Process and intermediates in the synthesis of MRTX0902

Abstract

The present invention relates to a novel synthetic route for the preparation of MRTX0902. The present invention also provides intermediates used in the provided synthetic route, and the fumarate salt of MRTX0902.

Description

[Technical Field]

[0001] The present invention relates to a new and improved synthetic route for the synthesis of MRTX0902, as well as the fumarate salt of MRTX0902. [Background technology]

[0002] The Ras family, which includes the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and Harvey murine sarcoma viral oncogene (HRAS), critically regulates cell division, growth, and function under normal and altered conditions, including cancer (see, e.g., Simanshu et al. Cell, 2017. 170(1): pp. 17-33; Matikas et al., Crit Rev Oncol Hematol, 2017. 110: pp. 1-12). RAS proteins are activated by upstream signals, including receptor tyrosine kinases (RTKs), and signal several downstream pathways, such as the mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) pathway. Hyperactivation of RAS signaling is frequently observed in cancer as a result of mutations or alterations in RAS genes or other genes in the RAS pathway. Identification of strategies to inhibit RAS and RAS signaling is predicted to be useful in the treatment of cancer and RAS-regulated disease states.

[0003] RAS proteins are guanosine triphosphate phosphatases (GTPases) that alternate between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate-bound state. Son of sevenless homolog 1 (SOS1) is a guanine nucleotide exchange factor (GEF) that mediates the exchange of GDP for GTP, thereby activating RAS proteins. RAS proteins hydrolyze GTP to GDP through their intrinsic GTPase activity, which is greatly facilitated by GTPase-activating proteins (GAPs). This regulation via GAPs and GEFs provides a mechanism by which activation and inactivation are tightly controlled under normal conditions. Mutations at several residues in all three RAS proteins are frequently observed in cancer, resulting in RAS remaining predominantly activated (Sanchez-Vega et al., Cell, 2018. 173: pp. 321-337; Li et al., Nature Reviews Cancer, 2018. 18: pp. 767-777). Mutations at codons 12 and 13 are the most frequently mutated RAS residues, disrupting the interaction between GAP proteins and RAS, thereby preventing GAP-stimulated GTP hydrolysis. However, recent biochemical analysis has shown that these mutant proteins still require nucleotide cycling for activation, based on intrinsic GTPase activity and / or partial sensitivity to exogenous GTPases. Therefore, mutant RAS proteins are susceptible to inhibition of upstream factors such as SOS1 or SHP2, another upstream signaling molecule required for RAS activation (Hillig, 2019; Patricelli, 2016; Lito, 2016; Nichols, 2018).

[0004] Three major RAS-GEF families have been identified in mammalian cells: SOS, RAS-GRF, and RAS-GRP (Rojas, 2011). The SOS family is ubiquitous and plays a role in transducing RTK signaling, whereas RAS-GRF and RAS-GRP are expressed in central nervous system cells and hematopoietic cells, respectively. The SOS family includes SOS1 and SOS2, which share approximately 70% sequence identity. SOS1 appears to be much more active than SOS2, as SOS2 is rapidly degraded. SOS2 knockout mice are viable, whereas SOS1 knockouts are embryonic lethal. A tamoxifen-inducible SOS1 knockout mouse model was used to investigate the role of SOS1 and SOS2 in adult mice, showing that SOS1 knockouts are viable, whereas SOS1 / 2 double knockouts are not (Baltanas, 2013), suggesting functional redundancy and that selective inhibition of SOS1 may have a sufficient therapeutic index for the treatment of SOS1-RAS activated diseases.

[0005] SOS proteins are recruited to phosphorylated RTKs through interactions with growth factor receptor-bound protein 2 (GRB2). Recruitment to the plasma membrane brings SOS into close proximity with RAS, enabling SOS-mediated RAS activation. SOS proteins bind to RAS through a binding site that promotes nucleotide exchange and an allosteric site that binds to GTP-bound RAS family proteins and enhances SOS function (Freedman et al., Proc. Natl. Acad. Sci, USA 2006. 103(45): pp. 16692-97). Binding to the allosteric site relieves steric blockage of the RAS substrate binding site and is therefore required for nucleotide exchange. After interaction with the allosteric site, the catalytic site maintains its activated conformation by strengthening the interactions of the key domains in the activated state, maintaining their separation. SOS1 mutations are found in Noonan syndrome and several cancers, including lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and granular cell tumor of the skin (see, e.g., Denayer, E., et al, Genes Chromosomes Cancer, 2010. 49(3): p. 242-52).

[0006] GTPase-activating proteins (GAPs) stimulate the low intrinsic GTPase activity of RAS family members, thereby converting active GTP-bound RAS proteins into inactive GDP-bound RAS proteins (see, e.g., Simanshu, DK, Cell, 2017, Ras Proteins and Their Regulators in Human Disease). In cancer, activating alterations in the GEF SOS1 occur, while inactivating and loss-of-function alterations in the GAPs neurofibromin 1 (NF-1) or neurofibromin 2 (NF-2) also occur, leading to uninhibited SOS1 activation and increased activity of downstream pathways mediated by RAS proteins.

[0007] Therefore, compounds of the present invention that inhibit the interaction between SOS1 and RAS family members may prevent the recycling of KRas to its active GTP-bound form, thereby providing therapeutic effects against a wide range of cancers, particularly cancers associated with Ras family members. The compounds of the present invention have therapeutic effects as inhibitors of the SOS1-KRas interaction and may be useful for negatively modulating KRas activity in cells through inhibition of the SOS1-KRas interaction to treat various forms of cancer (Ras-associated cancers, SOS1-associated cancers, and NF1 / NF2-associated cancers).

[0008] The SOS1 inhibitor compound (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (also known as MRTX0902) has the following structure: [ka] It has. MRTX0902 is described, for example, in Examples 12-10 of PCT Application WO 2021 / 127429. While WO 2021 / 127429 describes methods for making MRTX0902, there is a need in the art for new and improved synthetic routes to make MRTX0902. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2021 / 127429 [Non-patent literature]

[0010] [Non-Patent Document 1] Simanshu et al. Cell, 2017. 170(1): p. 17-33 [Non-patent document 2] Matikas et al., Crit Rev Oncol Hematol, 2017. 110: p. 1-12 [Non-patent document 3] Sanchez-Vega et al., Cell, 2018. 173: p. 321-337 [Non-patent document 4] Li et al., Nature Reviews Cancer, 2018. 18: p. 767-777 [Non-Patent Document 5] Freedman et al., Proc. Natl. Acad. Sci, USA 2006. 103(45): p. 16692-97 [Non-patent document 6] Denayer, E., et al, Genes Chromosomes Cancer, 2010. 49(3): p. 242-52 [Non-Patent Document 7] Simanshu, DK, Cell, 2017, Ras Proteins and their Regulators in Human Disease Summary of the Invention

[0011] The present invention, in some embodiments, provides new and improved methods for preparing MRTX0902 (i.e., (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile).

[0012] In one embodiment, the present invention provides a method for synthesizing (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: a) the following structure: [ka] with hydrazine or a hydrazine salt in the presence of an acid and a solvent to give a compound having the following structure: [ka] and preparing the final compound of step a) represented by The present invention provides a method of synthesis comprising:

[0013] In some embodiments, step a) is carried out at a temperature of about 30°C to about 150°C.

[0014] In certain embodiments, the solvent is selected from the group consisting of dimethylacetamide (DMAc), dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), toluene, and an alcohol of the formula R—OH, where R is alkyl, allyl, or aryl.

[0015] In a more preferred embodiment, the solution is ethanol.

[0016] In certain embodiments, the acid is selected from the group consisting of inorganic acids and organic acids.

[0017] In certain embodiments, the acid is an inorganic acid selected from the group consisting of hydrogen halides of the general formula HX, where X is F, Cl, Br, or I, nitric acid, phosphoric acid, sulfuric acid, boric acid, and perchloric acid.

[0018] In another embodiment, the acid is an organic acid selected from the group consisting of sulfonic acids of the general formula RSO3H, where R is alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or aryl, and carboxylic acids (having one or more carboxylic acid moieties) of the general formula RCOH, where R is alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or aryl. In certain embodiments, the organic acid is selected from the group consisting of lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, and tartaric acid.

[0019] In a more preferred embodiment, the acid is acetic acid.

[0020] In one embodiment, the method comprises:

[0021] b) reacting the final compound of step a) with a chlorinating agent in the presence of an aprotic solvent to give a compound of the following structure: [ka] and preparing the final compound of step b) shown in Further includes:

[0022] In some embodiments, step b) is carried out at a temperature of about 30°C to about 150°C.

[0023] In certain embodiments, the chlorinating agent is selected from the group consisting of phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, thionyl chloride, diaryl or dialkyl chlorophosphates, diaryl chlorophosphites, and dialkyl chlorophosphites.

[0024] In a more preferred embodiment, the chlorinating agent is phosphorus oxychloride.

[0025] In certain embodiments, the aprotic solvent is selected from the group consisting of chloroform, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, toluene, tertiary amines, and NMP.

[0026] In a more preferred embodiment, the aprotic solvent is MeCN.

[0027] In one embodiment, the method comprises:

[0028] c) reacting the final compound of step b) with benzylamine or a benzylamine salt in the presence of a base, a Lewis acid, and a high boiling point solvent to produce a compound of the following structure: [ka] and preparing the final compound of step c) shown in Further includes:

[0029] In some embodiments, step c) is carried out at a temperature of about 50°C to about 170°C.

[0030] In certain embodiments, the base is selected from the group consisting of organic bases and inorganic bases.

[0031] In certain embodiments, the base is an organic base selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0032] In a more preferred embodiment, the organic base is DIPEA.

[0033] In another embodiment, the base is an inorganic base selected from the group consisting of carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

[0034] In certain embodiments, the Lewis acid is selected from the group consisting of magnesium salts, calcium salts, aluminum-based reagents, and boron-based reagents.

[0035] In a more preferred embodiment, the Lewis acid is magnesium chloride.

[0036] In some embodiments, the high boiling point solvent is selected from the group consisting of toluene, DMAc, DMF, 1,4-dioxane, DMSO, NMP, and alcohols of the formula R—OH, where R is alkyl, allyl, or aryl.

[0037] In a more preferred embodiment, the high boiling point solvent is tAmOH (tert-amyl alcohol).

[0038] In one embodiment, the present invention provides a method for preparing (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising:

[0039] The following structure: [ka] With hydrazine or a hydrazine salt in the presence of an acid and a solvent to give a compound of the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0040] More preferred embodiments regarding solvents, acids, and temperature ranges are as described above for step a).

[0041] In another embodiment, the present invention provides a method for preparing (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: [ka] is reacted with a chlorinating agent in the presence of an aprotic solvent to produce a compound of the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0042] More preferred embodiments regarding the chlorinating agent, aprotic solvent, and temperature range are as described above for step b).

[0043] In another embodiment, the present invention provides a method for producing MRTX0902, comprising the steps of: [ka] is reacted with benzylamine or a benzylamine salt in the presence of a base, a Lewis acid, and a high boiling point solvent to give the compound of the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0044] More preferred embodiments regarding the base, Lewis acid, high boiling point solvent, and temperature range are as described above for step c).

[0045] In another embodiment, the present invention provides a method for preparing (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: The following structure: [ka] With hydrazine or a hydrazine salt in the presence of an acid and a solvent to give a compound of the following structure: [ka] preparing a compound represented by the formula: [ka] is reacted with a chlorinating agent in the presence of an aprotic solvent to produce a compound of the following structure: [ka] preparing a compound represented by the formula: [ka] is reacted with benzylamine in the presence of a base, a Lewis acid, and a high boiling point solvent to give the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0046] More preferred embodiments regarding solvents, acids, chlorinating agents, aprotic solvents, bases, Lewis acids, high boiling point solvents, and temperature ranges are as described above for steps a), b), and c).

[0047] In one embodiment, the present invention provides a method for preparing (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: The following structure: [ka] is reacted with hydrazine hydrate in the presence of acetic acid and ethanol to give the compound of the following structure: [ka] preparing a compound represented by the formula: [ka] is reacted with phosphorus oxychloride in the presence of MeCN to give the following structure: [ka] preparing a compound represented by the formula: [ka] in the presence of DIPEA, MgCl2, and tAmOH [ka] to react with the compound having the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0048] In another embodiment, the present invention provides a method for preparing a fumarate salt of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: The following structure: [ka] With hydrazine or a hydrazine salt in the presence of an acid and a solvent to give a compound of the following structure: [ka] preparing a compound represented by the formula: [ka] is reacted with a chlorinating agent in the presence of an aprotic solvent to give the compound of the following structure: [ka] preparing a compound represented by the formula: [ka] is reacted with benzylamine in the presence of a base, a Lewis acid, and a high boiling point solvent to give the following structure: [ka] preparing a compound of the formula: [ka] is reacted with fumaric acid in the presence of a solvent to give the compound of the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0049] More preferred embodiments regarding solvents, acids, chlorinating agents, aprotic solvents, bases, Lewis acids, high boiling point solvents, and temperature ranges are as described above for steps a), b), and c).

[0050] In certain embodiments, in the fourth step (reacting (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile with fumaric acid), the solvent is selected from the group consisting of DMAc, DMF, THF, 2-MeTHF, MeCN, DMSO, NMP, toluene, and an alcohol of the formula R—OH, where R is alkyl, allyl, or aryl. In a more preferred embodiment, the solvent is ethanol.

[0051] In a more preferred embodiment, the solvent is ethanol.

[0052] In some embodiments, the fourth step is carried out at a temperature of about 15°C to about 135°C.

[0053] In another embodiment, the present invention provides a method for preparing a fumarate salt of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: The following structure: [ka] is reacted with hydrazine hydrate in the presence of acetic acid and ethanol to give the compound of the following structure: [ka] preparing a compound represented by the formula: [ka] is reacted with phosphorus oxychloride in the presence of MeCN to give the following structure: [ka] preparing a compound represented by the formula: [ka] in the presence of DIPEA, MgCl2, and tAmOH. [ka] to react with the compound having the following structure: [ka] preparing a compound of the formula: [ka] is reacted with fumaric acid in the presence of ethanol to give the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0054] In another embodiment, the present invention provides novel intermediates such as: [ka]

[0055] In another embodiment, the present invention provides a compound having the following structure: [ka] The present invention provides a fumarate salt of MRTX0902 having the formula: DETAILED DESCRIPTION OF THE INVENTION

[0056] The present invention relates to novel synthetic routes for synthesizing MRTX0902, as well as novel intermediates used in the provided routes, and fumarate salts of MRTX0902.

[0057] While there are known methods for synthesizing MRTX0902 (see WO 2021 / 127429), the synthesis provided in the present invention is a significant improvement in that it involves fewer steps and provides higher overall isolated yields and higher purity.

[0058] Additionally, the expensive chiral benzylamine was introduced into the final synthesis, thus maximizing its usage. The reaction sequence was also modified to improve yield and selectivity, avoiding the use of laborious purification methods while automatically reducing the associated costs and significantly improving purity.

[0059] The overall MRTX0902 yield was increased almost four-fold (from 18% to 69%) using the described process, demonstrating multi-kilogram scale (8 kg) with a shorter time cycle.

[0060] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications referenced herein are hereby incorporated by reference.

[0061] As used herein, "KRas G12C" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The amino acid codon assignments and residue positions of human KRas are based on the amino acid sequence identified in UniProtKB / Swiss-Prot P01116: Variant p.Gly12Cys.

[0062] As used herein, "KRas G12C-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12C mutation. Examples of KRas G12C-associated diseases or disorders include, but are not limited to, KRas G12C-associated cancers.

[0063] As used herein, the term "MRTX0902" refers to the compound having the name (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile and the following structure: [ka] It refers to a compound represented by the formula:

[0064] MRTX0902 is described, for example, in Examples 12-10 of PCT Application WO 2021 / 127429.

[0065] The term "MRTX0902" encompasses all chiral (enantiomers and diastereomers) and racemic forms of the compound.

[0066] In certain embodiments, the term "MRTX0902" refers to a salt of the above compound, for example, a salt formed with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid), an organic acid (acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, arginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and fumaric acid), -NRZ- (wherein R is hydrogen, alkyl, or benzyl and Z is a counterion (e.g., chloride ion, bromide ion), , iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, benzilate, and diphenylacetate).

[0067] As used herein, "SOS1" refers to the mammalian Son of sevenless homolog 1 (SOS1) enzyme.

[0068] As used herein, "SOS1-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having an active SOS1 mutation. Examples of active SOS1 mutations include SOS1 N233S and SOS1 N233Y mutations.

[0069] As used herein, "SOS1-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having an active SOS1 mutation. Examples of active SOS1 mutations include SOS1 N233S and SOS1 N233Y mutations.

[0070] As used herein, "SOS1 N233S" refers to a mutant form of a mammalian SOS1 protein that contains an amino acid substitution of glutamine with serine at amino acid position 233. The amino acid codon assignments and residue positions for human SOS1 are based on the amino acid sequence identified in UniProtKB / Swiss-Prot Q07889: Variant p.Gln233Ser.

[0071] As used herein, "SOS1 N233Y" refers to a mutant form of a mammalian SOS1 protein containing an amino acid substitution of glutamine with tyrosine at amino acid position 233. The amino acid codon assignments and residue positions for human SOS1 are based on the amino acid sequence identified in UniProtKB / Swiss-Prot Q07889: Variant p.Gln233Tyr.

[0072] Whenever this application refers to a compound, unless otherwise specified, the compound includes all chiral (enantiomers and diastereomers) and racemic forms of that compound.

[0073] Unless otherwise specified in this application, "R" refers to a group such as alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, carbocycle, cycloalkyl, heteroalkyl, heterocycle, aryl, aralkyl, or arylalkyl.

[0074] The term "alkyl" is intended to mean a straight or branched chain aliphatic group having from 1 to 12 carbon atoms, alternatively 1 to 8 carbon atoms, alternatively 1 to 6 carbon atoms. Other examples of alkyl groups have from 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms, alternatively 2 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like. A "C0" alkyl (as in "C0-C3 alkyl") is a covalent bond.

[0075] The term "alkenyl" is intended to mean an unsaturated straight- or branched-chain aliphatic group having from 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms, alternatively 2 to 6 carbon atoms, and having one or more carbon-carbon double bonds. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0076] The term "alkynyl" is intended to mean an unsaturated straight- or branched-chain aliphatic group having from 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms, alternatively 2 to 6 carbon atoms, and having one or more carbon-carbon triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0077] As used herein, the terms "alkylene," "alkenylene," or "alkynylene" are intended to mean an alkyl, alkenyl, or alkynyl group, respectively, as defined above, that is positioned between and serves to connect two other chemical groups. Examples of alkylenes include, but are not limited to, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene. Examples of alkylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0078] As used herein, the term "carbocycle" is intended to mean a cycloalkyl or cycloaryl moiety.

[0079] The term "cycloalkyl" is intended to mean a saturated or unsaturated monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group having 3 to 15 carbon atoms, alternatively 3 to 12 carbon atoms, alternatively 3 to 8 carbon atoms, alternatively 3 to 6 carbon atoms, alternatively 5 or 6 carbon atoms. In certain embodiments, the cycloalkyl group is fused with an aryl, heteroaryl, or heterocyclic group. Examples of cycloalkyl groups include, but are not limited to, cyclopenten-2-enone, cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, etc.

[0080] The term "heteroalkyl" is intended to mean a saturated or unsaturated straight or branched chain aliphatic group, in which one or more carbon atoms of the group are independently replaced with a heteroatom selected from the group consisting of O, S, and N.

[0081] The term "aryl" is intended to mean a monocyclic, bicyclic, tricyclic, or polycyclic aromatic moiety, e.g., a C6-C14 aromatic moiety consisting of one to three aromatic rings. Alternatively, the aryl group is a C6-C10 aryl group, or a C6 aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0082] The term "aralkyl" or "arylalkyl" is intended to mean a group comprising an aryl group covalently bonded to an alkyl group. When an aralkyl group is described as "optionally substituted," it is intended that both or either of the aryl and alkyl portions are independently optionally substituted or unsubstituted. Alternatively, the aralkyl group is (C-C) alkyl(C-C) aryl ((C-C) alk(C-C) aryl), including, but not limited to, benzyl, phenethyl, and naphthylmethyl. For brevity, when the term "arylalkyl" and related terms are used, it is intended to indicate the order of groups in the compound as "aryl-alkyl." Similarly, "alkyl-aryl" is intended to indicate the order of groups in the compound as "alkyl-aryl."

[0083] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compound and exhibits minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to, acid addition salts formed from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and acid addition salts formed from organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid). The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, including, among others, quaternary ammonium salts of the formula -NRZ-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion such as chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, benzilate, and diphenylacetate).

[0084] As used herein, the term "mineral acid" (or "inorganic acid") refers to any acid derived from an inorganic compound that dissociates in water to produce hydrogen ions (H+). Examples of inorganic acids include, but are not limited to, hydrogen halides of the general formula HX (where X is F, Cl, Br, or I), nitric acid, phosphoric acid, sulfuric acid, boric acid, and perchloric acid.

[0085] As used herein, the term "organic acid" refers to any organic compound having acidic properties. Examples of organic acids include, but are not limited to, sulfonic acids of the general formula RSO3H, where R can be alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or aryl, as defined above, and carboxylic acids (having one or more carboxylic acid moieties) of the general formula RCO2H, where R can be alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or aryl, as defined above. Examples of organic acids include, but are not limited to, lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, and tartaric acid.

[0086] Synthesis scheme In one embodiment, the present invention provides a method for synthesizing MRTX0902, comprising: a) the following structure: [ka] with hydrazine or a hydrazine salt in the presence of an acid and a solvent to give a compound having the following structure: [ka] and preparing the final compound of step a) represented by The present invention provides a method of synthesis comprising:

[0087] In some embodiments, step a) is carried out at a temperature of about 30°C to about 150°C.

[0088] In certain embodiments, the solvent is selected from the group consisting of dimethylacetamide (DMAc), dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), toluene, and an alcohol of the formula R—OH, where R is alkyl, allyl, or aryl.

[0089] In certain embodiments, the solvent includes, but is not limited to, one or more of dimethylacetamide (DMAc), dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), toluene, and alcohols of the formula R—OH, where R is alkyl, allyl, or aryl.

[0090] In a more preferred embodiment, the solution is ethanol.

[0091] In certain embodiments, the acid is selected from the group consisting of inorganic acids and organic acids.

[0092] In certain embodiments, the acid is an inorganic acid selected from the group consisting of hydrogen halides of the general formula HX, where X is F, Cl, Br, or I, nitric acid, phosphoric acid, sulfuric acid, boric acid, and perchloric acid.

[0093] In certain embodiments, the acid is an inorganic acid, including, but not limited to, one or more of hydrogen halides of the general formula HX (wherein X is F, Cl, Br, or I), nitric acid, phosphoric acid, sulfuric acid, boric acid, and perchloric acid.

[0094] In another embodiment, the acid is an organic acid selected from the group consisting of sulfonic acids of the general formula RSO3H, where R is alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or aryl, and carboxylic acids (having one or more carboxylic acid moieties) of the general formula RCOH, where R is alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or aryl. In certain embodiments, the organic acid is selected from the group consisting of lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, and tartaric acid.

[0095] In certain embodiments, the acid is an organic acid including, but not limited to, one or more sulfonic acids of the general formula RSO3H, where R is alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or aryl, and carboxylic acids (having one or more carboxylic acid moieties) of the general formula RCO2H, where R is alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or aryl.

[0096] In a more preferred embodiment, the acid is acetic acid.

[0097] In one embodiment, the method comprises:

[0098] b) reacting the final compound of step a) with a chlorinating agent in the presence of an aprotic solvent to give a compound of the following structure: [ka] and preparing the final compound of step b) shown in Further includes:

[0099] In some embodiments, step b) is carried out at a temperature of about 30°C to about 150°C.

[0100] In certain embodiments, the chlorinating agent is selected from the group consisting of phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, thionyl chloride, diaryl or dialkyl chlorophosphates, diaryl chlorophosphites, and dialkyl chlorophosphites.

[0101] In certain embodiments, the chlorinating agent includes, but is not limited to, one or more of phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, thionyl chloride, diaryl or dialkyl chlorophosphates, diaryl chlorophosphites, and dialkyl chlorophosphites.

[0102] In a more preferred embodiment, the chlorinating agent is phosphorus oxychloride.

[0103] In certain embodiments, the aprotic solvent is selected from the group consisting of chloroform, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, toluene, tertiary amines, and NMP.

[0104] In certain embodiments, aprotic solvents include, but are not limited to, one or more of chloroform, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, toluene, tertiary amines, and NMP.

[0105] In a more preferred embodiment, the aprotic solvent is MeCN.

[0106] In one embodiment, the method comprises:

[0107] c) reacting the final compound of step b) with benzylamine or a benzylamine salt in the presence of a base, a Lewis acid, and a high boiling point solvent to give the compound of the following structure: [ka] and preparing the final compound of step c) shown in Further includes:

[0108] In some embodiments, step c) is carried out at a temperature of about 50°C to about 170°C.

[0109] In certain embodiments, the base is selected from the group consisting of organic bases and inorganic bases.

[0110] In certain embodiments, the base is an organic base selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0111] In certain embodiments, the base is an organic base, including, but not limited to, one or more of DIPEA, Et3N, DABCO, and DBU.

[0112] In a more preferred embodiment, the organic base is DIPEA.

[0113] In another embodiment, the base is an inorganic base selected from the group consisting of carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

[0114] In another embodiment, the base is an inorganic base, including but not limited to one or more of carbonates, bicarbonates, and phosphates (including monobasic, dibasic, and tribasic phosphates).

[0115] In certain embodiments, the Lewis acid is selected from the group consisting of magnesium salts, calcium salts, aluminum-based reagents, and boron-based reagents.

[0116] In certain embodiments, Lewis acids include, but are not limited to, one or more of magnesium salts, calcium salts, aluminum-based reagents, and boron-based reagents.

[0117] In a more preferred embodiment, the Lewis acid is magnesium chloride.

[0118] In some embodiments, the high boiling point solvent is selected from the group consisting of toluene, DMAc, DMF, 1,4-dioxane, DMSO, NMP, and alcohols of the formula R—OH, where R is alkyl, allyl, or aryl.

[0119] In some embodiments, high boiling point solvents include, but are not limited to, one or more of toluene, DMAc, DMF, 1,4-dioxane, DMSO, NMP, and alcohols of the formula R—OH, where R is alkyl, allyl, or aryl.

[0120] In a more preferred embodiment, the high boiling point solvent is tAmOH (tert-amyl alcohol).

[0121] In one embodiment, the present invention provides a method for producing MRTX0902, comprising the steps of:

[0122] The following structure: [ka] with hydrazine or a hydrazine salt in the presence of an acid and a solvent to give a compound of the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0123] More preferred embodiments regarding solvents, acids, and temperature ranges are as described above for step a).

[0124] In another embodiment, the present invention provides a method for producing MRTX0902, comprising the steps of:

[0125] [ka] is reacted with a chlorinating agent in the presence of an aprotic solvent to produce a compound of the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0126] More preferred embodiments regarding the chlorinating agent, aprotic solvent, and temperature range are as described above for step b).

[0127] In another embodiment, the present invention provides a method for producing MRTX0902, comprising the steps of: [ka] is reacted with benzylamine or a benzylamine salt in the presence of a base, a Lewis acid, and a high boiling point solvent to give the compound of the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0128] More preferred embodiments regarding the base, Lewis acid, high boiling point solvent, and temperature range are as described above for step c).

[0129] In another embodiment, the present invention provides a method for producing MRTX0902, comprising the steps of: The following structure: [ka] With hydrazine or a hydrazine salt in the presence of an acid and a solvent to give a compound of the following structure: [ka] preparing a compound represented by the formula: [ka] is reacted with a chlorinating agent in the presence of an aprotic solvent to produce a compound of the following structure: [ka] preparing a compound represented by the formula: [ka] is reacted with benzylamine or a benzylamine salt in the presence of a base, a Lewis acid, and a high boiling point solvent to give the compound of the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0130] More preferred embodiments regarding solvents, acids, chlorinating agents, aprotic solvents, bases, Lewis acids, high boiling point solvents, and temperature ranges are as described above for steps a), b), and c).

[0131] In one embodiment, the present invention provides a method for producing MRTX0902, comprising the steps of: The following structure: [ka] is reacted with hydrazine hydrate in the presence of acetic acid and ethanol to give the compound of the following structure: [ka] preparing a compound represented by the formula: [ka] is reacted with phosphorus oxychloride in the presence of MeCN to give the following structure: [ka] preparing a compound represented by the formula: [ka] in the presence of DIPEA, MgCl2, and tAmOH [ka] to react with the compound having the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0132] In another embodiment, the present invention provides a method for preparing a fumarate salt of MRTX0902, comprising the steps of: The following structure: [ka] With hydrazine or a hydrazine salt in the presence of an acid and a solvent to give a compound of the following structure: [ka] preparing a compound represented by the formula: [ka] is reacted with a chlorinating agent in the presence of an aprotic solvent to give the compound of the following structure: [ka] preparing a compound represented by the formula: [ka] is reacted with benzylamine or a benzylamine salt in the presence of a base, a Lewis acid, and a high boiling point solvent to give the compound of the following structure: [ka] preparing a compound of the formula: [ka] is reacted with fumaric acid in the presence of a solvent to give the compound of the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0133] More preferred embodiments regarding solvents, acids, chlorinating agents, aprotic solvents, bases, Lewis acids, high boiling point solvents, and temperature ranges are as described above for steps a), b), and c).

[0134] In some embodiments, in the fourth step (reacting MRTX0902 with fumaric acid), the solvent is selected from the group consisting of DMAc, DMF, THF, 2-MeTHF, MeCN, DMSO, NMP, toluene, and an alcohol of the formula R-OH, where R is alkyl, allyl, or aryl. In a more preferred embodiment, the solvent is ethanol.

[0135] In certain embodiments, in the fourth step (reacting MRTX0902 with fumaric acid), the solvent includes, but is not limited to, one or more of DMAc, DMF, THF, 2-MeTHF, MeCN, DMSO, NMP, toluene, and an alcohol of the formula R—OH, where R is alkyl, allyl, or aryl.

[0136] In a more preferred embodiment, the solvent is ethanol.

[0137] In some embodiments, the fourth step is carried out at a temperature of about 15°C to about 135°C.

[0138] In another embodiment, the present invention provides a method for preparing a fumarate salt of MRTX0902, comprising the steps of: The following structure: [ka] is reacted with hydrazine hydrate in the presence of acetic acid and ethanol to give the compound of the following structure: [ka] preparing a compound represented by the formula: [ka] is reacted with phosphorus oxychloride in the presence of MeCN to give the following structure: [ka] preparing a compound represented by the formula: [ka] in the presence of DIPEA, MgCl2, and tAmOH. [ka] to react with the compound having the following structure: [ka] preparing a compound of the formula: [ka] is reacted with fumaric acid in the presence of ethanol to give the following structure: [ka] preparing a compound represented by The present invention provides a method of manufacturing a semiconductor device, comprising:

[0139] In another embodiment, the present invention provides novel intermediates such as: [ka]

[0140] In another embodiment, the present invention provides a compound having the following structure: [ka] The present invention provides a fumarate salt of MRTX0902 having the formula: [Example]

[0141] The following examples are intended to further illustrate particular embodiments of the present invention, but are not intended to limit the scope of the invention.

[0142] Example 1 Step (a) [ka] To a 100 L reactor, tert-butyl 5-acetyl-2-morpholinoisonicotinate [7.90 kg, 25.8 mol, 1.0 equiv.] was added, followed by EtOH [55.3 L]. Acetic acid [1.58 kg, 25.8 mol, 1.0 equiv.] was then added to the stirred suspension at 20 °C. Hydrazine hydrate 80% [3.2 kg, 51.6 mol, 2.0 equiv.] was slowly added while controlling the temperature below 35 °C. At the end of the addition, the temperature was raised to 75 °C. The mixture was reacted at 75 °C until the starting material was below 1.0 area % by HPLC analysis (typically 5-10 hours). The reaction was cooled to 20 °C. The precipitated solid was filtered, and the cake was washed with EtOH (7.9 L x 2). The wet cake was then dried under vacuum at 50° C. to give 5.96 kg of 4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1(2H)-one in 94% yield.

[0143] Mp:249.0℃ (degree Celsius temperature).

[0144] 1 HNMR (400MHz, DMSO-d6) δ 12.25(s,1H),8.89(s,1H),7.23(s,1H),3.74-3.72(m,4H),3.67-3.67(m,4H),2.47(s,3H).

[0145] 13 CNMR (101MHz, DMSO-d6) δ 156.0,159.2,149.4,143.2,135.2,116.2,98.4,66.3,45.2,18.1.

[0146] HRMS(ESI) C 12 H 15 Calculated for N4O2: 247.1190 [M+H] + , Actual value: 247.1190.

[0147] Example 2 Step (b) [ka] To a 100 L reactor, 4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1(2H)-one [5.93 kg, 24.1 mol, 1.0 equiv.] was added, followed by MeCN [59.3 L]. Phosphorus oxychloride [7.40 kg, 48.2 mol, 2.0 equiv.] was then added at a controlled temperature of 15-30 °C. At the end of the addition, the temperature was raised to 75 °C. The mixture was reacted at 80 °C until the starting material reached 1.0 area % or less by HPLC analysis (typically 4-7 hours). The reaction was cooled to 20 °C, and the volatiles were removed under reduced pressure. CHCl [29.5 L] was then added. Water [56.9 L], followed by sodium carbonate, was added to achieve a pH of 7-8. The aqueous layer was discarded, and the volatiles were removed under reduced pressure. iPrOH [26.7 L] was then added, and the mixture was heated to 50 °C for 2 hours. The reaction was cooled to 20°C over 3 hours. The precipitated solid was filtered and the cake was washed once with 2-propanol [5.9 L]. The wet cake was then dried under vacuum at 50°C to give 6.12 kg of 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)morpholine in 96% yield.

[0148] Mp:184.1-184.2℃.

[0149] 1 H NMR (400MHz, DMSO-d6) δ 9.29 (s, 1H), 6.90 (s, 1H), 3.74 (m, 8H), 2.82 (s, 3H).

[0150] 13CNMR (101MHz, DMSO-d6) δ 160.1,157.5,152.6,151.7,131.4,115.2,93.4,66.3,45.2,18.7.

[0151] HRMS(ESI) C 12 H 14 Calculated for ClNO: 265.0851 [M+H] + , Actual value: 265.0852.

[0152] Example 3 Step (c) [ka] To a 100 L reactor, 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)morpholine [6.12 kg, 23.1 mol, 1.0 equiv.] and tAmOH [61.2 L] were added. (R)-3-(1-aminoethyl)-2-methylbenzonitrile hydrochloride [5.02 kg, 25.5 mol, 1.1 equiv.] was then added, followed by MgCl2 [3.30 kg, 34.7 mol, 1.5 equiv.] and DIPEA [9.04 kg, 69.9 mol, 3.0 equiv.]. At the end of the addition, the temperature was raised to 75 °C for 1 hour. The reaction was then heated to 100 °C and allowed to react until the starting material was below 3.0 area % by HPLC analysis (typically 36-48 hours). The reaction mixture was cooled to 25 °C, and ethyl acetate [55.2 L] was added to the reaction mixture. Water [61.2 L] was added to the mixture at a controlled temperature of 20-30°C. The aqueous layer was discarded, and the volatiles were removed under reduced pressure. Acetonitrile [36.7 L] was added to the resulting mixture, and the precipitate was filtered. The filtrate was concentrated under reduced pressure. Acetonitrile [18.4 L] was added, and the mixture was heated to 50°C. Upon addition of water, seeding, and cooling to 20°C, crystallization was observed. The precipitated solid was filtered and washed once with a premixed solution of water [6.1 L] and acetonitrile [3.0 L]. The wet cake was then dried under vacuum at 50°C to give 7.85 kg of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile dihydrate in 78% yield.

[0153] Mp: 122.3-122.4℃.

[0154] 1HNMR(400MHz,DMSO-d6) δ 8.99(s,1H),7.71(dd,J=7.8,1.4Hz,1H),7.61(dd,J=7.8,1.4Hz,1H),7.53(d,J=6.8Hz,1H),7.40(s,1H),7.31(m,1H),5.52 (p,J=6.9Hz,1H),3.78(dd,J=5.8,3.8Hz,4H),3.68(dd,J=5.8,3.8Hz,4H),2.65(s,3H),2.55(s,3H),1.54(d,J=6.9Hz,3H).

[0155] 13 CNMR(101MHz,DMSO-d6) δ 159.8,151.2,149.4,147.6,146.4,139.2,131.3,129.7,127.4,125.1,119.0,114.5,112.7,93.6,66.3,47.1,45.5,21.9,18.5,17.2.

[0156] HRMS(ESI) C 22 H 25 Calculated for NO: 389.2085 [M+H] + , Actual value: 389.2085.

[0157] Example 4 Manufacturing steps for MRTX0902 fumarate salt [ka] A 500 L reactor was charged with (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile [7.85 kg, 20.2 mol, 1.0 equiv.] and EtOH [86.4 L]. The suspension was heated to 75° C. Crystalline seed material of the final product [39.5 g] was added. A prepared solution of fumaric acid [2.40 kg, 20.2 mol, 1.0 equiv.] in 95% aqueous ethanol [52.2 L] was then added dropwise. Crystallization was observed immediately upon addition of the fumaric acid solution, and stirring was continued at 75° C. for 2 hours after the addition was complete. The reaction mixture was cooled to 20° C. over 4 hours, and then stirring was continued at the same temperature for 4 hours. The suspension was filtered, and the collected solid was rinsed with EtOH [23.6 L]. The wet cake was then dried under vacuum at 50° C. to give 8.93 kg of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile fumarate in 97% yield.

[0158] Mp:253.2-253.3℃.

[0159] 1 HNMR(400MHz,DMSO-d6) δ 9.01(s,1H),7.71(dd,J=7.9,1.4Hz,1H),7.64-7.55(m,2H),7.42(s,1H),7.32(t,J=7.8Hz,1H),6.61(s, 2H),5.51(s,1H),3.80-3.74(m,4H),3.73-3.66(m,4H),2.65(s,3H),2.56(s,3H),1.54(d,J=7.0Hz,3H).

[0160] 13 CNMR(101MHz,DMSO-d6) δ 16.7,17.7,21.4,45.0,46.7,65.8,93.2,112.3,113.8,118.5,124.9,127 .0,129.2,130.8,134.1,138.7,145.8,147.2,149.3,150.8,159.5,166.2.

[0161] HRMS(ESI) C 22 H 25 Calculated for NO: 389.2085 [M+H] + , Actual value: 389.2085.

[0162] Example 5 Separate manufacturing steps for MRTX0902 fumarate [ka] To a 20 mL vial was added (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile [920 mg, 2.4 mmol, 1.0 equiv.], fumaric acid monoethyl ester [410 mg, 2.8 mmol, 1.2 equiv.], and EtOH [10 mL]. The reaction was heated to 75° C. on a shaker for 1 hour. The reaction mixture was then cooled to 20° C. over 15 minutes. The suspension was filtered and the collected solid was dried under vacuum to give 1.22 g of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (E)-4-ethoxy-4-oxobut-2-enoate in 97% yield.

[0163] Mp:196.2-196.3℃.

[0164] 1 HNMR(400MHz,DMSO-d6) δ 9.01(s,1H),7.71(dd,J=7.9,1.3Hz,1H),7.67-7.58(m,2H),7.41(s,1H),7.32(t,J=7.8Hz,1H),6.75-6.59(m,2H),5.54-5.48(m,1H) ,4.19(q,J=7.1Hz,2H),3.81-3.73(m,4H),3.72-3.64(m,4H),2.65(s,3H),2.56(s,3H),1.54(d,J=7.1Hz,3H),1.24(t,J=7.1Hz,3H).

[0165] 13CNMR(101MHz,DMSO-d6) δ 166.3,165.1,159.9,151.3,149.7,147.6,146.3,139.2,135.7,132.6,131.3,129.7,1 27.4,125.3,119.0,114.4,112.7,93.7,66.3,61.4,47.1,45.5,21.9,18.3,17.2,14.4.

[0166] C by HRMS (ESI) 22 H 25 Calculated for NO: 389.2085 [M+H] + , Actual value: 389.2085.

[0167] While the invention has been described with respect to specific embodiments thereof, it is understood that further modifications are possible, and this application is intended to cover, in general, any variation, use, or application of the invention in accordance with the principles of the invention, including any known or conventional developments from this disclosure in the art to which the invention pertains, to the extent applicable to the essential features described above and within the scope of the appended claims.

Claims

1. 1. A method for producing (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: a) a molecule having the following structure: 【Chemistry 1】 with hydrazine or a hydrazine salt in the presence of an acid and a solvent to give a compound having the following structure: 【Chemistry 2】 preparing the final compound of step a) represented by A manufacturing method comprising:

2. 2. The method of claim 1, wherein the solvent is selected from the group consisting of dimethylacetamide (DMAc), dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), toluene, and an alcohol of the formula R—OH, where R is alkyl, allyl, or aryl.

3. The method of claim 1 wherein the solvent is ethanol.

4. 2. The method of claim 1, wherein the acid is an inorganic acid or an organic acid.

5. 5. The method of claim 4, wherein the acid is an inorganic acid.

6. 6. The method of claim 5, wherein the inorganic acid is selected from the group consisting of hydrogen halides of the general formula HX (wherein X is F, Cl, Br, or I), nitric acid, phosphoric acid, sulfuric acid, boric acid, and perchloric acid.

7. The method of claim 4 wherein the acid is an organic acid.

8. The organic acid has the general formula RSO ３ H, where R is alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or aryl, and sulfonic acids of the general formula RCO ２ 8. The method of claim 7, wherein the carboxylic acid is selected from the group consisting of carboxylic acids (having one or more carboxylic acid moieties) represented by the formula: H, where R is alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, or aryl.

9. 8. The method of claim 7, wherein the organic acid is selected from the group consisting of lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, and tartaric acid.

10. 2. The method of claim 1, wherein the acid is acetic acid.

11. b): The final compound of step a) is reacted with a chlorinating agent in the presence of an aprotic solvent to give a compound of the following structure: 【Transformation 3】 and preparing the final compound of step b) represented by The method of claim 1 further comprising:

12. 12. The method of claim 11, wherein the chlorinating agent is selected from the group consisting of phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, thionyl chloride, diaryl chlorophosphates, dialkyl chlorophosphates, diaryl chlorophosphites, and dialkyl chlorophosphites.

13. 12. The method of claim 11, wherein the chlorinating agent is phosphorus oxychloride.

14. 12. The method of claim 11, wherein the aprotic solvent is selected from the group consisting of chloroform, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, toluene, tertiary amines, and NMP.

15. 15. The method of claim 14, wherein the aprotic solvent is MeCN.

16. c): The final compound of step b) is reacted with benzylamine or a benzylamine salt in the presence of a base, a Lewis acid, and a high boiling point solvent to give the compound of the following structure: 【Chemistry 4】 and preparing the final compound of step c) represented by The method of claim 11 further comprising:

17. 17. The method of claim 16, wherein the base is selected from the group consisting of organic bases and inorganic bases.

18. 18. The method of claim 17, wherein the base is an organic base.

19. The organic base is DIPEA, Et ３ 19. The method of claim 18, wherein the hydroxybenzoate is selected from the group consisting of N, DABCO, and DBU.

20. 20. The method of claim 19, wherein the organic base is DIPEA.

21. 18. The method of claim 17, wherein the base is an inorganic base.

22. 22. The method of claim 21, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates.

23. 17. The method of claim 16, wherein the Lewis acid is selected from the group consisting of magnesium salts, calcium salts, aluminum-based reagents, and boron-based reagents.

24. 24. The method of claim 23, wherein the Lewis acid is magnesium chloride.

25. 17. The method of claim 16, wherein the high boiling point solvent is selected from the group consisting of toluene, DMAc, DMF, 1,4-dioxane, DMSO, NMP, and an alcohol of the formula R—OH, where R is alkyl, allyl, or aryl.

26. 26. The method of claim 25, wherein the high boiling point solvent is tAmOH.

27. 1. A method for producing (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: The following structure: 【Transformation 5】 is reacted with a chlorinating agent in the presence of an aprotic solvent to give a compound of the following structure: 【Transformation 6】 preparing a compound represented by A manufacturing method comprising:

28. 28. The method of claim 27, wherein the chlorinating agent is selected from the group consisting of phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, thionyl chloride, diaryl or dialkyl phosphates, diaryl or dialkyl phosphites.

29. 28. The method of claim 27, wherein the chlorinating agent is phosphorus oxychloride.

30. 28. The method of claim 27, wherein the aprotic solvent is selected from the group consisting of chloroform, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, toluene, tertiary amines, and NMP.

31. 31. The method of claim 30, wherein the aprotic solvent is MeCN.

32. 1. A method for producing (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: 【Transformation 7】 is reacted with benzylamine or a benzylamine salt in the presence of a base, a Lewis acid, and a high boiling point solvent to produce the compound of the following structure: 【Transformation 8】 preparing a compound having A manufacturing method comprising:

33. 33. The method of claim 32, wherein the base is selected from the group consisting of organic bases and inorganic bases.

34. 34. The method of claim 33, wherein the base is an organic base.

35. The organic base is DIPEA, Et ３ 35. The method of claim 34, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

36. 36. The method of claim 35, wherein the organic base is DIPEA.

37. 34. The method of claim 33, wherein the base is an inorganic salt.

38. 38. The method of claim 37, wherein the inorganic salt is selected from the group consisting of carbonates, bicarbonates, and phosphates.

39. 33. The method of claim 32, wherein the Lewis acid is selected from the group consisting of magnesium salts, calcium salts, aluminum-based reagents, and boron-based reagents.

40. 40. The method of claim 39, wherein the Lewis acid is magnesium chloride.

41. 33. The method of claim 32, wherein the high boiling point solvent is selected from the group consisting of toluene, DMAc, DMF, 1,4-dioxane, DMSO, NMP, and an alcohol of the formula R-OH, where R is alkyl, allyl, or aryl.

42. 42. The method of claim 41, wherein the high boiling point solvent is tAmOH.

43. 1. A method for producing (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: The following structure: 【Chemistry 9】 is reacted with a chlorinating agent in the presence of an aprotic solvent to give a compound having the following structure: 【Chemistry 10】 preparing a compound of the formula: 【Chemistry 11】 is reacted with benzylamine or a benzylamine salt in the presence of a base, a Lewis acid, and a high boiling point solvent to produce the compound of the following structure: 【Chemistry 12】 preparing a compound represented by A manufacturing method comprising:

44. 1. A method for producing (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: The following structure: 【Chemistry 13】 is reacted with hydrazine hydrate in the presence of acetic acid and ethanol to give the compound of the following structure: 【Chemistry 14】 preparing a compound of the formula: 【Chemistry 15】 is reacted with phosphorus oxychloride in the presence of MeCN to give the following structure: 【Chemistry 16】 preparing a compound of the formula: 【Chemistry 17】 DIPEA, MgCl ２ , and in the presence of tAmOH [Chemistry 18] to form a compound having the following structure: 【Chemistry 19】 preparing a compound represented by A manufacturing method comprising:

45. 1. A method for preparing a fumarate salt of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: The following structure: 【Chemistry 20】 With hydrazine or a hydrazine salt in the presence of an acid and a solvent to give a compound of the following structure: 【Chemistry 21】 preparing a compound of the formula: 【Chemistry 22】 is reacted with a chlorinating agent in the presence of an aprotic solvent to give the compound of the following structure: 【Chemistry 23】 preparing a compound of the formula: 【Chemistry 24】 is reacted with benzylamine or a benzylamine salt in the presence of a base, a Lewis acid, and a high boiling point solvent to produce the compound of the following structure: 【Chemistry 25】 preparing a compound of the formula: 【Chemistry 26】 is reacted with fumaric acid in the presence of a solvent to give the compound of the following structure: 【Chemistry 27】 preparing a compound represented by A manufacturing method comprising:

46. 1. A method for preparing a fumarate salt of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: The following structure: 【Chemistry 28】 is reacted with fumaric acid in the presence of a solvent to give a compound of the following structure: 【Chemistry 29】 preparing a compound represented by A manufacturing method comprising:

47. 47. The method of claim 46, wherein the solvent is selected from the group consisting of DMAc, DMF, THF, 2-MeTHF, MeCN, DMSO, NMP, toluene, and an alcohol of the formula R-OH, where R is alkyl, allyl, or aryl.

48. 47. The method of claim 46, wherein the solvent is ethanol.

49. 1. A method for preparing a fumarate salt of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile, comprising: The following structure: 【Transformation 30】 is reacted with hydrazine hydrate in the presence of acetic acid and ethanol to give the compound of the following structure: 【Chemistry 31】 preparing a compound of the formula: 【Chemistry 32】 is reacted with phosphorus oxychloride in the presence of MeCN to give the following structure: 【Transformation 33】 preparing a compound of the formula: 【Transformation 34】 DIPEA, MgCl ２ , and in the presence of tAmOH, 【Chemistry 35】 to form a compound having the following structure: 【Transformation 36】 preparing a compound of the formula: 【Chemistry 37】 is reacted with fumaric acid in the presence of ethanol to give the following structure: 【Transformation 38】 preparing a compound represented by A manufacturing method comprising:

50. below: 【Chemistry 39】 A compound selected from the group consisting of:

51. The following structure: 【Chemistry 40】 A compound represented by the formula:

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