Salts of SOS1 inhibitors

Abstract

The present invention relates to compounds that inhibit the activity of non-7 kinase homolog 1 (SOS1). In particular, the invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the invention.

Description

Field of the Invention

[0001] The present invention relates to compounds that inhibit non-7 kinase homolog 1 (SOS1) GTP-mediated nucleotide exchange. In particular, the present invention relates to compounds, salts thereof, pharmaceutical compositions comprising the compounds, and methods of use thereof. Background of the Invention

[0003] The Ras family includes v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS) and Harvey murine sarcoma viral oncogene (HRAS), and critically regulates cell division, growth and function in normal and altered states (including cancer) (see, e.g., Simanshu et al., Cell, 2017.170(1): p.17-33; Matikas et al., Crit Rev Oncol Hematol, 2017.110: p.1-12). RAS proteins are activated by upstream signals (including receptor tyrosine kinases (RTKs)) and transmit signals to a variety of downstream signaling pathways, such as mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) pathways. Overactivation of RAS signaling is often observed in cancer due to mutations or changes in RAS genes or other genes in the RAS pathway. The identification of strategies to inhibit RAS and RAS signaling is predicted to aid in the treatment of cancer and RAS-regulated disease states.

[0004] RAS protein is guanosine triphosphatase (GTPases), which circulates between an inactive guanosine diphosphate (GDP) binding state and an active guanosine triphosphate (GTP) binding state. Non-7 kinase sub-homolog 1 (SOS1) is a guanine nucleotide exchange factor (GEF), which mediates the exchange of GDP and GTP, thereby activating RAS protein. RAS protein hydrolyzes GTP into GDP by its intrinsic GTPase activity, and the activity is greatly enhanced by GTPase activating protein (GAP). This regulation by GAP and GEF is a mechanism for strictly regulating activation and inactivation under normal conditions. Mutations of several residues in all three RAS proteins are often observed in cancer, and cause RAS to remain mainly in an activated state (Sanchez-Vega et al., Cell, 2018.173: p.321-337 Li et al., Nature Reviews Cancer, 2018.18: p.767-777). Mutations at codons 12 and 13 are the most commonly mutated RAS residues and prevent GAP-stimulated GTP hydrolysis by blocking the interaction of GAP proteins and RAS. However, recent biochemical analyses have shown that these mutant proteins still require nucleotide cycling for activation, based on their intrinsic GTPase activity and / or partial sensitivity to extrinsic GTPases. Therefore, mutant RAS proteins are sensitive to inhibition by upstream factors such as SOS1 or SHP2, another upstream signaling molecule required for RAS activation (Hillig, 2019; Patricelli, 2016; Lito, 2016; Nichols, 2018).

[0005] The three major RAS-GEF families that have been identified in mammalian cells are SOS, RAS-GRF, and RAS-GRP (Rojas, 2011). RAS-GRF and RAS-GRP are expressed in central nervous system cells and hematopoietic cells, respectively, while the SOS family is widely expressed and is responsible for conducting RTK signaling. The SOS family includes SOS1 and SOS2, and these proteins share approximately 70% sequence identity. Due to the rapid degradation of SOS2, SOS1 appears to be much more active than SOS2. Mouse SOS2 knockout is viable, while SOS1 knockout is embryonic lethal. The tamoxifen-induced SOS1 knockout mouse model was used to study the role of SOS1 and SOS2 in adult mice, and it was demonstrated that SOS1 knockout was viable, but SOS1 / 2 double knockout was not viable (Baltanas, 2013), indicating functional redundancy and that selective inhibition of SOS1 may have a sufficient therapeutic index for the treatment of diseases with SOS1-RAS activation.

[0006] SOS protein is recruited to phosphorylated RTK by interacting with growth factor receptor binding protein 2 (GRB2). Recruiting to the plasma membrane makes SOS close to RAS, and realizes SOS-mediated RAS activation. SOS protein binds to RAS through the binding site that promotes nucleotide exchange and the allosteric site that binds to GTP and binds to RAS family proteins and enhances SOS function (Freedman et al., Proc.Natl.Acad.Sci, USA2006.103(45):p.16692-97). The combination with the allosteric site alleviates the spatial closure (steric occlusion) of the RAS substrate binding site, and is therefore necessary for nucleotide exchange. Due to the enhanced interaction of the key domains in the activated state, after interacting with the allosteric site, the retention of the active conformation of the catalytic site remains in a separated state. SOS1 mutations are found in Noonan syndrome and several cancers, including lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and granular cell tumor of the skin (see, eg, Denayer, E. et al., Genes Chromosomes Cancer, 2010. 49(3): p. 242-52).

[0007] GTPase activating proteins (GAPs) are proteins that stimulate the low intrinsic GTPase activity of RAS family members, thereby converting active GTP-bound RAS proteins into inactive GDP-bound RAS proteins (e.g., see Simanshu, DK, Cell, 2017, Ras Proteins and their Regulators in Human Disease). Although activation changes in the GEF SOS1 occur in cancer, inactivating mutations and loss-of-function changes in the GAPs neurofibromin 1 (NF-1) or neurofibromin 2 (NF-2) also occur, creating a state in which SOS1 activity is unhindered and downstream activity through the pathway of RAS proteins is elevated.

[0008] Therefore, the compounds of the present invention that block the interaction between SOS1 and Ras family members prevent KRas from recycling to the active GTP-bound form, and thus can provide therapeutic benefits for a wide range of cancers, particularly cancers associated with Ras family members. The compounds of the present invention provide potential therapeutic benefits as inhibitors of SOS1-KRas interactions, and can negatively regulate the activity of KRas by blocking the SOS1-KRas interaction in cells to treat various forms of cancer, including Ras-related cancers, SOS1-related cancers, and NF1 / NF2-related cancers. SUMMARY OF THE INVENTION

[0010] There is a need to develop new SOS1 inhibitors that can block the interaction between SOS1 and Ras family members and prevent KRas from recycling to the active GTP-bound form, which may provide therapeutic benefits for a wide range of cancers, particularly including Ras-related cancers, SOS1-related cancers, and NF1 / NF2-related cancers.

[0011] In one aspect of the present invention, there is provided a compound represented by the following formula:

[0012]

[0013] This representation of the fumarate salt is also intended to describe and include salt forms where the fumaric acid is partially deprotonated and the MRTX-0902 is partially protonated.

[0014] The compound is the fumarate salt of MRTX-0902 and is of the type of Examples 12-10 of WO 2021 / 127429A1, the contents of which are incorporated herein by reference in their entirety.

[0015] In another aspect of the present invention, the present invention provides a maleate salt of MRTX-0902 having the following structure:

[0016]

[0017] This representation of the maleate salt is also intended to describe and include salt forms where the maleic acid is partially deprotonated and where the MRTX-0902 is partially protonated.

[0018] In another aspect of the present invention, a pharmaceutical composition is provided, which comprises a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0019] In yet another aspect, the invention provides a method for inhibiting the activity of a Ras family member by inhibiting the association between a Ras family member and SOS1 in a cell, the method comprising contacting the cell with a provided compound. In one embodiment, the contact is in vitro. In one embodiment, the contact is in vivo.

[0020] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of a provided compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein.

[0021] Also provided herein are methods for treating cancer in an individual in need thereof, the methods comprising (a) determining that the cancer is associated with a Ras family member mutation (e.g., KRAS G12C-associated cancer) (e.g., using an assay or kit approved by a regulatory agency (e.g., FDA-approved); and (b) administering to the patient a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0022] Also provided herein are methods for treating cancer in an individual in need thereof, the methods comprising (a) determining that the cancer is associated with an SOS1 mutation (e.g., an SOS1-associated cancer) (e.g., using an assay or kit approved by a regulatory agency (e.g., FDA-approved); and (b) administering to the patient a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0023] Also provided herein are methods for treating cancer in an individual in need thereof, the methods comprising (a) determining that the cancer is associated with a NF-1 or NF-2 loss-of-function mutation (e.g., a NF1 / NF2-associated cancer) (e.g., determined using an assay or kit approved by a regulatory agency (e.g., FDA-approved); and (b) administering to the patient a therapeutically effective amount of a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0024] Also provided herein is the use of a provided compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for inhibiting SOS1 activity.

[0025] Also provided herein is the use of a provided compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating a SOS1-related disease or disorder. DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention relates to SOS1 inhibitors. In particular, the present invention relates to compounds that inhibit SOS1 activity, pharmaceutical compositions comprising therapeutically effective amounts of the compounds, and methods of use thereof.

[0028] definition

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention belongs. All patents, patent applications and publications cited herein are incorporated herein by reference to the extent they are consistent with the present disclosure. Terms and scopes have their commonly defined definitions unless otherwise explicitly defined.

[0030] For simplicity, chemical moieties are mainly defined and referred to as monovalent chemical moieties (e.g., alkyl, aryl, etc.) throughout the text. However, in the case of appropriate structures clearly known to those skilled in the art, such terms may also be used to represent corresponding multivalent moieties. For example, although "alkyl" moieties generally refer to monovalent groups (e.g., CH3-CH2-), divalent linking moieties may be "alkyl" in some cases, in which case those skilled in the art will understand that alkyl is a divalent group (e.g., -CH2-CH2-), which is equivalent to the term "alkylidene". (Similarly, in the case of needing a divalent moiety and expressing it as "aryl", those skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, arylidene). All atoms are understood to have their normal number of valencies for bond formation (i.e., carbon is 4, N is 3, O is 2, and S is 2, 4 or 6, depending on the oxidation state of S).

[0031] As used herein, "KRas G12C" refers to a mutant form of mammalian KRas protein containing an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Cys.

[0032] As used herein, "KRas G12D" refers to a mutant form of mammalian KRas protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 12. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp.

[0033] As used herein, "KRas G12S" refers to a mutant form of mammalian KRas protein containing an amino acid substitution of serine for glycine at amino acid position 12. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Ser.

[0034] As used herein, "KRas G12A" refers to a mutant form of mammalian KRas protein containing an amino acid substitution of alanine for glycine at amino acid position 12. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Ala.

[0035] As used herein, "KRas G13D" refers to a mutant form of mammalian KRas protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 13. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly13Asp.

[0036] As used herein, "KRas G13C" refers to a mutant form of mammalian KRas protein containing an amino acid substitution of cysteine ​​for glycine at amino acid position 13. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly13Cys.

[0037] As used herein, "KRas Q61L" refers to a mutant form of mammalian KRas protein containing an amino acid substitution of leucine for glutamine at amino acid position 61. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gln61Leu.

[0038] As used herein, "KRas A146T" refers to a mutant form of mammalian KRas protein containing an amino acid substitution of threonine for alanine at amino acid position 146. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Ala146Thr.

[0039] As used herein, "KRas A146V" refers to a mutant form of mammalian KRas protein containing an amino acid substitution of valine for alanine at amino acid position 146. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Ala146Val.

[0040] As used herein, "KRas A146P" refers to a mutant form of mammalian KRas protein containing an amino acid substitution of proline for alanine at amino acid position 146. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Ala146Pro.

[0041] As used herein, "HRas G12C" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The arrangement of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: Variant p.Gly12Cys.

[0042] As used herein, "HRas G12D" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 12. The arrangement of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: Variant p.Gly12Asp.

[0043] As used herein, "HRas G12S" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of serine for glycine at amino acid position 12. The arrangement of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: Variant p.Gly12Ser.

[0044] As used herein, "HRas G12A" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of alanine for glycine at amino acid position 12. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: Variant p.Gly12Ala.

[0045] As used herein, "HRas G13D" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 13. The arrangement of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: Variant p.Gly13Asp.

[0046] As used herein, "HRas G13C" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of cysteine ​​for glycine at amino acid position 13. The arrangement of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: Variant p.Gly13Cys.

[0047] As used herein, "HRas Q61L" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of leucine for glutamine at amino acid position 61. The arrangement of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: Variant p.Gln61Leu.

[0048] As used herein, "HRas A146T" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of threonine for alanine at amino acid position 146. The arrangement of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: Variant p.Ala146Thr.

[0049] As used herein, "HRas A146V" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of valine for alanine at amino acid position 146. The arrangement of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: Variant p.Ala146Val.

[0050] As used herein, "HRas A146P" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of proline for alanine at amino acid position 146. The arrangement of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: Variant p.Ala146Pro.

[0051] As used herein, "NRas G12C" refers to a mutant form of a mammalian NRas protein containing an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The arrangement of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: Variant p.Gly12Cys.

[0052] As used herein, "NRas G12D" refers to a mutant form of a mammalian NRas protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 12. The arrangement of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: Variant p.Gly12Asp.

[0053] As used herein, "NRas G12S" refers to a mutant form of a mammalian NRas protein containing an amino acid substitution of serine for glycine at amino acid position 12. The arrangement of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: Variant p.Gly12Ser.

[0054] As used herein, "NRas G12A" refers to a mutant form of the mammalian NRas protein containing an amino acid substitution of alanine for glycine at amino acid position 12. The arrangement of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: Variant p.Gly12Ala.

[0055] As used herein, "NRas G13D" refers to a mutant form of a mammalian NRas protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 13. The arrangement of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: Variant p.Gly13Asp.

[0056] As used herein, "HNRas G13C" refers to a mutant form of a mammalian NRas protein containing an amino acid substitution of cysteine ​​for glycine at amino acid position 13. The arrangement of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: Variant p.Gly13Cys.

[0057] As used herein, "HRas Q61L" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of leucine for glutamine at amino acid position 61. The arrangement of amino acid codons and residue positions of human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: Variant p.Gln61Leu.

[0058] As used herein, "NRas A146T" refers to a mutant form of a mammalian NRas protein containing an amino acid substitution of threonine for alanine at amino acid position 146. The arrangement of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: Variant p.Ala146Thr.

[0059] As used herein, "NRas A146V" refers to a mutant form of a mammalian NRas protein containing an amino acid substitution of valine for alanine at amino acid position 146. The arrangement of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: Variant p.Ala146Val.

[0060] As used herein, "NRas A146P" refers to a mutant form of a mammalian NRas protein containing an amino acid substitution of proline for alanine at amino acid position 146. The arrangement of amino acid codons and residue positions of human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: Variant p.Ala146Pro.

[0061] As used herein, "Ras family member" or "Ras family" refers to KRas, HRas, NRas, and activating mutants thereof, including at positions G12, G13, Q61, and A146.

[0062] As used herein, "Ras family-related disease or disorder" refers to a disease or disorder associated with, mediated by, or having an activating Ras mutation, such as at position G12, G13, Q61, or A146. Non-limiting examples of Ras family-related diseases or disorders are KRas, HRas, or NRas G12C-related cancers, KRas, HRas, or NRas G12D-related cancers, KRas, HRas, or NRas G12S-related cancers, KRas, HRas, or NRasG12A-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.

[0063] As used herein, "SOS1" refers to the mammalian non-7 kinase homolog 1 (SOS1) enzyme.

[0064] As used herein, "SOS1-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having an activating SOS1 mutation. Examples of activating SOS1 mutations include SOS1 N233S and SOS1 N233Y mutations.

[0065] As used herein, "SOS1 N233S" refers to a mutant form of a mammalian SOS1 protein containing an amino acid substitution of serine for glutamine at amino acid position 233. The arrangement of amino acid codons and residue positions of human SOS1 is based on the amino acid sequence identified by UniProtKB / Swiss-Prot Q07889: Variant p.Gln233Ser.

[0066] As used herein, "SOS1 N233Y" refers to a mutant form of a mammalian SOS1 protein containing an amino acid substitution of tyrosine for glutamine at amino acid position 233. The arrangement of amino acid codons and residue positions of human SOS1 is based on the amino acid sequence identified by UniProtKB / Swiss-Prot Q07889: Variant p.Gln233Tyr.

[0067] As used herein, "SOS1 inhibitors" refer to compounds of the present invention represented by the structures described herein. These compounds are capable of negatively inhibiting all or part of the interaction between SOS1 and Ras family mutants or negatively inhibiting SOS1-activating mutations, thereby reducing and / or modulating the nucleotide exchange activity of the Ras family member-SOS1 complex.

[0068] As used herein, "NF-1 / NF-2 related diseases or disorders" refers to diseases or disorders associated with, mediated by, or having a loss-of-function mutation in the neurofibromin 1 (NF-1) gene or the neurofibromin 2 (NF-2) gene.

[0069] As used herein, "loss-of-function mutation" refers to any point mutation, splice site mutation, fusion, nonsense mutation (amino acid mutation to a stop codon), in-frame mutation or frameshift mutation, including insertions and deletions, and homozygous deletions of a gene encoding a protein in a target cell or cancer cell that results in partial or complete loss of the presence, activity and / or function of the encoded protein.

[0070] The term "amino" refers to -NH2.

[0071] The term "acetyl" refers to -C(O)CH3.

[0072] As used herein, the term "acyl" refers to an alkylcarbonyl or arylcarbonyl substituent, wherein the alkyl and aryl portions are as defined herein.

[0073] As used herein, the term "alkyl" refers to straight and branched chain aliphatic groups having 1 to 12 carbon atoms. Thus, "alkyl" includes 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.

[0074] As used herein, the term "alkenyl" refers to an unsaturated straight or branched chain aliphatic group having 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. Thus, "alkenyl" includes 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.

[0075] As used herein, the term "alkynyl" refers to an unsaturated straight or branched chain aliphatic group having 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. Thus, "alkynyl" includes 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.

[0076] "Alkylene", "alkenylene" or "alkynylene" is an alkyl, alkenyl or alkynyl group as defined above that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene and butylene. Exemplary alkenylene groups include, but are not limited to, vinylene, propenylene and butenylene. Exemplary alkynylene groups include, but are not limited to, ethynylene, propynylene and butynylene.

[0077] The term "alkoxy" refers to an -OC1-C6 alkyl group.

[0078] As used herein, the term "cycloalkyl" is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 12 carbon atoms. Thus, "cycloalkyl" includes C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 Cyclic hydrocarbon groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0079] The term "heteroalkyl" refers to an alkyl group as defined above in which one or more carbon atoms in the chain are independently replaced by O, S or NR x Instead, where R x is hydrogen or a C1-C3 alkyl group. Examples of the heteroalkyl group include methoxymethyl, methoxyethyl and methoxypropyl.

[0080] "Aryl" is a C6-C 14 Aromatic moieties. Thus, "aryl" includes C6, C 10 , C 13 and C 14 Cyclic hydrocarbon groups. Exemplary aryl groups are C6-C 10 Aryl. In particular, aryl includes, but is not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl. "Aryl" also includes fused polycyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic, such as indenyl.

[0081] "Aralkyl" or "arylalkyl" includes an aryl group covalently linked to an alkyl group, wherein the moiety is linked to another group through the alkyl moiety. Exemplary aralkyl groups are -(C1-C6)alkyl(C6-C10)aryl groups, including but not limited to benzyl, phenethyl and naphthylmethyl.

[0082] "Heterocyclyl" or "heterocycle" is a monocyclic or bicyclic (fused, spiro or bridged) ring structure of 3 to 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms), or of 3 to 13 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 atoms), e.g., 4 to 8 atoms, wherein one or more of the ring atoms is independently -C(O)-, N, NR 4 , O, S or S (O) 2, and the remaining ring atoms are quaternary carbon or carbonyl carbon. The example of heterocyclic radical includes but is not limited to epoxy, oxiranyl, oxetanyl, azetidinyl, aziridine radical, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thietanyl, dithiacyclohexane, trithiacyclohexane, azathiacyclohexane, oxathiacyclohexane, dioxolanyl, oxazolidinyl, oxazolidinone, decahydroquinolyl, piperidone, 4-piperidone, thiomorpholinyl, dimethylmorpholinyl and morpholinyl.

[0083] As used herein, "heterocyclyl" refers to a heterocyclic group covalently linked to another group through a bond.

[0084] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms; having 6, 10 or 14 pi electrons shared in a cyclic array, which may include 1, 2 or 3 rings, and having one to three heteroatoms in addition to carbon atoms, each of which is independently N, O or S. "Heteroaryl" also includes fused polycyclic (e.g., bicyclic, tricyclic) ring systems in which one or more of the fused rings is non-aromatic (regardless of which ring is attached), provided that at least one ring is aromatic and at least one ring contains N, O or S ring atoms.

[0085] Examples of heteroaryl groups include acridinyl, azinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazole oxadiazolyl, imidazolyl, 1H-indazolyl, indolene, indolyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrenyl pyridinyl, pyridoxiranyl, pyridoimidazole, pyridothiazole, pyridoxiranyl ... , quinuclidine, tetrahydroisoquinolyl, tetrahydroquinolyl, 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, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.

[0086] "Heteroaralkyl" or "heteroarylalkyl" includes a heteroaryl group covalently attached to another group via a bond. Examples of heteroalkyl include C1-C6 alkyl and heteroaryl groups with 5, 6, 9 or 10 ring atoms. Examples of heteroaralkyl include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolylmethyl, quinolylethyl, benzofuranylmethyl, indolylethyl, isoquinolylmethyl, isoindolylmethyl, cinnolinylmethyl and benzothienylethyl. Particularly excluded from the scope of this term are compounds with adjacent ring O and / or S atoms.

[0087] "Arylene", "heteroarylene" or "heterocyclylene" is a divalent aryl, heteroaryl or heterocyclyl group, respectively, as defined above, which is positioned between two other chemical groups and serves to link the two chemical groups.

[0088] As used herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as "optionally substituted" without specifying the substituents, it means that the group optionally has one to four, preferably one to three, more preferably one or two non-hydrogen substituents.

[0089] As used herein, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0090] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens are replaced by a halogen. Exemplary haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0091] The term "hydroxyalkyl" refers to an -alkylene-OH group.

[0092] As used herein, the terms "subject" or "patient" are used interchangeably and refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the individual has experienced and / or exhibited at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the individual has been identified or diagnosed as having a cancer with a KRas G12 or G13 mutation (e.g., determined using an assay or kit approved by a regulatory agency (e.g., FDA approved)). In some embodiments, the individual has a tumor that is positive for 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 agency). The individual can be a tumor that is positive for 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 to be positive using a regulatory agency-approved (e.g., FDA-approved) assay or kit). The individual can be an individual whose tumor has 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., where the tumor itself is determined using a regulatory agency-approved (e.g., FDA-approved) kit or assay). In some embodiments, the individual is suspected of having a KRas G12 or G13 gene-related cancer. In some embodiments, the individual has a clinical record indicating that the individual has a tumor with a KRas G12C mutation (and optionally, the clinical record indicates that the individual should be treated with any composition provided herein).

[0093] As used herein, the term "pediatric patient" refers to a patient under the age of 16 years at the time of diagnosis or treatment. The term "pediatric" can be further divided into multiple subgroups, including: neonates (from birth to the first month of life); infants (1 month to 2 years); children (2 years to 12 years); and adolescents (12 years to 21 years (up to but not including the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th ed., Philadelphia: WB 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.

[0094] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit SOS1 enzyme activity.

[0095] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to improve or alleviate symptoms in some way or to stop or reverse the progression of a disease, or to negatively regulate or inhibit SOS1 activity. This amount can be administered as a single dose, or can be administered according to an effective regimen.

[0096] As used herein, "treating" refers to any manner in which the symptoms or pathology of a condition, disorder or disease in a patient are ameliorated or otherwise beneficially altered.

[0097] As used herein, "amelioration of symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition" refers to any relief, whether permanent or temporary, lasting or transient, attributable to or associated with the administration of the composition.

[0098] Compound

[0099] In one aspect of the present invention, there is provided a compound represented by the following formula:

[0100]

[0101] The compound is called the fumarate salt of MRTX-0902.

[0102] In another aspect of the present invention, the present invention provides a maleate salt of MRTX-0902 having the following structure:

[0103]

[0104] Provided compounds can be formulated into pharmaceutical compositions.

[0105] Fumarate salt of MRTX-0902 It can be prepared as follows:

[0106] -Will In the presence of a solvent, it reacts with fumaric acid to generate a compound having the following structure:

[0107] In one embodiment, the solvent is selected from dimethylacetamide (DMAc), dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), toluene and an alcohol of formula R-OH, wherein R is an alkyl, allyl or aryl group. In a preferred embodiment, the solvent is ethanol.

[0108] The maleate salt of MRTX-0902, It can be prepared using similar techniques (eg, reacting MRTX-0902 with maleic acid in the presence of a solvent).

[0109] Pharmaceutical composition

[0110] In another aspect, the present invention provides a pharmaceutical composition comprising an SOS1 inhibitor of the present invention and a pharmaceutically acceptable carrier, excipient or diluent. The compounds of the present invention can be formulated by any method known in the art and can be prepared for administration by any route, including but not limited to parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal or rectal. In certain embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In certain other embodiments, administration may preferably be by oral route.

[0111] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic substance that is compatible with a biological system such as a cell, a cell culture, a tissue or an organism, and does not interfere with the effectiveness of the biological activity of the active ingredient. Therefore, in addition to the inhibitor, the composition of the present invention may also include diluents, fillers, salts, buffers, stabilizers, solubilizers and other substances well known in the art. The preparation of pharmaceutically acceptable preparations is described in, for example, Remington's Pharmaceutical Sciences, 18th edition, edited by A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0112] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the above-mentioned compounds and exhibits minimal or no undesirable toxicological 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 salts formed with organic acids, such as 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, naphthalene disulfonic acid, fumaric acid, and polygalacturonic acid. The compounds can also be administered in the form of pharmaceutically acceptable quaternary salts known to those skilled in the art, which particularly include 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, methanesulfonate, sulfonate, phosphate or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzylate and diphenylacetate).

[0113] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing severe toxic effects in the treated patient. For all of the above conditions, the dosage range of the active compound is about 0.01 to 300 mg / kg, preferably 0.1 to 100 mg / kg / day, more generally 0.5 to about 25 mg / kg recipient body weight / day. Typical local dosage ranges are 0.01-3% wt / wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative itself exhibits activity, the effective dose can be estimated using the weight of the derivative as described above or by other methods known to those skilled in the art.

[0114] Pharmaceutical compositions comprising compounds of the invention can be used in the methods described herein.

[0115] How to use

[0116] In yet another aspect, the present invention provides a method for inhibiting SOS1 activity in a cell, comprising contacting a cell in need of inhibiting SOS1 activity in vitro with an effective amount of a provided compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof.

[0117] The compositions and methods provided herein are particularly contemplated to be useful for inhibiting SOS1 activity in cells. In one embodiment, cells in need of inhibiting SOS1 activity are contacted in vivo with a therapeutically effective amount of a provided compound to negatively regulate the activity of SOS1. In other embodiments, a therapeutically effective amount of a pharmaceutically acceptable salt or a pharmaceutical composition containing a provided compound may be used. In one embodiment, the cell contains an activating mutation in a Ras family member such as KRas, HRas, or NRas. In one embodiment, the cell has abnormal SOS1 activity. In one embodiment, the abnormal SOS1 activity is the result of an activating mutation in SOS1. In one embodiment, the SOS1 activating mutation is an N233S or N233Y mutation. In one embodiment, the cell has abnormal NF-1 or NF-2 activity. In one embodiment, the abnormal NF-1 or NF-2 activity is the result of an activating mutation in NF-1 or NF-2.

[0118] By negatively regulating the activity of SOS1, methods are designed to block the interaction between SOS1 and Ras family members and increase the GTP loading of RAS proteins, thereby reducing or inhibiting GTP nucleotide exchange and locking Ras family members in a GDP-bound, inactive form, resulting in inhibition of downstream Ras-mediated signaling. Cells can be contacted with a single dose or multiple doses according to a particular treatment regimen to affect the desired negative regulation of SOS1.

[0119] In another aspect, a method of treating cancer is provided, comprising administering to a patient suffering from cancer a therapeutically effective amount of a provided compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is a Ras family-related cancer. In one embodiment, the cancer is a SOS-1-related cancer. In one embodiment, the cancer is a NF-1 / NF-2-related cancer.

[0120] The compositions and methods provided herein can be used to treat a variety of cancers, including tumors, such as prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and thyroid cancer and sarcomas. More particularly, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; Lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitinoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagon urogenital tract: kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma), and testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma). Cancer, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: hepatoma (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary carcinoma, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochronfroma) (osteocartilagino usexostoses), benign enchondromas, chondroblastomas, chondromyxofibromas, osteoids and giant cell tumors; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecology: Uterus (endometrial cancer), Cervix (cervical cancer, preneoplastic cervical dysplasia), Ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), Granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, Germinoma, malignant teratoma), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), Fallopian tube (carcinoma); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi), lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). ;

[0121] In one embodiment, the cancer is a Ras family-related cancer, such as a KRas, NRas or HRas-related cancer. In certain embodiments, the Ras family-related cancer is non-small cell lung cancer or pancreatic cancer. In one embodiment, the cancer is a SOS1-related cancer. In certain embodiments, the SOS1-related cancer is a lung adenocarcinoma, embryonal rhabdomyosarcoma, testicular Sertoli cell testicular tumor, and skin granular cell tumor. In one embodiment, the cancer is a NF-1-related cancer.

[0122] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts may also be co-administered with other anti-tumor compounds such as chemotherapeutic agents, or used in combination with other treatments such as radiation or surgical interventions, as pre- or post-operative adjuvants.

[0123] General Reaction Schemes, Intermediates and Examples

[0124] General reaction scheme

[0125] The compounds of the present invention can be prepared using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, or can be prepared using other reagents and conventional methods well known to those skilled in the art.

[0126] For example, intermediates used to prepare compounds of the present invention can be prepared according to General Reaction Scheme III:

[0127] General Reaction Scheme III

[0128]

[0129] In this general reaction scheme III, compound 7 can be reacted with a suitable base such as cesium carbonate in a metal-catalyzed reaction or with a coupling partner such as an alcohol or an amine, HR 1 Nucleophilic substitution of 9 gave the title compound 5.

[0130] In the general reaction scheme III,

[0131] R 1 is hydrogen, hydroxy, 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, wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more R 2 or L-R2 substitution;

[0132] Each Q is independently a bond, O or NR 6 ;

[0133] X is N or CR 7 ;

[0134] Each R 2 are independently C1-C3 alkyl, oxo (ie, 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, wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl or heterocyclyl are each optionally substituted by one or more R 11 replace;

[0135] R 3 is hydrogen, C1-C6 alkyl, alkoxy, -N(R 10 )2. -LN(R 10 )2, cycloalkyl, haloalkyl or heterocyclic, wherein the C1-C6 alkyl, cycloalkyl and heterocyclic are each optionally substituted with one or more R 9 replace;

[0136] Y is a bond or a heteroarylene group;

[0137] R 4is aryl or heteroaryl, each optionally substituted by one or more R 5 replace;

[0138] Each R 5 are independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, C1-C3 alkyl, haloalkyl, haloalkyl-OH, -N(R 6 )2. -LN(R 6 )2 or -SO2 alkyl;

[0139] L is C1-C3 alkylene;

[0140] Each R 6 are independently hydrogen, C1-C3 alkyl, haloalkyl or cycloalkyl;

[0141] R 7 is hydrogen, cyano or alkoxy;

[0142] R 8 is C1-C2 alkyl or halogenated C1-C2 alkyl;

[0143] Each R 9 are independently hydroxy, halogen, amino, cyano, alkoxy or C1-C3 alkyl;

[0144] Each R 10 are independently hydrogen, C1-C3 alkyl or cycloalkyl;

[0145] Each R 11 are independently C1-C3 alkyl, halogen or haloalkyl; and

[0146] R 12 It is hydrogen, halogen or C1-C3 alkyl.

[0147] The following intermediates can be used to prepare the compounds of the present invention.

[0148] Intermediate A

[0149]

[0150] Step A: At 25 ℃, to 1-(2-bromophenyl)-N-methylmethylamine (6.50g, 32.5mmol, 1 equivalent) in THF (70.0mL) in the mixture of dropwise addition of Boc O (7.80g, 35.7mmol, 8.21mL, 1.10 equivalents), and the mixture was stirred at 25 ℃ for 1 hour. The reaction mixture is directly concentrated in a vacuum to obtain a residue. The residue is passed through column chromatography (SiO , petroleum ether / ethyl acetate=20 / 1 to 10 / 1) purifying to obtain tert-butyl (2-bromobenzyl) (methyl) carbamate (7.50g, 25.0mmol, 76.9% yield), as a colorless oil.

[0151] 1 H NMR (400MHz, CDCl3) δ7.55 (br d, J = 8.0Hz, 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).

[0152] 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 the mixture was then stirred at 110°C under nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give tert-butyl methyl(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.

[0153] 1 H NMR (400MHz, CDCl3) δ7.82 (br d, J = 7.2Hz, 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).

[0154] Intermediate B

[0155]

[0156] Step A: To 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 Ti(OEt)4 (8.09 g, 35.5 mmol, 7.35 mL, 2.00 equiv). The mixture was stirred at 70 °C for 2 hours. The mixture was poured into water (15.0 mL) and stirred for 5 minutes. The suspension was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was washed with petroleum ether / ethyl acetate = 5 / 1 (10 mL), filtered, and the filter cake was collected and dried in vacuo to give N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfenamide (3.00 g, 9.73 mmol, 54.9% yield) as a yellow solid.

[0157] 1 H NMR (400MHz, CDCl3) δ7.43 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 1.2 Hz, 1H), 2.72 (s, 3H), 1.30 (s, 9H).

[0158] Step B: 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) was added sodium borohydride (1.36 g, 36.0 mmol, 3.00 equiv) at 0°C. The reaction mixture was slowly warmed to 25°C and stirred for 2 hours. The mixture was poured into ice water (15.0 mL) and stirred at 0°C for 5 minutes. The aqueous phase was extracted with ethyl acetate (30.0 mL x 3). The combined organic phases were washed with brine (30.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give N-(1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (3.60 g, 9.51 mmol, 79.3% yield, 82.0% purity) as a yellow oil.

[0159] 1 H NMR (400MHz, CDCl3) δ7.15 (s, 1H), 6.98-6.96 (s, 1H), 4.81-4.75 (m, 1H), 3.55 (br d, J = 3.6Hz, 1H), 1.59 (d, J = 6.4Hz, 3H), 1.24 (s, 9H).

[0160] 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-butyl methyl(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) was added Pd(PPh3)4 (1.12 g, 967 μmol, 0.10 equiv) and cesium carbonate (9.45 g, 29.01 mmol, 3.00 equiv) under nitrogen atmosphere. The mixture was stirred at 110°C under nitrogen atmosphere for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 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.

[0161] Step D: To 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). The mixture was stirred at 50 °C for 30 minutes. The residue was poured into saturated aqueous sodium sulfite solution (30.0 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (15.0 mL×2). The combined organic phases were washed with brine (30.0 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl (2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (1.20 g, crude) as a yellow oil.

[0162] 1 H NMR (400MHz, CDCl3) δ7.36-7.28(m,3H),7.26-7.22(m,1H),7.01(s,1H),6.91(br s,1H),4.49(br d,J=19.2Hz,2H),4.40(q,J=6.4Hz,1H),2.72(br d,J=19.2Hz,3H),1.53(d,J=6.4Hz,3H),1.51-1.40(m,9H).

[0163] Intermediate C&D

[0164]

[0165] Step A: To a solution of 4-bromothiophene-2-carboxaldehyde (20.0 g, 104 mmol, 1.00 equiv) and (R)-2-methylpropane-2-sulfinamide (12.1 g, 99.5 mmol, 0.95 equiv) in THF (200 mL) was added titanium (IV) ethoxide (47.8 g, 209 mmol, 43.4 mL, 2.00 equiv). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was then poured into water (20.0 mL) and stirred for 5 minutes to give a suspension. The suspension was filtered and the filtrate was concentrated in vacuo to give (R, E)-N-((4-bromothiophene-2-yl)methylene)-2-methylpropane-2-sulfinamide (20.0 g, crude) as a yellow oil. LCMS [M+1]: 295.8.

[0166] Step B: Methylmagnesium bromide (3.00M, 2.04mL, 3.00 equiv) was added dropwise to a solution of (R,E)-N-((4-bromothiophene-2-yl)methylene)-2-methylpropane-2-sulfinamide (600mg, 2.04mmol, 1.00 equiv) in THF (200mL) at 0°C. The reaction mixture was then stirred at 25°C for 1 hour. Saturated aqueous ammonium chloride solution (3.00mL) was added to the reaction mixture and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00mL×2), and the combined organic phases were washed with brine (3.00mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give (R)-N-((S)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (1st elution, intermediate C) (120 mg, 19.0% yield) as a yellow oil and (R)-N-((R)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (2nd elution, intermediate D) (150 mg, 483 μmol, 23.7% yield) as a yellow oil.

[0167] Intermediate C: 1 H NMR (400MHz, CDCl3) δ7.15 (d, J = 1.6 Hz, 1H), 6.97 (s, 1H), 4.81-4.75 (m, 1H), 3.51 (br d, J = 3.2Hz, 1H), 1.59 (d, J = 6.8Hz, 3H), 1.24 (s, 9H).

[0168] Intermediate D: 1H NMR (400MHz, CDCl3) δ7.14 (d, J = 1.6 Hz, 1H), 6.89 (s, 1H), 4.81-4.74 (m, 1H), 3.39 (br d, J = 5.6Hz, 1H), 1.65 (d, J = 6.8Hz, 3H), 1.25 (s, 9H).

[0169] Intermediate E

[0170]

[0171] Step A: To a solution of (R)-N-((R)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (150 mg, 483 μmol, 1.00 equiv) and tert-butyl methyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (168 mg, 483 μmol, 1.00 equiv) in dioxane (1.00 mL) and water (0.20 mL) was added Pd(PPh3)4 (55.9 mg, 48.3 μmol, 0.10 equiv) and cesium carbonate (473 mg, 1.45 mmol, 3.00 equiv) under nitrogen atmosphere. The reaction mixture was stirred at 110°C under nitrogen atmosphere for 2 hours, then brought to 25°C and concentrated in vacuo to give a residue. The 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.

[0172] 1 H NMR (400MHz, CDCl3) δ7.37-7.29(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=16.0Hz,2H),3.44(br d,J=6.0Hz,1H),2.73(br d,J=12.8Hz,3H),1.71(d,J=6.4Hz,3H),1.27(s,9H),1.25(s,9H).

[0173] 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 reaction mixture was stirred at 50° C. for 1 hour. The reaction mixture was then cooled to 25° C., poured into saturated aqueous sodium sulfite solution (2.00 mL), and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00 mL×3), and the combined organic phases were washed with brine (3.00 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C1875×30mm×3um; mobile phase: [water (0.1% TFA)-ACN]; B%: 28%-38%) to give (R)-tert-butyl (2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (40.0 mg, 113 μmol, 42.3% yield, 97.5% purity) as a white oil.

[0174] 1 H NMR (400MHz, 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 = 6.8Hz, 3H), 1.51-1.36 (m, 9H).

[0175] Intermediate F

[0176]

[0177] Step A: To a solution of (R)-N-((S)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 322 μmol, 1.00 equiv) and tert-butyl methyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (112 mg, 322 μmol, 1.00 equiv) in dioxane (1.00 mL) and water (0.20 mL) was added Pd(PPh3)4 (37.2 mg, 32.2 μmol, 0.10 equiv) and cesium carbonate (315 mg, 967 μmol, 3.00 equiv) under nitrogen atmosphere. The reaction mixture was stirred at 110°C for 2 hours, then cooled to 25°C and concentrated in vacuo to give a residue. The 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.

[0178] 1 H NMR (400MHz, CDCl3) δ7.37-7.28(m,3H),7.26-7.22(m,1H),7.07(d,J=1.2Hz,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=6.8Hz,3H),1.52-1.41(m,9H),1.26(s,9H).

[0179] Step B: To 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 equiv) in THF (1.00 mL) and water (0.20 mL) was added iodine (16.9 mg, 66.6 μmol, 13.4 μL, 0.30 equiv). The reaction mixture was stirred at 50° C. for 1 hour, then cooled to 25° C. and poured into saturated aqueous sodium sulfite solution (2.00 mL), and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00 mL×3), and the combined organic phases were washed with brine (3.00 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 24%-54%) to give (S)-tert-butyl (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.

[0180] 1 H NMR(400MHz,CD3OD)δ7.40(d,J=1.2Hz,1H),7.38-7.22(m,5H),4.82-4.80(b rs,1H),4.48(s,2H),2.73(s,3H),1.75(d,J=6.8Hz,3H),1.50-1.35(m,9H).

[0181] Intermediate G

[0182]

[0183] Step A: To a solution of 2-methyl-3-(trifluoromethyl)benzaldehyde (300 mg, 1.59 mmol, 1.00 equiv) and 2-methylpropane-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). The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was poured into water (2.00 mL) and stirred for 5 minutes to give a suspension. The suspension was filtered and concentrated in vacuo to give 2-methyl-N-(2-methyl-3-(trifluoromethyl)benzylidene)propane-2-sulfinamide (360 mg, 1.24 mmol, 77.5% yield) as a white solid.

[0184] 1 H NMR (400MHz, CDCl3) δ = 8.98 (s, 1H), 8.13 (d, J = 7.6Hz, 1H), 7.78 (d, J = 7.6Hz, 1H), 7.40 (t, J = 7.6Hz, 1H), 2.70 (d, J = 0.8Hz, 3H), 1.29 (s, 9H).

[0185] Step B: Methylmagnesium bromide (227 mg, 3.00 M, 635 μL, 3.00 equiv) was added dropwise to a solution of 2-methyl-N-(2-methyl-3-(trifluoromethyl)benzylidene)propane-2-sulfinamide (185 mg, 635 μmol, 1.00 equiv) in THF (5.00 mL) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at 25°C for 3 hours and then slowly treated with saturated ammonium chloride solution (10.0 mL). The organic phase and the aqueous phase were separated and the aqueous phase 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 residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give 2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfenamide (150 mg, 488.0 μmol, 76.8% yield) as a yellow solid.

[0186] 1 H NMR (400MHz, 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).

[0187] Step C: A solution of 2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (150 mg, 488.0 μmol, 1.00 equiv) in HCl (4.0 M in dioxane, 1.00 mL) was stirred at 25 °C for 1 hour. The reaction mixture was filtered and the filter cake was concentrated in vacuo 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.

[0188] 1H NMR (400MHz, CD3OD) δ = 7.78-7.65 (m, 2H), 7.56-7.48 (m, 1H), 4.93-4.89 (m, 1H), 2.52 (d, J = 0.8Hz, 3H), 1.63 (d, J = 6.8Hz, 3H).

[0189] Intermediate H

[0190]

[0191] Step A: To a solution of 1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-one (8.00 g, 39.6 mmol, 1.00 equiv) and (S)-2-methylpropane-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). The reaction mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled at 25° C. and poured into ice water (w / w=1 / 1) (80.0 mL) and stirred for 15 minutes to give a suspension. The suspension was filtered and the filtrate was extracted with ethyl acetate (50.0 mL×3). The combined organic phases were washed with brine (30.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The 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)propane-2-sulfenamide (8.00 g, 26.2 mmol, 66.2% yield) as a yellow oil. LCMS [M+1]: 306.2.

[0192] 1 H NMR(400MHz,CD3OD)δ7.74(br t,J=7.2Hz,2H),7.57-7.51(m,1H),7.46(br t,J=7.6Hz,2H),7.43-7.30(m,1H),2.72(s,3H),2.54(J=6.8Hz,3H),2.48(s,3H),2.40(brd,J=16.0Hz,3H),1.31(s,9H),1.24(br d,J=12.4Hz,9H).

[0193] Step B: To a solution of S)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (8.00 g, 26.2 mmol, 1.00 equiv) in THF (80.0 mL) was added lithium tri-sec-butylborohydride (L-selectride) (7.47 g, 39.3 mmol, 8.59 mL, 1.50 equiv) dropwise at -78°C. The reaction mixture was stirred at -78°C for 2 hours. Water was added dropwise to the reaction mixture (10.0 mL) at 0°C and the resulting mixture was stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (30.0 mL x 3). The combined organic phases were washed with brine (30.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to give (S)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (3.50 g, 11.4 mmol, 43.5% yield) as a yellow oil. LCMS [M+1]: 308.0.

[0194] 1 H NMR (400MHz, CD3OD) δ = 7.70 (d, J = 8.0Hz, 1H), 7.57 (d, J = 7.6Hz, 1H), 7.39-7.33 (m, 1H), 4.94-4.88 (m, 1H), 2.48 (d, J = 1.2Hz, 3H), 1.54 (d, J = 6.4Hz, 3H), 1.20 (s, 9H).

[0195] Step C: A solution of (S)-2-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (1.30 g, 4.23 mmol, 1.00 equiv) in HCl (4M in dioxane, 15.0 mL) was stirred at 25 °C for 30 min. The reaction mixture was filtered and the filter cake was dried in vacuo to give (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (700 mg, 2.89 mmol, 68.4% yield, 99.1% purity, hydrochloride salt) as a white solid. LCMS [M+H]: 204.0.

[0196] 1 H NMR (400MHz, CD3OD) δ = 7.73 (t, J = 7.6Hz, 2H), 7.54-7.49 (m, 1H), 4.92-4.88 (m, 1H), 2.52 (d, J = 0.8Hz, 3H), 1.62 (d, J = 6.8Hz, 3H).

[0197] Intermediate I

[0198]

[0199] Step A: 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) were added 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), and the reaction mixture was stirred at 75° C. under nitrogen atmosphere for 12 hours. The reaction mixture was cooled to 25° C. and concentrated in vacuo to give a residue, which 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-sulfenamide (16.0 g, crude) as a yellow solid. LCMS [M+1]: 308.0.

[0200] Step B: To 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 sodium borohydride (3.93 g, 104 mmol, 2.00 equiv) at 0°C, and the reaction mixture was stirred at 20°C for 1 hour. Saturated aqueous sodium bicarbonate solution (20.0 mL) was added dropwise to the reaction mixture, and the mixture was then diluted with water (200 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 2 / 1) to give N-(1-(5-bromothien-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.

[0201] Intermediate J

[0202]

[0203] 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 reaction mixture was stirred at 70° C. under nitrogen atmosphere for 12 hours. The reaction mixture was cooled to 25° C., diluted with water (200 mL) and ethyl acetate (100 mL) to give a suspension, which was filtered and the filtrate was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfenamide (13.0 g, crude) as a brown oil. LCMS [M+1]: 308.2.

[0204] 1 H NMR (400MHz, CDCl3) δ=7.23 (d, J=4.0Hz, 1H), 7.04 (d, J=4.0Hz, 1H), 2.67 (s, 3H), 1.28 (s, 9H).

[0205] Step B: To a solution of (R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (13.0 g, 42.2 mmol, 1.00 equiv) in THF (150 mL) at 0°C was added sodium borohydride (4.79 g, 127 mmol, 3.00 equiv). The reaction mixture was stirred at 20°C under a nitrogen atmosphere for 2 hours. Saturated aqueous sodium bicarbonate solution (20.0 mL) was added dropwise to the mixture and diluted with water (200 mL), the resulting aqueous solution was extracted with ethyl acetate (100 mL×3), the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 2 / 1) to give (R)-N-((R)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (6.00 g, 17.4 mmol, 41.3% yield, 90.0% purity) as a brown solid. LCMS [M+1]: 309.9.

[0206] 1H NMR (400MHz, CDCl3) δ=6.90 (d, J=3.6Hz, 1H), 6.80 (d, J=3.6Hz, 1H), 4.84-4.66 (m, 1H), 3.50 (d, J=2.8Hz, 1H), 1.57 (d, J=6.4Hz, 3H), 1.23 (s, 9H).

[0207] Step C: To a solution of (R)-N-((R)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (2.00 g, 6.45 mmol, 1.00 equiv) and tert-butyl methyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (2.69 g, 7.74 mmol, 1.20 equiv) in dioxane (20.0 mL) and water (2.00 mL) was added cesium carbonate (6.30 g, 19.3 mmol, 3.00 equiv) and Pd(PPh3)4 (745 mg, 645 μmol, 0.10 equiv) under nitrogen atmosphere. The reaction mixture was stirred at 110°C under nitrogen atmosphere for 2 hours. The reaction mixture is then cooled to 25 ° C, diluted with water (100mL), and extracted with ethyl acetate (50.0mL×3). The combined organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue is passed through column chromatography (SiO2, petroleum ether / ethyl acetate=20 / 1 to 1 / 1) to purify to obtain tert-butyl (2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophene-2-yl)benzyl)(methyl)carbamate (2.60g, 5.19mmol, 80.6% yield, 90.0% purity), which is a yellow oil. LCMS[M+1]:451.4.

[0208] 1 H NMR (400MHz, 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=3.2Hz,1H),2.93-2.56(m,3H),1.64(d,J=6.4Hz,3H),1.56-1.36(m,9H),1.26(s,9H).

[0209] Step D: To 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 equiv) in THF (20.0 mL) and water (4.00 mL) was added iodine (439 mg, 1.73 mmol, 349 μL, 0.30 equiv) and the reaction mixture was stirred at 50° C. for 2 hours. 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 residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give (R)-tert-butyl (2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamate (1.50 g, 3.68 mmol, 63.8% yield, 85.0% purity) as a yellow oil. LCMS [2M+1]: 693.3.

[0210] 1 H NMR (400MHz, CDCl3) δ = 7.39-7.31 (m, 2H), 7.30-7.20 (m, 2H), 7.01 (d, J = 2.8Hz, 1H), 6.81 (d, J = 3. 2Hz, 1H), 4.61-4.48 (m, 3H), 4.04 (s, 2H), 2.73 (s, 3H), 1.64 (d, J = 6.4Hz, 3H), 1.57-1.33 (m, 9H).

[0211] Intermediate K

[0212]

[0213] Step A: To 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 cesium carbonate (1.58 g, 4.83 mmol, 3.00 equiv) and Pd(PPh3)4 (186 mg, 161 μmol, 0.10 equiv), then degassed and purged with nitrogen three times. The reaction mixture was stirred at 110°C under nitrogen atmosphere for 2 hours. After completion, the reaction mixture was cooled to 25 ° C, diluted with water (50.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The 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)thiophene-2-yl)ethyl)-2-methylpropane-2-sulfinamide (450 mg, 1.15 mmol, 71.3% yield, 93.0% purity) as a brown oil. LCMS[M+1]: 365.2.

[0214] Step B: To 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 equiv) in THF (4.00 mL) was added hydrochloric acid (3.00 M, 375 μL, 1.00 equiv) and the reaction mixture was stirred at 20 ° C for 2 hours. After completion, the reaction mixture was diluted with saturated sodium bicarbonate (50.0 mL) and extracted with ethyl acetate (20.0 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to dichloromethane / methanol = 10 / 1) to give 1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethanamine (200 mg, 691 μmol, 61.5% yield, 90.0% purity) as a yellow oil.

[0215] 1H NMR (400MHz, 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).

[0216] Intermediate L

[0217]

[0218] Step A: AIBN (145 mg, 884 μmol, 0.10 equiv) and NBS (1.42 g, 7.96 mmol, 0.9 equiv) were added to a solution of 6-chlorofurano[3,4-c]pyridin-1(3H)-one (1.50 g, 8.85 mmol, 1.00 equiv) in carbon tetrachloride (10.0 mL). The reaction mixture was stirred at 80 ° C for 12 hours. The reaction was filtered and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 10 / 1) to give 3-bromo-6-chlorofurano[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.

[0219] 1 H NMR (400MHz, CDCl3) δ = 8.84-8.80 (m, 1H), 7.84 (s, 1H), 7.47 (s, 1H).

[0220] Step B: To a solution of 3-bromo-6-chlorofurano[3,4-c]pyridin-1(3H)-one (1.20 g, 4.83 mmol, 1.00 equiv) in ethanol (20.0 mL) was added hydrazine hydrate (370 mg, 7.24 mmol, 359 μL, 1.50 equiv) at 0°C. The reaction mixture was stirred at 80°C for 30 minutes. The reaction was cooled to 25°C and poured into ice water (1.00 mL) to give a suspension. The suspension was filtered and the filter cake was collected and dried under vacuum 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.

[0221] 1H NMR (400MHz, DMSO-d6) δ = 13.08 (br s, 1H), 9.20 (s, 1H), 8.53 (s, 1H), 8.10 (s, 1H).

[0222] Step C: To a solution of 7-chloropyrido [3,4-d] pyridazine-1-ol (78.0 mg, 430 μmol, 1.00 equiv) in acetonitrile (2.00 mL) was added phosphorus (V) oxychloride (231 mg, 1.50 mmol, 139 μL, 3.50 equiv) at 25 ° C. The reaction mixture was stirred at 80 ° C for 2 hours. The reaction was cooled at 25 ° C, poured into saturated aqueous sodium bicarbonate solution (2.00 mL) and stirred at 0 ° C for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00 mL×3). The combined organic phases were washed with brine (2.00 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 1,7-dichloropyrido [3,4-d] pyridazine (65.0 mg, crude) as a red solid. LCMS [M+1]: 199.8.

[0223] Intermediate M

[0224]

[0225] Step A: At 0 ° C, over 1.5 hours, bromine (8.96 g, 56.1 mmol, 2.89 mL, 1.10 equivalents) in acetic acid (50.0 mL) was added to a mixture of methyl 3,4-dimethoxybenzoate (10.0 g, 51.0 mmol, 1.00 equivalents) in acetic acid (50.0 mL). Then the mixture was slowly brought to room temperature and stirred for 45 minutes. After completion, the reaction was quenched by pouring water (700 mL) and stirred for 30 minutes, then stirring was stopped, and the mixture was filtered after standing for 1 hour. The collected solid was washed with water (100 mL) and washed with sodium sulfite aqueous solution (100 mL). The solid portion was dried, dissolved in hot methanol (300 mL), and the resulting solution was cooled. The cold methanol solution was treated with water (200 mL) to give a suspension which was filtered and the filter cake was collected and dried in vacuo to give methyl 2-bromo-4,5-dimethoxybenzoate (9.00 g, 32.7 mmol, 64.2% yield) as a white powder. LCMS [M+1]: 275.3.

[0226] 1 H NMR (400MHz, DMSO-d6) δ = 7.36 (s, 1H), 7.24 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H).

[0227] 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) in acetonitrile (60.0 mL) was degassed and purged with nitrogen three times, and the reaction mixture was then stirred at 100 °C under nitrogen atmosphere for 16 hours. 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, which was used directly in the next step.

[0228] Step C: A mixture of methyl 2-(1-butoxyvinyl)-4,5-dimethoxybenzoate (6.00 g, 20.4 mmol, 1.00 equiv) in hydrochloric acid (10% in water, 61.2 g, 168 mmol, 60.0 mL, 8.23 ​​equiv) and THF (60.0 mL) was stirred at 20° C. for 1 hour. 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 bicarbonate solution, then washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether / ethyl acetate = 5 / 1 (50.0 mL) at 20° C. for 20 minutes to give a suspension, which was filtered, and the filter cake was collected and dried in vacuo to give methyl 2-acetyl-4,5-dimethoxybenzoate (3.00 g, 12.6 mmol, 61.8% yield) as a white solid.

[0229] 1H NMR (400MHz, 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).

[0230] Step D: To a solution of methyl 2-acetyl-4,5-dimethoxybenzoate (3.00 g, 12.6 mmol, 1.00 equiv) in ethanol (30.0 mL) was added hydrazine hydrate (2.22 g, 37.8 mmol, 2.16 mL, 3.00 equiv) at room temperature, and the reaction 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, and concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (50.0 mL) at 20 °C for 20 minutes to give a suspension, which was filtered, the filter cake collected and dried in vacuo to give 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.

[0231] 1H NMR (400MHz, 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).

[0232] Step E: A mixture of 6,7-dimethoxy-4-methylphthalazin-1(2H)-one (1.30 g, 5.90 mmol, 1.00 equiv) in phosphorus(V) oxychloride (13.0 mL) was stirred at 120° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give 1-chloro-6,7-dimethoxy-4-methylphthalazine (1.20 g, crude) as a yellow solid. LCMS [M+1]: 239.0.

[0233] 1H NMR (400MHz, DMSO-d6) δ = 7.80 (s, 1H), 7.64 (s, 1H), 4.13 (s, 3H), 4.12 (s, 3H), 3.08 (s, 3H).

[0234] Intermediate N

[0235]

[0236] 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) was added titanium (IV) ethoxide (2.27 g, 9.95 mmol, 2.06 mL, 5.00 equiv) and (R)-2-methylpropane-2-sulfinamide (724 mg, 5.97 mmol, 3.00 equiv). The mixture was stirred at 75 °C for 16 hours. At 25 °C, the reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate solution 20.0 mL. The 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 (20.0 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The 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-methylpropane-2-sulfenamide (0.36 g, 1.19 mmol, 59.8% yield, 95.0% purity) as a colorless oil.

[0237] 1 H NMR (400MHz, 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).

[0238] Step B: To a solution of (R,E)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (340 mg, 1.18 mmol, 1.00 equiv) in tetrahydrofuran (5.00 mL) was added sodium borohydride (89.5 mg, 2.37 mmol, 2.00 equiv). The mixture was stirred at 0 ° C for 1 hour. At 25 ° C, the reaction mixture was quenched by the addition of water 10.0 mL, and then 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, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-13% ethyl acetate / petroleum ether) to give (R)-N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfenamide (190 mg, 643 μmol, 54.4% yield, 98.0% purity) as a yellow oil. LCMS [M+1] + =290.1.

[0239] Step C: A mixture of (R)-N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (140 mg, 484 μmol, 1.00 equiv) in dioxane hydrochloride (4.00 M, 7.00 mL, 57.9 equiv) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-amine (110 mg, 475 μmol, 98.2% yield, 80.0% purity) as a white solid, which was used without further purification. LCMS [M+1] + =186.0.

[0240] Intermediate O

[0241]

[0242] Step A: To a solution of 3-bromo-2-methylbenzoic acid (100 g, 465 mmol, 1.00 equiv) and N,O-dimethylhydroxylamine hydrochloride (68.6 g, 512 mmol, 1.10 equiv, HCl) in DMF (1000 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (195 g, 512 mmol, 1.10 equiv) and N,N-diisopropylethylamine (180 g, 1.40 mol, 243 mL, 3.00 equiv). The mixture was stirred at 25 °C for 2 hours, then poured into water (1000 mL) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (1000 mL×3). The combined organic phases were washed with brine (1000 mL x 5), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-bromo-N-methoxy-N,2-dimethylbenzamide (120 g, crude) as a yellow oil. LCMS [M+1] + :258.0.

[0243] Step B: At 0°C, methylmagnesium bromide (3.0M, 180mL, 1.16 eq.) was added to a solution of 3-bromo-N-methoxy-N,2-dimethylbenzamide (120g, 465mmol, 1.00 eq.) in THF (100mL). The mixture was stirred between 0-40°C for 3 hours, then the mixture was cooled to 0°C, and hydrochloric acid (6.0N) (450mL) was added dropwise, and stirred between 40-45°C for 2 hours. The mixture was then cooled to 25°C and poured into a saturated ammonium chloride solution (9000mL). The aqueous phase was extracted with ethyl acetate (1500mL×3). The combined organic phases were washed with brine (1000 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 1-(3-bromo-2-methylphenyl)ethan-1-one (90.0 g, 422 mmol, 90.9% yield) as a yellow oil.

[0244] 1 H NMR (400MHz, CD3OD) δ=7.70 (dd, J=1.2, 8.0Hz, 1H), 7.62 (dd, J=0.8, 7.6Hz, 1H), 7.19 (t, J=8.0Hz, 1H), 2.56 (s, 3H), 2.46 (s, 3H).

[0245] Step C: To a solution of 1-(3-bromo-2-methylphenyl)ethan-1-one (88.0 g, 413 mmol, 1.00 equiv) and (S)-2-methylpropane-2-sulfinamide (60.1 g, 496 mmol, 1.20 equiv) in THF (100 mL) was added titanium (IV) ethoxide (471 g, 2.07 mol, 428 mL, 5.00 equiv) and diglyme (55.4 g, 413 mmol, 59.1 mL, 1.00 equiv). The mixture was stirred at 80° C. for 2 hours, then poured into water (300 mL) and stirred for 15 minutes. The mixture was then filtered and concentrated in vacuo to give a residue. The residue 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-sulfenamide (110 g, 348 mmol, 84.2% yield) as a yellow oil.

[0246] 1H NMR (400MHz, CD3OD) δ = 7.63 (br t, J = 6.8Hz, 2H), 7.28 (br d, J = 7.6Hz, 1H), 7.17 (t, J = 8.0Hz, 2H), 7.14-7.02 (m, 1H), 2.67 (s, 3H), 2.50 (br d,J=4.8Hz,3H),2.42(s,3H),2.31(br d,J=17.2Hz,3H),1.31-1.26(m,9H),1.24-1.16(m,9H)

[0247] Step D: To 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 tri-sec-butyl lithium borohydride (1.0 M, 689 mL, 2.00 equiv) at -78 ° C. The mixture was stirred at -78 ° C for 2 hours, then poured into a saturated aqueous ammonium chloride solution (1000 mL) and stirred at 25 ° C for 60 minutes. The aqueous phase was extracted with ethyl acetate (1000 mL×3). The combined organic phases were washed with brine (500 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1 to 2 / 1) to give a residue. The residue was further washed with petroleum ether to give (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfenamide (70.0 g, 220 mmol, 63.8% yield) as a white solid. LCMS [M+1] + :318.1.

[0248] 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 in vacuo to give (R)-1-(3-bromo-2-methylphenyl)ethan-1-amine (55.0 g, crude, HCl) as a white solid. LCMS [M+1] + :214.1.

[0249] Step F: To a solution of (R)-1-(3-bromo-2-methylphenyl)ethan-1-amine (55.0 g, 220 mmol, 1.00 equiv, HCl) and Boc2O (48.4 g, 222 mmol, 50.9 mL, 1.01 equiv) in dichloromethane (500 mL) was added N,N-diisopropylethylamine (56.7 g, 439 mmol, 76.5 mL, 2.00 equiv). The mixture was stirred between 0-25 °C for 30 minutes and then concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to give a residue. The residue was further washed with petroleum ether to give (R)-tert-butyl (1-(3-bromo-2-methylphenyl)ethyl)carbamate (51.0 g, 162 mmol, 73.9% yield) as a white solid. LCMS[M-55] + :258.0.

[0250] 1 H NMR (400MHz, CD3OD) δ = 7.43 (d, J = 8.0Hz, 1H), 7.32 (d, J = 8.0Hz, 1H), 7.10-7.03 (m, 1H), 4.93 (br d, J = 6.4Hz, 2H), 2.45 (s, 3H), 1.41 (br s, 9H), 1.33 (d, J = 6.8Hz, 3H).

[0251] Step G: To a solution of (R)-tert-butyl (1-(3-bromo-2-methylphenyl)ethyl)carbamate (51.0 g, 162 mmol, 1.00 equiv) in DMF (540 mL) was added zinc cyanide (22.9 g, 195 mmol, 12.4 mL, 1.20 equiv) and Pd(PPh3)4 (18.8 g, 16.2 mmol, 0.10 equiv). The mixture was stirred at 110°C for 3 hours, then cooled to 25°C and poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with brine (1000 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give (R)-tert-butyl (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.

[0252] 1H NMR (400MHz, CD3OD) δ = 7.63 (d, J = 7.6Hz, 1H), 7.54 (d, J = 7.2Hz, 1H), 7.39-7.30 (m, 1H), 4.93 (br d, J = 6.8Hz, 1H), 2.58 (s, 3H), 1.40 (br s, 9H), 1.34 (d, J = 7.2Hz, 3H).

[0253] Step H: To a solution of (R)-tert-butyl (1-(3-cyano-2-methylphenyl)ethyl)carbamate (49.0 g, 188 mmol, 1.00 equiv) in dichloromethane (400 mL) was added TFA (133 mL). The mixture was stirred at 0° C. for 30 minutes, then poured into a saturated sodium bicarbonate solution (200 mL) and stirred for another 30 minutes. The aqueous phase was extracted with ethyl acetate (1000 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum 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.

[0254] 1 H NMR(400MHz,DMSO-d6)δ=8.36(br s,2H),7.86(d,J=8.0Hz,1H),7.80(dd,J=0.8,7.6Hz,1H),7.51(t,J=8.0Hz,1H),4.68(q,J=6.8Hz,1H),2.55(s,3H),1.48(d,J=6.8Hz,3H).

[0255] SFC conditions: Column: Chiralpak IC-3 50×4.6 mm ID, 3 μm, mobile phase: phase A is CO2, and phase B is MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA), in CO2, 5%-40%, flow rate: 3 mL / min; detector: PDA, column temperature: 35°C; back pressure: 100 Bar.

[0256] Intermediate P

[0257]

[0258] To a solution of (R)-3-(1-aminoethyl)-2-methylbenzonitrile (16.0 g, 99.9 mmol, 1.00 equiv) and 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (21.4 g, 99.9 mmol, 1.00 equiv) in DMSO (130 mL) was added cesium fluoride (22.8 g, 150 mmol, 5.52 mL, 1.50 equiv), and the mixture was stirred at 130 ° C for 2 hours. The mixture was then cooled to 25 ° C, diluted with water (200 mL), and extracted with ethyl acetate (200 mL×3). The combined organic phases were washed with brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: Kromasil Eternity XT 250×80mm×10um; mobile phase: phase A: water (0.1% TFA), phase B: acetonitrile; B%: 25%-55%]. The combined fractions were combined and the pH was adjusted to pH=8 using aqueous sodium bicarbonate. The suspension was extracted with ethyl acetate (1000mL×3), and the combined organic phases were washed with brine (100mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R)-3-(1-((7-chloro-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (14.5g, 42.9mmol, 43.0% yield) as a yellow solid.

[0259] 1 H NMR (400 MHz, CDCl3) δ = 9.19 (d, J = 0.4 Hz, 1H), 7.74 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 1.2, 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 5.72 (quintet, J = 6.8 Hz, 1H), 5.40 (br d, J = 6.0 Hz, 1H), 2.86 (s, 3H), 2.69 (s, 3H), 1.63 (s, 3H).

[0260] Intermediate Q

[0261]

[0262] To a solution of (R)-3-(1-aminoethyl)-2-methylbenzonitrile (5.32 g, 19.4 mmol, 1.00 equiv., TFA) and 6-bromo-4-chloro-1-methylphthalazine (5.00 g, 19.4 mmol, 1.00 equiv.) in DMSO (30.0 mL) were added cesium fluoride (5.90 g, 38.8 mmol, 1.43 mL, 2.00 equiv.) and N,N-diisopropylethylamine (5.02 g, 38.8 mmol, 6.76 mL, 2.00 equiv.), and the mixture was stirred at 130° C. for 2 hours. The mixture was then cooled to 25° C., diluted with water (10.0 mL), and the aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 2 / 1) to give (R)-3-(1-((7-bromo-4-methylphthalazin-1-yl)amino)ethyl)-2-methylbenzonitrile (5.20 g, 13.6 mmol, 70.2% yield) as a yellow solid. LCMS [M+1] + :381.1.

[0263] Intermediate R

[0264]

[0265] Step A: A mixture of (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), titanium (IV) isopropoxide (60.0 g, 211 mmol, 62.3 mL, 5.00 equiv) in THF (90.0 mL) was degassed and purged with nitrogen three times and stirred at 80° C. for 12 hours. 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 phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give (R)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfenamide (7.23 g, 22.8 mmol, 54.1% yield) as a yellow solid. LCMS [M+3] + :318.0.

[0266] 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 ratio of E / Z isomers is ~1 / 1).

[0267] Step B: To 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) in portions at 0°C, and the reaction was stirred at 25°C for 1 hour. The reaction mixture was poured into water (30.0 mL) and stirred for 5 minutes. The resulting aqueous phase was extracted with ethyl acetate (150 mL×3), and the combined organic phases were washed with brine (150 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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-sulfenamide (200 mg, 628 μmol, 49.7% yield) as a brown oil.

[0268] Step C: To a mixture of (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 sulfone (3.00 mL) was added copper (I) iodide (15.0 mg, 78.6 μmol, 0.10 equiv) at 20° C., and the mixture was stirred at 130° C. under nitrogen atmosphere for 3 hours. To the mixture was added water (15.0 mL), and the mixture was extracted with ethyl acetate (20.0 mL×3). The combined organic phases were washed with brine (30.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The 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.

[0269] 1 H NMR (400MHz, DMSO-d6) δ = 7.85 (dd, J = 8.0, 1.2Hz, 1H), 7.78 (d, J = 7.6Hz, 1H), 7.46 (t, J = 8.0Hz, 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=6.8Hz,3H),1.09(s,9H).

[0270] 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) in hydrochloric acid (4.0 M in dioxane, 2.00 mL, 21.2 equiv) was stirred at 20° C. for 1 h. The mixture was concentrated under reduced pressure to give (R)-1-(2-methyl-3-(methylsulfonyl)phenyl)ethan-1-amine (91.0 mg, crude, HCl) as a white solid.

[0271] Intermediate S

[0272]

[0273] Step A: To a solution of methylamine (100 g, 1.48 mol, 3.01 eq., HCl salt) in THF (1.00 L) was added N,N-diisopropylethylamine (237 g, 1.84 mol, 3.73 eq.), 2-bromo-6-fluorobenzaldehyde (100 g, 493 mmol, 1.00 eq.), acetic acid (9.00 g, 150 mmol, 0.30 eq.) and sodium cyanoborohydride (62.0 g, 987 mmol, 2.00 eq.). The reaction mixture was stirred at 25 °C for 3 hours, then diluted with water (500 mL) and extracted with ethyl acetate (1.00 L x 2). The combined organic phases were washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give 1-(2-bromo-6-fluorophenyl)-N-methylmethanamine (120 g, 484 mmol, 88% purity) as an off-white solid, which was used directly in the next step. LCMS [M+1] + :218.0.

[0274] Step B: To a solution of 1-(2-bromo-6-fluorophenyl)-N-methylmethylamine (120 g, 484 mmol, 88% purity, 1.00 equivalent) in THF (1.00 L), di-tert-butyl dicarbonate (211 g, 968 mmol, 2.00 equivalent) was added, and the mixture was stirred at 25 ° C for 2 hours. The mixture was then concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 100 / 1) to give N-[(2-bromo-6-fluoro-phenyl) methyl]-N-methyl-carbamic acid tert-butyl ester (70.0 g, 220 mmol) as a brown oil. LCMS[M-55] + :261.9

[0275] 1 H NMR (400MHz, DMSO-d6) δ = 7.49 (d, J = 7.6Hz, 1H), 7.33-7.26 (m, 2H), 4.57 (s, 2H), 2.64 (s, 3H), 1.38 (s, 9H).

[0276] Step C: To 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'-bis(1,3,2-dioxaborolane) (60.0 g, 236 mmol, 1.25 equiv) in dioxane (600 mL) was added 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. under nitrogen atmosphere for 12 hours. The mixture was cooled to 25° C. and concentrated under vacuum to give a residue. The 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, 73% purity) as a yellow oil. LCMS [M-55] + :266.1.

[0277] Step D: To a solution of tert-butyl (2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate (80.0 g, 160 mmol, 73% purity, 1.00 equiv) and (R)-N-[(1R)-1-(5-bromo-2-thienyl)ethyl]-2-methyl-propane-2-sulfenamide (56.0 g, 180 mmol, 1.13 equiv) in dioxane (500 mL) and water (100 mL) under nitrogen atmosphere were added cesium carbonate (150 g, 460 mmol, 2.88 equiv) and Pd(PPh3)4 (20.0 g, 17.3 mmol, 0.10 equiv), and the mixture was stirred at 100°C under nitrogen atmosphere for 3 hours. The mixture was diluted with water (500 mL), extracted with ethyl acetate (1.00 L × 2), washed with organic phase brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The 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)thiophene-2-yl)-6-fluorobenzyl)(methyl)carbamate (84.0 g, 152 mmol, 85% purity) as a yellow oil. LCMS [M-100] + :369.1.

[0278] 1H 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 (quintet, 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).

[0279] Step E: To 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, 85% purity, 1.00 equiv) in THF (240 mL) and water (48.0 mL) was added iodine (6.80 g, 26.8 mmol, 0.19 equiv). The reaction was heated at 50 °C for 2 hours, then diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The organic phase was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 300 / 1 to 10 / 1) to give (R)-tert-butyl (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.

[0280] Intermediate T

[0281]

[0282] Step A: To 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 tributyl(1-ethoxyvinyl)tin (5.00 g, 13.8 mmol, 4.67 mL, 1.53 equiv) at 20° C., and the mixture was stirred at 80° C. under nitrogen atmosphere for 12 hours. Saturated potassium fluoride solution (100 mL) was then added to the mixture, and the solution was stirred at 20° C. for 1 hour. The mixture was extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1-(benzyloxy)-3-(1-ethoxyvinyl)-5-(trifluoromethyl)benzene (2.90 g, crude) as a yellow oil. The crude oil was used in the next step without further purification.

[0283] Step B: To a solution of 1-(benzyloxy)-3-(1-ethoxyvinyl)-5-(trifluoromethyl)benzene (2.90 g, 9.00 mmol, crude, 1.00 equiv) in tetrahydrofuran (30.0 mL) was added hydrochloric acid (3.0 M in THF, 10.0 mL, 3.33 equiv), and the solution was stirred at 20° C. for 1 hour. The mixture was then 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 residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=50 / 1 to 10 / 1) to give 1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethan-1-one (2.60 g, 8.84 mmol, 98.2% yield) as a yellow oil.

[0284] 1 H NMR (400MHz, CDCl3) δ = 7.79 (s, 1H), 7.74 (s, 1H), 7.45-7.39 (m, 6H), 5.16 (s, 2H), 2.63 (s, 3H).

[0285] Step C: To a solution of 1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethan-1-one (2.60 g, 8.84 mmol, 1.00 equiv) and (R)-2-methylpropane-2-sulfenamide (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 the solution was stirred at 70 °C for 12 h. The mixture was then concentrated under reduced pressure, and the 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-methylpropane-2-sulfenamide (2.20 g, 5.03 mmol, 57.0% yield) as a yellow oil.

[0286] 1 H NMR (400MHz, CDCl3) δ = 7.45 (d, J = 10.0Hz, 2H), 7.24-7.13 (m, 6H), 4.94 (s, 2H), 2.56 (s, 3H), 1.10 (s, 9H).

[0287] Step D: To 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) at 0°C was added sodium borohydride (270 mg, 7.14 mmol, 1.29 equiv), and the mixture was stirred at 20°C for 3 hours. Saturated aqueous ammonium chloride solution (80.0 mL) was added to the mixture and the resulting mixture was stirred at 20°C for 30 minutes. The mixture was then extracted with ethyl acetate (80.0 mL×3), and the combined organic phases were washed with brine (80.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 3 / 1) to give (R)-N-((R)-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (1.20 g, 3.00 mmol, 54.3% yield) as a yellow oil.

[0288] 1H NMR(400MHz, 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=2.8Hz,1H),1.53(d,J=6.4Hz,3H),1.25(s,9H).

[0289] Step E: 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) was added hydrochloric acid (4.0 M in dioxane, 751 μL, 1.00 equiv) and the solution was stirred at 20° C. for 20 min. The mixture was concentrated under reduced pressure to remove to give (R)-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethan-1-amine (1.20 g, crude, HCl) as a white solid which was used without further purification.

[0290] 1 H NMR (400MHz, CDCl3) δ = 8.82 (s, 2H), 7.44-7.31 (m, 8H), 5.09 (s, 2H), 4.42 (s, 1H), 1.43 (s, 3H).

[0291] Intermediate U

[0292]

[0293] Step A: To a solution of 3-acetyl-5-fluorobenzonitrile (2.00 g, 12.3 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL) was added titanium ethoxide (5.59 g, 24.5 mmol, 5.08 mL, 2.00 equiv) and (R)-2-methylpropane-2-sulfinamide (1.93 g, 15.9 mmol, 1.30 equiv). The mixture was degassed and purged with nitrogen three times, then stirred at 70° C. under nitrogen atmosphere for 12 hours. 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, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give (R,E)-N-(1-(3-cyano-5-fluorophenyl)ethylidene)-2-methylpropane-2-sulfenamide (1.01 g, 3.68 mmol, 30.0% yield, 97.5% purity) as a yellow oil. LCMS [M+1] + :267.1.

[0294] 1 H NMR (400MHz, 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).

[0295] Step B: To a solution of (R,E)-N-(1-(3-cyano-5-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (900 mg, 3.38 mmol, 1.00 equiv) in tetrahydrofuran (10.0 mL) was added sodium borohydride (383 mg, 10.1 mmol, 3.00 equiv) at 0°C. The mixture was then warmed to 20°C and stirred for 2 hours. At 25°C, the mixture was quenched with saturated aqueous ammonium chloride solution (20.0 mL), extracted with ethyl acetate (20.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to give (R)-N-((R)-1-(3-cyano-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfenamide (711 mg, 2.52 mmol, 74.5% yield, 95.3% purity) as a yellow oil. LCMS [M+1] + :269.1.

[0296] 1 H NMR (400MHz, CDCl3) δ = 7.46 (t, J = 1.2Hz, 1H), 7.46-7.33 (m, 1H), 7.31-7.29 (m, 1 H), 4.60-4.55 (m, 1H), 3.47 (d, J = 3.6Hz, 1H), 1.54 (d, J = 6.8Hz, 3H), 1.25 (s, 9H).

[0297] Step C: To a solution of (R)-N-((R)-1-(3-cyano-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (711 mg, 2.65 mmol, 1.00 equiv) in dioxane (3.00 mL) was added hydrochloric acid in ethyl acetate (4.0 M, 9.94 mL, 15.0 equiv). The mixture was stirred at 20 °C for 2 hours. The mixture was neutralized with saturated sodium bicarbonate solution (10.0 mL), extracted with ethyl acetate (10.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R)-3-(1-aminoethyl)-5-fluorobenzonitrile (330 mg, crude) as a yellow oil.

[0298] 1H NMR (400MHz, CD3OD) δ = 7.72-7.71 (m, 1H), 7.67-7.66 (m, 1H), 7.65-7.62 (m, 1H), 4.59 (q, J = 6.8Hz, 1H), 1.65 (d, J = 6.8Hz, 3H).

[0299] Intermediate V

[0300]

[0301] Step A: At 0°C, 1-bromo-2-methyl-3-(trifluoromethyl)benzene (10.0 g, 41.8 mmol, 1.00 equiv) was added to ice-cooled concentrated sulfuric acid (100 mL), followed by the slow addition of potassium nitrate (12.7 g, 125 mmol, 3.00 equiv), and the mixture was stirred 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, and concentrated under reduced pressure to give a residue. The 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.

[0302] 1 H NMR (400MHz, DMSO-d6) δ = 8.72 (d, J = 2.0Hz, 1H), 8.40 (d, J = 2.4Hz, 1H), 2.58-2.62 (m, 3H).

[0303] 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 3 times, and then the mixture was stirred at 80° C. under a nitrogen atmosphere for 10 hours. The reaction mixture was quenched with a saturated potassium fluoride solution (300 mL) and stirred at 25° C. for 2 hours. The suspension was then extracted with ethyl acetate (180 mL×3). The combined organic layers were washed with brine (200 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(1-ethoxyvinyl)-2-methyl-5-nitro-3-(trifluoromethyl)benzene (6.00 g, crude) as a black oil.

[0304] 1 H NMR (400MHz, CD3OD) δ = 8.47 (d, J = 2.0Hz, 1H), 8.32 (d, J = 2.0Hz, 1H), 4.58 (d, J = 2.8Hz, 1H ), 4.32 (d, J = 2.4Hz, 1H), 4.00-3.95 (m, 2H), 2.56 (d, J = 1.2Hz, 3H), 1.37 (t, J = 7.0Hz, 3H).

[0305] Step C: At 20 ° C, under nitrogen atmosphere, a mixture of 1-(1-ethoxyvinyl)-2-methyl-5-nitro-3-(trifluoromethyl)benzene (6.00 g, 21.8 mmol, 1.00 equivalent) and hydrochloric acid (3.0 M, 20.7 mL, 2.85 equivalents) in THF (80.0 mL) was stirred for 1 hour. The reaction mixture was quenched by adding water (100 mL) and then extracted with ethyl acetate (60.0 mL×3). The combined organic layer was washed with brine (70.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 10 / 1) to obtain 1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethan-1-one (4.10 g, 16.5 mmol, 76.0% yield) as a yellow oil.

[0306] 1 H NMR (400MHz, CD3OD) δ = 8.67 (s, 1H), 8.57 (s, 1H), 2.66 (s, 3H), 2.60 (s, 3H).

[0307] 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-methylpropane-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. under nitrogen atmosphere for 12 hours. 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, and concentrated under reduced pressure to give a residue. The 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)propane-2-sulfenamide (2.00 g, 5.71 mmol, 70.5% yield) as a yellow oil.

[0308] 1 H NMR (400MHz, CD3OD) δ = 8.43 (s, 1H), 8.30 (s, 1H), 2.75 (s, 3H), 2.58 (s, 3H), 1.30 (m, 9H).

[0309] Step E: To a solution of (R,E)-2-methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (2.00 g, 5.71 mmol, 1.00 equiv) in THF (23.0 mL) was added sodium borohydride (647 mg, 17.1 mmol, 3.00 equiv) at 0°C. The mixture was then stirred at 20°C for 2 hours, and saturated sodium bicarbonate was added, followed by dilution with water (100 mL). The mixture was extracted with ethyl acetate (60.0 mL x 3), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give (R)-2-methyl-N-((R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfenamide (700 mg, 1.75 mmol, 30.6% yield) as a dark brown oil. LCMS [M+1] + :353.0.

[0310] 1H NMR (400MHz, DMSO-d6) δ = 8.67 (d, J = 2.4Hz, 1H), 8.31 (d, J = 2.0Hz, 1H), 6.09 (d, J =7.2Hz,1H),4.83-4.79(m,1H),2.54(s,3H),1.43(d,J=6.8Hz,1H),1.11(m,9H).

[0311] Step F: A mixture of (R)-2-methyl-N-((R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (700 mg, 1.99 mmol, 1.00 equiv) and iodine (151 mg, 595 μmol, 120 μL, 0.30 equiv) in tetrahydrofuran (8.00 mL) and water (2.00 mL) was degassed and purged with nitrogen 3 times, and the mixture was then stirred at 50 °C under a nitrogen atmosphere for 2 hours. The reaction was quenched with saturated sodium bicarbonate (50.0 mL) and then extracted with ethyl acetate (30.0 mL×3). The combined organic phases were washed with brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 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.

[0312] 1 H NMR (400MHz, DMSO-d6) δ = 8.76 (d, J = 2.4Hz, 1H), 8.30 (d, J = 2.4Hz, 1H), 4.54-4.49 (m, 1H), 2.57 (s, 3H), 1.46 (d, J = 6.4Hz, 1H).

[0313] Intermediate W

[0314]

[0315] Step A: To 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 titanium ethoxide (6.09 g, 26.7 mmol, 5.53 mL, 3.00 equiv) and (R)-2-methylpropane-2-sulfinamide (1.40 g, 11.6 mmol, 1.30 equiv). The mixture was stirred at 70 ° C for 10 hours. The reaction mixture was quenched by sodium bicarbonate (50.0 mL) at 20 ° C and then stirred for 10 minutes. The solid was filtered 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, and concentrated under reduced pressure to give (R,E)-N-(1-(3-chloro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfenamide (2.40 g, crude) as a yellow oil. LCMS [M+1] + :272.0.

[0316] Step B: Sodium borohydride (850 mg, 22.5 mmol, 2.66 equiv) was added to a solution of (R, E)-N-(1-(3-chloro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (2.30 g, 8.46 mmol, 1.00 equiv) in tetrahydrofuran (30.0 mL) at -40 ° C, and the mixture was stirred at -40 ° C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (50.0 mL) at 20 ° C and then stirred for 10 minutes. 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, and concentrated under reduced pressure to give a residue. The 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-methylpropane-2-sulfenamide (1.50 g, 5.48 mmol, 64.7% yield) as a colorless oil. LCMS [M+1] + :274.1.

[0317] Step C: To 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) at 0°C was added hydrochloride (4.0 M, 30.0 mL) in ethyl acetate and the mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give (R)-1-(3-chloro-2-methylphenyl)ethan-1-amine (700 mg, crude) as a white solid. LCMS [M+1] + :170.1.

[0318] Intermediate X

[0319]

[0320] 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 under nitrogen atmosphere for 12 hours. 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 x 20.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to give (R,E)-2-methyl-N-(1-(3-methyl-5-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfenamide (750 mg, 2.46 mmol, 99.3% yield) as a yellow oil. LCMS [M+1] + :306.1.

[0321] 1 H NMR (400MHz, 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).

[0322] Step B: To a solution of (R,E)-2-methyl-N-(1-(3-methyl-5-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (650 mg, 2.13 mmol, 1.00 equiv) in THF (15.0 mL) at -40°C was added sodium borohydride (253 mg, 6.69 mmol, 3.14 equiv). The mixture was stirred at -40°C for 2 hours. Saturated sodium bicarbonate solution was added to the mixture and diluted with water (50.0 mL). The mixture was extracted with ethyl acetate (3 x 50.0 mL), the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give (R)-2-methyl-N-((R)-1-(3-methyl-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfenamide (320 mg, 1.04 mmol, 48.9% yield) as a light yellow solid. LCMS [M+1] + :308.1.

[0323] 1 H NMR (400MHz, 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).

[0324] Step C: A solution of (R)-2-methyl-N-((R)-1-(3-methyl-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfenamide (305 mg, 992 μmol, 1.00 equiv) in hydrochloric acid (4.0 M in ethyl acetate, 10.0 mL) was stirred at 25 °C for 1 hour. Concentration under reduced pressure gave (R)-1-(3-methyl-5-(trifluoromethyl)phenyl)ethan-1-amine (200 mg, crude) as a light yellow solid. The crude product was used directly in the next step without further purification. LCMS [M+1] + :204.0.

[0325] Intermediate Y

[0326]

[0327] Step A: To a solution of 1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethan-1-one (35.6 g, 175 mmol, 1.00 equiv) and (R)-2-methylpropane-2-sulfinamide (25.4 g, 209 mmol, 1.20 equiv) in THF (350 mL) was added titanium (IV) isopropoxide (149 g, 524 mmol, 155 mL, 3.00 equiv) and 1,2-dimethoxyethane (15.7 g, 175 mmol, 18.1 mL, 1.00 equiv). The reaction mixture was stirred at 80 °C for 12 h, then water (50.0 mL) was added to give a suspension. The suspension was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1 to 1 / 1) to give (R)-N-(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethylidene)-2-methylpropane-2-sulfenamide (44.0 g, 143 mmol, 82.0% yield) as a brown oil.

[0328] 1 H NMR (400MHz, CDCl3) δ = 7.45 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 4.56 (brs, 2H), 2.82 (s, 3H), 1.33 (s, 9H).

[0329] Step B: To a solution of (R)-N-(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (44.0 g, 143 mmol, 1.00 equiv) in THF (400 mL) was added sodium borohydride (16.3 g, 430 mmol, 3.00 equiv) in portions at 0°C, and the reaction was stirred at 0°C for 1 hour. The mixture was slowly poured into water (200 mL) and stirred for 5 minutes, then extracted with ethyl acetate (300 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The 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-sulfenamide (24.0 g, 76.2 mmol, 53.2% yield, 98.2% purity) as a brown oil.

[0330] 1H NMR (400MHz, CDCl3) δ = 6.63 (d, J = 2.0Hz, 1H), 6.56 (d, J = 2.0Hz, 1H), 5.06 (d, J = 6.0Hz, 1H), 4.69 (s, 2H), 4.46-4.39 (m, 1H), 1.45 (d, J = 6.8Hz, 3H), 1.27 (s, 9H).

[0331] Step C: A solution of (R)-N-((R)-1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (23.5 g, 76.0 mmol, 1.00 equiv) in HCl / dioxane (200 mL) was stirred for 2 hours at 25° C. The mixture was filtered and the filter cake was washed with ethyl acetate (100 mL), then the filter cake was collected and dried under vacuum to give (R)-2-(1-aminoethyl)-6-(trifluoromethyl)pyridin-4-amine (hydrochloride) as a white solid.

[0332] 1 H NMR (400MHz, DMSO-d6) δ = 8.43 (br s, 3H), 6.93 (br d, J = 2.0Hz, 2H), 6.74 (d, J = 1.6Hz, 1H), 4.34-4.27 (m, 1H), 1.45 (d, J = 6.8Hz, 3H).

[0333] Intermediate Z

[0334]

[0335] 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 to 1 / 1) to give (S)-2-methyl-N-(1-(2-methylpyridin-3-yl)ethylidene)propane-2-sulfenamide (1.25 g, 5.24 mmol, 88.6% yield) as a yellow oil. LCMS [M+1] + :239.2.

[0336] Step B: To a solution of (S)-2-methyl-N-(1-(2-methylpyridin-3-yl)ethylidene)propane-2-sulfinamide (1.25 g, 5.24 mmol, 1.00 equiv) in tetrahydrofuran (7.00 mL) was added dropwise tri-sec-butylborohydride (1.0 M in THF, 7.87 mL, 1.50 equiv) at -78°C over 30 minutes, and then stirred for another hour at -78°C. The reaction mixture was then quenched by the addition of saturated ammonium chloride solution (in water, 30.0 mL) at 0°C and stirred for another hour at 25°C. The solution was then 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 sulfate, filtered, and concentrated under reduced pressure. The residue was purified twice by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give (S)-2-methyl-N-((R)-1-(2-methylpyridin-3-yl)ethyl)propane-2-sulfenamide (600 mg, 2.50 mmol, 47.6% yield) as a white solid. LCMS [M+1] + :432.3.

[0337] 1 H NMR (400MHz, CDCl3) δ = 8.36 (dd, J = 1.2, 3.6Hz, 1H), 7.64 (dd, J = 1.6, 8.0Hz, 1H), 7.12 (dd ,J=4.8,7.6Hz,1H),4.81-4.70(m,1H),2.58(s,3H),1.47(d,J=6.8Hz,3H),1.14(s,9H).

[0338] SFC conditions: column: Chiralpak AD-3 50×4.6mm ID, 3um, mobile phase: phase A: CO2, and phase B: MeOH (0.05% diethylamine); gradient elution: MeOH (0.05% diethylamine), in CO2, 5%-40%, flow rate: 3mL / min; detector: PDA, column temperature: 35°C; back pressure: 100Bar.

[0339] 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) in HCl·dioxane (3.00 mL) was stirred at 0°C under nitrogen atmosphere for 30 minutes. Afterwards, a white precipitate was formed, and the suspension was filtered. The filter cake was collected and dried under vacuum, and the residue was further purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 um; mobile phase: phase A: water (0.05% ammonium hydroxide v / v), 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, 82% purity) as a colorless oil. LCMS [M-16] + :120.3.

[0340] Intermediate AA

[0341]

[0342] Step A: PdCl2(PPh3)2 (1.40 g, 2.00 mmol, 0.10 equiv) and tributyl(1-ethoxyvinyl)tin (21.7 g, 60.0 mmol, 20.3 mL, 3.00 equiv) were added 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), and the mixture was degassed and purged with nitrogen (3 times), then stirred at 100° C. under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and an aqueous potassium fluoride solution (2.0 M, 100 mL) was added to the residue. 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 which was used without further purification.

[0343] Step B: To a solution of 1-(difluoromethyl)-3-(1-ethoxyvinyl)-2-fluorobenzene (7.50 g, 34.7 mmol, 1.00 equivalent) in tetrahydrofuran (50.0 mL), aqueous hydrochloric acid (30.0 mL, 10% purity) was added, and the mixture was stirred at 25 ° C for 1 hour. Thereafter, the pH of the mixture was adjusted to 6-8 with aqueous sodium bicarbonate 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 residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1 / 0 to 5 / 1) to give 1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-one (6.01 g, 31.3 mmol, 90.2% yield, 98.0% purity) as a colorless oil. LCMS[M+1] + :189.1.

[0344] 1 H NMR (400MHz, CDCl3) δ = 8.02-7.97 (m, 1H), 7.80-7.76 (m, 1H), 7.34 (t, J = 8.0Hz, 1H), 6.94 (t, J = 14.8Hz, 1H), 2.66 (d, J = 5.2Hz, 3H).

[0345] Step C: A mixture of (S)-2-methylpropane-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) in 2-methyltetrahydrofuran (30.0 mL) was degassed and purged with nitrogen (3 times), then stirred at 75° C. under nitrogen atmosphere for 4 hours. The reaction mixture was then cooled, diluted with water (50.0 mL), extracted with ethyl acetate (50.0 mL×3), and 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 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-methylpropane-2-sulfenamide (1.80 g, 6.18 mmol, 38.8% yield). LCMS [M+1] + :292.2.

[0346] Step D: To a mixture of (S)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfenamide (1.80 g, 6.18 mmol, 1.00 equiv) in 2-methyltetrahydrofuran (30.0 mL) at -78°C under nitrogen atmosphere was added lithium tri-sec-butylborohydride (3.52 g, 18.5 mmol, 4.10 mL, 3.00 equiv), and the mixture was stirred at -78°C under nitrogen atmosphere for 3 hours. Thereafter, lithium tri-sec-butylborohydride (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 under nitrogen atmosphere for 9 hours. The mixture was cooled to room temperature, diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL x 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 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-sulfenamide (1.30 g, 4.34 mmol, 70.3% yield, 98% purity) as a colorless oil. LCMS [M+1] + :294.2.

[0347] 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 in 1,4-dioxane, 15.0 mL, 14.0 equiv), and the mixture was stirred at 25 °C for 30 minutes. The mixture was then diluted with water (30.0 mL), extracted with ethyl acetate (30.0 mL x 3), and the combined organic layers were washed with brine (30.0 mL x 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, which was used without further purification.

[0348] 1 H NMR (400MHz, CDCl3) δ = 7.52-7.47 (m, 2H), 7.24-7.19 (m, 1H), 6.88 (t, J = 14.8Hz, 1H), 4.85-4.92 (m, 1H), 1.57 (d, J = 6.8Hz, 3H).

[0349] Step F: A mixture of (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) in dimethyl sulfoxide (6.00 mL) was degassed and purged with nitrogen (3 times), and the mixture was stirred at 130° C. under a nitrogen atmosphere for 12 hours. 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 residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) and preparative HPLC [column: Phenomenex luna C18 150×25mm×10um; mobile phase: phase A: water (0.225% formic acid), 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, 92.3% purity) as a yellow solid. LCMS [M+1] + :367.2.

[0350] Intermediate AB

[0351]

[0352] Step A: To a solution of 3-bromo-5-fluoro-2-methylbenzoic acid (4.00 g, 17.2 mmol, 1.00 equiv) and N,O-dimethylhydroxylamine (1.84 g, 18.9 mmol, 1.10 equiv, HCl salt) in DMF (50.0 mL) was added N,N-diisopropylethylamine (6.66 g, 51.5 mmol, 8.97 mL, 3.00 equiv) and HATU (7.83 g, 20.6 mmol, 1.20 equiv), and the reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (50.0 mL), washed with brine (30.0 mL×3), and the combined organic phases were collected, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , 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.

[0353] Step B: At 0 ° C, methylmagnesium bromide (3.0M, 34.1mL, 6.00 equivalents) was added dropwise to a solution of 3-bromo-5-fluoro-N-methoxy-N,2-dimethyl-benzamide (4.70g, 17.0mmol, 1.00 equivalents) in THF (100mL). After the addition was complete, the reaction mixture was warmed to 45 ° C and stirred for 5 hours. The mixture was then cooled to 25 ° C, quenched with water (20.0mL), and extracted with ethyl acetate (50.0mL×3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=5 / 1) to give 1-(3-bromo-5-fluoro-2-methylphenyl) ethyl-1-ketone (3.80g, 16.5mmol, 96.6% yield) as a light yellow solid.

[0354] 1 H NMR (400MHz, CDCl3) δ = 7.43 (dd, J = 2.8, 7.6Hz, 1H), 7.19 (dd, J = 2.8, 8.4Hz, 1H), 2.55 (s, 3H), 2.45 (d, J = 0.4Hz, 3H).

[0355] 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-methylpropane-2-sulfinamide (2.79 g, 23.0 mmol, 1.40 equiv) in THF (60.0 mL) was 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 hours. The reaction mixture was then cooled to 25° C., diluted with ethyl acetate (100 mL) and water (10.0 mL) to give a suspension. The suspension was filtered, and the filtrate was concentrated under reduced pressure to remove all volatiles. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 20 / 1) to give (S)-N-(1-(3-bromo-5-fluoro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfenamide (4.70 g, 14.1 mmol, 85.5% yield) as a yellow oil. LCMS [M+3] + :336.0.

[0356] 1H NMR (400MHz, CDCl3) δ = 7.35 (br dd, J = 2.4, 7.6Hz, 1H), 6.92 (dd, J = 2.4, 8.4Hz, 1H), 2.66 (s, 3H), 2.37 (s, 3H), 1.30 (s, 9H).

[0357] Step D: To 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 equiv) in THF (80.0 mL) was added dropwise tri-sec-butylborohydride (1.0 M, 24.7 mL, 1.50 equiv) at -78°C, and the reaction mixture was warmed to 0°C and stirred for 2 hours. The mixture was then diluted with aqueous ammonium chloride (30.0 mL), and the resulting solution was extracted with ethyl acetate (50.0 mL x 2). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether (20.0 mL), filtered, and the filter cake was dried under vacuum to give (S)-N-((R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfenamide (3.20 g, 9.52 mmol, 57.8 % yield) as a white solid.

[0358] 1 H NMR (400MHz, CDCl3) δ = 7.24 (dd, J = 2.4, 7.6Hz, 1H), 7.10 (dd, J = 2.8, 10.0Hz, 1H), 4.90-4.82 (m, 1H), 3.30 (br d,J=2.8Hz,1H),2.42(s,3H),1.48(d,J=6.8Hz,3H),1.23(s,9H).

[0359] 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 equiv) in THF (20.0 mL) and water (5.00 mL) was added iodine (362 mg, 1.43 mmol, 288 μL, 0.30 equiv), and the mixture was stirred at 50° C. for 2 hours. The mixture was then cooled to 25° C., and the pH was adjusted to pH=7 with aqueous sodium bicarbonate solution. The resulting solution was extracted with DCM (20.0 mL×3), and the combined organic phases 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 light yellow oil. The crude oil was used without further purification.

[0360] Step F: To a solution of (R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethyl-1-amine (1.20 g, 5.17 mmol, 1.00 equiv) in THF (20.0 mL) was added di-tert-butyl dicarbonate (1.35 g, 6.20 mmol, 1.43 mL, 1.20 equiv), and the mixture was stirred at 20° C. for 3 hours. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO , petroleum ether / ethyl acetate=150 / 1 to 70 / 1) to give (R)-tert-butyl(1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)carbamate (1.45 g, 4.36 mmol, 84.4% yield) as a white solid.

[0361] Step G: A mixture of (R)-tert-butyl (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) in dimethylacetamide (20.0 mL) was degassed and purged with nitrogen (3 times), and the mixture was stirred at 120° C. under nitrogen atmosphere for 6 hours. The mixture was then diluted with ethyl acetate (60.0 mL), filtered, and the filtrate was washed with brine (30.0 mL×3), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to give (R)-tert-butyl(1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)carbamate (1.10 g, 3.95 mmol, 97.3% yield) as a light yellow solid.

[0362] Step H: To a solution of (R)-tert-butyl(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 TFA (1.88 g, 16.5 mmol, 1.22 mL, 4.18 equiv) and the mixture was stirred at 20°C for 1 hour. The mixture was then concentrated under reduced pressure and the residue was adjusted to pH = 7 with saturated aqueous sodium bicarbonate solution. The resulting solution was extracted with DCM (50.0 mL) and the organic phase was dried over sodium sulfate and concentrated in vacuo to give (R)-3-(1-aminoethyl)-5-fluoro-2-methylbenzonitrile (0.80 g, crude) as a brown oil which was used without further purification.

[0363] Intermediate AC

[0364]

[0365] Step A: Under nitrogen atmosphere, to 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 PdCl2(PPh3)2 (544 mg, 775 μmol, 0.10 equiv), and the mixture was stirred at 80°C for 12 hours. The reaction mixture was then cooled to 25°C, diluted with 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, and concentrated under reduced pressure to give compound 2-(1-ethoxyvinyl)-4-fluoro-6-(trifluoromethyl)aniline (4.00 g, crude) 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), aqueous hydrochloric acid (4.00 M, 20.0 mL, 1.33 equivalents) was added dropwise. The mixture was then stirred at 25 ° C for 1 hour, 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 residue was purified by column chromatography (petroleum ether / ethyl acetate=30 / 1 to 3 / 1) to give compound 1-(2-amino-5-fluoro-3-(trifluoromethyl)phenyl)ethan-1-one (5.60 g, 25.3 mmol, 42.0% yield, 99.9% purity) as a yellow solid.

[0366] 1 H NMR (400MHz, DMSO-d6) δ = 7.99 (d, J = 9.2Hz, 1H), 7.65-7.61 (m, 1H), 7.33 (s, 2H), 2.59 (s, 3H).

[0367] Step B: Sodium nitrite (2.27 g, 32.9 mmol, 1.30 equiv) was added in batches to 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), and potassium iodide (8.41 g, 50.6 mmol, 2.00 equiv) was then added to the mixture at 0°C. After the addition was complete, the reaction mixture was stirred at 25°C for 12 hours, 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 residue was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give compound 1-(5-fluoro-2-iodo-3-(trifluoromethyl)phenyl)ethan-1-one (5.60 g, 10.3 mmol, 40.8% yield, 61.2% purity) as a yellow solid.

[0368] 1 H NMR (400MHz, DMSO-d6) δ = 7.83-7.76 (m, 1H), 7.74-7.71 (m, 1H), 2.56 (s, 3H).

[0369] Step C: Under nitrogen atmosphere, to 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 Pd(dppf)Cl2 (400 mg, 542 μmol, 0.05 equiv) and potassium carbonate (7.49 g, 54.2 mmol, 5.00 equiv), and the mixture was stirred at 90°C for 12 hours. The 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 residue was purified by column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give 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.

[0370] 1 H NMR (400MHz, CDCl3) δ = 7.47 (dd, J = 2.8, 8.8Hz, 1H), 7.36-7.30 (m, 1H), 2.58 (s, 3H), 2.47 (s, 3H).

[0371] Step D: To 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-methylpropane-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 hours. The mixture was then cooled to 25° C. and diluted with water (50.0 mL) to give a suspension. The resulting suspension was filtered, and the filtrate was diluted with ethyl acetate (100 mL×3). The organic layer was washed with salt water (50.0 mL) and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate=10 / 1 to 3 / 1) to give compound (R)-N-(1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.50 g, 4.64 mmol, 46.4% yield), which was a yellow oil.

[0372] 1 H NMR (400MHz, CDCl3) δ = 7.39 (dd, J = 2.2, 8.8Hz, 1H), 7.10 (dd, J = 2.4, 8.4Hz, 1H), 2.68 (s, 3H), 2.41 (s, 3H), 1.30 (s, 9H).

[0373] Step E: To a solution of (R)-N-(1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.90 g, 5.88 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL) was added sodium borohydride (667 mg, 17.6 mmol, 3.00 equiv) in portions at 0°C. The reaction mixture was stirred at 0°C for 2 hours, then slowly diluted with saturated aqueous ammonium chloride solution (50.0 mL) and stirred for 30 minutes. The resulting mixture was extracted with ethyl acetate (100 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give (R)-N-((R)-1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (1.30 g, 4.00 mmol, 68.0% yield) as a yellow oil.

[0374] 1H NMR (400MHz, 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 = 6.4Hz, 3H), 1.23 (s, 9H).

[0375] Step F: To a solution of (R)-N-((R)-1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (1.30 g, 4.00 mmol, 1.00 equiv) in dichloromethane (5.00 mL) was added hydrochloric acid (4.00 M in 1,4-dioxane, 5.00 mL, 5.0 equiv) and the mixture was stirred at 25 °C for 1 hour. The mixture was then concentrated under reduced pressure to give compound (R)-1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (700 mg, 2.81 mmol, 70.4% yield, 88.9% purity, HCl salt) as a yellow oil which was used directly without further purification.

[0376] Intermediate AD

[0377]

[0378] Step A: To a solution of 3-bromo-2,5-difluorobenzaldehyde (4.00 g, 18.1 mmol, 1.00 equiv) and (R)-2-methylpropane-2-sulfenamide (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 give 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-methylpropane-2-sulfenamide (5.70 g, 17.6 mmol, 97.1% yield) as a white solid.

[0379] 1 H NMR (400MHz, 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).

[0380] Step B: At -60 ° C, to (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 methylmagnesium bromide (3.0 M, 17.0 mL, 3.00 equiv) dropwise, and the mixture was then warmed to 0 ° C and stirred for 1 hour. The mixture was diluted with aqueous ammonium chloride (50.0 mL), and the resulting aqueous solution was extracted with ethyl acetate (50.0 mL × 3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give (S)-N-((R)-1-(3-bromo-2,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfenamide (3.50 g, 10.3 mmol, 60.6% yield) as a white solid.

[0381] 1 H NMR (400MHz, CDCl3) δ = 7.31-7.26 (m, 1H), 7.16 (dd, J = 6.4, 8.8Hz, 1H), 4.89-4.78 (m, 1H), 3.35 (br d, J=4.0Hz, 1H), 1.56 (d, J=6.8Hz, 3H), 1.23 (s, 9H).

[0382] 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 hours. The mixture was then cooled to 25° C., and the pH was adjusted to pH=7 with aqueous sodium bicarbonate solution. The resulting aqueous solution was extracted with DCM (20.0 mL×3), and the combined organic phases 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) as a light yellow oil. The crude oil was used directly without further purification.

[0383] Step D: To a solution of (R)-1-(3-bromo-2,5-difluorophenyl)ethyl-1-amine (1.20 g, 5.08 mmol, 1.00 equiv) in THF (20.0 mL) was added 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 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO , petroleum ether / ethyl acetate=150 / 1 to 80 / 1) to give (R)-tert-butyl (1-(3-bromo-2,5-difluorophenyl)ethyl)carbamate (1.30 g, 3.87 mmol, 76.1% yield) as a white solid.

[0384] Step E: A mixture of (R)-tert-butyl (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) in dimethylacetamide (20.0 mL) was degassed and purged with nitrogen (3 times), and the mixture was stirred at 115° C. under nitrogen atmosphere for 3 hours. The mixture was then cooled to 25° C., diluted with ethyl acetate (100 mL), and the organic phase was washed with brine (50.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to give (R)-tert-butyl(1-(3-cyano-2,5-difluorophenyl)ethyl)carbamate (0.90 g, 3.19 mmol, 89.3% yield) as a light yellow solid.

[0385] Step F: To a solution of (R)-(1-(3-cyano-2,5-difluorophenyl)ethyl)carbamic acid tert-butyl ester (0.90 g, 3.19 mmol, 1.00 equiv) in DCM (10.0 mL) was added TFA (4.62 g, 40.5 mmol, 3.00 mL, 12.7 equiv), and the reaction mixture was stirred at 20 ° C for 1 hour. The reaction mixture was then concentrated under reduced pressure, and the residue was diluted with water (10.0 mL). The pH of the solution was adjusted to pH=7 with aqueous sodium bicarbonate, and the resulting aqueous solution was extracted with DCM (20.0 mL×2). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (R)-3-(1-aminoethyl)-2,5-difluorobenzonitrile (700 mg, crude) as a light yellow oil. The compound was used directly without further purification.

[0386] Intermediate AE

[0387]

[0388] 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 reaction mixture was stirred at 80 ° C for 16 hours. The mixture was then cooled to 25 ° C, diluted with ethyl acetate (1.00 L), and the organic phase was separated, washed with water (500 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=1 / 0 to 2 / 1) to give 3-bromo-2-(trifluoromethyl)benzonitrile (29.0 g, 116 mmol, 72.3% yield) as a white solid.

[0389] 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).

[0390] Step B: Under nitrogen atmosphere, to 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) in toluene (250 mL) solution was added Pd(PPh 3 ) 4 (6.70 g, 5.80 mmol, 0.05 equiv) and the mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to 25° C., diluted with water (500 mL) and ethyl acetate (200 mL), and potassium fluoride (50.0 g) solid was finally added. The mixture was stirred at 25° C. for 30 minutes, then the organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=20 / 1 to 5 / 1) to give a crude product. The crude product was triturated by petroleum ether (50.0 mL), filtered, and the filtrate was concentrated under reduced pressure to give 3-(1-ethoxyvinyl)-2-(trifluoromethyl)benzonitrile (8.00 g, 33.2 mmol, 23.0 % yield) as a light yellow oil.

[0391] 1H NMR (400MHz, CDCl3) δ = 7.82 (d, J = 7.2Hz, 1H), 7.70 (d, J = 7.2Hz, 1H), 7.65-7.59 (t, J = 7.6Hz, 1 H), 4.37 (d, J = 2.8Hz, 1H), 4.25 (d, J = 2.8Hz, 1H), 3.90 (q, J = 7.2Hz, 2H), 1.36 (t, J = 6.8Hz, 3H).

[0392] Step C: To a solution of 3-(1-ethoxyvinyl)-2-(trifluoromethyl)benzonitrile (7.00 g, 29.0 mmol, 1.00 equiv) in tetrahydrofuran (10.0 mL), hydrochloric acid (2.00 M, 29.0 mL, 2.00 equiv) was added, and the reaction mixture was stirred at 20 ° C for 2 hours. The pH of the mixture was then adjusted to pH=8 with aqueous sodium bicarbonate solution, and further diluted with water (100 mL). The resulting solution was extracted with ethyl acetate (50.0 mL×3), and the combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=20 / 1 to 5 / 1) to give 3-acetyl-2-(trifluoromethyl)benzonitrile (5.30 g, 24.8 mmol, 85.6% yield) as a colorless oil.

[0393] 1 H NMR (400MHz, DMSO-d6) δ = 8.25 (dd, J = 0.8, 7.6Hz, 1H), 8.07-7.94 (m, 2H), 2.60 (s, 3H).

[0394] Step D: To a solution of 3-acetyl-2-(trifluoromethyl)benzonitrile (1.00 g, 4.69 mmol, 1.00 equiv) and (R)-2-methylpropane-2-sulfinamide (625 mg, 5.16 mmol, 1.10 equiv) in tetrahydrofuran (2.00 mL) was added 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 the reaction mixture was stirred at 80° C. for 16 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL) and poured into a mixture of diatomaceous earth (20.0 g) and saturated sodium bicarbonate (10.0 g) in water (100 mL). The mixture is stirred, then filtered, and the filter cake is stirred and filtered with ethyl acetate (30.0mL), and the process is repeated three times until the product filter cake is washed off. The filtrate combined is separated, and the aqueous phase is extracted with ethyl acetate (100mL). The combined organic layer is washed with brine (50.0mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (ethyl acetate / petroleum ether, 0-30%) to obtain (R)-N-(1-(3-cyano-2-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (950mg, 2.99mmol, 63.7% yield, 99.5% purity), which is a light yellow oil. LCMS[M+1] + :317.1.

[0395] 1 H NMR (400MHz, 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).

[0396] Step E: To 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 sodium borohydride (610 mg, 16.0 mmol, 3.00 equiv) in portions at 0°C under nitrogen atmosphere. After the addition was complete, the mixture was stirred at this temperature for 30 minutes, then warmed to 25°C and stirred for an additional 3 hours. The mixture was then diluted dropwise with saturated aqueous ammonium chloride solution (100 mL) under nitrogen atmosphere at 25°C, and then extracted with ethyl acetate (150 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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, diastereoisomer mixture) as a white solid. LCMS [M+1] + :319.1.

[0397] 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. Afterwards, a white precipitate formed and the suspension was filtered. The filter cake was collected and dried under vacuum 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.

[0398] 1 H NMR (400MHz, DMSO-d6) δ = 8.84 (s, 3H), 8.38 (br d, J = 8.0Hz, 1H), 8.19 (d, J = 7.6Hz, 1H), 8.12-7.95 (m, 1H), 4.64 (br d, J=6.0Hz, 1H), 1.56 (d, J=6.4Hz, 3H).

[0399] 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.) in dimethyl sulfoxide (1.50 mL) was degassed and purged with nitrogen (3 times), and then the mixture was stirred at 130° C. under nitrogen atmosphere for 1 hour. The mixture was then cooled to 25° C. and ethyl acetate (60.0 mL) was added, and the organic solution was washed with brine (30.0 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The 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.

[0400] 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, 10 um); mobile phase: phase A: (0.1% NH4OH) in MeOH, phase B: CO2; B%: 20%-20%] to give the first eluting 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.

[0401] 1 H NMR (400MHz, CD3OD) δ = 9.24 (d, J = 0.8Hz, 1H), 8.46 (d, J = 0.8Hz, 1H), 8.05 (d, J = 8.4Hz, 1H), 7.80 (d,J=7.2Hz,1H),7.71-7.57(m,1H),5.74(q,J=6.8Hz,1H),2.74(s,3H),1.68(d,J=6.8Hz,3H).

[0402] Intermediate AF

[0403]

[0404] Step A: To a solution of 4-fluoro-3-nitro-5-(trifluoromethyl)benzoic acid (2.00 g, 7.90 mmol, 1.00 equiv) in tetrahydrofuran (15.0 mL) was added palladium on carbon (7.90 mmol, 10% purity, 1.00 equiv) under nitrogen atmosphere, and the mixture was stirred for 2 hours at 25° C. under hydrogen atmosphere (15 Psi). The mixture was then filtered and concentrated under reduced pressure to give compound 3-amino-4-fluoro-5-(trifluoromethyl)benzoic acid (1.60 g, 7.17 mmol, 90.8% yield) as a white solid.

[0405] 1 H NMR (400MHz, DMSO-d6) δ = 7.68-7.64 (m, 1H), 7.32-7.29 (m, 1H), 5.95-5.89 (m, 2H).

[0406] Step B: To 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 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 the mixture was stirred at 25° C. for 12 hours. The mixture was diluted with water (50.0 mL), 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 residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 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.

[0407] 1 H NMR (400MHz, CDCl3) δ = 7.38-7.34 (m, 2H), 3.57 (s, 3H), 3.36 (s, 3H)

[0408] 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) was 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 hours. The reaction mixture was diluted with water (50.0 mL), 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 residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 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.

[0409] 1 H NMR (400MHz, 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).

[0410] Step D: To 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) in tetrahydrofuran (20.0 mL) was added methylmagnesium bromide solution (3.00 M, 3.86 mL, 3.00 equiv) at 0°C, and the mixture was stirred at 0°C for 12 hours. 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 residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give compound tert-butyl (5-acetyl-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.10 g, 3.42 mmol, 88.7% yield) as a yellow oil.

[0411] 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).

[0412] Step E: To 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-methylpropane-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 hours. The mixture was then diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL×3). The organic layer merged is washed with salt water (50.0mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Residue is passed through column chromatography (petroleum ether / ethyl acetate=10 / 1 to 3 / 1) purifying, obtain compound (R)-(5-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)t-butylcarbamate (1.00g, 2.36mmol, 90.1% yield), is yellow oil.

[0413] 1 H NMR (400MHz, CDCl3) δ = 8.86 (d, J = 6.4Hz, 1H), 7.82 (d, J = 6.0Hz, 1H), 6.85 (s, 1H), 2.79 (s, 3H), 1.54 (s, 9H), 1.33 (s, 9H).

[0414] Step F: To a solution of (R)-tert-butyl(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 the mixture was stirred at 0°C for 2 hours. 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 to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 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.

[0415] 1H NMR (400MHz, CDCl3) δ = 8.34 (d, J = 6.4Hz, 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).

[0416] 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 hydrochloride (4.00 M in 1,4-dioxane, 5.00 mL, 13.76 equiv) and the mixture was stirred at 25 °C for 1 hour. The mixture was then concentrated under reduced pressure to give compound (R)-5-(1-aminoethyl)-2-fluoro-3-(trifluoromethyl)aniline (280 mg, 1.24 mmol, 85.5% yield, 98.6% purity, HCl salt) as a yellow oil. The compound was used directly without further purification.

[0417] Intermediate AG

[0418]

[0419] Step A: DIBAL-H (1.0 M, 65.5 mL, 3.00 eq.) was added dropwise to a solution of methyl 4,6-dichloropicolinate (4.50 g, 21.8 mmol, 1.00 eq.) in dichloromethane (40.0 mL) at -78 °C over 10 minutes, and the reaction mixture was stirred at -78 °C for 2 hours. The mixture was then diluted dropwise with water (2.50 mL) at 0 °C under a nitrogen atmosphere, followed by the addition of 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 give a suspension, and the suspension was filtered and the filtrate was concentrated under reduced pressure. The 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.

[0420] 1 H NMR (400MHz, DMSO-d6) δ = 7.65 (s, 1H), 7.52 (s, 1H), 5.69 (t, J = 6.0Hz, 1H), 4.53 (d, J = 6.0Hz, 2H).

[0421] Step B: At 0 ° C, to a solution of (4,6-dichloropyridin-2-yl)methanol (2.40g, 13.5mmol, 1.00 equivalent) in dichloromethane (20.0mL), Dess-Martin periodinane (11.4g, 27.0mmol, 8.35mL, 2.00 equivalent) was added in batches, and the mixture was stirred at 20 ° C for 2 hours. The mixture was then poured into water (10.0mL) and stirred for 15 minutes, then saturated aqueous sodium thiosulfate solution (20.0mL) was slowly added, and the mixture was stirred for another 15 minutes. The suspension was filtered, the layers were separated, and the aqueous phase was extracted with DCM (20.0mL×2). The combined organic layer was washed with brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , 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.

[0422] 1 H NMR (400MHz, DMSO-d6) δ = 9.87 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H).

[0423] Step C: Diethylaminosulfur trifluoride (2.01 g, 12.5 mmol, 1.65 mL, 2.00 equiv) was added dropwise to a solution of 4,6-dichloropyridinecarboxaldehyde (1.10 g, 6.25 mmol, 1.00 equiv) in dichloromethane (10.0 mL) at -20 ° C, and the mixture was stirred at 25 ° C for 1 hour. The mixture was then slowly poured into a saturated aqueous sodium bicarbonate solution (10.0 mL) at 25 ° C, and the resulting solution was extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were washed with brine (5.00 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , 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.

[0424] 1 H NMR (400MHz, CD3OD) δ = 7.75 (s, 1H), 7.74 (s, 1H), 6.82-6.55 (m, 1H).

[0425] Step D: Under nitrogen atmosphere, 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 (PPh 3 ) 2 Cl 2 (390 mg, 556 μmol, 0.10 equiv), and the mixture was stirred at 110° C. for 12 hours. The reaction mixture was cooled to 25° C. and slowly poured into a saturated aqueous potassium fluoride solution (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 residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 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, which was used directly in the next step.

[0426] 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 aqueous hydrochloric acid (2.00 M, 4.28 mL, 2.00 equiv) at 20°C, and the mixture was stirred at 20°C for 1 hour. The pH of the mixture was then adjusted to pH=8 by the addition of saturated sodium bicarbonate (15.0 mL), and extracted with ethyl acetate (30.0 mL×2). The combined organic phases were washed with brine (10.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 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.

[0427] 1 H NMR (400MHz, CD3OD) δ = 8.10-8.16 (m, 1H), 7.95 (d, J = 1.6Hz, 1H), 6.67-6.95 (m, 1H), 2.69 (s, 3H).

[0428] 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) under nitrogen atmosphere were added cesium carbonate (2.69 g, 8.27 mmol, 2.00 equiv), XPhos (394 mg, 827 μmol, 0.20 equiv) and palladium acetate (92.8 mg, 413 μmol, 0.10 equiv), and the mixture was stirred at 90 °C for 2 hours. The mixture was then cooled to 25° C. and concentrated under reduced pressure, and the residue was purified by column chromatography (SiO 2 , 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.

[0429] Step F: To 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-methylpropane-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 hours. The mixture was then cooled to 25° C. and poured into water (5.00 mL), the suspension was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give (S)-tert-butyl(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.

[0430] 1 H NMR (400MHz, CD3OD) δ = 8.30 (s, 1H), 7.94 (d, J = 1.6Hz, 1H), 6.52-6.82 (m, 1H), 2.81 (s, 3H), 1.54 (s, 9H), 1.35 (s, 9H).

[0431] Step G: To a solution of (S)-tert-butyl(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 lithium tri-sec-butylborohydride (1.0 M, 976 mg, 5.14 mmol, 1.12 mL, 2.00 equiv) dropwise at 0°C, and the mixture was stirred at 0-20°C for 1 hour. The mixture was poured into saturated aqueous ammonium chloride solution (15.0 mL) and stirred for 10 minutes, then extracted with ethyl acetate (15.0 mL×3). The combined organic phases were washed with brine (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 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, 89.5% purity) as a white solid.

[0432] 1 H NMR (400MHz, CD3OD) δ = 7.70 (s, 1H), 7.61 (d, J = 2.0Hz, 1H), 6.41-6.77 (m, 1H), 4.55 (q, J = 6.8Hz, 1H), 1.58 (d, J = 6.8Hz, 3H), 1.53 (s, 9H), 1.23 (s, 9H).

[0433] SFC: Column: Chiralcel OD-3 50×4.6mm ID, 3um mobile phase: phase A is CO2, phase B is MeOH (0.05% DEA); gradient elution: MeOH (0.05% DEA), in CO2, 5%-40%, flow rate: 3mL / min; detector: PDA, column temperature: 35°C; back pressure: 100Bar.

[0434] 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) in hydrochloric acid / dioxane (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 which was used directly in the next step without purification. LCMS [M+1]+ :288.2.

[0435] 1 H NMR (400MHz, CD3OD) δ = 7.74 (s, 1H), 7.65 (d, J = 1.6Hz, 1H), 6.82-6.51 (m, 1H), 4.60-4.45 (m, 2H), 1.61 (d, J = 6.8Hz, 3H), 1.54 (s, 9H).

[0436] Intermediate AH

[0437]

[0438] Step A: Under nitrogen atmosphere, to a solution of 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) was added titanium tetraisopropoxide (3.73 g, 13.1 mmol, 3.88 mL, 2.00 equiv), and the mixture was stirred at 70° C. under nitrogen atmosphere for 12 hours. The reaction mixture was cooled to 25° C. and poured into water (40.0 mL), and a suspension was obtained after stirring for 10 minutes. The suspension was filtered and the obtained 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 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-sulfenamide (1.50 g, 5.87 mmol, 89.4% yield) as a yellow solid. LCMS [M+1] + :256.2.

[0439] 1 H NMR (400MHz, DMSO-d6) δ = 7.46 (br t, J = 6.8Hz, 1H), 7.30-7.24 (m, 1H), 7.09-7.04 (m, 1H), 2.76 (br d, J=2.8Hz, 3H), 2.31 (d, J=2.4Hz, 3H), 1.31 (s, 9H).

[0440] Step B: To 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 tri-sec-butylborohydride lithium (1.0 M, 11.7 mmol, 11.8 mL, 2.00 equiv) at -78°C under a nitrogen atmosphere, and the mixture was stirred at -78°C for 2 hours. The reaction mixture was slowly poured into water (10.0 mL) and stirred for 10 minutes, 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 residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give (S)-N-(1-(2-fluoro-3-methylphenyl)ethyl)-2-methylpropane-2-sulfenamide (900 mg, 3.50 mmol, 59.5% yield) as a yellow oil. LCMS [M+1] + :258.4.

[0441] 1 H NMR (400MHz, DMSO-d6) δ = 7.16 (t, J = 7.6Hz, 1H), 7.13-7.08 (m, 1H), 7.04-6.99 (m, 1H ), 4.85 (q, J = 6.8Hz, 1H), 2.28 (d, J = 2.0Hz, 3H), 1.58 (d, J = 6.8Hz, 3H), 1.20 (s, 9H).

[0442] 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 in 1,4-dioxane, 5.00 mL, 5.72 equiv) under nitrogen atmosphere, and the mixture was stirred at 20° C. for 1 hour. The mixture was concentrated to give 1-(2-fluoro-3-methylphenyl)ethan-1-amine (390 mg, crude, hydrochloride) as a yellow solid which was used directly without further purification.

[0443] At 130 ° C, under a nitrogen atmosphere, a solution of 1-(2-fluoro-3-methylphenyl)ethyl-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.) in dimethyl sulfoxide (5.00 mL) was stirred for 1 hour. 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 residue was purified by preparative HPLC [column: Welch Xtimate C18 150×25mm×5um; mobile phase: phase A: water (0.05% HCl), 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.

[0444] 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 (250 mm×30 mm, 10 um); mobile phase: phase A: 0.1% NH4OH in MeOH, phase B: CO2; B%: 30%-30%] to give (R)-7-chloro-N-(1-(2-fluoro-3-methylphenyl)ethyl)-4-methylpyrido[3,4-d]pyridazin-1-amine as the first eluting isomer (80.0 mg, 0.24 mmol, 40.0% yield) as a yellow solid.

[0445] The following examples are intended to illustrate further certain embodiments of the present invention but are not intended to limit the scope of the present invention.

[0446] Example 12-1

[0447] (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

[0448]

[0449] Step A: To a solution of 7-chloro-4-methylpyrido[3,4-d]pyridazin-1(2H)-one (5.00 g, 25.6 mmol, 1.00 equiv) in POCl3 (137 g, 893 mmol, 83.0 mL, 34.9 equiv) was added N,N-diisopropylethylamine (9.91 g, 76.7 mmol, 13.4 mL, 3 equiv) dropwise at 25°C, and the reaction was stirred at 110°C for 2 hours. Afterwards, the mixture was cooled to 25°C and concentrated under vacuum to give a residue, which was diluted with ethyl acetate (300 mL) at 0°C and adjusted to pH=7 by slowly adding saturated aqueous sodium bicarbonate. The combined organic phases were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (4.10 g, 19.2 mmol, 74.9% yield) as a pink solid.

[0450] 1 H NMR (400MHz, DMSO-d6) δ = 9.65 (s, 1H), 8.22 (s, 1H), 3.02 (s, 3H).

[0451] Step B: To 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 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). The mixture was stirred at 130 °C for 12 hours, then cooled to room temperature and water (20.0 mL) was added. The mixture was extracted with ethyl acetate (10.0 mL x 3), and the combined organic layers were washed with brine (5.00 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The 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.

[0452] Step C: A mixture of (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) in dioxane (1.00 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 80° C. under nitrogen atmosphere for 10 hours. The reaction mixture was quenched at 20° C. by the addition of water (15.0 mL), and then extracted with ethyl acetate (5.00 mL×3). The combined organic layers were washed with brine (5.00 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 um; mobile phase: phase A: water (0.04% HCl), 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 light yellow solid. LCMS [M+1] + :511.1.

[0453] 1 H NMR (400MHz, 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, 1 H),7.25(s,1H),5.63(quintet,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).

[0454] Example 12-2

[0455] 7-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-4-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazin-1-amine

[0456]

[0457] To a solution of (R)-7-chloro-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazin-1-amine (50.0 mg, 131 μmol, 1.00 equiv) and 6-oxa-3-azabicyclo[3.1.1]heptane (35.6 mg, 263 μmol, 2.00 equiv, HCl) in dioxane (2.00 mL) was added cesium carbonate (171 mg, 525 μmol, 4.00 equiv), RuPhos (6.10 mg, 13.1 μmol, 0.10 equiv) and Pd2(dba)3 (6.00 mg, 6.60 μmol, 0.05 equiv) under nitrogen atmosphere. The mixture was stirred at 110° C. for 2 hours, then cooled to 25° C., filtered, and the filtrate was quenched with water (10.0 mL), then extracted with ethyl acetate (30.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters XbridgeBEH C18 100×25 mm×5 um; mobile phase: phase A: water (10 mM NH4HCO3), phase B: acetonitrile; gradient: B%: 30%-60%) to give 7-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-4-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazin-1-amine (8.64 mg, 18.9 μmol, 14.4% yield) as a yellow solid. LCMS [M+1] + :444.1.

[0458] 1 H NMR (400MHz, DMSO-d6) δ=9.03(s,1H),7.74(d,J=7.6Hz,1H),7.57(s,1H),7.52(d,J=8.0Hz,1H),7.31(t,J=8.0Hz,1H),7.27(s,1H),5.66(t,J=7.2 Hz,1H),4.80(d,J=6.4Hz,2H),3.91-3.90(m,2H),3.75-3.68(m,2H),3.2 3-3.16(m,1H),2.57(s,6H),1.95(d,J=9.2Hz,1H),1.55(d,J=7.2Hz,3H).

[0459] SFC conditions: Chiralcel OD-3 3μm, 0.46cm id×5cm L; mobile phase: A is SFC CO2 and B is MeOH (0.05% isopropylamine); gradient: B in A, 10% to 40% in 3 minutes; flow rate: 4.0mL / min; column temperature: 35℃; wavelength: 220nm; system back pressure: 100Bar.

[0460] Following the teachings of General Reaction Scheme III and the procedures described in Preparative Examples 12-1 and 12-2, the compounds of Example 12-10 shown in Table 1 below were prepared.

[0461] Table 1

[0462]

[0463]

[0464] The fumarate salt of MRTX-0902 is prepared by reacting MRTX-0902 with fumaric acid in the presence of a solvent.

[0465] The maleate salt of MRTX-0902 can be prepared using similar techniques, for example, by reacting MRTX-0902 with maleic acid in the presence of a solvent.

[0466] Example A

[0467] This example demonstrates that exemplary compounds of the invention bind to SOS1 and prevent the labeled tracer ligand from occupying the SOS1 binding site.

[0468] The ability of the provided compounds to bind to SOS1 was measured using an HTRF displacement assay. Recombinant human SOS1 polypeptide (corresponding to amino acids 560-1049, expressed in E. coli, with an N-terminal His-TEV-AviTag-SOS1 (MW = 59.4 kDa)) and lanthanide-labeled streptavidin (CisBio) were incubated with exemplary provided compounds (in 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 consisting of a custom-made Cy5-labeled tracer and Mab anti-6HIS Tb cryptate Gold (Cisbio 61HI2TLA) in buffer was added to the solution containing the SOS1 polypeptide and the exemplary provided compounds. After incubation for 1 hour at room temperature, the HTRF signal was measured using a Clairostar plate reader (BMG Labtech) according to the manufacturer's instructions. An excitation filter EX-TR was used and emission 1 was detected at 650-610 nm and emission 2 was detected at 620-610 nm. The HTRF ratio was calculated using the following formula: [emission 1 / emission 2]*10000.

[0469] Background signal was calculated from wells with 10 μM inhibitor (known to inhibit 100% at this concentration). The signal after background subtraction was converted to % binding relative to DMSO control. The competitive binding data were analyzed using Morrison's equation using XLFIT software (IDBS) and the Ki of the provided compounds was generated.

[0470] For Example 12-10, K i (nM) is 1.78.

[0471] Thus, exemplary compounds of the present invention effectively inhibit the binding of SOS1-labeled tracers to SOS1 protein.

[0472] Example B

[0473] This example demonstrates that exemplary compounds of the present invention prevent KRas-mediated GTP nucleotide exchange mediated by SOS1 to inhibit KRas activity, thereby inhibiting the production of the downstream effector pERK.

[0474] MKN1 cells (15,000 / w) or H358 (30,000 / w) were seeded in black transparent flat-bottom 96-well cell culture plates (Corning, #3904) and incubated at 37°C overnight. On the first day of the assay, the cells were administered with a 10 μM starting concentration of the compound of the invention, and serially diluted 3×, for a total of 9 concentrations. The cells were incubated at 37°C with the compound dissolved in DMSO for about 0.5-1 hour. Cells were immediately fixed by adding 50 μL 4% formaldehyde to all wells in a fume hood, and the plates were incubated at room temperature for 20 minutes. Formaldehyde was discarded from the culture plate, and 150 μL ice-cold methanol was added to permeabilize the cells at -20°C for 10 minutes. Methanol was discarded from each plate, and any liquid remaining in the plate was patted on a paper towel by patting the plate. The cells were then blocked with 150 μL of Odyssey blocking buffer (LI-COR Biosciences #927-50010) using 0.05% Tween for 1 hour at room temperature on a shaker. 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 plate was incubated overnight at 4°C on a shaker.

[0475] On the second day of the assay, the primary antibody solution was removed. Each plate was washed 3 times with 150 μL 1×PBST (PBS+0.1% Tween 20) and incubated with 50 μL secondary antibodies: anti-rabbit (LI-COR Biosciences#926-32211) and anti-mouse (LI-CORBiosciences#68070) were diluted 1:800 in Odyssey blocking buffer containing Tween and incubated on a oscillator for 2 hours at room temperature (protected from light). The secondary antibody solution was removed and each plate was washed 3 times with PBST. Any remaining liquid was discarded and the plate was imaged using the Licor Odyssey machine according to the manufacturer's instructions, using a set focal length of 3 mm and 800 nm and 700 nm filters. The GAPDH standardized scan value of each well was divided by the average value of the carrier well to obtain pERK inhibition%. IC was then calculated using Graph pad Prism software 50 value.

[0476] IC of Example 12-10 50 (nM) is 46.

[0477] This result indicates that the compound of the present invention can effectively inhibit the activation and formation of pERK mediated by KRas, thereby blocking the intracellular KRas-mediated signal transduction.

[0478] Example C

[0479] Preparation of MRTX0902 fumarate

[0480]

[0481] A 500 L reactor was charged with (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile [7.85 kg, 20.2 mol, 1.0 equiv] and EtOH [86.4 L]. The suspension was heated to 75 °C. Crystallization seed material for the final product [39.5 g] was added. A prepared solution of fumaric acid [2.40 kg, 20.2 mol, 1.0 equiv] in 95% aqueous ethanol [52.2 L] was then added dropwise. Crystallization was observed after addition of the fumaric acid solution, and stirring was continued at 75 °C for 2 hours after the addition was complete. Over a period of 4 hours, the reaction mixture was cooled to 20 °C and stirring was continued at the same temperature for 4 hours. The suspension was filtered and the collected solids were rinsed with EtOH [23.6 L]. The wet cake was then dried at 50° C. under vacuum to give 8.93 kg of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile fumarate in 97% yield.

[0482] Mp: 253.2-253.3℃.

[0483] 1 H NMR(400MHz, DMSO-d6)δ9.01(s,1H),7.71(dd,J=7.9,1.4Hz,1H),7.64-7.55(m,2H),7.42(s,1H),7.32(t,J=7.8Hz,1 H), 6.61 (s, 2H), 5.51 (s, 1H), 3.80-3.74 (m, 4H), 3.73-3.66 (m, 4H), 2.65 (s, 3H), 2.56 (s, 3H), 1.54 (d, J = 7.0Hz, 3H).

[0484] 13 C NMR(101MHz,DMSO-d6)δ16.7,17.7,21.4,45.0,46.7,65.8,93.2,112.3,113.8,118.5 ,124.9,127.0,129.2,130.8,134.1,138.7,145.8,147.2,149.3,150.8,159.5,166.2.

[0485] For C 22 H25 N6O, HRMS (ESI) calculated value: 389.2085 [M+H] + , measured value: 389.2085.

[0486] Although the present invention has been described in conjunction with specific embodiments thereof, it will be understood that it is capable of further modification, and this application is intended to cover any changes, uses or adaptations of the invention which generally follow the principles of the invention, and include those which are known or customary in the art to which the invention pertains, and which may be applied to the basic features set forth above, as well as departures from the present disclosure which fall within the scope of the claims appended hereto.

Claims

1. A compound selected from:

2. The compound according to claim 1, wherein the compound is 3. The compound according to claim 1, wherein the compound is 4. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

5. A method for inhibiting SOS1 activity in a cell, comprising contacting a cell in which SOS1 activity needs to be inhibited with an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 4.

6. The method of claim 5, wherein the cell has an activating mutation in a RAS family member gene.

7. The method of claim 5, wherein the cell has an activating mutation in the SOS1 gene.

8. The method of claim 5, wherein the cell has an activating mutation in the NF-1 or NF-2 gene.

9. A method for treating cancer, comprising administering to a patient suffering from cancer a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent.

10. The method of claim 9, wherein the therapeutically effective amount of the compound is about 0.01 to 300 mg / kg per day.

11. The method of claim 10, wherein the therapeutically effective amount of the compound is about 0.1 to 100 mg / kg per day.

12. The method of claim 9, wherein the cancer is selected from the group consisting of cardiac: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchial cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilage hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma ), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Gynecology: uterus (endometrial carcinoma (serous cell carcinoma), endometrial carcinoma, cerebral infarction ... =Fluid cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecoma cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); Hematology: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: neuroblastoma.

13. The method of claim 9, wherein the cancer is a Ras family-related cancer.

14. The method of claim 13, wherein the Ras family-related cancer is a Kras, HRas or NRas G12C-related cancer, a KRas, HRas or NRas G12D-related cancer, a KRas, HRas or NRas G12S-related cancer, a KRas, HRas or NRas G12A-related cancer, a KRas, HRas or NRas G13D-related cancer, a KRas, HRas or NRas G13C-related cancer, a KRas, HRas or NRas Q61X-related cancer, a KRas, HRas or NRas A146T-related cancer, a KRas, HRas or NRasA146V-related cancer or a KRas, HRas or NRas A146P-related cancer.

15. The method of claim 14, wherein the Ras family-related cancer is a KRas G12C-related cancer.

16. The method of claim 15, wherein the Ras family-related cancer is non-small cell lung cancer or pancreatic cancer.

17. The method of claim 9, wherein the cancer is a SOS1-associated cancer.

18. The method of claim 17, wherein the SOS1-related cancer is a SOS1 N233S-related cancer or a SOS1 N233Y-related cancer.

19. The method of claim 17, wherein the SOS1-associated cancer is lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, or cutaneous granular cell tumor.

20. The method of claim 9, wherein the cancer is a NF-1 / NF-2 related cancer.

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