amount of acid chloride than the stoichiometric amount in the reaction significantly reduced the amount of impurities from the acid chloride side reactions.

[0309] As provided herein, compound 1 is reacted with fumaric acid to produce compound 1-hemifumarate. Due to the low solubility of the hemifumarate salt, bright filtration, which is typically performed in the API stage to remove impurities, was carried out in the free base stage. As such, a large amount of solvent (50 v / w for Compound 4) was used. Despite this high volume, product precipitation was observed during the water phase removal in the scale-up. To address this issue, the organic phase was heated to 55–60°C and then bright filtration was performed.

[0310] Salt formation of compound 1·hemifumarate was performed in advance in a mixture of THF and water. After polished filtration, THF was replaced with IPA. However, the crystalline product was found to still contain high levels of THF. Attempts to remove THF by high-temperature grinding in the solvent and high-temperature vacuum drying were unsuccessful. To solve 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 lattices forming their respective solvates.

[0311] It was realized that when salt is formed in solution, THF is incorporated into the crystalline product and a solvate is formed that cannot be removed by drying under vacuum even at 60-80°C. Attempts to remove residual THF by suspending the salt in refluxed IPA were also unsuccessful.

[0312] Our study suggested that salts can be formed from a slurry of the free base of Compound 1. It was further found that suspension salt formation can be carried out using ACN, IPA, or EtOH as long as the reaction temperature is above 70°C. Under these slurry conditions, the conversion was slow (>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 a minimal amount of solvent (no solvate formation was observed). The conversion of the free base to hemifumarate is 1 It was monitored using ¹H NMR (d6DMSO) by observing the integration ratio of the fumaric acid peak at δ 6.64 ppm (corresponding to 2 protons) compared to the aromatic peak of Compound 1 at δ 6.47 ppm (corresponding to 1 proton). The complete transformation shows a 1:1 ratio of these two signals.

[0313] It was found that the conversion was faster in the presence of water in EtOH. Therefore, in an alternative example, the reaction in 10% water in an EtOH solution was completed after 5 hours at 62-65°C. The yield obtained was moderate, but generally, higher yields were obtained when the solvent volume was reduced. However, a large amount of solvent was required to dissolve fumaric acid to enable polish filtration at ambient temperature. To reduce the reaction volume, the amount of fumaric acid used for Compound 1 was reduced to 0.8-0.82 equivalents. Higher temperatures were also used to dissolve fumaric acid (40-45°C), which made it possible to dissolve the acid in 2.48 vol of 20% water in EtOH for Compound 1. Therefore, by using 2-3 times (or 2.2-2.8 times, or 2.4-2.6 times) the volume of 20% water in EtOH, the weight of Compound 1 and the yield of Compound 1·hemifumarate for dissolving Compound 1 were significantly improved by UPLC from approximately 58% (by using pure ethanol) to >95% (97%) with a product purity of over 99%. No solvate formation was observed. The table below summarizes the solvents used for dissolving fumaric acid and their corresponding yields.

[0314]

[0315] The present invention is illustrated by the following non-limiting embodiments.

[0316] Examples

[0317] Materials and Sources

[0318]

[0319] Reaction Scheme 1: Preparation process of Compound 1 and Compound 1 hemifumarate

[0320]

[0321] Example 1: Synthesis of 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide (3)

[0322]

[0323] Methyl 4-chloro-7-methoxyquinoline-6-carboxylate in THF (20 mL) 2 Methylamine (33% w / w, 8 M, 20 mL, 160 mmol) and H2O (10 mL) in EtOH were added to a suspension of (2 g, 8 mmol). The resulting mixture was stirred at room temperature. The mixture turned into a clear solution within about 10 minutes and remained a clear solution throughout the reaction. Stirring was continued until the starting material was completely consumed, as demonstrated by LCMS and HPLC. This took approximately 3 hours. The mixture was then concentrated, the residue was slurried in 20 mL of water, and filtered. Using some EtOAc, the material was transferred from the flask to a filter funnel. The product was dried to obtain 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide as a white solid (yield 1.8 g, 90%, HPLC purity > 97%).

[0324] Example 2: Synthesis of 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (4)

[0325]

[0326] 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide in a 5L, 3-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer ( 3 ; 300 g; 1 eq.), 4-aminophenol ( 5 ; 195.9 g; 1.5 eq.), and DMA (1500 mL) were filled. The resulting solution was stirred at room temperature, and sodium dissolved in anhydrous THF (313 mL) tA solution of pentoxide (184.52 g; 1.4 eq.) was added while stirring for 5 minutes. Subsequently, the reaction mixture was heated to 75-80 °C and stirred for an additional 2-6 hours. Then, the reaction mixture was cooled to room temperature, water (3 L) was added, and stirring was continued for at least an additional 1 hour. The product was filtered and washed twice with 600 mL of 1:1 DMA / water, followed by one wash with 1200 mL of water. The product was transferred to a crystallization dish and dried in a vacuum oven at 40-45 °C for at least 18 hours to obtain a light brown, shiny solid (370-377 g; 96-97%).

[0327] Example 3A: Synthesis of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (7)

[0328]

[0329] 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid ( in a 250 mL, 3-neck round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer 6 , 19.11 g; 1.3 eq.), 75 mL of anhydrous THF, and 0.25 mL of DMF (catalyst) were added. The mixture was stirred until all solids were dissolved, cooled to 5-10°C, and then oxalyl chloride (7.13 mL; 1.28 equivalents) was added. The resulting mixture was aged at 10-15°C for 2-3 hours, and reaction completion was confirmed by IPC (in process control). Upon reaction completion, the resulting product mixture was used in the next step without further purification.

[0330] Example 3B: Synthesis of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (7) [alternative method]

[0331]

[0332] 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid ( in a 250 mL, 3-neck round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer 6, 19.11 g; 1.3 eq.), 75 mL of anhydrous THF, and 0.25 mL of DMF (catalyst) were added. The mixture was stirred until all solids were dissolved, cooled to 5-15°C, and then oxalyl chloride (7.13 mL; 1.28 equivalents) was added. The resulting mixture was heated to room temperature and then stirred for 2-4 hours. The resulting product mixture was used in the next step without further purification.

[0333] Example 4A: Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1)

[0334]

[0335] 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide in a 500 mL, 3-neck round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer ( 4A solution consisting of 21.3 g (21.3 g; 1.0 eq.), 210 mL of anhydrous THF, potassium carbonate (27.32 g; 3 eq), and 100 mL of water was filled. The added aqueous K2CO3 solution was rinsed forward with an additional 6.4 mL of water. While vigorously stirring, the reaction mixture containing Compound 7 of the previous example was transferred to the main reaction mixture over a period of at least 30 minutes while maintaining an internal temperature of 20 to 25°C. The transfer equipment was rinsed with 32 mL of anhydrous THF. The reaction mixture was stirred at ambient temperature for 0.5 to 1 hour. The resulting mixture was heated to 35-40°C and phases were separated. The lower aqueous layer was discarded, and the upper organic phase was heated to 55-60°C, then polished and filtered, and rinsed with 21 mL of THF. The filtered organic phase was transferred to a 1L, three-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and mechanical stirrer, and filled with water at 55-60°C. Compound 1 was seeded into the resulting solution, and water was added as a reverse solvent over 4-4.5 hours while maintaining a temperature of 50-55°C on the resulting seed layer. The resulting slurry was cooled to 20-25°C and aged for at least 2 hours. Subsequently, the product was filtered, washed with water / THF, and dried.

[0336] Example 4B: Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1) [Alternative method]

[0337]

[0338] 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide in a 500 mL, 3-neck round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer ( 4A solution consisting of 210 mL of anhydrous THF, 27.3 g of potassium carbonate (27.32 g; 3 eq.), 21.3 g of potassium carbonate, and 100 mL of water was filled. The added aqueous K2CO3 solution was rinsed forward with an additional 6.4 mL of water. While vigorously stirring, the reaction mixture containing Compound 7 from the previous example was transferred to the main reaction mixture over a period of 0.5–1 hour while maintaining the internal temperature below 27 °C. The transfer equipment was rinsed with 32 mL of anhydrous THF. The reaction mixture was stirred at ambient temperature for 0.5–1 hour. The resulting mixture was heated to 35–40 °C and the phases were separated. The lower aqueous layer was discarded, and the upper organic phase was heated to 45–50 °C, filtered through filter paper, and rinsed with 21 mL of THF. The filtered organic phase was transferred to a 1L, three-necked round-bottom flask equipped with a thermometer, a nitrogen inlet, and a mechanical stirrer, and filled with 694 mL of filtered water over a period of at least 1 hour. The resulting mixture was stirred at 20-25°C for at least 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 filter paper at room temperature or in a vacuum oven at 40-45°C to obtain a white to beige solid (31.36 g, 90%).

[0339] Example 5: Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide·1 / 2 fumaric acid (1·hemifumarate) - Method 1

[0340]

[0341] 1.2 L of a 2000 mL, 3-necked round-bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was filled with fumaric acid (80 g; 0.82 equivalents) and a 20% solution of water in ethanol. The mixture was heated to 45-50°C and stirred until all solids were dissolved. N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide ( 1500 g (1.0 eq.) was filled. The fumaric acid solution was purified through filter paper at 40-45°C and transferred to a flask containing Compound 1 at 40-45°C. A 2000 mL round-bottom flask was rinsed with a 20% water solution in 300 mL of ethanol at 45-50 °C. The resulting mixture was refluxed (75-80°C) and stirred for 4-6 hours. Subsequently, the reaction mixture was cooled to room temperature, the product was filtered, and the filter cake was washed twice with 300 mL of a 20% water solution in ethanol. The product was then dried on filter paper at room temperature or in a vacuum oven at 40-45°C to obtain a white to beige solid (472-474 g, 97%).

[0342] Example 6: Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide·1 / 2 fumaric acid (1·hemifumarate) - Method 2

[0343]

[0344] Fumaric acid (2.68 g, 1 equivalent) and EtOH / acetone, 1:1 (48 mL) were added to a 2-piece EasyMax (EM) reaction vessel and heated to a reaction temperature of 50°C to dissolve all substances. A 1-piece EM vessel containing Compound 1 (12.0 g, 1 equivalent) in an adjacent EM port was set to a jacket temperature of 50°C. The fumaric acid solution was transferred to the vessel containing Compound 1. Seed was added (2% seed, 0.244 g), and the vessel was refluxed (-65°C). After 1 hour, 0.5 mL of the slurry was filtered, washed with EtOH (6 x 1.5 mL), and analyzed by HPLC to determine the fumaric acid content (the result should be approximately 10%). Subsequently, the slurry was cooled to 25°C over 1 hour and stirred for an additional 1 hour. Next, the solid was filtered, washed with 1:1 EtOH / acetone (2 x 3 V), and dried under vacuum at 25°C for a weekend. 1 H NMR 700 MHz (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 F NMR 700 MHz (DMSO-d6; ref. -63.72ppm사진 타후오로파르었) δ -121.460. 13 C NMR 700 MHz (DMSO-d6) δ 15.46, δ 26.47, δ 31.60, δ 56.15, δ 102.91, δ 107.83, δ 114.55, δ 115.05 (d, 2 J 19F-13C = 22.2 Hz), δ 121.15, δ 122.23, δ 122.43 (d, 3 J 19F-13C = 7.6 Hz), δ 124.35, δ 125.24, δ 134.03, δ 135.22 (d, 4 J 19F-13C = 2.4 Hz), δ 136.73, δ 149.08, δ 151.46, δ 153.18, δ 157.94, δ 158.30 (d, 1 J 19F-13C= 240.2 Hz), δ 161.76, δ 164.89, δ 168.16, and δ 168.16. 15 N NMR 700 MHz (DMSO-d6) δ 106.25 ( 15 N), δ 127.79 ( 15 N), δ 128.86 ( 15 N), δ 166.04, δ 289.56 ( 15 N).

[0345] Other embodiments

[0346] The foregoing disclosure has been described in detail as an illustration and example for clarity and understanding. The present invention is described by reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made within the spirit and scope of the present invention. It is evident to those skilled in the art that variations and modifications may be made within the scope of the appended description. Accordingly, it should be understood that the foregoing description is illustrative and not intended to be limiting.

[0347] Accordingly, the scope of the present invention should be determined without reference to the foregoing description and instead by reference to the following appended claims together with the entire scope of equivalents to such claims.

Claims

Claim 1 A process for preparing compound 1 or a pharmaceutically acceptable salt thereof, and: Compound 4 compound of chemical formula III' A process comprising the step of contacting in the presence of a solvent and a base (wherein LG is a leaving group selected from Cl, Br, and I), and optionally further comprising the step of contacting compound 1 with an acid to produce a pharmaceutically acceptable salt of compound 1. Claim 2 In claim 1, the base is an inorganic base selected from NaOH, Na2CO3, K2CO3, NaHCO3, and KHCO3, and the solvent is a mixture of water and an organic solvent, wherein the organic 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. Claim 3 A process according to claim 1 or 2, wherein the solvent is a mixture of water and tetrahydrofuran. Claim 4 A process according to paragraph 3 in which the solvent is a 2:1 tetrahydrofuran:water to 3:1 tetrahydrofuran:water ratio. Claim 5 A process according to claim 1 or 2, wherein the step of contacting compound 4 with a compound of formula III' comprises adding a solution of the compound of formula III' dissolved in tetrahydrofuran to a solution of compound 4 dissolved in tetrahydrofuran:water in a 2:1 ratio to produce a reaction mixture. Claim 6 A process according to claim 5, wherein the reaction mixture is maintained at a temperature of 20 to 25°C, then heated to 35 to 40°C and left to stand to separate into an organic phase and an aqueous phase, subsequently discarding the aqueous phase, heating the organic phase to 55 to 60°C, and subsequently filtering the organic phase at 55 to 60°C. Claim 7 A process according to claim 6 further comprising the step of adding water to an organic phase to produce a second mixture while maintaining a temperature of 50 to 55°C over a period of at least 1 hour, stirring the second mixture for 2 hours or more, and obtaining a solid product. Claim 8 In paragraph 1 or 2, compound 6 React with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride to form compound 7 A process that additionally includes a step of manufacturing. Claim 9 A process according to claim 8, wherein the reagent is oxalyl chloride, and the process is carried out at a temperature between 5°C and 15°C in the presence of a catalytic amount of dimethylformamide and tetrahydrofuran organic solvent. Claim 10 In paragraph 1 or 2, compound 3 React with 4-aminophenol (5) to form compound 4 A process that additionally includes a step of providing Claim 11 In claim 10, the reaction of compound 3 and 4-aminophenol (5) is carried out in the presence of an organic solvent selected from acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, hexamethylphosphate triamide (HMPT), tetrahydrofuran, 1,4-dioxane, and dichloromethane. Claim 12 A process in which the organic solvent in Clause 11 is dimethylacetamide. Claim 13 In claim 10, the reaction of compound 3 and 4-aminophenol (5) is carried out in the presence of a base selected from 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, and cesium t-pentoxide. Claim 14 In paragraph 13, the process in which the base is sodium t-pentoxide. Claim 15 In claim 10, the reaction of compound 3 and 4-aminophenol (5) is carried out at a temperature of 75 to 80°C, and compound 4 is isolated by adding water to the reaction mixture and providing solid compound 4. Claim 16 In claim 1 or 2, compound 1 is reacted with fumaric acid to form compound 1-hemifumarate A process that additionally includes a step of providing Claim 17 A process according to claim 16 in which the reaction of compound 1 with fumaric acid is carried out in the presence of a solvent selected from water, an alcoholic solvent, THF, DMF, MEK, acetonitrile, 1,4-dioxane, and MTBE, or a combination thereof. Claim 18 In paragraph 17, the process in which the solvent is a 20% solution of water in ethanol. Claim 19 A process according to claim 16, comprising the step of reacting compound 1 with fumaric acid by adding a mixture of fumaric acid dissolved in a solvent of 20% water solution in ethanol at 45 to 50°C to compound 1 to produce a reaction mixture, further comprising the steps of reflux heating the reaction mixture, stirring the reaction mixture under reflux for 4 to 6 hours, cooling the reaction mixture, and separating compound 1-hemifumarate from the solvent. Claim 20 A process for preparing compound 1 or a pharmaceutically acceptable salt thereof, and: Compound 3 dimethylacetamide and sodium t - React with 4-aminophenol (5) at a temperature of 75 to 80°C in the presence of pentoxide to produce compound 4 A step of providing a first reaction mixture comprising, a step of adding water to the first reaction mixture to precipitate compound 4 as a solid and isolate it, compound 6 compound 7 is reacted with oxalyl chloride at a temperature of 5 to 15°C in the presence of tetrahydrofuran and a catalytic amount of dimethylformamide. A process comprising the steps of: preparing a second reaction mixture comprising; preparing a fourth reaction mixture by adding the second reaction mixture to a third reaction mixture comprising a solvent of 2:1 tetrahydrofuran:water, a base of K2CO3, and compound 4 over a period of at least 30 minutes, wherein the temperature of the fourth reaction mixture is maintained below 27°C during the addition; heating the fourth reaction mixture to 35 to 40°C and allowing it to stand to separate it into an organic phase and an aqueous phase; discarding the aqueous phase and heating the organic phase to 55 to 60°C, and subsequently filtering the organic phase at 55 to 60°C; adding water to the organic phase over a period of at least 1 hour to produce a fifth reaction mixture; stirring the fifth reaction mixture for at least 2 hours; and isolating compound 1 as a solid product, optionally further comprising the step of contacting compound 1 with an acid to prepare a pharmaceutically acceptable salt of compound 1. Claim 21 It is a process for manufacturing compound 1-hemifumarate, and: A mixture of fumaric acid dissolved in a solvent of a 20% water solution in ethanol at 45 to 50°C, Compound 1 A process comprising the steps of: adding to produce a reaction mixture; heating the reaction mixture under reflux; stirring the reaction mixture under reflux for 4 to 6 hours; cooling the reaction mixture; and filtering the reaction mixture to obtain compound 1·hemifumarate as a solid. 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