SOS1 inhibitors

Abstract

The present invention relates to a compound that inhibits the activity of a homolog 1 (Son of seveness homog 1, SOS1) without a seven of the seven. Specifically, the invention relates to a compound, a pharmaceutical composition and application of the compound, for example, the application of the compound and the pharmaceutical composition in preparation of medicines for treating cancers.

Description

[0001] This invention is a divisional application of Chinese invention patent application 202080097272.1, filed on December 18, 2020, entitled "SOS1 Inhibitor". Technical Field

[0002] The present invention relates to compounds that inhibit GTP-mediated nucleotide exchange of Son of sevenless homolog 1 (SOS1). Specifically, the present invention relates to compounds, pharmaceutical compositions comprising the compounds, and methods of use thereof. Background Art

[0003] The Ras family includes v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma Ras viral oncogene homolog (NRAS), and Harvey rat 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): 17-33; Matikas et al., Crit Rev Oncol-Hemol, 2017, 110: 1-12). RAS proteins are activated by upstream signals including receptor tyrosine kinases (RTKs) and transduce signals to several downstream signaling pathways, such as the mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) pathway. Overactivation of RAS signaling is often observed in cancer due to mutations or alterations in RAS genes or other genes in the RAS pathway. Research on strategies to inhibit RAS and RAS signaling is expected to aid in the treatment of cancer and RAS-regulated disease states.

[0004] RAS proteins are guanosine triphosphatases (GTPases) that cycle between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state. Son of no seven homolog 1 (SOS1) is a guanine nucleotide exchange factor (GEF) that mediates the exchange of GDP for GTP, thereby activating RAS proteins. RAS proteins hydrolyze GTP to GDP through their intrinsic GTPase activity, and GTPase activity is greatly enhanced by GTPase activating proteins (GAPs). This regulation by GAPs and GEFs is a mechanism that strictly regulates activation and inactivation under normal conditions. Mutations in several residues in all three RAS proteins are frequently observed in cancer, and these mutations cause RAS to remain primarily in an activated state (Sanchez-Vega et al., Cell, 2018, 173: 321-337; Li et al., Nature Reviews Cancer, 2018, 18: 767-777). Mutations at codons 12 and 13, the most common RAS residue mutations, prevent GAP-stimulated GTP hydrolysis by blocking the interaction between 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. Consequently, 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 identified in mammalian cells are SOS, RAS-GRF, and RAS-GRP (Rojas, 2011). RAS-GRF and RAS-GRP are expressed in cells of the central nervous system and hematopoietic cells, respectively, while the SOS family is ubiquitously expressed and responsible for RTK signaling. The SOS family includes SOS1 and SOS2, proteins that share approximately 70% sequence identity. Due to the rapid degradation of SOS2, SOS1 appears to be more active than SOS2. SOS2 knockout in mice is viable, whereas SOS1 knockout is embryonic lethal. A tamoxifen-induced SOS1 knockout mouse model was used to study the roles of SOS1 and SOS2 in adult mice and demonstrated that SOS1 knockout is viable, but SOS1 / 2 double knockout is not (Baltanas, 2013). This suggests functional redundancy and that selective inhibition of SOS1 may have sufficient therapeutic potential to treat diseases involving SOS1-RAS activation.

[0006] SOS protein is recruited to phosphorylated RTKs through interaction with growth factor receptor-binding protein 2 (GRB2). Recruitment to the plasma membrane brings SOS into close proximity with RAS and supports SOS-mediated RAS activation. SOS protein binds to RAS through binding sites that promote nucleotide exchange and through allosteric sites that bind to GTP-bound RAS family proteins and increase SOS function (Freedman et al., Proceedings of the National Academy of Sciences of the United States of America (Proc. Natl. Acad. Sci. USA), 2006, 103(45): p. 16692-97). Binding to the allosteric site relieves the spatial occlusion of the RAS substrate binding site and is therefore required 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 in the catalytic site remains in an isolated state. SOS1 mutations are found in Noonan syndrome and several cancers, including lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumors, and granular cell tumors of the skin (see Denayer, E. et al., Genes-Chromosomes-Cancer, 2010, 49(3): 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). While activating alterations of the GEF SOS1 occur in cancer, inactivating mutations and loss-of-function alterations in the GAPs neurofibromin 1 (NF-1) or neurofibromin 2 (NF-2) also occur, resulting in unchecked SOS1 activity and increased activity downstream through the RAS protein pathway.

[0008] Therefore, 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, thereby providing therapeutic benefits for a variety of cancers, particularly cancers associated with Ras family members. Compounds of the present invention offer potential therapeutic benefits as inhibitors of the SOS1-KRas interaction, which can be used to negatively regulate KRas activity by blocking the SOS1-KRas interaction in cells to treat various forms of cancer, including Ras-associated cancers, SOS1-associated cancers, and NF1 / NF2-associated cancers. Summary of the Invention

[0009] 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, thereby providing therapeutic benefits for a variety of cancers, particularly Ras-related cancers, SOS1-related cancers, and NF1 / NF2-related cancers.

[0010] In one aspect of the present invention, there is provided a compound represented by formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein:

[0013] 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, -C-heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl and the heteroaryl are each optionally substituted by one or more R 2 or L-R2 substitution;

[0014] Each Q is independently a bond, O or NR 6 ;

[0015] X is N or CR 7 ;

[0016] 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;

[0017] R 3 is hydrogen, C1-C6 alkyl, alkoxy, -N(R 10 )2、-LN(R 10 ) 2, cycloalkyl, haloalkyl or heterocyclic group, wherein the C1-C6 alkyl, the cycloalkyl and the heterocyclic group are each optionally substituted by one or more R9 replace;

[0018] Y is a bond or a heteroarylene group;

[0019] R 4 is aryl or heteroaryl, each optionally substituted by one or more R 5 replace;

[0020] 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;

[0021] L is C1-C3 alkylene;

[0022] Each R 6 are independently hydrogen, C1-C3 alkyl, haloalkyl or cycloalkyl;

[0023] R 7 is hydrogen, cyano or alkoxy;

[0024] R 8 is C1-C2 alkyl or halogenated C1-C2 alkyl;

[0025] Each R 9 are independently hydroxy, halogen, amino, cyano, alkoxy or C1-C3 alkyl;

[0026] Each R 10 are independently hydrogen, C1-C3 alkyl or cycloalkyl;

[0027] Each R 11 are independently C1-C3 alkyl, halogen or haloalkyl; and

[0028] R 12 is hydrogen, halogen or C1-C3 alkyl.

[0029] In another aspect of the present invention, a pharmaceutical composition is provided, comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0030] In another aspect, the present 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, comprising contacting the cell with a compound of formula (I). In one embodiment, the contact is performed in vitro. In one embodiment, the contact is performed in vivo.

[0031] 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 compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein.

[0032] Also provided herein are methods for treating cancer in an individual in need thereof, comprising: (a) determining that the cancer is associated with a Ras family member mutation (e.g., a KRasG12C-associated cancer) (e.g., using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0033] Also provided herein are methods for treating cancer in an individual in need thereof, 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, such as an FDA-approved assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0034] Also provided herein are methods for treating cancer in an individual in need thereof, comprising: (a) determining that the cancer is associated with a NF-1 or NF-2 loss-of-function mutation (e.g., an NF1 / NF2-associated cancer) (e.g., using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0035] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for inhibiting SOS1 activity.

[0036] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating an SOS1-associated disease or disorder. DETAILED DESCRIPTION

[0037] The present invention relates to SOS1 inhibitors. Specifically, the present invention relates to compounds that inhibit SOS1 activity, pharmaceutical compositions comprising therapeutically effective amounts of the compounds, and methods of use thereof.

[0038] definition

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference to the extent consistent with this disclosure. Unless expressly defined otherwise, terms and scopes have their general definitions.

[0040] For simplicity, chemical moieties are primarily defined and referred to as monovalent chemical moieties (e.g., alkyl, aryl, etc.) throughout the text. However, such terms may also be used to convey corresponding multivalent moieties in the context of appropriate structures that are clear to those skilled in the art. For example, although an "alkyl" moiety typically refers to a monovalent group (e.g., CH3-CH2-), in some cases, a divalent linking moiety may be an "alkyl," in which case a person skilled in the art will understand that an alkyl group is a divalent group (e.g., -CH2-CH2-), equivalent to the term "alkylene." (Similarly, where a divalent moiety is required and the divalent moiety is stated as "aryl," a person skilled in the art will understand that the term "aryl" refers to the corresponding divalent moiety, i.e., arylene.) All atoms are understood to have normal bond-forming valences (i.e., carbon is 4-valent, nitrogen is 3-valent, oxygen is 2-valent, and sulfur is 2, 4, or 6-valent, depending on the oxidation state of S).

[0041] As used herein, "KRas G12C" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly12Cys.

[0042] As used herein, "KRas G12D" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of aspartic acid instead of glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly12Asp.

[0043] As used herein, "KRas G12S" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of serine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly12Ser.

[0044] As used herein, "KRas G12A" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of alanine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly12Ala.

[0045] As used herein, "KRas G13D" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of aspartic acid instead of glycine at amino acid position 13. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly13Asp.

[0046] As used herein, "KRas G13C" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of cysteine ​​for glycine at amino acid position 13. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gly13Cys.

[0047] As used herein, "KRas Q61L" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of leucine for glutamine at amino acid position 41. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Gln61Leu.

[0048] As used herein, "KRas A146T" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of threonine instead of alanine at amino acid position 146. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Ala146Thr.

[0049] As used herein, "KRas A146V" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of valine instead of alanine at amino acid position 146. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Ala146Val.

[0050] As used herein, "KRas A146P" refers to a mutant form of the mammalian KRas protein containing an amino acid substitution of proline instead of alanine at amino acid position 146. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: variant p.Ala146Pro.

[0051] 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 assignment of amino acid codons and residue positions for human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: variant p.Gly12Cys.

[0052] As used herein, "HRas G12D" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of aspartic acid instead of glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: variant p.Gly12Asp.

[0053] 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 assignment of amino acid codons and residue positions for human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: variant p.Gly12Ser.

[0054] 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 assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: variant p.Gly12Ala.

[0055] As used herein, "HRas G13D" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of aspartic acid instead of glycine at amino acid position 13. The assignment of amino acid codons and residue positions for human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: variant p.Gly13Asp.

[0056] 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 assignment of amino acid codons and residue positions for human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: 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 41. The assignment of amino acid codons and residue positions for human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: variant p.Gln61Leu.

[0058] As used herein, "HRas A146T" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of threonine instead of alanine at amino acid position 146. The assignment of amino acid codons and residue positions for human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: variant p.Ala146Thr.

[0059] As used herein, "HRas A146V" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of valine instead of alanine at amino acid position 146. The assignment of amino acid codons and residue positions for human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: variant p.Ala146Val.

[0060] As used herein, "HRas A146P" refers to a mutant form of the mammalian HRas protein containing an amino acid substitution of proline instead of alanine at amino acid position 146. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: variant p.Ala146Pro.

[0061] As used herein, "NRas G12C" refers to a mutant form of the mammalian NRas protein containing an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: variant p.Gly12Cys.

[0062] As used herein, "NRas G12D" refers to a mutant form of the mammalian NRas protein containing an amino acid substitution of aspartic acid instead of glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: variant p.Gly12Asp.

[0063] As used herein, "NRas G12S" refers to a mutant form of the mammalian NRas protein containing an amino acid substitution of serine instead of glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: variant p.Gly12Ser.

[0064] 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 assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: variant p.Gly12Ala.

[0065] As used herein, "NRas G13D" refers to a mutant form of the mammalian NRas protein containing an amino acid substitution of aspartic acid instead of glycine at amino acid position 13. The assignment of amino acid codons and residue positions for human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: variant p.Gly13Asp.

[0066] As used herein, "HNRas G13C" refers to a mutant form of the mammalian NRas protein containing an amino acid substitution of cysteine ​​for glycine at amino acid position 13. The assignment of amino acid codons and residue positions for human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: variant p.Gly13Cys.

[0067] 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 41. The assignment of amino acid codons and residue positions for human HRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01112: variant p.Gln61Leu.

[0068] As used herein, "NRas A146T" refers to a mutant form of the mammalian NRas protein containing an amino acid substitution of threonine instead of alanine at amino acid position 146. The assignment of amino acid codons and residue positions for human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: variant p.Ala146Thr.

[0069] As used herein, "NRas A146V" refers to a mutant form of the mammalian NRas protein containing an amino acid substitution of valine instead of alanine at amino acid position 146. The assignment of amino acid codons and residue positions for human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: variant p.Ala146Val.

[0070] As used herein, "NRas A146P" refers to a mutant form of the mammalian NRas protein containing an amino acid substitution of proline instead of alanine at amino acid position 146. The assignment of amino acid codons and residue positions for human NRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01111: variant p.Ala146Pro.

[0071] As used herein, "Ras family member" or "Ras family" refers to KRas, HRas, NRas, and activating mutants thereof, comprising positions G12, G13, Q61, and A146.

[0072] As used herein, "Ras family-related disease or condition" refers to a disease or condition that is associated with, mediated by, or has an activating Ras mutation, such as a mutation at position G12, G13, Q61, or A146. Non-limiting examples of Ras family-related diseases or conditions 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 NRas G12A-related cancers, KRas, HRas, or NRas G13D-related cancers, KRas, HRas, or NRas G13C-related cancers, KRas, HRas, or NRas Q61X-related cancers, KRas, HRas, or NRas A146T-related cancers, KRas, HRas, or NRas A146V-related cancers, or KRas, HRas, or NRas A146P-related cancers.

[0073] As used herein, "SOS1" refers to the mammalian soleus homolog 1 (SOS1) enzyme.

[0074] 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.

[0075] As used herein, "SOS1 N233S" refers to a mutant form of the mammalian SOS1 protein containing an amino acid substitution of serine for glutamine at amino acid position 233. The assignment of amino acid codons and residue positions for human SOS1 is based on the amino acid sequence identified by UniProtKB / Swiss-Prot Q07889: variant p.Gln233Ser.

[0076] As used herein, "SOS1 N233Y" refers to a mutant form of the mammalian SOS1 protein containing an amino acid substitution of tyrosine for glutamine at amino acid position 233. The assignment of amino acid codons and residue positions for human SOS1 is based on the amino acid sequence identified by UniProtKB / Swiss-Prot Q07889: variant p.Gln233Tyr.

[0077] As used herein, "SOS1 inhibitors" refer to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively inhibiting all or part of the interaction of SOS1 with Ras family mutants or SOS1 activating mutations, thereby reducing and / or modulating the nucleotide exchange activity of the Ras family member-SOS1 complex.

[0078] As used herein, "NF-1 / NF-2 related disease or disorder" refers to a disease or disorder associated with, mediated by, or having a loss-of-function mutation in the neurofibromin (NF-1) gene or the neurofibromin 2 (NF-2) gene.

[0079] 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 or frameshift mutation, including insertions and deletions, and homozygous deletions of a gene encoding a protein in a target cell or cancer cell, which homozygous deletion results in partial or complete loss of the presence, activity and / or function of the encoded protein.

[0080] The term "amino" refers to -NH2.

[0081] The term "acetyl" refers to "-C(O)CH3".

[0082] The term "acyl," as used herein, refers to an alkylcarbonyl or arylcarbonyl substituent, wherein the alkyl and aryl portions are as defined herein.

[0083] As used herein, the term "alkyl" refers to straight and branched chain aliphatic groups having from 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.

[0084] As used herein, the term "alkenyl" refers to an unsaturated straight or branched chain aliphatic group having 2 to 12 carbon atoms and containing 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.

[0085] As used herein, the term "alkynyl" refers to an unsaturated straight or branched chain aliphatic group having 2 to 12 carbon atoms and containing 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.

[0086] "Alkylene," "alkenylene," or "alkynylene" is an alkyl, alkenyl, or alkynyl group as defined above that is positioned between and serves to link 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.

[0087] The term "alkoxy" refers to an -OC1-C6 alkyl group.

[0088] As used herein, the term "cycloalkyl" is a saturated and partially unsaturated cyclic hydrocarbon radical having from 3 to 12 carbon atoms. Thus, "cycloalkyl" includes C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 and C 12Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0089] The term "heteroalkyl" refers to an alkyl group as defined above wherein one or more carbon atoms in the chain are independently replaced by O, S or NR x Substituted, where R x is hydrogen or C1-C3 alkyl. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl and methoxypropyl.

[0090] "Aryl" is a C6-C 14 Aromatic moiety. Therefore, "aryl" includes C6, C 10 、C 13 and C 14 Cycloalkyl. Exemplary aryl is C6-C 10 Aryl. Specific aryl groups include, but are 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.

[0091] "Aralkyl" or "arylalkyl" includes an aryl group covalently linked to an alkyl group, wherein the moiety is linked to another group via the alkyl moiety. Exemplary aralkyl groups are -(C1-C6)alkyl(C6-C10)aryl, including but not limited to benzyl, phenethyl, and naphthylmethyl.

[0092] A "heterocyclyl" or "heterocyclic" group 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 12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 atoms), e.g., 4 to 8 atoms, in which one or more ring atoms is independently -C(O)-, N, NR 4 , O, S or S (O) 2, the remaining ring atoms are quaternary carbon or carbonyl carbon. Examples of heterocyclic groups include, but are not limited to, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrophenylthio, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thianyl, dithianyl, trithianyl, azathienyl, oxathienyl, dioxolanyl, oxazolidinyl, oxazolidinone, decahydroquinolinyl, piperidone, 4-piperidone, thiomorpholinyl, dimethyl-morpholinyl and morpholinyl.

[0093] As used herein, "heterocyclyl" refers to a heterocyclic group covalently linked to another group via a bond.

[0094] As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 10, 13 or 14 ring atoms; having 6, 10 or 14 shared pi electrons in a cyclic array, which may contain 1, 2 or 3 rings; and having, in addition to carbon atoms, 1 to 3 heteroatoms, 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 a N, O or S ring atom.

[0095] Examples of heteroaryl groups include acridinyl, azcinyl, 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, benzopyranyl, cinnoline, yl, furyl, furazolyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolene, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenantholinyl, phenanthiazinyl, phenanthiothiazinyl, phenanthioxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl , tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthanyl.

[0096] "Heteroaralkyl" or "heteroarylalkyl" includes a heteroaryl group covalently attached to another group via a bond. Examples of heteroalkyl groups include C1-C6 alkyl and heteroaryl groups with 5, 6, 9 or 10 ring atoms. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethylquinazolinylmethyl, quinolylmethyl, quinolylethyl, benzofuranylmethyl, indolinylethylisoquinolylmethyl, isoindolylmethyl, cinnolinylmethyl and benzothienylethyl. Particularly excluded from the scope of this term are compounds with adjacent ring O and / or S atoms.

[0097] "Arylene," "heteroarylene," or "heterocyclylene" is a divalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined above, positioned between and serving to link two other chemical groups.

[0098] 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 1 to 4, preferably 1 to 3, more preferably 1 or 2 non-hydrogen substituents.

[0099] As used herein, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0100] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen. Exemplary haloalkyl groups are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0101] The term "hydroxyalkyl" refers to an -alkylene-OH group.

[0102] As used herein, the terms "subject," "individual," or "patient" used interchangeably 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 subject has experienced and / or exhibits at least one symptom of the disease or condition to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a KRas G12 or G13 mutation (e.g., as determined using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit). In some embodiments, the subject 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., as determined using an assay or kit approved by a regulatory agency). The subject can be a subject having 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., identified as positive using an assay or kit approved by a regulatory agency, such as an FDA-approved assay or kit). The subject can be a subject 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., wherein the tumor is identified as such using a kit or assay approved by a regulatory agency, such as an FDA-approved kit or assay). In some embodiments, the subject is suspected of having a KRas G12 or G13 gene-related cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a KRas G12C mutation (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0103] As used herein, the term "pediatric patient" refers to a patient under the age of 16 at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years); children (two to 12 years); and adolescents (12 to 21 years (up to but not including the twenty-second 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.

[0104] As used herein, an "effective amount" of a compound is an amount sufficient to down-regulate or inhibit SOS1 enzyme activity.

[0105] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to improve or in some way alleviate symptoms or stop or reverse disease progression or downregulate or inhibit SOS1 activity. Said amount can be administered in a single dose or according to a regimen, whereby it is effective.

[0106] As used herein, "treating" refers to any manner in which the symptoms or pathology of a patient's condition, disorder, or disease are ameliorated or otherwise beneficially altered.

[0107] As used herein, "amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition" refers to any relief, whether permanent or temporary, sustained or transient, attributable to or associated with the administration of the composition.

[0108] Compound

[0109] In one aspect of the present invention, there is provided a compound represented by formula (I):

[0110]

[0111] or a pharmaceutically acceptable salt thereof,

[0112] in:

[0113] R1 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, -C-heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl and the heteroaryl are each optionally substituted by one or more R 2 or LR 2 replace;

[0114] Each Q is independently a bond, O or NR 6 ;

[0115] X is N or CR 7 ;

[0116] 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;

[0117] R 3 is hydrogen, C1-C6 alkyl, alkoxy, -N(R 10 )2、-LN(R 10 ) 2, cycloalkyl, haloalkyl or heterocyclic group, wherein the C1-C6 alkyl, the cycloalkyl and the heterocyclic group are each optionally substituted by one or more R 9 replace;

[0118] Y is a bond or a heteroarylene group;

[0119] R 4 is aryl or heteroaryl, each optionally substituted by one or more R 5 replace;

[0120] 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;

[0121] L is C1-C3 alkylene;

[0122] Each R 6 are independently hydrogen, C1-C3 alkyl, haloalkyl or cycloalkyl;

[0123] R 7 is hydrogen, cyano or alkoxy;

[0124] R 8 is C1-C2 alkyl or halogenated C1-C2 alkyl;

[0125] Each R 9 are independently hydroxy, halogen, amino, cyano, alkoxy or C1-C3 alkyl;

[0126] Each R 10 are independently hydrogen, C1-C3 alkyl or cycloalkyl;

[0127] Each R 11 are independently C1-C3 alkyl, halogen or haloalkyl; and

[0128] R 12 is hydrogen, halogen or C1-C3 alkyl.

[0129] In one embodiment of the compound of formula (I), X is N. In certain embodiments wherein X is N, R 1 In one embodiment, the alkoxy group is methoxy.

[0130] In one embodiment of the compound of formula (I), X is N. In certain embodiments wherein X is N, R 1 is optionally replaced by one or more R 2 In certain embodiments, R 1 is -Q-heterocyclyl, and wherein Q is a bond, the heterocyclyl is optionally substituted by one or more R 2 In certain embodiments, the heterocyclyl group is morpholinyl or piperazinyl, Y is a bond, and R 4 is optionally replaced by one or more R 5 In one embodiment, the heterocyclic group is morpholinyl, piperazinyl or piperazinone, Y is heteroarylene, R 4 is optionally replaced by one or more R 5 Substituted aryl.

[0131] In certain embodiments of the present invention, R 1 is -Q-heterocyclyl, and wherein the heterocyclyl is a bridged morpholinyl, a bridged piperazinyl, or a bridged piperazinone.

[0132] In certain embodiments of the present invention, R 1 Is -Q-heterocyclyl, and wherein the heterocyclyl is a spirocyclic ring system containing two or more rings. In certain embodiments of these embodiments, the spirocyclic ring system includes two rings each containing a heteroatom. In certain other embodiments of these embodiments, the spirocyclic ring system contains a ring without a heteroatom (i.e., one ring has a heteroatom and one ring does not have a heteroatom).

[0133] In certain embodiments of the present invention, R 1 is a heteroaryl group, wherein the heterocyclic group is optionally substituted by one or more R 2 or LR 2 In certain of these embodiments, the heteroaryl group is a bicyclic or tricyclic ring system that includes non-aromatic rings in addition to one or more aromatic rings, such as a bicyclic or tricyclic ring system, such as 5,6,7,8-tetrahydro-[1,2,4]triazolopyrazinyl, 5,6,7,8-tetrahydroimidazopyrazinyl, 2,4,5,6-tetrahydropyrrolopyrazolyl, 1,2,3,4-tetrahydrobenzo[4,5]imidazopyrazinyl, or 4,5,6,7-tetrahydropyrazolopyrazinyl.

[0134] In one embodiment of the compounds of formula (I), X is CR 7 In one embodiment, when X is CR 7 When R 7 It's cyano.

[0135] In one embodiment of the compounds of formula (I), X is CR 7 In one embodiment, when X is CR 7 When R 7 It's hydrogen.

[0136] In one embodiment of the compounds of formula (I), X is CR 7 , R 7 is hydrogen, R 1 In another embodiment, R 1 In certain embodiments, R 1 Yes-N(R 6 )2. In one embodiment, wherein R 1 Yes-N(R 6 )2, and each R 6 In one embodiment, each C1-C3 alkyl group is methyl. In other embodiments, R 1 Yes-NR 6 C(O)R 6In one embodiment, each C1-C3 alkyl group is methyl. In one embodiment, the NR 6 R in 6 is hydrogen, and the C(O)R 6 R in 6 It is a C1-C3 alkyl group.

[0137] In another embodiment, when X is CR 7 And R 7 When it is hydrogen, R 1 Yes-C(O)N(R 6 )2. In one embodiment, each C1-C3 alkyl group is methyl. In one embodiment, each C1-C3 alkyl group is hydrogen. In certain embodiments, R 1 is -SO2alkyl or -SO2NR 6 In one embodiment, R1 is -SO2NR 6 Alkyl, and R 6 is hydrogen. In other embodiments, R 1 is optionally replaced by one or more R 2 In one embodiment, the cycloalkyl group is cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with one or more R 2 In one embodiment, the cyclobutyl, cyclopentyl or cyclohexyl is replaced by one R 2 Substituted, where R 2 is C1-C3 alkyl, alkoxy, hydroxy or -N(R 6 )2. In one embodiment, R 2 Yes-N(R 6 )2, and each R 6 In one embodiment, each C1-C3 alkyl group is methyl.

[0138] In another embodiment, when X is CR 7 And R 7 When it is hydrogen, R 1 is optionally replaced by one or more R 2 In one embodiment, Q is a bond and the heterocyclyl is morpholinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, piperazinone, 1-methyl-piperazin-2-one, diazepanyl, 6,6-difluoro-1,4-diazepan-1-yl or 4-methylthiomorpholine 1,1-dioxide. In another embodiment, Q is a bond and the heterocyclyl is pyrrolidinyl or tetrahydropyranyl, each optionally substituted by one or more R 2 In one embodiment, the pyrrolidinyl or tetrahydropyranyl is replaced by one R 2Substituted, where R 2 is C1-C3 alkyl, alkoxy, hydroxy or -N(R 6 )2.

[0139] In another embodiment, when X is CR 7 And R 7 When it is hydrogen, R 1 is -Q-heterocyclyl, Q is a bond, and the heterocyclyl is separated by an R 2 Substituted piperazinyl, wherein R 2 is optionally replaced by one or more R 11 In one embodiment, the heteroaryl group is substituted by two R 11 Substituted pyrazolyl, wherein each R 11 It is a C1-C3 alkyl group.

[0140] In another embodiment, when X is CR 7 And R 7 When it is hydrogen, R 1 is -Q-heterocyclyl, Q is a bond, and the heterocyclyl is separated by an R 2 Substituted piperazinyl, wherein R 2 is -C(O)cycloalkyl or -C(O)heterocyclyl, wherein the cycloalkylheterocyclyl portion of said -C(O)cycloalkyl or -C(O)heterocyclyl is each optionally substituted by one or more R 11 In one embodiment, R 2 is -C(O)cycloalkyl, and the cycloalkyl is supported by one R 11 Substituted cyclopropyl, wherein R 11 is C1-C3 alkyl or haloalkyl. In one embodiment, R 2 is -C(O)heterocyclyl, wherein the heterocyclyl is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.

[0141] In one embodiment, Q is a bond, and the heterocyclyl is a bicyclic heterocyclyl. In certain embodiments, the bicyclic heterocyclyl is diazabicyclo[3.2.0]hept-2-yl, (1R,5R)-2,6-diazabicyclo[3.2.0]hept-2-yl, diazabicyclo[3.2.0]hept-6-yl, (1R,5R)-2,6-diazabicyclo[3.2.0]hept-6-yl, 6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl, 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl, 1,3-dimethyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl, or (R)-2-methylhexahydropyrrolo[1,2-a]pyrazin-6(2H)-one.

[0142] In yet another embodiment, Q is O, and the heterocyclyl is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, or piperidinyl.

[0143] In another embodiment, when X is CR 7 And R 7 When it is hydrogen, R 1 is optionally replaced by one or more R 2 In one embodiment, the aryl group is optionally substituted with one or more R 2 In certain embodiments, the phenyl group is replaced by one R 2 Substituted, where R 2 is C1-C3 alkyl, alkoxy, hydroxy or -N(R 6 )2. In one embodiment, R 2 Yes-N(R 6 )2, and each R 6 In one embodiment, each C1-C3 alkyl group is methyl. In other embodiments, R 1 is optionally replaced by one or more R 2 In one embodiment, the heteroaryl group is optionally substituted with one or more R 2 In one embodiment, the pyrazolyl group is replaced by one R 2 Substituted, where R 2 is C1-C3 alkyl, alkoxy, hydroxy or -N(R 6 )2. In one embodiment, R 2 Yes-N(R 6 )2, and each R 6 In one embodiment, each C1-C3 alkyl group is methyl.

[0144] In one embodiment of the compounds of formula (I), X is CR 7 , and R 7 is alkoxy. In one embodiment, the alkoxy is methoxy. Wherein X is CR 7 And R 7 In certain embodiments where R is alkoxy, 1 In one embodiment, the R 7 The alkoxy group is a methoxy group, and the R 1 Alkoxy is methoxy.

[0145] In which X is N or CR 7 In certain embodiments of the compound of formula (I), Y is heteroarylene. In one embodiment, the heteroarylene is thienylene.

[0146] In which X is N or CR 7 In certain embodiments of the compound of Formula (I), Y is a bond.

[0147] In certain embodiments of the compound of formula (I), R 4 is aryl or heteroaryl, each optionally substituted by one or more R 5 In one embodiment, R 4 is optionally replaced by one or more R 5 In one embodiment, the aryl group is optionally substituted with one or more R 5 In certain embodiments, the phenyl group is replaced by one R 5 Substituted, where R 5 is C1-C4 alkyl, haloalkyl or -LN(R 6 )2.

[0148] In one embodiment, R 5 Yes-LN(R 6 )2, wherein L is methylene, and one R 6 It is hydrogen, the second R 6 In one embodiment, the C1-C3 alkyl group is methyl. In another embodiment, R 5 Yes-LN(R 6 )2, wherein L is methylene, and each R 6 In one embodiment, each of said C1-C3 alkyl groups is a methyl group.

[0149] In which R 4 In certain embodiments where R is aryl, 4 It is two R 5 Substituted phenyl, one of which R 5 is a C1-C4 alkyl group, and the second R 5 In one embodiment, the C1-C4 alkyl group is methyl, and the haloalkyl group is trifluoromethyl. In certain embodiments, R 4 It is two R 5 Substituted phenyl, one of which R 5 is a C1-C4 alkyl group, and the second R 5 Yes-LN(R 6 )2. In one embodiment, L is methylene, and each R 6 It is a C1-C3 alkyl group.

[0150] In one embodiment of the compounds of formula (I), R 3 It's hydrogen.

[0151] In certain embodiments of the compound of formula (I), R 3 is optionally replaced by one or more R 9 Substituted C1-C6 alkyl. In one embodiment, the C1-C6 alkyl is methyl, ethyl or isopropyl.

[0152] In certain embodiments of the compound of formula (I), R 3 In one embodiment, the alkoxy group is methoxy.

[0153] In certain embodiments of the compound of formula (I), R 3 In one embodiment, the haloalkyl group is trifluoromethyl.

[0154] In certain embodiments of the compound of formula (I), R 3 is optionally replaced by one or more R 9 In one embodiment, the cycloalkyl group is cyclopropyl. In one embodiment, the cycloalkyl group is replaced by one R 9 substituted, wherein one R 9 is halogen, amino, hydroxy or alkoxy.

[0155] In certain embodiments of the compound of formula (I), R 3 Yes-N(R 10 )2. In one embodiment, each R 10 In certain embodiments, each C1-C3 alkyl group is methyl.

[0156] In certain embodiments of the compound of formula (I), R 3 Yes-LN(R 10 )2. In one embodiment, each R 10 In certain embodiments, each C1-C3 alkyl group is methyl.

[0157] In certain embodiments of the compound of formula (I), R 3 is a heterocyclic group, an aryl group or a heteroaryl group, wherein the heterocyclic group, the aryl group and the heteroaryl group are each optionally substituted by one or more R 9 replace.

[0158] In certain embodiments of the compound of formula (I), R 8 In one embodiment, the C1-C2 alkyl group is methyl.

[0159] In certain embodiments of the compound of formula (I), R 8In one embodiment, the halo-substituted C1-C2 alkyl group is fluoromethyl, difluoromethyl or trifluoromethyl.

[0160] In one embodiment, the compound of formula (I) is:

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180] and pharmaceutically acceptable salts of the above compounds.

[0181] The compounds of formula (I) can be formulated into pharmaceutical compositions.

[0182] Pharmaceutical composition

[0183] In another aspect, the present invention provides a pharmaceutical composition comprising an SOS1 inhibitor according to the present invention and a pharmaceutically acceptable carrier, excipient, or diluent. The compounds of the present invention can be formulated by any method well 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 administration. In certain embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In certain other embodiments, administration may be preferably by the oral route.

[0184] The carrier characteristics will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic material that is compatible with biological systems such as cells, cell cultures, tissues or organisms and does not interfere with the effectiveness of the biological activity of one or more active ingredients. Therefore, the compositions according to the present invention may also contain diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials well known in the art, in addition to containing inhibitors. The preparation of pharmaceutically acceptable formulations is described in, for example, Remington's Pharmaceutical Sciences, 18th edition, editor A. Gennaro, Mack Publishing Co., Easton, Pa., Easton, Pennsylvania, in 1990.

[0185] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compound identified above 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 (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid). The compounds can also be administered in the form of pharmaceutically acceptable quaternary salts known to those skilled in the art, specifically including 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, tosylate, methanesulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzoate, and diphenylacetate).

[0186] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing serious toxic effects in the treated patient. For all of the above conditions, the dosage range of the active compound is based on the body weight of the recipient, about 0.01 to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, more generally 0.5 to about 25 mg / kg per day. The typical local dose range in a suitable carrier will be 0.01-3% wt / wt. The effective dose 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 as above using the weight of the derivative or by other means known to those skilled in the art.

[0187] Pharmaceutical compositions comprising compounds of the invention are useful in the methods described herein.

[0188] How to use

[0189] In another aspect, the present invention provides a method for inhibiting SOS1 activity in cells, comprising contacting cells in which SOS1 activity needs to be inhibited in vitro with an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof.

[0190] The compositions and methods provided herein are believed to be particularly useful for inhibiting SOS1 activity in cells. In one embodiment, cells in which SOS1 activity is to be inhibited are contacted in vivo with a therapeutically effective amount of a compound of Formula (I) to negatively regulate SOS1 activity. In other embodiments, a therapeutically effective amount of a pharmaceutically acceptable salt or pharmaceutical composition containing a compound of Formula (I) may be used. In one embodiment, the cells contain an activating mutation in a Ras family member, such as KRas, HRA, or NRas. In one embodiment, the cells have aberrant SOS1 activity. In one embodiment, the aberrant SOS1 activity is the result of an activating SOS1 mutation. In one embodiment, the SOS1 activating mutation is an N233S or N233Y mutation. In one embodiment, the cells have aberrant NF-1 or NF-2 activity. In one embodiment, the aberrant NF-1 or NF-2 activity is the result of an activating NF-1 or NF-2 mutation.

[0191] By negatively regulating SOS1 activity, the method is designed to block the interaction between SOS1 and Ras family members, increase the GTP loading of the Ras protein, thereby reducing or inhibiting GTP nucleotide exchange, and locking the Ras family members in a GDP-bound, inactive form, thereby inhibiting downstream Ras-mediated signaling. Cells can be exposed to a single dose or multiple doses, depending on the specific treatment regimen, to achieve the desired negative regulation of SOS1.

[0192] In another aspect, a method for treating cancer is provided, comprising administering to a patient suffering from cancer a therapeutically effective amount of a compound of formula (I), 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-associated cancer. In one embodiment, the cancer is an SOS-1-associated cancer. In one embodiment, the cancer is an NF-1 / NF-2-associated cancer.

[0193] The compositions and methods provided herein can be used to treat a wide variety of cancers, including tumors, such as prostate tumors, breast tumors, brain tumors, skin tumors, 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, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: 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's sarcoma), Genitourinary tract: Kidney (adenocarcinoma, Wilm's 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, adenomatous tumor, lipoma); Liver: Liver cancer (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 sarcoma), malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondrofibroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, blastomas (pinealomas), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecology: Uterus (endometrial cancer), Cervix (cervical cancer, preneoplastic cervical atypia), Ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecoma, 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 (embryonic rhabdomyosarcoma)), Fallopian tube (carcinoma); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease disease), non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0194] In one embodiment, the cancer is a Ras family-associated cancer, such as a KRas, NRas, or HRas-associated cancer. In certain embodiments, the Ras family-associated cancer is non-small cell lung cancer or pancreatic cancer. In one embodiment, the cancer is an SOS1-associated cancer. In certain embodiments, the SOS1-associated cancer is a lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and granular cell tumor of the skin. In one embodiment, the cancer is an NF-1-associated cancer.

[0195] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions comprising such compounds and salts can also be co-administered as pre- or post-operative adjuvants with other anti-tumor compounds, such as chemotherapy, or in combination with other therapeutic approaches such as radiation or surgical intervention.

[0196] General reaction schemes, intermediates and examples

[0197] General reaction scheme

[0198] 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.

[0199] For example, intermediates used to prepare compounds of the present invention and compounds of formula (I) can be prepared according to general reaction schemes I-VI:

[0200] General Reaction Scheme I

[0201]

[0202] For general reaction scheme I, compound 5 is an example of formula (I). In this general reaction scheme I, 1 is reacted with an amine such as intermediate 2, which can be a nucleophilic substitution or a metal catalyzed reaction, to produce compound 3. Compound 3 can then be reacted with, for example, a boronic acid derivative YR in the presence of a suitable base such as sodium carbonate. 3 The coupling partner of 4 undergoes a metal-catalyzed reaction to form the title compound 5.

[0203] General Reaction Scheme II

[0204]

[0205] For general reaction scheme II, compound 5 is an example of formula (I). In this general reaction scheme II, 6 is reacted with an amine such as intermediate 2, which can be a nucleophilic substitution or a metal catalyzed reaction, to produce compound 7. Compound 7 can then be reacted with, for example, a boronic acid derivative YR in the presence of a suitable base such as sodium carbonate. 1 The coupling partner of 8 undergoes a metal-catalyzed reaction to form the title compound 5.

[0206] General Reaction Scheme III

[0207]

[0208] For general reaction scheme III, compound 5 is an example of formula (I). In this general reaction scheme III, compound 7 can be reacted with, for example, an alcohol or an amine HR in the presence of a suitable base such as cesium carbonate. 1 The coupling partner of 9 undergoes metal-catalyzed reaction or nucleophilic substitution to form the title compound 5.

[0209] General Reaction Scheme IV

[0210]

[0211] For general reaction scheme IV, compound 5 is an example of formula (I). In this general reaction scheme IV, compound 10 is reacted with an amine such as intermediate 2, which can be a nucleophilic substitution or a metal catalyzed reaction to produce compound 5.

[0212] General Reaction Scheme V

[0213]

[0214] For general reaction scheme V, compound 5 is an example of formula (I). In this general reaction scheme V, 11 is reacted with an amine such as intermediate 2, which can be a nucleophilic substitution or a metal catalyzed reaction, to produce compound 12. Compound 12 can then be reacted with, for example, a boronic acid derivative YR in the presence of a suitable base such as sodium carbonate. 3 The coupling partner of 4 undergoes a metal catalyzed reaction to form compound 7. Compound 7 can then be reacted with, for example, a boronic acid derivative YR in the presence of a suitable base such as sodium carbonate. 1 The coupling partner of 8 undergoes a metal-catalyzed reaction to form the title compound 5.

[0215] General Reaction Scheme VI

[0216]

[0217] For general reaction scheme VI, compound 5 is an example of formula (I). In this general reaction scheme VI, compound 13 can be reacted with, for example, an alcohol, a halide, a tosylate or a mesylate salt XR in the presence of a suitable base or coupling partner such as cesium carbonate or diethyl azodicarboxylate. 1 The coupling partner of 14 undergoes a substitution reaction to form the title compound 5.

[0218] The following intermediates can be used to prepare the compounds of the present invention.

[0219] Intermediate A

[0220]

[0221] Step A: To a mixture of 1-(2-bromophenyl)-N-methylmethanamine (6.50 g, 32.5 mmol, 1 eq.) in THF (70.0 mL) was added dropwise Boc O (7.80 g, 35.7 mmol, 8.21 mL, 1.10 eq.) at 25° C., and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was directly concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO , petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to give tert-butyl (2-bromobenzyl)(methyl)carbamate (7.50 g, 25.0 mmol, 76.9% yield) as a colorless oil.

[0222] 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).

[0223] Step B: A mixture of tert-butyl (2-bromobenzyl)(methyl)carbamate (7.00 g, 23.3 mmol, 1.00 eq.), bis(pinacolato)diboron (8.88 g, 35.0 mmol, 1.50 eq.), Pd(dppf)Cl (1.71 g, 2.33 mmol, 0.10 eq.) and potassium acetate (5.72 g, 58.3 mmol, 2.50 eq.) in dioxane (80.0 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 110° C. under nitrogen atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which 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.

[0224] 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).

[0225] Intermediate B

[0226]

[0227] Step A: To a solution of 1-(4-bromothiophen-2-yl)ethan-1-one (4.00 g, 19.5 mmol, 1.10 eq.) and 2-methylpropane-2-sulfinamide (2.15 g, 17.7 mmol, 1.00 eq.) in THF (56.0 mL) was added Ti(OEt)4 (8.09 g, 35.5 mmol, 7.35 mL, 2.00 eq.). 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-bromothien-2-yl)ethylidene)-2-methylpropane-2-sulfenamide (3.00 g, 9.73 mmol, 54.9% yield) as a yellow solid.

[0228] 1H 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).

[0229] 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 eq.) in THF (40.0 mL) was added sodium borohydride (1.36 g, 36.0 mmol, 3.00 eq.) 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×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 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.

[0230] 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).

[0231] 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 eq.) 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 eq.) in dioxane (35.0 mL) and water (8.00 mL) was added Pd(PPh3)4 (1.12 g, 967 μmol, 0.10 eq.) and cesium carbonate (9.45 g, 29.01 mmol, 3.00 eq.) under a nitrogen atmosphere. The mixture was stirred at 110°C for 2 hours under a nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , 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.

[0232] 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 eq.) in THF (15.0 mL) and water (5.00 mL) was added iodine (232 mg, 1.46 mmol, 295 μL, 0.30 eq.). 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.

[0233] 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).

[0234] Intermediates C and D

[0235]

[0236] Step A: To a solution of 4-bromothiophene-2-carboxaldehyde (20.0 g, 104 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfinamide (12.1 g, 99.5 mmol, 0.95 eq.) in THF (200 mL) was added titanium (IV) ethoxide (47.8 g, 209 mmol, 43.4 mL, 2.00 eq.). The reaction mixture was stirred at 25 ° C for 1 hour. Then, the mixture was poured into water (20.0 mL) and stirred for 5 minutes to obtain a suspension. The suspension was filtered and the filtrate was concentrated in vacuo to obtain (R, E)-N-((4-bromothiophene-2-yl)methylene)-2-methylpropane-2-sulfinamide (20.0 g, crude product) as a yellow oil. LCMS[M+1]: 295.8.

[0237] Step B: To a solution of (R,E)-N-((4-bromothiophen-2-yl)methylene)-2-methylpropane-2-sulfinamide (600 mg, 2.04 mmol, 1.00 eq.) in THF (200 mL) was added methylmagnesium bromide (3.00 M, 2.04 mL, 3.00 eq.) dropwise at 0°C. The reaction mixture was then stirred at 25°C for 1 hour. Saturated aqueous ammonium chloride solution (3.00 mL) was added to the reaction mixture and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (3.00 mL x 2), and the combined organic phases were washed with brine (3.00 mL x 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 (first 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 (second elution, intermediate D) (150 mg, 483 μmol, 23.7% yield) as a yellow oil.

[0238] Intermediate product 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).

[0239] Intermediate product D: 1 H 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).

[0240] Intermediate E

[0241]

[0242] Step A: To a solution of (R)-N-((R)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfenamide (150 mg, 483 μmol, 1.00 eq.) and tert-butyl methyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (168 mg, 483 μmol, 1.00 eq.) in dioxane (1.00 mL) and water (0.20 mL) was added Pd(PPh3)4 (55.9 mg, 48.3 μmol, 0.10 eq) and cesium carbonate (473 mg, 1.45 mmol, 3.00 eq.) under nitrogen. The reaction mixture was stirred at 110°C for 2 hours under nitrogen, then stirred to 25°C and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO 2 , 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.

[0243] 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).

[0244] 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 eq.) in THF (1.00 mL) and water (0.20 mL) was added iodine (20.3 mg, 79.9 μmol, 16.1 μL, 0.30 eq.), 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 C18 75×30 mm×3 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 28%-38%) to give tert-butyl (R)-(2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (40.0 mg, 113 μmol, 42.3% yield, 97.5% purity) as a white oil.

[0245] 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).

[0246] Intermediate F

[0247]

[0248] Step A: To a solution of (R)-N-((S)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfenamide (100 mg, 322 μmol, 1.00 eq.) and tert-butyl methyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (112 mg, 322 μmol, 1.00 eq.) in dioxane (1.00 mL) and water (0.20 mL) was added Pd(PPh3)4 (37.2 mg, 32.2 μmol, 0.10 eq.) and cesium carbonate (315 mg, 967 u mmol, 3.00 eq.) 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 (SiO 2 , 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.

[0249] 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).

[0250] 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 eq.) in THF (1.00 mL) and water (0.20 mL) was added iodine (16.9 mg, 66.6 μmol, 13.4 μL, 0.30 eq.). The reaction mixture was stirred at 50° C. for 1 hour, then cooled to 25° C., poured into a 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 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 24%-54%) to give tert-butyl (S)-(2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (45.0 mg, 97.7 μmol, 44.0% yield, TFA salt) as a white oil. LCMS [M+1] = 347.2.

[0251] 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).

[0252] Intermediate G

[0253]

[0254] Step A: To a solution of 2-methyl-3-(trifluoromethyl)benzaldehyde (300 mg, 1.59 mmol, 1.00 eq.) and 2-methylpropane-2-sulfenamide (213 mg, 1.75 mmol, 1.10 eq.) in THF (5.00 mL) was added titanium(IV) ethoxide (727 mg, 3.19 mmol, 661 μL, 2.00 eq.). 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-sulfenamide (360 mg, 1.24 mmol, 77.5% yield) as a white solid.

[0255] 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).

[0256] Step B: To a solution of 2-methyl-N-(2-methyl-3-(trifluoromethyl)benzylidene)propane-2-sulfenamide (185 mg, 635 μmol, 1.00 eq.) in THF (5.00 mL) was added methylmagnesium bromide (227 mg, 3.00 M, 635 μL, 3.00 eq.) dropwise 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 layer and 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 (SiO 2 , 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.

[0257] 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).

[0258] C: A solution of 2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (150 mg, 488.0 μmol, 1.00 eq.) 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 afford 1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (45.0 mg, 38.5% yield) as a red solid. LCMS [M+1] = 204.3.

[0259] 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).

[0260] Intermediate H

[0261]

[0262] Step A: To a solution of 1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-one (8.00 g, 39.6 mmol, 1.00 eq.) and (S)-2-methylpropane-2-sulfenamide (5.28 g, 43.5 mmol, 1.10 eq.) in THF (80.0 mL) was added titanium (IV) ethoxide (18.1 g, 79.1 mmol, 16.4 mL, 2.00 eq.). The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was cooled to 25°C, 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 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 a residue. The residue was purified by column chromatography (SiO 2 , 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.

[0263] 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).

[0264] Step B: To a solution of S)-2-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfenamide (8.00 g, 26.2 mmol, 1.00 eq.) in THF (80.0 mL) was added lithium tri-sec-butylborohydride (7.47 g, 39.3 mmol, 8.59 mL, 1.50 eq.) 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 (SiO 2 , 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-sulfenamide (3.50 g, 11.4 mmol, 43.5% yield) as a yellow oil. LCMS [M+1]: 308.0.

[0265] 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).

[0266] 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 eq.) in HCl (4 M in dioxane, 15.0 mL) was stirred at 25° C. for 30 minutes. The reaction mixture was filtered and the filter cake was dried under vacuum to afford (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (700 mg, 2.89 mmol, 68.4% yield, 99.1% purity, hydrochloride) as a white solid. LCMS [M+H]: 204.0.

[0267] 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).

[0268] Intermediate I

[0269]

[0270] Step A: To a solution of 1-(5-bromothiophen-2-yl)ethan-1-one (11.0 g, 53.6 mmol, 1.00 eq.) in THF (120 mL) were added 2-methylpropane-2-sulfinamide (8.45 g, 69.7 mmol, 1.30 eq.) and titanium (IV) ethoxide (24.5 g, 107 mmol, 22.3 mL, 2.00 eq.), and the reaction mixture was stirred at 75° C. under a 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-bromothien-2-yl)ethylidene)-2-methylpropane-2-sulfenamide (16.0 g, crude) as a yellow solid. LCMS [M+1]: 308.0.

[0271] 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 eq.) in THF (150 mL) was added sodium borohydride (3.93 g, 104 mmol, 2.00 eq.) 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 (SiO 2 , petroleum ether / ethyl acetate = 30 / 1 to 2 / 1) to give N-(1-(5-bromothien-2-yl)ethyl)-2-methylpropane-2-sulfenamide (12.0 g, 38.7 mmol, 74.5% yield) as a yellow oil. LCMS [M+1]: 309.9.

[0272] Intermediate J

[0273]

[0274] Step A: To a solution of 1-(5-bromothiophen-2-yl)ethan-1-one (10.0 g, 48.8 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfinamide (7.68 g, 63.4 mmol, 1.30 eq.) in THF (120 mL) was added titanium (IV) ethoxide (22.3 g, 97.5 mmol, 20.2 mL, 2.00 eq.), and the reaction mixture was stirred at 70° C. under a 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 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-bromothien-2-yl)ethylidene)-2-methylpropane-2-sulfenamide (13.0 g, crude) as a brown oil. LCMS [M+1]: 308.2.

[0275] 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).

[0276] Step B: To a solution of (R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfenamide (13.0 g, 42.2 mmol, 1.00 eq.) in THF (150 mL) was added sodium borohydride (4.79 g, 127 mmol, 3.00 eq.) at 0°C. 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 x 3), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 30 / 1 to 2 / 1) to give (R)-N-((R)-1-(5-bromothien-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.

[0277] 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).

[0278] Step C: To a solution of (R)-N-((R)-1-(5-bromothien-2-yl)ethyl)-2-methylpropane-2-sulfenamide (2.00 g, 6.45 mmol, 1.00 eq.) 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 eq.) in dioxane (20.0 mL) and water (2.00 mL) was added cesium carbonate (6.30 g, 19.3 mmol, 3.00 eq.) and Pd(PPh3)4 (745 mg, 645 μmol, 0.10 eq.) under nitrogen atmosphere. The reaction mixture was stirred at 110°C for 2 hours under nitrogen atmosphere. The reaction mixture is then cooled to 25 DEG 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 give residue. The residue is purified by column chromatography (SiO2, petroleum ether / ethyl acetate=20 / 1 to 1 / 1) to give (2-(5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)thiophene-2-yl)benzyl) (methyl) tert-butyl carbamate (2.60g, 5.19mmol, 80.6% yield, 90.0% purity) as a yellow oil. LCMS[M+1]: 451.4.

[0279] 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).

[0280] 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 eq.) in THF (20.0 mL) and water (4.00 mL) was added iodine (439 mg, 1.73 mmol, 349 μL, 0.30 eq.) and the 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 (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give tert-butyl (R) -(R) -(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.

[0281] 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).

[0282] Intermediate K

[0283]

[0284] Procedure: To a solution of N-(1-(5-bromothien-2-yl)ethyl)-2-methylpropane-2-sulfenamide (0.50 g, 1.61 mmol, 1.00 eq.) 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 eq.) in dioxane (5.00 mL) and water (0.50 mL) was added cesium carbonate (1.58 g, 4.83 mmol, 3.00 eq.) and Pd(PPh3)4 (186 mg, 161 μmol, 0.10 eq.), followed by degassing and purging with nitrogen three times. The reaction mixture was stirred at 110°C under a nitrogen atmosphere for 2 hours. After completion, the reaction mixture is cooled to 25 DEG C, diluted with water (50.0mL) and extracted with ethyl acetate (20.0mL×3). The combined organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue is purified by column chromatography (SiO , 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 (450mg, 1.15mmol, 71.3% yield, 93.0% purity) as a brown oil. LCMS [M+1]: 365.2.

[0285] 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 eq.) in THF (4.00 mL) was added hydrochloric acid (3.00 M, 375 μL, 1.00 eq.) and the reaction mixture was stirred at 20° C. for 2 hours. Upon 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.

[0286] 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).

[0287] Intermediate product L

[0288]

[0289] Step A: AIBN (145 mg, 884 μmol, 0.10 eq.) and NBS (1.42 g, 7.96 mmol, 0.9 eq.) were added to a solution of 6-chlorofuran [3, 4-c] pyridine -1 (3H) -one (1.50 g, 8.85 mmol, 1.00 eq.) in carbon tetrachloride (10.0 mL). The reaction mixture was stirred for 12 hours at 80 ° C. The reactants were filtered and the filtrate was concentrated in vacuo 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-chlorofuran [3, 4-c] pyridine -1 (3H) -one (1.20 g, 4.83 mmol, 54.6% yield) as a yellow oil. LCMS [M + 3]: 249.8.

[0290] 1 H NMR (400MHz, CDCl3) δ = 8.84-8.80 (m, 1H), 7.84 (s, 1H), 7.47 (s, 1H).

[0291] Step B: To a solution of 3-bromo-6-chlorofuro[3,4-c]pyridin-1(3H)-one (1.20 g, 4.83 mmol, 1.00 eq.) in ethanol (20.0 mL) was added hydrazine hydrate (370 mg, 7.24 mmol, 359 μL, 1.50 eq.) at 0°C. 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, 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.

[0292] 1H NMR (400MHz, DMSO-d6) δ = 13.08 (br s, 1H), 9.20 (s, 1H), 8.53 (s, 1H), 8.10 (s, 1H).

[0293] Step C: To a solution of 7-chloropyrido [3,4-d] pyridazin-1-ol (78.0 mg, 430 μmol, 1.00 eq.) in acetonitrile (2.00 mL) was added phosphorus (V) oxychloride (231 mg, 1.50 mmol, 139 μL, 3.50 eq.) at 25 ° C. The reaction mixture was stirred at 80 ° C for 2 hours. The reactants were cooled at 25 ° C, poured into a 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 product) as a red solid. LCMS [M + 1]: 199.8.

[0294] Intermediate product M

[0295]

[0296] Step A: To a mixture of methyl 3,4-dimethoxybenzoate (10.0 g, 51.0 mmol, 1.00 eq.) in acetic acid (50.0 mL) was added a solution of bromine (8.96 g, 56.1 mmol, 2.89 mL, 1.10 eq.) in acetic acid (50.0 mL) at 0 ° C. over 1.5 hours. The mixture was then slowly warmed to room temperature and stirred for 45 minutes. Upon completion, the reactants were quenched by pouring into 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 was partially dried, dissolved in hot methanol (300 mL), and the resulting solution was cooled. The cooled methanol solution was treated with water (200 mL) to give a suspension, which was filtered and the filter cake was collected and dried under vacuum 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.

[0297] 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).

[0298] Step B: A mixture of methyl 2-bromo-4,5-dimethoxybenzoate (6.00 g, 21.8 mmol, 1.00 eq.), 1-(vinyloxy)butane (10.9 g, 109 mmol, 14.0 mL, 5.00 eq.), Pd(OAc)2 (490 mg, 2.18 mmol, 0.10 eq.), triphenylphosphine (1.14 g, 4.36 mmol, 0.20 eq.) and triethylamine (2.65 g, 26.2 mmol, 3.64 mL, 1.20 eq.) in acetonitrile (60.0 mL) was degassed and purged with nitrogen three times, and then the reaction mixture was 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.

[0299] Step C: A mixture of methyl 2-(1-butoxyvinyl)-4,5-dimethoxybenzoate (6.00 g, 20.4 mmol, 1.00 eq.) in hydrochloric acid (10% in water, 61.2 g, 168 mmol, 60.0 mL, 8.23 ​​eq.) 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 x 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 obtain 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.

[0300] 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).

[0301] Step D: To a solution of methyl 2-acetyl-4,5-dimethoxybenzoate (3.00 g, 12.6 mmol, 1.00 eq.) in ethanol (30.0 mL) was added hydrazine hydrate (2.22 g, 37.8 mmol, 2.16 mL, 3.00 eq.) at room temperature, and 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 yield a residue. The residue was triturated with ethyl acetate (50.0 mL) at 20°C for 20 minutes to yield a suspension. The suspension was filtered, and the filter cake was collected and dried under vacuum to yield 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.

[0302] 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).

[0303] Step E: A mixture of 6,7-dimethoxy-4-methylphthalazin-1(2H)-one (1.30 g, 5.90 mmol, 1.00 eq.) in phosphorus(V) oxychloride (13.0 mL) was stirred at 120° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to afford 1-chloro-6,7-dimethoxy-4-methylphthalazine (1.20 g, crude) as a yellow solid. LCMS [M+1]: 239.0.

[0304] 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).

[0305] Intermediate N

[0306]

[0307] Step A: To a solution of 1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-one (0.37 g, 1.99 mmol, 1.00 eq.) in tetrahydrofuran (10.0 mL) was added titanium (IV) ethoxide (2.27 g, 9.95 mmol, 2.06 mL, 5.00 eq.) and (R)-2-methylpropane-2-sulfenamide (724 mg, 5.97 mmol, 3.00 eq.). The mixture was stirred at 75° C. for 16 hours. The reaction mixture was quenched by the addition of 20.0 mL of saturated aqueous sodium bicarbonate at 25° C. The mixture was filtered, and the filtrate was extracted with 45.0 mL (15.0 mL×3) of ethyl acetate. The combined organic layers were washed with 20.0 mL (20.0 mL×1) of brine, 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.

[0308] 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).

[0309] Step B: To a solution of (R,E)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfenamide (340 mg, 1.18 mmol, 1.00 eq.) in tetrahydrofuran (5.00 mL) was added sodium borohydride (89.5 mg, 2.37 mmol, 2.00 eq.). The mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched by the addition of 10.0 mL of water at 25°C and then extracted with 30.0 mL (10.0 mL x 3) of ethyl acetate. The combined organic layers were washed with brine (10.0 mL x 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.

[0310] Step C: A mixture of (R)-N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (140 mg, 484 μmol, 1.00 eq.) in dioxane hydrochloride (4.00 M, 7.00 mL, 57.9 eq) 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.

[0311] Intermediate O

[0312]

[0313] Step A: To a solution of 3-bromo-2-methylbenzoic acid (100 g, 465 mmol, 1.00 eq.) and N,O-dimethylhydroxylamine hydrochloride (68.6 g, 512 mmol, 1.10 eq., HCl) in DMF (1000 mL) were added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (195 g, 512 mmol, 1.10 eq.) and N,N-diisopropylethylamine (180 g, 1.40 mol, 243 mL, 3.00 eq.). 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 x 3). The combined organic phase was 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.

[0314] Step B: To a solution of 3,3-bromo-N-methoxy-N,2-dimethylbenzamide (120 g, 465 mmol, 1.00 eq.) in THF (100 mL) was added methylmagnesium bromide (3.0 M, 180 mL, 1.16 eq.) at 0°C. The mixture was stirred between 0-40°C for 3 hours, then cooled to 0°C, hydrochloric acid (6.0 N) (450 mL) 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 (9000 mL). The aqueous phase was extracted with ethyl acetate (1500 mL × 3). The combined organic phases were washed with brine (1000 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 1-(3-bromo-2-methylphenyl)ethane-1-one (90.0 g, 422 mmol, 90.9% yield) as a yellow oil.

[0315] 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).

[0316] Step C: To a solution of 1-(3-bromo-2-methylphenyl)ethane-1-one (88.0 g, 413 mmol, 1.00 eq.) and (S)-2-methylpropane-2-sulfinamide (60.1 g, 496 mmol, 1.20 eq.) in THF (100 mL) was added titanium (IV) ethoxide (471 g, 2.07 mol, 428 mL, 5.00 eq.) and diethylene glycol dimethyl ether (55.4 g, 413 mmol, 59.1 mL, 1.00 eq.). 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.

[0317] 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).

[0318] Step D: To a solution of (S)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfenamide (109 g, 345 mmol, 1.00 eq.) in THF (1100 mL) was added lithium tri-sec-butylborohydride (1.0 M, 689 mL, 2.00 eq.) at -78°C. The mixture was stirred at -78°C for 2 hours, then poured into a saturated aqueous solution of ammonium chloride (1000 mL) and stirred at 25°C for 60 minutes. The aqueous phase was extracted with ethyl acetate (1000 mL x 3). The combined organic phases were washed with brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 2 / 1) to obtain 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.

[0319] Step E: A solution of (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfenamide (71.0 g, 223 mmol, 1.00 eq.) in HCl / dioxane solution (300 mL) and MeOH (300 mL) was stirred at 0° C. for 30 minutes. 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.

[0320] Step F: To a solution of (R)-1-(3-bromo-2-methylphenyl)ethane-1-amine (55.0 g, 220 mmol, 1.00 eq., HCl) and Boc2O (48.4 g, 222 mmol, 50.9 mL, 1.01 eq.) in dichloromethane (500 mL) was added N,N-diisopropylethylamine (56.7 g, 439 mmol, 76.5 mL, 2.00 eq.). The mixture was stirred between 0-25 ° C for 30 minutes and 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 a residue. The residue was further washed with petroleum ether to give tert-butyl (R)-(1-(3-bromo-2-methylphenyl)ethyl)carbamate (51.0 g, 162 mmol, 73.9% yield) as a white solid. LCMS[M-55] + :258.0.

[0321] 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).

[0322] Step G: To a solution of tert-butyl (R)-(1-(3-bromo-2-methylphenyl)ethyl)carbamate (51.0 g, 162 mmol, 1.00 eq.) in DMF (540 mL) was added zinc cyanide (22.9 g, 195 mmol, 12.4 mL, 1.20 eq.) and Pd(PPh3)4 (18.8 g, 16.2 mmol, 0.10 eq.). The mixture was stirred at 110°C for 3 hours, then cooled to 25°C and poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (1000 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , 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.

[0323] 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).

[0324] Step H: To a solution of (R)-tert-butyl (1-(3-cyano-2-methylphenyl)ethyl)carbamate (49.0 g, 188 mmol, 1.00 eq.) in dichloromethane (400 mL) was added TFA (133 mL). The mixture was stirred at 0°C for 30 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 in vacuo 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.

[0325] 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).

[0326] SFC conditions: column: Chiralpak IC-3 50×4.6 mm I.D., 3 μm mobile phase: CO2 as phase A, MeOH (0.05% DEA) as phase B; gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar.

[0327] Intermediate product P

[0328]

[0329] To a solution of (R)-3-(1-aminoethyl)-2-methylbenzonitrile (16.0 g, 99.9 mmol, 1.00 eq.) and 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (21.4 g, 99.9 mmol, 1.00 eq.) in DMSO (130 mL) was added cesium fluoride (22.8 g, 150 mmol, 5.52 mL, 1.50 eq.), 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 x 3). The combined organic phases were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: Kromasil Eternity XT 250 × 80 mm × 10 μm; 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 (1000 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 (R)-3-(1-((7-chloro-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (14.5 g, 42.9 mmol, 43.0% yield) as a yellow solid.

[0330] 1 H NMR (400MHz, CDCl3) δ = 9.19 (d, J = 0.4Hz, 1H), 7.74 (s, 1H), 7.63 (d, J = 8.0Hz, 1H), 7. 50(dd,J=1.2,7.6Hz,1H),7.23(t,J=7.6Hz,1H),5.72(quin,J=6.8Hz,1H),5.40(br d,J=6.0Hz,1H),2.86(s,3H),2.69(s,3H),1.63(s,3H).

[0331] Intermediate product Q

[0332]

[0333] To a solution of (R)-3-(1-aminoethyl)-2-methylbenzonitrile (5.32 g, 19.4 mmol, 1.00 eq., TFA) and 6-bromo-4-chloro-1-methylphthalazine (5.00 g, 19.4 mmol, 1.00 eq.) in DMSO (30.0 mL) were added cesium fluoride (5.90 g, 38.8 mmol, 1.43 mL, 2.00 eq.) and N,N-diisopropylethylamine (5.02 g, 38.8 mmol, 6.76 mL, 2.00 eq.), 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 (SiO 2 , 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.

[0334] Intermediate product R

[0335]

[0336] Step A: A mixture of (R)-2-methylpropane-2-sulfinamide (5.12 g, 42.2 mmol, 1.00 eq.), 1-(3-bromo-2-methylphenyl)ethane-1-one (9.00 g, 42.2 mmol, 1.00 eq.), titanium (IV) isopropoxide (60.0 g, 211 mmol, 62.3 mL, 5.00 eq.) 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 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 (SiO 2 , 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.

[0337] 1H NMR (400 MHz, CD3OD) δ = 7.67-7.58 (m, 2H), 7.28 (br d, J = 7.6 Hz, 1H), 7.17 (t, J = 8.0 Hz, 2H), 7.14-7.01 (m, 1H), 2.67 (s, 3H), 2.50 (br d, J = 4.0 Hz, 3H), 2.42 (s, 3H), 2.31 (br d, J = 17.2 Hz, 3H), 1.28 (s, 9H), 1.21 (br d, J = 11.2 Hz, 9H). The E / Z isomer ratio is approximately 1 / 1.

[0338] Step B: To a solution of (R)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfenamide (400 mg, 1.26 mmol, 1.00 eq.) in THF (5.00 mL) was added portionwise sodium borohydride (239 mg, 6.32 mmol, 5.00 eq.) 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 x 3), and the combined organic phases were washed with brine (150 mL x 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 = 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.

[0339] 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 eq.), sodium methanesulfinate (176 mg, 1.73 mmol, 2.20 eq.), potassium carbonate (326 mg, 2.36 mmol, 3.00 eq.) and L-proline (18.1 mg, 157 μmol, 0.20 eq.) in dimethyl sulfoxide (3.00 mL) was added copper (I) iodide (15.0 mg, 78.6 μmol, 0.10 eq.) at 20° C., and the mixture was stirred at 130° C. under a 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 phase was washed with brine (30.0 mL × 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.

[0340] 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).

[0341] 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 eq.) in hydrochloric acid (4.0 M in dioxane, 2.00 mL, 21.2 eq.) was stirred at 20° C. for 1 hour. 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.

[0342] Intermediate S

[0343]

[0344] Step A: To a solution of methylamine (100 g, 1.48 mol, 3.01 eq. HCl salt) in THF (1.00 L) were 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×2). The combined organic phases were washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 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.

[0345] Step B: To a solution of 1-(2-bromo-6-fluorophenyl)-N-methylmethanamine (120 g, 484 mmol, 88% purity, 1.00 eq.) in THF (1.00 L) was added di-tert-butyl dicarbonate (211 g, 968 mmol, 2.00 eq.), 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 (SiO , petroleum ether / ethyl acetate=1 / 0 to 100 / 1) to give tert-butyl N-[(2-bromo-6-fluoro-phenyl) methyl]-N-methyl-carbamate (70.0 g, 220 mmol) as a brown oil. LCMS[M-55]+: 261.9

[0346] 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).

[0347] Step C: To a solution of tert-butyl (2-bromo-6-fluorobenzyl)(methyl)carbamate (60.0 g, 189 mmol, 1.00 eq.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (60.0 g, 236 mmol, 1.25 eq.) in dioxane (600 mL) was added Pd(dppf)Cl2.CH2Cl2 (15.0 g, 18.4 mmol, 0.10 eq.) and potassium acetate (72.0 g, 734 mmol, 3.89 eq.). The reaction mixture was degassed with nitrogen (3 times) and stirred at 100°C under a nitrogen atmosphere for 12 hours. The mixture was cooled to 25°C and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , 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.

[0348] 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 eq.) and (R)-N-[(1R)-1-(5-bromo-2-thienyl)ethyl]-2-methyl-propane-2-sulfenamide (56.0 g, 180 mmol, 1.13 eq.) in dioxane (500 mL) and water (100 mL) were added cesium carbonate (150 g, 460 mmol, 2.88 eq.) and Pd(PPh3)4 (20.0 g, 17.3 mmol, 0.10 eq.) under nitrogen atmosphere and the mixture was stirred at 100°C for 3 hours under nitrogen atmosphere. The mixture was diluted with water (500 mL), extracted with ethyl acetate (1.00 L × 2), washed with brine (200 mL) for the organic phase, dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO , 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.

[0349] 1H NMR (400MHz, DMSO-d6) δ=7.44-7.36(m,1H),7.27-7.17(m,2H),7.08(br d,J=2.8Hz,1H),6.96(d,J=3.6Hz,1H),5.88(br d,J=6.8Hz,1H),4.65(quin,J=6.4Hz,1H),4.56(s,2H),2.48(s,3H),1.55(br d,J=6.8Hz,3H),1.33(br s,9H),1.13(s,9H).

[0350] 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 eq.) in THF (240 mL) and water (48.0 mL) was added iodine (6.80 g, 26.8 mmol, 0.19 eq.). The reaction was heated to 50° C. for 2 hours, then diluted with water (500 mL) and extracted with ethyl acetate (500 mL×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 (SiO 2 , dichloromethane / methanol = 300 / 1 to 10 / 1) to give tert-butyl (R)-(2-(5-(1-aminoethyl)thiophen-2-yl)-6-fluorobenzyl)(methyl)carbamate (40.0 g, 110 mmol) as a yellow oil. LCMS [M-16] + :348.1.

[0351] Intermediate product T

[0352]

[0353] Step A: To a mixture of 1-(benzyloxy)-3-bromo-5-(trifluoromethyl)benzene (3.00 g, 9.06 mmol, 1.00 eq.) and Pd(dppf)Cl2 (663 mg, 906 μmol, 0.10 eq.) in dioxane (50.0 mL) was added tributyl(1-ethoxyvinyl)tin (5.00 g, 13.8 mmol, 4.67 mL, 1.53 eq.) at 20° C., and the mixture was stirred at 80° C. for 12 hours under a nitrogen atmosphere. To this mixture was then added a saturated potassium fluoride solution (100 mL), and the solution was stirred at 20° C. for 1 hour. The mixture was extracted with ethyl acetate (100 mL x 3), and the combined organic phases were washed with brine (100 mL x 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. This crude oil was used in the next step without further purification.

[0354] Step B: To a solution of 1-(benzyloxy)-3-(1-ethoxyvinyl)-5-(trifluoromethyl)benzene (2.90 g, 9.00 mmol, crude, 1.00 eq.) in tetrahydrofuran (30.0 mL) was added hydrochloric acid (3.0 M in THF, 10.0 mL, 3.33 eq.) 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.

[0355] 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).

[0356] Step C: To a solution of 1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethane-1-one (2.60 g, 8.84 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfenamide (1.39 g, 11.5 mmol, 1.30 eq.) in tetrahydrofuran (40.0 mL) was added titanium (IV) ethoxide (5.02 g, 17.7 mmol, 5.22 mL, 2.00 eq.) under nitrogen atmosphere and the solution was stirred at 70°C for 12 hours. Then, the mixture was 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.

[0357] 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).

[0358] Step D: To a mixture of (R)-N-(1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfenamide (2.20 g, 5.54 mmol, 1.00 eq.) in tetrahydrofuran (30.0 mL) was added sodium borohydride (270 mg, 7.14 mmol, 1.29 eq.) at 0°C, and the mixture was stirred at 20°C for 3 hours. To the mixture was added saturated aqueous ammonium chloride solution (80.0 mL), and the resulting mixture was stirred at 20°C for 30 minutes. Then, the mixture was 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.

[0359] 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).

[0360] Step E: To a solution of (R)-N-((R)-1-(3-(benzyloxy)-5-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (1.20 g, 3.00 mmol, 1.00 eq.) was added hydrochloric acid (4.0 M in dioxane, 751 μL, 1.00 eq.) 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.

[0361] 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).

[0362] Intermediate U

[0363]

[0364] Step A: To a solution of 3-acetyl-5-fluorobenzonitrile (2.00 g, 12.3 mmol, 1.00 eq.) in tetrahydrofuran (20.0 mL) was added titanium ethoxide (5.59 g, 24.5 mmol, 5.08 mL, 2.00 eq.) and (R)-2-methylpropane-2-sulfenamide (1.93 g, 15.9 mmol, 1.30 eq.). The mixture was degassed and purged with nitrogen three times, then stirred at 70° C. under a 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 obtain a residue. The residue was purified by column chromatography (SiO 2 , 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.

[0365] 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).

[0366] Step B: To a solution of (R,E)-N-(1-(3-cyano-5-fluorophenyl)ethylidene)-2-methylpropane-2-sulfenamide (900 mg, 3.38 mmol, 1.00 eq.) in tetrahydrofuran (10.0 mL) was added sodium borohydride (383 mg, 10.1 mmol, 3.00 eq.) at 0°C. The mixture was then warmed to 20°C and stirred for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride (20.0 mL) at 25°C, extracted with ethyl acetate (20.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , 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.

[0367] 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).

[0368] Step C: To a solution of (R)-N-((R)-1-(3-cyano-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfenamide (711 mg, 2.65 mmol, 1.00 eq.) in dioxane (3.00 mL) was added hydrochloric acid in ethyl acetate (4.0 M, 9.94 mL, 15.0 eq.). 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×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.

[0369] 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).

[0370] Intermediate V

[0371]

[0372] Step A: ice-cold concentrated sulfuric acid (100 mL) was added to 1-bromo-2-methyl-3-(trifluoromethyl)benzene (10.0 g, 41.8 mmol, 1.00 eq.), followed by the slow addition of potassium nitrate (12.7 g, 125 mmol, 3.00 eq.) at 0 ° C. The mixture was stirred for 1 hour at 100 ° C. 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 (SiO , 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.

[0373] 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).

[0374] Step B: A mixture of 1-bromo-2-methyl-5-nitro-3-(trifluoromethyl)benzene (5.20 g, 18.3 mmol, 1.00 eq.), tributyl(1-ethoxyvinyl)tin (8.60 g, 23.8 mmol, 8.03 mL, 1.30 eq.) and Pd(PPh ) Cl (385 mg, 549 μmol, 0.03 eq.) in dioxane (60.0 mL) was degassed and purged with nitrogen three times, and then stirred at 80° C. under a nitrogen atmosphere for 10 hours. The reaction mixture was quenched with 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.

[0375] 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).

[0376] Step C: under nitrogen atmosphere at 20 DEG C by 1- (1-ethoxy vinyl) -2- methyl -5- nitro -3- (trifluoromethyl) benzene (6.00g, 21.8mmol, 1.00eq.) and hydrochloric acid (3.0M, 20.7mL, 2.85eq.) in THF (80.0mL) mixture is stirred for 1 hour. By adding water (100mL), reaction mixture is quenched, then extracted with ethyl acetate (60.0mL × 3). The combined organic layer is washed with brine (70.0mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain residue. The residue is purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 10 / 1) to obtain 1- (2- methyl -5- nitro -3- (trifluoromethyl) phenyl) ethane -1- ketone (4.10g, 16.5mmol, 76.0% yield) as a yellow oil.

[0377] 1 H NMR (400MHz, CD3OD) δ = 8.67 (s, 1H), 8.57 (s, 1H), 2.66 (s, 3H), 2.60 (s, 3H).

[0378] 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 eq.) and (R)-2-methylpropane-2-sulfinamide (1.27 g, 10.5 mmol, 1.30 eq.) in THF (20.0 mL) was added Ti(OEt)4 (3.69 g, 16.1 mmol, 3.36 mL, 2.00 eq.), and the mixture was stirred at 70°C under a 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 x 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.

[0379] 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).

[0380] Step E: To a solution of (R,E)-2-methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfenamide (2.00 g, 5.71 mmol, 1.00 eq.) in THF (23.0 mL) was added sodium borohydride (647 mg, 17.1 mmol, 3.00 eq.) 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 (SiO 2 , 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.

[0381] 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).

[0382] 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 eq.) and iodine (151 mg, 595 μmol, 120 μL, 0.30 eq.) in tetrahydrofuran (8.00 mL) and water (2.00 mL) was degassed and purged with nitrogen three times, and then the mixture was 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 (SiO 2 , 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.

[0383] 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).

[0384] Intermediate product W

[0385]

[0386] Step A: To a solution of 1-(3-chloro-2-methylphenyl)ethan-1-one (1.50 g, 8.90 mmol, 1.00 eq.) in tetrahydrofuran (30.0 mL) was added titanium ethoxide (6.09 g, 26.7 mmol, 5.53 mL, 3.00 eq.) and (R)-2-methylpropane-2-sulfenamide (1.40 g, 11.6 mmol, 1.30 eq.). The mixture was stirred at 70° C. for 10 hours. The reaction mixture was quenched with 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.

[0387] Step B: To a solution of (R,E)-N-(1-(3-chloro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfenamide (2.30 g, 8.46 mmol, 1.00 eq.) in tetrahydrofuran (30.0 mL) was added sodium borohydride (850 mg, 22.5 mmol, 2.66 eq.) 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 (SiO 2 , 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.

[0388] 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 eq.) in ethyl acetate (20.0 mL) was added hydrochloride in ethyl acetate (4.0 M, 30.0 mL) at 0° C. 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.

[0389] Intermediate Product X

[0390]

[0391] Step A: To a solution of 1-(3-methyl-5-(trifluoromethyl)phenyl)ethan-1-one (500 mg, 2.47 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfinamide (689 mg, 5.69 mmol, 2.30 eq.) in THF (7.00 mL) was added Ti(OEt)4 (1.30 g, 5.69 mmol, 1.18 mL, 2.30 eq.) and the mixture was stirred at 70°C under a 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 (SiO 2 , 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.

[0392] 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).

[0393] Step B: To a solution of (R,E)-2-methyl-N-(1-(3-methyl-5-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfenamide (650 mg, 2.13 mmol, 1.00 eq.) in THF (15.0 mL) was added sodium borohydride (253 mg, 6.69 mmol, 3.14 eq.) at -40°C. 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), 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 (SiO 2 , 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 pale yellow solid. LCMS [M+1] + :308.1.

[0394] 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).

[0395] 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 eq.) 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 pale yellow solid. The crude product was used directly in the next step without further purification. LCMS [M+1] + :204.0.

[0396] Intermediate product Y

[0397]

[0398] Step A: To a solution of 1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethan-1-one (35.6 g, 175 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfinamide (25.4 g, 209 mmol, 1.20 eq.) in THF (350 mL) was added titanium(IV) isopropoxide (149 g, 524 mmol, 155 mL, 3.00 eq.) and 1,2-dimethoxyethane (15.7 g, 175 mmol, 18.1 mL, 1.00 eq.). The reaction mixture was stirred at 80° C. for 12 hours, after which 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.

[0399] 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).

[0400] 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 eq.) in THF (400 mL) was added sodium borohydride (16.3 g, 430 mmol, 3.00 eq.) portionwise 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 x 3). The combined organic phases were washed with brine (200 mL x 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-sulfinamide (24.0 g, 76.2 mmol, 53.2% yield, 98.2% purity) as a brown oil.

[0401] 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).

[0402] 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 eq) in HCl / dioxane (200 mL) was stirred at 25° C. for 2 hours. The mixture was filtered and the filter cake was washed with ethyl acetate (100 mL) which was then collected and dried under vacuum to afford (R)-2-(1-aminoethyl)-6-(trifluoromethyl)pyridin-4-amine (hydrochloride) as a white solid.

[0403] 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).

[0404] Intermediate Z

[0405]

[0406] Step A: To a solution of 1-(2-methylpyridin-3-yl)ethan-1-one (800 mg, 5.92 mmol, 1.00 eq.) and (S)-2-methylpropane-2-sulfenamide (933 mg, 7.69 mmol, 1.30 eq.) in tetrahydrofuran (8.00 mL) were added titanium (IV) ethoxide (2.70 g, 11.8 mmol, 2.45 mL, 2.00 eq.) and 1,2-dimethoxyethane (533 mg, 5.92 mmol, 615 μL, 1.00 eq.), 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 (SiO 2 , 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.

[0407] Step B: To a solution of (S)-2-methyl-N-(1-(2-methylpyridin-3-yl)ethylidene)propane-2-sulfenamide (1.25 g, 5.24 mmol, 1.00 eq.) in tetrahydrofuran (7.00 mL) was added lithium tri-sec-butylborohydride (1.0 M in THF, 7.87 mL, 1.50 eq.) dropwise at -78°C over 30 minutes, followed by stirring at -78°C for an additional hour. The reaction mixture was then quenched at 0°C by the addition of saturated ammonium chloride solution (in water, 30.0 mL) and stirred at 25°C for an additional hour. The solution was then extracted with ethyl acetate (50.0 mL x 3), and the combined organic layers were washed with brine (30.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified twice by column chromatography (SiO 2 , 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.

[0408] 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).

[0409] SFC conditions: column: Chiralpak AD-3 50×4.6 mm I.D., 3 um mobile phase: phase A: CO2, and phase B: MeOH (0.05% diethylamine); gradient elution: MeOH (0.05% diethylamine) in CO2 from 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar.

[0410] Step C: A mixture of (S)-2-methyl-N-((R)-1-(2-methylpyridin-3-yl)ethyl)propane-2-sulfenamide (600 mg, 2.50 mmol, 1.00 eq.) in HCl·dioxane (3.00 mL) was stirred at 0° C. under a nitrogen atmosphere for 30 minutes. Afterwards, a white precipitate 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 μm; 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.

[0411] Intermediate AA

[0412]

[0413] Step A: To a solution of 1-bromo-3-(difluoromethyl)-2-fluorobenzene (commercially available, 4.50 g, 20.0 mmol, 1.00 eq.) in 1,4-dioxane (50.0 mL) was added PdCl2(PPh3)2 (1.40 g, 2.00 mmol, 0.10 eq.) and tributyl(1-ethoxyvinyl)tin (21.7 g, 60.0 mmol, 20.3 mL, 3.00 eq.), the mixture was degassed and purged with nitrogen (3 times), and 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.

[0414] Step B: To a solution of 1-(difluoromethyl)-3-(1-ethoxyvinyl)-2-fluorobenzene (7.50 g, 34.7 mmol, 1.00 eq.) in tetrahydrofuran (50.0 mL) was added aqueous hydrochloric acid solution (30.0 mL, 10% purity) and the mixture was stirred at 25 ° C for 1 hour. After that, the pH of the mixture was adjusted to a pH value of about 6-8 with aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic layer was 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)ethane-1-one (6.01 g, 31.3 mmol, 90.2% yield, 98.0% purity) as a colorless oil. LCMS[M+1] + :189.1.

[0415] 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).

[0416] Step C: A mixture of (S)-2-methylpropane-2-sulfenamide (2.32 g, 19.1 mmol, 1.20 eq.), 1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-one (3.00 g, 16.0 mmol, 1.00 eq.) and titanium(IV) ethoxide (7.27 g, 31.9 mmol, 6.60 mL, 2.00 eq.) in 2-methyltetrahydrofuran (30.0 mL) was degassed and purged with nitrogen (3 times), then stirred at 75° C. under a 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.

[0417] 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 eq.) in 2-methyltetrahydrofuran (30.0 mL) was added lithium tri-sec-butylborohydride (3.52 g, 18.5 mmol, 4.10 mL, 3.00 eq.) at -78°C under a nitrogen atmosphere, and the mixture was stirred at -78°C under a nitrogen atmosphere for 3 hours. Thereafter, additional lithium tri-sec-butylborohydride (1.76 g, 9.30 mmol, 2.00 mL, 1.50 eq.) was added, the solution was degassed and purged with nitrogen (3 times), and stirred at -78°C under a 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-sulfinamide (1.30 g, 4.34 mmol, 70.3% yield, 98% purity) as a colorless oil. LCMS[M+1] + :294.2.

[0418] Step E: To a solution of (S)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfenamide (1.29 g, 4.43 mmol, 1.00 eq.) was added hydrochloric acid (4.00 M in 1,4-dioxane, 15.0 mL, 14.0 eq.), and the mixture was stirred at 25°C for 30 minutes. The mixture was then 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 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.

[0419] 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).

[0420] Step F: A mixture of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (300 mg, 1.59 mmol, 1.00 eq.), 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (339 mg, 1.59 mmol, 1.00 eq.), and potassium fluoride (461 mg, 7.93 mmol, 186 μL, 5.00 eq.) in dimethyl sulfoxide (6.00 mL) was degassed and purged with nitrogen (3 times). 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 150×25 mm×10 um; 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.

[0421] Intermediate product AB

[0422]

[0423] Step A: To a solution of 3-bromo-5-fluoro-2-methylbenzoic acid (4.00 g, 17.2 mmol, 1.00 eq.) and N,O-dimethylhydroxylamine (1.84 g, 18.9 mmol, 1.10 eq., HCl salt) in DMF (50.0 mL) were added N,N-diisopropylethylamine (6.66 g, 51.5 mmol, 8.97 mL, 3.00 eq.) and HATU (7.83 g, 20.6 mmol, 1.20 eq.), 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.

[0424] Step B: Methylmagnesium bromide (3.0M, 34.1mL, 6.00eq.) was added dropwise to a solution of 3-bromo-5-fluoro-N-methoxy-N,2-dimethyl-benzamide (4.70g, 17.0mmol, 1.00eq.) in THF (100mL) at 0°C. After the dropwise 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)ethane-1-one (3.80g, 16.5mmol, 96.6% yield) as a light yellow solid.

[0425] 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).

[0426] Step C: To a solution of 1-(3-bromo-5-fluoro-2-methylphenyl)ethan-1-one (3.80 g, 16.5 mmol, 1.00 eq.) and (S)-2-methylpropane-2-sulfinamide (2.79 g, 23.0 mmol, 1.40 eq.) in THF (60.0 mL) was added titanium (IV) ethoxide (7.50 g, 32.9 mmol, 6.82 mL, 2.00 eq.) and 1,2-dimethoxyethane (1.48 g, 16.5 mmol, 1.71 mL, 1.00 eq.), and the mixture was stirred at 70° C. for 12 hours. The reaction mixture was then cooled to 25° C. and 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 (SiO 2 , 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.

[0427] 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).

[0428] Step D: To a solution of (S)-N-(1-(3-bromo-5-fluoro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfenamide (5.50 g, 16.5 mmol, 1.00 eq.) in THF (80.0 mL) was added lithium tri-sec-butylborohydride (1.0 M, 24.7 mL, 1.50 eq.) dropwise 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 in vacuo 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.

[0429] 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).

[0430] Step E: To a solution of (S)-N-((R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.60 g, 4.76 mmol, 1.00 eq.) in THF (20.0 mL) and water (5.00 mL) was added iodine (362 mg, 1.43 mmol, 288 μL, 0.30 eq.), and the mixture was stirred at 50° C. for 2 hours. The mixture was then cooled to 25° C. and the pH was adjusted to pH=7 with aqueous sodium bicarbonate. 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 afford (R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethan-1-amine (1.20 g, crude) as a pale yellow oil. This crude oil was used without further purification.

[0431] Step F: To a solution of (R)-1-(3-bromo-5-fluoro-2-methylphenyl)ethane-1-amine (1.20 g, 5.17 mmol, 1.00 eq.) in THF (20.0 mL) was added di-tert-butyl dicarbonate (1.35 g, 6.20 mmol, 1.43 mL, 1.20 eq.), 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 tert-butyl (R)-(1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)carbamate (1.45 g, 4.36 mmol, 84.4% yield) as a white solid.

[0432] Step G: A mixture of tert-butyl (R)-(1-(3-bromo-5-fluoro-2-methylphenyl)ethyl)carbamate (1.35 g, 4.06 mmol, 1.00 eq.), zinc cyanide (954 mg, 8.13 mmol, 516 μL, 2.00 eq.), DPPF (451 mg, 813 μmol, 0.20 eq.), zinc powder (26.6 mg, 406 μmol, 0.10 eq.) and Pd2(dba)3 (372 mg, 406 μmol, 0.10 eq.) 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 (SiO 2 , 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.

[0433] Step H: To a solution of tert-butyl (R)-(1-(3-cyano-5-fluoro-2-methylphenyl)ethyl)carbamate (1.10 g, 3.95 mmol, 1.00 eq.) in DCM (5.00 mL) was added TFA (1.88 g, 16.5 mmol, 1.22 mL, 4.18 eq.), 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. 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.

[0434] Intermediate product AC

[0435]

[0436] Step A: To a solution of 2-bromo-4-fluoro-6-(trifluoromethyl)aniline (2.00 g, 7.75 mmol, 1.00 eq.) and tributyl(1-ethoxyvinyl)tin (2.80 g, 7.75 mmol, 2.62 mL, 1.00 eq.) in dioxane (20.0 mL) was added PdCl2(PPh3)2 (544 mg, 775 μmol, 0.10 eq.) under a nitrogen atmosphere, 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 x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 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 (4.00g, crude product) in tetrahydrofuran (50.0mL) was added dropwise aqueous hydrochloric acid (4.00M, 20.0mL, 1.33eq.). The mixture was then stirred at 25°C for 1 hour, diluted with water (100mL) and extracted with ethyl acetate (300mL×3). The combined organic layer was washed with brine (200mL), 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 obtain compound 1-(2-amino-5-fluoro-3-(trifluoromethyl)phenyl)ethane-1-one (5.60g, 25.3mmol, 42.0% yield, 99.9% purity) as a yellow solid.

[0437] 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).

[0438] Step B: To a solution of 1-(2-amino-5-fluoro-3-(trifluoromethyl)phenyl)ethane-1-one (5.60 g, 25.3 mmol, 1.00 eq.) in hydrochloric acid (50.0 mL) and water (100 mL) was added portionwise sodium nitrite (2.27 g, 32.9 mmol, 1.30 eq.), and then potassium iodide (8.41 g, 50.6 mmol, 2.00 eq.) was 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.

[0439] 1 H NMR (400MHz, DMSO-d6) δ = 7.83-7.76 (m, 1H), 7.74-7.71 (m, 1H), 2.56 (s, 3H).

[0440] Step C: To a solution of methylboronic acid (1.62 g, 27.1 mmol, 2.50 eq.) and 1-(5-fluoro-2-iodo-3-(trifluoromethyl)phenyl)ethan-1-one (3.60 g, 10.8 mmol, 1.00 eq.) in dioxane (20.0 mL) was added Pd(dppf)Cl2 (400 mg, 542 μmol, 0.05 eq.) and potassium carbonate (7.49 g, 54.2 mmol, 5.00 eq.) under a nitrogen atmosphere, 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 x 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.

[0441] 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).

[0442] 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 eq.) and (R)-2-methylpropane-2-sulfenamide (2.42 g, 20.0 mmol, 2.00 eq.) in tetrahydrofuran (15.0 mL) were added titanium (IV) isopropoxide (5.68 g, 20.0 mmol, 5.90 mL, 2.00 eq.) and 1-methoxy-2-(2-methoxyethoxy)ethane (4.12 g, 30.7 mmol, 4.40 mL, 3.08 eq.), 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 of merging is washed with brine (50.0mL), is dried over sodium sulfate, filtered and concentrated under reduced pressure.The residue is purified by column chromatography (petroleum ether / ethyl acetate=10 / 1 to 3 / 1) to obtain compound (R)-N-(1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.50g, 4.64mmol, 46.4% yield) as a yellow oil.

[0443] 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).

[0444] Step E: To a solution of (R)-N-(1-(5-fluoro-2-methyl-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfenamide (1.90 g, 5.88 mmol, 1.00 eq.) in tetrahydrofuran (20.0 mL) was added sodium borohydride (667 mg, 17.6 mmol, 3.00 eq.) portionwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours, then slowly diluted with saturated aqueous ammonium chloride (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.

[0445] 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).

[0446] 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 eq.) in dichloromethane (5.00 mL) was added hydrochloric acid (4.00 M in 1,4-dioxane, 5.00 mL, 5.0 eq.), 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.

[0447] Intermediate AD

[0448]

[0449] Step A: To a solution of 3-bromo-2,5-difluorobenzaldehyde (4.00 g, 18.1 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfenamide (3.07 g, 25.3 mmol, 1.40 eq.) in THF (50.0 mL) were added titanium (IV) ethoxide (8.26 g, 36.2 mmol, 7.51 mL, 2.00 eq.) and 1,2-dimethoxyethane (1.63 g, 18.1 mmol, 1.88 mL, 1.00 eq.), and the mixture was stirred at 70° C. for 12 hours. 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.

[0450] 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).

[0451] Step B: To a solution of (S)-N-(3-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (5.50 g, 17.0 mmol, 1.00 eq.) in DCM (60.0 mL) was added methylmagnesium bromide (3.0 M, 17.0 mL, 3.00 eq.) dropwise at -60 ° C., 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 (SiO 2 , 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.

[0452] 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).

[0453] 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 eq.) in THF (20.0 mL) and water (5.00 mL) was added iodine (336 mg, 1.32 mmol, 266 μL, 0.30 eq.), 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. The resulting aqueous solution was extracted with DCM (20.0 mL x 3), and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford (R)-1-(3-bromo-2,5-difluorophenyl)ethane-1-amine (1.20 g, crude) as a pale yellow oil. This crude oil was used directly without further purification.

[0454] Step D: To a solution of (R)-1-(3-bromo-2,5-difluorophenyl)ethane-1-amine (1.20 g, 5.08 mmol, 1.00 eq.) in THF (20.0 mL) was added di-tert-butyl dicarbonate (1.22 g, 5.59 mmol, 1.28 mL, 1.10 eq.), 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 tert-butyl (R)-(1-(3-bromo-2,5-difluorophenyl)ethyl)carbamate (1.30 g, 3.87 mmol, 76.1% yield) as a white solid.

[0455] Step E: A mixture of (R)-tert-butyl (1-(3-bromo-2,5-difluorophenyl)ethyl)carbamate (1.20 g, 3.57 mmol, 1.00 eq.), zinc cyanide (838 mg, 7.14 mmol, 453 μL, 2.00 eq.), zinc (23.3 mg, 357 μmol, 0.10 eq.), DPPF (396 mg, 714 μmol, 0.20 eq.) and Pd2(dba)3 (327 mg, 357 μmol, 0.10 eq.) 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 (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to give tert-butyl (R)-(1-(3-cyano-2,5-difluorophenyl)ethyl)carbamate (0.90 g, 3.19 mmol, 89.3% yield) as a light yellow solid.

[0456] Step F: To a solution of (R)-tert-butyl (1-(3-cyano-2,5-difluorophenyl)ethyl)carbamate (0.90 g, 3.19 mmol, 1.00 eq.) in DCM (10.0 mL) was added TFA (4.62 g, 40.5 mmol, 3.00 mL, 12.7 eq.), 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 solution, 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. This compound was used directly without further purification.

[0457] Intermediate product AE

[0458]

[0459] Step A: To a solution of 1-bromo-3-fluoro-2-(trifluoromethyl)benzene (39.0 g, 160 mmol, 1.00 eq.) in dimethyl sulfoxide (200 mL) was added zinc cyanide (11.5 g, 176 mmol, 7.56 mL, 1.10 eq.) 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.

[0460] 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).

[0461] Step B: To a solution of 3-bromo-2-(trifluoromethyl)benzonitrile (29.0 g, 116 mmol, 1.00 eq.) and tributyl(1-ethoxyvinyl)tin (50.3 g, 139 mmol, 47.0 mL, 1.20 eq.) in toluene (250 mL) was added Pd(PPh 3 ) 4 (6.70 g, 5.80 mmol, 0.05 eq.) under a nitrogen atmosphere, 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 finally potassium fluoride (50.0 g) was added as a solid. 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 the crude product. The crude product was triturated with 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 pale yellow oil.

[0462] 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).

[0463] Step C: To a solution of 3-(1-ethoxyvinyl)-2-(trifluoromethyl)benzonitrile (7.00 g, 29.0 mmol, 1.00 eq.) in tetrahydrofuran (10.0 mL) was added hydrochloric acid (2.00 M, 29.0 mL, 2.00 eq.), 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 (SiO , 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.

[0464] 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).

[0465] Step D: To a solution of 3-acetyl-2-(trifluoromethyl)benzonitrile (1.00 g, 4.69 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfenamide (625 mg, 5.16 mmol, 1.10 eq.) in tetrahydrofuran (2.00 mL) was added 1,2-dimethoxyethane (423 mg, 4.69 mmol, 488 μL, 1.00 eq.) and titanium (IV) ethoxide (3.21 g, 14.1 mmol, 2.92 mL, 3.00 eq.), 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 celite (20.0 g) and saturated sodium bicarbonate (10.0 g) in water (100 mL). The mixture was stirred and then filtered, and the filter cake was stirred and filtered with ethyl acetate (30.0 mL), and this process was repeated three times until the product filter cake was washed off. The combined filtrate was separated and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layer was washed with brine (50.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was 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 (950 mg, 2.99 mmol, 63.7% yield, 99.5% purity) as a light yellow oil. LCMS[M+1] + :317.1.

[0466] 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).

[0467] Step E: To a solution of (R)-N-(1-(3-cyano-2-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfenamide (1.70 g, 5.37 mmol, 1.00 eq.) in tetrahydrofuran (20.0 mL) was added sodium borohydride (610 mg, 16.0 mmol, 3.00 eq.) portionwise at 0° C. under a nitrogen atmosphere. After the addition, the mixture was stirred at this temperature for 30 minutes, then warmed to 25° C. and stirred for an additional 3 hours. The mixture was then diluted dropwise with saturated aqueous ammonium chloride (100 mL) under a nitrogen atmosphere while stirring at 25° C., and then extracted with ethyl acetate (150 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , 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, mixture of diastereomers) as a white solid. LCMS [M + 1] + :319.1.

[0468] Step F: A mixture of (R)-N-(1-(3-cyano-2-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (1.4 g, 4.40 mmol, 1.00 eq.) in HCl·dioxane (10.0 mL) was stirred at 5° C. for 30 min. After this time, 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.

[0469] 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).

[0470] Step G: A mixture of 3-(1-aminoethyl)-2-(trifluoromethyl)benzonitrile (300 mg, 1.40 mmol, 1.00 eq., HCl salt), 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (300 mg, 1.40 mmol, 1.00 eq.), diisopropylethylamine (499 mg, 3.86 mmol, 673 μL, 2.76 eq.), and cesium fluoride (400 mg, 2.63 mmol, 97.0 μL, 1.88 eq.) in dimethyl sulfoxide (1.50 mL) was degassed and purged with nitrogen (3 times), and then the mixture was stirred at 130° C. under a 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 (SiO 2 , 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.

[0471] 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 μm); mobile phase: phase A: (0.1% NH 4 OH) in MeOH, phase B: CO 2; 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.

[0472] 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).

[0473] Intermediate product AF

[0474]

[0475] Step A: To a solution of 4-fluoro-3-nitro-5-(trifluoromethyl)benzoic acid (2.00 g, 7.90 mmol, 1.00 eq.) in tetrahydrofuran (15.0 mL) was added palladium on carbon (7.90 mmol, 10% purity, 1.00 eq.) under nitrogen atmosphere, and the mixture was stirred at 25° C. under hydrogen atmosphere (15 PSI) for 2 hours. 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.

[0476] 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).

[0477] Step B: To a solution of 3-amino-4-fluoro-5-(trifluoromethyl)benzoic acid (1.50 g, 6.72 mmol, 1.00 eq.) and N,O-dimethylhydroxylamine (830 mg, 13.45 mmol, 2.00 eq.) in N,N-dimethylformamide (10.0 mL) were added HATU (5.11 g, 13.5 mmol, 2.00 eq.) and N,N-diisopropylethylamine (2.61 g, 20.2 mmol, 3.50 mL, 3.00 eq.), and the mixture was stirred at 25°C for 12 hours. The mixture was diluted with water (50.0 mL) and then extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL x 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.

[0478] 1 H NMR (400MHz, CDCl3) δ = 7.38-7.34 (m, 2H), 3.57 (s, 3H), 3.36 (s, 3H)

[0479] 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 eq.) in dichloromethane (10.0 mL) was added di-tert-butyl dicarbonate (3.69 g, 16.9 mmol, 3.88 mL, 3.00 eq.) and 4-dimethylaminopyridine (688 mg, 5.64 mmol, 1.00 eq.), and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was diluted with water (50.0 mL) and then extracted with ethyl acetate (50.0 mL×3). The combined organic layers were washed with brine (50.0 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 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.

[0480] 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).

[0481] 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 eq.) in tetrahydrofuran (20.0 mL) was added methylmagnesium bromide solution (3.00 M, 3.86 mL, 3.00 eq.) 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 tert-butyl (5-acetyl-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.10 g, 3.42 mmol, 88.7% yield) as a yellow oil.

[0482] 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).

[0483] Step E: To a solution of tert-butyl (5-acetyl-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.10 g, 2.61 mmol, 1.00 eq.) and (R)-2-methylpropane-2-sulfinamide (950 mg, 7.83 mmol, 3.00 eq.) in tetrahydrofuran (10.0 mL) was added titanium (IV) isopropoxide (1.48 g, 5.22 mmol, 1.54 mL, 2.00 eq.) and 1-methoxy-2-(2-methoxyethoxy)ethane (1.87 g, 13.97 mmol, 2.00 mL, 5.35 eq.), 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 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 (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give compound (R)-tert-butyl(5-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.00 g, 2.36 mmol, 90.1% yield) as a yellow oil.

[0484] 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).

[0485] Step F: To a solution of tert-butyl (R)-(5-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (1.00 g, 2.36 mmol, 1.00 eq.) in tetrahydrofuran (10.0 mL) was added sodium borohydride (268 mg, 7.07 mmol, 3.00 eq.) 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 x 3). The combined organic layers were washed with brine (50.0 mL x 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 the compound tert-butyl (5-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-2-fluoro-3-(trifluoromethyl)phenyl)carbamate (620 mg, 1.45 mmol, 61.7% yield) as a white solid.

[0486] 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).

[0487] 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 eq.) in dichloromethane (5.00 mL) was added hydrochloride (4.00 M in 1,4-dioxane, 5.00 mL, 13.76 eq.), and the mixture was stirred at 25° C. for 1 hour. The mixture was then concentrated under reduced pressure to give (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. This compound was used directly without further purification.

[0488] Intermediate product AG

[0489]

[0490] Step A: To a solution of methyl 4,6-dichloropicolinate (4.50 g, 21.8 mmol, 1.00 eq.) in dichloromethane (40.0 mL) was added DIBAL-H (1.0 M, 65.5 mL, 3.00 eq.) dropwise 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 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, which was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , 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

[0491] 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).

[0492] Step B: Dess-Martin periodinane (11.4 g, 27.0 mmol, 8.35 mL, 2.00 eq.) was added portionwise to a solution of (4,6-dichloropyridin-2-yl)methanol (2.40 g, 13.5 mmol, 1.00 eq.) in dichloromethane (20.0 mL) at 0 ° C., and the mixture was stirred at 20 ° C. for 2 hours. Then, the mixture was poured into water (10.0 mL) and stirred for 15 minutes, and then saturated aqueous sodium thiosulfate solution (20.0 mL) 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 (20.0 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give 4,6-dichloropicolinaldehyde (1.60 g, 9.09 mmol, 67.4% yield) as a red oil.

[0493] 1 H NMR (400MHz, DMSO-d6) δ = 9.87 (s, 1H), 8.14 (d, J = 1.6Hz, 1H), 8.01 (d, J = 1.6Hz, 1H).

[0494] Step C: To a solution of 4,6-dichloropyridinecarboxaldehyde (1.10 g, 6.25 mmol, 1.00 eq.) in dichloromethane (10.0 mL) was added diethylaminosulfur trifluoride (2.01 g, 12.5 mmol, 1.65 mL, 2.00 eq.) dropwise 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 x 3). The combined organic phases were washed with brine (5.00 mL x 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.

[0495] 1 H NMR (400MHz, CD3OD) δ = 7.75 (s, 1H), 7.74 (s, 1H), 6.82-6.55 (m, 1H).

[0496] Step D: To a solution of tributyl(1-ethoxyvinyl)tin (2.01 g, 5.56 mmol, 1.88 mL, 1.00 eq.) and 2,4-dichloro-6-(difluoromethyl)pyridine (1.10 g, 5.56 mmol, 1.00 eq.) in dioxane (10.0 mL) was added Pd(PPh3)2Cl2 (390 mg, 556 μmol, 0.10 eq.) under a nitrogen atmosphere, 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 x 3), and the combined organic layers were washed with brine (30.0 mL x 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.

[0497] To a solution of 4-chloro-2-(difluoromethyl)-6-(1-ethoxyvinyl)pyridine (1.00 g, 4.28 mmol, 1.00 eq) in dioxane (5.00 mL) was added aqueous hydrochloric acid (2.00 M, 4.28 mL, 2.00 eq) at 20 ° C, and the mixture was stirred for 1 hour at 20 ° C. The pH of the mixture was then adjusted to pH=8 by adding 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)ethane-1-one (800 mg, 3.89 mmol, 90.9% yield) as a white solid.

[0498] 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).

[0499] 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 eq.) and tert-butyl carbamate (1.45 g, 12.4 mmol, 3.00 eq.) in dioxane (6.00 mL) were added cesium carbonate (2.69 g, 8.27 mmol, 2.00 eq.), XPhos (394 mg, 827 μmol, 0.20 eq.) and palladium acetate (92.8 mg, 413 μmol, 0.10 eq.) under nitrogen atmosphere 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.

[0500] Step F: To a solution of tert-butyl (2-acetyl-6-(difluoromethyl)pyridin-4-yl)carbamate (1.00 g, 3.49 mmol, 1.00 eq.) and (S)-2-methylpropane-2-sulfinamide (508 mg, 4.19 mmol, 1.20 eq.) in THF (10.0 mL) was added titanium (IV) ethoxide (7.97 g, 34.9 mmol, 7.24 mL, 10.0 eq.), 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 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 tert-butyl (S)-(2-(1-((tert-butylsulfinyl)imino)ethyl)-6-(difluoromethyl)pyridin-4-yl)carbamate (1.00 g, 2.57 mmol, 73.5% yield) as a yellow solid.

[0501] 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).

[0502] Step G: To a solution of tert-butyl (S)-(2-(1-((tert-butylsulfinyl)imino)ethyl)-6-(difluoromethyl)pyridin-4-yl)carbamate (1.00 g, 2.57 mmol, 1.00 eq.) in THF (10.0 mL) was added lithium tri-sec-butylborohydride (1.0 M, 976 mg, 5.14 mmol, 1.12 mL, 2.00 eq.) 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.

[0503] 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).

[0504] SFC: Column: Chiralcel OD-3 50×4.6 mm I.D., 3 um mobile phase: CO2 as phase A, MeOH (0.05% DEA) as phase B; gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar.

[0505] 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 eq.) 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 in the next step without purification. LCMS [M+1]+ :288.2.

[0506] 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).

[0507] Intermediate product AH

[0508]

[0509] Step A: To a solution of 1-(2-fluoro-3-methylphenyl)ethan-1-one (1.00 g, 6.57 mmol, 1.00 eq.) and (S)-2-methylpropane-2-sulfenamide (1.04 g, 8.54 mmol, 1.30 eq.) in tetrahydrofuran (20.0 mL) was added titanium tetraisopropoxide (3.73 g, 13.1 mmol, 3.88 mL, 2.00 eq.) under a nitrogen atmosphere, and the mixture was stirred at 70° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25° C. and poured into water (40.0 mL). After stirring for 10 minutes, a suspension was obtained. The suspension was filtered, and the resulting aqueous solution was extracted with ethyl acetate (40.0 mL×3). The combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The 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.

[0510] 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).

[0511] Step B: To a solution of (S)-N-(1-(2-fluoro-3-methylphenyl)ethylidene)-2-methylpropane-2-sulfenamide (1.50 g, 5.87 mmol, 1.00 eq.) in tetrahydrofuran (20.0 mL) was added lithium tri-sec-butylborohydride (1.0 M, 11.7 mmol, 11.8 mL, 2.00 eq.) 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.

[0512] 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).

[0513] Step C: To a solution of (S)-N-(1-(2-fluoro-3-methylphenyl)ethyl)-2-methylpropane-2-sulfenamide (900 mg, 3.50 mmol, 1.00 eq.) in dichloromethane (5.00 mL) was added HCl (4.00 M in 1,4-dioxane, 5.00 mL, 5.72 eq.) 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.

[0514] A solution of 1-(2-fluoro-3-methylphenyl)ethan-1-amine (300 mg, 1.96 mmol, 1.00 eq., hydrochloride), 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (419 mg, 1.96 mmol, 1.00 eq.), N,N-diisopropylethylamine (506 mg, 3.92 mmol, 2.00 eq.), and potassium fluoride (341 mg, 5.87 mmol, 0.14 mL, 3.00 eq.) in dimethyl sulfoxide (5.00 mL) was stirred at 130°C under a nitrogen atmosphere 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 x 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 25 mm × 5 μm; mobile phase: phase A: water (0.05% HCl), phase B: acetonitrile; B%: 14%-44%]. 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) was obtained as a yellow solid. LCMS [M+1] + :331.2.

[0515] 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 eq.) 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.

[0516] The following examples are intended to further illustrate certain embodiments of the present invention and are not intended to limit the scope of the invention.

[0517] Example 1-1

[0518] 6,7-Dimethoxy-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazin-1-amine

[0519]

[0520] Step A: A mixture of 1-chloro-6,7-dimethoxyphthalazine (120 mg, 534 μmol, 1.00 eq.), tert-butyl (2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (130 mg, 374 μmol, 0.70 eq.), BrettPhos PdG3 (48.4 mg, 53.4 μmol, 0.10 eq.), and potassium tert-butoxide (150 mg, 1.34 mmol, 2.50 eq.) in toluene (3.00 mL) was degassed and purged with nitrogen three times, then the reaction mixture was stirred at 100° C. under nitrogen atmosphere for 1 hour. The reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , dichloromethane / methanol = 10 / 1) to give tert-butyl (2-(5-(1-((6,7-dimethoxyphthalazin-1-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (70.0 mg, 24.5% yield) as a brown solid. LCMS [M+1]: 535.5.

[0521] Step B: To a solution of tert-butyl (2-(5-(1-((6,7-dimethoxyphthalazin-1-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (60.0 mg, 112 μmol, 1.00 eq.) in acetonitrile (1.00 mL) was added HCl (4.0 M in dioxane, 0.20 mL). The reaction mixture was stirred at 25° C. for 10 minutes, then filtered and the mixture concentrated under reduced pressure at 25° C. to give a residue. The residue was dissolved in methanol (2.00 mL) and adjusted to pH=7 with solid sodium bicarbonate (approximately 30.0 mg) to give a suspension. The suspension was filtered and purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 19%-49%, 9 min) and the filtrate was lyophilized to afford 6,7-dimethoxy-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazin-1-amine (16.6 mg, 33.8% yield, 99.6% purity) as a white solid. LCMS [M+1]: 435.1.

[0522] 1H NMR (400MHz, CD3OD) δ8.73(d,J=2.4Hz,1H),7.75(s,1H),7.51-7.46(m,1H),7.43-7.37(m,3H),7.35(d,J=5.2Hz,1H),7.19( d,J=1.2Hz,1H),7.16(s,1H),5.93-5.81(m,1H),4.10(s,2H),4.05(s,3H),4.00(s,3H),2.45(s,3H),1.83(d,J=6.8Hz,3H).

[0523] Example 1-2

[0524] (R)-7-(1-methyl-1H-pyrazol-4-yl)-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazin-1-amine

[0525]

[0526] Step A: To a solution of 7-bromophthalazin-1-ol (950 mg, 4.22 mmol, 1.00 eq.) in acetonitrile (19.0 mL) was added phosphorus (V) oxychloride (2.27 g, 14.8 mmol, 1.37 mL, 3.50 eq.) and the reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to 25° C. and concentrated in vacuo to remove the solvent. The remaining residue was diluted with DCM (50.0 mL) cooled to 0° C., and the organic layer was adjusted to pH = 7 with saturated aqueous sodium bicarbonate solution (30.0 mL). The organic phase was separated, washed with brine (30.0 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 7-bromo-1-chlorophthalazine (900 mg, 3.70 mmol, 87.6% yield) as a brown solid. LCMS [M+3]: 244.8.

[0527] 1 H NMR (400MHz, CDCl3) δ9.44 (d, J = 0.8Hz, 1H), 8.52-8.49 (m, 1H), 8.10 (dd, J = 2.0, 8.8Hz, 1H), 7.90 (d, J = 8.4Hz, 1H).

[0528] Step B: To a solution of 7-bromo-1-chlorophthalazine (100 mg, 411 μmol, 1.00 eq.) in DMSO (2.00 mL) was added tert-butyl (R)-(2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate (129 mg, 370 μmol, 0.90 eq.), potassium fluoride (71.6 mg, 1.23 mmol, 28.8 μL, 3.00 eq.), and diisopropylethylamine (106 mg, 821 μmol, 143 μL, 2.00 eq.). The reaction mixture was stirred at 130° C. under a nitrogen atmosphere for 4 hours. Thereafter, the reaction mixture was cooled to 25° C. Ethyl acetate (10.0 mL) and water (8.00 mL) were added to the reaction mixture, the layers were separated, and the aqueous phase was extracted with ethyl acetate (10.0 mL×2). The combined organic layers were washed with brine (10.0 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO , petroleum ether / ethyl acetate = 1 / 1) to give (R)-tert-butyl(2-(5-(1-((7-bromophthalazin-1-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (80.0 mg, 35.2% yield) as a yellow solid. LCMS[M+1]: 553.0.

[0529] 1 H NMR (400MHz, CD3OD) δ8.80(s,1H),8.56(s,1H),8.20(s,1H),8.12-8.07(m,2H),7.91(br d,J=8.4Hz,1H),7.33-7.25(m,3H),7.19(br d,J=7.2Hz,1H),7.15-7.03(m,2H),5.90-5.97(m,1H),4.45(br d,J=14.8Hz,2H),3.97(s,3H),2.66(s,3H),1.84(d,J=6.8Hz,3H),1.46-1.29(m,9H).

[0530] Step D: To a solution of tert-butyl (R)-methyl(2-(5-(1-((7-(1-methyl-1H-pyrazol-4-yl)phthalazin-1-yl)amino)ethyl)thiophen-3-yl)benzyl)carbamate (18.0 mg, 32.5 μmol, 1.00 eq.) in DCM (1.00 mL) was added TFA (770 mg, 6.75 mmol, 0.50 mL, 208 eq.). The reaction mixture was stirred at 25° C. for 10 minutes. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 13%-33%) and lyophilized to afford (R)-7-(1-methyl-1H-pyrazol-4-yl)-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazin-1-amine (9.02 mg, 55.7% yield, 91.1% purity) as an off-white solid. LCMS [M+1]: 455.2.

[0531] 1 H NMR (400MHz, CD3OD) δ9.10(br s,1H),8.49(s,1H),8.39(dd,J=1.2,8.4Hz,1H),8.29(s,1H),8.23(br d,J=8.4Hz,1H),8.17(s,1H),8.08(s,1H),7.60-7.57(m,1H),7.50-7.45(m,2H),7.44-7.40(m,1H),7 .39-7.34(m,2H),5.78(q,J=6.4Hz,1H),4.30(s,2H),4.04(s,2H),4.01(s,3H),2.62(s,3H),1.98(br d,J=6.8Hz,3H).

[0532] Examples 1-3

[0533] (R)-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinophthalazin-1-amine

[0534]

[0535]

[0147] Step A: A mixture of tert-butyl (R)-(2-(5-(1-((7-bromophthalazin-1-yl)amino)ethyl)thiophen-3-yl)benzyl)(methyl)carbamate (45.0 mg, 81.3 μmol, 1.00 eq.), morpholine (10.6 mg, 122 μmol, 10.7 μL, 1.50 eq.), Pd(dba) (7.44 mg, 8.13 μmol, 0.10 eq.), RuPhos (7.59 mg, 16.3 μmol, 0.20 eq.) and potassium tert-butoxide (1.00 M in THF, 163 μL, 2.00 eq.) in toluene (3.00 mL) was degassed and purged with nitrogen three times, then the reaction mixture was stirred at 110°C under nitrogen atmosphere for 1 hour. The reaction mixture was cooled to 25°C and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO , dichloromethane / methanol = 100 / 1 to 20 / 1) to give tert-butyl (R)-methyl(2-(5-(1-((7-morpholinophthalazin-1-yl)amino)ethyl)thiophen-3-yl)benzyl)carbamate (40.0 mg, 57.2 μmol, 70.3% yield, 80.0% purity) as a yellow solid. LCMS [M+1]: 560.2.

[0536] 1 H NMR (400MHz, CDCl3) δ8.81(s,1H),7.72(d,J=8.8Hz,1H),7.46-7.41(m,1H),7.35-7.28(m,3H),7.26-7.06(m,3H),7.03(d,J=1.2Hz,1 H),6.15-5.95(m,1H),4.80-4.40(m,2H),3.96-3.86(m,4H),3.46-3.28(m,4H),2.80-2.52(m,3H),1.83(d,J=6.8Hz,3H),1.42(s,9H).

[0537] Step B: To a mixture of tert-butyl (R)-methyl(2-(5-(1-((7-morpholinophthalazin-1-yl)amino)ethyl)thiophen-3-yl)benzyl)carbamate (37.0 mg, 52.9 μmol, 1.00 eq.) in acetonitrile (1.00 mL) was added HCl (4.00 M in dioxane, 0.50 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. Methanol (2.00 mL) was added to the mixture and adjusted to pH=7 with solid sodium bicarbonate (about 30.0 mg) to give a suspension, which was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 um; mobile phase: [A: water (10 mM NH 4 HCO 3 -B: ACN]; B%: 22%-52%] to give (R)-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinophthalazin-1-amine (18.3 mg, 38.5 μmol, 72.7% yield, 96.6% purity) as a white solid. LCMS [M+1]: 460.2.

[0538] 1 H NMR (400MHz, CD3OD) δ8.66(s,1H),7.82(dd,J=1.2,8.8Hz,1H),7.65-7.60(m,1H),7.55(d,J=2.0Hz,1H),7.46-7.41(m,1H),7.36-7.30(m ,3H),7.18(d,J=5.2Hz,2H),5.94(q,J=6.8Hz,1H),3.93-3.87(m,4H),3.81(s,2H),3.49-3.43(m,4H),2.28(s,3H),1.84(d,J=6.8Hz,3H).

[0539] Examples 1-4

[0540] (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-morpholinophthalazin-1-amine

[0541]

[0542] Step A: To a solution of 7-bromo-1-chlorophthalazine (244 mg, 1.00 mmol, 1.00 eq.) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (242 mg, 1.00 mmol, 1.00 eq., hydrochloride) in DMSO (3.00 mL) was added potassium fluoride (175 mg, 3.00 mmol, 70.4 μL, 3.00 eq.) and DIEA (259 mg, 2.00 mmol, 349 μL, 2.00 eq.), and the reaction mixture was stirred at 130° C. under a nitrogen atmosphere for 12 hours. The reaction mixture was cooled to 25° C. and diluted with ethyl acetate (20.0 mL), and the organic layer was washed with brine (20.0 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give (R)-7-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (280 mg, 683 μmol, 68.2% yield) as a brown solid. LCMS [M+1]: 409.9.

[0543] 1 H NMR (400MHz, CDCl3) δ8.92(s,1H),7.94(s,1H),7.91(dd,J=1.6,8.4Hz,1H),7.71(d,J=8.4Hz,1 H),7.68(d,J=7.6Hz,1H),7.58(d,J=8.0Hz,1H),7.32-7.28(m,1H),6.02-5.94(m,1H),5.14(br d,J=6.4Hz,1H),2.58(s,3H),1.70(d,J=6.8Hz,3H).

[0544] Step B: To a solution of (R)-7-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (30.0 mg, 73.1 μmol, 1.00 eq.) and morpholine (12.7 mg, 146 μmol, 12.9 μL, 2.00 eq.) in dioxane (1.00 mL) was added Pd2(dba)3 (6.70 mg, 7.31 μmol, 0.10 eq.), RuPhos (6.82 mg, 14.6 μmol, 0.20 eq.) and cesium carbonate (47.7 mg, 146 μmol, 2.00 eq.) under a nitrogen atmosphere. The reaction mixture was stirred at 110°C for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to 25°C, filtered and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (dichloromethane / methanol = 10 / 1) to give a crude product, which was then purified by preparative HPLC (column: Waters Xbridge C18 150×50 mm×10 μm; mobile phase: [A: water (10 mM NH 4 HCO 3 ), B: ACN]; B%: 40%-70%) to give (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-morpholinophthalazin-1-amine (11.0 mg, 26.2 μmol, 35.8% yield, 99.2% purity) as a white solid. LCMS [M+1]: 417.1.

[0545] 1 H NMR (400MHz, CD3OD) δ = 8.56 (s, 1H), 7.79-7.75 (m, 1H), 7.72 (d, J = 8.0Hz, 1H), 7.62-7.57 (m, 2H), 7.49 (d, J = 7.2Hz, 1H), 7.25(t,J=7.6Hz,1H),5.77(q,J=6.8Hz,1H),3.94-3.84(m,4H),3.51-3.42(m,4H),2.61(s,3H),1.64(d,J=7.2Hz,3H).

[0546] Following the teachings of General Reaction Scheme III and the procedures described for the preparation of Examples 1-1 to 1-4, the following compounds of Formula (I), Examples 1-5 to 1-50 shown in Table 1 were prepared:

[0547] Table 1

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559] Example 2-1

[0560] (R)-N-(1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinophthalazin-1-amine

[0561]

[0562] To a solution of (R)-N-(1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinophthalazin-1-amine (15.0 mg, 32.6 μmol, 1.00 eq.) in dimethylformamide (0.50 mL) was added potassium hydroxide (2.75 mg, 49.0 μmol, 1.50 eq.) at 15° C., and the reaction mixture was stirred at 15° C. for 1 hour. A solution of methyl 4-methylbenzenesulfonate (7.90 mg, 42.4 μmol, 1.3 eq.) in dimethylformamide (0.20 mL) was added dropwise to the reaction mixture. After the dropwise addition was completed, the reaction mixture was heated to 50° C. and stirred for 2 hours. The reaction mixture was then cooled to 25° C., and ethyl acetate (3.00 mL) and water (3.00 mL) were added to the mixture. The layers were separated and the organic phases were combined, washed twice with water (3.00 mL) and dried over anhydrous sodium sulfate to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 32%-62%, 10 min) to give (R)-N-(1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinophthalazin-1-amine (1.61 mg, 3.39 μmol, 10.4% yield, 99.7% purity) as an off-white solid. LCMS[M+1]: 474.3.

[0563] 1 H NMR (400MHz, CD3OD) δ8.65(s,1H),7.81(d,J=8.8Hz,1H),7.61(dd,J=2.4,9.2Hz,1H),7.54(d,J=2.4Hz,1H),7.48-7.41(m,1H),7.37-7.29(m,3H),7. 21(d,J=1.2Hz,1H),7.18-7.12(m,1H),5.91(q,J=6.8Hz,1H),3.90-3.85( m, 4H), 3.60 (s, 2H), 3.48-3.42 (m, 4H), 2.17 (s, 6H), 1.82 (d, J = 6.8Hz, 3H).

[0564] Example 2-2

[0565] N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S)-pyrrolidin-3-yl)oxy)phthalazin-1-amine

[0566]

[0567] Step A: To a solution of (R)-7-bromo-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (80.0 mg, 195 μmol, 1.00 eq.) in toluene (2.00 mL) was added sodium hydride (15.6 mg, 390 μmol, 60.0% purity, 2.00 eq.) under nitrogen atmosphere at 0° C. Then, (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (110 mg, 585 μmol, 3.00 eq.), Pd2(dba)3 (17.9 mg, 19.5 μmol, 0.10 eq.) and Tol-BINAP (132 mg, 195 μmol, 1.00 eq.) were added to the reaction mixture, and the mixture was heated to 100° C. over 1 hour. The reaction mixture was cooled to 25° C., poured into water (20.0 mL) and extracted with ethyl acetate (20.0 mL×3). The combined organic phases were concentrated in vacuo to give a residue. The residue was purified by reverse phase HPLC [water (0.1% TFA)-ACN] to give (S)-tert-butyl 3-((4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-yl)oxy)pyrrolidine-1-carboxylate (35.0 mg, 44.0 μmol, 23.0% yield, 65.0% purity) as a yellow solid. LCMS [M+1]: 517.0.

[0568] Step B: To a solution of (S)-tert-butyl 3-((4-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-yl)oxy)pyrrolidine-1-carboxylate (35.0 mg, 44.0 μmol, 1.00 eq.) in acetonitrile (1.00 mL) was added HCl (4.00 M in dioxane, 11.0 μL, 1.00 eq.) dropwise under nitrogen at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and then concentrated in vacuo to give a residue. The residue was purified by reverse phase preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-35%) to give N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S)-pyrrolidin-3-yl)oxy)phthalazin-1-amine (8.01 mg, 18.2 μmol, 41.0% yield, 95% purity) as a yellow solid. LCMS [M+1]: 417.1.

[0569] 1 H NMR (400MHz, CD3OD) δ=9.15(s,1H),8.28-8.21(m,2H),7.80-7.72(m,2H),7.59(d,J=7.6Hz,1H),7.37-7.27(t,J=7.6H z,1H),5.67-5.57(m,2H),3.80-3.67(m,2H),3.64-3.47(m,2H),2.63(s,3H),2.55-2.46(m,2H),1.73(d,J=6.8Hz,3H).

[0570] Following the teachings of General Reaction Scheme III and the procedures described for the preparation of Example 2-2, the following compounds of Formula (I), Examples 2-3 to 2-12 shown in Table 2 were prepared:

[0571] Table 2

[0572]

[0573]

[0574]

[0575] Example 3-1

[0576] (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-amine

[0577]

[0578] Step A: To a solution of 1,7-dichloropyrido[3,4-d]pyridazine (40.0 mg, 200 μmol, 1.00 eq.) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (40.6 mg, 200 μmol, 1.00 eq.) in DMSO (1.00 mL) was added diisopropylethylamine (77.5 mg, 600 μmol, 105 μL, 3.00 eq.) and potassium fluoride (34.8 mg, 600 μmol, 14.05 μL, 3.00 eq.) under nitrogen. The reaction mixture was stirred at 130° C. for 1 hour under nitrogen, then cooled to 25° C., poured into water (3.00 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (5.00 mL × 3), and the combined organic phases were washed with brine (3.00 mL × 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)-7-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazine-1-amine (30.0 mg, 81.8 μmol, 40.9% yield) as a yellow solid. LCMS[M+1]: 367.2.

[0579] 1 H NMR (400MHz, CD3OD) δ = 9.14 (s, 1H), 8.95 (s, 1H), 8.49 (s, 1H), 7.69 (d, J = 7.6Hz, 1H), 7.51 (d, J =7.6Hz, 1H), 7.26 (t, J = 8.0Hz, 1H), 5.76 (q, J = 6.8Hz, 1H), 2.63 (s, 3H), 1.64 (d, J = 6.8Hz, 3H).

[0580] Step B: To a solution of (R)-7-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido[3,4-d]pyridazin-1-amine (18.0 mg, 49.1 μmol, 1.00 eq.) and tert-butyl piperazine-1-carboxylate (13.7 mg, 73.6 μmol, 1.50 eq.) in dioxane (0.50 mL) was added potassium tert-butoxide (1.00 M, 98.2 μL, 2.00 eq.) and RuPhos-Pd-G3 (4.10 mg, 4.91 μmol, 0.10 eq.) under nitrogen. The reaction mixture was stirred at 100° C. for 1 hour, then cooled to 25° C. and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO 2 , petroleum ether / ethyl acetate = 1 / 1) to give (R)-tert-butyl 4-(1-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate (18.0 mg, crude) as a yellow solid. LCMS [M+1]: 517.3.

[0581] Step C: To a solution of (R)-tert-butyl 4-(1-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)piperazine-1-carboxylate (11.0 mg, 21.3 μmol, 1.00 eq.) in acetonitrile (1.00 mL) was added HCl in dioxane (3 M, 0.50 mL). The reaction mixture was stirred at 0° C. for 1 hour and then concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 10%-40%) to give (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperazin-1-yl)pyrido[3,4-d]pyridazin-1-amine (4.50 mg, 8.48 μmol, 39.8% yield, trifluoroacetate salt) as a white solid. LCMS [M+1] = 417.1.

[0582] 1H NMR (400MHz, CD3OD) δ = 9.18 (s, 1H), 9.05 (s, 1H), 7.76 (s, 1H), 7.71 (d, J = 8.0Hz, 1H), 7.56 (d, J = 7.2Hz, 1H), 7.3 6-7.27(m,1H),5.58(q,J=6.8Hz,1H),4.30-4.21(m,4H),3.50-3.38(m,4H),2.61(s,3H),1.69(d,J=6.8Hz,3H).

[0583] SFC: Chiralpak OJ-3 (50×4.6 mm ID, 3 μm); Mobile phase: CO₂ as phase A, MeOH (0.05% DEA) as phase B; Gradient elution: 50% MeOH (0.05% DEA) in CO₂ from 5% to 40%. Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 bar.

[0584] Following the teachings of General Reaction Scheme III and the procedures described for the preparation of Example 3-1, the following compounds of Formula (I), Examples 3-2 to 3-6, shown in Table 3, were prepared:

[0585] Table 3

[0586]

[0587]

[0588] Example 4-1

[0589] (R)-6,7-Dimethoxy-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine

[0590]

[0591] A mixture of 1-chloro-6,7-dimethoxy-4-methylphthalazine (100 mg, 419 μmol, 1.00 eq.), (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (85.1 mg, 419 μmol, 1.00 eq.), BrettPhos Pd G3 (38.0 mg, 41.9 μmol, 0.10 eq.), and potassium tert-butoxide (1.00 M, 1.26 mL, 3.00 eq.) in toluene (2.00 mL) was degassed and purged with nitrogen three times. The reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 1 hour, then cooled to 25° C., filtered, and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEHC18 100×25 mm×5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35%-65%) to give (R)-6,7-dimethoxy-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (8.24 mg, 20.3 μmol, 4.84% yield, 99.8% purity) as a white solid. LCMS [M+1]: 406.2.

[0592] 1H NMR (400MHz, DMSO-d6) δ=7.83(s,1H),7.76(d,J=7.6Hz,1H),7.51(d,J=8.0Hz,1H),7.39(d,J=6.8Hz,1H),7.3 3-7.27(m,1H),7.22(s,1H),5.73-5.64(m,1H),4.01(s,3H),3.95(s,3H),2.58(s,6H),1.55(d,J=7.2Hz,3H).

[0593] Following the teachings of General Reaction Scheme IV and the procedures described for the preparation of Example 4-1, the following compounds of Formula (I), Examples 4-2 to 4-4, shown in Table 4, were prepared:

[0594] Table 4

[0595]

[0596]

[0597] Example 5-1

[0598] (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-4-isopropyl-6,7-dimethoxyphthalazin-1-amine

[0599]

[0600] Step A: A mixture of (R)-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethan-1-amine (200 mg, 768 μmol, 0.90 eq.), 1,4-dichloro-6,7-dimethoxy-phthalazine (221 mg, 853 μmol, 1.00 eq.), N,N-diisopropylethylamine (331 mg, 2.56 mmol, 446 μL, 3.00 eq.) and potassium fluoride (149 mg, 2.56 mmol, 60.0 μL, 3.00 eq.) in DMSO (3.00 mL) was stirred at 130° C. for 12 hours. The reaction mixture was then cooled to 25° C., and ethyl acetate (5.00 mL) and water (8.00 mL) were added and the layers separated. The aqueous phase was extracted with ethyl acetate (10.0 mL × 2), and the combined organic layers were washed with brine (10.0 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO , petroleum ether / ethyl acetate = 1 / 1) to give (R) -4-chloro-N- (1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) -6,7- dimethoxyphthalazin-1-amine (100 mg, 24.3% yield) as a yellow solid. LCMS [M + 1]: 483.0.

[0601] 1 H NMR (400MHz, CDCl3) δ=7.53-7.49(m,1H),7.44(s,1H),7.44-7.40(m,1H),7.34-7.29(m,2H),7.13-7.05(m,2H) ), 6.99 (s, 1H), 6.06-5.96 (m, 1H), 4.09 (s, 3H), 4.07 (s, 3H), 3.60 (s, 2H), 2.27 (s, 6H), 1.84 (d, J = 6.4Hz, 3H).

[0602] Step B: To a solution of (R)-4-chloro-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxyphthalazin-1-amine (40.0 mg, 82.8 μmol, 1.00 eq.) and iron(III) acetylacetonate (80.0 mg, 226 μmol, 2.74 eq.) in THF (1.00 mL) and 1-methyl-2-pyrrolidone (0.01 mL) was added isopropylmagnesium chloride (3.00 M in THF, 600 μL, 21.7 eq.) dropwise at 0°C. After the addition, the mixture was stirred at 25°C for 10 minutes. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (5.00 mL) and extracted with ethyl acetate (1.00 mL x 3). The combined organic layers were washed with brine (2.00 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 16%-46%) and lyophilized to afford (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-4-isopropyl-6,7-dimethoxyphthalazin-1-amine (10.3 mg, 20.4% yield, 99.0% purity, trifluoroacetate) as an off-white solid. LCMS [M+1]: 491.3.

[0603] 1 H NMR (400MHz, CD3OD) δ = 8.11 (s, 1H), 7.68 (s, 1H), 7.66-7.63 (m, 1H), 7.56-7.47 (m, 3H), 7.26-7.21 (m, 1H), 7.04 (d, J = 3.6Hz, 1H), 5 .73-5.60(m,1H),4.52(s,2H),4.12(s,3H),4.11(s,3H),3.97-3.88(m,1H),2.73(s,6H),1.91(d,J=6.8Hz,3H),1.53-1.42(m,6H).

[0604] SFC conditions: column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: CO2 as phase A, MeOH (0.05% DEA) as phase B; gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar.

[0605] Following the teachings of General Reaction Scheme I and the procedures described for the preparation of Example 5-1, the following compounds of Formula (I), Examples 5-2 to 5-3, shown in Table 5, were prepared:

[0606] Table 5

[0607]

[0608] Example 5-4

[0609] (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxy-4-(trifluoromethyl)phthalazin-1-amine

[0610]

[0611] Step A: To a solution of 2-bromo-4,5-dimethoxybenzoic acid (0.30 g, 1.15 mmol, 1.00 eq.) in tetrahydrofuran (20.0 mL) was added n-BuLi (1.60 M, 1.72 mL, 2.40 eq.) at -78°C under a nitrogen atmosphere. After stirring at -78°C for 1 hour, ethyl 2,2,2-trifluoroacetate (163 mg, 1.15 mmol, 159 μL, 1.00 eq.) was added dropwise at the same temperature. The mixture was stirred at -78°C for 1 hour, warmed to 20°C, and stirred at 20°C for 3 hours. The reaction mixture was poured into ice water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The combined organic phases were washed with brine (20.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give 4,5-dimethoxy-2-(2,2,2-trifluoroacetyl)benzoic acid (0.10 g, 30.9% yield) as a yellow oil. LCMS [M+1] + =279.0.

[0612] 1 H NMR (400MHz, CDCl3) δ = 7.30 (s, 1H), 7.11 (s, 1H), 4.03 (s, 3H), 3.98 (s, 3H).

[0613] Step B: To a suspension of 4,5-dimethoxy-2-(2,2,2-trifluoroacetyl)benzoic acid (0.10 g, 359 μmol, 1.00 eq.) in ethanol (10.0 mL) was added NH2NH2·H2O (180 mg, 3.59 mmol, 175 μL, 10.0 eq.) at 20°C. The mixture was stirred at 100°C for 3 hours. Upon completion, the reaction was concentrated under reduced pressure to give 6,7-dimethoxy-4-(trifluoromethyl)phthalazin-1(2H)-one (80.0 mg, crude) as a yellow solid. LCMS [M+1] + =316.1.

[0614] 1 H NMR (400MHz, DMSO-d6) δ = 7.70 (s, 1H), 7.15 (s, 1H), 3.98 (s, 3H), 3.96 (s, 3H).

[0615] Step C: To a solution of 6,7-dimethoxy-4-(trifluoromethyl)phthalazin-1(2H)-one (300 mg, 1.09 mmol, 1.00 eq.) in POCl3 (4.95 g, 32.3 mmol, 3.00 mL, 29.5 eq.) was added N,N-diisopropylethylamine (707 mg, 5.47 mmol, 953 μL, 5.00 eq.) at 25°C. The mixture was stirred at 100°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain a residue. The mixture was then diluted with ethyl acetate (10.0 mL) and poured into ice water (10.0 mL), and extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give 1-chloro-6,7-dimethoxy-4-(trifluoromethyl)phthalazine (50.2 mg, 171 μmol, 15.7% yield) as a yellow solid. LCMS [M+1] + =293.0.

[0616] 1 H NMR (500MHz, CDCl3) δ = 7.60 (s, 1H), 7.44 (d, J = 1.0Hz, 1H), 4.15 (s, 3H), 4.12 (s, 3H).

[0617] Step D: To a solution of (R)-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethan-1-amine (50.0 mg, 168 μmol, 1.00 eq., HCl) and 1-chloro-6,7-dimethoxy-4-(trifluoromethyl)phthalazine (49.3 mg, 168 μmol, 1.00 eq.) in DMSO (1.00 mL) were added N,N-diisopropylethylamine (87.1 mg, 674 μmol, 117 μL, 4.00 eq.) and potassium fluoride (2.94 mg, 50.5 μmol, 1.18 μL, 0.30 eq.). After completion, the reaction mixture was filtered, and the residue was purified by preparative HPLC (column: Agela DuraShell C18 150×25 mm×5 μm; mobile phase: phase A: [water (0.05% NH 3 H 2 O + 10 mM NH 4 HCO 3 )], phase B: acetonitrile; B%: 60%-90%) to give (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-6,7-dimethoxy-4-(trifluoromethyl)phthalazin-1-amine (4.51 mg, 8.72 μmol, 5.18% yield, 99.9% purity) as a white solid. LCMS [M+1] + =517.1.

[0618] 1 H NMR (500MHz, CDCl3) δ=7.51-7.46(m,1H),7.43(dd,J=1.5,7.0Hz,1H),7.36(d,J=1.5Hz,1H),7.35-7.28(m,2H),7.13(s,2H),6.99(br s,1H),6.20-6.13(m,1H),5.39(br s,1H),4.08(s,3H),4.07(s,3H),3.53(br s,2H),2.25(br s,6H),1.87(d,J=6.5Hz,3H).

[0619] Example 6-1

[0620] (R)-4-Methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(4-methylpiperazin-1-yl)phthalazin-1-amine

[0621]

[0622] Step A: A mixture of methyl 5-bromo-2-iodobenzoate (5.00 g, 14.7 mmol, 1.00 eq.), tributyl(1-ethoxyvinyl)stannane (5.60 g, 15.4 mmol, 5.20 mL, 1.05 eq.) and Pd(PPh ) Cl (309 mg, 440 μmol, 0.03 eq.) in dioxane (50.0 mL) was degassed and purged with nitrogen three times, and then the reaction mixture was stirred at 80° C. under a nitrogen atmosphere for 10 hours. The reaction mixture was cooled to 25° C., quenched by the addition of water (50.0 mL), and then extracted with ethyl acetate (50.0 mL×3). The combined organic layers were washed with brine (20.0 mL x 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl 5-bromo-2-(1-ethoxyvinyl)benzoate (6.00 g, crude) as a yellow oil, which was used directly in the next step.

[0623] Step B: to a solution of 5-bromo-2-(1-ethoxyvinyl) methyl benzoate (6.00g, crude product) in THF (50.0mL), aqueous hydrochloric acid solution (10%, 25.0mL) is added. The reaction mixture is stirred for 1 hour at 20°C. Water (50.0mL) is added to the reaction mixture, and the aqueous layer is extracted with ethyl acetate (100mL×3). The combined organic layer is washed with salt water (30.0mL×2), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain residue. The residue is purified by column chromatography (SiO , petroleum ether / ethyl acetate=1 / 0 to 50 / 1) to obtain 2-acetyl-5-bromobenzoic acid methyl ester (2.50g, 67.0% yield) as a yellow oil.

[0624] 1 H NMR (400MHz, CDCl3) δ=7.97 (d, J=2.0Hz, 1H), 7.70 (dd, J=2.0, 8.2Hz, 1H), 7.32 (d, J=8.4Hz, 1H), 3.91 (s, 3H), 2.53 (s, 3H).

[0625] Step C: To a solution of methyl 2-acetyl-5-bromobenzoate (1.50 g, 5.83 mmol, 1.00 eq.) in ethanol (30.0 mL) was added hydrazine hydrate (876 mg, 17.5 mmol, 851 μL, 3.00 eq.). The reaction mixture was stirred at 95° C. for 30 minutes. The reaction mixture was then cooled to 25° C. and concentrated under reduced pressure to give a residue. The residue was triturated with ethanol for 10 minutes to give a suspension, which was filtered, and the filter cake was collected and dried under vacuum to give 7-bromo-4-methylphthalazin-1(2H)-one (0.70 g, 2.93 mmol, 50.2% yield) as a white solid. LCMS [M+1]+ :239.0.

[0626] 1 H NMR (400MHz, DMSO-d6) δ = 12.57 (br s, 1H), 8.32 (d, J = 2.0Hz, 1H), 8.11 (dd, J = 2.0, 8.4Hz, 1H), 7.88 (d, J = 8.4Hz, 1H), 2.50 (s, 3H).

[0627] Step D: A mixture of 7-bromo-4-methyl-phthalazin-1-ol (1.00 g, 4.18 mmol, 1.00 eq), 1-methylpiperazine (628 mg, 6.27 mmol, 696 μL, 1.50 eq), RuPhos (195 mg, 418 μmol, 0.10 eq), Pd2(dba)3 (192 mg, 209 μmol, 0.05 eq) and t-BuOK (1 M in THF, 8.37 mL, 2.00 eq) in dioxane (10.0 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 110 ° C under N2 atmosphere for 1.5 hours. The reaction mixture was quenched by adding water (20 mL) and then extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (5 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (3 mL) for 10 min to give 4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1(2H)-one (800 mg, 3.10 mmol, 74.0% yield) as a yellow solid. LCMS [M+1] + :259.1.

[0628] 1 H NMR (400MHz, DMSO-d6) δ=12.13(s,1H),7.74(d,J=8.8Hz,1H),7.56(dd,J=2.8,9.0Hz,1H ), 7.50 (d, J = 2.6Hz, 1H), 3.40-3.34 (m, 4H), 2.49-2.45 (m, 4H), 2.43 (s, 3H), 2.23 (s, 3H).

[0629] Step E: Add a solution of 4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1(2H)-one (100 mg, 387 μmol, 1.00 eq) in phosphorus oxychloride (1.61 g, 10.5 mmol, 976 μL, 27.1 eq.). The mixture was stirred at 110 ° C for 16 hours. The reaction mixture was then cooled to 25 ° C and concentrated in vacuo to give a residue. The residue was dissolved in water (10.0 mL), adjusted to pH = 9 with saturated sodium sulfate, and extracted with ethyl acetate (5.00 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-chloro-1-methyl-6-(4-methylpiperazin-1-yl)phthalazine (70.0 mg, crude product) as a brown solid, which was used directly without purification. LCMS [M+1] + :277.1.

[0630] Step F: To a solution of 1-chloro-1-methyl-6-(4-methylpiperazin-1-yl)phthalazine (60.0 mg, 217 μmol, 1.00 eq.) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (48.5 mg, 238 μmol, 1.10 eq.) in dimethyl sulfoxide (3.00 mL) were added cesium fluoride (98.8 mg, 650 μmol, 24.0 μL, 3.00 eq.) and N,N-diisopropylethylamine (140 mg, 1.08 mmol, 189 μL, 5.00 eq.). The mixture was then stirred at 120° C. for 16 hours. The reaction mixture was then poured into water (1.50 mL) and purified by preparative HPLC (column: Boston Green ODS 150×30 mm×5 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-45%, 10 min). The product was further purified by preparative HPLC (column: Agela DuraShell C18 150×25 mm×5 μm; mobile phase: [water (0.05% NH 3 H 2 O + 10 mM NH 4 HCO 3 )-ACN]; B%: 38%-68%, 10 min) to give (R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(4-methylpiperazin-1-yl)phthalazin-1-amine (17.0 mg, 3.83 μmol, 17.6% yield, 99.9% purity) as a white solid. LCMS[M+1] + :444.1.

[0631] 1H NMR (500MHz, CD3OD) δ = 7.91 (d, J = 9.50Hz, 1H), 7.70 (d, J = 8.50Hz, 1H), 7.55-7.63 (m, 2H), 7.48(d,J=8.00Hz,1H),7.23(t,J=7.50Hz,1H),5.75-5.70(m,1H),3.55(brs,4H),2.68(br t,J=5.00Hz,4H),2.59-2.63(m,6H),2.40(s,3H),1.63(d,J=7.00Hz,3H).

[0632] Example 6-2

[0633] (R)-4-Methyl-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinopyrido[3,4-d]pyridazin-1-amine

[0634]

[0635] Step A: To a solution of 5-bromo-2-chloroisonicotinic acid (12.0 g, 50.6 mmol, 1.00 eq) in MeOH (100 mL) was added dropwise SOCl2 (7.25 g, 60.9 mmol, 4.42 mL, 1.20 eq), and the mixture was heated to 75 ° C and stirred for 8 hours. The reaction mixture was then concentrated under reduced pressure to give a residue. The residue was diluted with EtOAc (100 mL), washed with saturated NaHCO3 (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-bromo-2-chloroisonicotinic acid methyl ester (12.0 g, crude product) as a yellow oil. LCMS [M+1] + :252.0.

[0636] 1 H NMR (400MHz, DMSO-d6) δ = 8.78 (s, 1H), 7.89 (s, 1H), 3.91 (s, 3H).

[0637] Step B:5-bromo-2-chloroisonicotinate (11.0g, 43.92mmol, 1.00eq), tributyl (1-ethoxyvinyl) stannane (16.7g, 46.1mmol, 15.6mL, 1.05eq) and Pd (PPh ) 2Cl 2 (1.23g, 1.76mmol, 0.04eq) in dioxane (110mL) solution degassed and purged 3 times with N , then heated the mixture at 80 ℃ under N 2 atmosphere for 16 hours.Then, the reaction mixture was quenched by adding water (400mL), followed by extraction with EtOAc (150mL×3).The combined organic layer was washed with brine (200mL), dried over Na 2SO 4, filtered and concentrated under reduced pressure to give 2-chloro-5- (1-ethoxyvinyl) isonicotinate (10.6g, crude product) as a yellow oil.

[0638] Step C: HCl (102g, 280mmol, 100mL, 10% purity in water, 6.38eq) is added dropwise to a solution of 2-chloro-5-(1-ethoxyvinyl)isonicotinate (10.6g, 43.9mmol, 1.00eq) in THF (100mL), and the mixture is stirred at 20°C for 16 hours. The reaction mixture is then quenched with NaHCO (300mL) at 0°C and extracted with EtOAc (100mL×3). The combined organic layer is washed with brine (100mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by column chromatography (SiO, petroleum ether / ethyl acetate=1 / 0 to 3 / 1) to give 5-acetyl-2-chloroisonicotinate (4.50g, 21.1mmol, 48.0% yield) as a white solid.

[0639] 1 H NMR (400MHz, DMSO-d6) δ = 8.98 (s, 1H), 7.85 (s, 1H), 3.84 (s, 3H), 2.61 (s, 3H).

[0640] Step D: To a solution of methyl 5-acetyl-2-chloroisonicotinate (1.00 g, 4.68 mmol, 1.00 eq) in EtOH (15.0 mL) was added hydrazine hydrate (703 mg, 14.0 mmol, 683 μL, 3.00 eq) and the mixture was stirred at 95 ° C for 30 minutes. The reaction mixture was then filtered and the filter cake was concentrated under reduced pressure to give a residue to obtain 7-chloro-4-methylpyrido [3, 4-d] pyridazin-1 (2H) -one (0.85 g, crude) as a white solid. LCMS [M + 1] + :196.1.

[0641] 1 H NMR (400MHz, DMSO-d6) δ = 9.20 (s, 1H), 8.10 (s, 1H), 2.58 (s, 3H).

[0642] Step E: A solution of 7-chloro-4-methylpyrido[3,4-d]pyridazin-1(2H)-one (750 mg, 3.83 mmol, 1.00 eq), morpholine (668 mg, 7.67 mmol, 675 μL, 2.00 eq) in dioxane (10.0 mL), t-BuOK (1.00 M in THF, 11.5 mL, 3.00 eq), RuPhos (179 mg, 383 μmol, 0.10 eq), Pd2(dba)3 (176 mg, 192 μmol, 0.05 eq) was degassed and purged with nitrogen three times, and the mixture was stirred at 110°C under nitrogen atmosphere for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70 mm, 15 um); mobile phase: [water (0.05% HCl)-ACN]; B%: 10%-40%) to give 4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1(2H)-one (500 mg, 2.03 mmol, 49.2% yield) as a white solid. LCMS [M+1] + :247.0.

[0643] 1 H NMR (400MHz, DMSO-d6) δ = 12.26 (s, 1H), 8.89 (s, 1H), 7.23 (s, 1H), 3.75-3.70 (m, 4H), 3.68-3.63 (m, 4H), 2.46 (s, 3H).

[0644] Step F: A solution of -methyl-7-morpholinopyrido[3,4-d]pyridazine-1(2H)-one (500 mg, 2.03 mmol, 1.00 eq) in POCl3 (6.23 g, 40.6 mmol, 3.77 mL, 20.0 eq) was stirred at 110 ° C for 3 hours. The reaction mixture was then concentrated under reduced pressure to remove POCl3. The residue was diluted with H2O (100 mL), then adjusted to pH=8 using NaHCO3 solid, and then extracted with ethyl acetate (50.0 mL×3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(1-chloro-4-methylpyrido[3,4-d]pyridazine-7-yl)morpholine (500 mg, crude product) as a yellow solid. LCMS[M+1] + :264.9.

[0645] 1 H NMR (400MHz, CDCl3) δ = 9.13 (s, 1H), 6.89 (s, 1H), 3.92-3.86 (m, 4H), 3.81-3.75 (m, 4H), 2.91 (s, 3H).

[0646] Step G: To a mixture of 4-(1-chloro-4-methylpyrido[3,4-d]pyridazin-7-yl)morpholine (50.0 mg, 189 μmol, 1.00 eq.) and (R)-tert-butyl(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamate (65.5 mg, 189 μmol, 1.00 eq.) in dimethyl sulfoxide (2.00 mL) was added cesium fluoride (57.4 mg, 378 μmol, 13.9 μL, 2.00 eq.) and N,N-diisopropylethylamine (48.8 mg, 378 μmol, 65.8 μL, 2.00 eq.) in a glove box. The mixture was stirred at 130° C. for 3 h and then cooled to room temperature. Water (30.0 mL) was added to the reaction mixture and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Agela DuraShell C18 150 × 25 mm × 5 um; using water (0.04% NH4OH + 10 mM NH4HCO3) and acetonitrile as eluents, mobile phase A: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3) -ACN, mobile phase B: acetonitrile; gradient: 24% -54% B) to give (R)-methyl (2-(5-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)carbamic acid tert-butyl ester (20.0 mg, 34.8 μmol, 18.4% yield) as a yellow solid. LCMS [M+1] + :575.4.

[0647] 1H NMR (400MHz, CD3OD) δ = 9.25 (s, 1H), 7.42 (s, 1H), 7.17-7.37 (m, 5H), 7.10 (d, J = 3.6Hz, 1H), 6.86 (br s,1H),5.59-5.68(m,1H),4.46-4.52(m,2H),3.92(br s,4H),3.76-3.84(m,4H),2.84(s,3H),2.70(s,3H),1.80(d,J=7.2Hz,3H),1.45(br s,9H).

[0648] Step H: To a mixture of tert-butyl (R)-methyl(2-(5-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)carbamate (20.0 mg, 34.8 μmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (0.20 mL). After completion, the mixture was concentrated and the residue was purified by preparative HPLC (column: Agela DuraShell C18 150×25 mm×5 um; using water (0.04% NH 3 H 2 O + 10 mM NH 4 HCO 3 ) and acetonitrile as eluents, mobile phase A: water (0.04% NH 4 OH + 10 mM NH 4 HCO 3 ), mobile phase B: acetonitrile; gradient: 35%-65% B) to give (R)-4-methyl-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholinopyrido[3,4-d]pyridazin-1-amine (4 mg, 8.43 μmol, 24.2% yield) as a white solid. LCMS [M+1] + :475.3.

[0649] 1 H NMR (400MHz, CD3OD) δ=9.04(s,1H),7.43(br d,J=6.4Hz,1H),7.25-7.36(m,4H),7.08(d,J=2.8Hz,1H),6.92(d,J=3.2Hz,1H),5.83(br d,J=6.8Hz,1H),3.80-3.86(m,6H),3.70-3.77(m,4H),2.69(s,3H),2.28(s,3H),1.79(d,J=6.8Hz,3H).

[0650] Following the teachings of General Reaction Schemes II and IV and the procedures described for the preparation of Examples 6-1, 6-2, 10-1, and 10-2, the following compounds of Formula (I), Examples 6-3 to 6-19 shown in Table 6 were prepared:

[0651] Table 6

[0652]

[0653]

[0654]

[0655]

[0656]

[0657] Example 7-1

[0658] 4-Methyl-N-((R)-1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazin-1-amine

[0659]

[0660]

[0661] Step A: To a mixture of 1-(4-(benzyloxy)-2-hydroxyphenyl)ethane-1-one (5.00 g, 20.6 mmol, 1.00 eq) and pyridine (4.90 g, 61.9 mmol, 5.00 mL, 3.00 eq) in DCM (100 mL) was slowly added dropwise trifluoromethylsulfonyl trifluoromethanesulfonate (11.7 g, 41.3 mmol, 6.81 mL, 2.00 eq) at 0° C. under a nitrogen atmosphere. The reaction mixture was then stirred at 20° C. for 16 hours. The reaction mixture was poured into water (100 mL) and stirred for 5 minutes. The aqueous phase was extracted with DCM (50.0 mL×3). The combined organic phases were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 2-acetyl-5-(benzyloxy)phenyl trifluoromethanesulfonate (7.40 g, 17.8 mmol, 86.2% yield, 90% purity) as a yellow solid. LCMS [M+1] + :374.8.

[0662] 1H NMR (400MHz, CDCl3) δ=7.85 (d, J=8.8Hz, 1H), 7.44-7.36 (m, 5H), 7.03 (dd, J=2.4, 8.8Hz, 1H), 6.90 (d, J=2.4Hz, 1H), 5.14 (s, 2H), 2.60 (s, 3H).

[0663] Step B: To a mixture of 2-acetyl-5-(benzyloxy)phenyl trifluoromethanesulfonate (13.0 g, 34.7 mmol, 1.00 eq) and 1,1-bis(diphenylphosphino)ferrocene (1.93 g, 3.47 mmol, 0.10 eq) in DMF (100 mL) and methanol (10.0 mL) was added triethylamine (17.6 g, 174 mmol, 24.2 mL, 5.00 eq) and palladium (II) acetate (780 mg, 3.47 mmol, 0.10 eq) in a single portion at 20 ° C under a nitrogen atmosphere. The reaction mixture was heated to 80 ° C and stirred under an atmosphere of carbon monoxide (50 Psi) for 16 hours. The mixture was then cooled to 15 ° C and concentrated under reduced pressure at 40 ° C to obtain a residue. The residue was poured into water (100 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (50.0 mL × 3). The combined organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO , petroleum ether / ethyl acetate=5 / 1 to 4 / 1) to give methyl 2-acetyl-5-(benzyloxy)benzoate (5.60 g, 16.9 mmol, 48.8% yield, 86% purity) as a yellow solid. LCMS[M+1] + :285.0.

[0664] 1 H NMR (400MHz, CDCl3) δ = 7.58 (d, J = 8.8Hz, 1H), 7.44-7.35 (m, 5H), 7.26 (d, J = 2. 8Hz, 1H), 7.08 (dd, J = 2.4, 8.4Hz, 1H), 5.14 (s, 2H), 3.91 (s, 3H), 2.53 (s, 3H).

[0665] Step C: To a solution of methyl 2-acetyl-5-(benzyloxy)benzoate (4.60 g, 16.2 mmol, 1.00 eq) in ethanol (50.0 mL) was slowly added dropwise hydrazine hydrate (2.48 g, 48.5 mmol, 2.41 mL, 98% purity, 3.00 eq) at 25 ° C., and the reaction mixture was stirred at 95 ° C. for 30 minutes. The reaction mixture was cooled to 15 ° C., poured into ice water (w / w = 1 / 1) (100 mL) and stirred for 5 minutes to obtain a suspension. The resulting suspension was filtered, the filter cake was collected and dried under reduced pressure to give 7- (benzyloxy) -4-methylphthalazin-1 (2H) -one (4.00 g, crude product) as a yellow solid. LCMS [M + 1] + :267.0.

[0666] Step D: 7-(benzyloxy)-4-methylphthalazine-1(2H)-one (860 mg, 3.23 mmol, 1.00 eq) was added portionwise to phosphorus oxychloride (14.2 g, 92.6 mmol, 8.60 mL, 28.7 eq) at 25 ° C, and the reaction mixture was stirred at 120 ° C for 3 hours. The mixture was cooled to 25 ° C and concentrated under reduced pressure to give a residue. The residue was slowly poured into ice water (50.0 mL), adjusted to pH = 8 with saturated sodium bicarbonate aqueous solution (50.0 mL), and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (50.0 mL × 3). The combined organic phase was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 66-(benzyloxy)-4-chloro-1-methylphthalazine (740 mg, crude product) as a white solid. LCMS [M+1] + :284.9.

[0667] Step E: To a solution of 6-(benzyloxy)-4-chloro-1-methylphthalazine (120 mg, 421 μmol, 1.00 eq.) and tert-butyl (R)-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamate (102 mg, 295 μmol, 0.70 eq.) in dimethyl sulfoxide (1.00 mL) was added cesium fluoride (192 mg, 1.26 mmol, 46.6 μL, 3.00 eq.). The mixture was stirred at 130° C. for 16 hours and diluted with ethyl acetate (30.0 mL). The combined organic fractions were washed with brine (3×8 mL), dried over sodium sulfate, filtered, and the solvent evaporated under reduced pressure to give a residue. The residue was purified by flash chromatography on a silica gel column (12 g), eluting with petroleum ether / ethyl acetate (0-100%) to afford tert-butyl (R)-(2-(5-(1-((7-(benzyloxy)-4-methylphthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (60.0 mg, 44.2 μmol, 10.5% yield, 43.8% purity) as a brown solid. LCMS [M+1]+: 595.3.

[0668] Step F: To a solution of tert-butyl (R)-(2-(5-(1-((7-(benzyloxy)-4-methylphthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (60.0 mg, 100 μmol, 1.00 eq.) in methanol (3.00 mL) was added Pd / C (10.7 mg, 10.1 μmol, 10% purity, 0.10 eq.). The mixture was then stirred at 30° C. for 3 hours. The mixture was then filtered, and the filter cake was washed with methanol (5.00 mL) and dichloromethane (10.0 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (column: Phenomenex Synergi C18 150×30 mm 4 μm; mobile phase: phase A: [water (0.1% TFA)], phase B: acetonitrile; B%: 42%-62%) to give (R)-tert-butyl(2-(5-(1-((7-hydroxy-4-methylphthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (15.0 mg, 29.7 μmol, 29.5% yield) as a white solid. LCMS [M+1] + :505.3.

[0669] Step G: To a solution of tert-butyl (R)-(2-(5-(1-((7-hydroxy-4-methylphthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (13.0 mg, 25.8 μmol, 1.00 eq.) and (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (9.16 mg, 30.9 μmol, 1.20 eq.) in DMF (0.10 mL) was added cesium fluoride (15.0 mg, 98.8 μmol, 3.64 μL, 3.83 eq.). The mixture was stirred at 90° C. for 2 h, then poured into water (5.00 mL) and filtered. The filtrate was extracted with ethyl acetate (10 mL x 2), and the combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give tert-butyl methyl (2-(5-((R)-1-((4-methyl-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)carbamate (14.8 mg, 25.8 μmol, 100% yield) as a yellow oily residue, which was used without further purification. LCMS [M+1] + :575.3.

[0670] Step H: To a solution of tert-butyl methyl(2-(5-((R)-1-((4-methyl-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)carbamate (10.0 mg, 17.4 μmol, 1.00 eq.) in dichloromethane (0.50 mL) was added 2,6-lutidine (18.6 mg, 173 μmol, 20.3 μL, 10.0 eq.) and then TMSOTf (19.3 mg, 87.0 μmol, 15.7 μL, 5.00 eq.) was added to the mixture. The mixture was stirred at 20° C. for 1 hour and then the solvent was evaporated under a nitrogen atmosphere. The crude product was purified by reverse phase HPLC (column: Agela DuraShell C18 150×25 mm×5 μm; mobile phase: phase A: [water (0.05% NH 3 H 2 O + 10 mM NH 4 HCO 3 )], phase B: acetonitrile; B%: 36%-66%) to give 4-methyl-N-((R)-1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazin-1-amine (2.20 mg, 4.64 μmol, 26.6% yield) as a white solid. LCMS [M+1] + :475.2.

[0671] 1H NMR (400MHz, CD3OD) δ = 8.02 (d, J = 8.8Hz, 1H), 7.70 (d, J = 2.4Hz, 1H), 7.39-7.52 (m, 2H), 7.2 5-7.38(m,3H),7.09(d,J=2.8Hz,1H),6.92(d,J=3.2Hz,1H),5.90(q,J=6.8Hz,1H),5.30(br s,1H),3.88-4.09(m,4H),3.81(s,2H),2.72(s,3H),2.29-2.44(m,1H),2.26(s,3H),2.18(br dd,J=5.6,12.0Hz,1H),1.81(d,J=7.2Hz,3H).

[0672] Following the teachings of General Reaction Scheme VI and the procedures described for the preparation of Example 7-1, the following compounds of Formula (I), Examples 7-2 to 7-7, shown in Table 7, were prepared.

[0673] Table 7

[0674]

[0675]

[0676] Following the teachings of General Reaction Scheme IV and the procedures described for the preparation of Example 8-3 (below), the following compound of Formula (I), Example 8-1, can be prepared, and Example 8-2 shown in Table 8 was prepared:

[0677] Example 8-1

[0678] (R)-4,7-Dimethyl-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazin-1-amine

[0679]

[0680] Table 8

[0681]

[0682] Example 8-3

[0683]

[0684] (R)-7-Methoxy-4-methyl-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazin-1-amine

[0685]

[0686] Step A: To a solution of methyl 2-bromo-5-methoxybenzoate (3.00 g, 12.2 mmol, 1.00 eq.) and tributyl(1-ethoxyvinyl)stannane (4.64 g, 12.9 mmol, 4.34 mL, 1.05 eq.) in dioxane (30.0 mL) was added Pd(PPh ) Cl (258 mg, 367 μmol, 0.03 eq.). The mixture was then stirred at 80° C. under a nitrogen atmosphere for 18 hours. The reaction mixture was then poured into water (30.0 mL) and extracted with ethyl acetate (30.0 mL×2). The organic layer was washed with brine (30.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was used without further purification to give methyl 2-(1-ethoxyvinyl)-5-methoxybenzoate (2.80 g, 11.9 mmol, 96.8% yield, assuming 100% purity) as a brown oil. LCMS [M+1] + :237.1.

[0687] Step B: A mixture of 2-(1-ethoxyvinyl)-5-methoxybenzoic acid (2.50 g, 10.6 mmol, 1.00 eq.) and 10% aqueous hydrogen chloride solution (386 mg, 10.6 mmol, 378 μL, 1.00 eq.) in THF (20.0 mL) was stirred at 20 ° C for 1 hour. The reaction mixture was then poured into water (20.0 mL) and extracted with ethyl acetate (25.0 mL×3). The organic layer was washed with brine (50.0 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (0-20% ethyl acetate / petroleum ether) to give methyl 2-acetyl-5-methoxybenzoate (1.40 g, 5.72 mmol, 54.1% yield, 85.1% purity) as a yellow oil. LCMS[M+1] + :209.0.

[0688] 1 H NMR (400MHz, CD3OD) δ = 2.51 (s, 3H) 3.86 (d, J = 10.0Hz, 6H) 7.06-7.15 (m, 2H) 7.70-7.79 (m, 1H).

[0689] Step C: To a solution of methyl 2-acetyl-5-methoxybenzoate (1.30 g, 6.24 mmol, 1.00 eq.) in ethanol (15.0 mL) was added hydrazine hydrate (938 mg, 18.7 mmol, 910 μL, 98% purity, 3.00 eq.). The mixture was then stirred at 80 ° C for 1 hour under a nitrogen atmosphere. The reaction mixture was then poured into water (20.0 mL) and extracted with ethyl acetate (30.0 mL × 2). The organic layer was washed with brine (30.0 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue. The crude product was used in the next step without purification to give 7-methoxy-4-methylphthalazin-1 (2H) -one (1.10 g, 5.74 mmol, 91.9% yield, 99.3% purity) as a white solid. LCMS [M+1] + :191.0.

[0690] Step D: A mixture of 7-methoxy-4-methylphthalazin-1 (2H) -one (0.90 g, 4.73 mmol, 1.00 eq.) and phosphorus oxychloride (15.2 g, 99.4 mmol, 9.23 mL, 21.0 eq.) was stirred at 115 ° C for 18 hours. The mixture was then poured into water (25.0 mL). A saturated sodium carbonate solution was added until pH = 9. The mixture was extracted with ethyl acetate (2 × 25.0 mL). The combined organic phases were washed with brine (saturated, 20.0 mL), dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on preparative TLC (SiO2, dichloromethane: methanol = 10: 1) to give 4-chloro-6-methoxy-1-methylphthalazine (240 mg, 1.14 mmol, 24.0% yield, 98.8% purity) as a white solid. LCMS [M + 1] + :209.0.

[0691] Step E: A mixture of tert-butyl (R)-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamate (49.3 mg, 142 μmol, 0.99 eq.), 4-chloro-6-methoxy-1-methylphthalazine (30.0 mg, 144 μmol, 1.00 eq.) and cesium fluoride (66.0 mg, 435 μmol, 16.0 μL, 3.02 eq.) in dimethyl sulfoxide (1.00 mL) was stirred at 130° C. for 18 hours. The mixture was then cooled to 25° C., diluted with ethyl acetate (5.00 mL), washed with brine (3.00×5 mL), dried over sodium sulfate, filtered, and the solvent evaporated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150×30 mm×5 μm; mobile phase: phase A: [water (0.1% TFA)], phase B: acetonitrile; B%: 38%-68%) to give (R)-tert-butyl(2-(5-(1-((7-methoxy-4-methylphthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (10.0 mg, 18.7 μmol, 13.0% yield, 96.8% purity) as a white solid. LCMS [M+1] + :519.2.

[0692] Step F: To a mixture of tert-butyl (R)-(2-(5-(1-((7-methoxy-4-methylphthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (8.00 mg, 15.4 μmol, 1.00 eq.) and 2,6-lutidine (16.5 mg, 154 μmol, 18.0 μL, 10.0 eq.) in dichloromethane (2.00 mL) was added TMSOTf (24.0 mg, 108 μmol, 19.5 μL, 7.00 eq.), which was then stirred under a nitrogen atmosphere at 20° C. for 2 hours. To the mixture was added N,N-diisopropylethylamine (0.10 mL), and the mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Agela DuraShell C18 150×25 mm×5 μm; mobile phase: phase A: [water (0.05% NH 3 H 2 O + 10 mM NH 4 HCO 3 )], phase B: acetonitrile; B%: 38%-68%) to give (R)-7-methoxy-4-methyl-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)phthalazin-1-amine (3.00 mg, 7.10 μmol, 46.0% yield, 99.0% purity) as a white solid. LCMS [M+1] + :419.2.

[0693] 1 H NMR (500MHz, CD3OD) δ = 8.01 (d, J = 9.0Hz, 1H), 7.73 (d, J = 2.5Hz, 1H), 7.49 (dd, J = 9.0, 2.5Hz, 1H), 7.44 (d, J = 6.5Hz, 1H), 7.33-7.37 (m, 2H), 7.26-7.3 4(m,1H),7.10(d,J=3.0Hz,1H),6.93(d,J=3.5Hz,1H),5.85-5.96(m,1H), 4.02(s,3H),3.86(s,2H),2.73(s,3H),2.29(s,3H),1.82(d,J=7.0Hz,3H).

[0694] Example 9-1

[0695] (R)-4-Methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperazin-1-yl)phthalazin-1-amine

[0696]

[0697]

[0698] Step A: To a solution of 6-bromo-2,3-dihydrophthalazine-1,4-dione (3.00 g, 12.4 mmol, 1.00 eq.) in phosphorus oxychloride (40.0 mL) was added N,N-diisopropylethylamine (4.02 g, 31.1 mmol, 5.42 mL, 2.50 eq.) dropwise at 25°C. The reaction was then stirred at 120°C for 12 hours. The mixture was cooled to 25°C and concentrated in vacuo to remove most of the phosphorus oxychloride and obtain a residue. The residue was poured into ice water (100 mL), and the resulting aqueous solution was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution and then extracted with dichloromethane (50.0 mL x 2). The combined organic phases were washed with brine (30.0 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 6-bromo-1,4-dichlorophthalazine (1.20 g, 4.32 mmol, crude) as a yellow solid without further purification. LCMS [M+3] + :279.0.

[0699] Step B: To a mixture of 6-bromo-1,4-dichlorophthalazine (500 mg, 1.80 mmol, 1.00 eq.) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (365 mg, 1.80 mmol, 1.00 eq.) in DMSO (10.0 mL) under a nitrogen atmosphere were added potassium fluoride (313 mg, 5.40 mmol, 126 μL, 3.00 eq.) and N,N-diisopropylethylamine (465 mg, 3.60 mmol, 627 μL, 2.00 eq.). The reaction mixture was then stirred at 130°C for 3 hours. Afterwards, the reaction was cooled to 25°C, diluted with ethyl acetate (20.0 mL), washed with brine (5.00 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield a residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 3 / 1) to give (R)-7-bromo-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (360 mg, 769 μmol, 42.7% yield) as a white solid. LCMS [M+3] + :446.1.

[0700] 1 H NMR (400MHz, CDCl3) δ=8.15-8.01(m,2H),7.99-7.79(m,1H),7.63(d,J=8.0Hz,1H),7.56-7.50(m,1H),7.23(s,1H),5.91-5.77(m,1H),5.45(br d,J=6.4Hz,1H),2.55(s,3H),1.65(d,J=6.8Hz,3H).

[0701] Step C: To a mixture of (R)-7-bromo-4-chloro-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (330 mg, 742 μmol, 1.00 eq.) in methanol (5.00 mL) was added sodium methoxide (200 mg, 3.71 mmol, 5.00 eq.) under nitrogen. The reaction mixture was stirred at 110° C. in a microwave reactor for 2 hours. The reaction mixture was then cooled to 25° C. and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO , petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give (R)-7-bromo-4-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (281 mg, 638 μmol, 86.0% yield) as a white solid.

[0702] Step D: To a solution of (R)-7-bromo-4-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (240 mg, 545 μmol, 4.00 eq.) and tert-butyl piperazine-1-carboxylate (25.4 mg, 136 μmol, 1.00 eq.) in dioxane (5.00 mL) was added RuPhos Pd G3 (5.70 mg, 6.81 μmol, 0.05 eq.) and cesium carbonate (178 mg, 545 μmol, 4.00 eq.) in a single portion at 20° C. under a nitrogen atmosphere. The mixture was stirred at 110° C. for 3 hours. LCMS showed that the reaction was complete. The suspension was filtered through a pad of celite and the filter cake was washed with ethyl acetate (30.0 mL). The combined filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×30 mm×4 um, mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; gradient: 49% to 69% B) to give (R)-tert-butyl 4-(1-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-yl)piperazine-1-carboxylate (70.0 mg, 128 μmol, 94.1% yield) as a white solid. LCMS [M+1] + :546.3.

[0703] Step E: To a mixture of (R)-tert-butyl 4-(1-methoxy-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-yl)piperazine-1-carboxylate (50.0 mg, 91.6 μmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (0.20 mL). The mixture was stirred at 20° C. for 1 hour. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 100×21.2 mm×4 μm, using TFA water and acetonitrile as eluents, mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; gradient: 14% to 44% B) to give (R)-4-methoxy-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperazin-1-yl)phthalazin-1-amine (35.0 mg, 78.6 μmol, 85.7% yield) as a white solid. LCMS [M+1] + :446.2.

[0704] 1H NMR (400MHz, CD3OD) δ = 8.18 (d, J = 9.2Hz, 1H), 8.06 (d, J = 2.8Hz, 1H), 7.82 (dd, J = 2.4, 9.2Hz, 1H), 7.64-7.77 (m, 2H), 7.36- 7.46(m,1H),5.42(q,J=6.4Hz,1H),4.07(s,3H),3.75-3.86(m,4H),3.38-3.47(m,4H),2.51(s,3H),1.80(d,J=6.8Hz,3H).

[0705] Following the teachings of General Reaction Scheme III and the procedures described for the preparation of Example 9-1, the following compounds of Formula (I), Example 9-2, shown in Table 9, were prepared:

[0706] Table 9

[0707]

[0708] Example 10-1

[0709] (R)-4-Methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperidin-4-yl)phthalazin-1-amine

[0710]

[0711] Step A: Under N2 atmosphere at 20 ℃, a mixture of 7-bromo-4-methylphthalazin-1 (2H) -one (4g, 16.73mmol, 1.00eq) in POCl3 (75.54g, 492.66mmol, 45.78mL, 29.44eq) was stirred, then heated to 100 ℃ and stirred for 5 hours. The mixture was cooled to 20 ℃ and concentrated under reduced pressure. The residue was slowly poured into water and neutralized with saturated NaHCO3 until pH=8. Then, ethyl acetate (100mL) was added to the mixture and stirred at 25 ℃ for 30 minutes. The mixture was filtered and the filter cake was collected. The residue was purified using a silica gel column (0-55% petroleum ether / EtOAc) to obtain 6-bromo-4-chloro-1-methylphthalazine (2.2g, 8.54mmol, 51.06% yield) as a yellow solid.

[0712] 1 H NMR (500MHz, DMSO-d6) δ8.41 (d, J = 1.5Hz, 1H), 8.29-8.34 (m, 1H), 8.24-8.28 (m, 1H), 2.89-2.93 (m, 3H).

[0713] Step B: To a mixture of 6-bromo-4-chloro-1-methylphthalazine (0.6 g, 2.32 mmol, 1.00 eq) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethane-1-amine (472 mg, 2.32 mmol, 1.00 eq) in DMSO (4 mL) at 20 ° C under N2 atmosphere was added N, N-diisopropylethylamine (602 mg, 2.33 mmol, 810 μL, 2.00 eq) and CsF (706 mg, 4.66 mmol, 2.00 eq) in one portion. The mixture was stirred at 130 ° C for 3 hours. Afterwards, the reaction was cooled to room temperature, water (50 mL) was added to the reaction mixture, and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (saturated, 20 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified using preparative TLC plates eluting with 50% EtOAc / petroleum ether to afford (R)-7-bromo-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (0.6 g, 1414 μmol, 60.70% yield) as a yellow oil.

[0714] Note: The reaction needs to be carried out in a glove box under N2 atmosphere to avoid moisture. All reagents including the solvent (DMSO) need to be dried.

[0715] 1 H NMR (400MHz, CDCl3) δ7.97 (s, 1H), 7.87-7.93 (m, 1H), 7.79-7.85 (m, 1H), 7.66 (d, J = 7. 6Hz,1H),7.54(d,J=7.6Hz,1H),7.26-7.29(m,1H),5.88(quint,J=6.4Hz,1H),5.12(br s,1H),2.78(s,3H),2.57(s,3H),1.66(d,J=6.8Hz,3H).

[0716] Step C: To a mixture of (R)-7-bromo-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (35.0 mg, 82.5 μmol, 1.00 eq.) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (38.3 mg, 124 μmol, 1.50 eq.) in tetrahydrofuran (3.00 mL) and water (0.60 mL) at 20° C. under nitrogen atmosphere were added sodium carbonate (26.2 mg, 247 μmol, 3.00 eq.) and Pd(dppf)Cl2 (6.04 mg, 8.25 μmol, 0.10 eq.) in one portion. The mixture was stirred at 80 ° C for 2 hours, then cooled to room temperature, and the mixture was diluted with ethyl acetate (30.0 mL) and washed with water (10.0 mL × 3). The combined organic layer was washed with brine (20.0 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to give a crude product in the form of a yellow oil. This yellow oil was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2 / 1) to give (R) -4- (1- methyl -4- ((1- (2- methyl -3- (trifluoromethyl) phenyl) ethyl) amino) phthalazine -6- bases) -3,6- dihydropyridine -1 (2H) -carboxylic acid tert-butyl ester (32.0 mg, 60.8 μmol, 73.7% yield) as a yellow oil. LCMS [M + 1] + :527.3.

[0717] Step D: To a solution of tert-butyl (R)-4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (14.0 mg, 26.6 μmol, 1.00 eq.) in methanol (3.00 mL) was added Pd / C (3.62 mg, 3.41 μmol, 10% purity, 0.13 eq.) under a nitrogen atmosphere. The suspension was degassed in vacuo and purged with hydrogen several times. The mixture was stirred under hydrogen (15.0 psi) at 25° C. for 2 hours, then filtered through a pad of celite, and the filter cake was washed with ethyl acetate (30.0 mL). The combined filtrates were concentrated to give (R)-tert-butyl 4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-yl)piperidine-1-carboxylate (14.0 mg, 26.5 μmol, 99.6% yield) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS [M+1] + :529.3.

[0718] Step E: A mixture of (R)-tert-butyl 4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-yl)piperidine-1-carboxylate (14 mg, 26.5 μmol, 1.00 eq.) in dichloromethane (2.00 mL) and trifluoroacetic acid (0.40 mL) was stirred at 20°C for 2 hours and then concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×30 mm×4 μm, using TFA water and acetonitrile as eluents; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; gradient: 20%-50% B) to give (R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperidin-4-yl)phthalazin-1-amine (9.00 mg, 21.0 μmol, 79.3% yield) as a yellow solid. LCMS [M+1] + :429.1.

[0719] 1 H NMR (400MHz, CD3OD) δ = 8.67 (s, 1H), 8.37 (d, J = 8.8Hz, 1H), 8.12 (d, J = 8.4Hz, 1H), 7.73 (d, J=8.4Hz,1H),7.55(d,J=8.0Hz,1H),7.29(t,J=7.6Hz,1H),5.57(q,J=6.8Hz,1H),3.61(br d,J=12.8Hz,2H),3.20-3.30(m,3H),2.87(s,3H),2.63(s,3H),2.21-2.32(m,2H),2.05-2.20(m,2H),1.71(d,J=6.8Hz,3H).

[0720] Example 10-2

[0721] (R)-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-N-morpholino-4-(trifluoromethyl)phthalazin-1-amine

[0722]

[0723]

[0724] Step A: To a solution of dimethyl 4-bromophthalate (2.00 g, 7.32 mmol, 1.00 eq.) in 1,2-dimethoxyethane (25.0 mL) was added CsF (223 mg, 1.46 mmol, 54.0 μL, 0.20 eq.) and TMSCF3 (1.25 g, 8.79 mmol, 1.20 eq.). The mixture was stirred at 0-25°C for 1 hour. The mixture was then partitioned between ethyl acetate (1.00 mL) and water (15.0 mL). The organic phase was separated, washed with brine (15.0 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a mixture of 6-bromo-3-methoxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one and 5-bromo-3-methoxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one (2.20 g, crude) as a colorless oil.

[0725] Step B: To a solution of 6-bromo-3-methoxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one and 5-bromo-3-methoxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one (2.20 g, 7.07 mmol, 1.00 eq.) in THF (25.0 mL) was added hydrazine hydrate (708 mg, 14.6 mmol, 688 μL, 2.00 eq.). The mixture was stirred at 75° C. for 18 hours and then concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel chromatography (SiO , petroleum ether / ethyl acetate = 10 / 1 to 8 / 1) to give 7-bromo-4-(trifluoromethyl)phthalazin-1(2H)-one (680 mg, 2.32 mmol, 32.8% yield) as a white solid.

[0726] 1 H NMR (400MHz, CD3OD) δ = 8.54 (d, J = 1.71 Hz, 1H), 8.15 (dd, J = 8.68, 2.08 Hz, 1H), 7.91 (dd, J = 8.80, 1.47 Hz, 1H).

[0727] Step C: To a solution of 7-bromo-4-(trifluoromethyl)phthalazin-1(2H)-one (200 mg, 683 μmol, 1.00 eq.) in POCl (3.30 g, 21.5 mmol, 2.00 mL, 31.5 eq.) was added pyridine (108 mg, 1.37 mmol, 110 μL, 2.00 eq.) at 20° C. The mixture was stirred at 105° C. for 1.5 hours and then concentrated under reduced pressure to give 6-bromo-4-chloro-1-(trifluoromethyl)phthalazine (210 mg, crude) as a white solid.

[0728] Step D: To a solution of 6-bromo-4-chloro-1-(trifluoromethyl)phthalazine (135 mg, 433 μmol, 1.50 eq.) in DMSO (2.00 mL) was added N,N-diisopropylethylamine (112 mg, 866 μmol, 151 μL, 3.00 eq.), KF (1.68 mg, 28.8 μmol, 6.76 μL, 0.10 eq.) and tert-butyl (R)-(2-(5-(1-aminoethyl)thiophen-2-yl)benzyl)(methyl)carbamate (0.10 g, 289 μmol, 100 eq.). The mixture was stirred in a microwave at 130° C. for 45 minutes. The mixture was diluted with water (2.00 mL) and extracted with ethyl acetate (2.00 mL×3). The combined organic layers were washed with water (2.00 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO , petroleum ether:ethyl acetate = 5:1) to give (R)-tert-butyl(2-(5-(1-((7-bromo-4-(trifluoromethyl)phthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (46.0 mg, 74.0 μmol, 25.6% yield) as a yellow oil.

[0729] Step E: A mixture of tert-butyl (R)-(2-(5-(1-((7-bromo-4-(trifluoromethyl)phthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (0.046 g, 74.0 μmol, 1.00 eq.), morpholine (7.74 mg, 88.8 μmol, 7.82 μL, 1.20 eq.), Cs2CO3 (72.3 mg, 222 μmol, 3.00 eq.), Pd2(dba)3 (6.78 mg, 7.40 μmol, 0.100 eq.) and RuPhos (6.91 mg, 14.8 μmol, 0.20 eq.) in dioxane (0.10 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 110°C under nitrogen atmosphere for 1 hour. In the mixture of 4- (trifluoromethyl) phthalazin-1-yl) amino) thiophene-2-yl) benzyl) carbamic acid tert-butyl ester (43.0 mg, 68.5 μmol, 92.6% yield) was obtained.

[0730] Step F: To a solution of tert-butyl (R)-methyl(2-(5-(1-((7-morpholino-4-(trifluoromethyl)phthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)carbamate (50.0 mg, 79.7 μmol, 1.00 eq.) in dichloromethane (1.00 mL) was added trifluoroacetic acid (770 mg, 6.75 mmol, 0.50 mL, 84.8 eq.). The mixture was stirred at 25 °C for 20 minutes, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 100×21.2 mm×4 um; mobile phase: phase A: [water (0.1% TFA)], phase B: ACN; B%: 17%-47%) to give (R)-N-(1-(5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)-7-morpholino-4-(trifluoromethyl)phthalazin-1-amine (17.5 mg, 33.1 μmol, 41.6% yield) as a white solid.

[0731] 1 H NMR(500MHz,DMSO-d6)δ8.87(s,2H),8.50(s,1H),7.89-7.39(m,6H),7.19(s,1H),7.08(s,1H) ,6.07-5.96(m,1H),4.23(s,2H),3.80(s,4H),3.46(s,4H),2.56(s,3H),1.80(d,J=6.9Hz,3H).

[0732] Following the teachings of General Reaction Scheme III and the procedures described for the preparation of Examples 10-1 and 10-2, the following compounds of Formula (I), Examples 10-3 to 10-87, shown in Table 10, were prepared.

[0733] Table 10

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758] Example 11-1

[0759] (R)-(4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-yl)piperazin-1-yl)(oxetan-3-yl)methanone

[0760]

[0761] To a solution of (R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(piperazin-1-yl)phthalazin-1-amine (20.0 mg, 46.6 μmol, 1.00 eq.) and oxetane-3-carboxylic acid (5.70 mg, 55.9 μmol, 1.20 eq.) in DMF (0.50 mL) were added HATU (21.3 mg, 55.9 μmol, 1.20 eq.) and N,N-diisopropylethylamine (18.1 mg, 140 μmol, 24.3 μL, 3.00 eq.). The mixture was stirred at 25° C. for 1 hour and then purified by preparative HPLC (Waters Xbridge 150×25 mm×5 μm; mobile phase: mobile phase A: [water (10 mM NH 4 HCO 3 ), mobile phase B: acetonitrile]; B%: 27%-57%) to give (R)-(4-(1-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-yl)piperazin-1-yl)(oxetan-3-yl)methanone (9.00 mg, 17.4 μmol, 37.4% yield, 99.4% purity) as an off-white solid. LCMS [M+1] + :514.3.

[0762] 1 H NMR (400MHz, CD3OD) δ=8.02(d,J=9.2Hz,1H),7.73-7.63(m,3H),7.50(d,J=7.6Hz,1H),7.25(t,J=8.0Hz,1H),5.63(q,J=7.2Hz,1H),4.89(br s,4H),4.33-4.22(m,1H),3.89-3.78(m,2H),3.69-3.58(m,4H),3.55-3.47(m,2H),2.67(s,3H),2.61(s,3H),1.64(d,J=6.8Hz,3H).

[0763] Following the teachings of General Reaction Scheme III and the procedures described for the preparation of Example 11-1, the following compounds of Formula (I), Examples 11-2 to 11-6, shown in Table 11, were prepared.

[0764] Table 11

[0765]

[0766]

[0767] Example 12-1

[0768] (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

[0769]

[0770] 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 eq.) in POCl3 (137 g, 893 mmol, 83.0 mL, 34.9 eq.) was added N,N-diisopropylethylamine (9.91 g, 76.7 mmol, 13.4 mL, 3 eq.) dropwise at 25°C, and the reaction was stirred at 110°C for 2 h. Afterwards, the mixture was cooled to 25°C and concentrated in vacuo to give a residue, which was diluted with ethyl acetate (300 mL) at 0°C and adjusted to pH = 7 by slow addition of saturated aqueous sodium bicarbonate solution. The combined organic phases were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (4.10 g, 19.2 mmol, 74.9% yield) as a pink solid.

[0771] 1 H NMR (400MHz, DMSO-d6) δ = 9.65 (s, 1H), 8.22 (s, 1H), 3.02 (s, 3H).

[0772] Step B: To a solution of 1,7-dichloro-4-methylpyrido[3,4-d]pyridazine (300 mg, 1.40 mmol, 1.00 eq.) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (285 mg, 1.40 mmol, 1.00 eq.) in DMSO (5.00 mL) was added potassium fluoride (244 mg, 4.20 mmol, 98.5 μL, 3.00 eq.) and N,N-diisopropylethylamine (543 mg, 4.20 mmol, 732 μL, 3.00 eq.). 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 (SiO 2 , 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.

[0773] 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 eq.), 1-(1-methyl-1H-pyrazol-4-yl)piperazine (58.9 mg, 210 μmol, 2.00 eq., TFA salt), cesium carbonate (171 mg, 525 μmol, 5.00 eq.), RuPhos Pd G3 (8.79 mg, 10.5 μmol, 0.10 eq.) in dioxane (1.00 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 80° C. under a nitrogen atmosphere for 10 hours. The reaction mixture was quenched by the addition of water (15.0 mL) at 20° C. 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.

[0774] 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(quin,J=6.8Hz,1H),3.88-3.83(m,4H),3.75(s,2H) ,3.78-3.72(m,1H),3.04-2.98(m,4H),2.56(s,6H),1.55(d,J=6.8Hz,3H).

[0775] Example 12-2

[0776] 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

[0777]

[0778] 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 eq.) and 6-oxa-3-azabicyclo[3.1.1]heptane (35.6 mg, 263 μmol, 2.00 eq., HCl) in dioxane (2.00 mL) were added cesium carbonate (171 mg, 525 μmol, 4.00 eq.), RuPhos (6.10 mg, 13.1 μmol, 0.10 eq.) and Pd2(dba)3 (6.00 mg, 6.60 μmol, 0.05 eq.) 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) and 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 Xbridge BEH C18 100×25 mm×5 μm; mobile phase: phase A: water (10 mM NH 4 HCO 3 ), 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.

[0779] 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).

[0780] SFC conditions: Chiralcel OD-3 3μm, 0.46cm id×5cm L; mobile phase: SFC CO2 as A, MeOH (0.05% isopropylamine) as B; gradient: B in A from 10% to 40% in 3 minutes; flow rate: 4.0mL / min; column temperature: 35℃; wavelength: 220nm; system back pressure: 100bar.

[0781] Following the teachings of General Reaction Scheme III and the procedures described for the preparation of Examples 12-1 and 12-2, the following compounds of Formula (I), Examples 12-3 to 12-134, shown in Table 12, were prepared.

[0782] Table 12

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818] Example 13-1

[0819] 4-Methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazin-1-amine

[0820]

[0821] To a solution of (R)-7-bromo-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (70.0 mg, 164 μmol, 1.00 eq.) in toluene (1.00 mL) was added sodium hydride (13.2 mg, 329 μmol, 60.0% in mineral oil, 2.00 eq.) under a nitrogen atmosphere at 0° C., and then (S)-tetrahydrofuran-3-ol (43.6 mg, 494 μmol, 3.00 eq.), Pd2(dba)3 (15.1 mg, 16.5 μmol, 0.10 eq.) and Tol-BINAP (22.4 mg, 33.0 μmol, 0.20 eq.) were added to the mixture. The reaction mixture was heated to 100° C. and stirred under a nitrogen atmosphere for 1 hour. After that, the mixture was cooled to 25 ° C., slowly quenched with saturated aqueous ammonium chloride solution (30.0 mL), and then extracted with ethyl acetate (20.0 mL×3). The combined organic phase was washed with brine (30.0 mL), 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 80×40 mm×3 μm; mobile phase: phase A: water with 0.04% HCl, phase B: acetonitrile; B% gradient: 30%-52%) to give 4-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazin-1-amine (6.31 mg, 14.0 μmol, 8.5% yield, HCl salt) as a white solid. LCMS [M+1] + :432.1

[0822] 1 H NMR (400MHz, DMSO-d6) δ=15.31(s,1H),8.91(s,1H),8.90-8.34(m,2H),7.82-7.77(m,2H),7.56(d,J=8.0Hz,1H),7.35(t,J=8.0Hz,1H),5.56(s,1H ),5.52-5.47(m,1H),4.05-4.03(m,1H),3.93-3.84(m,3H),2.79(s,3H), 2.58(s,3H),2.45-2.43(m,1H),2.08-2.06(m,1H),1.63(d,J=7.2Hz,3H).

[0823] SFC conditions: Chiralcel OD-3 3 μm, 0.46 cm id×5 cm L; mobile phase: MeOH (0.05% isopropylamine); gradient: B in A from 10% to 40% in 3 minutes; flow rate: 4.0 mL / min; column temperature: 35°C; wavelength: 220 nm

[0824] Example 13-2

[0825] (R)-4-Methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(oxetan-3-yloxy)phthalazin-1-amine

[0826]

[0827] A mixture of (R)-7-bromo-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (100 mg, 236 μmol, 1.00 eq.), oxetan-3-ol (26.2 mg, 354 μmol, 1.50 eq.), sodium tert-butoxide (68.0 mg, 707 μmol, 3.00 eq.), and [2-(2-aminophenyl)phenyl]-methanesulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (18.7 mg, 23.6 μmol, 0.10 eq.) in dioxane (2.00 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100° C. under a nitrogen atmosphere for 1 hour. The mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO 2 , dichloromethane / methanol = 20 / 1) and then by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: phase A: water (0.225% TFA), phase B: acetonitrile; phase B gradient: 17%-47%) to give (R)-4-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-(oxetan-3-yloxy)phthalazin-1-amine (5.20 mg, 12.4 μmol, 5.25% yield, 99.4% purity) as an off-white solid. LCMS [M+1] + :418.0.

[0828] 1H NMR (400MHz, CD3OD) δ=8.19(d,J=8.8Hz,1H),7.78-7.73(m,1H),7.71(d,J=8.0Hz,1H),7.61-7.56(m,1H),7.52(d,J=7.6Hz,1H), 7.26(t,J=8.0Hz,1H),5.69-5.59(m,2H),5.21-5.12(m,2H),4.81-4.75(m,2H),2.75(s,3H),2.63(s,3H),1.67(d,J=7.2Hz,3H).

[0829] Following the teachings of General Reaction Scheme III and the procedures described for the preparation of Examples 13-1 and 13-2, the following compounds of Formula (I), Example 13-3, shown in Table 13, were prepared.

[0830] Table 13

[0831]

[0832] Example 14-1

[0833]

[0834] Step A: To a solution of 6-bromo-4-chloro-1-methylphthalazine (500 mg, 1.94 mmol, 1.00 eq.) in chloroform (8.00 mL) was added NBS (380 mg, 2.14 mmol, 1.10 eq.) and AIBN (48.0 mg, 0.29 mmol, 0.15 eq.), and the reaction mixture was stirred at 90 ° C for 3 hours. The reaction mixture was then cooled to 25 ° C, quenched with water (20.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (25.0 mL × 2), 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 = 10 / 1 to 1 / 1) to obtain 6-bromo-1-(bromomethyl)-4-chlorophthalazine (180 mg, 535 μmol, 27.6% yield) as a yellow solid. LCMS[M+3] + :336.6.

[0835] 1 H NMR (400MHz, DMSO-d6) δ = 8.52-8.50 (m, 1H), 8.41 (dd, J = 1.2, 3.6Hz, 2H), 5.42 (s, 1H), 5.31 (s, 1H).

[0836] Step B: To a solution of dimethylamine (48.2 mg, 1.07 mmol, 0.05 mL, 2.00 eq., HCl salt) in tetrahydrofuran (10.0 mL) was added N,N-diisopropylethylamine (207 mg, 1.61 mmol, 0.28 mL, 3.00 eq.), followed by the addition of 6-bromo-1-(bromomethyl)-4-chlorophthalazine (180 mg, 0.54 mmol, 1.00 eq.) to the reaction mixture, and the mixture was stirred at 25°C for 12 hours. The mixture was 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 x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , petroleum ether / ethyl acetate = 1 / 1, Rf = 0.4) to give 1-(6-bromo-4-chlorophthalazin-1-yl)-N,N-dimethylmethanamine (80.0 mg, 266 μmol, 49.7% yield) as a yellow solid. LCMS [M+3] + :301.9

[0837] 1 H NMR (400MHz, DMSO-d6) δ = 8.51 (d, J = 8.8Hz, 1H), 8.44 (d, J = 1.6Hz, 1H), 8.30 (dd, J = 2.0, 8.8Hz, 1H), 4.02 (s, 2H), 2.22 (s, 6H).

[0838] Step C: To a solution of 1-(6-bromo-4-chlorophthalazin-1-yl)-N,N-dimethylmethanamine (120 mg, 0.40 mmol, 1.00 eq.) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (89.2 mg, 0.44 mmol, 1.10 eq.) in dimethyl sulfoxide (3.00 mL) was added potassium fluoride (69.6 mg, 1.20 mmol, 0.03 mL, 3.00 eq.), and the reaction was stirred at 130° C. for 2 hours. The reaction was cooled to 25° C., quenched with water (20.0 mL) and extracted with ethyl acetate (20.0 mL×3). The combined organic layers were washed with brine (20.0 mL×2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , petroleum ether / ethyl acetate = 1 / 1, Rf = 0.2) to give (R)-7-bromo-4-((dimethylamino)methyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (90.0 mg, 192 μmol, 48.2% yield) as a yellow oil. LCMS [M+1] + :467.0.

[0839] Step D: To a solution of (R)-7-bromo-4-((dimethylamino)methyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (60.0 mg, 0.13 mmol, 1.00 eq.), morpholine (28.0 mg, 0.32 mmol, 0.03 mL, 2.50 eq.), cesium carbonate (125 mg, 0.39 mmol, 3.00 eq.) and RuPhos (12.0 mg, 0.03 mmol, 0.20 eq.) in dioxane (8.00 mL) was added Pd2(dba)3 (11.8 mg, 0.02 mmol, 0.10 eq.), followed by degassing and purging with nitrogen three times and stirring the reaction mixture at 100°C under nitrogen atmosphere for 2 hours. The reactant was cooled to 25 ° C, diluted with water (20.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layer was washed with brine (25.0 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give (R) -4- ((dimethylamino) methyl) -N- (1- (2- methyl -3- (trifluoromethyl) phenyl) ethyl) -7-morpholinophthalazine -1- amine (5.75 mg, 12.1 μmol, 9.45% yield, 99.9% purity) as a yellow solid. LCMS [M + 1] + :474.3.

[0840] 1 H NMR (400MHz, DMSO-d6) δ = 8.09 (d, J = 8.8Hz, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.62 (s, 1H), 7.58 (dd, J = 2.0, 8.8Hz, 1H), 7.52 (br d,J=7.2Hz,2H),7.32(t,J=7.6Hz,1H),5.77-5.67(m,1H),3.86-3.80(m,4H),3.45-3.40(m,4H),3.31(br s,2H),2.58(s,3H),2.16(br s, 6H), 1.56 (d, J = 7.2Hz, 3H).

[0841] SFC conditions: Chiralcel OD-3 50×4.6 mm I.D., 3 μm; mobile phase: CO2 as phase A, MeOH (0.05% DEA) as phase B; gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 Bar.

[0842] Example 14-2

[0843]

[0844] Step A: To a mixture of 6-bromo-1-(bromomethyl)-4-chlorophthalazine (150 mg, 446 μmol, 1.00 eq.) in dimethylformamide (15.0 mL) was added potassium phthalimide (116 mg, 624 μmol, 1.40 eq.) at 25 ° C under a nitrogen atmosphere. The mixture was stirred at 85 ° C for 2 hours and then cooled to 25 ° C. The mixture was then diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to give 2-((6-bromo-4-chlorophthalazine-1-yl)methyl)isoindoline-1,3-dione (150 mg, 373 μmol, 83.6% yield) as a yellow solid. LCMS[M+1] + :404.0.

[0845] 1 H NMR (400MHz, DMSO-d6) δ = 8.55 (m, 2H), 8.40 (m, 1H), 7.95 (m, 2H), 7.90 (m, 2H), 5.60 (s, 2H).

[0846] Step B: To a solution of 2-((6-bromo-4-chlorophthalazin-1-yl)methyl)isoindoline-1,3-dione (130 mg, 323 μmol, 1.00 eq.) and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethan-1-amine (65.6 mg, 323 μmol, 1.00 eq.) in dimethyl sulfoxide (7.00 mL) was added N,N-diisopropylethylamine (125 mg, 969 μmol, 169 μL, 3.00 eq.) and potassium fluoride (56.3 mg, 969 μmol, 22.7 μL, 3.00 eq.) and stirred in a sealed tube at 130° C. for 12 hours. The reaction was cooled to 25° C., diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL×3). The combined organic phase was washed with brine (100 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 = 5 / 1) to give (R)-2-((6-bromo-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-1-yl)methyl)isoindoline-1,3-dione (130 mg, 228 μmol, 70.7% yield) as a yellow solid. LCMS [M+1]+ :472.2.

[0847] 1 H NMR (400MHz, DMSO-d6) δ = 8.91 (s, 1H), 8.20-8.07 (m, 2H), 7.97-7.80 (m, 5H), 7.74 (d, J = 8.0Hz, 1H), 7.51 (d ,J=8.0Hz,1H),7.31(t,J=8.0Hz,1H),5.72-5.60(m,1H),5.25(s,2H),2.44(s,3H),1.50(d,J=7.2Hz,3H).

[0848] Step C: To a solution of (R)-2-((6-bromo-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-1-yl)methyl)isoindoline-1,3-dione (100 mg, 176 μmol, 1.00 eq.) and morpholine (61.2 mg, 703 μmol, 61.8 μL, 4.00 eq.) in methylbenzene (10.0 mL) was added BINAP (21.9 mg, 35.1 μmol, 0.20 eq.), cesium carbonate (172 mg, 527 μmol, 3.00 eq.) and Pd2(dba)3 (16.1 mg, 17.6 μmol, 0.10 eq.) at 25°C under nitrogen atmosphere. The mixture was stirred at 100°C for 1 hour. The reaction was complete and cooled to 25°C. The reaction mixture was quenched with water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic phase was washed with brine (100 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 / 1) to give (R) -2- ((4- ((1- (2-methyl-3- (trifluoromethyl) phenyl) ethyl) amino) -6- morpholinophthalazin-1-yl) methyl) isoindoline -1,3- dione (65.0 mg, 113 μmol, 64.3% yield) as a yellow solid. LCMS [M + 1] + :576.3.

[0849] 1H NMR (400MHz, DMSO-d6) δ = 8.03 (br d, J = 10.0Hz, 1H), 7.94-7.85 (m, 4H), 7.74 (br d, J = 7.2Hz, 1H), 7.65 (br s, 2H), 7.51 (br d, J = 8.0Hz, 1H), 7.43 (br d,J=7.2Hz,1H),7.31(br t,J=6.8Hz,1H),5.72-5.67(m,1H),5.18(s,2H),3.83(m,4H),3.45(m,4H),2.44(s,3H),1.51(d,J=7.2Hz,3H).

[0850] Step D: To a solution of (R)-2-((4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-morpholinophthalazin-1-yl)methyl)isoindoline-1,3-dione (60.0 mg, 104 μmol, 1.00 eq.) in ethanol (6.00 mL) was added hydrazine hydrate (47.0 mg, 938 μmol, 45.6 μL, 9.00 eq.) at 25° C. under a nitrogen atmosphere. The mixture was stirred at 25° C. for 1 hour, then quenched with water (10.0 mL) and extracted with ethyl acetate (10.0 mL×3). The combined organic layers were washed with brine (30.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (water (0.04% HCl) / CH3CN) to give (R)-4-(aminomethyl)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7-morpholinophthalazin-1-amine (5.81 mg, 13.0 μmol, 12.5% ​​yield, hydrochloride salt) as a yellow solid. LCMS [M+1] + :446.1.

[0851] 1 H NMR (400MHz, DMSO-d6) δ=8.62(br s,3H),8.12(br s,2H),7.79(br d,J=7.6Hz,2H),7.61(br d,J=8.0Hz,1H),7.38(br t,J=8.0Hz,1H),5.66(br d,J=6.4Hz,1H),4.56(br s,2H),3.81(br t,J=4.8Hz,4H),3.62(br s,4H),2.53(m,3H),1.70(br d,J=5.6Hz,3H).

[0852] Example 14-3

[0853] 3-((R)-1-((7-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-((methylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0854]

[0855] Step A: To a solution of (R)-3-(1-((7-chloro-4-methylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (30.0 mg, 88.8 μmol, 1.00 eq.) in dioxane (1.00 mL) was added selenium dioxide (19.7 mg, 178 μmol, 19.3 μL, 2.00 eq.), and the mixture was stirred at 100° C. for 1 hour. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO , petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give (R)-3-(1-((7-chloro-4-formylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (16.0 mg, 45.5 μmol, 51.2% yield) as a yellow solid.

[0856] 1 H NMR (400MHz, DMSO-d6) δ=10.06(s,1H),9.99(s,1H),9.09(br d,J=6.8Hz,1H),8.76(s,1H),7.78(br d,J=8.0Hz,1H),7.66(br d,J=7.6Hz,1H),7.36(br t, J=8.0Hz, 1H), 5.81 (br d, J=6.4Hz, 1H), 2.69 (s, 3H), 1.63 (br d, J=6.8Hz, 3H).

[0857] Step B: To a solution of (R)-3-(1-((7-chloro-4-formylpyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (106 mg, 301 μmol, 1.00 eq.) and methylamine tetrahydrofuran solution (2.0 M, 360 μL, 2.39 eq.) in THF (3.00 mL) was added acetic acid (1.81 mg, 30.1 μmol, 1.72 μL, 0.10 eq.), and the mixture was stirred at 50° C. for 30 min. Thereafter, sodium triacetoxyborohydride (192 mg, 904 μmol, 3.00 eq.) was added, and shortly thereafter, the mixture was poured into water (5.00 mL). The aqueous phase was extracted with ethyl acetate (10.0 mL x 3), and the combined organic phases were washed with brine (10.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R)-3-(1-((7-chloro-4-((methylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (65.0 mg, 177 μmol, 58.8% yield) as a yellow solid. LCMS [M+1] + :367.2.

[0858] Step C: To a solution of (R)-3-(1-((7-chloro-4-((methylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (34.0 mg, 92.7 μmol, 1.00 eq.) and (Boc)2O (22.3 mg, 102 μmol, 23.4 μL, 1.10 eq.) in DCM (0.50 mL) was added DMAP (1.13 mg, 9.27 μmol, 0.10 eq.) and the mixture was stirred at 25°C for 1 h. The mixture was then concentrated under reduced pressure and the residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2:1) to give tert-butyl (R)-((7-chloro-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)pyrido[3,4-d]pyridazin-4-yl)methyl)(methyl)carbamate (35.0 mg, 75.0 μmol, 80.9% yield) as a yellow solid.

[0859] 1 H NMR (400MHz, CD3OD) δ = 9.43 (br s,1H),8.50(s,1H),7.72(d,J=7.2Hz,1H),7.52(dd,J=1.2,7.6Hz,1H),7.29-7.24(m,1H),5 .68-5.62(m,1H),2.78-2.75(m,5H),1.63(d,J=7.2Hz,3H),1.49-1.41(m,9H),1.22(s,3H).

[0860] Step D: To a solution of tert-butyl (R)-((7-chloro-1-((1-(3-cyano-2-methylphenyl)ethyl)amino)pyrido[3,4-d]pyridazin-4-yl)methyl)(methyl)carbamate (30.0 mg, 64.3 μmol, 1.00 eq.) and ((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (7.01 mg, 51.7 μmol, 0.8 eq., HCl) in DMSO (0.10 mL) were added cesium fluoride (19.5 mg, 128 μmol, 4.74 μL, 2.00 eq.) and N,N-diisopropylethylamine (16.6 mg, 128 μmol, 22.4 μL , 2.00eq.), and the mixture was stirred at 130 ° C for 1 hour. The solution was then cooled to 25 ° C, poured into water (10.0 mL), and the aqueous phase was extracted with ethyl acetate (10.0 mL × 3). The combined organic phase was washed with brine (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give ((7-((1R, 4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)pyrido[3,4-d]pyridazine-4-yl)methyl)(methyl)carbamic acid tert-butyl ester (30.0 mg, crude product) as a yellow solid. LCMS[M+1] + :530.2.

[0861] Step E: To a solution of tert-butyl ((7-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-1-(((R)-1-(3-cyano-2-methylphenyl)ethyl)amino)pyrido[3,4-d]pyridazin-4-yl)methyl)(methyl)carbamate (18.0 mg, 34.0 μmol, 1.00 eq.) in acetonitrile (1.50 mL) was added hydrochloric acid in dioxane (0.50 mL), and the mixture was stirred at 0°C for 30 minutes. The mixture was then poured into water (5.00 mL), and the aqueous phase was extracted with ethyl acetate (5.00 mL x 3). The combined organic phases were washed with brine (5.00 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: 3-Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: phase A: water (0.05% HCl), phase B: acetonitrile; B%: 7%-27%] to give 3-((R)-1-((7-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-((methylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (7.00 mg, 14.9 μmol, 43.8% yield, 99.1% purity, hydrochloride) as a yellow solid. LCMS [M+1] + :430.3.

[0862] 1 H NMR (400MHz, CD3OD) δ=9.09(s,1H),7.83(br d,J=7.6Hz,1H),7.71(d,J=7.6Hz,1H),7.63-7.40(m,2H),5.56(q,J=6.4Hz,1H),5.41(br s,1H),4.83(s,3H),3.96(d,J=6.8Hz,1H),3.84(br s,1H),3.69(br d,J=9.6Hz,1H),3.49(br d,J=3.2Hz,1H),2.93(s,3H),2.64(s,3H),2.09(br s, 2H), 1.84 (d, J = 6.8Hz, 3H).

[0863] Example 14-4

[0864] 3-((R)-1-((7-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-((dimethylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile

[0865]

[0866] To a solution of 3-((R)-1-((7-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-((methylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (12.0 mg, 27.9 μmol, 1.00 eq.) and paraformaldehyde (1.68 mg) in methanol (1.00 mL) were added acetic acid (168 μg, 2.79 μmol, 0.16 μL, 0.10 eq.) and sodium cyanoborohydride (3.51 mg, 55.9 μmol, 2.00 eq.), and the mixture was stirred at 25° C. for 1 hour. The mixture was then poured into water (5.00 mL), and the aqueous phase was extracted with ethyl acetate (5.00 mL×3). The combined organic phases were washed with brine (5.00 mL × 3), dried over anhydrous sodium, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: 3-Phenomenex Luna C18 75 × 30 mm × 3 um; mobile phase: phase A: water (0.05% HCl), phase B: acetonitrile; B%: 9%-29%] to give 3-((R)-1-((7-((1R, 4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-((dimethylamino)methyl)pyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-2-methylbenzonitrile (5.20 mg, 11.4 μmol, 40.8% yield, 97.2% purity, hydrochloride) as a yellow solid. LCMS [M+1] + :444.3.

[0867] 1 H NMR (400MHz, CD3OD) δ=9.11(s,1H),7.83(br d,J=7.6Hz,1H),7.71(d,J=7.6Hz,1H),7.58-7.29(m,2H),5.56(q,J=6.4Hz,1H),5.42(br s,1H),5.04-4.93(m,2H),4.83-4.81(m,1H),3.95(br d,J=7.6Hz,1H),3.82(br s,1H),3.67(br s,1H),3.48(br s,1H),3.11(s,6H),2.64(s,3H),2.08(br s,2H),1.84(br d,J=6.8Hz,3H).

[0868] Following the teachings of General Reaction Scheme III and the procedures described for the preparation of Examples 14-3 to 14-4, the following compounds of Formula (I), Examples 14-5 to 14-6, shown in Table 14, were prepared.

[0869] Table 14

[0870]

[0871] Example 15-1

[0872] N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazin-1-amine

[0873]

[0874] Step A: To a solution of 6-bromo-4-chloro-1-methylphthalazine (605 mg, 2.35 mmol, 1.10 eq.) in DMSO (1.50 mL) was added potassium fluoride (372 mg, 6.41 mmol, 150 μL, 3.00 eq.) and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine (commercially available, 500 mg, 2.14 mmol, 1.00 eq.). The mixture was stirred at 130° C. for 2 hours. The reaction mixture was quenched by the addition of water (3.00 mL) at 20° C., then diluted with ethyl acetate (5.00 mL) and extracted with ethyl acetate (5.00 mL×3). The combined organic layers were washed with brine (5.00 mL×3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , petroleum ether:ethyl acetate, 1:1) to give (R)-7-bromo-4-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (260 mg, 571 μmol, 26.8% yield) as a yellow oil. LCMS [M+1] + :455.0.

[0875] Step B: To a solution of (R)-7-bromo-4-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (20.0 mg, 43.9 μmol, 1.00 eq.) in dioxane (0.50 mL) and water (0.30 mL) were added potassium hydroxide (4.93 mg, 87.9 μmol, 2.00 eq.) and t-BuXPhos Pd G3 (3.49 mg, 4.39 μmol, 0.10 eq.). The mixture was stirred at 80° C. for 2 hours. The mixture was diluted with water (3.00 mL) and extracted with ethyl acetate (3.00 mL×2). The combined organic layers were washed with brine (3.00 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product (R)-1-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-ol (16.0 mg, 40.8 umol) as a brown oil, which was used in the next step without further purification. LCMS [M+1] + :393.1.

[0876] Step C: To a solution of (R)-1-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-ol (16.0 mg, 40.8 μmol, 1.00 eq.) in DMF (1.50 mL) was added cesium carbonate (39.9 mg, 122 μmol, 3.00 eq.) and (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (14.8 mg, 61.2 μmol, 1.50 eq.). The mixture was stirred at 80° C. for 12 hours. The residue was diluted with water (2.00 mL) and extracted with ethyl acetate (3.00 mL×3). The combined organic layers were washed with brine (5.00 mL×2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product 4-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazin-1-amine (18.0 mg, 38.93 μmol, crude) was used in the next step as a brown oil without further purification. LCMS [M+1] + :463.1.

[0877] Step D: To a solution of 1-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazin-1-amine (18.0 mg, 38.9 μmol, 1.00 eq.) in ethanol (1.00 mL) and water (0.20 mL) were added iron powder (10.9 mg, 195 μmol, 5.00 eq.) and ammonium chloride (10.4 mg, 195 μmol, 5.00 eq.). The mixture was stirred at 80° C. for 2 hours. The residue was diluted with methanol (3.00 mL), filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC [Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: phase A: water (10 mM NH4HCO3), phase B: MeCN; B%: 25%-55%] to give N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-(((S)-tetrahydrofuran-3-yl)oxy)phthalazin-1-amine (7.00 mg, 16.2 μmol, 41.6% yield) as an off-white solid. LCMS [M+1] + :433.2.

[0878] 1 H NMR (400MHz, CD3OD) δ = 8.00 (d, J = 8.8Hz, 1H), 7.77 (d, J = 2.4Hz, 1H), 7.49 (dd, J = 2.4, 9.2Hz, 1H), 6.98 (br d,J=2.4Hz,2H),6.76(s,1H),5.42(q,J=6.8Hz,1H),5.34(br dd,J=4.4,6.0Hz,1H),4.13-3.90(m,4H),2.67(s,3H),2.46-2.32(m,1H),2.26-2.15(m,1H),1.64(d,J=7.2Hz,3H).

[0879] Example 15-2

[0880]

[0881] Step A: In a sealed tube, a solution of (R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethan-1-amine (250 mg, 1.01 mmol, 1.00 eq.) and 6-bromo-4-chloro-1-methylphthalazine (259 mg, 1.01 mmol, 1.00 eq.) in dimethyl sulfoxide (3.00 mL), N,N-diisopropylethylamine (390 mg, 3.02 mmol, 526 μL, 3.00 eq.) and potassium fluoride (175 mg, 3.02 mmol, 70.7 μL, 3.00 eq.) was stirred under nitrogen at 130° C. for 12 hours. The reaction was cooled to 25° C., quenched with water (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 preparative TLC (SiO , petroleum ether / ethyl acetate = 0 / 1) to give (R)-7-bromo-4-methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (200 mg, 426 μmol, 42.3% yield) as a yellow solid. LCMS [M+1] + :469.0.

[0882] 1 H NMR (400MHz, DMSO-d6) δ = 8.81 (s, 1H), 8.80 (s, 1H), 8.25 (s, 1H), 8.07-8.04 (m, 1H), 7 .96-7.92(m,2H),5.68-5.64(m,1H),2.74(s,3H),2.60(s,3H),1.58(d,J=6.8Hz,3H).

[0883] Step B: To a solution of morpholine (44.5 mg, 511 μmol, 45.0 μL, 3.00 eq.), (R)-7-bromo-4-methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)phthalazin-1-amine (80.0 mg, 170 μmol, 1.00 eq.) and cesium carbonate (166 mg, 511 μmol, 3.00 eq.) in dioxane (2.00 mL) was added RuPhos (15.9 mg, 34.1 μmol, 0.20 eq.) and Pd2(dba)3 (15.6 mg, 17.0 μmol, 0.10 eq.) under nitrogen atmosphere. The mixture was stirred at 110°C for 1 hour, then cooled to 25°C, quenched with water (40.0 mL), and extracted with ethyl acetate (20.0 mL×3). The combined organic phases were washed with brine (40.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO , dichloromethane:methanol = 10 / 1) to give (R)-4-methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)-7-morpholinophthalazin-1-amine (50.0 mg, 105 μmol, 61.6% yield) as a yellow solid.

[0884] 1 H NMR (400MHz, DMSO-d6) δ = 8.57 (d, J = 2.4Hz, 1H), 8.24 (d, J = 2.4Hz, 1H), 7.82 (d, J = 8.8Hz, 1H), 7.62-7.58 (m, 2 H),5.67-5.64(m,1H),3.85-3.82(m,4H),3.44-3.43(m,4H),2.74(s,3H),2.51(s,3H),1.59(d,J=7.2Hz,3H).

[0885] Step C: To a solution of (R)-4-methyl-N-(1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethyl)-7-morpholinophthalazin-1-amine (45.0 mg, 94.6 μmol, 1.00 eq.) and ammonium chloride (50.6 mg, 946 μmol, 10.0 eq.) in ethanol (1.20 mL) and water (0.40 mL) was added iron powder (52.8 mg, 946.4 μmol, 10.0 eq.) under nitrogen at 90° C. The reaction mixture was stirred at 90° C. for 1 hour and then cooled to 25° C. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC [column: Phenomenex luna C18 80×40 mm×3 μm; mobile phase: phase A: water (0.04% HCl), phase B: acetonitrile; B%: 12%-38%] to give (R)-N-(1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)-4-methyl-7-morpholinophthalazin-1-amine (20.0 mg, 44.8 μmol, 47.3% yield, hydrochloride salt) as a white solid. LCMS [M+1] + :446.1.

[0886] 1 H NMR (400MHz, DMSO-d6) δ = 14.85 (s, 1H), 8.62 (s, 1H), 8.16 (d, J = 9.2Hz, 1H), 7.93 (s, 1H), 7.77-7.74 (m, 1H), 7.23-7.22 (m, 1 H),7.08(s,1H),5.37-5.34(m,1H),3.83-3.81(m,4H),3.70-3.68(m,4H),2.73(s,3H),2.43(s,3H),1.59(d,J=6.8Hz,3H).

[0887] SFC conditions: Chiralcel OD-3 3μm, 0.46cm id×5cm L; mobile phase: SFC CO2 as A, MeOH (0.05% isopropylamine) as B; gradient: B in A from 10% to 40% in 3 minutes; flow rate: 4.0mL / min; column temperature: 35℃; wavelength: 220nm; system back pressure: 100bar.

[0888] Following the teachings of General Reaction Scheme VI and the procedures described for the preparation of Examples 15-1 to 15-2, the following compounds of Formula (I), Example 15-3, shown in Table 15, were prepared.

[0889] Table 15

[0890]

[0891] Example 16-1

[0892] (R)-N-(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-4-methyl-7-morpholinophthalazin-1-amine

[0893]

[0894] Step A: To a solution of (R)-2-(1-aminoethyl)-6-(trifluoromethyl)pyridin-4-amine (6.00 g, 24.8 mmol, 1.00 eq., hydrochloride), 6-bromo-4-chloro-1-methylphthalazine (7.03 g, 27.3 mmol, 1.10 eq.) and N,N-diisopropylethylamine (12.8 g, 99.3 mmol, 17.3 mL, 4.00 eq.) in DMSO (1.00 mL) was added cesium fluoride (5.66 g, 37.3 mmol, 1.37 mL, 1.50 eq.) and the mixture was stirred at 130 °C under nitrogen atmosphere for 2 h. The mixture was then cooled to 25°C, diluted with ethyl acetate (300 mL), washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to dichloromethane / methanol = 10 / 1) to give (R)-N-(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-bromo-4-methylphthalazin-1-amine (9.00 g, 21.1 mmol, 85.0% yield) as a brown solid.

[0895] 1 H NMR (400MHz, CDCl3) δ = 8.11 (d, J = 2.0Hz, 1H), 7.89 (dd, J = 1.6, 8.8Hz, 1H), 7.78 (d, J = 8.8Hz, 1H), 6.94 (d, J = 1.6Hz, 1H), 6.87 (br s,1H),6.80(d,J=2.0Hz,1H),5.58-5.49(m,1H),4.89(br s,2H),2.77(s,3H),1.68(d,J=6.4Hz,3H).

[0896] Step B: To a solution of (R)-N-(1-(4-amino-6-(trifluoromethyl)pyridin-2-yl)ethyl)-7-bromo-4-methylphthalazin-1-amine (10.0 g, 23.5 mmol, 1.00 eq.) and DMAP (287 mg, 2.35 mmol, 0.10 eq.) in THF (100 mL) was added di-tert-butyl dicarbonate (10.5 g, 48.1 mmol, 11.1 mL, 2.05 eq.) and the reaction mixture was stirred at 40° C. for 30 min and then concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give tert-butyl (R)-(2-(1-((7-bromo-4-methylphthalazin-1-yl)amino)ethyl)-6-(trifluoromethyl)pyridin-4-yl)(tert-butoxycarbonyl)carbamate (7.45 g, 11.9 mmol, 50.7% yield) as a brown solid. LCMS [M+3] + :628.0.

[0897] Step C: To a solution of morpholine (4.09 g, 46.9 mmol, 4.13 mL, 4.00 eq.) and tert-butyl (R)-(2-(1-((7-bromo-4-methylphthalazin-1-yl)amino)ethyl)-6-(trifluoromethyl)pyridin-4-yl)(tert-butoxycarbonyl)carbamate (7.35 g, 11.7 mmol, 1.00 eq.) in dioxane (100 mL) was added Pd(dba) (1.07 g, 1.17 mmol, 0.10 eq.), RuPhos (1.09 g, 2.35 mmol, 0.20 eq.) and cesium carbonate (11.5 g, 35.2 mmol, 3.00 eq.) under nitrogen and the reaction mixture was stirred at 105° C. for 1 hour. The reaction mixture was cooled to 25° C., filtered, and the filter cake was washed with methanol (200 mL). 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 DCM / methanol = 10 / 1) to give tert-butyl (R)-(2-(1-((4-methyl-7-morpholinophthalazin-1-yl)amino)ethyl)-6-(trifluoromethyl)pyridin-4-yl)carbamate (4.75 g, 8.92 mmol, 76.0% yield) as a brown solid. LCMS [M+1] + :433.3.

[0898] Step D: To a solution of tert-butyl (R)-(2-(1-((4-methyl-7-morpholinophthalazin-1-yl)amino)ethyl)-6-(trifluoromethyl)pyridin-4-yl)carbamate (4.75 g, 8.92 mmol, 1.00 eq.) in acetonitrile (20.0 mL) was added HCl / dioxane (20.0...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, in: 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, -C-heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl and the heteroaryl are each optionally substituted by one or more R 2 or LR 2 replace; Each Q is independently a bond, O or NR 6 ; X is N or CR 7 ; Each R 2 are independently C1-C3 alkyl, oxo, 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; 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, the cycloalkyl and the heterocyclic are each optionally substituted by one or more R 9 replace; Y is a bond or a heteroarylene group; R 4 is aryl or heteroaryl, each optionally substituted by one or more R 5 replace; 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; L is C1-C3 alkylene; Each R 6 are independently hydrogen, C1-C3 alkyl, haloalkyl or cycloalkyl; R 7 is hydrogen, cyano, CF3, F or alkoxy; R 8 is C1-C2 alkyl or halo-C1-C2 alkyl; Each R 9 are independently hydroxy, halogen, amino, cyano, alkoxy or C1-C3 alkyl; Each R 10 are independently hydrogen, C1-C3 alkyl or cycloalkyl; Each R 11 are independently C1-C3 alkyl, halogen or haloalkyl; and R 12 It is hydrogen, halogen or C1-C3 alkyl.

2. The compound according to claim 1, wherein X is N.

3. The compound according to claim 1, wherein X is CR 7 .

4. The compound according to claim 1, wherein R 1 is alkoxy or -Q-heterocyclyl, wherein the heterocyclyl is optionally substituted by one or more R 2 or LR 2 replace.

5. The compound according to claim 4, wherein R 1 is -Q-heterocyclyl, and wherein Q is a bond or -O-, and the heterocyclyl is morpholinyl, piperazinyl or piperazinone.

6. The compound according to claim 5, wherein R 1 is -Q-heterocyclyl, and wherein the heterocyclyl is a bridged morpholinyl, a bridged piperazinyl, or a bridged piperazinone.

7. The compound according to claim 4, wherein R 1 is -Q-heterocyclyl, and wherein the heterocyclyl is a spiro ring system containing two or more rings.

8. The compound according to claim 1, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 in the preparation of a medicament for treating cancer.

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