Salt of an SOS1 inhibitor

Abstract

The present invention relates to compounds that inhibit Son of sevenless homolog 1 (SOS1) activity. In particular, the present invention relates to such compounds, pharmaceutical compositions, and methods of use (e.g., methods of treating cancer using the compounds and pharmaceutical compositions of the present invention).

Description

Technical Field

[0001] The present invention relates to compounds that inhibit Son of sevenless homolog 1 (SOS1) which exchanges nucleotides via GTP. In particular, the present invention relates to compounds, salts thereof, pharmaceutical compositions containing the compounds, and methods of using the same.

Background Art

[0002] The Ras family is composed of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and Harvey murine sarcoma virus oncogene (HRAS), and critically controls the division, growth, and function of cells in normal and altered states (including cancer) (see, for example, Simanshu et al. Cell, 2017. 170(1): p. 17-33; Matikas et al., Crit Rev Oncol Hematol, 2017. 110: p. 1-12). The RAS protein is activated by upstream signals such as receptor tyrosine kinases (RTKs) and transmits signals to multiple downstream signal pathways such as the mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) pathway. Hyperactivation of RAS signaling is frequently seen in cancer as a result of mutations or alterations in the RAS gene or other genes in the RAS pathway. Strategies to inhibit RAS and RAS signaling are predicted to be useful for the treatment of cancer and diseases associated with RAS.

[0003] The RAS protein is a guanosine triphosphatase (GTPase) that cycles between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-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 the RAS protein. The RAS protein hydrolyzes GTP to GDP by the activity of an endogenous GTPase, but its hydrolysis activity is greatly enhanced in the presence of a GTPase-activating protein (GAP). This regulation via GAP and GEF is a mechanism by which activation and inactivation are tightly controlled under normal conditions. In cancer, mutations at multiple residues in all three RAS proteins are frequently seen, resulting in a predominance of RAS remaining in the activated state (Sanchez-Vega et al., Cell, 2018. 173: p. 321-337 Li et al., Nature Reviews Cancer, 2018. 18: p. 767-777). Codons 12 and 13 are the most frequently mutated RAS residues, and these mutations inhibit GTP hydrolysis by GAP stimulation by inhibiting the interaction between the GAP protein and RAS. However, recent biochemical analysis has shown that these mutant proteins still require nucleotide exchange for activity based on their endogenous GTPase activity and / or partial sensitivity to exogenous GTPases. That is, it can be seen that mutant RAS proteins are sensitive to inhibition by upstream factors (e.g., SOS1 or SHP2, another upstream signaling molecule required for RAS activation) (Hillig, 2019; Patricelli, 2016; Lito, 2016; Nichols, 2018).

[0004] The three major RAS-GEF families identified in mammalian cells are SOS, RAS-GRF, and RAS-GRP (Rojas, 2011). RAS-GRF and RAS-GRP are expressed in cells of the central nervous system and hematopoietic cells, respectively, while the SOS family is ubiquitously expressed and is responsible for RTK signaling. The SOS family consists of SOS1 and SOS2, and approximately 70% of these proteins have the same sequence. Since SOS2 is rapidly degraded, SOS1 is thought to be much more active than SOS2. SOS2 knockout mice are viable, whereas SOS1 knockout results in embryonic lethality. Using a tamoxifen-inducible SOS1 knockout mouse model to examine the roles of SOS1 and SOS2 in adult mice, SOS1 knockout was viable, but SOS1 / 2 double knockout mice were non-viable (Baltanas, 2013). This suggests functional redundancy and that selective inhibition of SOS1 can provide a sufficient therapeutic index for the treatment of SOS1-RAS activation diseases.

[0005] The SOS protein is recruited to phosphorylated RTKs via interaction with growth factor receptor-bound protein 2 (GRB2). By accumulating on the cell membrane, SOS comes into proximity with RAS, enabling SOS-mediated RAS activation. The SOS protein binds to RAS via a binding site that promotes nucleotide exchange and an allosteric site that binds to GTP-bound RAS family proteins to enhance the function of SOS (Freedman et al., Proc. Natl. Acad. Sci, USA 2006. 103(45): p. 16692-97). Binding to the allosteric site relieves the steric inhibition of the RAS substrate-binding site, and thus this binding is required for nucleotide exchange. Retention of the activated form in the catalytic site following interaction with the allosteric site is maintained independently by strengthening the interaction of the major domains in the activated state. SOS1 mutations are found in multiple cancers, including Noonan syndrome, lung adenocarcinoma, fetal rhabdomyosarcoma, Sertoli cell testicular tumors, and cutaneous granular cell tumors (see Denayer, E., et al, Genes Chromosomes Cancer, 2010. 49(3): p. 242-52).

[0006] GTPase-activating protein (GAP) is a protein that stimulates the slow intrinsic GTPase activity of RAS family members, converting the GTP-bound active form of the RAS protein to the GDP-bound inactive form of the RAS protein (see, for example, Simanshu, D.K., Cell, 2017, Ras Proteins and their Regulators in Human Disease). In cancer, while activating changes in SOS1, which is a GEF, occur, inactivating mutations or loss-of-function mutations in neurofibromin 1 (NF-1) or neurofibromin 2 (NF-2), which are GAPs, also occur, resulting in a state where the activity of SOS1 is not inhibited and the activity of the downstream pathway via the RAS protein is increased.

[0007] Therefore, the compounds of the present invention that inhibit the interaction between SOS1 and Ras family members can prevent the conversion to the GTP-bound active form of KRas, thereby providing an effective treatment for a wide range of cancers (especially cancers related to Ras family members). The compounds of the present invention may be effective therapeutic agents as inhibitors of the SOS1-KRas interaction, and are useful for suppressing the activity of KRas by inhibiting the intracellular SOS1-KRas interaction in order to treat various forms of cancer including Ras-related cancers, SOS1-related cancers, and NF1 / NF2-related cancers.

[0008] Summary of the Invention There is a need to develop novel SOS1 inhibitors that can inhibit the interaction between SOS1 and Ras family members, prevent the conversion of KRas to its GTP-bound active form, and thereby provide an effective treatment for a wide range of cancers, including in particular Ras-related cancers, SOS1-related cancers, and NF1 / NF2-related cancers.

[0009] In one aspect of the present invention, the following formula:

Chemical formula

[0010] The description of the fumarate salt also indicates that the salt form in which the fumaric acid moiety is deprotonated and the MRTX-0902 moiety is protonated is included.

[0011] This compound is the fumarate salt of MRTX-0902, which is part of Examples 12-10 of WO 2021 / 127429A1, incorporated herein by reference in its entirety.

[0012] In another aspect of the present invention, the present invention provides the maleate salt of MRTX-0902 having the following structure:

Chemical formula

[0013] The description of the maleate salt also indicates and includes a salt form in which the maleic acid moiety is deprotonated and the MRTX-0902 moiety is protonated.

[0014] In another aspect of the invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0015] In yet another aspect, the invention provides a method of inhibiting the activity of a Ras family member by inhibiting the association between the Ras family member and SOS1 in a cell, the method comprising contacting the cell with a compound of the present application. In certain embodiments, the contacting is performed in vitro. In certain embodiments, the contacting is performed in vivo.

[0016] The present application also provides a method of inhibiting in vitro or in vivo cell proliferation, the method comprising contacting a cell with an effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0017] The present application provides a method of treating cancer in a patient in need thereof, comprising: (a) determining that the cancer is associated with a mutation in a Ras family member (e.g., KRas G12C-associated cancer) (e.g., using an assay or kit approved by a regulatory authority (e.g., the FDA)); and (b) administering to the patient a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0018] The present application provides a method of treating cancer in a patient in need thereof, comprising: (a) determining that the cancer is associated with a mutation in SOS1 (e.g., SOS1-associated cancer) (e.g., using an assay or kit approved by a regulatory authority (e.g., the FDA)); and (b) administering to the patient a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0019] The present application provides a method for treating cancer in a patient in need of treatment, comprising: (a) determining that the cancer is associated with a loss-of-function mutation in NF-1 or NF-2 (e.g., NF1 / NF2-related cancer) (e.g., by using an assay or kit approved by a regulatory authority (e.g., the FDA)); and (b) administering to the patient a therapeutically effective amount of a compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0020] The present application also provides the use of a compound of the present application as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for inhibiting the activity of SOS1.

[0021] The present application also provides the use of a compound of the present application as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating SOS1-related diseases or disorders.

Mode for Carrying Out the Invention

[0022] The present invention relates to SOS1 inhibitors. In particular, the present invention relates to compounds that inhibit SOS1 activity, pharmaceutical compositions comprising a therapeutically effective amount of such compounds, and methods of using the same.

[0023] Definition Unless otherwise specified, 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 mentioned herein are incorporated by reference to the extent consistent with the present disclosure. Terms and ranges mean generally defined definitions unless specifically defined.

[0024] For simplicity, throughout the text, chemical groups are mainly defined and referred to as monovalent chemical groups (e.g., alkyl, aryl, etc.). However, in appropriate structures that are obvious to those skilled in the art, these terms may be used to indicate the corresponding polyvalent groups. For example, an "alkyl" group generally refers to a monovalent group (e.g., CH3-CH2-), but depending on the situation, a divalent linking group may be "alkyl", in which case those skilled in the art will understand that the alkyl is a divalent group corresponding to the term "alkylene" (e.g., -CH2-CH2-) (similarly, in situations where a divalent group is required and is described as "aryl", those skilled in the art will understand that the term "aryl" refers to the corresponding divalent group, arylene). All atoms are understood to have their normal valences for forming bonds (i.e., carbon has 4, N has 3, O has 2, and S varies depending on the oxidation state of S and can be 2, 4, or 6).

[0025] As used herein, "KRas G12C" refers to a mutant of the mammalian KRas protein in which the 12th amino acid is substituted from glycine to cysteine. The arrangement of the amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by the variant p.Gly12Cys of UniProtKB / Swiss-Prot P01116.

[0026] As used herein, "KRas G12D" refers to a mutant of the mammalian KRas protein in which the 12th amino acid is substituted from glycine to aspartic acid. The arrangement of the amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by the variant p.Gly12Asp of UniProtKB / Swiss-Prot P01116.

[0027] As used herein, "KRas G12S" refers to a mutant of mammalian KRas protein in which the 12th amino acid is substituted from glycine to serine. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by the variant p.Gly12Ser of UniProtKB / Swiss-Prot P01116.

[0028] As used herein, "KRas G12A" refers to a mutant of mammalian KRas protein in which the 12th amino acid is substituted from glycine to alanine. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by the variant p.Gly12Ala of UniProtKB / Swiss-Prot P01116.

[0029] As used herein, "KRas G13D" refers to a mutant of mammalian KRas protein in which the 13th amino acid is substituted from glycine to aspartic acid. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by the variant p.Gly13Asp of UniProtKB / Swiss-Prot P01116.

[0030] As used herein, "KRas G13C" refers to a mutant of mammalian KRas protein in which the 13th amino acid is substituted from glycine to cysteine. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by the variant p.Gly13Cys of UniProtKB / Swiss-Prot P01116.

[0031] As used herein, "KRas Q61L" refers to a mutant of mammalian KRas protein in which the 61st amino acid is substituted from glutamine to leucine. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by the variant p.Gln61Leu of UniProtKB / Swiss-Prot P01116.

[0032] As used herein, "KRas A146T" refers to a mutant of the mammalian KRas protein in which the 146th amino acid is substituted from alanine to threonine. The amino acid codons and residue positions of human KRas are based on the amino acid sequence identified by the variant p.Ala146Thr of UniProtKB / Swiss-Prot P01116.

[0033] As used herein, "KRas A146V" refers to a mutant of the mammalian KRas protein in which the 146th amino acid is substituted from alanine to valine. The amino acid codons and residue positions of human KRas are based on the amino acid sequence identified by the variant p.Ala146Val of UniProtKB / Swiss-Prot P01116.

[0034] As used herein, "KRas A146P" refers to a mutant of the mammalian KRas protein in which the 146th amino acid is substituted from alanine to proline. The amino acid codons and residue positions of human KRas are based on the amino acid sequence identified by the variant p.Ala146Pro of UniProtKB / Swiss-Prot P01116.

[0035] As used herein, "HRas G12C" refers to a mutant of the mammalian HRas protein in which the 12th amino acid is substituted from glycine to cysteine. The amino acid codons and residue positions of human HRas are based on the amino acid sequence identified by the variant p.Gly12Cys of UniProtKB / Swiss-Prot P01112.

[0036] As used herein, "HRas G12D" refers to a mutant of the mammalian HRas protein in which the 12th amino acid is substituted from glycine to aspartic acid. The amino acid codons and residue positions of human HRas are based on the amino acid sequence identified by the variant p.Gly12Asp of UniProtKB / Swiss-Prot P01112.

[0037] As used herein, "HRas G12S" refers to a mutant of mammalian HRas protein in which the 12th amino acid is substituted from glycine to serine. The arrangement of the amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by the variant p.Gly12Ser of UniProtKB / Swiss-Prot P01112.

[0038] As used herein, "HRas G12A" refers to a mutant of mammalian HRas protein in which the 12th amino acid is substituted from glycine to alanine. The arrangement of the amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by the variant p.Gly12Ala of UniProtKB / Swiss-Prot P01112.

[0039] As used herein, "HRas G13D" refers to a mutant of mammalian HRas protein in which the 13th amino acid is substituted from glycine to aspartic acid. The arrangement of the amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by the variant p.Gly13Asp of UniProtKB / Swiss-Prot P01112.

[0040] As used herein, "HRas G13C" refers to a mutant of mammalian HRas protein in which the 13th amino acid is substituted from glycine to cysteine. The arrangement of the amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by the variant p.Gly13Cys of UniProtKB / Swiss-Prot P01112.

[0041] As used herein, "HRas Q61L" refers to a mutant of mammalian HRas protein in which the 61st amino acid is substituted from glutamine to leucine. The arrangement of the amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by the variant p.Gln61Leu of UniProtKB / Swiss-Prot P01112.

[0042] As used herein, "HRas A146T" refers to a mutant of mammalian HRas protein in which the 146th amino acid is substituted from alanine to threonine. The amino acid codons and residue positions of human NRas are based on the amino acid sequence identified by the variant p.Ala146Thr of UniProtKB / Swiss-Prot P01112.

[0043] As used herein, "HRas A146V" refers to a mutant of mammalian HRas protein in which the 146th amino acid is substituted from alanine to valine. The amino acid codons and residue positions of human NRas are based on the amino acid sequence identified by the variant p.Ala146Val of UniProtKB / Swiss-Prot P01112.

[0044] As used herein, "HRas A146P" refers to a mutant of mammalian HRas protein in which the 146th amino acid is substituted from alanine to proline. The amino acid codons and residue positions of human NRas are based on the amino acid sequence identified by the variant p.Ala146Pro of UniProtKB / Swiss-Prot P01112.

[0045] As used herein, "NRas G12C" refers to a mutant of mammalian NRas protein in which the 12th amino acid is substituted from glycine to cysteine. The amino acid codons and residue positions of human NRas are based on the amino acid sequence identified by the variant p.Gly12Cys of UniProtKB / Swiss-Prot P01111.

[0046] As used herein, "NRas G12D" refers to a mutant of mammalian NRas protein in which the 12th amino acid is substituted from glycine to aspartic acid. The amino acid codons and residue positions of human NRas are based on the amino acid sequence identified by the variant p.Gly12Asp of UniProtKB / Swiss-Prot P01111.

[0047] As used herein, "NRas G12S" refers to a mutant of the mammalian NRas protein in which the 12th amino acid is substituted from glycine to serine. The amino acid codons and residue positions of human NRas are based on the amino acid sequence identified by the variant p.Gly12Ser of UniProtKB / Swiss-Prot P01111.

[0048] As used herein, "NRas G12A" refers to a mutant of the mammalian NRas protein in which the 12th amino acid is substituted from glycine to alanine. The amino acid codons and residue positions of human KRas are based on the amino acid sequence identified by the variant p.Gly12Ala of UniProtKB / Swiss-Prot P01111.

[0049] As used herein, "NRas G13D" refers to a mutant of the mammalian NRas protein in which the 13th amino acid is substituted from glycine to aspartic acid. The amino acid codons and residue positions of human NRas are based on the amino acid sequence identified by the variant p.Gly13Asp of UniProtKB / Swiss-Prot P01111.

[0050] As used herein, "HNRas G13C" refers to a mutant of the mammalian NRas protein in which the 13th amino acid is substituted from glycine to cysteine. The amino acid codons and residue positions of human NRas are based on the amino acid sequence identified by the variant p.Gly13Cys of UniProtKB / Swiss-Prot P01111.

[0051] As used herein, "HRas Q61L" refers to a mutant of the mammalian HRas protein in which the 61st amino acid is substituted from glutamine to leucine. The amino acid codons and residue positions of human HRas are based on the amino acid sequence identified by the variant p.Gln61Leu of UniProtKB / Swiss-Prot P01112.

[0052] As used herein, "NRas A146T" refers to a mutant of the mammalian NRas protein in which the 146th amino acid is substituted from alanine to threonine. The amino acid codons and residue positions of human NRas are based on the amino acid sequence identified by the variant p.Ala146Thr of UniProtKB / Swiss-Prot P01111.

[0053] As used herein, "NRas A146V" refers to a mutant of the mammalian NRas protein in which the 146th amino acid is substituted from alanine to valine. The amino acid codons and residue positions of human NRas are based on the amino acid sequence identified by the variant p.Ala146Val of UniProtKB / Swiss-Prot P01111.

[0054] As used herein, "NRas A146P" refers to a mutant of the mammalian NRas protein in which the 146th amino acid is substituted from alanine to proline. The amino acid codons and residue positions of human NRas are based on the amino acid sequence identified by the variant p.Ala146Pro of UniProtKB / Swiss-Prot P01111.

[0055] As used herein, "Ras family member" or "Ras family" refers to KRas, HRas, NRas, and their active mutants such as G12, G13, Q61, and A146.

[0056] As used herein, "Ras family-related disease or disorder" refers to a disease or disorder in which an activated Ras mutation (e.g., a Ras mutation at the position of G12, G13, Q61 or A146) is associated or involved or present. By way of example, but not limited to, Ras family-related diseases or disorders include KRas, HRas or NRas G12C-related cancers, KRas, HRas or NRas G12D-related cancers, KRas, HRas or NRas G12S-related cancers, KRas, HRas or NRas G12A-related cancers, KRas, HRas or NRas G13D-related cancers, KRas, HRas or NRas G13C-related cancers, KRas, HRas or NRas Q61X-related cancers, KRas, HRas or NRas A146T-related cancers, KRas, HRas or NRas A146V-related cancers or KRas, HRas or NRas A146P-related cancers.

[0057] As used herein, "SOS1" refers to the mammalian Son of sevenless homolog 1 (SOS1) enzyme.

[0058] As used herein, "SOS1-related disease or disorder" refers to a disease or disorder in which an activated SOS1 mutation is associated or involved or present. Examples of activated SOS1 mutations include the SOS1 N233S and SOS1 N233Y mutations.

[0059] As used herein, "SOS1 N233S" refers to a variant of the mammalian SOS1 protein in which the 233rd amino acid is substituted from glutamine to serine. The placement of the amino acid codons and residues of human SOS1 is based on the amino acid sequence identified by the variant p.Gln233Ser of UniProtKB / Swiss-Prot Q07889.

[0060] As used herein, "SOS1 N233Y" refers to a mutant of mammalian SOS1 protein in which the 233rd amino acid is substituted from glutamine to tyrosine. The arrangement of the amino acid codons and residue positions of human SOS1 is based on the amino acid sequence identified by the variant p.Gln233Tyr of UniProtKB / Swiss-Prot Q07889.

[0061] As used herein, "SOS1 inhibitor" refers to the compounds of the present invention represented by the structures described herein. These compounds can suppressively inhibit all or part of the interaction between SOS1 and Ras family variants or SOS1 active variants, thereby reducing and / or regulating the nucleotide exchange activity of the Ras family member-SOS1 complex.

[0062] As used herein, "NF-1 / NF-2 related disease or disorder" refers to a disease or disorder in which a loss-of-function mutation in the neurofibromin (NF-1) gene or the neurofibromin 2 (NF-2) gene is associated or involved or present.

[0063] As used herein, "loss-of-function mutation" refers to any point mutation, splicing abnormality, fusion, nonsense mutation (mutation in which the amino acid codon changes to a stop codon), in-frame mutation or frameshift mutation, including insertions and deletions and homozygous deletions of genes encoding proteins in target cells or target cancer cells, which means that the presence, activity and / or function of the encoded protein is partially or completely lost.

[0064] The term "amino" refers to -NH2.

[0065] The term "acetyl" refers to -C(O)CH3.

[0066] As used herein, the term "acyl" refers to alkylcarbonyl or arylcarbonyl, where the alkyl and aryl moieties are substituents defined herein.

[0067] As used herein, the term "alkyl" refers to straight-chain and branched-chain aliphatics containing 1 to 12 carbon atoms. Therefore, "alkyl" includes groups of C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 and C 12 . Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0068] As used herein, the term "alkenyl" means an unsaturated straight-chain or unsaturated branched-chain aliphatic containing 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. Therefore, "alkenyl" includes groups of C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 and C 12 . Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0069] As used herein, the term "alkynyl" means an unsaturated straight-chain or unsaturated branched-chain aliphatic containing 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. Therefore, "alkynyl" includes groups of C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 and C 12 . Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0070] The terms "alkylene", "alkenylene", or "alkynylene" group refer to an alkyl, alkenyl, or alkynyl group as defined above, positioned between and connecting two other chemical groups. Examples of alkylene groups 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 alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0071] The term "alkoxy" refers to -OC1-C6 alkyl.

[0072] As used herein, the term "cycloalkyl" refers to a saturated and partially unsaturated cyclic hydrocarbon group containing 3 to 12 carbons. Thus, "cycloalkyl" includes cyclic hydrocarbon groups of C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 . Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0073] The term "heteroalkyl" refers to an alkyl group as defined above, wherein one or more carbon atoms in the chain are independently replaced by O, S, or NR x , where R x is hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0074] An "aryl" group is a C6-C 14 aromatic moiety containing one to three aromatic rings. Thus, "aryl" includes cyclic hydrocarbon groups of C6, C 10 , C 13 , and C 14 . An aryl group is, for example, C6-C 10It is an aryl group. Specific aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. The "aryl" group also includes condensed polycyclic (e.g., bicyclic) rings where one or more of the fused rings are non-aromatic but at least one ring is aromatic (e.g., indenyl).

[0075] The "aralkyl" or "arylalkyl" group includes an aryl group covalently bonded to an alkyl group that is bonded to another group through the alkyl moiety. The aralkyl group is, for example, -(C1-C6)alkyl(C6-C10)aryl and includes, but is not limited to, benzyl, phenethyl, and naphthylmethyl.

[0076] The "heterocyclyl" or "heterocyclic" group is a monocyclic or bicyclic (fused ring, spiro ring, or bridged ring) structure containing 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms), or 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 atoms) (e.g., where one or more ring atoms are independently -C(O)-, N, NR 4 , O, S, or S(O)2 and the remaining ring atoms are quaternary or carbonyl carbons, 4 to 8 atoms). Examples of heterocyclic groups include, but are not limited to, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thianyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethylmorpholinyl, and morpholinyl.

[0077] As used herein, "heterocyclyl" refers to a heterocyclyl group covalently bonded to another group through a bond.

[0078] As used herein, the term "heteroaryl" refers to a group containing 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms; sharing 6, 10, or 14 π electrons in a cyclic structure containing one, two or three rings; and further containing 1 to 3 heteroatoms (each independently N, O, or S) in addition to carbon atoms. "Heteroaryl" also includes fused polycyclic (e.g., bicyclic, tricyclic) ring systems in which one or more of the fused rings are non-aromatic (regardless of which rings are fused), provided that at least one ring is aromatic and at least one ring contains a ring atom of N, O, or S.

[0079] Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benz[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, benzothiophenyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0080] The term "heteroalkyl" or "heteroarylalkyl" group includes a heteroaryl group that is covalently bonded to another group through a linkage. Examples of heteroalkyl groups include C1-C6 alkyl groups and heteroaryl groups having 5, 6, 9, or 10 ring atoms. Examples of heteroalkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl, isoquinolinylmethyl, isoindolylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Compounds containing adjacent O and / or S ring atoms are specifically excluded from the scope of this term.

[0081] The terms "arylene", "heteroarylene", or "heterocyclylene" group refer to a divalent aryl, heteroaryl, or heterocyclyl group as defined above, respectively, located between and connecting two other chemical groups.

[0082] When a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described herein as "optionally substituted" without explicitly indicating substituents, it means that the moiety may optionally have 1 to 4, preferably 1 to 3, more preferably 1 or 2 non-hydrogen substituents.

[0083] As used herein, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0084] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens are substituted with halogen. Haloalkyls are, for example, trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0085] The term "hydroxyalkyl" refers to -alkylene-OH.

[0086] As used herein, the terms "subject", "individual", or "patient" are used interchangeably and refer to any animal, including mammals (e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans). In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or developed at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a mutated KRas G12 or G13 (e.g., determined using an assay or kit approved by a regulatory authority (e.g., the FDA)). In some embodiments, the subject is a patient with a tumor exhibiting a KRas G12C mutation, a KRas G12D mutation, a KRas G12S mutation, a KRas G12A mutation, a KRas G13D mutation, or a KRas G13C mutation (e.g., determined using an assay or kit approved by a regulatory authority). The subject can be a patient with a tumor exhibiting a KRas G12C mutation, a KRas G12D mutation, a KRas G12S mutation, a KRas G12A mutation, a KRas G13D mutation, or a KRas G13C mutation (e.g., identified using an assay or kit approved by a regulatory authority (e.g., the FDA)). The subject can be a patient with a tumor having a KRas G12C mutation, a KRas G12D mutation, a KRas G12S mutation, a KRas G12A mutation, a KRas G13D mutation, or a KRas G13C mutation (e.g., the tumor has been identified as having the mutation using a kit or assay approved by a regulatory authority (e.g., the FDA)). In some embodiments, the subject is suspected of having a cancer associated with the KRas G12 or G13 gene. In some embodiments, there is a medical record suggesting that the subject is a patient with a tumor having a KRas G12C mutation (the medical record may appropriately suggest that the subject should be treated with the compositions of the present application).

[0087] As used herein, the term "pediatric patient" refers to a patient who is less than 16 years of age at the time of diagnosis or treatment. The term "pediatrics" can be subdivided into various subpopulations: neonates (from birth to 1 month of age); infants (from 1 month to 2 years of age); children (from 2 years to 12 years of age); and adolescents (from 12 years to 21 years of age (including up to but not including the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994

[0088] As used herein, an "effective amount" of a compound is an amount sufficient to suppress or inhibit SOS1 enzyme activity.

[0089] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to improve a condition, alleviate any symptoms, arrest or reverse the progression of symptoms, or suppress or inhibit SOS1 activity. Such amount can be administered as a single dose or effectively administered according to a regimen.

[0090] As used herein, "treatment" means any method by which the condition, disorder or disease symptoms or lesions of a patient improve or otherwise change in a favorable direction.

[0091] As used herein, "improvement of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition" refers to any alleviation, whether permanent or temporary, persistent or transient, that may result from or be related to the administration of the composition.

[0092] Compound In certain embodiments of the present invention, the following formula:

Chemical formula

[0093] The above compound is known as the fumarate salt of MRTX-0902.

[0094] In another embodiment of the present invention, the present invention has the following structure:

Chemical formula

[0095] The compounds of the present application may be formulated into pharmaceutical compositions.

[0096] Fumarate salt of MRTX-0902:

Chemical formula

Chemical formula

Chemical formula

[0097] 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 alcohols of the formula R-OH wherein R is alkyl, allyl or aryl. In a preferred embodiment, the solvent is ethanol.

[0098] Maleate of MRTX-0902

Chem.

[0099] Pharmaceutical Composition In another aspect, the present invention provides a pharmaceutical composition comprising an SOS1 inhibitor described in the present invention and a pharmaceutically acceptable carrier, excipient, or diluent. The compounds of the present invention may be formulated by any method well known in the art and may be manufactured for administration by any route including, but not limited to, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or rectal administration. In certain embodiments, the compounds of the present invention are administered intravenously in a hospital. In certain other embodiments, administration may preferably be oral administration.

[0100] The characteristics of the carrier vary depending on the route of administration. As used herein, the term "pharmaceutically acceptable" means a substance that is compatible with a biological system (e.g., a cell, cell culture, tissue, or organism) and is non-toxic and does not inhibit the biological activity effectiveness of the active ingredient. Thus, the compositions described in the present invention may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizing agents, and other substances well known in the art. The manufacture of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0101] As used herein, the term "pharmaceutically acceptable salt" refers to salts that maintain the desired biological activity of the above compounds while minimizing or eliminating undesirable toxic effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, fumaric acid, and polygalacturonic acid). The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, particularly quaternary ammonium salts of the formula --NR+Z- (wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzyloate, and diphenylacetate)).

[0102] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing significant toxic effects to the treated patient. The dosage of the active compound that meets all of the above conditions ranges from about 0.01 to 300 mg / kg per day, preferably from 0.1 to 100 mg / kg per day, and more typically from 0.5 to about 25 mg / kg (of the recipient's body weight) per day. A typical topical dosage is in the range of 0.01 to 3% wt / wt in a suitable carrier. The effective dosage range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound being delivered. If the derivative is itself active, the effective dosage can be estimated using the weight of the derivative as described above or by another method known to those skilled in the art.

[0103] The pharmaceutical composition containing the compound of the present invention may be used in the methods described herein.

[0104] Method of Use In another aspect, the present invention provides a method for inhibiting the SOS1 activity of a cell, comprising contacting, in vitro, a cell in which inhibition of the SOS1 activity is desired with an effective amount of a compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0105] The compositions and methods of the present application are believed to be particularly useful for inhibiting SOS1 activity in cells. In certain embodiments, a cell in which inhibition of SOS1 activity is desired is contacted, in vivo, with a therapeutically effective amount of a compound of the present application, and the SOS1 activity is suppressed. In other embodiments, a therapeutically effective amount of a pharmaceutically acceptable salt or pharmaceutical composition comprising a compound of the present application may be used. In certain embodiments, the cell has an activating mutation of a Ras family member (e.g., KRas, HRas, or NRas). In certain embodiments, the cell has abnormal SOS1 activity. In certain embodiments, the abnormal SOS1 activity is the result of an SOS1 activating mutation. In certain embodiments, the SOS1 activating mutation is an N233S or N233Y mutation. In certain embodiments, the cell has abnormal NF-1 or NF-2 activity. In certain embodiments, the abnormal NF-1 or NF-2 activity is the result of an NF-1 or NF-2 activating mutation.

[0106] This method is designed to inhibit the interaction between SOS1 and Ras family members by suppressing SOS1 activity, increase the GTP-bound form of RAS protein, thereby reducing or inhibiting the GTP nucleotide exchange reaction, fixing the Ras family members in the GDP-bound inactive form, and inhibiting downstream Ras-mediated signal transduction. It may be administered to the cell once or multiple times according to a specific treatment plan for desired SOS1 suppression.

[0107] In another aspect, provided is a method for treating cancer, which comprises administering to a cancer patient a therapeutically effective amount of the compound of the present application, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of the present application or a pharmaceutically acceptable salt thereof. In certain embodiments, the cancer is a Ras family-related cancer. In certain embodiments, the cancer is a SOS1-related cancer. In certain embodiments, the cancer is a NF1 / NF2-related cancer.

[0108] The compositions and methods of the present application may be used for the treatment of various cancers, including, for example, tumors of the prostate, breast, brain, skin, cervical cancer, testicular cancer, and the like. In particular, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, for example, epithelial malignancies and sarcomas of astrocytes, breast, neck, colorectal, endometrium, esophagus, stomach, head and neck, hepatocytes, larynx, lung, mouth, ovary, prostate, and thyroid. More specifically, these compounds are used for sarcomas of the heart (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; cancers of the lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, pulmonary hamartoma, mesothelioma; cancers of the digestive tract: cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), cancers of the stomach (epithelial malignancy, lymphoma, leiomyosarcoma), cancers of the pancreas (pancreatic ductal adenocarcinoma, insulin-producing islet cell tumor, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, VIP-producing tumor), cancers of the small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), cancers of the large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma); cancers of the urogenital tract: cancers of the kidney (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), cancers of the bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), cancers of the prostate (adenocarcinoma, sarcoma), cancers of the testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, non-epithelial malignancy, interstitial cell tumor, fibroma, fibroadenoma, adenomatoid tumor, lipoma); cancers of the liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; cancers of the biliary tract: gallbladder cancer, spleen cancer, cholangiocarcinoma; cancers of the bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor of bone;Cancers of the nervous system: cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), cancers of the meninges (meningioma, meningothelial non - epithelial malignant tumor, gliomatosis), brain tumors (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynecological cancers: cancers of the uterus (endometrial cancer), cancers of the cervix (cervical cancer, cervical dysplasia), cancers of the ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, undifferentiated carcinoma), granulosa cell tumor, Sertoli - Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), cancers of the vulva (squamous cell carcinoma, intraepithelial cancer, adenocarcinoma, fibrosarcoma, melanoma), cancers of the vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (fetal rhabdomyosarcoma), fallopian tube cancer); blood cancers: myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin lymphoma, non - Hodgkin lymphoma (malignant lymphoma); skin cancers: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and cancers of the adrenal gland: may treat neuroblastoma. In certain embodiments, the cancer is diffuse large B - cell lymphoma (DLBCL).;

[0109] In certain embodiments, the cancer is a Ras - family related cancer (e.g., KRas, NRas or HRas related cancer). In certain embodiments, a Ras - family related cancer is non - small cell lung cancer or pancreatic cancer. In certain embodiments, the cancer is a SOS1 - related cancer. In certain embodiments, a SOS1 - related cancer is lung adenocarcinoma, fetal rhabdomyosarcoma, Sertoli cell testicular tumor and granular cell tumor of the skin. In certain embodiments, the cancer is a NF1 - related cancer.

[0110] The concentration and route of administration to the patient vary depending on the cancer being treated. The compounds of the present application, their pharmaceutically acceptable salts, and pharmaceutical compositions containing the compounds and salts may be used in combination with another anti-tumor drug compound (e.g., chemotherapy), or may be used in combination with another treatment (e.g., as adjuvant therapy before or after radiotherapy or surgery).

[0111] General Reaction Scheme, Intermediates and Examples General reaction scheme The compounds of the present invention may be prepared using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, or may be prepared using other reagents and conventional methods well known to those skilled in the art.

[0112] For example, an intermediate in the preparation of the compounds of the present invention is shown in General Reaction Scheme III:

Chemical formula

[0113] In General Reaction Scheme III, compound 7 may undergo a nucleophilic substitution reaction with a coupling partner (e.g., alcohol or amine, H-R 1 (9)) in the presence of a metal catalyst reaction or an appropriate base (e.g., cesium carbonate) to obtain the title compound 5.

[0114] In the above General Reaction Scheme III, R 1 is hydrogen, hydroxyl, C1-C6 alkyl, alkoxy, -N(R 6 )2, -NR 6 C(O)R 6 , -C(O)N(R 6 )2, -SO2 alkyl, -SO2NR 6 alkyl, cycloalkyl, -Q-heterocyclyl, aryl, or heteroaryl, where the cycloalkyl, heterocyclyl, aryl, and heteroaryl each have one or more R 2 or L-R 2may be appropriately substituted as needed; Each Q is independently a bond, O, or NR 6 and; X is N or CR 7 and; Each R 2 is independently C1-C3 alkyl, oxo (i.e., C=O), hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -C(O)N(R 6 )2, -N(R 6 )2, -SO2 alkyl, -NR 6 C(O)C1-C3 alkyl, -C(O)cycloalkyl, -C(O)C1-C3 alkyl, -C(O)heterocyclyl, aryl, heteroaryl, or heterocyclyl, where the cycloalkyl, heterocyclyl, aryl, heteroaryl, or heterocyclyl may each be appropriately substituted with one or more R 11 as needed; R 3 is hydrogen, C1-C6 alkyl, alkoxy, -N(R 10 )2, -L-N(R 10 )2, cycloalkyl, haloalkyl, or heterocyclyl, where the C1-C6 alkyl, cycloalkyl, and heterocyclyl may each be appropriately substituted with one or more R 9 as needed; Y is a bond or heteroarylene; R 4 is aryl or heteroaryl, each of which may be appropriately substituted with one or more R 5 as needed; Each R 5 is independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, haloalkyl-OH, -N(R 6 )2, -L-N(R 6 )2, or -SO2 alkyl; L is C1-C3 alkylene; Each R 6 is independently hydrogen, C1-C3 alkyl, haloalkyl, or cycloalkyl; R7 is hydrogen, cyano, or alkoxy; R 8 is C1-C2 alkyl or halo C1-C2 alkyl; each R 9 is independently hydroxy, halogen, amino, cyano, alkoxy, or C1-C3 alkyl; each R 10 is independently hydrogen, C1-C3 alkyl or cycloalkyl; each R 11 is independently C1-C3 alkyl, halogen or haloalkyl; and R 12 is hydrogen, halogen or C1-C3 alkyl.

[0115] The following intermediates may be used to produce the compounds of the present invention.

[0116] Intermediate A

Chemical formula

[0117] Step A: To a mixture of 1-(2-bromophenyl)-N-methylmethanamine (6.50 g, 32.5 mmol, 1 equivalent) / THF (70.0 mL), Boc2O (7.80 g, 35.7 mmol, 8.21 mL, 1.10 equivalents) was added dropwise at 25 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure as it was to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain tert-butyl (2-bromobenzyl)(methyl)carbamate (7.50 g, 25.0 mmol, 76.9% yield) as a colorless oil. 11H NMR (400 MHz, CDCl3) δ 7.55 (br d, J = 8.0 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.22 - 7.08 (m, 2H), 4.61 - 4.42 (m, 2H), 2.94 - 2.78 (m, 3H), 1.60 - 1.33 (m, 9H)

[0118] Step B: A mixture of tert-butyl (2-bromobenzyl)(methyl)carbamate (7.00 g, 23.3 mmol, 1.00 equiv), bis(pinacolato)diboron (8.88 g, 35.0 mmol, 1.50 equiv), Pd(dppf)Cl2 (1.71 g, 2.33 mmol, 0.10 equiv), and potassium acetate (5.72 g, 58.3 mmol, 2.50 equiv) in dioxane (80.0 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 110 °C for 12 h under a nitrogen atmosphere. The resulting reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 - 10 / 1) to afford tert-butylmethyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (8.00 g, 23.0 mmol, 98.8% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3) δ 7.82 (br d, J = 7.2 Hz, 1H), 7.48 - 7.37 (m, 1H), 7.27 - 7.21 (m, 2H), 4.85 - 4.63 (m, 2H), 2.92 - 2.73 (m 3H), 1.54 - 1.41 (m, 9H), 1.35 (s, 12H)

[0119] Intermediate B

Chemical formula

[0120] Step A: A solution of 1-(4-bromothiophen-2-yl)ethan-1-one (4.00 g, 19.5 mmol, 1.10 equiv) and 2-methylpropane-2-sulfinamide (2.15 g, 17.7 mmol, 1.00 equiv) in THF (56.0 mL) was added with Ti(OEt)4 (8.09 g, 35.5 mmol, 7.35 mL, 2.00 equiv) and stirred at 70 °C for 2 h. The mixture was poured into water (15.0 mL) and stirred for 5 min. The suspension was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was washed with petroleum ether / ethyl acetate = 5 / 1 (10 mL), filtered, the filter cake was recovered, dried under reduced pressure, and N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (3.00 g, 9.73 mmol, 54.9% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 1.2 Hz, 1H), 2.72(s, 3H), 1.30(s, 9H)

[0121] Step B: Sodium borohydride (1.36 g, 36.0 mmol, 3.00 equiv) was added to a solution of N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (3.70 g, 12.0 mmol, 1.00 equiv) in THF (40.0 mL) at 0 °C, slowly warmed to 25 °C, and stirred for 2 h. The reaction mixture was poured into ice water (15.0 mL) and stirred at 0 °C for 5 min. The aqueous layer was extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and N-(1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (3.60 g, 9.51 mmol, 79.3% yield, 82.0% purity) was obtained as a yellow oil. 11H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 6.98 - 6.96 (s, 1H), 4.81 - 4.75 (m, 1H), 3.55 (br d, J = 3.6 Hz, 1H), 1.59 (d, J = 6.4 Hz, 3H), 1.24 (s, 9H)

[0122] Step C: To a solution of N-(1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (3.00 g, 9.67 mmol, 1.00 equiv) and tert-butylmethyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (5.04 g, 14.5 mmol, 1.50 equiv) in dioxane (35.0 mL) and water (8.00 mL), Pd(PPh3)4 (1.12 g, 967 μmol, 0.10 equiv) and cesium carbonate (9.45 g, 29.01 mmol, 3.00 equiv) were added under a nitrogen atmosphere. The mixture was stirred at 110 °C for 2 h under a nitrogen atmosphere. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 - 1 / 1) to give tert-butyl(2-(5-(1-((tert-butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (1.40 g, 3.11 mmol, 32.1% yield) as a yellow oil. LCMS [M+1]: 451.2

[0123] Step D: A solution of tert-butyl (2-(5-(1-((tert-butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (1.40 g, 4.88 mmol, 1.00 equiv) in THF (15.0 mL) and water (5.00 mL) was added iodine (232 mg, 1.46 mmol, 295 μL, 0.30 equiv), and the mixture was stirred at 50 °C for 30 minutes. The resulting residue was poured into a saturated aqueous sodium sulfite solution (30.0 mL) and stirred for 5 minutes. The aqueous layer was extracted with ethyl acetate (15.0 mL × 2), the combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl (2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (1.20 g, crude product) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.28 (m, 3H), 7.26 - 7.22 (m, 1H), 7.01 (s, 1H), 6.91 (br s, 1H), 4.49 (br d, J = 19.2 Hz, 2H), 4.40 (q, J = 6.4 Hz, 1H), 2.72 (br d, J = 19.2 Hz, 3H), 1.53 (d, J = 6.4 Hz, 3H), 1.51 - 1.40 (m, 9H)

[0124] Intermediates C and D

Chemical Structure

[0125] Step A: (R,E)-N-((4-Bromothiophen-2-yl)methylene)-2-methylpropan-2-sulfinamide (20.0 g, 104 mmol, 1.00 equiv) and (R)-2-methylpropan-2-sulfinamide (12.1 g, 99.5 mmol, 0.95 equiv) in THF (200 mL), titanium(IV) ethoxide (47.8 g, 209 mmol, 43.4 mL, 2.00 equiv) was added, and the mixture was stirred at 25 °C for 1 h. The resulting mixture was then poured into water (20.0 mL), stirred for 5 min to obtain a suspension. The suspension was filtered, and the filtrate was concentrated under reduced pressure to obtain (R,E)-N-((4-bromothiophen-2-yl)methylene)-2-methylpropan-2-sulfinamide (20.0 g, crude) as a yellow oil. LCMS [M+1]: 295.8

[0126] Step B: (R,E)-N-((4-Bromothiophen-2-yl)methylene)-2-methylpropan-2-sulfinamide (600 mg, 2.04 mmol, 1.00 equiv) in THF (200 mL), methylmagnesium bromide (3.00 M, 2.04 mL, 3.00 equiv) was added dropwise at 0 °C, and the mixture was stirred at 25 °C for 1 h. Saturated aqueous ammonium chloride solution (3.00 mL) was added to this reaction mixture, and the mixture was stirred for 5 min. The aqueous layer was extracted with ethyl acetate (3.00 mL × 2), the combined organic layers were washed with brine (3.00 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The resulting residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to obtain (R)-N-((S)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropan-2-sulfinamide (the first eluate, Intermediate C, 120 mg, 19.0% yield) as a yellow oil, and (R)-N-((R)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropan-2-sulfinamide (the second eluate, Intermediate D, 150 mg, 483 μmol, 23.7% yield) as a yellow oil. Intermediate C: 11H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 1.6 Hz, 1H), 6.97 (s, 1H), 4.81 - 4.75 (m, 1H), 3.51 (br d, J = 3.2 Hz, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.24 (s, 9H) Intermediate D 1 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 1.6 Hz, 1H), 6.89 (s, 1H), 4.81 - 4.74 (m, 1H), 3.39 (br d, J = 5.6 Hz, 1H), 1.65 (d, J = 6.8 Hz, 3H), 1.25 (s, 9H)

[0127] Intermediate E

Chemical formula

[0128] Step A: (R)-N-((R)-1-(4-Bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (150 mg, 483 μmol, 1.00 equivalent) and tert-butylmethyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (168 mg, 483 μmol, 1.00 equivalent) in a solution of dioxane (1.00 mL) and water (0.20 mL) were added with Pd(PPh3)4 (55.9 mg, 48.3 μmol, 0.10 equivalent) and cesium carbonate (473 mg, 1.45 mmol, 3.00 equivalents) under a nitrogen atmosphere, stirred at 110 °C for 2 hours under a nitrogen atmosphere, then concentrated under reduced pressure at 25 °C to obtain a residue. The obtained residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl(2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (120 mg, 266 μmol, 55.1% yield) as a white solid. LCMS [M + 1] = 451.1 11H NMR (400 MHz, CDCl3) δ 7.37 - 7.29 (m, 3H), 7.25 (s, 1H), 7.06 (s, 1H), 6.95 (br s, 1H), 4.88 - 4.81 (m, 1H), 4.48 (br d, J = 16.0 Hz, 2H), 3.44 (br d, J = 6.0 Hz, 1H), 2.73 (br d, J = 12.8 Hz, 3H), 1.71 (d, J = 6.4 Hz, 3H), 1.27 (s, 9H), 1.25 (s, 9H)

[0129] Step B: To a solution of tert-butyl (2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (120 mg, 266 μmol, 1.00 equiv) in THF (1.00 mL) and water (0.20 mL) was added iodine (20.3 mg, 79.9 μmol, 16.1 μL, 0.30 equiv), and the mixture was stirred at 50 °C for 1 h. The reaction mixture was then cooled to 25 °C, poured into saturated aqueous sodium sulfite solution (2.00 mL), and stirred for 5 min. The aqueous layer was extracted with ethyl acetate (3.00 mL × 3), the combined organic layers were washed with brine (3.00 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3um; mobile phase: [water (0.1% TFA) / ACN]; B%: 28% - 38%) to give tert-butyl (R)-(2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (40.0 mg, 113 μmol, 42.3% yield, purity 97.5%) as a white oil. 1 1H NMR (400 MHz, CD3OD) δ 7.41 - 7.23 (m, 6H), 4.84 - 4.79 (m, 1H), 4.48 (s, 2H), 2.73 (s, 3H), 1.76 (d, J = 6.8 Hz, 3H), 1.51 - 1.36 (m, 9H)

[0130] Intermediate F [Chemical]

[0131] Step A: (R)-N-((S)-1-(4-Bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 322 μmol, 1.00 equiv) and tert-butylmethyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (112 mg, 322 μmol, 1.00 equiv) / in a solution of dioxane (1.00 mL) and water (0.20 mL), Pd(PPh3)4 (37.2 mg, 32.2 μmol, 0.10 equiv) and cesium carbonate (315 mg, 967 μmol, 3.00 equiv) were added under a nitrogen atmosphere, and the mixture was stirred at 110 °C for 2 h. It was then cooled to 25 °C and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl(2-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (100 mg, 266 μmol, 68.9% yield) as a yellow oil. LCMS [M+1] = 451.1 1 H NMR (400 MHz, CDCl3) δ 7.37 - 7.28 (m, 3H), 7.26 - 7.22 (m, 1H), 7.07 (d, J = 1.2 Hz, 1H), 7.03 (br s, 1H), 4.90 - 4.83 (m, 1H), 4.55 - 4.41 (m, 2H), 3.71 - 3.55 (m, 1H), 2.80 - 2.65 (m, 3H), 1.64 (d, J = 6.8 Hz, 3H), 1.52 - 1.41 (m, 9H), 1.26 (s, 9H)

[0132] Step B: A solution of tert-butyl (2-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (100 mg, 266 μmol, 1.00 eq) in THF (1.00 mL) and water (0.20 mL) was added iodine (16.9 mg, 66.6 μmol, 13.4 μL, 0.30 eq), and the mixture was stirred at 50 °C for 1 h. It was then cooled to 25 °C, poured into saturated aqueous sodium bisulfite (2.00 mL), and stirred for 5 min. The aqueous layer was extracted with ethyl acetate (3.00 mL × 3), and the combined organic layers were washed with brine (3.00 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10um; mobile phase: [water (0.1% TFA) / ACN]; B%: 24% - 54%) to give tert-butyl (S)-(2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (45.0 mg, 97.7 μmol, 44.0% yield, TFA salt) as a white oil. LCMS [M+1]=347.2 1 H NMR(400MHz, CD3OD) δ 7.40(d, J=1.2Hz, 1H), 7.38 - 7.22(m, 5H), 4.82 - 4.80(br s, 1H), 4.48(s, 2H), 2.73(s, 3H), 1.75(d, J=6.8Hz, 3H), 1.50 - 1.35(m, 9H)

[0133] Intermediate G

Chemical Structure

[0134] Step A: A solution of 2-methyl-3-(trifluoromethyl)benzaldehyde (300 mg, 1.59 mmol, 1.00 equiv) and 2-methylpropan-2-sulfinamide (213 mg, 1.75 mmol, 1.10 equiv) in THF (5.00 mL) was added titanium(IV) ethoxide (727 mg, 3.19 mmol, 661 μL, 2.00 equiv), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (2.00 mL) and stirred for 5 min to obtain a suspension. The resulting suspension was filtered and concentrated under reduced pressure to give 2-methyl-N-(2-methyl-3-(trifluoromethyl)benzylidene)propan-2-sulfinamide (360 mg, 1.24 mmol, 77.5% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ = 8.98 (s, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 2.70 (d, J = 0.8 Hz, 3H), 1.29 (s, 9H)

[0135] Step B: To a solution of 2-methyl-N-(2-methyl-3-(trifluoromethyl)benzylidene)propan-2-sulfinamide (185 mg, 635 μmol, 1.00 equiv) in THF (5.00 mL) was added dropwise methylmagnesium bromide (227 mg, 3.00 M, 635 μL, 3.00 equiv) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 25 °C for 3 h. Then it was slowly treated with saturated ammonium chloride solution (10.0 mL). The organic and aqueous layers were separated, and the aqueous layer was extracted with ethyl acetate (5.00 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 - 1 / 1) to give 2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (150 mg, 488.0 μmol, 76.8% yield) as a yellow solid. 11H NMR (400 MHz, CDCl3) δ = 7.65 - 7.54 (m, 4H), 7.35 - 7.28 (m, 2H), 5.00 - 4.87 (m, 2H), 2.49 (s, 6H), 1.54 - 1.50 (m, 6H), 1.26 - 1.24 (m, 9H), 1.22 (s, 9H)

[0136] Step C: A solution of 2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (150 mg, 488.0 μmol, 1.00 equiv) / HCl (4.0 M, dioxane, 1.00 mL) was stirred at 25 °C for 1 hour. The reaction mixture was filtered and the filter cake was concentrated under reduced pressure to give 1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (45.0 mg, 38.5% yield) as a red solid. LCMS [M+1] = 204.3 1 1H NMR (400 MHz, CD3OD) δ = 7.78 - 7.65 (m, 2H), 7.56 - 7.48 (m, 1H), 4.93 - 4.89 (m, 1H), 2.52 (d, J = 0.8 Hz, 3H), 1.63 (d, J = 6.8 Hz, 3H)

[0137] Intermediate H

Chemical Structure

[0138] Step A: A solution of 1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-one (8.00 g, 39.6 mmol, 1.00 equiv) and (S)-2-methylpropan-2-sulfinamide (5.28 g, 43.5 mmol, 1.10 equiv) in THF (80.0 mL) was added titanium(IV) ethoxide (18.1 g, 79.1 mmol, 16.4 mL, 2.00 equiv), and the mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to 25 °C, poured into ice water (w / w = 1 / 1, 80.0 mL), and stirred for 15 min to obtain a suspension. The suspension was filtered, and the filtrate was extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to give (S)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (8.00 g, 26.2 mmol, 66.2% yield) as a yellow oil. LCMS [M+1]: 306.2 1 1H NMR (400 MHz, CD3OD) δ 7.74 (br t, J = 7.2 Hz, 2H), 7.57 - 7.51 (m, 1H), 7.46 (br t, J = 7.6 Hz, 2H), 7.43 - 7.30 (m, 1H), 2.72 (s, 3H), 2.54 (J = 6.8 Hz, 3H), 2.48 (s, 3H), 2.40 (br d, J = 16.0 Hz, 3H), 1.31 (s, 9H), 1.24 (br d, J = 12.4 Hz, 9H)

[0139] Step B: A solution of (S)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (8.00 g, 26.2 mmol, 1.00 equiv) in THF (80.0 mL) was added dropwise with L-selectride (7.47 g, 39.3 mmol, 8.59 mL, 1.50 equiv) at -78 °C and stirred at -78 °C for 2 h. To this reaction mixture, water (10.0 mL) was added dropwise at 0 °C and stirred for 5 min. The aqueous layer was extracted with ethyl acetate (30.0 mL × 3), and the combined organic layers were washed with brine (30.0 mL × 2). Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 - 3 / 1) to give (S)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (3.50 g, 11.4 mmol, 43.5% yield) as a yellow oil. LCMS [M+1]: 308.0 1 1H NMR (400 MHz, CD3OD) δ = 7.70 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.39 - 7.33 (m, 1H), 4.94 - 4.88 (m, 1H), 2.48 (d, J = 1.2 Hz, 3H), 1.54 (d, J = 6.4 Hz, 3H), 1.20 (s, 9H)

[0140] Step C: A solution of (S)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (1.30 g, 4.23 mmol, 1.00 equiv) in HCl (4M, dioxane solution, 15.0 mL) was stirred at 25 °C for 30 min. The reaction mixture was filtered, and the filter cake was dried under reduced pressure to obtain (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (700 mg, 2.89 mmol, 68.4% yield, purity 99.1%, hydrochloride) as a white solid. LCMS [M+H]: 204.0 11H NMR (400 MHz, CD3OD) δ = 7.73 (t, J = 7.6 Hz, 2H), 7.54 - 7.49 (m, 1H), 4.92 - 4.88 (m, 1H), 2.52 (d, J = 0.8 Hz, 3H), 1.62 (d, J = 6.8 Hz, 3H)

[0141] Intermediate I

Chem.

[0142] Step A: To a solution of 1-(5-bromothiophen-2-yl)ethan-1-one (11.0 g, 53.6 mmol, 1.00 equiv) in THF (120 mL) were added 2-methylpropane-2-sulfinamide (8.45 g, 69.7 mmol, 1.30 equiv) and titanium(IV) ethoxide (24.5 g, 107 mmol, 22.3 mL, 2.00 equiv), and the mixture was stirred at 75 °C for 12 h under a nitrogen atmosphere. The reaction mixture was cooled to 25 °C and concentrated under reduced pressure to give a residue. The obtained residue was diluted with water (200 mL) and ethyl acetate (200 mL), filtered, and the filtrate was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (16.0 g, crude) as a yellow solid. LCMS [M+1]: 308.0

[0143] Step B: A solution of N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (16.0 g, 51.9 mmol, 1.00 equiv) in THF (150 mL) was added with sodium borohydride (3.93 g, 104 mmol, 2.00 equiv) at 0 °C, and the mixture was stirred at 20 °C for 1 h. A saturated aqueous sodium hydrogen carbonate solution (20.0 mL) was added dropwise to this reaction mixture, and then the mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 2 / 1) to obtain N-(1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (12.0 g, 38.7 mmol, 74.5% yield) as a yellow oil. LCMS [M+1]: 309.9

[0144] Intermediate J

Chemical formula

[0145] Step A: To a solution of 1-(5-bromothiophen-2-yl)ethan-1-one (10.0 g, 48.8 mmol, 1.00 equiv) and (R)-2-methylpropane-2-sulfinamide (7.68 g, 63.4 mmol, 1.30 equiv) in THF (120 mL) was added titanium(IV) ethoxide (22.3 g, 97.5 mmol, 20.2 mL, 2.00 equiv), and the mixture was stirred at 70 °C for 12 h under a nitrogen atmosphere. The reaction mixture was cooled to 25 °C, diluted with water (200 mL) and ethyl acetate (100 mL) to obtain a suspension. The suspension was filtered, and the filtrate was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure to obtain (R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (13.0 g, crude product) as a brown oil. LCMS [M+1]: 308.2 11H NMR (400 MHz, CDCl3) δ = 7.23 (d, J = 4.0 Hz, 1H), 7.04 (d, J = 4.0 Hz, 1H), 2.67 (s, 3H), 1.28 (s, 9H)

[0146] Step B: (R,E)-N-(1-(5-Bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (13.0 g, 42.2 mmol, 1.00 equiv) / THF (150 mL) solution was added with sodium borohydride (4.79 g, 127 mmol, 3.00 equiv) at 0 °C, and stirred at 20 °C for 2 h under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution (20.0 mL) was added dropwise to the mixture, diluted with water (200 mL), and the resulting aqueous solution was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 2 / 1) to obtain (R)-N-((R)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (6.00 g, 17.4 mmol, 41.3% yield, purity 90.0%) as a brown solid. LCMS [M+1]: 309.9 1 1H NMR (400 MHz, CDCl3) δ = 6.90 (d, J = 3.6 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 4.84 - 4.66 (m, 1H), 3.50 (d, J = 2.8 Hz, 1H), 1.57 (d, J = 6.4 Hz, 3H), 1.23 (s, 9H)

[0147] Step C: (R)-N-((R)-1-(5-Bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (2.00 g, 6.45 mmol, 1.00 equiv) and tert-butylmethyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (2.69 g, 7.74 mmol, 1.20 equiv) / a solution of dioxane (20.0 mL) and water (2.00 mL) were added with cesium carbonate (6.30 g, 19.3 mmol, 3.00 equiv) and Pd(PPh3)4 (745 mg, 645 μmol, 0.10 equiv) under a nitrogen atmosphere, and the mixture was stirred at 110 °C for 2 h under a nitrogen atmosphere. The reaction mixture was then cooled to 25 °C, diluted with water (100 mL), and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~1 / 1) to give tert-butyl(2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (2.60 g, 5.19 mmol, 80.6% yield, purity 90.0%) as a yellow oil. LCMS [M+1]: 451.4 1 1H NMR (400 MHz, CDCl3) δ = 7.40 - 7.32 (m, 2H), 7.31 - 7.27 (m, 1H), 7.26 - 7.22 (m, 1H), 7.01 (s, 1H), 6.83 (s, 1H), 4.95 - 4.79 (m, 1H), 4.67 - 4.44 (m, 2H), 3.56 (d, J = 3.2 Hz, 1H), 2.93 - 2.56 (m, 3H), 1.64 (d, J = 6.4 Hz, 3H), 1.56 - 1.36 (m, 9H), 1.26 (s, 9H)

[0148] Step D: A solution of tert-butyl (2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (2.60 g, 5.77 mmol, 1.00 eq) in THF (20.0 mL) and water (4.00 mL) was added iodine (439 mg, 1.73 mmol, 349 μL, 0.30 eq), and the mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to 25 °C, diluted with saturated sodium bicarbonate (50.0 mL), and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give (R)-tert-butyl (R)-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamate (1.50 g, 3.68 mmol, 63.8% yield, purity 85.0%) as a yellow oil. LCMS [2M+1]: 693.3 1 H NMR (400 MHz, CDCl3) δ = 7.39 - 7.31 (m, 2H), 7.30 - 7.20 (m, 2H), 7.01 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 3.2 Hz, 1H), 4.61 - 4.48 (m, 3H), 4.04 (s, 2H), 2.73 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H), 1.57 - 1.33 (m, 9H)

[0149] Intermediate K

Chemical Structure

[0150] Step A: A solution of N-(1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (0.50 g, 1.61 mmol, 1.00 equiv) and N,N-dimethyl-1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (505 mg, 1.93 mmol, 1.20 equiv) in dioxane (5.00 mL) and water (0.50 mL) was added with cesium carbonate (1.58 g, 4.83 mmol, 3.00 equiv) and Pd(PPh3)4 (186 mg, 161 μmol, 0.10 equiv), and then degassed and purged with nitrogen three times. Under a nitrogen atmosphere, the mixture was stirred at 110 °C for 2 h. After completion of stirring, the mixture was cooled to 25 °C, diluted with water (50.0 mL), and extracted with ethyl acetate (20.0 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to give N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (450 mg, 1.15 mmol, 71.3% yield, purity 93.0%) as a brown oil. LCMS [M+1]: 365.2

[0151] Step B: A solution of N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (410 mg, 1.12 mmol, 1.00 eq) in THF (4.00 mL) was added with hydrochloric acid (3.00 M, 375 μL, 1.00 eq), and the mixture was stirred at 20 °C for 2 h. After completion of the stirring, the reaction mixture was diluted with saturated sodium hydrogen carbonate (50.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to dichloromethane / methanol = 10 / 1) to obtain 1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethanamine (200 mg, 691 μmol, 61.5% yield, purity 90.0%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ=7.48-7.42(m, 1H), 7.41-7.36(m, 1H), 7.34-7.28(m, 2H), 7.13(d, J=3.6Hz, 1H), 6.96-6.92(m, 1H), 4.29-4.21(m, 1H), 3.39(s, 2H), 2.14(s, 6H), 1.38(d, J=6.4Hz, 3H)

[0152] Intermediate L

Chemical formula

[0153] Step A: To a solution of 6-chlorofuro[3,4-c]pyridin-1(3H)-one (1.50 g, 8.85 mmol, 1.00 eq) in carbon tetrachloride (10.0 mL) were added AIBN (145 mg, 884 μmol, 0.10 eq) and NBS (1.42 g, 7.96 mmol, 0.9 eq), and the mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 - 10 / 1) to give 3-bromo-6-chlorofuro[3,4-c]pyridin-1(3H)-one (1.20 g, 4.83 mmol, 54.6% yield) as a yellow oil. LCMS [M+3]: 249.8 1 H NMR (400 MHz, CDCl3) δ = 8.84 - 8.80 (m, 1H), 7.84 (s, 1H), 7.47 (s, 1H)

[0154] Step B: To a solution of 3-bromo-6-chlorofuro[3,4-c]pyridin-1(3H)-one (1.20 g, 4.83 mmol, 1.00 eq) in ethanol (20.0 mL) was added hydrazine hydrate (370 mg, 7.24 mmol, 359 μL, 1.50 eq) at 0 °C, and the mixture was stirred at 80 °C for 30 min. The reaction mixture was cooled to 25 °C and poured into ice water (1.00 mL) to obtain a suspension. This suspension was filtered, and the filter cake was collected and dried in vacuo to give 7-chloropyrido[3,4-d]pyridazin-1-ol (800 mg, 4.41 mmol, 91.2% yield) as a yellow solid. LCMS [M+1] + : 182.0 1 H NMR (400 MHz, DMSO-d6) δ = 13.08 (br s, 1H), 9.20 (s, 1H), 8.53 (s, 1H), 8.10 (s, 1H)

[0155] Step C: A solution of 7-chloropyrido[3,4-d]pyridazin-1-ol (78.0 mg, 430 μmol, 1.00 equiv) in acetonitrile (2.00 mL) was added with phosphoryl chloride (231 mg, 1.50 mmol, 139 μL, 3.50 equiv) at 25 °C, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to 25 °C, poured into saturated aqueous sodium hydrogen carbonate solution (2.00 mL), and stirred at 0 °C for 5 min. The aqueous layer was extracted with ethyl acetate (3.00 mL × 3), and the combined organic layers were washed with brine (2.00 mL × 3). Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1,7-dichloropyrido[3,4-d]pyridazine (65.0 mg, crude product) as a red solid. LCMS [M+1]: 199.8

[0156] Intermediate M [Chemical formula]

[0157] Step A: To a mixture of methyl 3,4-dimethoxybenzoate (10.0 g, 51.0 mmol, 1.00 equiv) in acetic acid (50.0 mL) was added bromine (8.96 g, 56.1 mmol, 2.89 mL, 1.10 equiv) in acetic acid (50.0 mL) dropwise over 1.5 h at 0 °C. The mixture was then slowly warmed to room temperature and stirred for 45 min. After completion of stirring, the reaction was quenched by pouring into water (700 mL), and the mixture was stirred for 30 min. Then, the stirring was stopped, and the mixture was allowed to stand for 1 h and filtered. The recovered solid was washed with water (100 mL) and then with aqueous sodium sulfite solution (100 mL). A portion of the solid was dried and dissolved in hot methanol (300 mL), and the resulting solution was cooled. The cooled methanol solution was treated with water (200 mL) to obtain a suspension. The suspension was filtered, and the filter cake was recovered and dried under reduced pressure to obtain methyl 2-bromo-4,5-dimethoxybenzoate (9.00 g, 32.7 mmol, 64.2% yield) as a white powder. LCMS [M+1]: 275.3 11H NMR (400 MHz, DMSO-d6) δ = 7.36 (s, 1H), 7.24 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H)

[0158] Step B: A mixture of methyl 2-bromo-4,5-dimethoxy-benzoate (6.00 g, 21.8 mmol, 1.00 equiv), 1-(vinyloxy)butane (10.9 g, 109 mmol, 14.0 mL, 5.00 equiv), Pd(OAc)2 (490 mg, 2.18 mmol, 0.10 equiv), triphenylphosphine (1.14 g, 4.36 mmol, 0.20 equiv) and triethylamine (2.65 g, 26.2 mmol, 3.64 mL, 1.20 equiv) / acetonitrile (60.0 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was then cooled to 25 °C, filtered, and the filtrate was concentrated under reduced pressure to give methyl 2-(1-butoxyvinyl)-4,5-dimethoxybenzoate (6.00 g, crude) as a yellow oil. This was used directly in the next step.

[0159] Step C: A mixture of methyl 2-(1-butoxyvinyl)-4,5-dimethoxybenzoate (6.00 g, 20.4 mmol, 1.00 equiv) / hydrochloric acid (10% aqueous solution, 61.2 g, 168 mmol, 60.0 mL, 8.23 equiv) and THF (60.0 mL) was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were adjusted to pH = 7 with saturated aqueous sodium hydrogen carbonate, then the organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The obtained residue was triturated at 20 °C for 20 min using petroleum ether / ethyl acetate = 5 / 1 (50.0 mL) to give a suspension. The suspension was filtered, and the filter cake was collected and dried under reduced pressure to give methyl 2-acetyl-4,5-dimethoxybenzoate (3.00 g, 12.6 mmol, 61.8% yield) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ = 7.26 (s, 1H), 7.17 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.77 (s, 3H), 2.46 (s, 3H)

[0160] Step D: To a solution of methyl 2-acetyl-4,5-dimethoxybenzoate (3.00 g, 12.6 mmol, 1.00 eq) in ethanol (30.0 mL) was added hydrazine hydrate (2.22 g, 37.8 mmol, 2.16 mL, 3.00 eq) at room temperature, and then the mixture was stirred at 95 °C for 30 minutes. The reaction mixture was diluted with water (100 mL) and extracted several times with ethyl acetate. The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was triturated with ethyl acetate (50.0 mL) at 20 °C for 20 minutes to obtain a suspension. The suspension was filtered, and the filter cake was collected and dried under reduced pressure to obtain 6,7-dimethoxy-4-methylphthalazin-1(2H)-one (2.00 g, 9.08 mmol, 72.1% yield) as an off-white solid. LCMS [M+1]: 221.4 1 1H NMR (400 MHz, DMSO-d6) δ = 12.25 (s, 1H), 7.58 (s, 1H), 7.21 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 2.48 (s, 3H)

[0161] Step E: A mixture of 6,7-dimethoxy-4-methylphthalazin-1(2H)-one (1.30 g, 5.90 mmol, 1.00 eq) and phosphoryl chloride (13.0 mL) was stirred at 120 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain 1-chloro-6,7-dimethoxy-4-methylphthalazine (1.20 g, crude product) as a yellow solid. LCMS [M+1]: 239.0 1 1H NMR (400 MHz, DMSO-d6) δ = 7.80 (s, 1H), 7.64 (s, 1H), 4.13 (s, 3H), 4.12 (s, 3H), 3.08 (s, 3H)

[0162] Intermediate N

Chem.

[0163] Step A: To a solution of 1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-one (0.37 g, 1.99 mmol, 1.00 equiv) in tetrahydrofuran (10.0 mL) were added titanium(IV) ethoxide (2.27 g, 9.95 mmol, 2.06 mL, 5.00 equiv) and (R)-2-methylpropan-2-sulfinamide (724 mg, 5.97 mmol, 3.00 equiv), and the mixture was stirred at 75 °C for 16 h. To this was added saturated aqueous sodium hydrogen carbonate solution (20.0 mL) at 25 °C to quench the reaction. The resulting mixture was filtered, and the filtrate was extracted with ethyl acetate (45.0 mL, 15.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The obtained residue was purified by flash silica gel chromatography (0 - 12% ethyl acetate / petroleum ether) to give (R,E)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropan-2-sulfinamide (0.36 g, 1.19 mmol, 59.8% yield, purity 95.0%) as a colorless oil. 1 H NMR (400 MHz, CD3OD) δ = 7.55 - 7.62 (m, 1H), 7.16 - 7.51 (m, 2H), 6.79 - 7.13 (m, 1H), 2.48 - 2.73 (m, 3H), 2.27 - 2.47 (m, 3H), 1.19 - 1.30 (m, 9H)

[0164] Step B: (R,E)-N-(1-(3-(Difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (340 mg, 1.18 mmol, 1.00 eq) / tetrahydrofuran (5.00 mL) solution was added with sodium borohydride (89.5 mg, 2.37 mmol, 2.00 eq), and stirred at 0 °C for 1 hour. Water (10.0 mL) was added to this reaction mixture at 25 °C to quench it, and then it was extracted with ethyl acetate (30.0 mL, 10.0 mL×3). The combined organic layers were washed with brine (10.0 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and a residue was obtained. The obtained residue was purified by flash silica gel chromatography (0 - 13% ethyl acetate / petroleum ether) to obtain (R)-N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (190 mg, 643 μmol, 54.4% yield, purity 98.0%) as a yellow oil. LCMS [M+1] + =290.1

[0165] Step C: (R)-N-((R)-1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (140 mg, 484 μmol, 1.00 eq) / hydrochloric acid (4.00 M, dioxane solution, 7.00 mL, 57.9 eq) mixture was stirred at 25 °C for 1 hour. This reaction mixture was concentrated under reduced pressure to obtain (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-amine (110 mg, 475 μmol, 98.2% yield, purity 80.0%) of the crude product as a white solid. This was used without further isolation. LCMS [M+1] + =186.0

[0166] Intermediate O

Chemical formula

[0167] Step A: To a solution of 3-bromo-2-methylbenzoic acid (100 g, 465 mmol, 1.00 eq) and N,O-dimethylhydroxylamine hydrochloride (68.6 g, 512 mmol, 1.10 eq, HCl) in DMF (1000 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (195 g, 512 mmol, 1.10 eq) and N,N-diisopropylethylamine (180 g, 1.40 mol, 243 mL, 3.00 eq) were added, and the mixture was stirred at 25 °C for 2 h. Then it was poured into water (1000 mL) and stirred for 15 min. The aqueous layer was extracted with ethyl acetate (1000 mL × 3), the combined organic layers were washed with brine (1000 mL × 5), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 3-bromo-N-methoxy-N,2-dimethylbenzamide (120 g, crude) was obtained as a yellow oil. LCMS [M+1] + : 258.0

[0168] Step B: To a solution of 3-bromo-N-methoxy-N,2-dimethylbenzamide (120 g, 465 mmol, 1.00 eq) in THF (100 mL), methylmagnesium bromide (3.0 M, 180 mL, 1.16 eq) was added at 0 °C, and the mixture was stirred between 0 and 40 °C for 3 h. Then the mixture was cooled to 0 °C, hydrochloric acid (6.0 N, 450 mL) was added dropwise, and the mixture was stirred between 40 and 45 °C for 2 h. Then the mixture was cooled to 25 °C and poured into saturated ammonium chloride solution (9000 mL). The aqueous layer was extracted with ethyl acetate (1500 mL × 3), the combined organic extracts were washed with brine (1000 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 1-(3-bromo-2-methylphenyl)ethan-1-one (90.0 g, 422 mmol, 90.9% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, CD3OD) δ = 7.70 (dd, J = 1.2, 8.0 Hz, 1H), 7.62 (dd, J = 0.8, 7.6 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H), 2.46 (s, 3H)

[0169] Step C: To a solution of 1-(3-bromo-2-methylphenyl)ethan-1-one (88.0 g, 413 mmol, 1.00 eq) and (S)-2-methylpropane-2-sulfinamide (60.1 g, 496 mmol, 1.20 eq) in THF (100 mL) was added titanium(IV) ethoxide (471 g, 2.07 mol, 428 mL, 5.00 eq) and diglyme (55.4 g, 413 mmol, 59.1 mL, 1.00 eq), and the mixture was stirred at 80 °C for 2 h. It was then poured into water (300 mL) and stirred for 15 min. The mixture was then filtered and concentrated under reduced pressure to give a residue. The residue obtained was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 40 / 1) to give (S)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (110 g, 348 mmol, 84.2% yield) as a yellow oil. 1 H NMR (400 MHz, CD3OD) δ=7.63 (br t, J=6.8 Hz, 2H), 7.28 (br d, J=7.6 Hz, 1H), 7.17 (t, J=8.0 Hz, 2H), 7.14 - 7.02 (m, 1H), 2.67 (s, 3H), 2.50 (br d, J=4.8 Hz, 3H), 2.42 (s, 3H), 2.31 (br d, J=17.2 Hz, 3H), 1.31 - 1.26 (m, 9H), 1.24 - 1.16 (m, 9H)

[0170] Step D: A solution of (S)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (109 g, 345 mmol, 1.00 equiv) in THF (1100 mL) was added dropwise with L-selectride (1.0 M, 689 mL, 2.00 equiv) at -78 °C, and the mixture was stirred at -78 °C for 2 h. Then it was poured into saturated aqueous ammonium chloride solution (1000 mL) and stirred at 25 °C for 60 min. The aqueous layer was extracted with ethyl acetate (1000 mL × 3), and the combined organic layers were washed with brine (500 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 - 2 / 1) to obtain a residue. The obtained residue was further washed with petroleum ether to obtain (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (70.0 g, 220 mmol, 63.8% yield) as a white solid. LCMS [M+1] + : 318.1

[0171] Step E: A solution of (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (71.0 g, 223 mmol, 1.00 equiv) in HCl (dioxane solution, 300 mL) and MeOH (300 mL) was stirred at 0 °C for 30 min. The mixture was concentrated under reduced pressure to obtain (R)-1-(3-bromo-2-methylphenyl)ethan-1-amine (55.0 g, crude, HCl) as a white solid. LCMS [M+1] + : 214.1

[0172] Step F: (R)-1-(3-Bromo-2-methylphenyl)ethan-1-amine (55.0 g, 220 mmol, 1.00 eq, HCl) and Boc2O (48.4 g, 222 mmol, 50.9 mL, 1.01 eq) in dichloromethane (500 mL) was added N,N-diisopropylethylamine (56.7 g, 439 mmol, 76.5 mL, 2.00 eq). The mixture was stirred at 0 - 25 °C for 30 min and then concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 - 100 / 1) to give a residue. This residue was further washed with petroleum ether to give tert-butyl (R)-(1-(3-bromo-2-methylphenyl)ethyl)carbamate (51.0 g, 162 mmol, 73.9% yield) as a white solid. LCMS [M-55] + : 258.0 1 H NMR (400 MHz, CD3OD) δ = 7.43 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.10 - 7.03 (m, 1H), 4.93 (br d, J = 6.4 Hz, 2H), 2.45 (s, 3H), 1.41 (br s, 9H), 1.33 (d, J = 6.8 Hz, 3H)

[0173] Step G: To a solution of tert-butyl (R)-(1-(3-bromo-2-methylphenyl)ethyl)carbamate (51.0 g, 162 mmol, 1.00 eq) in DMF (540 mL) were added zinc cyanide (22.9 g, 195 mmol, 12.4 mL, 1.20 eq) and Pd(PPh3)4 (18.8 g, 16.2 mmol, 0.10 eq). The mixture was stirred at 110 °C for 3 h, then cooled to 25 °C and poured into water (500 mL). The aqueous layer was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (1000 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give tert-butyl (R)-(1-(3-cyano-2-methylphenyl)ethyl)carbamate (37.0 g, 142.1 mmol, 87.6% yield) as a white solid. LCMS [M-55] + : 205.0 1 H NMR (400 MHz, CD3OD) δ = 7.63 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.39 - 7.30 (m, 1H), 4.93 (br d, J = 6.8 Hz, 1H), 2.58 (s, 3H), 1.40 (br s, 9H), 1.34 (d, J = 7.2 Hz, 3H)

[0174] Step H: To a solution of tert-butyl (R)-(1-(3-cyano-2-methylphenyl)ethyl)carbamate (49.0 g, 188 mmol, 1.00 eq) in dichloromethane (400 mL) was added TFA (133 mL). The mixture was stirred at 0 °C for 30 min. Then it was poured into saturated sodium bicarbonate solution (200 mL) and stirred for an additional 30 min. The aqueous layer was extracted with ethyl acetate (1000 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give (R)-3-(1-aminoethyl)-2-methylbenzonitrile (26.0 g, 162 mmol, 86.2% yield) as a yellow oil. LCMS[M-16] + : 144.1 1 1H NMR (400 MHz, DMSO-d6) δ = 8.36 (br s, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.80 (dd, J = 0.8, 7.6 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 4.68 (q, J = 6.8 Hz, 1H), 2.55 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H) SFC conditions: Column: Chiralpak IC-3 50×4.6 mm I.D., 3 μm, Mobile phase: (Mobile phase A) CO2, and (Mobile phase B) MeOH (0.05% DEA); Gradient: MeOH (0.05% DEA) / CO2 = 5% - 40%, Flow rate: 3 mL / min; Detection: PDA column, Temperature: 35 °C; Back pressure: 100 Bar

[0175] Intermediate P

Chem.

[0176] Intermediate Q

Chemical Structure

[0177] Intermediate R [Chemical formula]

[0178] Step A: (R)-2-Methylpropane-2-sulfinamide (5.12 g, 42.2 mmol, 1.00 equiv), 1-(3-bromo-2-methylphenyl)ethan-1-one (9.00 g, 42.2 mmol, 1.00 equiv), and a mixture of titanium(IV) isopropoxide (60.0 g, 211 mmol, 62.3 mL, 5.00 equiv) / THF (90.0 mL) were degassed, purged three times with nitrogen, and stirred at 80 °C for 12 h. The mixture was cooled to 25 °C, quenched by the addition of water (100 mL), filtered, and the filtrate was partitioned between ethyl acetate (300 mL) and water (300 mL). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The residue obtained was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 - 5 / 1) to give (R)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (7.23 g, 22.8 mmol, 54.1% yield) as a yellow solid. LCMS [M+3] + : 318.0 1 1H NMR (400 MHz, CD3OD) δ = 7.67 - 7.58 (m, 2H), 7.28 (br d, J = 7.6 Hz, 1H), 7.17 (t, J = 8.0 Hz, 2H), 7.14 - 7.01 (m, 1H), 2.67 (s, 3H), 2.50 (br d, J = 4.0 Hz, 3H), 2.42 (s, 3H), 2.31 (br d, J = 17.2 Hz, 3H), 1.28 (s, 9H), 1.21 (br d, J = 11.2 Hz, 9H) (the E / Z isomer ratio was ~1 / 1)

[0179] Step B: A solution of (R)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (400 mg, 1.26 mmol, 1.00 equiv) in THF (5.00 mL) was added sodium borohydride (239 mg, 6.32 mmol, 5.00 equiv) portionwise at 0 °C, and then stirred at 25 °C for 1 h. The reaction mixture was poured into water (30.0 mL) and stirred for 5 min. The resulting aqueous layer was extracted with ethyl acetate (150 mL × 3), the combined organic layers were washed with brine (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give (R)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 628 μmol, 49.7% yield) as a brown oil.

[0180] Step C: (R)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (250 mg, 786 μmol, 1.00 equiv), sodium methanesulfinate (176 mg, 1.73 mmol, 2.20 equiv), potassium carbonate (326 mg, 2.36 mmol, 3.00 equiv) and L-proline (18.1 mg, 157 μmol, 0.20 equiv) in dimethyl sulfoxide (3.00 mL) was added copper(I) iodide (15.0 mg, 78.6 μmol, 0.10 equiv) at 20 °C, and stirred at 130 °C for 3 h under a nitrogen atmosphere. Water (15.0 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative TLC (silica gel plate, petroleum ether / ethyl acetate = 1 / 1) to give (R)-2-methyl-N-((R)-1-(2-methyl-3-(methylsulfonyl)phenyl)ethyl)propane-2-sulfinamide (120 mg, 378 μmol, 48.1% yield) as a yellow oil. LCMS[M+1] + : 318.1 1 1H NMR (400 MHz, DMSO-d6) δ = 7.85 (dd, J = 8.0, 1.2 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 5.42 - 5.50 (m, 1H), 4.71 - 4.80 (m, 1H), 3.22 (s, 3H), 2.65 (s, 3H), 1.46 (d, J = 6.8 Hz, 3H), 1.09 (s, 9H)

[0181] Step D: A mixture of (R)-2-methyl-N-((R)-1-(2-methyl-3-(methylsulfonyl)phenyl)ethyl)propane-2-sulfinamide (120 mg, 378 μmol, 1.00 equiv) / hydrochloric acid (4.0 M, dioxane solution, 2.00 mL, 21.2 equiv) was stirred at 20 °C for 1 hour. The resulting mixture was concentrated under reduced pressure to give (R)-1-(2-methyl-3-(methylsulfonyl)phenyl)ethan-1-amine (91.0 mg, crude, HCl salt) as a white solid.

[0182] Intermediate S

Chemical Structure

[0183] Step A: To a solution of methylamine (100 g, 1.48 mol, 3.01 equiv., HCl salt) / THF (1.00 L), N,N - diisopropylethylamine (237 g, 1.84 mol, 3.73 equiv.), 2 - bromo - 6 - fluorobenzaldehyde (100 g, 493 mmol, 1.00 equiv.), acetic acid (9.00 g, 150 mmol, 0.30 equiv.) and sodium cyanoborohydride (62.0 g, 987 mmol, 2.00 equiv.) were added, and the mixture was stirred at 25 °C for 3 h. Then it was diluted with water (500 mL) and extracted with ethyl acetate (1.00 L × 2). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure to obtain 1 - (2 - bromo - 6 - fluorophenyl) - N - methylmethanamine (120 g, 484 mmol, purity 88%) as an off - white solid. This was used directly in the next step. LCMS [M + 1] + : 218.0

[0184] Step B: To a solution of 1 - (2 - bromo - 6 - fluorophenyl) - N - methylmethanamine (120 g, 484 mmol, 88% purity, 1.00 equiv.) / THF (1.00 L), di - tert - butyl dicarbonate (211 g, 968 mmol, 2.00 equiv.) was added, and the mixture was stirred at 25 °C for 2 h. This mixture was then concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 - 100 / 1) to obtain tert - butyl N - [(2 - bromo - 6 - fluoro - phenyl)methyl] - N - methyl - carbamate (70.0 g, 220 mmol) as a brown oil. LCMS [M - 55]+: 261.9 1 1H NMR (400 MHz, DMSO - d6) δ = 7.49 (d, J = 7.6 Hz, 1H), 7.33 - 7.26 (m, 2H), 4.57 (s, 2H), 2.64 (s, 3H), 1.38 (s, 9H)

[0185] Step C: A solution of tert-butyl(2-bromo-6-fluorobenzyl)(methyl)carbamate (60.0 g, 189 mmol, 1.00 equiv) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (60.0 g, 236 mmol, 1.25 equiv) in dioxane (600 mL) was added with Pd(dppf)Cl2·CH2Cl2 (15.0 g, 18.4 mmol, 0.10 equiv) and potassium acetate (72.0 g, 734 mmol, 3.89 equiv). The reaction mixture was degassed with nitrogen (3 times) and stirred at 100 °C for 12 h under a nitrogen atmosphere. The mixture was cooled to 25 °C and concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to give tert-butyl(2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate (80.0 g, 160 mmol, purity 73%) as a yellow oil. LCMS [M-55] + : 266.1

[0186] Step D: tert-Butyl (2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate (80.0 g, 160 mmol, purity 73%, 1.00 eq) and (R)-N-[(1R)-1-(5-bromo-2-thienyl)ethyl]-2-methyl-propan-2-sulfinamide (56.0 g, 180 mmol, 1.13 eq) / in a solution of dioxane (500 mL) and water (100 mL), cesium carbonate (150 g, 460 mmol, 2.88 eq) and Pd(PPh3)4 (20.0 g, 17.3 mmol, 0.10 eq) were added under a nitrogen atmosphere, and the mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The mixture was diluted with water (500 mL), extracted with ethyl acetate (1.00 L × 2), the organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and a residue was obtained. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 5 / 1) to give tert-butyl (2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-2-yl)-6-fluorobenzyl)(methyl)carbamate (84.0 g, 152 mmol, purity 85%) as a yellow oil. LCMS [M-100] + : 369.1 1 H NMR (400 MHz, DMSO-d6) δ = 7.44 - 7.36 (m, 1H), 7.27 - 7.17 (m, 2H), 7.08 (br d, J = 2.8 Hz, 1H), 6.96 (d, J = 3.6 Hz, 1H), 5.88 (br d, J = 6.8 Hz, 1H), 4.65 (quin, J = 6.4 Hz, 1H), 4.56 (s, 2H), 2.48 (s, 3H), 1.55 (br d, J = 6.8 Hz, 3H), 1.33 (br s, 9H), 1.13 (s, 9H)

[0187] Step E: A solution of tert-butyl (2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophen-2-yl)-6-fluorobenzyl)(methyl)carbamate (80.0 g, 145 mmol, purity 85%, 1.00 eq) / THF (240 mL) and water (48.0 mL) was added iodine (6.80 g, 26.8 mmol, 0.19 eq), and heated at 50 °C for 2 h. Then it was diluted with water (500 mL) and extracted with ethyl acetate (500 mL × 2). The organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, dichloromethane / methanol = 300 / 1 to 10 / 1) to give tert-butyl (R)-(2-(5-(1-aminoethyl)thiophen-2-yl)-6-fluorobenzyl)(methyl)carbamate (40.0 g, 110 mmol) as a yellow oil. LCMS [M-16] + : 348.1

[0188] Intermediate T [Chemical formula]

[0189] Step A: A mixture of 1-(benzyloxy)-3-bromo-5-(trifluoromethyl)benzene (3.00 g, 9.06 mmol, 1.00 equiv) and Pd(dppf)Cl2 (663 mg, 906 μmol, 0.10 equiv) in dioxane (50.0 mL) was added with tributyl(1-ethoxyvinyl)tin (5.00 g, 13.8 mmol, 4.67 mL, 1.53 equiv) at 20 °C, and stirred at 80 °C for 12 h under a nitrogen atmosphere. Then, saturated potassium fluoride solution (100 mL) was added to this mixture, and the solution was stirred at 20 °C for 1 h. The mixture was extracted with ethyl acetate (100 mL × 3), and the combined organic layers were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 1-(benzyloxy)-3-(1-ethoxyvinyl)-5-(trifluoromethyl)benzene (2.90 g, crude product) was obtained as a yellow oil. This crude oil was used in the next step without further purification.

[0190] Step B: To a solution of 1-(benzyloxy)-3-(1-ethoxyvinyl)-5-(trifluoromethyl)benzene (2.90 g, 9.00 mmol, crude product, 1.00 equiv) in tetrahydrofuran (30.0 mL) was added hydrochloric acid (3.0 M, THF solution, 10.0 mL, 3.33 equiv), and the mixture was stirred at 20 °C for 1 h. Then, this mixture was diluted with water (60.0 mL), extracted with ethyl acetate (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 - 10 / 1) to obtain 1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethan-1-one (2.60 g, 8.84 mmol, 98.2% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ = 7.79 (s, 1H), 7.74 (s, 1H), 7.45 - 7.39 (m, 6H), 5.16 (s, 2H), 2.63 (s, 3H)

[0191] Step C: A solution of 1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethan-1-one (2.60 g, 8.84 mmol, 1.00 equiv) and (R)-2-methylpropan-2-sulfinamide (1.39 g, 11.5 mmol, 1.30 equiv) in tetrahydrofuran (40.0 mL) was added titanium(IV) ethoxide (5.02 g, 17.7 mmol, 5.22 mL, 2.00 equiv) under a nitrogen atmosphere and stirred at 70 °C for 12 h. The mixture was then concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give (R)-N-(1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethylidene)-2-methylpropan-2-sulfinamide (2.20 g, 5.03 mmol, 57.0% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ = 7.45 (d, J = 10.0 Hz, 2H), 7.24 - 7.13 (m, 6H), 4.94 (s, 2H), 2.56 (s, 3H), 1.10 (s, 9H)

[0192] Step D: A mixture of (R)-N-(1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (2.20 g, 5.54 mmol, 1.00 equiv) in tetrahydrofuran (30.0 mL) was added sodium borohydride (270 mg, 7.14 mmol, 1.29 equiv) at 0 °C and stirred at 20 °C for 3 h. Saturated aqueous ammonium chloride solution (80.0 mL) was added to this mixture and the resulting mixture was stirred at 20 °C for 30 min. This mixture was then extracted with ethyl acetate (80.0 mL × 3), the combined organic layers were washed with brine (80.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 - 3 / 1) to give (R)-N-((R)-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.20 g, 3.00 mmol, 54.3% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ = 7.53 - 7.32 (m, 5H), 7.23 - 7.12 (m, 3H), 5.12 (s, 2H), 4.62 - 4.53 (m, 1H), 3.43 (d, J = 2.8 Hz, 1H), 1.53 (d, J = 6.4 Hz, 3H), 1.25 (s, 9H)

[0193] Step E: Hydrochloric acid (4.0 M, dioxane solution, 751 μL, 1.00 equiv) was added to a solution of (R)-N-((R)-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.20 g, 3.00 mmol, 1.00 equiv) and stirred at 20 °C for 20 min. This mixture was concentrated under reduced pressure to remove, and (R)-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethan-1-amine (1.20 g, crude, HCl) was obtained as a white solid. This was used without further isolation. 11H NMR (400 MHz, CDCl3) δ = 8.82 (s, 2H), 7.44 - 7.31 (m, 8H), 5.09 (s, 2H), 4.42 (s, 1H), 1.43 (s, 3H)

[0194] Intermediate U

Chemical formula

[0195] Step A: To a solution of 3-acetyl-5-fluorobenzonitrile (2.00 g, 12.3 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL) were added titanium(IV) ethoxide (5.59 g, 24.5 mmol, 5.08 mL, 2.00 equiv) and (R)-2-methylpropan-2-sulfinamide (1.93 g, 15.9 mmol, 1.30 equiv). The mixture was degassed and purged with nitrogen three times, and then stirred at 70 °C for 12 h under a nitrogen atmosphere. The mixture was diluted with water (20.0 mL) and filtered. The filtrate was extracted with ethyl acetate (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 - 1 / 1) to give (R,E)-N-(1-(3-cyano-5-fluorophenyl)ethylidene)-2-methylpropan-2-sulfinamide (1.01 g, 3.68 mmol, 30.0% yield, purity 97.5%) as a yellow oil. LCMS [M+1] + : 267.1 1 1H NMR (400 MHz, CDCl3) δ = 7.93 (s, 1H), 7.82 - 7.79 (m, 1H), 7.45 - 7.52 (m, 1H), 2.79 (s, 3H), 1.35 (s, 9H)

[0196] Step B: A solution of (R,E)-N-(1-(3-cyano-5-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (900 mg, 3.38 mmol, 1.00 eq) in tetrahydrofuran (10.0 mL) was added with sodium borohydride (383 mg, 10.1 mmol, 3.00 eq) at 0 °C, heated to 20 °C, and stirred for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution (20.0 mL) at 25 °C, extracted with ethyl acetate (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~0 / 1) to give (R)-N-((R)-1-(3-cyano-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (711 mg, 2.52 mmol, 74.5% yield, purity 95.3%) as a yellow oil. LCMS [M+1] + : 269.1 1 H NMR (400 MHz, CDCl3) δ=7.46 (t, J = 1.2 Hz, 1H), 7.46 - 7.33 (m, 1H), 7.31 - 7.29 (m, 1H), 4.60 - 4.55 (m, 1H), 3.47 (d, J = 3.6 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.25 (s, 9H)

[0197] Step C: (R)-N-((R)-1-(3-cyano-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (711 mg, 2.65 mmol, 1.00 eq) in dioxane (3.00 mL) was added with hydrochloric acid / ethyl acetate (4.0 M, 9.94 mL, 15.0 eq), and stirred at 20 °C for 2 hours. The obtained mixture was neutralized with saturated sodium bicarbonate solution (10.0 mL), extracted with ethyl acetate (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain (R)-3-(1-aminoethyl)-5-fluorobenzonitrile (330 mg, crude product) as a yellow oil. 11H NMR (400 MHz, CD3OD) δ = 7.72 - 7.71 (m, 1H), 7.67 - 7.66 (m, 1H), 7.65 - 7.62 (m, 1H), 4.59 (q, J = 6.8 Hz, 1H), 1.65 (d, J = 6.8 Hz, 3H)

[0198] Intermediate V [Chemical formula]

[0199] Step A: Concentrated sulfuric acid (100 mL) was added to ice-cooled 1-bromo-2-methyl-3-(trifluoromethyl)benzene (10.0 g, 41.8 mmol, 1.00 equivalent), and then potassium nitrate (12.7 g, 125 mmol, 3.00 equivalents) was slowly added at 0 °C, followed by stirring at 100 °C for 1 hour. The mixture was then cooled to 25 °C, poured into ice water (500 mL), and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give 1-bromo-2-methyl-5-nitro-3-(trifluoromethyl)benzene (5.20 g, 16.9 mmol, 40.4% yield) as a white oil. 1 1H NMR (400 MHz, DMSO-d6) δ = 8.72 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 2.58 - 2.62 (m, 3H)

[0200] Step B: A mixture of 1-bromo-2-methyl-5-nitro-3-(trifluoromethyl)benzene (5.20 g, 18.3 mmol, 1.00 equiv), tributyl(1-ethoxyvinyl)tin (8.60 g, 23.8 mmol, 8.03 mL, 1.30 equiv) and Pd(PPh3)2Cl2 (385 mg, 549 μmol, 0.03 equiv) in dioxane (60.0 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 80 °C for 10 h under a nitrogen atmosphere. The reaction mixture was quenched with saturated potassium fluoride solution (300 mL) and stirred at 25 °C for 2 h. Then the suspension was extracted with ethyl acetate (180 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 1-(1-ethoxyvinyl)-2-methyl-5-nitro-3-(trifluoromethyl)benzene (6.00 g, crude product) as a black oil. 1 1H NMR (400 MHz, CD3OD) δ = 8.47 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 4.58 (d, J = 2.8 Hz, 1H), 4.32 (d, J = 2.4 Hz, 1H), 4.00 - 3.95 (m, 2H), 2.56 (d, J = 1.2 Hz, 3H), 1.37 (t, J = 7.0 Hz, 3H)

[0201] Step C: A mixture of 1-(1-ethoxyvinyl)-2-methyl-5-nitro-3-(trifluoromethyl)benzene (6.00 g, 21.8 mmol, 1.00 equiv) and hydrochloric acid (3.0 M, 20.7 mL, 2.85 equiv) / THF (80.0 mL) was stirred at 20 °C for 1 h under a nitrogen atmosphere. Water (100 mL) was added to the reaction mixture to quench it, and then it was extracted with ethyl acetate (60.0 mL × 3). The combined organic layers were washed with brine (70.0 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethan-1-one (4.10 g, 16.5 mmol, 76.0% yield) as a yellow oil. 1 1H NMR (400 MHz, CD3OD) δ = 8.67 (s, 1H), 8.57 (s, 1H), 2.66 (s, 3H), 2.60 (s, 3H)

[0202] Step D: To a solution of 1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethan-1-one (2.00 g, 8.09 mmol, 1.00 equiv) and (R)-2-methylpropan-2-sulfinamide (1.27 g, 10.5 mmol, 1.30 equiv) in THF (20.0 mL) was added Ti(OEt)4 (3.69 g, 16.1 mmol, 3.36 mL, 2.00 equiv), and the mixture was stirred at 70 °C for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with water (70.0 mL) and ethyl acetate (60.0 mL), filtered, and the filtrate was extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give (R,E)-2-methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (2.00 g, 5.71 mmol, 70.5% yield) as a yellow oil. 11H NMR (400 MHz, CD3OD) δ = 8.43 (s, 1H), 8.30 (s, 1H), 2.75 (s, 3H), 2.58 (s, 3H), 1.30 (m, 9H)

[0203] Step E: (R,E)-2-Methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (2.00 g, 5.71 mmol, 1.00 eq) / THF (23.0 mL) solution was added with sodium borohydride (647 mg, 17.1 mmol, 3.00 eq) at 0 °C, and then stirred at 20 °C for 2 h. Saturated sodium bicarbonate was added, and then diluted with water (100 mL). The mixture was extracted with ethyl acetate (60.0 mL × 3), the organic layers were combined, dried over sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 - 0 / 1) to obtain (R)-2-methyl-N-((R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (700 mg, 1.75 mmol, 30.6% yield) as a dark brown oil. LCMS [M+1] + : 353.0 1 1H NMR (400 MHz, DMSO-d6) δ = 8.67 (d, J = 2.4 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 6.09 (d, J = 7.2 Hz, 1H), 4.83 - 4.79 (m, 1H), 2.54 (s, 3H), 1.43 (d, J = 6.8 Hz, 1H), 1.11 (m, 9H)

[0204] Step F: (R)-2-Methyl-N-((R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (700 mg, 1.99 mmol, 1.00 eq) and iodine (151 mg, 595 μmol, 120 μL, 0.30 eq) / tetrahydrofuran (8.00 mL) and water (2.00 mL) mixture was degassed and purged three times with nitrogen, and then the mixture was stirred at 50 °C for 2 hours under a nitrogen atmosphere. The reaction was quenched with saturated sodium hydrogen carbonate (50.0 mL), and then extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 - 0 / 1) to give (R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethan-1-amine (250 mg, 1.01 mmol, 50.7% yield) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ = 8.76 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 2.4 Hz, 1H), 4.54 - 4.49 (m, 1H), 2.57 (s, 3H), 1.46 (d, J = 6.4 Hz, 1H)

[0205] Intermediate W

Chemical Structure

[0206] Step A: A solution of 1-(3-chloro-2-methylphenyl)ethan-1-one (1.50 g, 8.90 mmol, 1.00 equiv) in tetrahydrofuran (30.0 mL) was added with titanium(IV) ethoxide (6.09 g, 26.7 mmol, 5.53 mL, 3.00 equiv) and (R)-2-methylpropan-2-sulfinamide (1.40 g, 11.6 mmol, 1.30 equiv), and stirred at 70 °C for 10 h. The reaction mixture was quenched with sodium hydrogen carbonate (50.0 mL) at 20 °C and then stirred for 10 min. The solid was filtered off, and the filtrate was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and (R,E)-N-(1-(3-chloro-2-methylphenyl)ethylidene)-2-methylpropan-2-sulfinamide (2.40 g, crude) was obtained as a yellow oil. LCMS [M+1] + : 272.0

[0207] Step B: (R,E)-N-(1-(3-chloro-2-methylphenyl)ethylidene)-2-methylpropan-2-sulfinamide (2.30 g, 8.46 mmol, 1.00 equiv) in tetrahydrofuran (30.0 mL) was added with sodium borohydride (850 mg, 22.5 mmol, 2.66 equiv) at -40 °C and stirred at -40 °C for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (50.0 mL) at 20 °C and then stirred for 10 min. The solid was filtered off, and the filtrate was extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and a residue was obtained. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give (R)-N-((R)-1-(3-chloro-2-methylphenyl)ethyl)-2-methylpropan-2-sulfinamide (1.50 g, 5.48 mmol, 64.7% yield) as a colorless oil. LCMS [M+1] + : 274.1

[0208] Step C: A solution of (R)-N-((R)-1-(3-chloro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.10 g, 4.02 mmol, 1.00 equiv) in ethyl acetate (20.0 mL) was added with hydrochloric acid / ethyl acetate (4.0 M, 30.0 mL) at 0 °C and stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain (R)-1-(3-chloro-2-methylphenyl)ethan-1-amine (700 mg, crude product) as a white solid. LCMS [M+1] + : 170.1

[0209] Intermediate X

Chemical formula

[0210] Step A: To a solution of 1-(3-methyl-5-(trifluoromethyl)phenyl)ethan-1-one (500 mg, 2.47 mmol, 1.00 equiv) and (R)-2-methylpropane-2-sulfinamide (689 mg, 5.69 mmol, 2.30 equiv) in THF (7.00 mL) was added Ti(OEt)4 (1.30 g, 5.69 mmol, 1.18 mL, 2.30 equiv), and the mixture was stirred at 70 °C for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with water (30.0 mL) and ethyl acetate (20.0 mL), filtered, and the filtrate was extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain (R,E)-2-methyl-N-(1-(3-methyl-5-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (750 mg, 2.46 mmol, 99.3% yield) as a yellow oil. LCMS[M+1] + : 306.1 11H NMR (400 MHz, DMSO-d6) δ = 7.99 (s, 1H), 7.95 (s, 1H), 7.75 (s, 1H), 5.75 (s, 1H), 2.76 (s, 3H), 2.46 (s, 3H), 1.22 (s, 9H)

[0211] Step B: (R,E)-2-Methyl-N-(1-(3-methyl-5-(trifluoromethyl)phenyl)ethylidene)propan-2-sulfinamide (650 mg, 2.13 mmol, 1.00 equiv) / THF (15.0 mL) solution was added sodium borohydride (253 mg, 6.69 mmol, 3.14 equiv) at -40 °C and stirred at -40 °C for 2 h. Saturated sodium bicarbonate solution was added to this mixture and diluted with water (50.0 mL). The mixture was extracted with ethyl acetate (3 × 50.0 mL), the combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 - 2 / 1) to give (R)-2-methyl-N-((R)-1-(3-methyl-5-(trifluoromethyl)phenyl)ethyl)propan-2-sulfinamide (320 mg, 1.04 mmol, 48.9% yield) as a pale yellow solid. LCMS [M+1] + : 308.1 1 1H NMR (400 MHz, CD3OD) δ = 7.52 (s, 1H), 7.50 (s, 1H), 7.39 (s, 1H), 4.56 - 4.51 (m, 1H), 2.44 (s, 1H), 1.54 - 1.53 (d, 3H), 1.25 (s, 9H)

[0212] Step C: A solution of (R)-2-methyl-N-((R)-1-(3-methyl-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (305 mg, 992 μmol, 1.00 eq) in hydrochloric acid (4.0 M, ethyl acetate solution, 10.0 mL) was stirred at 25 °C for 1 hour. It was concentrated under reduced pressure to obtain (R)-1-(3-methyl-5-(trifluoromethyl)phenyl)ethan-1-amine (200 mg, crude product) as a pale yellow solid. The obtained crude product was used directly in the next step without further purification. LCMS [M+1] + : 204.0

[0213] Intermediate Y

Chemical Structure

[0214] Step A: To a solution of 1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethan-1-one (35.6 g, 175 mmol, 1.00 eq) and (R)-2-methylpropan-2-sulfinamide (25.4 g, 209 mmol, 1.20 eq) in THF (350 mL), titanium(IV) isopropoxide (149 g, 524 mmol, 155 mL, 3.00 eq), and 1,2-dimethoxyethane (15.7 g, 175 mmol, 18.1 mL, 1.00 eq) were added, and the mixture was stirred at 80 °C for 12 hours. After stirring, water (50.0 mL) was added to obtain a suspension. This suspension was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain (R)-N-(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethylidene)-2-methylpropan-2-sulfinamide (44.0 g, 143 mmol, 82.0% yield) as a brown oil. 1 H NMR (400 MHz, CDCl3) δ = 7.45 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 4.56 (br s, 2H), 2.82 (s, 3H), 1.33 (s, 9H)

[0215] Step B: (R)-N-(1-(4-Amino-6-(trifluoromethyl)pyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (44.0 g, 143 mmol, 1.00 eq) / THF (400 mL) solution was added portionwise with sodium borohydride (16.3 g, 430 mmol, 3.00 eq) at 0 °C, and then the reaction was stirred at 0 °C for 1 hour. This mixture was slowly poured into water (200 mL) and stirred for 5 minutes. Then it was extracted with ethyl acetate (300 mL × 3), the combined organic layers were washed with brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give (R)-N-((R)-1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (24.0 g, 76.2 mmol, 53.2% yield, purity 98.2%) as a brown oil. 1 H NMR (400 MHz, CDCl3) δ = 6.63 (d, J = 2.0 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 5.06 (d, J = 6.0 Hz, 1H), 4.69 (s, 2H), 4.46 - 4.39 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H), 1.27 (s, 9H)

[0216] Step C: (R)-N-((R)-1-(4-Amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (23.5 g, 76.0 mmol, 1.00 eq) / HCl·dioxane (200 mL) solution was stirred at 25 °C for 2 hours. This mixture was filtered, the filter cake was washed with ethyl acetate (100 mL), then the filter cake was recovered and dried in vacuo to give (R)-2-(1-aminoethyl)-6-(trifluoromethyl)pyridin-4-amine (hydrochloride) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ = 8.43 (br s, 3H), 6.93 (br d, J = 2.0 Hz, 2H), 6.74 (d, J = 1.6 Hz, 1H), 4.34 - 4.27 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H)

[0217] Intermediate Z

Chemical formula

[0218] Step A: To a solution of 1-(2-methylpyridin-3-yl)ethan-1-one (800 mg, 5.92 mmol, 1.00 equiv) and (S)-2-methylpropane-2-sulfinamide (933 mg, 7.69 mmol, 1.30 equiv) in tetrahydrofuran (8.00 mL) were added titanium(IV) ethoxide (2.70 g, 11.8 mmol, 2.45 mL, 2.00 equiv) and 1,2-dimethoxyethane (533 mg, 5.92 mmol, 615 μL, 1.00 equiv), and the mixture was stirred at 70 °C for 16 h. After cooling to 25 °C, the mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 - 1 / 1) to give (S)-2-methyl-N-(1-(2-methylpyridin-3-yl)ethylidene)propane-2-sulfinamide (1.25 g, 5.24 mmol, 88.6% yield) as a yellow oil. LCMS [M+1] + : 239.2

[0219] Step B: A solution of (S)-2-methyl-N-(1-(2-methylpyridin-3-yl)ethylidene)propan-2-sulfinamide (1.25 g, 5.24 mmol, 1.00 equiv) in tetrahydrofuran (7.00 mL) was added dropwise with L-selectride (1.0 M, THF solution, 7.87 mL, 1.50 equiv) at -78 °C over 30 minutes, and then stirred at -78 °C for an additional 1 hour. The reaction mixture was then quenched by adding saturated aqueous ammonium chloride solution (30.0 mL) at 0 °C and further stirred at 25 °C for 1 hour. The solution was then extracted with ethyl acetate (50.0 mL × 3), the combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified twice by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 - 0 / 1) to give (S)-2-methyl-N-((R)-1-(2-methylpyridin-3-yl)ethyl)propan-2-sulfinamide (600 mg, 2.50 mmol, 47.6% yield) as a white solid. LCMS [M+1] + : 432.3 1 1H NMR (400 MHz, CDCl3) δ = 8.36 (dd, J = 1.2, 3.6 Hz, 1H), 7.64 (dd, J = 1.6, 8.0 Hz, 1H), 7.12 (dd, J = 4.8, 7.6 Hz, 1H), 4.81 - 4.70 (m, 1H), 2.58 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H), 1.14 (s, 9H) SFC conditions: Column: Chiralpak AD-3 50×4.6 mm, I.D., 3 μm, Mobile phase: Mobile phase A: CO2, Mobile phase B: MeOH (0.05% diethylamine); Gradient: MeOH (0.05% diethylamine) / CO2 = 5% - 40% f Flow rate: 3 mL / min; Detection: PDA Column temperature: 35 °C; Back pressure: 100 Bar

[0220] Step C: A mixture of (S)-2-methyl-N-((R)-1-(2-methylpyridin-3-yl)ethyl)propane-2-sulfinamide (600 mg, 2.50 mmol, 1.00 equiv) and HCl·dioxane (3.00 mL) was stirred at 0 °C for 30 min under a nitrogen atmosphere. Subsequently, a white precipitate formed and the suspension was filtered. The cake was recovered, dried in vacuo, and the resulting residue was further purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 um; mobile phase: mobile phase A: water (0.05% ammonium hydroxide v / v), mobile phase B: MeCN; B%: 3% - 33%] to give (R)-1-(2-methylpyridin-3-yl)ethan-1-amine (370 mg, 2.23 mmol, 89.2% yield, purity 82%) as a colorless oil. LCMS [M-16] + : 120.3

[0221] Intermediate AA

Chemical formula

[0222] Step A: To a solution of 1-bromo-3-(difluoromethyl)-2-fluorobenzene (commercially available, 4.50 g, 20.0 mmol, 1.00 equiv) in 1,4-dioxane (50.0 mL) were added PdCl2(PPh3)2 (1.40 g, 2.00 mmol, 0.10 equiv) and tributyl(1-ethoxyvinyl)stannane (21.7 g, 60.0 mmol, 20.3 mL, 3.00 equiv). The mixture was degassed and purged with nitrogen (3 times), then stirred at 100 °C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. To the resulting residue was added an aqueous potassium fluoride solution (2.0 M, 100 mL). The mixture was extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 1-(difluoromethyl)-3-(1-ethoxyvinyl)-2-fluorobenzene (7.50 g, crude) as a brown oil. This was used without further isolation.

[0223] Step B: A solution of 1-(difluoromethyl)-3-(1-ethoxyvinyl)-2-fluorobenzene (7.50 g, 34.7 mmol, 1.00 eq) in tetrahydrofuran (50.0 mL) was added with hydrochloric acid (30.0 mL, purity 10%), and the mixture was stirred at 25 °C for 1 hour. Then, the mixture was adjusted to pH = 6 - 8 with an aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 0 - 5 / 1) to obtain 1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-one (6.01 g, 31.3 mmol, 90.2% yield, purity 98.0%) as a colorless oil. LCMS [M+1] + : 189.1 1 1H NMR (400 MHz, CDCl3) δ = 8.02 - 7.97 (m, 1H), 7.80 - 7.76 (m, 1H), 7.34 (t, J = 8.0 Hz, 1H), 6.94 (t, J = 14.8 Hz, 1H), 2.66 (d, J = 5.2 Hz, 3H)

[0224] Step C: (S)-2-Methylpropan-2-sulfinamide (2.32 g, 19.1 mmol, 1.20 equiv), 1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-one (3.00 g, 16.0 mmol, 1.00 equiv) and titanium(IV) ethoxide (7.27 g, 31.9 mmol, 6.60 mL, 2.00 equiv) / 2-methyltetrahydrofuran (30.0 mL) mixture was degassed and purged with nitrogen (3 times), then stirred at 75 °C for 4 h under a nitrogen atmosphere. The reaction mixture was then cooled, diluted with water (50.0 mL), extracted with ethyl acetate (50.0 mL × 3), the combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to give (S)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylidene)-2-methylpropan-2-sulfinamide (1.80 g, 6.18 mmol, 38.8% yield). LCMS [M+1] + : 292.2

[0225] Step D: A mixture of (S)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.80 g, 6.18 mmol, 1.00 equiv) in 2-methyltetrahydrofuran (30.0 mL) was added with L-selectride (3.52 g, 18.5 mmol, 4.10 mL, 3.00 equiv) at -78 °C under a nitrogen atmosphere, and then the mixture was stirred at -78 °C for 3 h under a nitrogen atmosphere. Then, an additional L-selectride (1.76 g, 9.30 mmol, 2.00 mL, 1.50 equiv) was added, the solution was degassed and purged with nitrogen (3 times), and stirred at -78 °C for 9 h under a nitrogen atmosphere. The resulting mixture was cooled to room temperature, diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to give (S)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.30 g, 4.34 mmol, 70.3% yield, 98% purity) as a colorless oil. LCMS [M+1] + : 294.2

[0226] Step E: To a solution of (S)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.29 g, 4.43 mmol, 1.00 equiv) was added hydrochloric acid (4.00 M, 1,4-dioxane solution, 15.0 mL, 14.0 equiv), and the mixture was stirred at 25 °C for 30 min. Then the mixture was diluted with water (30.0 mL), extracted with ethyl acetate (30.0 mL × 3), the combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (480 mg, 2.13 mmol, 48.0% yield, HCl salt) as a yellow oil. This was used without further isolation. 11H NMR (400 MHz, CDCl3) δ = 7.52 - 7.47 (m, 2H), 7.24 - 7.19 (m, 1H), 6.88 (t, J = 14.8 Hz, 1H), 4.85 - 4.92 (m, 1H), 1.57 (d, J = 6.8 Hz, 3H)

[0227] Step F: (R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethan-1-amine (300 mg, 1.59 mmol, 1.00 equiv), 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (339 mg, 1.59 mmol, 1.00 equiv) and potassium fluoride (461 mg, 7.93 mmol, 186 μL, 5.00 equiv) / dimethyl sulfoxide (6.00 mL) mixture was degassed and purged with nitrogen (3 times). Under nitrogen atmosphere, the mixture was stirred at 130 °C for 12 h. The mixture was then cooled to 25 °C, diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 - 1 / 1) and preparative HPLC [column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: mobile phase A: water (0.225% formic acid), mobile phase B: acetonitrile; B%: 20% - 50%] to give (R)-7-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-4-methylpyrido[3,4-d]pyridazin-1-amine (250 mg, 629 μmol, 39.7% yield, purity 92.3%) as a yellow solid. LCMS [M+1] + : 367.2

[0228] Intermediate AB

Chemical Structure

[0229] Step A: To a solution of 3-bromo-5-fluoro-2-methylbenzoic acid (4.00 g, 17.2 mmol, 1.00 eq) and N,O-dimethylhydroxylamine (1.84 g, 18.9 mmol, 1.10 eq, HCl salt) in DMF (50.0 mL), N,N-diisopropylethylamine (6.66 g, 51.5 mmol, 8.97 mL, 3.00 eq) and HATU (7.83 g, 20.6 mmol, 1.20 eq) were added, and the mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with ethyl acetate (50.0 mL), washed with brine (30.0 mL × 3), the combined organic layers were collected, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give 3-bromo-5-fluoro-N-methoxy-N,2-dimethylbenzamide (4.70 g, 17.0 mmol, 99.2% yield) as a white solid.

[0230] Step B: To a solution of 3-bromo-5-fluoro-N-methoxy-N,2-dimethyl-benzamide (4.70 g, 17.0 mmol, 1.00 eq) in THF (100 mL), methylmagnesium bromide (3.0 M, 34.1 mL, 6.00 eq) was added dropwise at 0 °C. After the dropwise addition was complete, the mixture was heated at 45 °C and stirred for 5 h. The resulting mixture was then cooled to 25 °C, quenched with water (20.0 mL), and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give 1-(3-bromo-5-fluoro-2-methylphenyl)ethan-1-one (3.80 g, 16.5 mmol, 96.6% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 7.43 (dd, J = 2.8, 7.6 Hz, 1H), 7.19 (dd, J = 2.8, 8.4 Hz, 1H), 2.55 (s, 3H), 2.45 (d, J = 0.4 Hz, 3H)

[0231] Step C: To a solution of 1-(3-bromo-5-fluoro-2-methylphenyl)ethan-1-one (3.80 g, 16.5 mmol, 1.00 equiv) and (S)-2-methylpropan-2-sulfinamide (2.79 g, 23.0 mmol, 1.40 equiv) in THF (60.0 mL) were added titanium(IV) ethoxide (7.50 g, 32.9 mmol, 6.82 mL, 2.00 equiv) and 1,2-dimethoxyethane (1.48 g, 16.5 mmol, 1.71 mL, 1.00 equiv), and the mixture was stirred at 70 °C for 12 h. The reaction mixture was then cooled to 25 °C, diluted with ethyl acetate (100 mL) and water (10.0 mL) to obtain a suspension. The suspension was filtered and the filtrate was concentrated under reduced pressure to remove all volatiles. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 - 20 / 1) to give (S)-N-(1-(3-bromo-5-fluoro-2-methylphenyl)ethylidene)-2-methylpropan-2-sulfinamide (4.70 g, 14.1 mmol, 85.5% yield) as a yellow oil. LCMS [M+3] + : 336.0 1 H NMR (400 MHz, CDCl3) δ = 7.35 (br dd, J = 2.4, 7.6 Hz, 1H), 6.92 (dd, J = 2.4, 8.4 Hz, 1H), 2.66 (s, 3H), 2.37 (s, 3H), 1.30 (s, 9H)

[0232] Step D: A solution of (S)-N-(1-(3-bromo-5-fluoro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (5.50 g, 16.5 mmol, 1.00 eq) in THF (80.0 mL) was added dropwise with L-selectride (1.0 M, 24.7 mL, 1.50 eq) at -78 °C, warmed to 0 °C and stirred for 2 h. The mixture was then diluted with aqueous ammonium chloride solution (30.0 mL), and the resulting solution was extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was triturated with petroleum ether (20.0 mL), filtered, and the filter cake was dried in vacuo to give (S)-N-((R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (3.20 g, 9.52 mmol, 57.8% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ=7.24 (dd, J=2.4, 7.6 Hz, 1H), 7.10 (dd, J=2.8, 10.0 Hz, 1H), 4.90 - 4.82 (m, 1H), 3.30 (br d, J=2.8 Hz, 1H), 2.42 (s, 3H), 1.48 (d, J=6.8 Hz, 3H), 1.23 (s, 9H)

[0233] Step E: To a solution of (S)-N-((R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.60 g, 4.76 mmol, 1.00 eq) in THF (20.0 mL) and water (5.00 mL) was added iodine (362 mg, 1.43 mmol, 288 μL, 0.30 eq), and the mixture was stirred at 50 °C for 2 h. The mixture was then cooled to 25 °C and adjusted to pH = 7 with aqueous sodium hydrogen carbonate solution. The resulting solution was extracted with DCM (20.0 mL × 3), the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give (R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethan-1-amine (1.20 g, crude) as a pale yellow oil. This crude oil was used without further isolation.

[0234] Step F: (R)-1-(3-Bromo-5-fluoro-2-methylphenyl)ethan-1-amine (1.20 g, 5.17 mmol, 1.00 equiv) / THF (20.0 mL) solution was added with di-tert-butyl dicarbonate (1.35 g, 6.20 mmol, 1.43 mL, 1.20 equiv), and stirred at 20 °C for 3 h. The mixture was then concentrated under reduced pressure, and the obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 150 / 1 to 70 / 1) to give tert-butyl (R)-(1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)carbamate (1.45 g, 4.36 mmol, 84.4% yield) as a white solid.

[0235] Step G: A mixture of tert-butyl (R)-(1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)carbamate (1.35 g, 4.06 mmol, 1.00 equiv), zinc cyanide (954 mg, 8.13 mmol, 516 μL, 2.00 equiv), DPPF (451 mg, 813 μmol, 0.20 equiv), zinc powder (26.6 mg, 406 μmol, 0.10 equiv) and Pd2(dba)3 (372 mg, 406 μmol, 0.10 equiv) / dimethylacetamide (20.0 mL) was degassed, purged with nitrogen (3 times), and stirred at 120 °C for 6 h under a nitrogen atmosphere. The mixture was then diluted with ethyl acetate (60.0 mL), filtered, the filtrate was washed with brine (30.0 mL × 3), dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to give tert-butyl (R)-(1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)carbamate (1.10 g, 3.95 mmol, 97.3% yield) as a pale yellow solid.

[0236] Step H: A solution of tert-butyl (R)-(1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)carbamate (1.10 g, 3.95 mmol, 1.00 equiv) in DCM (5.00 mL) was added dropwise with TFA (1.88 g, 16.5 mmol, 1.22 mL, 4.18 equiv), and the mixture was stirred at 20 °C for 1 h. The resulting mixture was then concentrated under reduced pressure, and the residue was adjusted to pH = 7 with saturated aqueous sodium hydrogen carbonate. The resulting solution was extracted with DCM (50.0 mL), the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and (R)-3-(1-aminoethyl)-5-fluoro-2-methylbenzonitrile (0.80 g, crude) was obtained as a brown oil. This was used without further isolation.

[0237] Intermediate AC [Chemical formula]

[0238] Step A: A solution of 2-bromo-4-fluoro-6-(trifluoromethyl)aniline (2.00 g, 7.75 mmol, 1.00 equiv) and tributyl(1-ethoxyvinyl)tin (2.80 g, 7.75 mmol, 2.62 mL, 1.00 equiv) in dioxane (20.0 mL) was added with PdCl2(PPh3)2 (544 mg, 775 μmol, 0.10 equiv) under a nitrogen atmosphere, and the mixture was stirred at 80 °C for 12 h. The reaction mixture was then cooled to 25 °C, diluted with an aqueous potassium fluoride solution (100 mL), and then extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure to obtain the compound: 2-(1-ethoxyvinyl)-4-fluoro-6-(trifluoromethyl)aniline (4.00 g, crude product) as a yellow oil. To a solution of 2-(1-ethoxyvinyl)-4-fluoro-6-(trifluoromethyl)aniline (4.00 g, crude product) in tetrahydrofuran (50.0 mL) was added dropwise hydrochloric acid (4.00 M, 20.0 mL, 1.33 equiv). The mixture was then stirred at 25 °C for 1 h, diluted with water (100 mL), and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 3 / 1) to obtain the compound: 1-(2-amino-5-fluoro-3-(trifluoromethyl)phenyl)ethan-1-one (5.60 g, 25.3 mmol, 42.0% yield, purity 99.9%) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ = 7.99 (d, J = 9.2 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.33 (s, 2H), 2.59 (s, 3H)

[0239] Step B: A solution of 1-(2-amino-5-fluoro-3-(trifluoromethyl)phenyl)ethan-1-one (5.60 g, 25.3 mmol, 1.00 equiv) in hydrochloric acid (50.0 mL) and water (100 mL) was added sodium nitrite (2.27 g, 32.9 mmol, 1.30 equiv) portionwise, and then potassium iodide (8.41 g, 50.6 mmol, 2.00 equiv) was added to this mixture at 0 °C. After the addition was complete, the mixture was stirred at 25 °C for 12 h, then diluted with water (100 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with sodium sulfite (200 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give the compound: 1-(5-fluoro-2-iodo-3-(trifluoromethyl)phenyl)ethan-1-one (5.60 g, 10.3 mmol, 40.8% yield, purity 61.2%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.83 - 7.76 (m, 1H), 7.74 - 7.71 (m, 1H), 2.56 (s, 3H)

[0240] Step C: A solution of methylboronic acid (1.62 g, 27.1 mmol, 2.50 equiv) and 1-(5-fluoro-2-iodo-3-(trifluoromethyl)phenyl)ethan-1-one (3.60 g, 10.8 mmol, 1.00 equiv) in dioxane (20.0 mL) was added with Pd(dppf)Cl2 (400 mg, 542 μmol, 0.05 equiv) and potassium carbonate (7.49 g, 54.2 mmol, 5.00 equiv) under a nitrogen atmosphere, and stirred at 90 °C for 12 h. The resulting mixture was then cooled to 25 °C, diluted with water (50.0 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give the compound: 1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethan-1-one (1.70 g, 7.72 mmol, 71.2% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ = 7.47 (dd, J = 2.8, 8.8 Hz, 1H), 7.36 - 7.30 (m, 1H), 2.58 (s, 3H), 2.47 (s, 3H)

[0241] Step D: A solution of 1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethan-1-one (2.20 g, 9.99 mmol, 1.00 equiv) and (R)-2-methylpropan-2-sulfinamide (2.42 g, 20.0 mmol, 2.00 equiv) in tetrahydrofuran (15.0 mL) was added titanium(IV) isopropoxide (5.68 g, 20.0 mmol, 5.90 mL, 2.00 equiv) and 1-methoxy-2-(2-methoxyethoxy)ethane (4.12 g, 30.7 mmol, 4.40 mL, 3.08 equiv), and the mixture was stirred at 75 °C for 12 h. The mixture was then cooled to 25 °C, diluted with water (50.0 mL) to obtain a suspension. The resulting suspension was filtered, and the filtrate was diluted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the compound: (R)-N-(1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropan-2-sulfinamide (1.50 g, 4.64 mmol, 46.4% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ = 7.39 (dd, J = 2.2, 8.8 Hz, 1H), 7.10 (dd, J = 2.4, 8.4 Hz, 1H), 2.68 (s, 3H), 2.41 (s, 3H), 1.30 (s, 9H)

[0242] Step E: (R)-N-(1-(5-Fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.90 g, 5.88 mmol, 1.00 eq) / tetrahydrofuran (20.0 mL) solution was added sodium borohydride (667 mg, 17.6 mmol, 3.00 eq) portionwise at 0 °C, stirred at 0 °C for 2 h, then slowly diluted with saturated aqueous ammonium chloride solution (50.0 mL) and stirred for 30 min. The resulting mixture was extracted with ethyl acetate (100 mL×3), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 - 3 / 1) to give (R)-N-((R)-1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.30 g, 4.00 mmol, 68.0% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ = 7.40 - 7.28 (m, 2H), 4.95 - 4.84 (m, 1H), 3.40 - 3.32 (m, 1H), 2.43 (s, 3H), 1.49 (d, J = 6.4 Hz, 3H), 1.23 (s, 9H)

[0243] Step F: (R)-N-((R)-1-(5-Fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.30 g, 4.00 mmol, 1.00 eq) / dichloromethane (5.00 mL) solution was added hydrochloric acid (4.00 M, 1,4-dioxane, 5.00 mL, 5.0 eq), and stirred at 25 °C for 1 h. The resulting mixture was then concentrated under reduced pressure to give the compound: (R)-1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (700 mg, 2.81 mmol, 70.4% yield, purity 88.9%, HCl salt) as a yellow oil. This was used directly without further purification.

[0244] Intermediate AD

Chemical formula

[0245] Step A: To a solution of 3-bromo-2,5-difluorobenzaldehyde (4.00 g, 18.1 mmol, 1.00 equiv) and (R)-2-methylpropan-2-sulfinamide (3.07 g, 25.3 mmol, 1.40 equiv) in THF (50.0 mL) were added titanium(IV) ethoxide (8.26 g, 36.2 mmol, 7.51 mL, 2.00 equiv) and 1,2-dimethoxyethane (1.63 g, 18.1 mmol, 1.88 mL, 1.00 equiv), and the mixture was stirred at 70 °C for 12 h. The mixture was then cooled to 25 °C and slowly diluted with ethyl acetate (50.0 mL) and water (5.00 mL) to obtain a suspension. The suspension was filtered, and the filtrate was concentrated under reduced pressure and then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give (S)-N-(3-bromo-2,5-difluorobenzylidene)-2-methylpropan-2-sulfinamide (5.70 g, 17.6 mmol, 97.1% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 8.81 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 6.0, 8.4 Hz, 1H), 7.44 (dd, J = 5.2, 8.8 Hz, 1H), 1.28 (s, 9H)

[0246] Step B: A solution of (S)-N-(3-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (5.50 g, 17.0 mmol, 1.00 equiv) in DCM (60.0 mL) was added dropwise with methylmagnesium bromide (3.0 M, 17.0 mL, 3.00 equiv) at -60 °C, then the mixture was warmed to 0 °C and stirred for 1 h. This mixture was diluted with an aqueous ammonium chloride solution (50.0 mL), and the resulting aqueous solution was extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 - 2 / 1) to give (S)-N-((R)-1-(3-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (3.50 g, 10.3 mmol, 60.6% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ = 7.31 - 7.26 (m, 1H), 7.16 (dd, J = 6.4, 8.8 Hz, 1H), 4.89 - 4.78 (m, 1H), 3.35 (br d, J = 4.0 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.23 (s, 9H)

[0247] Step C: To a solution of (S)-N-((R)-1-(3-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.50 g, 4.41 mmol, 1.00 equiv) in THF (20.0 mL) and water (5.00 mL) was added iodine (336 mg, 1.32 mmol, 266 μL, 0.30 equiv), and the mixture was stirred at 50 °C for 2 h. This mixture was then cooled to 25 °C and adjusted to pH = 7 with an aqueous sodium hydrogen carbonate solution. The resulting aqueous solution was extracted with DCM (20.0 mL × 3), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (R)-1-(3-bromo-2,5-difluorophenyl)ethan-1-amine (1.20 g, crude product) as a pale yellow oil. This crude oil was used directly without further purification.

[0248] Step D: (R)-1-(3-Bromo-2,5-difluorophenyl)ethan-1-amine (1.20 g, 5.08 mmol, 1.00 equiv) / THF (20.0 mL) solution was added with di-tert-butyl dicarbonate (1.22 g, 5.59 mmol, 1.28 mL, 1.10 equiv), and the mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 150 / 1 - 80 / 1) to obtain tert-butyl (R)-(1-(3-bromo-2,5-difluorophenyl)ethyl)carbamate (1.30 g, 3.87 mmol, 76.1% yield) as a white solid.

[0249] Step E: A mixture of tert-butyl (R)-(1-(3-bromo-2,5-difluorophenyl)ethyl)carbamate (1.20 g, 3.57 mmol, 1.00 equiv), zinc cyanide (838 mg, 7.14 mmol, 453 μL, 2.00 equiv), zinc (23.3 mg, 357 μmol, 0.10 equiv), DPPF (396 mg, 714 μmol, 0.20 equiv) and Pd2(dba)3 (327 mg, 357 μmol, 0.10 equiv) / dimethylacetamide (20.0 mL) was degassed and purged with nitrogen (3 times), and the mixture was stirred at 115 °C for 3 h under a nitrogen atmosphere. The mixture was then cooled to 25 °C, diluted with ethyl acetate (100 mL), the organic layer was washed with brine (50.0 mL × 3), dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 - 30 / 1) to obtain tert-butyl (R)-(1-(3-cyano-2,5-difluorophenyl)ethyl)carbamate (0.90 g, 3.19 mmol, 89.3% yield) as a pale yellow solid.

[0250] Step F: A solution of tert-butyl (R)-(1-(3-cyano-2,5-difluorophenyl)ethyl)carbamate (0.90 g, 3.19 mmol, 1.00 equiv) in DCM (10.0 mL) was added dropwise with TFA (4.62 g, 40.5 mmol, 3.00 mL, 12.7 equiv), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was diluted with water (10.0 mL). The solution was adjusted to pH = 7 with aqueous sodium bicarbonate solution, and the resulting aqueous solution was extracted with DCM (20.0 mL × 2). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, and (R)-3-(1-aminoethyl)-2,5-difluorobenzonitrile (700 mg, crude product) was obtained as a pale yellow oil. This compound was used directly without further purification.

[0251] Intermediate AE [Chemical formula]

[0252] Step A: To a solution of 1-bromo-3-fluoro-2-(trifluoromethyl)benzene (39.0 g, 160 mmol, 1.00 equiv) in dimethyl sulfoxide (200 mL) was added zinc cyanide (11.5 g, 176 mmol, 7.56 mL, 1.10 equiv), and the mixture was stirred at 80 °C for 16 h. The mixture was then cooled to 25 °C, diluted with ethyl acetate (1.00 L), and the organic layer was separated, washed with water (500 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 - 2 / 1) to obtain 3-bromo-2-(trifluoromethyl)benzonitrile (29.0 g, 116 mmol, 72.3% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.20 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H)

[0253] Step B: To a solution of 3-bromo-2-(trifluoromethyl)benzonitrile (29.0 g, 116 mmol, 1.00 equiv) and tributyl(1-ethoxyvinyl)tin (50.3 g, 139 mmol, 47.0 mL, 1.20 equiv) / toluene (250 mL) under a nitrogen atmosphere, Pd(PPh3)4 (6.70 g, 5.80 mmol, 0.05 equiv) was added and stirred at 100 °C for 16 h. The reaction mixture was cooled to 25 °C, diluted with water (500 mL) and ethyl acetate (200 mL), and finally solid potassium fluoride (50.0 g) was added and stirred at 25 °C for 30 min. The organic layer was then separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to obtain the crude product. The obtained crude product was triturated with petroleum ether (50.0 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain 3-(1-ethoxyvinyl)-2-(trifluoromethyl)benzonitrile (8.00 g, 33.2 mmol, 23.0% yield) as a pale yellow oil. 1 1H NMR (400 MHz, CDCl3) δ = 7.82 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.65 - 7.59 (t, J = 7.6 Hz, 1H), 4.37 (d, J = 2.8 Hz, 1H), 4.25 (d, J = 2.8 Hz, 1H), 3.90 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 6.8 Hz, 3H)

[0254] Step C: A solution of 3-(1-ethoxyvinyl)-2-(trifluoromethyl)benzonitrile (7.00 g, 29.0 mmol, 1.00 equiv) in tetrahydrofuran (10.0 mL) was added with hydrochloric acid (2.00 M, 29.0 mL, 2.00 equiv), and the mixture was stirred at 20 °C for 2 h. Then the mixture was adjusted to pH = 8 with an aqueous sodium hydrogen carbonate solution and further diluted with water (100 mL). The resulting solution was extracted with ethyl acetate (50.0 mL × 3), and the combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 - 5 / 1) to give 3-acetyl-2-(trifluoromethyl)benzonitrile (5.30 g, 24.8 mmol, 85.6% yield) as a colorless oil. 1 1H NMR (400 MHz, DMSO-d6) δ = 8.25 (dd, J = 0.8, 7.6 Hz, 1H), 8.07 - 7.94 (m, 2H), 2.60 (s, 3H)

[0255] Step D: A solution of 3-acetyl-2-(trifluoromethyl)benzonitrile (1.00 g, 4.69 mmol, 1.00 equiv) and (R)-2-methylpropan-2-sulfinamide (625 mg, 5.16 mmol, 1.10 equiv) in tetrahydrofuran (2.00 mL) was added with 1,2-dimethoxyethane (423 mg, 4.69 mmol, 488 μL, 1.00 equiv) and titanium(IV) ethoxide (3.21 g, 14.1 mmol, 2.92 mL, 3.00 equiv), and stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate (100 mL) and poured into a mixture of celite (20.0 g) and saturated sodium hydrogen carbonate (10.0 g) / water (100 mL). The mixture was stirred and then filtered, and the filter cake was stirred with ethyl acetate (30.0 mL) and filtered, and this process was repeated 3 times until the product cake was washed. The combined filtrates were separated, and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ethyl acetate / petroleum ether, 0 - 30%) to give (R)-N-(1-(3-cyano-2-(trifluoromethyl)phenyl)ethylidene)-2-methylpropan-2-sulfinamide (950 mg, 2.99 mmol, 63.7% yield, purity 99.5%) as a pale yellow oil. LCMS [M+1] + : 317.1 1 H NMR (400 MHz, CDCl3) δ = 7.92 - 7.80 (m, 1H), 7.77 - 7.65 (m, 1H), 7.61 - 7.37 (m, 1H), 2.74 - 2.38 (m, 3H), 1.29 - 1.24 (m, 9H)

[0256] Step E: A solution of (R)-N-(1-(3-cyano-2-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.70 g, 5.37 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL) was added portionwise with sodium borohydride (610 mg, 16.0 mmol, 3.00 equiv) at 0 °C under a nitrogen atmosphere. After the addition, the mixture was stirred at this temperature for 30 minutes, then warmed to 25 °C and stirred for an additional 3 hours. The resulting mixture was then diluted by dropwise addition of a saturated aqueous ammonium chloride solution (100 mL) with stirring at 25 °C under a nitrogen atmosphere, and then extracted with ethyl acetate (150 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give (R)-N-(1-(3-cyano-2-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.50 g, 4.71 mmol, 87.7% yield, a mixture of diastereomers) as a white solid. LCMS [M+1] + : 319.1

[0257] Step F: A mixture of (R)-N-(1-(3-cyano-2-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.4 g, 4.40 mmol, 1.00 equiv) in HCl·dioxane (10.0 mL) was stirred at 5 °C for 30 minutes. Thereafter, a white precipitate formed and the suspension was filtered. The filter cake was collected and dried in vacuo to give 3-(1-aminoethyl)-2-(trifluoromethyl)benzonitrile (850 mg, 3.39 mmol, 77.1% yield, HCl salt) as a white solid. LCMS [M+1] + : 215.1 1 1H NMR (400 MHz, DMSO-d6) δ = 8.84 (s, 3H), 8.38 (br d, J = 8.0 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.12 - 7.95 (m, 1H), 4.64 (br d, J = 6.0 Hz, 1H), 1.56 (d, J = 6.4 Hz, 3H)

[0258] Step G: A mixture of 3-(1-aminoethyl)-2-(trifluoromethyl)benzonitrile (300 mg, 1.40 mmol, 1.00 equiv, HCl salt), 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (300 mg, 1.40 mmol, 1.00 equiv), diisopropylethylamine (499 mg, 3.86 mmol, 673 μL, 2.76 equiv) and cesium fluoride (400 mg, 2.63 mmol, 97.0 μL, 1.88 equiv) / dimethyl sulfoxide (1.50 mL) was degassed and purged with nitrogen (3 times), and then the mixture was stirred at 130 °C for 1 hour under a nitrogen atmosphere. The mixture was then cooled to 25 °C, ethyl acetate (60.0 mL) was added, the organic solution was washed with brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give 3-(1-((7-chloro-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-(trifluoromethyl)benzonitrile (160 mg, 408 μmol, 29.2% yield) as a white solid. LCMS [M+1] + : 392.1 3-(1-((7-chloro-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-(trifluoromethyl)benzonitrile (160 mg) was further purified using SFC [column: DAICEL Chiralpak AD (250 mm × 30 mm, 10um); mobile phase: mobile phase A: (0.1% NH4OH) / MeOH, mobile phase B: CO2; B%: 20% - 20%] to obtain the first eluted isomer: (R)-3-(1-((7-chloro-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-(trifluoromethyl)benzonitrile (62.0 mg, 158 μmol, 39.0% yield) as a white solid. LCMS [M+1] + : 392.1 11H NMR (400 MHz, CD3OD) δ = 9.24 (d, J = 0.8 Hz, 1H), 8.46 (d, J = 0.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.71 - 7.57 (m, 1H), 5.74 (q, J = 6.8 Hz, 1H), 2.74 (s, 3H), 1.68 (d, J = 6.8 Hz, 3H)

[0259] Intermediate AF

Chem.

[0260] Step A: To a solution of 4-fluoro-3-nitro-5-(trifluoromethyl)benzoic acid (2.00 g, 7.90 mmol, 1.00 eq) in tetrahydrofuran (15.0 mL), palladium on carbon (7.90 mmol, 10% purity, 1.00 eq) was added under a nitrogen atmosphere, and the mixture was stirred at 25 °C for 2 h under a hydrogen atmosphere (15 Psi). The resulting mixture was then filtered and concentrated under reduced pressure to obtain the compound: 3-amino-4-fluoro-5-(trifluoromethyl)benzoic acid (1.60 g, 7.17 mmol, 90.8% yield) as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ = 7.68 - 7.64 (m, 1H), 7.32 - 7.29 (m, 1H), 5.95 - 5.89 (m, 2H)

[0261] Step B: A solution of 3-amino-4-fluoro-5-(trifluoromethyl)benzoic acid (1.50 g, 6.72 mmol, 1.00 equiv) and N,O-dimethylhydroxylamine (830 mg, 13.45 mmol, 2.00 equiv) in N,N-dimethylformamide (10.0 mL) was added with HATU (5.11 g, 13.5 mmol, 2.00 equiv) and N,N-diisopropylethylamine (2.61 g, 20.2 mmol, 3.50 mL, 3.00 equiv), and stirred at 25 °C for 12 h. The mixture was diluted with water (50.0 mL), and then extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 - 3 / 1) to give the compound: 3-amino-4-fluoro-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (1.50 g, 5.64 mmol, 83.9% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ = 7.38 - 7.34 (m, 2H), 3.57 (s, 3H), 3.36 (s, 3H)

[0262] Step C: To a solution of 3-amino-4-fluoro-N-methoxy-N-methyl-5-(trifluoromethyl)benzamide (1.50 g, 5.64 mmol, 1.00 equiv) in dichloromethane (10.0 mL) were added di-tert-butyl dicarbonate (3.69 g, 16.9 mmol, 3.88 mL, 3.00 equiv) and 4-dimethylaminopyridine (688 mg, 5.64 mmol, 1.00 equiv), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (50.0 mL) and then extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the compound: tert-butyl (tert-butoxycarbonyl)(2-fluoro-5-(methoxy(methyl)carbamoyl)-3-(trifluoromethyl)phenyl)carbamate (2.00 g, 4.29 mmol, 76.1% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 8.05 - 8.01 (m, 1H), 7.87 - 7.84 (m, 1H), 3.55 (s, 3H), 3.39 (s, 3H), 1.42 (s, 18H)

[0263] Step D: A solution of tert-butyl(tert-butoxycarbonyl)(2-fluoro-5-(methoxy(methyl)carbamoyl)-3-(trifluoromethyl)phenyl)carbamate (1.80 g, 3.86 mmol, 1.00 equiv) / tetrahydrofuran (20.0 mL) was added with methylmagnesium bromide solution (3.00 M, 3.86 mL, 3.00 equiv) at 0 °C and stirred at 0 °C for 12 h. The reaction mixture was then diluted with water (100 mL), and the solution was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1~3 / 1) to give the compound: tert-butyl(5-acetyl-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.10 g, 3.42 mmol, 88.7% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3) δ=8.98(d, J=6.4Hz, 1H), 7.90-7.87(m, 1H), 6.86(s, 1H), 2.65(s, 3H), 1.56(s, 9H)

[0264] Step E: A solution of tert-butyl (5-acetyl-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.10 g, 2.61 mmol, 1.00 equiv) and (R)-2-methylpropan-2-sulfinamide (950 mg, 7.83 mmol, 3.00 equiv) in tetrahydrofuran (10.0 mL) was added titanium(IV) isopropoxide (1.48 g, 5.22 mmol, 1.54 mL, 2.00 equiv) and 1-methoxy-2-(2-methoxyethoxy)ethane (1.87 g, 13.97 mmol, 2.00 mL, 5.35 equiv), and the mixture was stirred at 70 °C for 12 h. The mixture was then diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the compound: tert-butyl (R)-(5-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.00 g, 2.36 mmol, 90.1% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ = 8.86 (d, J = 6.4 Hz, 1H), 7.82 (d, J = 6.0 Hz, 1H), 6.85 (s, 1H), 2.79 (s, 3H), 1.54 (s, 9H), 1.33 (s, 9H)

[0265] Step F: A solution of tert-butyl (R)-(5-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.00 g, 2.36 mmol, 1.00 equiv) in tetrahydrofuran (10.0 mL) was added sodium borohydride (268 mg, 7.07 mmol, 3.00 equiv) at 0 °C and stirred at 0 °C for 2 h. The mixture was then diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 3), dried over sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 - 3 / 1) to give the compound: tert-butyl (5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (620 mg, 1.45 mmol, 61.7% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 8.34 (d, J = 6.4 Hz, 1H), 7.23 - 7.20 (m, 1H), 6.80 (s, 1H), 4.56 - 5.53 (m, 1H), 1.54 - 1.52 (m, 12H), 1.24 (s, 9H)

[0266] Step G: To a solution of tert-butyl (5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (620 mg, 1.45 mmol, 1.00 equiv) in dichloromethane (5.00 mL) was added hydrochloric acid (4.00 M, 1,4-dioxane solution, 5.00 mL, 13.76 equiv), and the mixture was stirred at 25 °C for 1 h. The mixture was then concentrated under reduced pressure to give the compound: (R)-5-(1-aminoethyl)-2-fluoro-3-(trifluoromethyl)aniline (280 mg, 1.24 mmol, 85.5% yield, purity 98.6%, HCl salt) as a yellow oil. This compound was used directly without further purification.

[0267] Intermediate AG [Chemical formula]

[0268] Step A: To a solution of methyl 4,6-dichloropicolinate (4.50 g, 21.8 mmol, 1.00 equiv) in dichloromethane (40.0 mL) was added dropwise DIBAL-H (1.0 M, 65.5 mL, 3.00 equiv) at -78 °C over 10 minutes, and the mixture was stirred at -78 °C for 2 hours. The mixture was then diluted by dropwise addition of water (2.50 mL) at 0 °C under a nitrogen atmosphere, followed by addition of an aqueous sodium hydroxide solution (2.50 mL, w / w = 15%) and water (6.26 mL). The mixture was then stirred at 0 °C for 30 minutes to obtain a suspension. The suspension was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give (4,6-dichloropyridin-2-yl)methanol (2.40 g, 13.5 mmol, 61.7% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 7.65 (s, 1H), 7.52 (s, 1H), 5.69 (t, J = 6.0 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H)

[0269] Step B: A solution of (4,6-dichloropyridin-2-yl)methanol (2.40 g, 13.5 mmol, 1.00 equiv) in dichloromethane (20.0 mL) was added portionwise with Dess-Martin periodinane (11.4 g, 27.0 mmol, 8.35 mL, 2.00 equiv) at 0 °C and stirred at 20 °C for 2 h. The mixture was then poured into water (10.0 mL), stirred for 15 min, then saturated aqueous sodium thiosulfate solution (20.0 mL) was slowly added and stirred for a further 15 min. The resulting suspension was filtered, the layers were separated, and the aqueous layer was extracted with DCM (20.0 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give 4,6-dichloropicolinaldehyde (1.60 g, 9.09 mmol, 67.4% yield) as a red oil. 1 1H NMR (400 MHz, DMSO-d6) δ = 9.87 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H)

[0270] Step C: To a solution of 4,6-dichloropicolinaldehyde (1.10 g, 6.25 mmol, 1.00 equiv) in dichloromethane (10.0 mL) was added dropwise diethylaminosulfur trifluoride (2.01 g, 12.5 mmol, 1.65 mL, 2.00 equiv) at -20 °C and stirred at 25 °C for 1 h. The mixture was then slowly poured into saturated aqueous sodium hydrogen carbonate solution (10.0 mL) at 25 °C and the resulting solution was extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (5.00 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give 2,4-dichloro-6-(difluoromethyl)pyridine (1.00 g, 5.05 mmol, 80.8% yield) as a yellow oil. 11H NMR (400 MHz, CD3OD) δ = 7.75 (s, 1H), 7.74 (s, 1H), 6.82 - 6.55 (m, 1H)

[0271] Step D: To a solution of tributyl(1 - ethoxyvinyl)tin (2.01 g, 5.56 mmol, 1.88 mL, 1.00 equiv) and 2,4 - dichloro - 6 - (difluoromethyl)pyridine (1.10 g, 5.56 mmol, 1.00 equiv) in dioxane (10.0 mL) was added Pd(PPh3)2Cl2 (390 mg, 556 μmol, 0.10 equiv) under a nitrogen atmosphere, and the mixture was stirred at 110 °C for 12 h. The reaction mixture was cooled to 25 °C and slowly poured into saturated aqueous potassium fluoride (20.0 mL). The resulting aqueous solution was extracted with ethyl acetate (50.0 mL × 3), and the combined organic layers were washed with brine (30.0 mL × 2), dried over anhydrous sodium, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 - 20 / 1) to give 4 - chloro - 2 - (difluoromethyl)-6-(1 - ethoxyvinyl)pyridine (1.20 g, 5.14 mmol, 92.5% yield) as a yellow oil. This was used directly in the next step. To a solution of 4 - chloro - 2 - (difluoromethyl)-6-(1 - ethoxyvinyl)pyridine (1.00 g, 4.28 mmol, 1.00 equiv) in dioxane (5.00 mL) was added hydrochloric acid (2.00 M, 4.28 mL, 2.00 equiv) at 20 °C, and the mixture was stirred at 20 °C for 1 h. Then saturated sodium hydrogen carbonate (15.0 mL) was added to adjust the mixture to pH = 8, and the mixture was extracted with ethyl acetate (30.0 mL × 2). The combined organic layers were washed with brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 - 10 / 1) to give 1-(4 - chloro - 6 - (difluoromethyl)pyridin - 2 - yl)ethan - 1 - one (800 mg, 3.89 mmol, 90.9% yield) as a white solid. 11H NMR (400 MHz, CD3OD) δ = 8.10 - 8.16 (m, 1H), 7.95 (d, J = 1.6 Hz, 1H), 6.67 - 6.95 (m, 1H), 2.69 (s, 3H)

[0272] Step E: To a solution of 1-(4-chloro-6-(difluoromethyl)pyridin-2-yl)ethan-1-one (0.85 g, 4.13 mmol, 1.00 equiv) and tert-butyl carbamate (1.45 g, 12.4 mmol, 3.00 equiv) in dioxane (6.00 mL) was added cesium carbonate (2.69 g, 8.27 mmol, 2.00 equiv), XPhos (394 mg, 827 μmol, 0.20 equiv), and palladium(II) acetate (92.8 mg, 413 μmol, 0.10 equiv) under a nitrogen atmosphere, and the mixture was stirred at 90 °C for 2 h. The mixture was then cooled to 25 °C and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give tert-butyl (2-acetyl-6-(difluoromethyl)pyridin-4-yl)carbamate (1.00 g, 3.49 mmol, 84.5% yield) as a white solid. LCMS [M+1] + : 287.1

[0273] Step F: A solution of tert-butyl (2-acetyl-6-(difluoromethyl)pyridin-4-yl)carbamate (1.00 g, 3.49 mmol, 1.00 equiv) and (S)-2-methylpropan-2-sulfinamide (508 mg, 4.19 mmol, 1.20 equiv) in THF (10.0 mL) was added titanium(IV) ethoxide (7.97 g, 34.9 mmol, 7.24 mL, 10.0 equiv), and the mixture was stirred at 75 °C for 12 h. The mixture was then cooled to 25 °C, poured into water (5.00 mL), and then the suspension was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give tert-butyl (S)-(2-(1-((tert-butylsulfinyl)imino)ethyl)-6-(difluoromethyl)pyridin-4-yl)carbamate (1.00 g, 2.57 mmol, 73.5% yield) as a yellow solid. 1 1H NMR (400 MHz, CD3OD) δ = 8.30 (s, 1H), 7.94 (d, J = 1.6 Hz, 1H), 6.52 - 6.82 (m, 1H), 2.81 (s, 3H), 1.54 (s, 9H), 1.35 (s, 9H)

[0274] Step G: A solution of tert-butyl (S)-(2-(1-((tert-butylsulfinyl)imino)ethyl)-6-(difluoromethyl)pyridin-4-yl)carbamate (1.00 g, 2.57 mmol, 1.00 equiv) in THF (10.0 mL) was added dropwise with L-selectride (1.0 M, 976 mg, 5.14 mmol, 1.12 mL, 2.00 equiv) at 0 °C, and the mixture was stirred at 0 - 20 °C for 1 hour. The resulting mixture was poured into a saturated aqueous ammonium chloride solution (15.0 mL), stirred for 10 minutes, and then extracted with ethyl acetate (15.0 mL × 3). The combined organic layers were washed with brine (15.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 - 5 / 1) to give tert-butyl (2-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-6-(difluoromethyl)pyridin-4-yl)carbamate (550 mg, 1.26 mmol, 49.0% yield, purity 89.5%) as a white solid. 1 1H NMR (400 MHz, CD3OD) δ = 7.70 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 6.41 - 6.77 (m, 1H), 4.55 (q, J = 6.8 Hz, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.53 (s, 9H), 1.23 (s, 9H) SFC: Column: Chiralcel OD-3 50×4.6 mm I.D., 3 um Mobile phase: Mobile phase A: CO2, Mobile phase B: MeOH (0.05% DEA); Gradient: MeOH (0.05% DEA) / CO2 = 5% - 40%; Flow rate: 3 mL / min; Detection: PDA column; Temperature: 35 °C; Back pressure: 100 Bar

[0275] Step H: A solution of tert-butyl (2-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-6-(difluoromethyl)pyridin-4-yl)carbamate (450 mg, 1.15 mmol, 1.00 equiv) / hydrochloric acid (dioxane solution, 2.00 mL) was stirred at 0-20 °C for 1 hour. The mixture was then concentrated under reduced pressure to give a mixture of (R)-2-(1-aminoethyl)-6-(difluoromethyl)pyridin-4-amine and tert-butyl (2-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-6-(difluoromethyl)pyridin-4-yl)carbamate as a white solid. This was used directly without purification in the next step. LCMS [M+1] + : 288.2 1 H NMR (400 MHz, CD3OD) δ = 7.74 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 6.82 - 6.51 (m, 1H), 4.60 - 4.45 (m, 2H), 1.61 (d, J = 6.8 Hz, 3H), 1.54 (s, 9H)

[0276] Intermediate AH

Chemical formula

[0277] Step A: 1-(2-Fluoro-3-methylphenyl)ethan-1-one (1.00 g, 6.57 mmol, 1.00 equiv) and (S)-2-methylpropane-2-sulfinamide (1.04 g, 8.54 mmol, 1.30 equiv) in tetrahydrofuran (20.0 mL) were added with tetraisopropyl orthotitanate (3.73 g, 13.1 mmol, 3.88 mL, 2.00 equiv) under a nitrogen atmosphere and stirred at 70 °C for 12 h under a nitrogen atmosphere. The reaction mixture was cooled to 25 °C, poured into water (40.0 mL), stirred for 10 min to obtain a suspension. The suspension was filtered, and the resulting aqueous solution was extracted with ethyl acetate (40.0 mL × 3). The combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1) to give (S)-N-(1-(2-fluoro-3-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.50 g, 5.87 mmol, 89.4% yield) as a yellow solid. LCMS [M+1] + : 256.2 1 H NMR (400 MHz, DMSO-d6) δ = 7.46 (br t, J = 6.8 Hz, 1H), 7.30 - 7.24 (m, 1H), 7.09 - 7.04 (m, 1H), 2.76 (br d, J = 2.8 Hz, 3H), 2.31 (d, J = 2.4 Hz, 3H), 1.31 (s, 9H)

[0278] Step B: A solution of (S)-N-(1-(2-fluoro-3-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.50 g, 5.87 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL) was added with L-selectride (1.0 M, 11.7 mmol, 11.8 mL, 2.00 equiv) at -78 °C under a nitrogen atmosphere and stirred at -78 °C for 2 h. The reaction mixture was slowly poured into water (10.0 mL), stirred for 10 min, and the resulting mixed solution was extracted with ethyl acetate (10.0 mL × 3). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 - 1 / 1) to give (S)-N-(1-(2-fluoro-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 3.50 mmol, 59.5% yield) as a yellow oil. LCMS [M+1] + : 258.4 1 H NMR (400 MHz, DMSO-d6) δ = 7.16 (t, J = 7.6 Hz, 1H), 7.13 - 7.08 (m, 1H), 7.04 - 6.99 (m, 1H), 4.85 (q, J = 6.8 Hz, 1H), 2.28 (d, J = 2.0 Hz, 3H), 1.58 (d, J = 6.8 Hz, 3H), 1.20 (s, 9H)

[0279] Step C: To a solution of (S)-N-(1-(2-fluoro-3-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (900 mg, 3.50 mmol, 1.00 equiv) in dichloromethane (5.00 mL) was added HCl (4.00 M, 1,4-dioxane solution, 5.00 mL, 5.72 equiv) under a nitrogen atmosphere and stirred at 20 °C for 1 h. The mixture was concentrated to give 1-(2-fluoro-3-methylphenyl)ethan-1-amine (390 mg, crude, hydrochloride) as a yellow solid. This was used directly without further purification. 1-(2-Fluoro-3-methylphenyl)ethan-1-amine (300 mg, 1.96 mmol, 1.00 equiv., hydrochloride), 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (419 mg, 1.96 mmol, 1.00 equiv.), N,N-diisopropylethylamine (506 mg, 3.92 mmol, 2.00 equiv.) and potassium fluoride (341 mg, 5.87 mmol, 0.14 mL, 3.00 equiv.) / dimethyl sulfoxide (5.00 mL) solution was stirred at 130 °C for 1 h under a nitrogen atmosphere. The mixture was then cooled to 25 °C, poured into water (20.0 mL), and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative HPLC [column: Welch Xtimate C18 150×25mm×5um; mobile phase: mobile phase A: water (0.05% HCl), mobile phase B: acetonitrile; B%: 14% - 44%] to give 7-chloro-N-(1-(2-fluoro-3-methylphenyl)ethyl)-4-methylpyrido[3,4-d]pyridazin-1-amine (100 mg, 0.30 mmol, 23.2% yield) as a yellow solid. LCMS [M+1] + : 331.2 Racemic 7-chloro-N-(1-(2-fluoro-3-methylphenyl)ethyl)-4-methylpyrido[3,4-d]pyridazin-1-amine (200 mg, 0.60 mmol, 1.00 equiv.) was purified by SFC [column: DAICEL Chiralpak IG (250mm×30mm, 10um); mobile phase: mobile phase A: 0.1% NH4OH / MeOH, mobile phase B: CO2; B%: 30% - 30%] to give the first eluting isomer: (R)-7-chloro-N-(1-(2-fluoro-3-methylphenyl)ethyl)-4-methylpyrido[3,4-d]pyridazin-1-amine (80.0 mg, 0.24 mmol, 40.0% yield) as a yellow solid.

[0280] The following examples are for further illustration of specific embodiments of the present invention and are not intended to limit the scope of the present invention.

[0281] Example 12-1 (R)-4-Methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazin-1-amine

Chemical formula

[0282] Step A: To a solution of 7-chloro-4-methylpyrido[3,4-d]pyridin-1(2H)-one (5.00 g, 25.6 mmol, 1.00 equivalent) / POCl3 (137 g, 893 mmol, 83.0 mL, 34.9 equivalents), N,N-diisopropylethylamine (9.91 g, 76.7 mmol, 13.4 mL, 3 equivalents) was added dropwise at 25 °C, and then the mixture was stirred at 110 °C for 2 hours. Then the mixture was cooled to 25 °C and concentrated under reduced pressure to obtain a residue. The obtained residue was diluted with ethyl acetate (300 mL) at 0 °C, and saturated aqueous sodium hydrogen carbonate solution was slowly added to adjust the pH to 7. The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (4.10 g, 19.2 mmol, 74.9% yield) as a pink solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.65 (s, 1H), 8.22 (s, 1H), 3.02 (s, 3H)

[0283] Step B: A solution of 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (300 mg, 1.40 mmol, 1.00 equiv) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (285 mg, 1.40 mmol, 1.00 equiv) in DMSO (5.00 mL) was added with potassium fluoride (244 mg, 4.20 mmol, 98.5 μL, 3.00 equiv) and N,N-diisopropylethylamine (543 mg, 4.20 mmol, 732 μL, 3.00 equiv), stirred at 130 °C for 12 h, then cooled to room temperature, and water (20.0 mL) was added. The mixture was extracted with ethyl acetate (10.0 mL × 3), the combined organic layers were washed with brine (5.00 mL × 2), dried over sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give (R)-7-chloro-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazin-1-amine (320 mg, 840 μmol, 60.0% yield) as a yellow solid. LCMS [M+1] + : 381.0

[0284] Step C: (R)-7-chloro-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazin-1-amine (40.0 mg, 105 μmol, 1.00 equiv), 1-(1-methyl-1H-pyrazol-4-yl)piperazine (58.9 mg, 210 μmol, 2.00 equiv, TFA salt), cesium carbonate (171 mg, 525 μmol, 5.00 equiv), RuPhos Pd G3 (8.79 mg, 10.5 μmol, 0.10 equiv) / dioxane (1.00 mL) mixture was degassed and purged with nitrogen three times, then the mixture was stirred at 80 °C for 10 h under a nitrogen atmosphere. Water (15.0 mL) was added at 20 °C to quench the reaction, and then the mixture was extracted with ethyl acetate (5.00 mL × 3). The combined organic layers were washed with brine (5.00 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure to give a residue. The obtained residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 um; mobile phase: mobile phase A: water (0.04% HCl), mobile phase B: acetonitrile; gradient: B%: 30% - 60%) to give (R)-4-methyl-7-(4-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazin-1-amine (9.51 mg, 15.1% yield, HCl salt) as a pale yellow solid. LCMS [M+1] + : 511.1 1 H NMR (400 MHz, DMSO-d6) δ=9.00(s, 1H), 7.72(d, J=7.6Hz, 1H), 7.57(d, J=6.4Hz, 1H), 7.52(d, J=7.6Hz, 1H), 7.48(s, 1H), 7.36(s, 1H), 7.35 - 7.29(m, 1H), 7.25(s, 1H), 5.63(quin, J=6.8Hz, 1H), 3.88 - 3.83(m, 4H), 3.75(s, 2H), 3.78 - 3.72(m, 1H), 3.04 - 2.98(m, 4H), 2.56(s, 6H), 1.55(d, J=6.8Hz, 3H)

[0285] Example 12-2 7-(6-Oxa-3-azabicyclo[3.1.1]heptan-3-yl)-4-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazin-1-amine

Chemical formula

[0286] Following the teachings of the general reaction scheme III and the procedures described in the preparation of Examples 12-1 and 12-2, the following compounds of Example 12-10 shown in Table 1 were prepared. [Table 1]

[0287] MRTX-0902 was reacted with fumaric acid in the presence of a solvent to produce the fumarate salt of MRTX-0902.

[0288] The maleate salt of MRTX-0902 can be prepared using a similar procedure (e.g., reacting MRTX-0902 with maleic acid in the presence of a solvent).

[0289] Example A This example shows that the exemplary compound of the present invention binds to SOS1 and prevents the labeled tracer ligand from occupying the SOS1 binding site.

[0290] The SOS1 binding ability of the compounds of the present application was measured using the HTRF assay. Recombinant human SOS1 polypeptide (corresponding to amino acids 560-1049, N-terminal His-TEV-Avi tag-SOS1 (MW = 59.4 kDa) and expressed in E. coli using lanthanide-labeled streptavidin (CisBio)) was incubated with the exemplary compounds of the present application (DMSO stock solution) in buffer (25 mM HEPES, pH 7.5, 25 mM NaCl, 1 mM DTT, 0.01% Brij 35, 0.02% BSA, 0.1% DMSO). After incubation at room temperature for 10-15 minutes, a solution containing a custom-made Cy5-labeled tracer and anti-6HIS-Tb gold cryptate mAb (Cisbio 61HI2TLA) / buffer was added to the solution containing the SOS1 polypeptide and the exemplary compounds of the present application. After incubation at room temperature for 1 hour, the HTRF signal was measured using a Clairostar plate reader (BMG Labtech) according to the manufacturer's instructions. Using the excitation filter EX-TR, luminescence 1 was detected at 650-610 nm and luminescence 2 was detected at 620-610 nm. The HTRF ratio was calculated using the formula: [luminescence 1 / luminescence 2]*10000.

[0291] The background signal was calculated from wells to which 10 μM inhibitor, known to inhibit 100% at a concentration of 10 μM, was added. The signal minus the background was converted to the binding rate relative to the DMSO control. The data were analyzed using XLFIT software (IDBS) using the Morrison equation for competitive binding to calculate the Ki of the compounds of the present application. The K of Example 12-10 i (nM) was 1.78. Therefore, the example compounds of the present invention strongly inhibited the binding of the SOS1-labeled tracer to the SOS1 protein.

[0292] Example B This example shows that the example compounds of the present invention inhibit the SOS1-mediated KRas-mediated GTP nucleotide exchange, inhibit KRas activity, and thereby inhibit the production of the downstream effector pERK. MKN1 cells (15,000 cells / well) or H358 (30,000 cells / well) were seeded into black clear-bottom 96-well cell culture plates (Corning, #3904) and incubated overnight at 37°C. On day 1 of the assay, the cells were administered the compounds of the present invention at a total of 9 concentrations with an initial concentration of 10 μM and serially diluted 3-fold. The cells were incubated with the compounds dissolved in DMSO at 37°C for approximately 0.5 - 1 hour. Immediately, 4% formaldehyde (50 μL) was added to all wells in the draft to fix the cells, and the plates were incubated at room temperature for 20 minutes. The formaldehyde was discarded from the plates, and ice-cold methanol (150 μL) was added to permeabilize the cells at -20°C for 10 minutes. The methanol was discarded from each plate, and the plates were gently tapped towards a paper towel to remove any remaining liquid on the plates. Next, the cells were blocked at room temperature for 1 hour on a shaker using 150 μL of Odyssey blocking buffer (LI-COR Biosciences #927-50010) with 0.05% Tween. The blocking buffer was discarded, and 50 μL of primary antibodies pERK (Cell Signaling Technology #9101L, rabbit, 1:500) and GapDH (Millipore #MAB34, mouse, 1:5000) diluted in Odyssey blocking buffer were added. The plates were incubated on a shaker overnight at 4°C. On the second day of the assay, the primary antibody solution was removed. Each plate was washed three times with 150 μL of 1× PBST (PBS + 0.1% Tween 20), and incubated with 50 μL of anti-rabbit secondary antibody (LI-COR Biosciences #926-32211) and anti-mouse secondary antibody (LI-COR Biosciences #68070) diluted 1:800 in Tween-containing Odyssey blocking buffer on a shaker (shielded from light) at room temperature for 2 hours. The secondary antibody solution was removed, and each plate was washed three times with PBST. Any remaining liquid was discarded, and the plates were imaged using Licor Odyssey according to the manufacturer's instructions (focal distance: 3 mm, filters: both 800 nm and 700 nm). To obtain the pERK inhibition rate, the GAPDH-normalized scan value of each well was divided by the average of the vehicle wells. Then, the IC 50 value was calculated using GraphPad Prism software. The IC 50 (nM) of Example 12-10 was 46. This result indicates that the compounds of the present invention can strongly inhibit activation via KRas and the formation of pERK, thereby blocking intracellular signal transduction via KRas.

[0293] Example C Production of fumarate of MRTX0902 [Chemical formula] Into a 500 L reaction vessel, (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 eq] and EtOH [86.4 L] were added, and the suspension was heated to 75 °C. Seeds of the final product [39.5 g] were added. Then, the prepared fumaric acid [2.40 kg, 20.2 mol, 1.0 eq] / 95% aqueous ethanol solution [52.2 L] was added dropwise. Crystallization was observed upon addition of the fumaric acid solution, and stirring was continued at 75 °C for 2 h after addition. The reaction mixture was cooled to 20 °C over 4 h and then stirring was continued at the same temperature for 4 h. The suspension was filtered, and the recovered solid was washed with EtOH [23.6 L]. The wet cake was then dried under reduced pressure at 50 °C to obtain (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile fumarate (8.93 kg, 97% yield). Melting point: 253.2~253.3 °C 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.71 (dd, J = 7.9, 1.4 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.42 (s, 1H), 7.32 (t, J = 7.8 Hz, 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 = 7.0 Hz, 3H) 13 C NMR (101 MHz, 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 HRMS (ESI) C 22 H 25 N6O calcd: 389.2085 [M + H] +, Observed value: 389.2085

[0294] Although the present invention has been described with respect to its specific embodiments, the present invention may be further modified and generally includes any variations, uses, or adaptations of the present invention in accordance with the essence of the present invention, and is applied to the essential features of the present application described above. It is understood that the present invention includes those developed from the present disclosure that are known or customary in the technical field to which the present invention belongs and is included in the following claims.

Claims

1. below, 【Chemistry 1】 and 【Chemistry 2】 A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt or solvate thereof.

2. The compound, 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. The compound, 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

4. A pharmaceutical composition comprising the compound described in Claim 1 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

5. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt or solvate thereof for inhibiting SOS1 activity in cells.

6. The pharmaceutical composition according to claim 5, wherein the cells have an activating mutation in a RAS family member gene.

7. The pharmaceutical composition according to claim 5, wherein the cells have an activating mutation in the SOS1 gene.

8. The pharmaceutical composition according to claim 5, wherein the cells have an active mutation in the NF1 gene or the NF2 gene.

9. A pharmaceutical composition comprising, alone or in combination with a pharmaceutically effective amount of, the compound described in claim 1, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of cancer.

10. The pharmaceutical composition according to claim 9, wherein the therapeutically effective dose of the above compound is approximately 0.01 to 300 mg / kg per day.

11. The pharmaceutical composition according to claim 10, wherein the therapeutically effective dose of the above compound is approximately 0.1 to 100 mg / kg per day.

12. The above cancers include cardiac sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; lung cancers: bronchial cancers (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrodysartoma, and mesothelioma; Cancers of the digestive system: Esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (epithelial malignant tumor, lymphoma, leiomyosarcoma), pancreatic cancer (pancreatic ductal adenocarcinoma, insulin-producing islet cell tumor, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, VIP-producing tumor), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); Cancers of the urinary tract and genitourinary system: kidney cancer (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminocarcinoma, teratoma, fetal carcinoma, teratocarcinoma, choriocarcinoma, non-epithelial malignant tumor, stromal cell tumor, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver cancer: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract cancer: gallbladder cancer, duodenal papilla cancer, cholangiocarcinoma; Bone cancers: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondrosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor of bone; nervous system cancers: skull cancers (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), meningeal cancers (meningioma, non-epithelial malignant tumors of the meninges, gliomas), brain cancers (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumors (pineal tumors), glioblastoma, oligodendroglioma, Schwann cell tumor, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecological cancers: Uterine cancer (endometrial cancer), serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer, granulosa cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma, vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (fetal rhabdomyosarcoma)), fallopian tube cancer;A pharmaceutical composition according to claim 9, selected from the group consisting of: blood cancers (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin lymphoma, non-Hodgkin lymphoma (malignant lymphoma); skin cancers: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, atypical nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal cancers: neuroblastoma.

13. The pharmaceutical composition according to claim 9, wherein the cancer is a Ras family-related cancer.

14. The pharmaceutical composition according to claim 13, wherein the above-mentioned Ras family-related cancer is KRas, HRas or NRas G12C-related cancer, KRas, HRas or NRas G12D-related cancer, KRas, HRas or NRas G12S-related cancer, KRas, HRas or NRas G12A-related cancer, KRas, HRas or NRas G13D-related cancer, KRas, HRas or NRas G13C-related cancer, KRas, HRas or NRas Q61L-related cancer, KRas, HRas or NRas A146T-related cancer, KRas, HRas or NRas A146V-related cancer, or KRas, HRas or NRas A146P-related cancer.

15. The pharmaceutical composition according to claim 14, wherein the Ras family-related cancer is a KRas G12C-related cancer.

16. The pharmaceutical composition according to claim 15, wherein the Ras family-related cancer is non-small cell lung cancer or pancreatic cancer.

17. The pharmaceutical composition according to claim 9, wherein the cancer is an SOS1-related cancer.

18. The pharmaceutical composition according to claim 17, wherein the SOS1-related cancer is SOS1 N233S-related cancer or SOS1 N233Y-related cancer.

19. The pharmaceutical composition according to claim 17, wherein the above-mentioned SOS1-related cancer is lung adenocarcinoma, fetal rhabdomyosarcoma, Sertoli cell testicular tumor, or granular cell tumor of the skin.

20. The pharmaceutical composition according to claim 9, wherein the cancer is an NF1 / NF2-related cancer.

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